didanosine and HIV-Infections
didanosine has been researched along with HIV-Infections* in 1075 studies
Reviews
111 review(s) available for didanosine and HIV-Infections
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Noncirrhotic portal hypertension associated with didanosine: a case report and literature review.
Noncirrhotic portal hypertension (NCPH) has recently been reported as a liver complication in human immunodeficiency virus (HIV)-infected patients and has been found to be associated with exposure to didanosine. Here, we describe the case of an HIV-infected patient with portal hypertension who initially presented with massive ascites and portal vein thrombosis. The patient's HIV-1 infection was well-controlled with highly active antiretroviral therapy (lamivudine/didanosine plus nevirapine) for 3 years since its diagnosis in 2007. He had no history of alcoholism, drug abuse, or liver diseases. An extensive work-up for other possible causes of liver disease was performed, but the results were inconclusive. In addition to reporting this case, we have reviewed the literature on didanosine-related NCPH and analyzed the findings of 61 similar previously reported cases. Topics: Aged, 80 and over; Antiretroviral Therapy, Highly Active; Ascites; Chemical and Drug Induced Liver Injury; Didanosine; Fatal Outcome; HIV Infections; HIV-1; Humans; Hypertension, Portal; Lamivudine; Male; Nevirapine; Portal Vein; Thrombosis; Tomography, X-Ray Computed | 2012 |
Antiviral hyperactivation-limiting therapeutics as a novel class for the treatment of HIV/AIDS: focus on VS411.
Immune activation plays a central pathogenetic role in both HIV-1 replication and depletion of CD4(+) T cells leading to disease progression and the onset of the AIDS. While current antiretroviral therapies suppress viral replication to undetectable levels, they do not normalize the excessive level of T-cell activation and proliferation. A new class of anti-HIV-1 drugs known as antiviral hyperactivation-limiting therapeutics (AV-HALTs) combines direct antiviral activity with an antiproliferative action to limit the hyperactivation of the immune system now recognized as the key driver of the progressive loss of CD4(+) T cells that occurs over the natural course of the HIV-1 infection.. Areas covered include preclinical, Phase I and Phase IIa studies of VS411, the first drug product in a novel class of anti-HIV drugs, AV-HALT agents.. The two drug combination VS411 safely achieved the goals established for the AV-HALT class based on the results of a Phase IIA proof-of-concept study. Additional work is underway to identify and develop new agents that combine the dual attributes of AV-HALTs, direct reduction of both HIV-1 viral load and markers of excessive immune activation, in a single molecule. Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Didanosine; Drug Combinations; Drug Evaluation, Preclinical; HIV Infections; Humans; Hydroxyurea; Lymphocyte Activation; Urea; Viral Load | 2011 |
Diagnosis and management of HIV-associated neuropathy.
Distal sensory polyneuropathy (DSP) is the most common neurologic complication of HIV infection and a major cause of morbidity in HIV-infected patients. DSP may occur secondary to HIV (HIV-DSP) or be due to antiretroviral drug toxicity. Timely detection of the symptoms and signs of DSP in patients who have HIV may allow for the reversal of the toxic effects of antiretrovirals and for the initiation of symptomatic treatment. The pathogenic mechanism of HIV-DSP is likely multifactorial. Restorative therapies for DSP are not currently available but recent advances have led to novel symptomatic therapies. This article highlights the risk factors, pathogenesis, pathology, clinical features, diagnostic studies, differential diagnosis, and treatment of HIV-associated neuropathy. Topics: Anti-Retroviral Agents; Chemokines; Cytokines; Diagnosis, Differential; Didanosine; HIV Infections; HIV Reverse Transcriptase; Humans; Macrophages; Peripheral Nervous System Diseases; Protease Inhibitors; Quality of Life | 2008 |
Incidence of pancreatitis in HIV-infected patients: comment on findings in EuroSIDA cohort.
Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Incidence; Pancreatitis; Stavudine | 2008 |
Didanosine enteric-coated capsule: current role in patients with HIV-1 infection.
Didanosine, which is a synthetic nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate. Currently, didanosine is mainly provided as an enteric-coated capsule. In vitro, the molecule is active against laboratory strains and clinical isolates of HIV-1 in resting and activated T cells and monocyte/macrophages. Didanosine may select for resistance mutations that may render the drug inactive against the virus; L74V and K65R remain as the main didanosine-related mutations. In vitro, phenotypic susceptibility to didanosine was decreased beyond a defined fold change clinical cut-off (1.7), and it is considered that genotypic resistance exists when five thymidine-associated mutations or four plus M184V are present. In vivo, clinical studies have shown that didanosine retains significant antiviral activity in patients who have up to five nucleoside analogue mutations at baseline. Didanosine is useful in patients with no previous therapy, as well as in experienced patients in whom one or more antiretroviral regimens has failed.Enteric-coated didanosine is taken once daily, its co-administration with food has been recently evaluated and a reduction of the efficacy of the antiretroviral treatment was not observed. Administered with lamivudine (or emtricitabine), it can be considered a good alternative for use in the nucleoside analogue backbone included in combination therapies for antiretroviral-naive patients. Didanosine could be used in initial treatments for patients intolerant of zidovudine, abacavir or tenofovir. It can be included in once-daily combination regimens, which are more convenient and patient friendly.Prospective, observational and open-label studies, as well as clinical trials (with durations between 24 and 96 weeks), have demonstrated the safety and efficacy of didanosine plus lamivudine (or emtricitabine) plus efavirenz (or nevirapine) in previously untreated HIV-1-infected patients. The administration of didanosine to treatment-experienced patients has been evaluated in two different contexts: patients in whom previous therapies have failed (rescue therapy) and those with controlled viraemia who are switched to a didanosine-containing regimen for simplification.Adverse events associated with the administration of didanosine have been well known since the initial clinical trials with the drug. Gastrointestinal intolerance, peripheral Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Tablets, Enteric-Coated | 2007 |
Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine therapy in HIV infection: a case report and literature review.
Topics: Adult; Anti-HIV Agents; Diabetes Insipidus, Nephrogenic; Didanosine; Fanconi Syndrome; HIV Infections; Humans; Male | 2007 |
Tenofovir plus didanosine as Nrti backbone in HIV-infected subjects.
Nucleoside reverse transcriptase inhibitors (NRTI) are essential components of highly active antiretroviral treatment (HAART). Although several combinations can be used as NRTI backbones, not all are associated with good virological and/or immunological results. In particular, some NRTI combinations should be avoided due to antagonism (zidovudine plus stavudine) or to high rate of toxicity (didanosine plus stavudine). Tenofovir (TDF) and didanosine (ddI) are among the more often prescribed NRTI for their convenient posology (one pill each per day), relatively high genetic barrier for resistance, quite acceptable safety profile and remarkable antiviral potency when such drugs have been used as single drug or in combinations with other NRTIs. However, antiretroviral regimens containing TDF and ddI have been associated with a high rate of virological failure in HIV-infected naïve patients due to possible drug-interactions. The virological efficacy of this backbone in HIV-infected, HAART pre-treated subjects, is still controversial. Aim of this review is to assess the possible role that antiretroviral regimens containing TDF and ddI can have in the treatment of HIV-positive subjects, focusing on their plasmatic and/or intracellular interactions to optimize the antiretroviral efficacy and minimize the toxicities of this combination. Topics: Adenine; Anti-HIV Agents; Didanosine; Drug Antagonism; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; Humans; Organophosphonates; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Tenofovir | 2006 |
Didanosine, lamivudine-emtricitabine and efavirenz as initial therapy in naive patients.
There are currently several suitable and different antiretroviral regimens to start highly active antiretroviral therapy (HAART), and many clinicians and patients prefer once-daily therapy. The efficacy and potency of efavirenz (EFV) has been established in many clinical trials and cohort studies; its pharmacokinetics, allowing for a convenient once-daily administration, make EFV one of the first agents to be included in once-daily regimens in naive patients. The two nucleoside reverse transcriptase inhibitors (NRTIs) accompanying the third drug have become the central skeleton, or the 'backbone' of the therapeutic scheme. Among the different NRTI pairs, a didanosine-lamivudine (3TC) or emtricitabine backbone for combination antiretroviral therapy may be a good option compared with any current NRTI-combinations due to its security, tolerance and once-daily dose. In this article, we review the advantages and drawbacks of didanosine-XTC-EFV as the initial regimen of HAART in HIV-infected patients. Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Deoxycytidine; Didanosine; Drug Resistance, Viral; Emtricitabine; HIV; HIV Infections; Humans; Lamivudine; Oxazines; Quality of Life; Reverse Transcriptase Inhibitors | 2006 |
Tenofovir and didanosine: a dangerous liaison.
Topics: Adenine; Anti-HIV Agents; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Organophosphonates; Tenofovir | 2005 |
Severe toxicity associated with the combination of tenofovir and didanosine: case report and review.
The combination of tenofovir and didanosine results in an increase in the didanosine plasma exposure and might augment the risk for didanosine toxicity. Although pharmacokinetic studies support a didanosine dose reduction to 250 mg when used concurrently with tenofovir in patients weighing at least 60 kg, no data are available in lower-weight patients. We describe a case of lactic acidosis and acute liver failure in a low-weight patient receiving tenofovir and a reduced dose of didanosine (200 mg/day). To our knowledge, this is the first case of severe toxicity associated with a reduced dose schedule of didanosine. Previous cases of severe toxicity associated with the combination of tenofovir and didanosine are reviewed. Topics: Acidosis, Lactic; Acute Disease; Adenine; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Liver Failure; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir | 2005 |
Sex differences in antiretroviral therapy-associated intolerance and adverse events.
Although women account for a substantial proportion of the global population infected with HIV, most clinical trials evaluating the safety and efficacy of specific antiretroviral therapy regimens have been preformed in predominantly male cohorts. Our knowledge of the sex differences associated with responses to these treatments is therefore limited. Potentially sex-specific influences, such as endogenous or exogenous hormones, could impact antiretroviral tolerance. Women also have different pharmacokinetic profiles for selected antiretrovirals compared with men. These factors could influence how women respond and react to antiretrovirals. Several observational studies have described a higher frequency of antiretroviral-related adverse effects among women compared with men. Women appear to be at an especially high risk for lactic acidosis, nevirapine-associated rashes and hepatotoxicity, and fat redistribution after highly active antiretroviral therapy exposure. Although a statistical association between antiretroviral toxicity and pregnancy has not been described, pregnancy may provide an additional influence on the toxicity of several antiretrovirals or antiretroviral combinations. Potential tolerability should be an important component in discussions of antiretroviral options among women. Topics: Acidosis, Lactic; Anti-Retroviral Agents; Didanosine; Exanthema; Female; HIV Infections; Humans; Liver Diseases; Male; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Randomized Controlled Trials as Topic; Sex Factors; Stavudine | 2005 |
Newer treatments for HIV in children.
Several new antiretroviral agents have been introduced into pediatric and adult use. This review will summarize information about these new agents and other recent advances in the care of HIV-infected children.. New drugs like tenofovir, emtricitabine, and enfuvirtide are being rapidly introduced into antiretroviral treatments for adult patients. In addition, some well-established drugs are being modified to make them more convenient (specifically didanosine and stavudine). Unfortunately, pediatric data lag for these new agents, in some cases because of complicated pharmacokinetics in children. At the same time, critical information on how to use established drugs like nelfinavir and efavirenz in younger children is slowly becoming available. Although antiretroviral treatment in children has often been initiated at standard doses of milligrams per kilogram, and susceptibility to drug was presumed in individuals without a previous history of exposure, recent data show that some primary infections are caused by drug-resistant virus, and there is a tremendous variability in serum drug levels in children. Researchers and clinicians should consider the role of baseline antiretroviral susceptibility testing and therapeutic drug monitoring to identify the optimal treatment for each child.. New therapeutic options for children with HIV infection are becoming available as the pharmacokinetics and best strategies for use of newer drugs are studied. Topics: Adenine; Anti-Bacterial Agents; Anti-HIV Agents; Child; Deoxycytidine; Didanosine; Drug Therapy, Combination; Emtricitabine; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Peptide Fragments; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir | 2004 |
Unusual muscle disease in HIV infected patients.
Two patients presented with proximal muscle weakness, a normal or minor elevation of creatine phosphokinase (CPK) and normal findings on electromyography. Muscle biopsy in one patient revealed CD8+ polymyositis, and in the other showed ddI induced myopathy. These cases illustrate the importance of muscle biopsy in identifying the underlying pathology in HIV infected patients with muscle weakness and little or no abnormality in laboratory investigations. Topics: Anti-HIV Agents; Biopsy; CD8-Positive T-Lymphocytes; Creatine Kinase; Diagnosis, Differential; Didanosine; Female; HIV Infections; Humans; Lymphocytosis; Male; Middle Aged; Muscle Weakness; Muscle, Skeletal; Polymyositis | 2004 |
Prognostic factors in lactic acidosis syndrome caused by nucleoside reverse transcriptase inhibitors: report of eight cases and review of the literature.
We conducted a retrospective study to identify prognostic factors in the lactic acidosis syndrome (LAS) caused by nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/AIDS. Fifty-eight cases of LAS were included in our analysis, 8 from our hospital spanning the years 1992-2002, and 50 reported in the English language literature from 1986 through 2002. Peak venous lactate level was the best predictor of mortality. Zidovudine was associated with higher lactate levels and higher mortality than stavudine and lamuvidine. Mortality declined progressively after 1986 when the first cases of NRTI-related LAS were described. Increased mortality with zidovudine in this study appears due in part to its greater use prior to 1990 when LAS was not widely recognized as a potential complication of NRTI therapy. Topics: Acidosis, Lactic; Adult; Didanosine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; New York; Reverse Transcriptase Inhibitors; Stavudine; Syndrome; Zidovudine | 2004 |
Editorial comment: drug-drug interactions, hepatitis C, and mitochondrial toxicity.
Topics: Acidosis, Lactic; Anti-HIV Agents; Antiviral Agents; Didanosine; DNA, Mitochondrial; Drug Synergism; Hepatitis C; HIV Infections; Humans; Metabolic Clearance Rate; Pancreatitis; Ribavirin | 2003 |
Effect of tenofovir on didanosine absorption in patients with HIV.
To evaluate the pharmacokinetic interaction between tenofovir and didanosine when used in combination as a highly active antiretroviral therapy regimen.. Literature retrieval was accessed through MEDLINE (1966-January 2003) using the terms tenofovir and didanosine. Abstracts from recent meetings, including the International AIDS Society, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were reviewed for relevant abstracts and poster presentations.. Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers. Tenofovir 300 mg administered concurrently with 400 mg didanosine results in a 48-64% increase in the didanosine maximum plasma concentration and AUC with no significant alterations in the tenofovir pharmacokinetic parameters. Tenofovir 300 mg and didanosine 250 mg has been compared with didanosine 400 mg alone. The results demonstrated equivalent didanosine AUCs.. When used concurrently, tenofovir significantly increases the maximum plasma concentration and the AUC of didanosine. Additional data in HIV-infected patients are needed to determine the long-term toxicities of this combination therapy. Didanosine dose reduction should be considered when these 2 agents are used concurrently. Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Area Under Curve; Clinical Trials as Topic; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Organophosphonates; Organophosphorus Compounds; Tenofovir | 2003 |
Contraindicated antiretroviral drug combinations.
The proper implementation of combination antiretroviral treatment regimens is fundamental to successful therapeutic outcomes for patients with HIV/AIDS. Unfortunately, some patients are still being prescribed contraindicated antiretroviral regimens that include: 1. stavudine plus zidovudine; 2. Invirase plus two nucleoside analog reverse transcriptase inhibitors (NRTIS); 3. zalcitabine plus didanosine; 4. zalcitabine plus stavudine; and, 5. zalcitabine plus lamivudine. Inappropriate regimens such as these either have limited effectiveness or potential severe toxicity. Topics: Anti-Retroviral Agents; Contraindications; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Saquinavir; Stavudine; Zalcitabine | 2003 |
The power of simplicity.
Many years of use have confirmed didanosine to be among the most potent of nucleoside analogues. Didanosine's potency has been demonstrated in mono-, dual- and triple-therapy. Didanosine is currently available as a once-daily, enteric-coated tablet, which has reduced gastrointestinal side effects compared with the older, buffered formulation. Once-daily dosing and good tolerability improve adherence, and hence also virological control. The prevalence of phenotypic nucleoside resistance to didanosine is low compared with that to zidovudine, lamivudine and abacavir. At least 6 nucleoside analogue mutations are needed in order for the virus to lose sensitivity to didanosine. Didanosine is effective in patients failing lamivudine therapy who have the M184V mutation. Enteric-coated didanosine is also an important component of early therapy, due to its potency and ease of administration. Topics: Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Interactions; Drug Resistance, Viral; HIV Infections; Humans | 2003 |
The continuing evolution of HIV therapy.
Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Delayed-Action Preparations; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Monitoring; Emtricitabine; Furans; HIV Infections; Humans; Lamivudine; Nevirapine; Oligopeptides; Organophosphates; Organophosphonates; Organophosphorus Compounds; Oxazines; Pyridines; Randomized Controlled Trials as Topic; Stavudine; Sulfonamides; Tenofovir; Treatment Outcome; Viral Load; Zidovudine | 2003 |
Oral and dental care and treatment protocols for the management of HIV-infected patients.
This paper describes the workings of the workshop dedicated to oral and dental care and treatment protocols for the management of HIV-infected patients. The questions addressed were: 1) What are the current ethical issues in dental care of HIV patients, do they need to be addressed? 2) Do we need to modify the dental care we give HIV-positive patients? 3) When is it necessary to give antibiotic prophylaxis to HIV-positive patients? 4) What is the evidence for the effective treatment of oral lesions associated with HIV? 5) What is the most successful palliative treatment for KS? 6) Can we provide clinical treatment that has a scientific basis rather being trial based? 7) Is ddI + hydroxy-urea an effective African alternative to HAART? 8) What is the influence of protease inhibitors and HAART on the excretion of HIV in saliva? 9) What is the effect of anti-HIV therapy on the oral mucosa and oral health? This workshop did not fully cover the issue of ddI and hydroxy-urea as an alternative HIV therapy as this was considered to be the remit of general physicians caring for patients with HIV and AIDS rather than that of oral health care workers. Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotic Prophylaxis; Antiretroviral Therapy, Highly Active; Clinical Protocols; Dental Care for Chronically Ill; Didanosine; Enzyme Inhibitors; Ethics, Dental; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Mouth Diseases; Mouth Mucosa; Mouth Neoplasms; Palliative Care; Reverse Transcriptase Inhibitors; Saliva; Sarcoma, Kaposi | 2002 |
[Treatment of chronic hepatitis C in patients coinfected with HIV: tolerability, drug interactions, therapeutic indications].
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Didanosine; Drug Interactions; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Life Style; Mitochondria; Monitoring, Physiologic; Multicenter Studies as Topic; Patient Selection; Randomized Controlled Trials as Topic; Retrospective Studies; Reverse Transcriptase Inhibitors; Ribavirin; Stavudine; Time Factors; Viral Load; Zidovudine | 2002 |
[Pharmacological and clinical properties of didanosine (VIDEX), a nucleoside reverse transcriptase inhibitor].
An active metabolite, ddATP, of didanosine that is an analogue of purine-nucleoside (a component of nucleic acid) was known to inhibit the activity of DNA polymerase for E. coli. In 1985, Dr. Michiya et al. of NCI reported that didanosine and ddA inhibited replication of the human immunodeficiency virus (HIV). This discovery led to the clinical application of both the compounds. Didanosine, after being uptaken into a cell, becomes an active metabolite, ddATP, to inhibit a reverse transcriptase of HIV. Compared with zidovudine, didanosine has weak cytotoxicity both in vitro and in vivo. Didanosine, which is recommended as a first-line therapy drug in the Japanese Guideline on an anti-HIV Infection Therapy, was approved as twice-daily Videx Tablet and Dry Syrup formulations for launch in June 1992. In March 2001, a once-daily Videx EC Capsule formulation was approved and launched, having expected adherence improvements in HIV/AIDS patients. Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Reverse Transcriptase Inhibitors | 2002 |
Update on didanosine.
Didanosine (ddl) has been a cornerstone of HIV management since it was made available in October 1991. Didanosine was originally introduced as an alternative to zidovudine (ZDV) for patients who were intolerant of ZDV or experienced disease progression during ZDV monotherapy. Didanosine is now used extensively as an integral component of multidrug combination regimens in both adults and children with HIV infection, and is now available for once-daily administration in the United States, Canada, and Europe. The recently approved Videx EC is an enteric-coated didanosine capsule dosed as one capsule, once daily. This paper provides an update of recently published studies on the use of ddl in combination anti-HIV therapy. In particular, these studies examine the rationale for the use of ddl as first-line anti-HIV therapy, and describe newer findings concerning its long-term efficacy, side effects, compliance, resistance, and once-daily use. The increased survival of HIV-infected patients is largely attributed to the introduction of the triple combination drug therapy but is probably also due to the long-term clinical efficacy of ddl. Topics: Adult; Anti-HIV Agents; Child; Didanosine; HIV Infections; Humans | 2002 |
Systematic review of combination antiretroviral therapy with didanosine plus hydroxyurea: a partial solution to Africa's HIV/AIDS problem?
Effective antiretroviral therapy remains beyond the reach of most human immunodeficiency virus (HIV)-infected persons living in the third world because of its tremendous cost. The cancer drug, hydroxyurea, inhibits HIV-1 replication in vitro and, when combined with didanosine (ddI), results in significant antiretroviral synergy. In vivo, hydroxyurea specifically targets quiescent lymphocytes and macrophages, important cellular reservoirs for HIV-1, and the combination of ddI plus hydroxyurea effectively reduces plasma HIV-1 RNA levels. Combination ddI-hydroxyurea costs about one-eighth as much as currently recommended triple drug combinations, and several countries in Africa are exploring the feasibility of widescale use of ddI-hydroxyurea for their HIV-infected populations. Intrigued by its potential relevance for Africa, the authors reviewed the literature on the in vitro and clinical efficacy of ddI plus hydroxyurea against HIV. The combination of ddI plus hydroxyurea is an effective and potentially more affordable regimen for HIV-infected persons living in poorer countries. Topics: Africa; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; MEDLINE; Treatment Outcome; Viral Load; Zidovudine | 2001 |
Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.
Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC).. To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival.. Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts.. Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events.. Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials.. Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009).. The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 2000 |
Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.
Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC).. To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival.. Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts.. Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events.. Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials.. Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009).. The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine | 2000 |
[Hydroxyurea and HIV infection].
Hydroxyurea is an anticancerous product, used recently in the treatment of HIV-1 infection thanks to its inhibitory action in viral replication, potentialization of the nucleosides activity (particularly ddI or didanosine) and its cytostatic properties on CD4 and CD8 lymphocytes. Many studies showed its efficiency, as further drug, in initial regimen of a tritherapy (containing ddI) and salvage therapy. The dosage of 500 mg bid seems tolerated well by adults, and 20 mg/kg by children. Long-term tolerance remains unknown. With ddI, it could be proposed in developing countries. Topics: Adult; Anti-HIV Agents; Child; Didanosine; Drug Synergism; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Nucleic Acid Synthesis Inhibitors; Virus Replication | 2000 |
Didanosine once daily: potential for expanded use.
Factors affecting patient adherence to therapy, such as frequent daily dosing and complex dosing schedules, are widely understood to be key obstacles to the durability of effective anti-HIV therapy. Didanosine, a nucleoside analogue reverse transcriptase inhibitor (NRTI) that is a core component of combination antiretroviral regimens, is currently indicated for twice-daily dosing. However, the active metabolite of didanosine (2',3'-dideoxyadenosine-5'-triphosphate) has a long intracellular half-life that supports the use of didanosine in a more patient-friendly, once-daily dosing schedule. Clinical studies in which didanosine was administered either once or twice daily, as monotherapy or in combination with another NRTI, have demonstrated the equivalence of both dosing schedules, with respect to safety and tolerability, virologic and immunologic endpoints, and short-term clinical effects (e.g., weight gain). Preliminary results from recent studies support the clinical efficacy and utility of once-daily didanosine in combination antiretroviral regimens that provide maximal drug exposure, while allowing for once- or twice-daily dosing of all component drugs. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Liver; Pancreatitis; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors | 2000 |
Hydroxyurea: overview of clinical data and antiretroviral and immunomodulatory effects.
Data from comparative trials involving more than 500 patients indicate that hydroxyurea is safe and augments suppression of HIV-1 replication when used in combination with didanosine or didanosine/stavudine as initial therapy or in patients without extensive antiretroviral experience. Additional studies will determine the optimum dosage and schedule for hydroxyurea and its effects when used with other agents and in patients with advanced disease or extensive pretreatment. Activities of hydroxyurea include inhibition of HIV-1 in active and resting CD4 lymphocytes and macrophages, potentiation of the activity of nucleoside reverse transcriptase inhibitors (NRTIs), compensation for resistance to adenosine analogue NRTIs, and potential increased phosphorylation of pyrimidine NRTIs. Recent attention, however, has focused on the potential immunomodulatory effects of hydroxyurea. The cytostatic effect of this agent on both CD4 and CD8 T cells may provide immunological benefits by reducing immune system overactivation, thus preventing both CD8 T cell exhaustion and CD4 T cell depletion. Accumulating evidence indicates that hydroxyurea-containing regimens may be associated with decreased levels of activated CD8 T cells, increased levels of naive CD4 and CD8 T cells, and preservation of the HIV-1-specific immune response. Further study of the potential for beneficial immunomodulation with hydroxyurea-containing regimens is needed to ascertain the clinical implications of these initial findings. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine | 1999 |
[Response of fetal macrophages in the placenta of pregnant HIV-positive patients with and without antiretroviral treatment].
We studied the cellular answer of placentary macrophages in pregnant women seropositive to the virus of human immunodefficiency (VIH-1) treated with zidovudina (AZT) and didanosine (ddl). Twenty eight pregnant women were studies; there were four groups of seven patients each: The control group; the group with seropositive women without treatment; the group given AZT, and the group that recieved AZT and ddl. Placentary specimens were obtained immediately after delivery. One hundred and fifty chorionic vellosities of cells. The control group showed an average of 26 Hofbauer cells; the seropositive women without antiretroviral treatment, was 115; the patients who received only AZT, the average was 65; and the ones who received a combine therapy AZT and ddl, cellular average was 44. There were no differences in the weight of the products in all the groups, nor congenital malformations in the newborns. The use of medication antiretroviral suppress viral replication, and so, there is a significant answer in the amount and size of Hofbauer cells. The administration of two medicaments is more effective in the cellular immune answer. Topics: Antiviral Agents; Didanosine; Female; HIV Infections; HIV Seropositivity; Humans; Macrophages; Pregnancy; Pregnancy Complications, Infectious; Retroviridae; Zidovudine | 1999 |
Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trialists' Collaborative Group.
To assess the effects of zidovudine, didanosine, and zalcitabine on HIV disease progression and survival, we undertook meta-analyses of individual patient data and tabular data from all randomised trials that compared these agents.. Individual patient data were available for 7722 participants without AIDS in the nine randomised trials of immediate versus deferred zidovudine, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus zalcitabine, or zidovudine alone. The main outcomes were mortality and disease progression (new AIDS-defining event or death before any such event).. In the comparison of immediate versus deferred zidovudine, during a median follow-up of 50 months, 1908 individuals progressed, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was zidovudine monotherapy in 94%). During the first year of follow-up, immediate zidovudine halved the rate of disease progression (p<0.0001), increasing the probability of AIDS-free survival at 1 year from 96% to 98%. This early delay did not persist: after 6 years, AIDS-free survival was 54% in both groups. At no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred zidovudine (rate ratio 1.04 [95% CI 0.94-1.15]). In the comparison of zidovudine plus didanosine or zalcitabine versus zidovudine alone, during a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of didanosine to zidovudine delayed both progression (rate ratio 0.74 [0.67-0.82], p<0.0001) and death (0.72 [0.64-0.82], p<0.0001). Similarly, the addition of zalcitabine to zidovudine also delayed progression (0.86 [0.78-0.94], p=0.001) and death (0.87 [0.77-0.98], p=0.02). After 3 years, the estimated percentages alive and without a new AIDS event were 53% for zidovudine plus didanosine, 49% for zidovudine plus zalcitabine, and 44% for zidovudine alone; the percentages alive were 68%, 63%, and 59%, respectively. Five of the six trials involved randomised comparisons of zidovudine plus didanosine versus zidovudine plus zalcitabine: in these, the zidovudine plus didanosine regimen had greater effects on disease progression (p=0.004) and death (p=0.009).. Although immediate use of zidovudine halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term. However, the use of didanosine and, to a lesser extent, zalcitabine delayed both disease progression and death, at least when added to zidovudine. The comparative effects of these different nucleoside analogues on long-term survival should inform the choice of which to combine with other types of drug, such as protease inhibitors. Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Didanosine; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Randomized Controlled Trials as Topic; Survival Rate; Time Factors; Zalcitabine; Zidovudine | 1999 |
Antiretrovirals.
Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects. Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine | 1999 |
Didanosine: an updated review of its use in HIV infection.
Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is converted to its active moiety, dideoxyadenosine-5'-triphosphate (ddATP), which inhibits HIV reverse transcriptase and terminates viral DNA growth. It is now well established that didanosine therapy produces beneficial effects on virological and immunological markers of HIV disease and improves clinical outcome in adults or children with HIV infection. In numerous clinical trials, pronounced and sustained decreases in plasma HIV RNA levels and increases in CD4+ cell counts occurred in previously untreated or antiretroviral therapy-experienced patients treated with didanosine in combination with at least 1 other antiretroviral drug; zidovudine, stavudine, lamivudine, nevirapine, nelfinavir and hydroxyurea (hydroxycarbamide) are among the drugs that have been given in combination with didanosine. Of note, HIV RNA levels decreased to below the limits of detection in some patients receiving triple or dual therapy with didanosine-containing regimens. In double-blind, placebo-controlled trials, triple therapy with didanosine, zidovudine and nevirapine was significantly more effective than dual therapy with various combinations of these agents in improving surrogate disease markers in treatment-naive patients and in delaying disease progression or death in treatment-experienced patients with advanced disease. Improvements in virological and immunological markers were greater with didanosine-containing triple regimens than with dual therapy or monotherapy in comparative trials. Triple therapy with didanosine, stavudine and indinavir showed efficacy similar to that of various other triple therapy regimens in nonblind comparative trials. Comparator regimens included combinations of stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and didanosine, stavudine and nevirapine. Combination therapy with didanosine plus hydroxyurea as dual therapy or with a third agent produced marked and sustained decreases in HIV RNA levels in the plasma and in lymph nodes. Combination therapy with didanosine and zidovudine delays disease progression and prolongs survival in patients with intermediate or advanced HIV infection. In large, randomised, double-blind, clinical trials, dual therapy with didanosine plus zidovudine was significantly more effective than zidovudine monotherapy in preventing disea. Didanosine is an effective and generally well tolerated drug in previously untreated and antiretroviral therapy-experienced patients with HIV infection. Given once or twice daily, it has an important role as a component of triple combination regimens for the treatment of patients with symptomatic or asymptomatic HIV infection. Topics: Adult; Anti-HIV Agents; Child; Didanosine; HIV Infections; HIV-1; Humans | 1999 |
Meta-analysis of two randomized controlled trials comparing combined zidovudine and didanosine therapy with combined zidovudine, didanosine, and nevirapine therapy in patients with HIV. INCAS study team.
To extend the range of CD4 counts in which a plasma viral load nadir (pVL) <20 copies/ml was known to be predictive of the duration of virologic response. To determine whether baseline pVL is predictive of virologic response during the study periods.. A meta-analysis was conducted of the original individual patient data from two randomized controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP).. In total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects on triple therapy with baseline pVL <100,000 copies/ml were more likely to achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml (OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir <20 copies/ml and between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26), respectively, compared with patients with a pVL nadir >400 copies/ml.. We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression. Topics: Adult; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis; Nevirapine; Proportional Hazards Models; Viral Load; Zidovudine | 1999 |
Nucleoside combinations for antiretroviral therapy: efficacy of stavudine in combination with either didanosine or lamivudine.
This paper reviews the results of three trials, HIV NAT002, AI455-053, and AIDS Clinical Trials Group (ACTG) 306, all of which evaluated the effectiveness of stavudine (d4T)-containing two-nucleoside combinations in antiretroviral-naive patients with human immunodeficiency virus type 1 (HIV-1) infection. The latter two studies directly compared d4T plus didanosine (ddI) or lamivudine (3TC) versus zidovudine (ZDV) plus each of these two nucleosides. The combined results of the three trials support the conclusion that d4T can be used effectively in combination with either ddI or 3TC to reduce viral loads and increase CD4 cell counts in patients with HIV-1 infection. The results of AI455-053 and ACTG 306 show further that combination of d4T with either ddI or 3TC is at least as effective as the use of ZDV with these nucleosides. Topics: Adult; Aged; Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Randomized Controlled Trials as Topic; Stavudine; Viral Load | 1998 |
Improving patient adherence with antiretroviral therapy: evaluation of once-daily administration of didanosine.
One important goal of antiretroviral therapy should be simplification of treatment regimens whenever possible, in order to enhance adherence and potentially improve treatment outcome. While the nucleoside didanosine (ddI) has generally been dosed twice daily in clinical trials, the long intracellular half-life (>12 h) of its active metabolite, dideoxyadenosine triphosphate, should permit once-daily administration of this antiretroviral agent. The STADI trial evaluated this possibility by administering once-daily ddI and twice-daily stavudine (d4T) to antiretroviral-naive patients with human immunodeficiency virus type 1 (HIV-1) infection. This combination was well tolerated and at the end of 24 weeks of therapy, viral load was reduced by -1.48 log copies/ml and HIV-1 RNA was below the lower limit of quantification (500 copies/ml) in 62% of patients. Twenty-four weeks of treatment with d4T plus once-daily ddI increased average CD4 cell counts by 139/ml. The effectiveness of once-daily administration of ddI will be evaluated further in a new multinational clinical trial, AI454-148, in which it will be combined with d4T and the protease inhibitor, nelfinavir. The primary endpoint of this trial will be durable reduction of plasma HIV-1 RNA below 400 copies/ml. Such a change in the treatment regimen for this nucleoside has the potential to improve patient adherence and, thus, treatment outcome. Topics: Adult; Anti-HIV Agents; Didanosine; Female; HIV Infections; HIV-1; Humans; Male; Patient Compliance; Randomized Controlled Trials as Topic; Viral Load | 1998 |
Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine.
Topics: Adult; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Child; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Immunosuppressive Agents; Models, Biological | 1998 |
Antiretroviral chemotherapy.
Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine | 1998 |
Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management.
Distal symmetrical peripheral neuropathy is a common adverse experience in persons with HIV infection. This condition, which presents as a pain, numbness. burning and/or dysaethesia initially in the feet, is often multi-factorial in its origin. Nucleoside analogue reverse transcriptase inhibitors represent an important contributor to peripheral neuropathy. Specifically, around 10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients may have to discontinue therapy with these agents due to neuropathy. Prompt withdrawal of these therapies enables gradual resolution of signs and symptoms in most patients, although a period of symptom intensification may occur shortly after withdrawal. Risk factors for developing peripheral neuropathy during nucleoside analogue therapy include low CD4+ cell count (<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm, a history of peripheral neuropathy, use of other neurotoxic agents including high alcohol (ethanol) consumption and nutritional deficiencies such as low serum hydroxocobalamin levels. Thus, patients at increased risk of peripheral neuropathy should potentially avoid the use of the neurotoxic nucleoside analogues or be more carefully monitored during therapy. Management of this problem includes patient education. prompt withdrawal of the likely causative agent (giving consideration not to leave the patient on a sub-optimal therapy regimen) and simple analgesia. with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe. New agents that may assist in managing this condition include levacecarnine (acetyl-L-carnitine) and nerve growth factors such as recombinant human nerve growth factor. Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine | 1998 |
Didanosine once daily: an overview.
The current focus on simplifying treatment regimens for patients with human immunodeficiency virus (HIV) infection has contributed to the interest in once-daily therapy. The triphosphate of didanosine (2',3'-dideoxyinosine or DDI) has a long intracellular half-life, which supports the use of didanosine in a once-daily dosing schedule. Early clinical studies found that changes in surrogate markers were similar whether didanosine was dosed once or twice daily, while toxic effects occurred less frequently with once-daily dosing. Didanosine once-a-day used in combination with other drugs has also been studied, and results of some of these trials are summarized in this paper. Topics: Clinical Trials as Topic; Didanosine; HIV Infections; Humans | 1998 |
Stavudine plus a non-thymidine nucleoside reverse transcriptase inhibitor as a backbone for highly active antiretroviral therapy.
Current guidelines for treatment of human immunodeficiency virus (HIV) disease favour the use of triple-drug combinations consisting of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor to achieve maximum suppression of HIV replication. There is considerable evidence for including one thymidine NRTI to target activated HIV host cells and one non-thymidine NRTI to target quiescent host cells as the backbone of such regimens. A number of recent studies have shown that stavudine in combination with didanosine or lamivudine is at least as effective as zidovudine-based combinations with regard to virological outcomes, with available data suggesting an enhanced effect on immunological outcome with stavudine-based combinations. When considered along with such advantageous characteristics of stavudine as infrequent and low-level resistance and good cerebrospinal fluid penetration, these findings indicate that stavudine in combination with didanosine or lamivudine should be considered for use as the backbone of multiple-agent highly active antiretroviral therapy (HAART). Topics: Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Retroviridae; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 1998 |
Antiretroviral therapy for pregnant women.
Reproductive-age women constitute an increasing percentage of individuals infected with human immunodeficiency virus. As clinical management issues particular to pregnancy become increasingly common, they are also becoming increasingly complex. With the approval of new antiretroviral agents, monotherapy with zidovudine, although still standard for prevention of mother-to-child transmission of human immunodeficiency virus, has become inadequate therapy for treatment of the mother. Clinicians must now consider alternative therapeutic strategies in spite of a dearth of experience in the setting of pregnancy. To facilitate optimal drug treatment of human immunodeficiency virus-infected pregnant women while maintaining a focus on prevention of transmission, we reviewed Medline, Reprotox, personal files, and pharmaceutical industry information about the antiretroviral agents currently approved. After summarizing potential beneficial and detrimental effects in both the pregnant and nonpregnant individual, we suggest clinical strategies and discuss the ethical and legal principles that should guide therapeutic decisions in pregnancy. Topics: Anti-HIV Agents; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Saquinavir; Zalcitabine; Zidovudine | 1997 |
Antiretroviral therapy: a guide to the most important trials.
AIDS and HIV infection have stimulated an unprecedented amount of research. In this review we have selected a few publications illustrating key issues. Viral load monitoring is useful because short-term changes in viremia, caused by antiretroviral treatment, predict long-term outcome. Combination therapy with AZT plus either ddl or ddC produces better results than therapy with AZT only, but the differences are slight and appeared only after several years of follow-up. In contrast, the effect of adding 3TC to AZT-containing regimens was statistically significant after only one year, halving mortality and the incidence of new AIDS-defining opportunistic infection. Adding ritonavir had a similar effect after 20 week's follow-up in far-advanced HIV infection. The most potent regimens combine AZT, 3TC, and either ritonavir or indinavir; in the majority of patients thus treated viremia became undetectable (< 500 copies/ml). Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Nevirapine; Pyridines; Ritonavir; Saquinavir; Stavudine; Viral Load; Zalcitabine; Zidovudine | 1997 |
The development of resistance of HIV-1 to zalcitabine.
Topics: Amino Acids; Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; Genetic Variation; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Models, Molecular; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Zalcitabine | 1997 |
[Infectious diseases that require world-wide control--HIV infections].
Topics: Anti-HIV Agents; Communicable Disease Control; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; International Cooperation; Protease Inhibitors; Reverse Transcriptase Inhibitors; Zidovudine | 1997 |
[Antiretroviral treatment in human immunodeficiency virus infection].
Topics: Antiviral Agents; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Ritonavir; Saquinavir; Stavudine; Treatment Outcome; Viral Load; Zalcitabine; Zidovudine | 1997 |
Toxicity of antiretroviral agents.
Topics: Anti-HIV Agents; Didanosine; Health Personnel; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Occupational Exposure; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine | 1997 |
Meta-analysis of five randomized controlled trials comparing continuation of zidovudine versus switching to didanosine in HIV-infected individuals.
A meta-analysis of the original data from 2411 patients in the ACTG 116A, ACTG116B/117, ACTG175, BMS010 and CTN002 trials was conducted to improve the estimate of the effect of switching from zidovudine to didanosine on rates of clinical progression, to better quantify the rates of neurological events (including AIDS dementia and peripheral neuropathy) and to examine the effects of switching from zidovudine to didanosine among women and racial subgroups. In total, 1012 patients received zidovudine therapy, 557 received high-dose didanosine and 842 received didanosine. The median duration of follow-up was 15 months. Ninety-one percent of patients were male, 78% were white, mean age was 36.5 years. The median CD4 count was 195 cells/mm3 (range: 0-762) and the median duration of prior zidovudine therapy was 14 months (range: 0.1-94). There were 336 deaths and 686 new AIDS-defining illnesses (ADIs) or deaths. After stratification by study and adjusting for baseline CD4 count and presence of an AIDS diagnosis prior to baseline, the relative risks of death associated with switching from zidovudine to high-dose didanosine or to didanosine were 0.94 (P = 0.64) and 0.77 (P = 0.07), respectively. The relative risks of a new ADI or death associated with switching from zidovudine to high-dose didanosine and didanosine were 0.78 (P = 0.01) and 0.66 (P = 0.0001), respectively. There were 21 documented cases of AIDS dementia complex (ADC) during the entire follow-up period. The rates per 100 person years of follow-up were 0.70, 0.65 and 0.41 for the zidovudine, high-dose didanosine and didanosine arms, respectively. There were no significant differences in risks of ADC between treatment arms (zidovudine versus high-dose didanosine: P = 0.30, zidovudine versus didanosine: P = 0.97, didanosine versus high-dose didanosine: P = 0.41). Our data confirm a clinical benefit and CD4 increase associated with a switch from zidovudine to didanosine therapy. No statistical differences were detected between doses of didanosine with respect to survival or progression to a new ADI or death. Furthermore, there was no statistical difference in the frequency of ADC between treatment arms. Topics: AIDS Dementia Complex; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; HIV Infections; Humans; Incidence; Randomized Controlled Trials as Topic; Zidovudine | 1997 |
Managing HIV. Part 4: Primary therapy. 4.1 Antiretroviral therapies for HIV.
Zidovudine (AZT) is not the only drug with some effect on HIV. New agents and better-directed use of established agents can delay progression of the disease and prevent the onset of symptoms for some time. Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Multicenter Studies as Topic; Zalcitabine; Zidovudine | 1996 |
Ups and downs--and ups in the antiviral therapy of HIV infection.
Topics: AIDS-Related Complex; AIDS-Related Opportunistic Infections; Antiviral Agents; Didanosine; HIV Infections; Humans; Quality of Life; Randomized Controlled Trials as Topic; Zidovudine | 1996 |
The role of antiretroviral therapy in the management of HIV infection in women.
Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Treatment Outcome; Zidovudine | 1996 |
The clinical use of didanosine.
Topics: Antiviral Agents; Didanosine; Female; HIV; HIV Infections; Humans; Pregnancy | 1996 |
Guide to major clinical trials of antiretroviral therapy administered to patients infected with human immunodeficiency virus.
Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Meta-Analysis as Topic; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine | 1996 |
Pediatric human immunodeficiency virus infection.
In the past decade, an increase in pediatric human immunodeficiency virus (HIV) infection has had a substantial impact on childhood morbidity and mortality worldwide. The vertical transmission of HIV from mother to infant accounts for the vast majority of these cases. Identification of HIV-infected pregnant women needs to be impoved so that appropriate therapy can be initiated for both mothers and infants. While recent data demonstrate a dramatic decrease in HIV transmission from a subset of women treated with zidovudine during pregnancy, further efforts at reducing transmission are desperately needed. This review focuses on vertically transmitted HIV infection in children, its epidemiology, diagnostic criteria, natural history, and clinical manifestations including infectious and noninfectious complications. An overview of the complex medical management of these children ensues, including the use of antiretroviral therapy. Opportunistic infection prophylaxis is reviewed, along with the important role of other supportive therapies. Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Central Nervous System Diseases; Child; Child, Preschool; Cytomegalovirus Infections; Didanosine; Disease Transmission, Infectious; Eye Diseases; Female; Gastrointestinal Diseases; Heart Diseases; Hematologic Diseases; Herpes Simplex; Herpes Zoster; HIV Infections; Humans; Incidence; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Kidney Diseases; Male; Neoplasms; Pregnancy; Prevalence; Risk Factors; Sexual Behavior; Skin Diseases; Transfusion Reaction; Zidovudine | 1996 |
Pediatric HIV infection: a primer for pharmacists.
Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Infant; Infant, Newborn; Male; Pharmacists; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1996 |
Didanosine. An update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease.
Didanosine is a dideoxynucleoside analogue, which is phosphorylated to the active metabolite dideoxyadenosine triphosphate (ddATP) intracellularly. At therapeutic concentrations, ddATP inhibits HIV replication by inhibiting HIV reverse transcriptase. Didanosine is established as a first-line treatment for patients with HIV disease and has recently been shown to be superior to zidovudine monotherapy in the treatment of patients with intermediate-stage HIV infection. In clinical practice, however, combination regimens of antiretroviral drugs are generally considered preferable to monotherapy as first-line treatment for most patients with HIV disease. Importantly, 2 large multicentre studies have demonstrated that combination therapy with didanosine and zidovudine was more effective than zidovudine monotherapy in delaying disease progression and death in patients with intermediate or advanced HIV disease. In other comparative studies, improvements in surrogate markers of HIV disease were generally greater in patients who received combination therapy than in recipients of antiretroviral drug monotherapy. Improvements in surrogate markers were also observed in children who received didanosine monotherapy in several clinical trials. Although the efficacy of combination antiretroviral drug therapy has not yet been investigated extensively in children, a combination regimen of didanosine and zidovudine was well tolerated and achieved beneficial effects on surrogate markers if HIV disease. In addition, preliminary findings of a larger study have shown that disease progression was delayed in children and adolescents who received didanosine plus zidovudine combination therapy compared with those receiving zidovudine monotherapy. Didanosine has a tolerability profile that is distinctly different from that of zidovudine. In particular, didanosine exhibits only minimal haematological toxicity when administered either as a single agent or in combination with zidovudine. The most serious dose-limiting adverse effects associated with didanosine treatment are peripheral neuropathy and pancreatitis. In conclusion, didanosine monotherapy is an effective treatment of HIV infection. However, combination antiretroviral therapy is the optimal treatment strategy for most patients, and didanosine is now firmly established as a component of combination antiretroviral drug regimens for the first-line treatment of patients with HIV disease. Topics: Anti-Bacterial Agents; Anti-HIV Agents; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic | 1996 |
[Anti-retroviral treatment. Approach to previously treated patients].
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1996 |
[Initial anti-retroviral treatment (therapeutic approach to patients without previous treatment)].
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; HIV Infections; Humans; Zalcitabine; Zidovudine | 1996 |
[Nucleoside analogs inhibiting reverse transcriptase: use in adult patient with HIV infection].
Topics: Adult; Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine | 1996 |
[Anti-retroviral treatment. Treatment modification: toxicity management].
Topics: Anti-HIV Agents; Didanosine; Drug Eruptions; Drug Therapy, Combination; Gastrointestinal Diseases; Hematologic Diseases; HIV Infections; Humans; Muscular Diseases; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1996 |
Pediatric antiretroviral therapy: from research to practice.
Topics: Adolescent; Age Factors; Anti-HIV Agents; Child; Child, Preschool; Didanosine; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Viral Load; Virus Replication; Zidovudine | 1996 |
Survival effects of ZDV, ddI, and ddC in patients with CD4 < or = 50 cells/mm3.
Seven major clinical trials for the treatment of HIV-infected individuals are investigated. The treatments used in these trials were zidovudine, dideoxyinosine, dideoxycytosine, and one combination for patients with CD4 cell counts < 500 cells/mm3. Patients in each trial are partitioned into two subgroups based on their baseline CD4 cell counts: patients with CD4 < or = 50 cells/mm3 and patients with CD4 > 50 cells/mm3. The difference between treatment effects, using survival as a measure of effect, within each subgroup is calculated separately for each trial; this difference is referred to as "subgroup response." For each trial the difference between the subgroup responses is calculated and standardized. A meta-analysis is conducted over all seven trials for the differences between subgroup responses; the consistency of responses is evaluated across all trials among patients within baseline CD4 subgroups. Based on the result of this meta-analysis we conclude that there is no evidence that the treatment effects in patients with CD4 < or = 50 cells/mm3 are different from those among patients with CD4 > 50 cells/mm3. This result is observed in patients with different antiviral experience and different baseline characteristics. Risk ratios as well as chi 2 statistics are used to quantify the response rates in different subgroups. Kaplan-Meier curves of survival for these trials are depicted for all patients and each subgroup separately. In most of the trials the Kaplan-Meier curves for the patients with CD4 < or = 50 cells/mm3 resemble those for all patients.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Didanosine; Double-Blind Method; HIV Infections; Humans; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Zalcitabine; Zidovudine | 1995 |
Pharmacokinetic optimisation of antiretroviral therapy in patients with HIV infection.
More than 7 years after the introduction of zidovudine for treatment of HIV infection, little use has been made of the pharmacokinetic properties of this or any of the subsequently approved antiretroviral agents to optimise therapy. This is partly because of the limits of technologies developed to measure clinically relevant forms and concentrations of these drugs, and partly because the clinical community has been slow to recognise the potential benefits of pharmacokinetic optimisation of nucleoside analogue therapy in any disease. Nonetheless, for some of these agents, progress in understanding the relationship between pharmacokinetics and pharmacodynamics has been made. With zidovudine, for example, even though plasma concentrations have little clinical utility, evidence suggests that concentrations of active phosphorylated forms of zidovudine inside target cells are related to disease progression and toxicity. Furthermore, a decreased ability to phosphorylate zidovudine might be a prerequisite for the emergence of zidovudine-resistant HIV strains. Measurements of phosphorylated zidovudine inside cells similarly suggest that 100 mg of oral zidovudine every 8 hours approximates the optimal initial dosage regimen in asymptomatic patients. Increased plasma didanosine concentrations have been associated with several measures of clinical improvement in patients, and may be associated with an increased risk of toxicity as well. For zalcitabine and stavudine, however, the picture is much less clear. Their pharmacokinetic and pharmacodynamic relationships have not been studied in patients. Furthermore, there is insufficient data on the effects of age, gender, race and concurrent underlying conditions on the pharmacokinetics of all of these agents. Mounting evidence suggests that monitoring of these compounds could lead to individually optimised intervention strategies. Given the marginal benefits of therapy with these agents, their proven toxic effects and the lack of proven alternatives, it is critical that the clinical community strive to make the most effective use of these agents in the treatment of their patients. Topics: Aging; Antineoplastic Agents; Antiviral Agents; Didanosine; Drug Interactions; Guidelines as Topic; HIV Infections; Humans; Phosphorylation; Racial Groups; Sex Characteristics; Stavudine; Zalcitabine; Zidovudine | 1995 |
An approach to antiretroviral treatment of HIV disease. Nucleoside monotherapy.
Despite hopes for attack of multiple viral targets, the licensed agents now in use are all of one type: the nucleoside analogue reverse transcriptase inhibitors, of which four, including zidovudine, are available, with a fifth likely to follow. Clinicians and patients are still struggling to learn how best to employ them; but even now, the available trial results can be distilled into rational management plans. Topics: Antiviral Agents; Didanosine; HIV Infections; HIV-1; Humans; Lamivudine; Nucleosides; Stavudine; Zalcitabine; Zidovudine | 1995 |
Human immunodeficiency virus infection in children.
The transmission, diagnosis, and clinical manifestations of human immunodeficiency virus (HIV) infection in children up to 13 years of age are reviewed, and maintenance and prophylactic drug therapies for these patients are discussed. HIV can be transmitted from mother to infant in utero, during delivery, or through breast milk. Perinatal transmission accounts for almost 90% of all pediatric HIV infections. HIV infection can be diagnosed with HIV culturing, polymerase chain reaction testing, the enzyme-linked immunosorbent assay, the Western blot antibody assay, or the p24 core-antigen assay. Testing should begin as soon as possible after the at-risk child reaches one month of age. CD4+ lymphocyte counts are also used in diagnosis and monitoring. The median age at diagnosis of AIDS in children with perinatally acquired HIV infection is 12-24 months. Among the many possible clinical features are Pneumocystis carinii pneumonia (PCP), cytomegalovirus infection, failure to thrive, encephalopathy, recurrent bacterial infection, thrush, lymphoid interstitial pneumonitis, lymphadenopathy, pancreatis, hepatitis, anemia, and thrombocytopenia. Zidovudine is considered the drug of choice for initial therapy in HIV-infected children and is indicated for asymptomatic infection, early symptomatic disease, and advanced disease. However, new research is questioning the role of zidovudine monotherapy. Didanosine is the only agent with FDA-approved labeling for use as second-line therapy in children who do not respond to or become resistant to zidovudine. Agents under investigation for pediatric use are zalcitabine, stavudine, lamivudine, and nevirapine. Drug combinations, such as zidovudine plus didanosine, are also being examined. Zidovudine appears to reduce the rate of maternal transmission of HIV. Agents used prophylactically against PCP in children are trimethoprim-sulfamethoxazole, dapsone, and inhaled or i.v. pentamidine. HIV-infected children should also received prophylaxis against recurrent bacterial infections. The standard pediatric immunization schedule is used, but inactivated injectable poliovirus vaccine must be given instead of the live oral vaccine. Zidovudine remains the first-line agent for treating HIV infection in children. Alternatives are available for those who do not respond to zidovudine. Topics: Adolescent; AIDS-Related Opportunistic Infections; Child; Child, Preschool; Dapsone; Didanosine; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Pentamidine; Pneumonia, Pneumocystis; Pregnancy; Pregnancy Complications, Infectious; Recurrence; Stavudine; Trimethoprim, Sulfamethoxazole Drug Combination; Zalcitabine; Zidovudine | 1995 |
[Anti-HIV therapy (1987-1994): from nothing to confusion].
Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Time Factors; Zalcitabine; Zidovudine | 1995 |
Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection.
Peripheral nerve disorders are among the most common neurological complications of HIV disease. Distal sensory polyneuropathy (DSP) is the most common form of neuropathy in patients with AIDS and can be caused by diverse mechanisms, including infectious, metabolic, inflammatory, nutritional, and toxic factors. Antiretroviral agents may cause or contribute to HIV-related DSP. Recognition of peripheral neuropathy has become increasingly important as more patients receive nucleoside analogue agents for the treatment of HIV disease. It is crucial to correctly distinguish between the neuropathies caused by toxic effects of nucleoside analogues and those that are primarily related to underlying HIV disease, because timely diagnosis and proper treatment of peripheral neuropathies may allow the continuation of antiretroviral therapy as well as improve the quality of life. The identification and treatment of peripheral neuropathies associated with use of the nucleoside drugs zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) are reviewed. Topics: Animals; Didanosine; Dideoxynucleosides; Disease Models, Animal; HIV Infections; Humans; Peripheral Nervous System Diseases; Stavudine; Zalcitabine | 1995 |
Controversies in anti-retroviral therapy of adults.
Much controversy surrounds the use of antiretroviral drugs in HIV-infected patients. The many studies involving large numbers of patients that have been and are being conducted have raised as many questions as they have sought to answer. Given that no cure exists and that all clinically available drugs have only limited activity despite their high toxicity, the question of which drug (or combination of drugs) to use, and in whom, continues to vex both the clinician and the patient. Only three specific antiretroviral agents are currently licensed for use: zidovudine (ZDV), didanosine (dideoxyinosine, ddI) and zalcitabine (dideoxycytidine, ddC). This article reviews the major studies comparing the clinical efficacy of these drugs and the possible benefits of adding acyclovir to zidovudine therapy. The questions of when to begin antiretroviral therapy and the role of combination chemotherapy are discussed. Whenever possible, 'clinical' endpoints (death or clinical progression) are distinguished from 'softer' endpoints (surrogate markers of progression, such as the CD4 lymphocyte count) in the studies reviewed. Recommendations for the use of antiretroviral agents based on currently available published data are made. Topics: Acquired Immunodeficiency Syndrome; Acyclovir; AIDS-Related Complex; AIDS-Related Opportunistic Infections; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Drug Tolerance; HIV Infections; HIV-1; Humans; Zalcitabine; Zidovudine | 1995 |
Nucleoside reverse transcriptase inhibitors and resistance of human immunodeficiency virus type 1.
Drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) emerge during long-term treatment with nucleoside reverse transcriptase inhibitors, such as zidovudine. The clinical significance of in vitro drug resistance to zidovudine has been difficult to determine. However, in a virologic analysis of baseline specimens from the AIDS Clinical Trials Group (ACTG) 116B/117 study, high-level zidovudine resistance, defined as an IC50 of > or = 1 microM at study entry, was significantly associated with clinical disease progression. High-level zidovudine resistance also was an independent predictor of death as an end point, although this finding does not imply a direct causal effect. Duration and cumulative dose of prior zidovudine therapy did not predict clinical disease progression. More potent antiretroviral agents are needed that can be used in combination to achieve more complete virus suppression and to reduce the selection of drug-resistant HIV-1 mutants. Topics: Clinical Trials as Topic; Didanosine; Dideoxynucleosides; Drug Resistance; HIV Infections; HIV-1; Humans; Zidovudine | 1995 |
Clinical pharmacokinetics of nucleoside antiretroviral agents.
The rapid clinical evaluation of new drugs active against human immunodeficiency virus (HIV) requires that pharmacologic properties be carefully considered to determine optimal exposure profiles in patients. The published pharmacokinetic data for the nucleoside antiretroviral agents zidovudine, didanosine, zalcitabine, stavudine, and lamivudine show that administration of fixed doses of certain agents results in a considerable degree of between-patient variability in in vivo drug exposure. Pharmacologic treatment of HIV infection requires development of strategies for individualized adjustment of doses of certain agents with a high degree of interpatient variability. Topics: Animals; Didanosine; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Stavudine; Zalcitabine; Zidovudine | 1995 |
Antiretroviral therapy of human immunodeficiency virus type-1 (HIV-1) infection.
Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine | 1995 |
[Didanosine].
Topics: Adult; Antiviral Agents; Child; Didanosine; Digestive System Diseases; Female; HIV Infections; Humans; Incidence; Pancreatitis; Peripheral Nervous System Diseases; Pregnancy; Reverse Transcriptase Inhibitors | 1995 |
Studies of zidovudine in combination with didanosine and zalcitabine.
A number of antiviral agents have been developed to treat individuals with HIV infection. Monotherapy treatment with the licensed reverse transcriptase (RT) inhibitors zidovudine (AZT), zalcitabine (ddC), and didanosine (ddI) has been shown to delay disease progression in the short term. However, after prolonged treatment viral resistance to these agents emerges. To overcome this development of resistance and subsequent destruction of the immune system leading to disease progression, combination therapies of two or more RT inhibitors have been investigated. In the past, studies have demonstrated that the antiviral drugs ddI and ddC have overlapping toxicities and show cross-resistance. Together, therefore, they are unlikely to prove successful as combination therapy. Conversely, AZT and ddI, and AZT and ddC, have additive or synergistic activities. Recent clinical trials have shown that these two combination therapies are well tolerated and are more effective than monotherapy in delaying the progression of HIV disease. Data from these studies suggest that the maximal benefit from combination therapies can be derived only if they are initiated early in the course of infection, e.g., when CD4 counts are greater than 150 cells/mm3. In clinical studies, AZT/ddI in combination, tended to have a more positive effect on CD4 cell count than the AZT/ddC combination, although the difference was statistically significant only when baseline CD4 count was greater than 100 cells/mm3. No serious side effects have been observed with either combination therapy (AZT/ddC or AZT/ddI) although not surprisingly, patients receiving ddI were more likely to suffer gastrointestinal side effects and those receiving ddC were more likely to suffer from peripheral neuropathy. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Disease Progression; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Safety; Zalcitabine; Zidovudine | 1995 |
Resistance of human immunodeficiency virus type 1 to antiretroviral agents: a review.
Topics: Antiviral Agents; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1994 |
Pharmacologic therapy for human immunodeficiency virus infection: a review.
Topics: Antiviral Agents; Didanosine; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors; Stavudine; Structure-Activity Relationship; Zidovudine | 1994 |
Combination therapy for infection due to human immunodeficiency virus type 1.
The preliminary results of the Concorde trial demonstrated the transient clinical benefit of monotherapy with zidovudine (AZT) in asymptomatic persons infected with human immunodeficiency virus type 1 (HIV-1). This result, which has been widely disseminated and discussed, was predictable given the previous demonstration of the development of resistance to AZT in isolates from individuals receiving prolonged treatment with the drug and given the finding that didanosine (ddI) is more efficacious than continued therapy with AZT in individuals who have received > or = 6 months of AZT monotherapy. On the basis of these findings, interest in combinations of antiretroviral agents has continued to grow. Many in vitro studies of nucleoside and nonnucleoside inhibitors of reverse transcriptase combined with interferon-alpha or inhibitors of protease have been published. In addition, numerous clinical trials of various combinations have been completed or are under way. Dr. Martin Hirsch and his colleagues at the Massachusetts General Hospital have been among the leaders of this effort. He and Dr. Angela Caliendo review, in this AIDS Commentary, the current state of our knowledge regarding the potential utility of combination therapy for infection with HIV-1. Topics: Acyclovir; Antiviral Agents; CD4 Antigens; Clinical Trials as Topic; Combined Modality Therapy; Didanosine; Drug Therapy, Combination; Foscarnet; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; In Vitro Techniques; Interferon alpha-2; Interferon-alpha; Recombinant Proteins; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1994 |
Pancreatic lesions in HIV-infected patients.
The pancreas is frequently involved during HIV infection, especially by disseminated infections or neoplasms. These lesions are generally asymptomatic and are discovered at autopsy. However, hypoglycaemia secondary to massive pancreatic infiltration by a tumour or tuberculous necrosis may occur. The most important cause of pancreatic dysfunction in HIV-infected patients is a drug toxic effect (intravenous pentamidine, didanosine, zalcitabine). Hypoglycaemia, which may or may not be followed by diabetes, can develop during intravenous pentamidine therapy. In cases with increased serum amylase and/or lipase levels, potentially toxic drugs must be promptly discontinued to avoid major pancreatic involvement. Topics: Acute Disease; AIDS-Related Opportunistic Infections; Didanosine; HIV Infections; Humans; Pancreas; Pancreatic Diseases; Pancreatitis; Pentamidine; Trimethoprim, Sulfamethoxazole Drug Combination; Zalcitabine | 1994 |
HIV therapy advances. Pediatric antiretroviral choices.
Zidovudine is the initial treatment of choice in HIV-infected children. Zalcitabine or didanosine may be used in children who do not respond adequately or who are intolerant of zidovudine. Several studies of the latter agents are reviewed.. Zalcitabine at 0.005 or 0.01 mg/kg three times a day was associated with stabilization of growth and a decline in p24 antigen levels in more than 50% of treated children. In a dose-ranging study of didanosine, 30% of children showed an increase in CD4 cell counts and gained weight. There was a correlation between the plasma didanosine concentration and an improvement in IQ (Intelligence Quotient) and p24 status.. In a 12-18 month trial of zidovudine/zalcitabine in 13 children, most gained weight and more than half showed improved CD4 cell counts. The combination of various doses of didanosine with zidovudine was associated with a reduction in viral titer, a significant increase in CD4 cell counts and a trend towards increased weight in many children.. Zidovudine or placebo was administered to women throughout pregnancy and during labor and to their new-born infants up to 6 weeks of age. The infection rate for the zidovudine-treated group was 8.3% compared with 25.5% for the placebo group (P = 0.000056).. Zalcitabine and didanosine are useful drugs in the treatment of HIV-infected children. Zidovudine is associated with a reduced rate of mother to infant viral transmission. Topics: Body Weight; Clinical Trials as Topic; Didanosine; Female; Growth; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Treatment Failure; Zalcitabine; Zidovudine | 1994 |
Future treatment strategies in HIV infection.
EFFECTIVENESS OF EARLY TREATMENT WITH ZIDOVUDINE: In terms of progression to AIDS-related complex, AIDS or death, clinical trials have not yet shown any long-term benefit for early compared with deferred treatment with zidovudine. The Concorde trial showed a short-term benefit, as did two of the AIDS Clinical Trials Group studies, but the number of deaths in these short-term trials was too small to draw definitive conclusions. USE OF CD4 CELL COUNTS AS A MARKER OF AIDS: Most trials of zidovudine treatment have shown a slower decline in CD4 cell counts. However, it is still not clear whether these markers can predict long-term survival although they appear to have some value in predicting short-term benefits. SECOND-LINE THERAPY: In patients who are intolerant of or have failed to respond adequately to zidovudine, treatment with didanosine or zalcitabine has shown some short-term benefit, mainly in asymptomatic patients or those with AIDs-related complex. No substantial long-term benefit was observed. Zalcitabine appeared to show a slight increase in survival compared with didanosine.. Treatment strategies still being developed include multidrug combinations, the combination of a nucleoside with a non-nucleoside reverse transcriptase inhibitor, or the use of a combination of drugs that affect different stages of the HIV life cycle, such as proteinase inhibitors. More sensitive assays, such as RNA polymerase chain reaction, may allow treatment to be tailored more closely to the needs of the individual patient. Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Antiviral Agents; Biomarkers; CD4 Lymphocyte Count; Didanosine; Forecasting; HIV Infections; Humans; Zalcitabine; Zidovudine | 1994 |
Acute rhabdomyolysis in patients infected by human immunodeficiency virus.
To delineate the spectrum of rhabdomyolysis associated with human immunodeficiency virus (HIV) infection, we reviewed the clinical and pathologic data from nine HIV-infected individuals with acute rhabdomyolysis, and pooled data with those of 11 previously reported cases. Patients with rhabdomyolysis were at all stages of HIV infection and could be classified into three groups: (1) HIV-associated rhabdomyolysis (7 of 20), including rhabdomyolysis in primary HIV infection, recurrent rhabdomyolysis, and isolated rhabdomyolysis; (2) rhabdomyolysis induced by drugs (6 of 20), including didanosine; and (3) rhabdomyolysis at the end stage of acquired immunodeficiency syndrome (7 of 20), including opportunistic infections of muscle and rhabdomyolysis without a definite cause. Because prognosis, in part, depends on the cause of rhabdomyolysis, recognition of drug-induced or opportunistic infectious muscle disorders is required. Topics: Acute Disease; Adult; Didanosine; Female; HIV Infections; Humans; Male; Rhabdomyolysis | 1994 |
[Antiretroviral therapy. Current status and perspectives].
Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; Humans; Stavudine; Zalcitabine; Zidovudine | 1994 |
Managing occupational risks in the dental office: HIV and the dental professional.
Despite universal precautions, work behavior modifications and technological advances, health care workers continue to experience occupational exposures to HIV and other bloodborne pathogens. Although the risk for infection is low when compared with other bloodborne pathogens, 39 documented cases of HIV seroconversion have been recorded. Recent attention has focused on secondary prevention of HIV infection through post-exposure chemoprophylaxis. Topics: Blood-Borne Pathogens; Dental Staff; Didanosine; HIV Infections; HIV Seropositivity; Humans; Needlestick Injuries; Occupational Exposure; Risk Factors; Universal Precautions; Zidovudine | 1994 |
Perspectives on the use of antiretroviral drugs in the treatment of HIV infection.
Topics: Didanosine; Dideoxynucleosides; Drug Administration Schedule; HIV Infections; Humans; Stavudine; Zalcitabine; Zidovudine | 1994 |
[Range of neuromuscular involvement in 47 patients infected with the human immunodeficiency virus].
Over a 30 month period, 47 out of 749 patients infected with the human immunodeficiency virus had various neuromuscular symptoms. Based on clinical and electrophysiological data, 47% had distal symmetric polyneuropathy, 11% chronic inflammatory demyelinating polyneuropathy (CIDP), 8.5% toxic neuropathy related to 2-3-dideoxyinosine (DDI), 8.5% cranial neuropathy, 8.5% mononeuropathy multiplex or isolated focal neuropathy, 8.5% progressive lumbosacral polyradiculopathy, and 8.5% myopathy. Half of the patients exhibited previous or concomitant signs of central nervous system involvement and 18 patients died during the study period. CIDP and cranial neuropathies usually appeared early in the course of the disease and consequently showed neurological improvement. Nerve conduction studies of DDI related toxic neuropathies showed distal axono-myelinic sensitivo-motor neuropathy, differing from CIDP by the absence of a conduction block. Distal symmetric polyneuropathies, frequent in the advanced systemic illness, do not systematically require an extended workup, but more unusual peripheral neuropathies which might be treatable necessitate further investigations (electromyography, radiology, serological blood tests; protein chemistry and routine workup of the cerebrospinal fluid). For example, progressive lumbosacral polyradiculopathies responded to early treatment, with a better outcome in one case of herpetic origin than in another case due to cytomegalovirus infection. Our observations suggest that myopathies in HIV infected patients should first be tackled by temporary interruption of virostatic medication, followed by muscle biopsy if the symptoms persist. Topics: Adult; Aged; AIDS Dementia Complex; Central Nervous System Diseases; Cranial Nerve Diseases; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Neural Conduction; Neuromuscular Diseases; Peripheral Nervous System Diseases | 1994 |
Clinical pharmacology of zidovudine and other 2',3'-dideoxynucleoside analogues.
Since the discovery of the acquired immunodeficiency syndrome (AIDS) in 1981, considerable progress has been made in the development of agents with anti-HIV activity. Zidovudine was one of the first 2'-3'-dideoxynucleosides to cause inhibition of human immunodeficiency virus (HIV) replication in vitro, by inhibiting the viral reverse transcriptase. Early trials showed that zidovudine results in clinical and immunological improvements and prolonged life in patients with AIDS or AIDS-related complex. However, haematological toxicity is the main drawback associated with zidovudine therapy. The initial recommended dose of zidovudine was 1500 mg per day, but recent studies have shown that dosages as low as 300 mg per day could be just as effective, without the severe haematological toxicity. Because zidovudine readily crosses the blood-brain barrier, it is used for the treatment of neurological diseases associated with HIV disease with some success. However, Kaposi's sarcoma does not respond to therapy with the drug. Apart from haematological toxicity, patients on long-term therapy with zidovudine may also develop resistance. Zidovudine use has also been associated with improvements in neurodevelopmental and growth velocity in HIV-infected children. The use of zidovudine as a prophylaxis has also been suggested, but the value of this is questionable. The combination of zidovudine with other agents, such as acyclovir and interferon, has a synergistic effect on the anti-HIV activity, with reduced drug toxicity. Other 2',3'-dideoxynucleoside analogues, such as dideoxycytidine (ddC) and dideoxyinosine (ddI) are effective anti-HIV agents and their use is also associated with both clinical and immunological improvements.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Acquired Immunodeficiency Syndrome; Adult; Child; Didanosine; Dideoxynucleosides; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Interferons; Needlestick Injuries; Sarcoma, Kaposi; Zalcitabine; Zidovudine | 1993 |
Antiretroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art conference. National Institute of Allergy and Infectious Diseases State-of-the-Art Panel on Anti-Retroviral Therapy for Adult HIV-Infected Patients.
This document summarizes recommendations from a state-of-the-art conference convened to evaluate the role of nucleoside analogue reverse transcriptase inhibitors in the treatment of human immunodeficiency virus (HIV) infection. Data from controlled clinical trials of zidovudine, didanosine, and zalcitabine were reviewed by an expert panel, which then formulated guidelines to assist clinicians and HIV-infected patients in the use of these agents. Recommendations were framed in the context of clinical scenarios for patients with asymptomatic HIV infection who have not had prior antiretroviral therapy; those with signs and symptoms of HIV-related disease who have not received prior therapy; clinically stable patients who are tolerating initial zidovudine therapy; patients experiencing clinical progression while on zidovudine therapy; and those who are intolerant of antiretroviral therapy. The panel concluded that physicians need to integrate up-to-date scientific knowledge with other relevant needs to improve the care of HIV-infected patients. Topics: Adult; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Didanosine; Dideoxynucleosides; Drug Resistance; Guidelines as Topic; HIV Infections; Humans; Leukocyte Count; Zalcitabine; Zidovudine | 1993 |
Zalcitabine and didanosine.
Topics: Adult; Antiviral Agents; Child; Didanosine; DNA Replication; DNA, Viral; Drug Interactions; HIV; HIV Infections; Humans; Virus Replication; Zalcitabine | 1993 |
Monitoring the activity of antiviral therapy for HIV infection using a polymerase chain reaction method coupled with reverse transcription.
To monitor the anti-HIV-1 activity of antiretroviral agents in patients with HIV-1 infection.. Quantification of viral RNA copy in plasma or serum using a polymerase chain reaction method coupled with reverse transcription.. The HIV-1 RNA copy number represents the HIV-1 viremia status in patients with HIV-1 infection. This copy number is likely to be useful in monitoring the effectiveness of antiviral therapy and the method is likely to be built into every clinical trial of anti-HIV-1 therapy in the near future. Topics: Antiviral Agents; Didanosine; Drug Resistance, Microbial; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Polymerase Chain Reaction; Reproducibility of Results; RNA, Viral; Sensitivity and Specificity; Transcription, Genetic; Viremia; Virus Replication | 1993 |
[Therapy of HIV infection with nucleoside analogs].
Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; Humans; Nucleosides; Zalcitabine; Zidovudine | 1993 |
Pharmacodynamics of antiretroviral chemotherapy.
It has been demonstrated that systemic exposure to antiretroviral agents drives both the therapeutic and the toxic effects seen in clinical trials. Consequently, it is necessary to determine plasma concentrations of drugs and their metabolites (and possibly intracellular concentrations) during the course of Phase 1 and 2 evaluations. It also has been demonstrated that having precise mathematical relationships between exposure and response as well as between exposure and toxicity allows rational selection of drug dose for evaluation in larger Phase 2 and 3 clinical trials. This can be seen with AZT, where the exposure-efficacy relationship is clearly at a plateau by 600 mg/day, while the exposure-toxicity relationship predicts increasing toxicity (and, because of the plateauing of the effect relationship, without better therapeutic response). It can be seen most clearly with ddI, where the exposure-efficacy relationship pointed to longer-term therapy with lower doses ultimately being as efficacious as higher dose therapy. When coupled with the long-term tolerance data for ddI, this led to a prospective prediction of superiority of lower-dose therapy, which was validated later. Finally, some problems with current Phase 1 and 2 trial design have been pointed out, in that bioavailability needs to be recognized explicitly as an important evaluation factor in oral antiretroviral therapy. Perhaps most notably, the importance of initial susceptibility of the virus to the study drug has been suggested by the data of Drusano et al. Clearly, the microbiology of the patient needs to be taken into consideration in the evaluation of Phase 1 and 2 antiretroviral trial results.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Antiviral Agents; Biological Availability; CD4 Antigens; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dextran Sulfate; Didanosine; HIV Core Protein p24; HIV Infections; Humans; T-Lymphocytes; Zidovudine | 1993 |
Roundtable discussion: management issues in didanosine therapy.
Topics: Didanosine; Dose-Response Relationship, Drug; Health Personnel; HIV Infections; Humans; Occupational Exposure; Pancreatitis; Peripheral Nervous System Diseases; Zidovudine | 1993 |
Therapy for human immunodeficiency virus infection.
Topics: Didanosine; Drug Resistance; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Protease Inhibitors; Zalcitabine; Zidovudine | 1993 |
Current management of HIV infection in children.
Topics: AIDS-Related Opportunistic Infections; Antiviral Agents; Child; Child, Preschool; Didanosine; Drug Monitoring; HIV Infections; Humans; Infant; Infant, Newborn; Zidovudine | 1993 |
Pediatric HIV: Australian perspective.
Pediatric infection with human immunodeficiency virus (HIV) in Australia, as elsewhere, now reflects HIV seroprevalence in women of childbearing age although numbers remain small. A perinatal transmission rate of approximately 30% has been observed. The rate appears to be higher for breast-fed babies; exclusively bottle-fed babies of HIV-infected mothers appear to have a risk of < 20% of acquiring HIV perinatally. Although the seroprevalence rate in women of childbearing age in Australia remains low, routine antenatal screening will not be cost-effective. Although passively acquired maternal antibody may confound serodiagnosis for up to 18 months, in practice, HIV infection, when present, can be detected clinically or with use of other laboratory parameters (p24, polymerase chain reaction, viral culture, hyperglobulinemia) during the first 6 months of life. Zidovudine appears to be relatively nontoxic in children and effective in producing weight gain and preventing opportunistic infection. Although experience with didanosine is limited, this drug appears to have a very acceptable toxicity profile and the advantage of twice-daily dosing. However, the bioavailability and penetration into the cerebrospinal fluid are poor. Neurological disease can improve when absorption is adequate. Residential family camps may help to reduce isolation for families and provide them with an opportunity for improving their understanding of HIV through interaction with peers and professionals. Topics: Adult; Australia; Didanosine; Female; HIV Infections; Humans; Infant; Infant, Newborn; Male; Social Support | 1993 |
New developments in the clinical use of didanosine.
Didanosine (ddI) is a purine analogue that demonstrates in vitro anti-human immunodeficiency virus (HIV) activity, effects on the surrogate markers CD4+ T-lymphocytes and p24 antigen, and has adequate oral bio-availability. Recently, 500 mg/day of ddI in sachet form demonstrated clinical effectiveness compared with zidovudine (ZDV) for delaying HIV disease progression in patients with AIDS or AIDS related complex (ARC) and less than 300 CD4+ T-lymphocytes, or asymptomatic individuals with less than 200 CD4+ T-lymphocytes. All patients tolerated a minimum of 16 weeks of prior ZDV treatment. ddI treatment was associated with an increase in serum amylase and pancreatitis, however, there was no significant difference in the incidence of pancreatitis between the 500 mg ddI and ZDV groups. There was significantly more hematologic toxicity associated with ZDV and no difference between ddI and ZDV groups with respect to peripheral neuropathy. ddI is presently available in tablet form with 125% the bioavailability of the sachet form of ddI; therefore, the 500-mg sachet formulation corresponds to a 400-mg daily tablet dose of ddI. Future studies of ddI will involve ddI's effects on antiretroviral naive patients and the potential of combining ddI with other agents. Topics: Didanosine; Dose-Response Relationship, Drug; HIV Infections; Humans | 1993 |
Arguments against the chemoprophylactic use of zidovudine following occupational exposure to the human immunodeficiency virus.
Following the paradigm of the hospitals of the National Institutes of Health and the University of California at San Francisco, many medical facilities have instituted a policy of administering zidovudine to health care workers after exposure to blood potentially contaminated with the human immunodeficiency virus. There is no clinical evidence proving the efficacy of such chemoprophylaxis. Toxic effects associated with zidovudine are usual and at times severe. The institutional administration of zidovudine to anyone other than individuals infected with the human immunodeficiency virus should be discontinued except under the auspices of a randomized, placebo-controlled trial. Topics: Didanosine; Health Personnel; HIV Infections; Humans; Occupational Exposure; Zidovudine | 1993 |
New developments in antiretroviral drug therapy for HIV infection.
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Combinations; Drug Therapy, Combination; Gene Products, tat; HIV Infections; HIV-1; Humans; Protease Inhibitors; tat Gene Products, Human Immunodeficiency Virus; Zalcitabine; Zidovudine | 1992 |
The use of nucleoside analogues in the treatment of HIV-infected children.
Topics: Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Infant; Infant, Newborn; Zalcitabine; Zidovudine | 1992 |
Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: combination therapy.
Combination antiretroviral therapy is an important development in the management of HIV infection. AZT with ddC is the first such combination to be approved for clinical use. Several issues remain, however, including the precise clinical benefit and toxicity of combination therapy, its effect on drug resistance, and the development of ever more effective therapeutic strategies. Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Zalcitabine; Zidovudine | 1992 |
Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: adverse effects.
The three approved nucleoside analogues are fairly well tolerated, and only a few patients have to discontinue therapy permanently. However, because clinical experience is limited, especially with ddI and ddC, delayed toxicities are likely to emerge over time. In addition, physicians should be vigilant for overlapping toxicities from combination therapy with these and other medications. Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Zalcitabine; Zidovudine | 1992 |
Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: monotherapy.
At present, the nucleoside analogues are the cornerstone of therapy for HIV infection. Of the three that have been approved for clinical use, AZT is the only one that has clearly proved to prolong survival. ddI is indicated for patients who develop toxicity or resistance to AZT. Current data do not support ddC monotherapy as first-line treatment. Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Resistance, Microbial; HIV Infections; HIV-1; Humans; Time Factors; Zalcitabine; Zidovudine | 1992 |
HIV disease: therapy, related systemic and oral conditions--an update.
Topics: Acquired Immunodeficiency Syndrome; Bacterial Infections; Didanosine; HIV Infections; Humans; Mouth Diseases; Mycoses; Sarcoma, Kaposi; Virus Diseases; Zalcitabine; Zidovudine | 1992 |
Primary care for HIV infection.
Topics: CD4-Positive T-Lymphocytes; Clinical Protocols; Clinical Trials as Topic; Didanosine; Drug Monitoring; HIV Infections; HIV-1; Humans; Immunization; Leukocyte Count; Pneumonia, Pneumocystis; Primary Health Care; Sex Counseling; Zidovudine | 1992 |
Current status of therapy for human immunodeficiency virus type 1.
The past year has been refinement in our ability to delay the progression of human immunodeficiency virus type 1 infection through the use of nucleoside analogues, singly or in combination. Progress has also been made in our ability to detect drug-resistant isolates of human immunodeficiency virus type 1 and to begin to put the laboratory observations of resistance into a clinical context. Topics: CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Didanosine; Drug Resistance; HIV Infections; HIV Seropositivity; HIV-1; Humans; T-Lymphocytes, Helper-Inducer; Zalcitabine; Zidovudine | 1992 |
[Anti-HIV treatment, today and in the near future].
Topics: Antiviral Agents; Didanosine; Dideoxynucleosides; DNA, Viral; Drug Therapy, Combination; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine; Transcription, Genetic; Zalcitabine; Zidovudine | 1992 |
Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection.
Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse transcriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations. In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in 1 study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity. Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest. Topics: Acquired Immunodeficiency Syndrome; Didanosine; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans | 1992 |
[Treatments of human immunodeficiency virus infection. Current developments].
Topics: Acquired Immunodeficiency Syndrome; Didanosine; HIV; HIV Infections; Humans; Zalcitabine; Zidovudine | 1991 |
New developments in dideoxynucleoside antiretroviral therapy for HIV infection.
Topics: Acquired Immunodeficiency Syndrome; Didanosine; Dideoxynucleosides; HIV Infections; Humans; Zalcitabine; Zidovudine | 1991 |
Anti-retroviral therapy of human immunodeficiency virus infection: current strategies and challenges for the future.
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Resistance; HIV; HIV Infections; Humans; Lymphoma, Non-Hodgkin; Retroviridae; Reverse Transcriptase Inhibitors; T-Lymphocytes, Helper-Inducer; Virus Replication; Zalcitabine; Zidovudine | 1991 |
Zidovudine and other reverse transcriptase inhibitors in the management of human immunodeficiency virus-related disease.
Licensed in 1987, zidovudine remains the only medication with proved efficacy for the treatment of disease caused by the human immunodeficiency virus (HIV). New information on the pharmacology (adults and children), effects of kidney and liver dysfunction on the disposition of the drug, and drug-drug interactions have improved the way we use and monitor this agent. The serious toxicity associated with zidovudine has led researchers to develop safer dosage regimens. Also, recognition that zidovudine slows but does not halt progression of disease has increased the search for effective alternatives. The best-studied agents are didanosine (2',3'-dideoxyinosine, ddl), zalcitabine (2',3'-dideoxycytidine, ddC), and foscarnet. Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; Child; Didanosine; Female; Foscarnet; HIV Infections; Humans; Phosphonoacetic Acid; Pregnancy; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1991 |
Chemotherapy of human immunodeficiency virus infections: current practice and future prospects.
As human immunodeficiency virus type 1 (HIV-1) has become better understood, numerous drugs have been developed that act at virus-specific sites. These are challenging our ability to evaluate them thoroughly and rapidly. Zidovudine (AZT) remains the mainstay of anti-HIV-1 drugs. Recent controlled trials indicate it should be used early in infection (in those with CD4 cell counts less than 500/mm3) and in lower doses (500-600 mg/day). Prolonged AZT treatment in patients with AIDS, however, is often associated with viral resistance. Newer reverse transcriptase-inhibiting nucleoside derivatives are currently in phase II-III clinical trials. Other HIV-1 replicative sites under attack in clinical studies include binding and entry of virus, envelope protein glycosylation, and viral assembly and release. Agents that target HIV-1 proteinase, integrase, ribonuclease H, and products of regulatory genes such as tat are under development. Combination therapies that target different viral replicative sites likely will allow use of individual agents below their toxic concentrations and help prevent drug resistance. Innovative programs for expanded access to experimental drugs are needed that will permit expeditious clinical trials, optimize the gathering of useful information, and permit the widest access to promising treatments. Topics: Animals; Antiviral Agents; Didanosine; DNA Nucleotidyltransferases; DNA Replication; Drug Therapy, Combination; Endopeptidases; HIV Infections; HIV-1; Humans; Integrases; RNA-Directed DNA Polymerase; Virus Replication; Zalcitabine; Zidovudine | 1990 |
Trials
316 trial(s) available for didanosine and HIV-Infections
Article | Year |
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Efavirenz Capsule Sprinkle and Liquid Formulations With Didanosine and Emtricitabine in HIV-1-infected Infants and Children 3 Months to 6 Years of Age: Study AI266-922.
AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years).. Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle.. Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 μM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 μM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance.. Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported. Topics: Alkynes; Benzoxazines; Child, Preschool; Cyclopropanes; Didanosine; Emtricitabine; Female; HIV Infections; Humans; Infant; Male; Prospective Studies | 2015 |
Pharmacokinetics of sifuvirtide in treatment-naive and treatment-experienced HIV-infected patients.
The pharmacokinetics assessment in two clinical studies of sifuvirtide (a novel HIV fusion inhibitor) was first reported in Chinese HIV patients. Nineteen treatment-naive HIV patients were treated with s.c.(subcutaneous injection) sifuvirtide [10 or 20 mg q.d.(quaque die)] for 28 days in study 1, and eight treatment-experienced HIV patients were treated with s.c. sifuvirtide (20 mg q.d.) in combination with HAART drugs (lamivudine, didanosine, and Kaletra) for 168 days in study 2. In study 1, T1/2 was 17.8 ± 3.7 h for 10 mg group and 39.0 ± 3.5 h for 20 mg group; the mean Cmax of last dose was 498 ± 54 ng/mL for 10 mg group and 897 ± 136 ng/mL for 20 mg group. In study 2, T1/2 was 6.71 ± 2.17 h in treatment-experienced patients. Cmax was 765 ± 288 ng/mL after last 168th dosage. Sifuvirtide showed improved clinical pharmacokinetics characteristics compared with Enfuvirtide, and showed very different pharmacokinetic characteristics between treatment-naive and treatment-experienced patients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4038-4047, 2014. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Double-Blind Method; Drug Combinations; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Peptide Fragments; Peptides; Ritonavir | 2014 |
Pre-antiretroviral therapy serum selenium concentrations predict WHO stages 3, 4 or death but not virologic failure post-antiretroviral therapy.
A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (<85 μg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 μg/L (Interquartile range (IQR): 57.28-99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86-95.10 μg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50; 95% confidence intervals (CI): 1.30-9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium. Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Body Mass Index; C-Reactive Protein; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Didanosine; Disease Progression; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Logistic Models; Male; Multivariate Analysis; Oligopeptides; Prospective Studies; Pyridines; Risk Factors; Selenium; World Health Organization; Zidovudine | 2014 |
Prevalence, incidence and predictors of peripheral neuropathy in African adults with HIV infection within the DART trial.
We investigated the prevalence, incidence and predictors of new peripheral neuropathy episodes in previously untreated, symptomatic HIV-infected Ugandan/Zimbabwean adults initiating zidovudine-based antiretroviral therapy (ART).. An open-label, multicentre, randomized trial.. Peripheral neuropathy was self-reported at 12-weekly clinic visits. Cox regression models (excluding participants reporting preexisting peripheral neuropathy at ART initiation), considered sex; pre-ART WHO stage, age and CD4(+) cell count; CD4(+) cell count versus no CD4(+) cell count monitoring; and time-updated CD4(+) cell count, weight and use of stavudine, isoniazid and didanosine.. Four hundred and twenty-one out of 3316(13%) patients reported preexisting peripheral neuropathy at ART initiation. Median (interquartile range, IQR) follow-up in 2895 participants without preexisting peripheral neuropathy was 4.9 (4.7-5.4) years. Three hundred and fifty-four (12%) took stavudine as first-line substitution and 518 (18%) took isoniazid during follow-up. Two hundred and ninety (11%) participants developed a new peripheral neuropathy episode, an incidence of 2.12 per 100 person-years. Eighteen (0.1%) had a grade 3/4 episode. Independent predictors of peripheral neuropathy were current stavudine use [adjusted hazard ratio (a)HR 4.16 (95% confidence interval, 95% CI 3.06-5.66], current isoniazid use [aHR 1.59 (95% CI 1.02-2.47)] and current didanosine use [aHR 1.60 (95% CI 1.19-2.14)]. Higher risks were independently associated with higher pre-ART weight [aHR (per+5 kg) 1.07 (95% CI 1.01-1.13)] and older age aHR (per 10 years older) 1.29 (95% CI 1.12-1.49), but there was no significant effect of sex (P = 0.13), pre-ART CD4(+) cell count (P = 0.91) or CD4(+) cell count monitoring (P = 0.73).. Current stavudine, didanosine or isoniazid use continue to increase peripheral neuropathy risks, as does older age and weight at ART initiation; however, we found no evidence of increased risk in women in contrast to previous studies. The incidence of peripheral neuropathy may now be lower in ART programmes, as stavudine and didanosine are no longer recommended. All patients receiving isoniazid, either as part of antituberculosis (TB) chemotherapy or TB-preventive therapy, should receive pyridoxine as recommended in national guidelines. Topics: Adolescent; Adult; Aged; Anti-Retroviral Agents; Antitubercular Agents; Didanosine; Female; HIV Infections; Humans; Incidence; Isoniazid; Male; Middle Aged; Peripheral Nervous System Diseases; Prevalence; Risk Factors; Stavudine; Uganda; Young Adult; Zidovudine; Zimbabwe | 2014 |
A novel pharmacokinetic approach to predict virologic failure in HIV-1-infected paediatric patients.
The objective of this study was to develop in children an HIV dynamic model able to predict simultaneously the viral load and CD4 lymphocyte evolutions, and to take into account, through a composite inhibition score, the relative contribution of each drug of the combination efavirenz-didanosine-lamivudine and use this score as a predictor of treatment failure in a multidrug therapy.. Open phase II trial (BURKINAME - ANRS 12103) registered in the ClinicalTrials.gov database (http://clinicaltrials.gov) with the no. NCT00122538.. Forty-nine children aged from 2.5 to 15 years were administered once-daily dose of lamivudine, didanosine and efavirenz. The three drugs effect was then characterized by a composite inhibition score combining the effect of each drug, according to their site and mechanism of action and their relative contribution.. Efavirenz was the most potent antiretroviral and was responsible for 65% of the total effect, and then didanosine for 23% and lamivudine was the less potent with 12% of the total observed effect. An EC90 for efavirenz was determined (3.3 mg/l). AUC90 was estimated for lamivudine and didanosine: 8.4 and 1.5 mg h/l, respectively. The composite inhibition score was the best predictor of virologic failure compared with the concentrations of each drug taken independently [hazard ratio (HR) 0.6 per 10% increase, 95% confidence interval (CI) 0.41-0.88].. The relative contributions of three combined drugs were assessed on plasma viral load and CD4 lymphocyte count kinetics in HIV-1-infected children. Pharmacokinetics targets have been suggested for lamivudine and didanosine. A composite inhibition score has been determined to be a high predictor of treatment failure in a multidrug therapy. Topics: Adolescent; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Models, Theoretical; Predictive Value of Tests; Treatment Failure; Viral Load | 2013 |
24-Month adherence, tolerance and efficacy of once-a-day antiretroviral therapy with didanosine, lamivudine, and efavirenz in African HIV-1 infected children: ANRS 12103/12167.
There is no data on long-term benefit of once-a-day antiretroviral therapy (ART) with combination of DDI, 3TC and EFV to allow its use in future therapeutic strategies.. To assess 24-month immuno-virological, adherence, tolerance, and effectiveness of a once-a-day ART with DDI, 3TC and EFV.. A phase 2 open trial including 51 children aged from 30 months to 15 years, monitored a once-a-day regimen for 24 months from 2006 to 2008 in the Departement de Pediatrie du CHUSS, at Bobo-Dioulasso in Burkina Faso. We tested immunological and virological response, adherence, tolerance and resistance of the treatment.. Children with CD4 >25% at 24 months were 67.4% (33/49) CI 95% [54%, 80%]. The proportion of children with viral plasma RNA <300 cp / ml at 24 months of treatment was 81.6 % (40/49) CI [68.0% 91.2%]. Good adherence was obtained with more than 88% adherence > 95% over the 24 months. Drugs were well tolerated.. Given the limited number of antiretroviral drugs available in Africa and the inadequacy of laboratory monitoring in support program, once-a-day treatment and especially the DDI-based combination strategies could be an attractive operational option. Topics: Adolescent; Africa; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Confidence Intervals; Cyclopropanes; Didanosine; Female; HIV Infections; Humans; Lamivudine; Male; Medication Adherence; RNA, Viral; Surveys and Questionnaires; Viral Load | 2013 |
VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof-of-concept study for antiviral-hyperactivation limiting therapeutics.
A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects.. Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests.. VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4(+) T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log(10) copies/mL; CD4(+) T cell count: +135 cells/mm(3)) and fewest adverse events.. VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component.. ITEudraCT 2007-002460-98. Topics: Adult; Analysis of Variance; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Delayed-Action Preparations; Deoxyadenine Nucleotides; Didanosine; Dideoxynucleotides; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Immunomodulation; Male; Placebos; RNA, Viral; Urea; Viral Load | 2012 |
Four year follow-up of simplification therapy with once-daily emtricitabine, didanosine and efavirenz in HIV-infected patients (ALIZE ANRS 099 trial).
once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine.. the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of <400 copies/mL under a protease inhibitor-based regimen, who were randomized to remain on this regimen or to switch to a once-daily regimen of emtricitabine, didanosine and efavirenz for 48 weeks. An extended 4 year follow-up was available for the 178 patients who switched to the efavirenz-containing regimen, and assessed plasma HIV RNA levels, CD4 cell counts, safety and tolerability.. after a median follow-up of 42 months, 121 patients (68%) remained on an efavirenz-based regimen, and 62% and 57% had plasma HIV RNA levels of <400 and <50 copies/mL, respectively, in an intent-to-continue analysis with missing data and treatment discontinuation considered as failure. There was a significant increase in CD4 cell count of 41 cells/mm(3). Drug-related adverse events were the main reason for treatment discontinuation in 26 patients (15%), and 15 were reported during the first year of therapy (58%). There was no emergence of clinically defined lipodystrophy, and lipid and glucose profiles were favourable with a significant increase from baseline of high-density lipoprotein cholesterol levels (median increase 12 mg/dL, P < 10(-4)).. a once-daily regimen of emtricitabine, didanosine and efavirenz provided a durable antiretroviral response and was well tolerated through 4 years of therapy. Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Didanosine; Emtricitabine; Female; Follow-Up Studies; HIV Infections; Humans; Male; RNA, Viral; Treatment Outcome; Viral Load | 2011 |
Long-term effectiveness and safety of didanosine combined with lamivudine and efavirenz or nevirapine in antiretroviral-naive patients: a 9-year cohort study in Senegal.
The use of didanosine (ddI) in first-line antiretroviral therapy has been recently promoted for resource-limited settings. We therefore compared the long-term effectiveness and safety of the regimen combining ddI, lamivudine, and efavirenz or nevirapine with that of the WHO-recommended regimen of zidovudine (ZDV), lamivudine, and efavirenz or nevirapine in antiretroviral-naïve patients in Senegal.. Observational cohort study of patients enrolled between January 2000 and April 2002 in the Senegalese antiretroviral drug access initiative. Multivariate analyses were performed to compare, between the ddI and ZDV groups, the proportion of patients with a viral load <500 copies/ml during follow-up; the increase in the CD4 cell count; survival; treatment changes and severe adverse events.. Of 151 patients, 71 received the ddI-based treatment and 80 received the ZDV-based treatment. Throughout follow-up, 80-95% of patients had a viral load below 500 copies/ml in both the ddI and ZDV groups (P = 0.5). The CD4 cell count increased after treatment initiation from 176 to 497 cells/mm(3) in the ddI group and from 176 to 567 cells/mm(3) in the ZDV group (P > 0.3). The rate of death tended to be higher in the ddI group (P = 0.06). ddI was less commonly discontinued than ZDV (P = 0.03).. The combination of ddI, lamivudine, and efavirenz or nevirapine resulted in sustained viral suppression and immunological recovery. Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Treatment Outcome; Viral Load; Zidovudine | 2011 |
Intracellular nucleotide levels during coadministration of tenofovir disoproxil fumarate and didanosine in HIV-1-infected patients.
Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study. Topics: Adenine; Adult; Aged; Anti-HIV Agents; Chromatography, Liquid; Deoxyadenine Nucleotides; Deoxyguanine Nucleotides; Didanosine; Dideoxynucleotides; Female; HIV Infections; Humans; Male; Middle Aged; Nucleotides; Organophosphonates; Tandem Mass Spectrometry; Tenofovir; Young Adult | 2011 |
Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial).
The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL).. In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined.. In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event.. The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Australasia; Body Mass Index; Didanosine; DNA, Mitochondrial; DNA, Viral; Europe; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; North America; Polymerase Chain Reaction; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Factors; RNA; RNA, Mitochondrial; RNA, Viral; Sex Factors; South America; Stavudine | 2011 |
Short-term virological efficacy, immune reconstitution, tolerance, and adherence of once-daily dosing of didanosine, lamivudine, and efavirenz in HIV-1-infected African children: ANRS 12103 Burkiname.
Access to antiretroviral therapy (ART) and routine laboratory monitoring are limited for HIV-1-infected children from sub-Saharan Africa. This trial conducted in Bobo-Dioulasso, Burkina Faso, aimed to describe the biological efficacy, tolerance, and adherence of the combination of didanosine, lamivudine, efavirenz in once-daily administration among eligible HIV-1-infected children. From February 2006 to November 2007, 51 HIV-1-infected children aged from 30 months to 15 years and eligible for ART were enrolled in a phase II open clinical trial with follow-up visits every 3 months. HIV-1 genotype testing was performed in children with plasma viral load (PVL) >1000 copies per milliliter after ART initiation. Children were followed for a median of 13.4 months [interquartile range (IQR) 12.8-14.2]. At enrollment, median CD4 count was 8% (IQR = 4.5-12). PVL was 341,032 (IQR = 127,838-761,539) copies per milliliter. At 12 months, median CD4 increased significantly by +15% (P < 10(-3)), and median PVL decreases significantly by -290,500 copies per milliliter (P < 10(-4)). Hemoglobin and platelets counts increased significantly by +1.05 g/dL (P < 10(-5)) and 108,500 cells per milliliter (P < 10(-3)), respectively. Based on pill count, mean yearly adherence was 97.3%, and 48% of the children had an adherence rate ≥ 95% at the four quarterly visits. Adherence was better for girls than for boys independently of other sociodemographic variables or markers of HIV disease progression. Drug-resistant mutations were found in 11 children (21.6%). This once-daily drug combination is associated with excellent virological efficacy, immune reconstitution, and good adherence. However, the high prevalence of drug resistance mutations is a matter of concern. Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Child; Cyclopropanes; Didanosine; Female; HIV Infections; Humans; Lamivudine; Male; Patient Compliance; Reverse Transcriptase Inhibitors; Viral Load | 2011 |
The impact of once-nightly versus twice-daily dosing and baseline beliefs about HAART on adherence to efavirenz-based HAART over 48 weeks: the NOCTE study.
To determine the impact of once-nightly versus twice-daily dosing and beliefs about highly active antiretroviral therapy (HAART) on adherence to efavirenz-based HAART in antiretroviral-naive patients.. A multicenter, open-label, 48-week, randomized controlled trial. Participants were randomized to receive once nightly didanosine plus lamivudine, or twice-daily combivir (zidovudine plus lamivudine) both in combination with efavirenz. Medication Event Monitoring Systems were used to compile drug-dosing histories. Beliefs about HAART (necessity and concerns) were measured at baseline using validated questionnaires. Perceptions of HAART intrusiveness were assessed after 4 weeks.. Eighty-seven patients were randomized (44 once-nightly and 43 twice-daily). Overall adherence was higher among the once-nightly arm (P = 0.0327). Eighty-one percent once-nightly and 62% twice-daily patients persisted with treatment for 48 weeks (P = 0.0559). Regimen execution was similar between both arms. Participants were significantly less likely to persist with HAART if their initial concerns about HAART were high relative to their perceived need for treatment (P = 0.025).. The difference in adherence observed between once-nightly and twice-daily dosing was driven by a difference in persistence with treatment. Psychological preparation for starting HAART should address patients' perceptions of necessity for HAART and concerns about adverse effects to maximize persistence with treatment. Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Culture; Cyclopropanes; Didanosine; Drug Combinations; Female; HIV Infections; Humans; Lamivudine; Male; Medication Adherence; Middle Aged; Surveys and Questionnaires; Zidovudine | 2010 |
Mitochondrial changes during D-drug-containing once-daily therapy in HIV-positive treatment-naive patients.
Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells.. A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays.. No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus.. An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug. Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA, Mitochondrial; Drug Administration Schedule; Female; HIV; HIV Infections; Humans; Lamivudine; Male; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; RNA; RNA, Mitochondrial; Tenofovir | 2010 |
Switch from protease inhibitor- to efavirenz-based antiretroviral therapy improves quality of life, treatment satisfaction and adherence with low rates of virological failure in virologically suppressed patients.
Regimen selection in antiretroviral therapy can impact treatment adherence, quality of life (QoL) and treatment satisfaction, and may influence clinical outcome. We evaluated the effect of regimen switching on virological, safety and patient-reported outcomes. In this 48-week, open-label, randomized, non-inferiority study, 262 HIV-1-infected adult patients with a viral load <50 copies/mL on protease inhibitor (PI)-based regimens were switched to either once-daily efavirenz, lamivudine and enteric-coated didanosine (efavirenz-A [QD]) or once-daily efavirenz plus continuation of current nucleoside reverse transcriptase inhibitors (efavirenz-B). In the primary outcome of patients who maintained virological suppression at week 48, efavirenz-A (QD) was non-inferior to efavirenz-B (81% versus 79%, respectively). Both regimens were associated with low virological failure rates and significant improvements in treatment satisfaction, adherence and QoL after switching from PI-based therapy, with no differences between regimens. Switching from a PI- to an efavirenz-based regimen was generally safe and well tolerated. Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Patient Compliance; Patient Satisfaction; Quality of Life; Reverse Transcriptase Inhibitors; Treatment Outcome; United States; Viral Load | 2010 |
Efficacy and safety of unboosted atazanavir in combination with lamivudine and didanosine in naive HIV type 1 patients in Senegal.
The use of ritonavir as a protease inhibitor boost is rare in sub-Saharan Africa because a heat-stable formula is not available. We report the results of an open-label pilot trial with unboosted atazanavir in combination with lamivudine and didanosine as first-line therapy conducted in Senegal. Treatment-naive HIV-1 infected adult patients without active opportunistic disease were included. The primary endpoint was the proportion of patients with plasma HIV-1 RNA <400 copies/ml at week 48. Forty patients (12 men and 28 women; mean age +/- SD: 40 +/- 9 years) were included. Treatment was changed during the study for two patients (pregnancy, tuberculosis); one patient was lost to follow-up and one patient died (gastroenteritis with cachexia). At week 48, 78% [95% confidence interval (CI): 65-90%] and 68% (95% CI: 53-82%) of the patients had HIV-1 RNA <400 and <50 copies/ml, respectively (intent-to-treat analysis; not completer = failure). Among the seven patients with HIV-1 RNA >or=400 copies/ml at week 48, five were not compliant; genotyping analysis (n = 4) did not reveal a major mutation for protease inhibitors. The mean CD4 cell count change from baseline to week 48 was +238 +/- 79 cells/mm(3). The combination of unboosted atazanavir with lamivudine and didanosine was efficient and well tolerated in HIV-1-infected patients with results similar to those observed in Northern countries. These results suggest that unboosted atazanavir with its high genetic barrier could be a valuable alternative to NNRTIs in resource-limited countries in some HIV-1-infected patients in case of compliance issues with NNRTIs, intolerance to NNRTIs, resistance mutations to NNRTIs, in women with childbearing potential, or as a maintenance therapy in patients with virological suppression. Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Pilot Projects; Pyridines; Reverse Transcriptase Inhibitors; RNA, Viral; Senegal; Treatment Outcome | 2010 |
Is the recommended once-daily dose of lamivudine optimal in West African HIV-infected children?
We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter.h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P=0.01). The target mean AUC of 8.9 mg/liters.h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed. Topics: Adolescent; Africa, Western; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Reverse Transcriptase Inhibitors; Treatment Outcome | 2010 |
Effectiveness and safety of didanosine, lamivudine and efavirenz versus zidovudine, lamivudine and efavirenz for the initial treatment of HIV-infected patients from the Spanish VACH cohort.
Preliminary data suggest that a once-daily combination of lamivudine, didanosine and efavirenz is an effective alternative regimen for antiretroviral-naive HIV-1-infected patients. However, data from randomized trials comparing this combination versus standard first-line regimens are not available yet. In an observational study, we analyse the efficacy and tolerability of didanosine plus lamivudine and efavirenz versus zidovudine plus lamivudine and efavirenz in a cohort of therapy naive patients.. We performed an observational study on prospectively collected data from patients participating in a multicentre Spanish treatment-naive cohort (VACH cohort). Efficacy was assessed comparing time to therapeutic failure and CD4 cell recovery. Safety was analysed comparing the proportion of patients who discontinued therapy for toxicity or any other reason.. Overall, 219 patients treated with once-daily didanosine/lamivudine/efavirenz and 409 patients receiving twice-daily zidovudine/lamivudine (Combivir) plus efavirenz were evaluated. By intent-to treat analysis (non-completers and therapeutic change=failure), time to treatment failure was similar in both groups of treatment: 40.0 months (95% CI 23.3-56.8 months) among patients on didanosine/lamivudine/efavirenz and 33.3 months (95% CI 25.6-41.1 months) in patients treated with zidovudine/lamivudine/efavirenz (P=0.253). The risk of failure due to treatment change was almost double among patients treated with zidovudine/lamivudine/efavirenz compared with those who received didanosine/lamivudine/efavirenz.. Our data suggest that didanosine/lamivudine/efavirenz is a combination with an efficacy comparable to zidovudine/lamivudine/efavirenz as first-line therapy for HIV infection. The risk of treatment change was significantly higher among patients treated with zidovudine/lamivudine/efavirenz than in those starting therapy with didanosine/lamivudine/efavirenz. Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Didanosine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Prospective Studies; Spain; Treatment Outcome | 2009 |
Response to zidovudine/didanosine-containing combination antiretroviral therapy among HIV-1 subtype C-infected adults in Botswana: two-year outcomes from a randomized clinical trial.
Numerous national antiretroviral (ARV) treatment initiatives offering protease inhibitor-sparing combination antiretroviral therapy (cART) have recently commenced in southern Africa, the first of which began in Botswana in January 2002. Evaluation of the efficacy and tolerability of various protease inhibitor-sparing cART regimens requires intensive study in the region, as does investigation of the development of drug resistance and the optimal means of sustaining adherence. The "Tshepo" Study is the first large-scale, randomized, clinical trial that addresses these important issues among HIV-1 subtype C-infected ARV treatment-naive adults in southern Africa.. The Tshepo Study is a completed, open-labeled, randomized study that enrolled 650 ARV-naive adults between December 2002 and 2004. The study is a 3 x 2 x 2 factorial design comparing the efficacy and tolerability among factors: (1) 3 combinations of nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (ZDV) + lamivudine (3TC), ZDV + didanosine (ddI), and stavudine (d4T) + 3TC; (2) 2 different nonnucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine and efavirenz; and (3) 2 different adherence strategies: the current national "standard of care" versus an "intensified adherence strategy" incorporating a "community-based directly observed therapy." Study patients were stratified into 2 balanced CD4 T-cell count groups: less than 201 versus 201-350 cells per cubic millimeter with viral load greater than 55,000 copies per milliliter. Following Data Safety Monitoring Board recommendations in April 2006, ZDV/ddI-containing arms were discontinued due to inferiority in primary end point, namely, virologic failure with resistance. We report both overall data and pooled data from patients receiving ZDV/ddI- versus ZDV/3TC- and d4T/3TC-containing cART through April 1, 2006.. Four hundred fifty-one females (69.4%) and 199 males with a median age of 33.3 years were enrolled into the study. The median follow-up as of April 1, 2006, was 104 weeks, and loss to follow-up rate at 2 years was 4.1%. The median baseline CD4 T-cell count was 199 cells per cubic millimeter [interquartile ratio (IQR) 136-252], and the median plasma HIV-1 RNA level was 193,500 copies per milliliter (IQR 69-250, 472-500). The proportion of participants with virologic failure and genotypic resistance mutations was 11% in those receiving ZDV/ddI-based cART versus 2% in those receiving either ZDV/3TC- or d4T/3TC-based cART (P = 0.002). The median CD4 T-cell count increase at 1 year was 137 cells per cubic millimeter (IQR 74-223) and 199 cells per cubic millimeter (IQR 112-322) at 2 years with significantly lower gain in the ZDV/ddI arm. At 1 and 2 years, respectively, 92.0% and 88.8% of patients had an undetectable plasma HIV-1 RNA level (< or = 400 copies/mL). Kaplan-Meier survival estimates at 1 and 2 years were 96.6% and 95.4%. One hundred twenty patients (18.2%) had treatment-modifying toxicities, of which the most common were lipodystrophy, anemia, neutropenia, and Stevens-Johnson syndrome. There was a trend toward difference in time to treatment-modifying toxicity by pooled dual-NRTI combination and no difference in death rates.. The preliminary study results show overall excellent efficacy and tolerability of NNRTI-based cART among HIV-1 subtype C-infected adults. ZDV/ddI-containing cART, however, is inferior to the dual NRTIs d4T/3TC or ZDV/3TC when used with an NNRTI for first-line cART. Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Botswana; CD4 Lymphocyte Count; Didanosine; Drug Tolerance; Female; HIV Infections; HIV-1; Humans; Male; Patient Compliance; RNA, Viral; Survival Analysis; Time Factors; Viremia; Zidovudine | 2009 |
Didanosine population pharmacokinetics in West African human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment.
Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (Cmax), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and Cmax (P < or = 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter x h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing. Topics: Adolescent; Africa, Western; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Drug Administration Schedule; HIV Infections; Humans; Treatment Outcome | 2009 |
[Therapeutic effect and safety evaluation on 6-year highly active antiretroviral therapy for Chinese HIV-1 infected patients].
To evaluate the long-term efficacy and safety of nevirapine (NVP)-based regimens for HIV-infected Chinese patients in routine clinical practice.. From October 2002 to May 2004, 57 HIV-1-infected patients commenced highly active antiretroviral therapy (HAART), and were followed to December 2008. They originally received 2 nucleoside reverse transcriptase inhibitors (NRTIs) and nevirapine. HIV RNA levels, T lymphocyte subsets and safety were assessed. Blood routine test and main laboratory parameter changes were traced. If apparent side effects or virological failure appeared we would, if necessary, terminate the therapy or change the regimen.. Of the 57 subjects, 34 were followed-up for more than 4 years. After 5-6 years, 63.3% of the subjects (19/30) had HIV RNA levels<50 copies/microL, and the median increase in CD4(+) cell count from the baseline was 329 cells/microL. The mean decrease in CD8(+) cell count was 128 cells/microL. At the same time, the CD4(+) CD45RA+CD62L cell count and CD4(+)CD45RO(+) cell gradually increased, and the counts of CD8(+)CD38(+) cell declined gradually. These changes are apparent 2 years after HAART. The increase rate slowed down after 2 years. But they did not recover completely as well as healthy people at year 6. About 56% (32/57) of HIV-infected patients developed various drug-related side effects. The most common was gastrointestinal side effect, followed nervous disorder, baldness, and rashes, mostly happened in 6 months. Gamma-GT increased occurred in 29.8% of patients (17/57), and serum cholesterol and triglyceride elevated in 26.3% of the patients (15/57). Six patients developed lipodystrophy, mainly in female patients, and 25 patients showed abnormal blood picture and liver function, renal function changes and amylase elevation. Grade 3-4 adverse events occurred in 3 cases (2 peripheral neuropathy, and 1 suspected lactic acidosis). One subject experienced grade 3 rashes.. Antiretroviral therapy with NVP-based regimens is safe and effective by suppressing HIV viremia and producing continued CD4 cell increases in subjects with HIV or AIDS for 6 years. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; China; Didanosine; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Viral Load; Young Adult | 2009 |
Antiretroviral drug-resistant mutations at baseline and at time of failure of antiretroviral therapy in HIV type 1-coinfected TB patients.
There is limited information on the prevalence and pattern of HIV drug-resistant mutations (DRMs) among HIV-1-coinfected tuberculosis (TB) patients before and after antiretroviral treatment. Patients with HIV-1 and TB were recruited into a clinical trial from two different once-daily antiretroviral regimens and followed for a period of 6 months after ART initiation. Patients were treated with standard short-course anti-TB treatment (2EHRZ3/4RH3) and were randomized to receive ddI/3TC with either nevirapine or efavirenz, once daily. Genotypic drug resistance (DR) testing was carried out for the pol gene at baseline and at the time of virological failure. At baseline, major DRMs with respect to NNRTIs (G190GA) and TAMs (T215S and I) were observed in 3 out of 107 patients. Of 15 treatment failures, 14 had more than one major NRTI and NNRTI mutation. V106M was the major NNRTI mutation that emerged in EFZ and Y181C in the NVP group. Among NRTI mutations, M184V was the commonest followed by L74I/V. Primary drug resistance to antiretroviral drugs was low among HIV-1 co-infected TB patients in south India. A once-daily regimen of ddI/3TC/EFZ or NVP results in a specific pattern of NNRTI mutations and negligible thymidine analog mutations (TAMs). Topics: Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; India; Lamivudine; Male; Mutation; Nevirapine; Reverse Transcriptase Inhibitors; Treatment Failure; Tuberculosis | 2009 |
Long-term efficacy and safety of first-line therapy with once-daily saquinavir/ritonavir.
The aim of this study was to assess the long-term efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs).. A total of 272 antiretroviral-naive patients with a CD4+ T-cell count of 200-350 cells/mm3 were treated with two NRTIs and saquinavir/ritonavir 1,600/100 mg per day for > 24 weeks. Patients were followed up every 12 weeks for CD4+ T-cell counts, HIV RNA levels, clinical and laboratory toxicities. Intention-to-treat analyses were used for the first 24 weeks of treatment and as-treated analysis after week 24.. The median baseline CD4+ T-cell count was 269 cells/mm3 and HIV RNA was 4.7 log10 copies/ml. At a median follow-up time of 56 (interquartile range [IQR] 25-113) weeks, 262/272 (96.3%) had HIV RNA < 400 copies/ml, with a median HIV RNA decline of -2.89 (IQR 3.31--2.37) log10 copies/ml (P < 0.001) and a median rise in CD4+ T-cell count of 192 (IQR 117-317) cells (P < 0.001). At weeks 24, 48, 72 and 96, 249/272 (91.5%), 157/164 (95.7%), 113/126 (89.7%) and 84/90 (93.3%) had HIV RNA < 400 copies/ml, respectively; at the same time points, 83.8%, 92.7%, 85.7% and 85.6% had HIV RNA < 50 copies/ml. Drug-related adverse events were reported in 6.30%. Significant rises in total cholesterol, triglyceride, low-density lipoprotein and high-density lipoprotein were seen.. First-line highly active antiretroviral therapy with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy. Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Combinations; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Thailand; Time Factors; Treatment Outcome; Viral Load | 2008 |
Switch from zidovudine- to non-zidovudine-containing regimens is associated with modest haematological improvement and no obvious clinical benefit: a substudy of the ANRS 099 ALIZE trial.
Zidovudine, the first antiretroviral agent, has short-term haematological toxicity. However, it is unclear whether patients tolerating long-term zidovudine-containing regimens will benefit from a switch to non-zidovudine-containing regimens.. One hundred and fifty-eight patients enrolled in the ALIZE trial receiving zidovudine at baseline were analysed. These patients were randomized to continue their regimen or to switch to a combination of emtricitabine, didanosine and efavirenz for 48 weeks. Changes from baseline in haemoglobin (Hb), neutrophil and platelet counts were compared between arms as well as the occurrence of cardiovascular events, bacterial infections, use of haematopoietic growth factors, blood transfusion and quality of life using the Medical Outcome Study HIV (MOS-HIV) health survey.. Eighty-one patients continued their regimen and 77 switched. At 48 weeks, mean change from baseline in Hb were +0.73 and -0.37 g/dL in the switch and maintenance groups, respectively (P < 0.01). Mean neutrophil counts increased by 592 and 51 cells/mm(3) in the switch and maintenance groups, respectively (P = 0.02). The occurrence of cardiovascular events or bacterial infections was similar in both treatment arms with no use of haematopoietic growth factors or blood transfusion. Also, mean change from baseline in MOS-HIV physical and mental health summary scores was similar in both arms.. A switch from a long-standing zidovudine- to a non-zidovudine-containing regimen modestly improves haematological parameters and is not associated with obvious clinical benefit. Topics: Adult; Alkynes; Anti-HIV Agents; Bacterial Infections; Benzoxazines; Blood Platelets; Cardiovascular Diseases; Cyclopropanes; Deoxycytidine; Didanosine; Emtricitabine; Female; Hemoglobins; HIV Infections; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Pancytopenia; Platelet Count; Prevalence; Zidovudine | 2008 |
Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients.
Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs)--abacavir and didanosine--may each be associated with excess risk of myocardial infarction. The reproducibility of this finding in an independent dataset was explored and plausible biological mechanisms were sought.. Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N = 2752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included.. Current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical myocardial infarction (n = 19), major CVD (myocardial infarction, stroke, surgery for coronary artery disease, and CVD death; n = 70), expanded CVD (major CVD plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed deaths; n = 112) were 4.3 [95% confidence interval (CI): 1.4-13.0], 1.8 (1.0-3.1), and 1.9 (1.3-2.9). At baseline in a subset of patients with biomarker data, high sensitivity-C-reactive protein and interleukin-6 were 27% (P = 0.02) and 16% (P = 0.02) higher for patients receiving abacavir (N = 175) compared with those receiving other NRTIs (N = 500). Didanosine was associated neither with altered risk of CVD nor with altered levels of biomarkers.. Abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event. Topics: Adult; Anti-Retroviral Agents; Biomarkers; C-Reactive Protein; Didanosine; Dideoxynucleosides; Electrocardiography; Female; HIV Infections; HIV-1; Humans; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Risk; Serum Amyloid A Protein; Serum Amyloid P-Component | 2008 |
Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903.
The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials.. We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log(10) or > or =5.0 log(10) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of <50 copies/mL at week 48, determined by intention-to-treat analysis.. Three hundred sixty-nine patients were randomized: 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment. Both groups were well matched in terms of baseline characteristics; 19.3% of patients received a Centers for Disease Control and Prevention assessment of clinical category C, median HIV RNA level was 5.0 log(10) copies/mL, and median CD4(+) cell count was 208 cells/microL. At week 48, by intention-to-treat analysis, 70% of patients in the ddI/3TC/EFV group and 63% of patients in the COM/EFV group had an HIV-1 RNA level of <50 copies/mL (treatment difference, 7.1%; 95% confidence interval, -2.39% to 16.59%). Fourteen patients (8%) in the ddI/3TC/EFV arm (not the COM/EFV arm) and 26 patients (14%) in the COM/EFV arm (not the ddI/3TC/EFV arm) [corrected] discontinued the study medication because of adverse events (P = .046). One patient (1%) in the ddI/3TC/EFV arm and 11 patients (6%) in the COM/EFV arm discontinued medication because of hematological toxicity (P = .003).. At week 48, ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment. A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events, mainly because of hematological toxicity.. NCT00256828. Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Prospective Studies; RNA, Viral; Severity of Illness Index; Treatment Outcome; Viral Load; Zidovudine | 2008 |
Long-term assessment of didanosine, lamivudine, and efavirenz in antiretroviral-naive patients: 3-year follow-up.
The aim of this study was to evaluate the long-term efficacy and safety of didadosine (ddI), lamivudine (3TC), and efavirenz (EFV). This was a follow-up to the VESD study, a 12-month open-label, observational, multicenter study of adult patients with HIV infection who started antiretroviral treatment with the ddI-3TC-EFV once-daily regimen. Of the 167 patients originally included, 106 patients remained on the same triple therapy at the end of the study (1 year), and they were offered an extra 24 months of follow-up; 96 were enrolled in this study (VESD-2). Seventy patients out of the initial cohort were still on the same regimen at month 36, with 97% of them with plasma viral load <50 copies /ml. An intention-to-treat analysis showed that the percentage of patients with plasma viral load <50 copies/ml was 73% at 36 months. CD4 cell counts increased 344 cells/microl over the 36 months. Safety and tolerance were good with no unexpected long-term toxicity. After 3 years of treatment with ddI-3TC-EFV, more than 40% of the patients were still receiving the initial antiretroviral therapy with sustained, durable immunovirological benefit and good acceptance. Long-term toxicity and virological failure were low. Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load | 2008 |
Effect of food on the antiviral activity of didanosine enteric-coated capsules: a pilot comparative study.
To determine the effect of food on the antiviral activity of enteric-coated (EC) capsules of didanosine (ddI).. We conducted a pilot, randomized, open-label study of 28-day ddI-EC capsules monotherapy-administered in a fasted state (group 1, n=11) or with food (group 2, n=10) to treatment-naïve chronically HIV-1-infected individuals. To assess the antiviral efficacy, HIV-1 RNA was determined at baseline, day 3, day 7 and weekly thereafter. The area under the HIV-1 RNA curve minus baseline weighted by time (AUCMB/day) was calculated.. Mean baseline HIV-1 RNA was 4.2 log(10) copies/mL in group 1 and 3.8 log(10) copies/mL in group 2. After 28 days, the mean HIV-1 RNA reduction was 0.99 log(10) copies/mL [95% confidence interval (CI) 0.45-1.53] for group 1 and 0.89 log(10) copies/mL (95% CI 0.38-1.40) for group 2. AUCMB/day values were 0.775 log(10) copies/mL (95% CI 0.33-1.22) and 0.774 log(10) copies/mL (95% CI 0.48-1.07), respectively, showing no difference in the rate of decrease of HIV-1 RNA (P=0.995). Mean ddI plasma levels at day 28 were 0.0234 mg/L for group 1 and 0.0227 mg/L for group 2 (P=0.96).. In this pilot study, the administration of food did not have any significant effect on the antiviral activity of ddI-EC capsules. Topics: Administration, Oral; Adult; Capsules; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Fasting; Female; Food; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral | 2008 |
Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine--a Staccato trial substudy.
Stavudine is widely used in Thailand and is associated with mitochondrial toxicity. Here, we evaluated the effect of switching from stavudine/didanosine to tenofovir/lamivudine on measures of metabolic and mitochondrial toxicity in Thai patients.. Thirty-five Thai patients with full HIV RNA suppression were switched from stavudine/didanosine to tenofovir/lamivudine while receiving saquinavir/ritonavir 1600/100 mg once daily. Patients were assessed at the time of switch and 24 and 48 weeks after for lipids, liver enzymes, lactate, mitochondrial DNA content and limb/total fat mass by dual energy X-ray absorptiometry (DEXA) scanning.. Forty-eight weeks after the switch, there were significant reductions in lipids and lactate, but no change in liver enzymes. There was reversal of lipoatrophy, as shown by rises in limb fat mass (+0.38 kg, P = 0.006) and total fat mass (+0.69 kg, P = 0.02) on DEXA scan. Patients perceived weight improvement, but did not report reversal of lipoatrophy of individual body parts. The mitochondrial DNA/nuclear DNA ratio rose (+1.06, P < 0.0001).. After the nucleoside reverse transcriptase inhibitor switch, reversal of mitochondrial toxicity was consistent with switch studies of mainly Caucasian patients, although the peripheral mononuclear cell mitochondrial DNA rise exceeded previous reports. Topics: Absorptiometry, Photon; Adenine; Adult; Anti-HIV Agents; Body Fat Distribution; Didanosine; DNA, Mitochondrial; HIV Infections; Humans; Lamivudine; Lipids; Liver Function Tests; Organophosphonates; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Tenofovir; Thailand | 2008 |
The risk of developing peripheral neuropathy induced by nucleoside reverse transcriptase inhibitors decreases over time: evidence from the Delta trial.
Peripheral neuropathy (PN) in HIV-infected individuals is thought be due to a toxic effect on mitochondria induced by some nucleoside reverse transcriptase inhibitors (NRTI).. A time-to-event analysis was performed using data from the Delta trial to study the incidence of PN in HIV-infected individuals receiving zidovudine (AZT) alone or in combination with didanosine (ddl) or zalcitabine (ddC). In an on-treatment analysis, changes in the incidence of PN by duration of treatment were directly estimated using a flexible parametric survival model.. A total of 3,195 patients (total follow-up 4,593 person-years) were included in the analysis. AZT+ddC was associated with a higher incidence of PN (6.2 cases/100 person-years) compared with AZT monotherapy (3.0 cases/100 person-years) and AZT+ddl (2.2 cases/100 person-years). The risk of PN peaked around day 90 following randomization (at 8.9 events/100 person-years in the AZT+ddC arm). PN was also associated with age at entry (hazard ratio (HR)=2.35 for those aged 35-44 years compared with <30) and current CD4+ T-cell count (HR=2.27 for CD4+ T-cell counts <150 cell/mm3 compared with >350).. Our findings challenge the common supposition that PN arises from cumulative exposure to NRTIs. We found that patients who developed PN tended to do so shortly after exposure to antiretroviral therapy. Therefore, our results support the hypothesis of a susceptibility in a subgroup of patients. These results will be of direct interest to those working in resource-limited countries where potentially neurotoxic dideoxynucleosides are still widely used. Topics: Adult; Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors; Zalcitabine; Zidovudine | 2008 |
Phenotypic susceptibility to didanosine is associated with antiviral activity in treatment-experienced patients with HIV-1 infection.
We investigated the relationship between human immunodeficiency virus (HIV) phenotypic susceptibility to didanosine and the antiviral activity of didanosine (ddI) in the JAGUAR study.. Baseline plasma HIV phenotypic susceptibility to ddI was assessed using a phenotype assay of patients randomized to receive ddI or placebo for 4 weeks in addition to their current regimen. Phenotypic susceptibility scores (PSSs) were then calculated for each sample. Associations between PSS and week 4 reductions in plasma HIV-1 RNA load or virologic response were assessed using linear regression and Jonckherre's test and the Wilcoxon and Cochran-Armitage tests, respectively.. In the ddI arm, a significant association between reduction in viral load and continuous PSS was observed (P<.0001). Using distinct categories, an increasing fold change (FC) in susceptibility to ddI was strongly associated with smaller reductions in plasma HIV-1 RNA load (P<.0001). The proportion of virologic responders was 83% (15/18) for patients with a ddI FC < or =1.3, 50% (33/66) for patients with an FC of 1.3-2.2, and 29% (4/14) for patients with an FC > or =2.2 (P=.0008). After we determined these findings, 3 ddI FC categories were defined using 1.3 and 2.2 as thresholds.. The relationship between phenotypic susceptibility to ddI and reduction in plasma HIV-1 RNA load describes a continuum. The establishment of a lower clinical cutoff at 1.3 and an upper clinical cutoff at 2.2 are clinically relevant. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Endpoint Determination; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; RNA, Viral; Species Specificity; Viral Load | 2007 |
Changes in the peripheral blood mtDNA levels in naive patients treated by different nucleoside reverse transcriptase inhibitor combinations and their association with subsequent lipodystrophy.
Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients. Topics: Adult; Anti-HIV Agents; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Leukocytes, Mononuclear; Logistic Models; Male; Reverse Transcriptase Inhibitors; Stavudine; Surveys and Questionnaires; Time Factors; Zidovudine | 2007 |
Metabolic and anthropometric changes one year after switching from didanosine/stavudine to tenofovir in HIV-infected patients.
Nucleoside analogues such as Didanosine and Stavudine are known to cause metabolic and body habitus changes during antiretroviral therapy. The most frequently observed are lactic acidosis, hypercholesterinaemia, hypertriglyceridaemia and lipodystrophy.. Over one year we monitored a cohort of 43 patients who switched from either Stavudine, Didanosine or the combination of both to Tenofovir. A group of 11 patients was kept on their original regimen and acted as control group. Blood samples were taken every 3 months from baseline, anthropometric measurements were performed at baseline, after 6 and 12 months.. During observation the levels of lactic acid and cholesterol decreased significantly in the switch group while virologic and immunologic efficacy remained stable. Serum creatinine levels rose significantly in patients switched to Tenofovir, but remained within physiological limits. The mean skin fold thickness increased significantly by 1.8 mm in the switch group after 6 months (p < or =0.001 - p = 0.032).. These results implicate an improvement of lipid profiles, serum lactate and lipodystrophy in HIV-positive patients after switch to Tenofovir. As a moderate increase in serum creatinine levels was observed, the renal function of patients on a Tenofovir-based regimen should be monitored closely. Topics: Adenine; Adult; Aged; Anti-HIV Agents; Body Weight; CD4 Lymphocyte Count; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Didanosine; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Hemoglobins; HIV Infections; Humans; Lactic Acid; Male; Middle Aged; Organophosphonates; Phosphates; Skinfold Thickness; Stavudine; Tenofovir; Treatment Outcome; Triglycerides; Uric Acid; Viral Load | 2007 |
US and UK versions of the EQ-5D preference weights: does choice of preference weights make a difference?
Most US studies that estimate EQ-5D index score generally apply the UK preference weights. We compared the validity of a newly-developed US weights to the UK weights for use of EQ-5D as a measure of health-related quality of life.. Data were collected from a randomized clinical trial for patients with HIV (n = 1,126) in the US. Convergent validity was examined by comparing Pearson correlations of EQ-5D index scores with the MOS-HIV Health Survey scale scores and Physical and Mental Health Summary (PHS, MHS) scores using the US and UK weights. Known-groups validity of EQ-5D US versus UK index scores was compared using clinical variables (CD4+ cell count and HIV viral load), and the MOS-HIV PHS and MHS. Score changes in the EQ-5D index from baseline to week 50 were examined using effect size (ES) estimates.. The mean EQ-5D index scores was slightly higher using US weights than UK weights (0.87 vs. 0.84, respectively). The correlation coefficient for EQ-5D utilities using the US and UK weights was 0.98. The correlations of EQ-5D index scores with the MOS-HIV scores were moderate and similar using the US and UK weights. The EQ-5D index scores discriminated equally well for both versions between levels of CD4+ count, HIV viral load, and PHS and MHS scores (P < 0.05), suggesting equivalent known-groups validity. The changes in EQ-5D index scores from baseline to week 50 were similar for both versions (ES: 0.21 vs. 0.22 for US and UK, respectively), suggesting equivalent responsiveness to score changes.. EQ-5D index scores generated using UK and US preference weights showed equivalent psychometric properties. For assessing treatment benefit in a single population, the use of either the UK or US weights as a measure of HRQOL will not change inferences. However, for comparisons across US and UK populations, the choice between these two weights should be based on their relevance to the study population. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Delavirdine; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Patient Satisfaction; Psychometrics; Quality of Life; Quality-Adjusted Life Years; Reverse Transcriptase Inhibitors; Sickness Impact Profile; United Kingdom; United States; Viral Load | 2007 |
A virological benefit from an induction/maintenance strategy: the Forte trial.
To evaluate whether the addition of a fourth drug for up to 32 weeks to a standard three-drug antiretroviral combination decreases the risk of virological failure without increasing toxicity in treatment-naive patients.. Induction/maintenance (IM) therapy [two nucleoside reverse transcriptase inhibitors (NRTIs) + one non-NRTI (NNRTI) + one protease inhibitor for 24-32 weeks until plasma HIV RNA viral load (VL) < or =50 copies/ml then two NRTIs + NNRTI] was compared with standard therapy (ST) (two NRTIs + NNRTI). The primary endpoint was virological failure: VL >50 copies/ml at 32 (and 24) weeks or subsequent rebound to >400 copies/ml.. 122 (62 IM, 60 ST) participants were randomized and followed for a median of 81 weeks (IQR 64-145). 52% were asymptomatic; median CD4+ T-cell count was 160 x 10(6)/l (IQR 92-260) and median VL 98,830 copies/ml (IQR 37,500-241,290). In an intent-to-treat analysis, the proportion of participants with virological failure at or after 32 weeks was higher in the ST arm [26 (43%) versus 11 (18%), P = 0.002]. The mean decrease in VL at 48 weeks was 0.84 95% confidence interval (CI) (0.15, 1.53) log10 copies/ml greater in the IM arm (P = 0.02). There were no significant differences between the two arms in the change in CD4+ T-cell count from baseline to 48 weeks, the number of participants with adverse events or the frequency of progression to AIDS/death. Drug resistance at failure was detected less frequently in the IM arm.. Starting antiretroviral therapy with an IM strategy improved virological outcomes compared with a three-drug regimen, without significantly increasing toxicity. Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Nelfinavir; Nevirapine; Patient Compliance; Remission Induction; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Time Factors; Treatment Failure; United Kingdom; Viral Load | 2007 |
The effect of lamivudine therapy and M184V on the antiretroviral activity of didanosine.
Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Lamivudine; Point Mutation | 2007 |
Effects of potent antiretroviral therapy on free testosterone levels and fat-free mass in men in a prospective, randomized trial: A5005s, a substudy of AIDS Clinical Trials Group Study 384.
Low testosterone levels are commonly reported in patients with advanced human immunodeficiency virus disease. The effects of initiation of different antiretroviral regimens on testosterone levels and changes in fat-free mass have not been reported.. Antiretroviral-naive men (n=213) were randomized to receive nelfinavir, efavirenz, or both plus either zidovudine and lamivudine or stavudine and didanosine. Patients underwent measurements of metabolic parameters, including determination of free testosterone level by equilibrium dialysis and bioelectrical impedance analysis, over a 64-week period.. At baseline, the median free testosterone level was 92 pg/mL; the level was subnormal (i.e., <50 pg/mL) in 6%. Lower CD4 cell count at the time of study entry, higher weight, and greater age were independently associated with lower baseline free testosterone level. At week 64, the median free testosterone level increased more in zidovudine-lamivudine recipients (48 of whom had paired values available; change, +31 pg/mL) than in stavudine-didanosine recipients (57 of whom had paired values; change, +3 pg/mL; P=.001, by Wilcoxon rank sum test), and it increased more in efavirenz recipients (37 of whom had paired values; change, +30 pg/mL) than in nelfinavir recipients (28 of whom had paired values; change, -3 pg/mL; P=.05). The median fat-free mass for the entire group increased by 1.2 kg at week 64 (change, +2.0%; P<.001); the increase was greater in the zidovudine-lamivudine group (n=70; change, +1.8 kg) than in the stavudine-didanosine group (n=79; change, +0.5 kg; P=.04), and the increase was also greater for efavirenz recipients (n=53; change, +2.1 kg) than among nelfinavir recipients (n=47; change, +0.4 kg; P=.003). White race, lower CD4 cell count at study entry, assignment to the efavirenz treatment arm, and assignment to the zidovudine-lamivudine treatment arm independently predicted greater absolute change in fat-free mass at week 64.. Subnormal free testosterone levels occurred infrequently among these antiretroviral-naive men. Free testosterone and fat-free mass levels increased after initiation of antiretroviral therapy, with greater increases at 64 weeks among zidovudine-lamivudine recipients than among stavudine-didanosine recipients and among efavirenz recipients than among nelfinavir recipients. Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Didanosine; Double-Blind Method; HIV Infections; Humans; Lamivudine; Longitudinal Studies; Male; Nelfinavir; Prospective Studies; Stavudine; Testosterone; Zidovudine | 2007 |
More on the treatment-tropism relationship: the impact of prior antiretroviral treatment on HIV coreceptor tropism among subjects entering AIDS clinical trials group 175.
Topics: Adult; Anti-Retroviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Middle Aged; Receptors, CCR5; Receptors, CXCR4; Zalcitabine; Zidovudine | 2007 |
Long-term body fat outcomes in antiretroviral-naive participants randomized to nelfinavir or efavirenz or both plus dual nucleosides. Dual X-ray absorptiometry results from A5005s, a substudy of Adult Clinical Trials Group 384.
Long-term regional body fat outcomes have not been well described in randomized antiretroviral drug trials.. Dual x-ray absorptiometry (DXA) scans were performed every 16 weeks on a subset of 157 antiretroviral-naive participants who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine, in a multicenter trial. Participants with any available data after baseline up to week 144 contributed to this as-treated analysis.. Limb fat increased similarly in all groups during the first 32 weeks. After week 32, limb fat changed by - 1.7% per year for zidovudine-lamivudine and by -19.0% per year for didanosine-stavudine (mixed model analysis of variance [MMANOVA], P < 0.0001). Adjusting for nucleoside backbone, there was an additional decrease in limb fat of -8.7% per year for the combined nelfinavir and nelfinavir + efavirenz group compared with the efavirenz group (MMANOVA, P = 0.03). Among participants receiving zidovudine-lamivudine, after week 32, limb fat changed by +2.7% per year with efavirenz and by -7.9% per year for the combined nelfinavir and nelfinavir + efavirenz group (MMANOVA, P = 0.03).. Over 144 weeks, zidovudine-lamivudine was superior to didanosine-stavudine with regard to limb fat loss. The combination of zidovudine, lamivudine, and efavirenz showed no overall pattern suggesting limb fat loss over time and was significantly superior to the pooled zidovudine-lamivudine-nelfinavir (with and without efavirenz) arms. Topics: Absorptiometry, Photon; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Body Composition; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Prospective Studies; Stavudine; Time Factors; Treatment Outcome; United States; Zidovudine | 2007 |
Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial).
Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported.. This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability.. After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol.. A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy. Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzoxazines; CD4 Lymphocyte Count; Cholesterol; Cyclopropanes; Deoxycytidine; Didanosine; Drug Tolerance; Emtricitabine; Female; France; HIV Infections; HIV-1; Humans; Lipids; Lipoproteins; Male; RNA, Viral; Time Factors; Treatment Outcome | 2007 |
Compromised immunologic recovery in patients receiving tipranavir/ritonavir coadministered with tenofovir and didanosine in Randomized Evaluation of Strategic Intervention in multidrug-resiStant patients with tipranavir (RESIST) studies.
Topics: Adenine; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Organophosphonates; Pyridines; Pyrones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sulfonamides; Tenofovir; Treatment Outcome; Viral Load | 2007 |
Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021.
Compliance with complex antiretroviral therapy regimens is a problem for HIV-1-infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success.. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for > or = 96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV < 400 or 50 HIV copies per mL and safety and tolerability of the regimen.. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to < 400 RNA copies per mL, and 26 (72%) of 37 subjects maintained sustained suppression at < 50 copies per mL through week 96. The median baseline CD4 count was 310 per microL (17%), which increased at week 96 by a median of +329 cells per microL (by +18% CD4). Pharmacokinetic results were as predicted for emtricitabine, didanosine, and efavirenz capsules, whereas efavirenz concentrations in children receiving efavirenz oral solution were lower than anticipated, requiring a dose escalation after the planned assessment point.. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study. Topics: Adolescent; Adult; Alkynes; Benzoxazines; Child; Child, Preschool; Clinical Protocols; Cyclopropanes; Deoxycytidine; Didanosine; Drug Administration Schedule; Emtricitabine; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; Time | 2007 |
Low-level K65R mutation in HIV-1 reverse transcriptase of treatment-experienced patients exposed to abacavir or didanosine.
Prior abacavir (ABC) or didanosine (ddI) therapy can result in the L74V/I or K65R mutation in HIV-1 reverse transcriptase. Preexisting K65R may have an impact on the treatment response to tenofovir disoproxil fumarate (TDF).. An allele-specific polymerase chain reaction (AS-PCR) assay was developed to detect K65R with a lower limit of quantitation of 0.5%.. Among baseline plasma samples from 63 treatment-naive patients, no K65R was detected by AS-PCR. Among baseline samples from 154 treatment-experienced patients, 8 had K65R and 44 had L74V/I by population sequencing. Low-level K65R was detected in an additional 11 patients by AS-PCR, 3 of whom subsequently developed full K65R. Baseline K65R correlated with absence of thymidine analog mutations (TAMs; P = 0.003) and use of ABC or ddI (P = 0.004). Patients with full or low-level K65R at baseline or with L74V/I showed a diminished TDF response. Multivariate analyses confirmed that multiple TAMs, K65R, and L74V/I were independent predictors of diminished TDF response.. Prior therapy with ABC or ddI can result in a population genotype that shows K65R or L74V/I but does not reveal low-level K65R present in some patients. Subsequent treatment intensification with TDF resulted in a poor virologic response and may result in expansion of the preexisting K65R mutant. Topics: Adenine; Alleles; Didanosine; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Organophosphonates; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome | 2007 |
Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz.
The presence of drug-associated mutations among ART-naive, HIV-1(+) patients may compromise the response to antiviral therapy. We evaluated the effect of preexisting drug-associated resistance mutations to the response in treatment-naive patients to therapy with emtricitabine (FTC) or stavudine (d4T) in combination with didanosine (ddI) and efavirenz (EFV). Study FTC-301A compared emtricitabine once daily (QD) with stavudine twice daily in combination with didanosine and efavirenz in ART-naive patients. Genotypic analysis was performed on baseline plasma HIV-1 RNA for all available samples and at time of virologic failure (VF). Drug resistance mutations present at baseline were evaluated as predictors of VF using logistic regression. VF rates were compared between subgroups using a two-sided exact test. Baseline drug resistance mutations were observed in 90/546 (16.5%) patients: 56/90 (62.2%) with nonnucleoside analogue (NNRTI) mutations and 42/90 (46.6%) with nucleoside analogue mutations. In a stepwise, multiple regression analysis, the presence of the K103N mutation at initiation of therapy was associated with VF in both arms (p = 0.001), however, there was a higher incidence of VF in the stavudine arm compared to the emtricitabine arm regardless of the presence or absence of mutations at baseline (p = 0.001). In this study, the presence of drug-associated resistance mutations in ART-naive patients was significantly correlated with subsequent development of virologic failure underscoring the utility of testing for resistance in addition to the use of potent and well-tolerated first line regimens in treatment-naive patients. Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Deoxycytidine; Didanosine; Drug Resistance, Viral; Emtricitabine; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Regression Analysis; Stavudine; Treatment Failure | 2007 |
Observational study on HIV-infected subjects failing HAART receiving tenofovir plus didanosine as NRTI backbone.
We evaluated the efficacy of tenofovir (TDF) - and didanosine (ddI)-containing backbones in HIV-infected experienced subjects. We included in the study 245 subjects who started a TDF/ddI-containing HAART with HIV-RNA > 3 log(10) cp/ml and an available genotypic resistance test at baseline. At baseline, median CD4 counts and HIV-RNA were 278 cell/mmc and 4.32 log(10) cp/ml, respectively. Seventy-four subjects (30.2%) discontinued TDF and/or ddI, 23 of them for drug-related toxicities or intolerance. One-hundred and twenty-six (51.4%) subjects achieved virologic success (HIV-RNA < 50 copies/ml in two consecutive determinations) in a median time of 6.1 months; higher HIV-RNA levels (HR: 0.66, 95% CI: 0.54- 0.79, p < 0.001 for each additional log(10) copies/ml), and the total number of mutations either for PI and NNRTI at baseline (HR: 0.87, 95% CI: 0.81-0.92, p < 0.001 for each additional mutation) were both predictors of virologic success. M184V was marginally associated with virologic success (HR: 1.34, 95% CI: 0.94-1.90, p = 0.10 vs no M184V), whilst the number of TAMs was not associated. One-hundred-thirty-three (54.3%) subjects achieved immunologic success (increase of > or = 100 cells/mm(3) from baseline) in a median time of 7.5 months; immunologic success was associated with HIV-RNA levels at baseline (HR: 0.91, 95% CI: 0.79-0.98, p = 0.04 for each additional log(10) copies/ml), the total number of mutations either for PI or NNRTI (HR: 0.91, 95% CI: 0.85-0.98, p = 0.01 for each additional mutation) and CD4 count at baseline (HR: 1.11, 95% CI: 1.00-1.23, p = 0.05 for each additional 100 cells/mm(3)). Results obtained by the on-treatment analyses were comparable. In our study, HAART containing TDF/ddI seem associated with a virologic and immunologic response, when such regimens are chosen according to a genotypic resistance test. Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Tenofovir; Treatment Outcome | 2007 |
Effect of hydroxyurea and dideoxyinosine on intracellular 3'-deoxyadenosine-5'-triphosphate concentrations in HIV-infected patients.
Hydroxyurea (HU) significantly enhances the antiretroviral effects of the adenosine analog reverse transcriptase inhibitor dideoxyinosine (ddI). This is believed to be due to a reduction in intracellular de-oxyadenosine triphosphate (dATP) concentrations resulting from HU-mediated inhibition of ribonucleotide reductase (RnR). The effect of combined HU-ddI treatment on intracellular dATP pools in vivo has not been examined. We measured intracellular dATP concentrations in peripheral blood mononuclear cells (PBMCs) from 69 HIV-infected patients receiving 1000 or 1500 mg HU daily for 14 days, 200 mg ddI twice daily for 14 days, or a combination of the two drugs. Median intracellular dATP concentrations decreased from base-line to day 14 by 46% in the ddI + 1000 mg HU arm and by 62% in the ddI + 1500 mg HU arm. When compared to the HU monotherapy arms, these changes proved statistically significant (p = 0.018; stratified Wilcoxon rank-sum test). These findings support reduced intracellular dATP as the mechanism of ddI-HU synergistic activity, and indicate that changes in intracellular nucleotides contribute to HU activity and toxicity in patients. Since a significant reduction in dATP was measurable only when ddI was combined with HU, the antiretroviral activity of ddI may be more complex than previously assumed. Topics: Anti-HIV Agents; Cytosol; Deoxyadenine Nucleotides; Didanosine; Double-Blind Method; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Leukocytes, Mononuclear | 2007 |
Poor efficacy and tolerability of stavudine, didanosine, and efavirenz-based regimen in treatment-naive patients in Senegal.
To study the effectiveness and tolerance of an antiretroviral therapy (ART) regimen composed of the antiretroviral agents (ARVs) stavudine (d4T) plus didanosine (ddI) plus efavirenz (EFV) in patients with advanced HIV infection in Senegal.. This was an open-label, single-arm, 18-month trial in treatment-naive patients. The primary virologic end point was the percentage of patients with plasma HIV RNA < 500 copies/mL at months 6 (M6), 12 (M12) and 18 (M18). The primary analysis was done as intent-to-treat.. The staging of HIV disease, performed using the definitions of the US Centers for Disease Control and Prevention (CDC), was CDC stage B or C for all 40 recruited patients. At baseline, the mean CD4+ cell count was 133 +/- 92/mcL (+/- standard deviation [SD]; range 1-346), and 23% of patients had CD4+ cell counts below 50/mcL. The mean baseline plasma HIV RNA level was 5.5 +/- 0.4 log(10) copies/mL (+/- SD; range 4.6-5.9). The proportion of patients with plasma HIV-1 RNA below 500 copies/mL fell during the study from 73% (95% CI [56; 85]) at M6 to 56% (95% CI [41; 73]) at M12 and 43% (95% CI [27; 59]) at M18. Plasma HIV-RNA was below 50 copies/mL in 50% of study subjects (95% CI [31; 66]) at M6, 43% (95% CI [27; 59]) at M12, and 33% (95% CI [19; 49]) at M18. The mean increase in the CD4+ cell count was 105 +/- 125/mcL (n = 38) at M3 and 186 +/- 122/mcL (n = 21) at M18. Eight patients died, including 6 because of infectious complications. The last viral load (VL) value before death was < 500 copies/mL in all these patients except 1 nonadherent patient. Fifteen patients (37.5%) had peripheral neuropathy that was severe enough in 5 patients (12.5%) to require ddI and d4T discontinuation.. Virologic efficacy combination therapy with d4T, ddI, and EFV was measured by the percentage of patients with plasma HIV RNA values below 500 copies/mL and 50 copies/mL; for both parameters, virologic efficacy decreased during the study period. This is explained by the high mortality rate (20%) and treatment modifications due to adverse events (13%). These data strengthen the recently revised World Health Organization (WHO) guidelines advocating initiation of highly active antiretroviral therapy (HAART) before profound CD4 lymphocyte depletion occurs and avoiding HAART regimens containing d4T and ddI because of treatment-limiting side effects. Topics: Administration, Oral; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Developing Countries; Didanosine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; Humans; Male; Maximum Tolerated Dose; Patient Compliance; Risk Assessment; RNA, Viral; Senegal; Severity of Illness Index; Stavudine; Survival Rate; Treatment Outcome; Viral Load | 2007 |
A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naïve people.
While hearing loss in HIV-infected people after beginning nucleoside reverse transcriptase inhibitors (NRTIs) has been reported, there have been no prospective studies that measured hearing changes longitudinally in treatment-naïve HIV-infected subjects following initiation of regimens containing NRTIs. The goal of this study was to conduct a prospective assessment of the contribution of zidovudine (ZDV) and didanosine (ddI) to hearing loss.. A prospective observational pilot study to determine whether ZDV or ddI, alone or in combination, are associated with sensorineural hearing loss in HIV-infected persons. Changes in hearing levels at all frequencies and in low and high frequency pure tone averages were measured at baseline, 16, and 32 weeks after initiating antiretroviral therapy.. Treatment with ZDV and ddI did not result in loss of hearing, even after taking into account noise exposure, immune status and age. The results of this prospective pilot study do not support the notion that treatment with nucleoside antiretrovirals damages hearing. Topics: Adult; Aging; Anti-HIV Agents; Didanosine; Female; Hearing Loss; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Zidovudine | 2006 |
96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures.
In BMS Study 045, once-daily (QD) atazanavir/ritonavir (ATV/RTV) demonstrated comparable efficacy and safety to twice-daily (BID) lopinavir/ritonavir (LPV/RTV) over 48 weeks in treatment-experienced patients. Results of extended follow-up to 96 weeks are presented.. BMS Study 045 was an open-label, randomized, multi-national trial of HIV-infected patients with virologic failure on two or more prior HAART regimens designed to evaluate the efficacy and safety of ATV/RTV (300/100 mg) QD and LPV/RTV (400/100 mg) BID, each with tenofovir (300 mg) QD and one nucleoside reverse transcriptase inhibitor. The primary efficacy measure was the time-averaged difference (TAD) in reduction in HIV RNA from baseline. Secondary objectives included evaluation of safety and plasma lipid levels through week 96.. Over 96 weeks, the ATV/RTV regimen demonstrated similar virologic efficacy to the LPV/RTV regimen. Mean reductions from baseline in HIV RNA were -2.29 and -2.08 log10 copies/ml, respectively [TAD (97.5% confidence interval): 0.14 log10 copies/ml (-0.13, 0.41)]. The LPV/RTV regimen resulted in significant increases in total cholesterol (+9%) and fasting triglycerides (+30%) in comparison with the ATV/RTV regimen, which demonstrated decreases in these parameters [-7 and -2%, respectively, (P < 0.0001)]. Grade 2-4 diarrhoea occurred less frequently in ATV/RTV patients (3%) in comparison with LPV/RTV patients (13%) (P < 0.01). Grade 3-4 elevations in bilirubin were more common in ATV/RTV patients (53%) than LPV/RTV patients (< 1%) (P < 0.0001), with no resulting discontinuations.. Regimens containing once-daily ATV/RTV demonstrated comparable efficacy and safety, with significant reductions in total cholesterol and fasting triglycerides and improved gastrointestinal-tolerability in comparison with twice-daily regimens containing LPV/RTV over 96 weeks in treatment-experienced patients. Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipids; Lopinavir; Male; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Saquinavir; Tenofovir; Time Factors; Treatment Outcome | 2006 |
[Clinical trial comparing efficacy and safety of four highly active antiretroviral therapy (HAART) in antiretroviral-naive treatment with advanced HIV infection].
Comparison of efficacy and safety of four highly active antiretroviral therapy regimens (HAART) including two nucleoside analogues (NA) and a protease inhibitor (PI) in HIV positive patients with advanced infection and antiretroviral naive.. Multicenter, randomized and open labeled clinical trial in ten community hospitals of Castilla-La Mancha and Madrid. Regimen 1 contains zidovudine (AZT), lamivudine (3TC) and indinavir (IDV) regimen 2 includes AZT, 3TC and ritonavir (RTV), regimen 3 was didanosine (DDI), estavudine (D4T) and IDV, and regimen 4 included DDI, D4T and RTV. Decrease in viral load of HIV (VC) has been assessed as primary endpoint and as secondary one, the increase of the numbers of CD4 lymphocytes, percentage of disease progression, adverse reactions and adherence. Measurements were made at baseline visit and at 6, 12, 24, 36 and 48 weeks.. A total of 98 patients with a mean baseline CD4 count of 122 x 10(6)/l (range of 5-340) and a baseline viral load of 5.1 log copies/ml were included. At 48 weeks, a mean increase of the CD4 and decrease of the viral load without significant difference between the 4 regimens (103 cells/2.62 log in regimen 1; 169 cells/2.86 log in regimen 2; 171 cells/2.56 log in regimen 3 and 141 cells/1.71 log in regimen 4) were observed in the analysis of the patients in treatment. Treatment was discontinued due to adverse reactions: 24% in regimen 1, 48% in regimen 2, 26% in regimen 3 and 32% in regimen 4, without significant difference. Analyzing by PI groups, 41% of the patients with RTV and 25% of those with IDV discontinued treatment due to adverse effects. There was withdrawal from treatment due to disease progression in 7% of the RTV patients and in 9% of IDV patients.. In the HIV positive patients with advanced infection, efficacy between the four regimens of HAART is similar, but there is a tendency to require more withdrawal due to adverse effects in the RTV group than in those of IDV, the two used as single PI. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Disease Progression; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Ritonavir; Stavudine; Zidovudine | 2006 |
Antiviral activity of nucleoside analogues during short-course monotherapy or dual therapy: its role in preventing HIV infection in infants.
This is the first report on the preliminary efficacy of 4 different short-course nucleoside analogue regimens (stavudine [d4T], didanosine [ddI], d4T+ddI, and zidovudine [ZDV]) for the prevention of mother-to-child transmission of HIV-1 (MTCT) in a resource-limited setting.. This prospective open-label, randomized 4-arm study (May 1999 to May 2000) conducted in South Africa enrolled 373 women from 34 weeks of gestation; medication was continued through delivery and for 6 weeks to infants. MTCT rates were ascertained at birth, 6, 12, and 24 weeks of age.. Mean maternal HIV-1 RNA levels decreased rapidly on treatment in all groups. At week 4, the mean decrease was 1.91 log10 copies/mL (c/mL) in the d4T+ddI group, 1.33 log10 c/mL in the ddI group, 1.12 log10 c/mL in the d4T group, and 0.76 log10 c/mL in the ZDV group. Among the 362 evaluable mother-infant pairs, 11 infants in the d4T group, 10 in the ddI group, 5 in the ZDV group, and 4 in the d4T+ddI group were infected by 24 weeks of age. Eleven infections occurred in utero. Treatment with d4T and ddI was not associated with lactic acidosis or hepatic steatosis.. The abbreviated use of nucleoside analogues for the prevention of MTCT appears safe and effective. Topics: Acidosis, Lactic; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Fatty Liver; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Mothers; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; RNA, Viral; South Africa; Stavudine; Viral Load; Zidovudine | 2006 |
Long-term assessment of nevirapine-containing highly active antiretroviral therapy in antiretroviral-naive HIV-infected patients: 3-year follow-up of the VIRGO study.
Data on the durability of antiretroviral regimens over a 3-year period have only rarely been reported. The aim of this study was to evaluate the long-term efficacy and safety of one or two daily doses of nevirapine (NVP), in combination with stavudine (d4T) and didanosine (ddI), in HIV-infected patients.. This study was a follow-up of the VIR (amune) Grand Ouest (VIRGO) study, a 12-month open-label trial to assess the safety and immunovirological activity of NVP-d4T-ddI combination therapy in antiretroviral-naive HIV-1-infected adults with baseline CD4 counts > or =200 cells/microL and plasma viral loads > or =5000 HIV-1 RNA copies/mL. Of the 100 patients included in the study, the 67 patients remaining on the initial triple therapy at the end of the study (1 year) were offered an extra 24 months of follow-up.. Of the 60 patients who extended follow-up, 46 were still being treated with d4T-ddI-NVP at month 36; 91% (39/43) had a plasma viral load <500 copies/mL (data were missing for three patients). CD4 cell counts increased over 36 months. Safety and tolerance were good with no unexpected long-term toxicity.. After 3 years of treatment with NVP-d4T-ddI, nearly half of the patients were still receiving the initial antiretroviral therapy with a sustained and durable immunovirological benefit. Long-term toxicity was mainly related to the nucleoside reverse transcriptase inhibitor components of the regimen. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Female; Follow-Up Studies; France; HIV Infections; Humans; Male; Nevirapine; Stavudine; Treatment Outcome; Viral Load | 2006 |
Therapeutic potential of chloroquine added to zidovudine plus didanosine for HIV-1 infected children.
To evaluate the efficacy and safety of CHQ in a combination treatment with ZDV/ddI in HIV-1-infected children.. Fifty five HIV-infected children were randomly enrolled into 3 treatment groups: (I) ZDV + ddI (n = 25); and (II) ZDV + ddI + CHQ (n = 21); and (III) ZDV + ddI experienced children were non-randomly added CHQ (n = 9). Weight, CD4+ T-lymphocytes and plasma HIV-RNA were measured at weeks 0, 8 and 24.. Fifteen, 16 and 8 children from Groups I, II and III were evaluated. No significant improvement in the mean Z-score for weight in groups I and II, but a decrease occurred in group III after 6 months of therapy. In group I, II and III, the respective change in the mean CD4+ T-lymphocyte percentage was +6.7, +4.0 and -0.6. The decrease in the plasma HIV-RNA log was 0.9, 1.1 and 0.7, respectively. There was a trend for more nausea/vomiting in group II/III and more opportunistic infections in group III.. 1. The addition of chloroquine in ZDV/ddI regimen provided no significant improvement in clinical, immunological and virological parameters. 2. Chloroquine induced immunosuppression and nausea complicated its use. Topics: Anti-HIV Agents; Antimalarials; Child; Child, Preschool; Chloroquine; Didanosine; Female; HIV Infections; HIV-1; Humans; Male; Zidovudine | 2006 |
Impact of HIV-1 reverse transcriptase polymorphism at codons 211 and 228 on virological response to didanosine.
To determine the potential impact of reverse transcriptase (RT) mutations, other than those currently known to confer nucleoside reverse transcriptase inhibitors (NRTIs) resistance, on the virological response to didanosine (ddl).. In the placebo-controlled Jaguar trial, 168 patients were randomly assigned to receive ddl (n=111) or placebo (n=57) in addition to their currently failing regimen for 4 weeks.. The virological response was a reduction of HIV-1 RNA from baseline to week 4. In an univariate analysis, we investigated the impact on the virological response to ddl of all the mutations in the RT gene (codons 21-236), except those known to confer NRTI resistance. Using the removing procedure, with a test for trend (Jonckheere's test), a new potential score was calculated incorporating all potential mutations associated to the week 4 virological response.. Two RT polymorphisms were associated with a reduced virological response to ddl, R211A/D/G/K/S and L228H/M/R, and one with a better virological response: F214L. A mutation score (M41L+D67N+T69D-K70R +L74V-M 1 84V/I+T21 5Y/F+ K219Q/E+ R211A/D/G/K/S+ L228H/M/R), including two RT polymorphisms not previously described to be associated with ddl resistance (211 and 228) and RT mutations previously described, was associated with a continuum of virological response and increased the predictability of virological response to ddl.. RT polymorphisms should be taken into account to define algorithms able to correctly define resistance to NRTIs and more specifically ddl. Topics: Anti-HIV Agents; Codon; Didanosine; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load | 2006 |
Hydroxychloroquine, hydroxyurea and didanosine as initial therapy for HIV-infected patients with low viral load: safety, efficacy and resistance profile after 144 weeks.
To evaluate the long-term safety and efficacy of the combination of hydroxychloroquine, hydroxyurea and didanosine.. We recruited antiretroviral-naive patients with viral loads less than 100 000 HIV-1 RNA copies/mL and CD4 counts greater than 150 cells/microL. All patients received hydroxychloroquine (200 mg), hydroxyurea (500 mg) and didanosine (125-200 mg) twice daily. Clinical and laboratory safety assessments and measurements of viral load and CD4 count were made at regular intervals, and genotypic resistance testing was performed on samples with detectable viral load at 48, 96 and 144 weeks.. Fourteen of the 17 patients who commenced therapy remained on treatment at 144 weeks. Treatment was well tolerated but caused neutropenia, usually mild and transient, in 12 patients (71%). Mean viral load was reduced by 1.6 log(10) copies/mL below baseline (P<0.001), eight patients (47%) had undetectable viral load (<400 copies/mL), and two patients (12%) had detectable viral load but no detectable resistance mutations at week 144. Four patients (24%) had detectable viral load together with major resistance mutations (three with both 74 V and 184 V, and one with both 62 V and 65R) at week 144, but still had viral load suppression below baseline. Mean CD4 count was increased by 106 cells/microL above baseline (P=0.07) at week 144.. This novel and well-tolerated combination controls viral replication during long-term follow up, with development of few resistance mutations. With careful monitoring it may be a useful strategy for delaying highly active antiretroviral therapy (HAART) and associated toxicity in selected patients with low initial viral loads. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Hydroxychloroquine; Hydroxyurea; Male; Mutation; Treatment Outcome; Viral Load | 2005 |
Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine.
Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI+d4T) vs. abacavir and lamivudine- (ABC+3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI+d4T- and 50 received ABC+3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI+d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC+3TC, with the 2 arms being significantly different (P<0.05). For high-density lipoprotein cholesterol rates of change, ddI+d4T decreased, while ABC+3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI+d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI+d4T or ABC+3TC. Topics: Adult; Anti-HIV Agents; Body Composition; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Male; Middle Aged; Prospective Studies; Stavudine | 2005 |
Bayesian parameter estimates of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1.
The objective of the present study was to develop a population pharmacokinetic model for nelfinavir mesylate (NFV) and nelfinavir hydroxy-tert-butylamide (M8), the most abundant metabolite of NFV, in infants vertically infected with human immunodeficiency virus type 1 and participating in the Paediatric European Network for Treatment of AIDS 7 study. Plasma NFV concentrations were determined during repeated NFV administrations (two to three times a day). Eighteen infants younger that age 2 years participated in this study. The doses administered ranged from 71 to 203 mg/kg of body weight/day. Pharmacokinetic parameter estimates were obtained by a compartmental approach by using a kinetic model to simultaneously fit NFV and M8 (active metabolite) concentrations. M8 was shown to be formation rate limited and was characterized by first-order rate constants of formation and elimination. Body weight was found to be a more appropriate predictor than age of the changes in (i) the rate of metabolism, (ii) the elimination rate constant of NFV, and (iii) NFV clearance. Population parameters were computed to account for the relationship between the rate of metabolism and body weight. The estimated NFV and M8 elimination half-lives were 4.3 and 2.04 h, respectively. The estimated NFV clearance was 2.13 liters/h/kg. The M8 concentration-to-NFV concentration ratio was 0.64 +/- 0.44. In conclusion, the population pharmacokinetic model describing the dispositions of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy. Topics: Aging; Bayes Theorem; Body Weight; Chromatography, High Pressure Liquid; Didanosine; Drug Interactions; Half-Life; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Infant, Newborn; Models, Biological; Nelfinavir; Reverse Transcriptase Inhibitors; Spectrometry, Mass, Electrospray Ionization; Stavudine | 2005 |
Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial.
We assessed a once-daily combination to simplify therapy in patients infected with human immunodeficiency virus type 1 (HIV-1).. A total of 355 adults with plasma HIV-1 RNA levels <400 copies/mL were randomly assigned to either switch to once-daily emtricitabine, didanosine, and efavirenz (n=178) or maintain their protease inhibitor (PI)-based regimens (n=177). The primary end point was sustained suppression of plasma HIV-1 RNA levels to <400 copies/mL.. At week 48, the proportion of patients meeting the end point was 87.6% in the PI group and 90.5% in the once-daily group, with a treatment difference of -2.9% (upper bound of the 1-tailed 95% confidence interval, 2.6%). The proportion of patients with HIV-1 RNA levels <50 copies/mL was higher in the once-daily group (87%) than in the PI group (79%) (P<.05). Resistance mutations to efavirenz and emtricitabine were detected in all patients in the once-daily group who experienced virologic failure while receiving study medication. The proportion of patients discontinuing study medication because of adverse events was similar between the once-daily group (9%) and the PI group (10%) (P=.8).. Substituting a convenient once-daily combination of emtricitabine, didanosine, and efavirenz for a PI-based regimen was well tolerated and associated with sustained virologic suppression. Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Didanosine; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome | 2005 |
Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial.
The antiviral efficacy of didanosine in patients experiencing virological failure is not well known.. A total of 168 patients (139 men and 29 women) receiving stable antiretroviral therapy with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL were randomly assigned to have didanosine (n=111) or placebo (n=57) added to their currently failing regimen for 4 weeks. The primary efficacy end point was the change in HIV-1 RNA level from baseline to week 4.. At baseline, the median HIV-1 RNA level was 3.8 log(10) copies/mL, the median CD4 cell count was 378 cells/mm(3), and the median number of nucleoside reverse-transcriptase inhibitor-associated mutations (NAMs) was 4. At week 4, a significant decrease in the median HIV-1 RNA level was observed in the didanosine group, compared with that in the placebo group (-0.56 vs. +0.07 log(10) copies/mL, respectively) (P<.0001). A total of 33 patients (31%) in the didanosine group, compared with 3 (6%) in the placebo group, had HIV-1 RNA levels <400 copies/mL (P<.001). Significant antiviral activity of didanosine was observed in patients with up to 5 NAMs at baseline. Diarrhea occurred in 5 patients (5%) in the didanosine group and 2 patients (4%) in the placebo group.. In HIV-1-infected patients experiencing failure of antiretroviral therapy, didanosine retains short-term antiviral activity. Topics: Adult; Aged; Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Failure; Treatment Outcome | 2005 |
Early virological failure with a combination of tenofovir, didanosine and efavirenz.
To describe the occurrence of a high early virological failure (VF) rate and development of resistance mutations in antiretroviral-naive patients receiving tenofovir, didanosine and efavirenz.. HIV-infected antiretroviral-naive patients with viral load > or =30 000 copies/ml were enrolled in a pilot randomized trial of tenofovir/didanosine (250 mg)/ efavirenz with (arm A) or without (arm B) lopinavir/r for the first 12 weeks. As six cases of early VF (a drop of <2 log at month 3, or a rebound of >1 log from the nadir) were detected (five in arm B and one in arm A who had previously stopped lopinavir/r) an unplanned interim analysis was performed.. A total of 29 out of 36 enrolled patients completed at least 3 months of follow-up and were included in the interim analysis. An intent-to-treat analysis showed treatment failure in 7/15 (46.7%) patients in arm B (five VF, one lost, one switched) versus 2/14 (14.3%) in arm A (one lost, one switched) (P=0.109). The patient in arm A who interrupted lopinavir/r at day 3 and continued with tenofovir/didanosine/efavirenz later developed VF. At baseline, 6/6 VF patients had VL >100000 copies/ml and an advanced stage of disease (CD4 <200 plus CDC stage C or B3) versus 0/8 non-VF patients taking the triple drug regimen (P<0.001). At failure, G190S/E alone or associated with K103N and K101R mutations was detected in five patients, and K103N/L1001/V108l in the sixth patient. Additionally, L74V/I and K65R were detected in four and two patients, respectively.. A high early virological failure rate and the occurrence of resistance mutations were detected in a group of antiretroviral-naive patients treated with tenofovir/didanosine/efavirenz. Topics: Adenine; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Organophosphonates; Oxazines; Pyrimidinones; RNA, Viral; Tenofovir; Time Factors; Treatment Failure; Viremia | 2005 |
Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.
Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects.. HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed.. Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss.. Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome. Topics: Adenine; Adult; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; Humans; Lymphopenia; Male; Organophosphonates; Retrospective Studies; Tenofovir; Virus Replication | 2005 |
Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside/protease inhibitor-containing regimens.
Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy.. A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA < or = 400 copies/mL after > or = 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24).. Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (< 400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; < 50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed.. ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events. Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Hydroxyurea; Male; Middle Aged; Oxazines; RNA, Viral; Time Factors; Treatment Failure | 2005 |
Clinically relevant genotype interpretation of resistance to didanosine.
We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as -1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E - K70R - M184V/I; P = 4.5 x 10(-9)) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 x 10(-7)). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log(10) copies/ml when they were ranked as having a genotypic score II of -2, -1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI. Topics: Adult; Aged; Algorithms; Anti-HIV Agents; Data Interpretation, Statistical; Didanosine; Double-Blind Method; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral | 2005 |
Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients.
Recent work has demonstrated the existence of a systemic interaction between didanosine (ddI) and tenofovir disoproxyl fumarate (TDF) that leads to a significant increase in plasma ddI levels when coadministered with TDF (40 to 50% increase). These two drugs are, respectively, nucleoside and nucleotide analogues of adenosine and efficiently inhibit the human immunodeficiency virus (HIV) reverse transcriptase when transformed to their triphosphate moieties in the intracellular (IC) medium (ddA-TP and TFV-DP, respectively). Since ddI and TDF partly share the same IC metabolic pathway leading to the active triphosphates, we investigated a putative IC interaction. We used high-performance liquid chromatography-tandem mass spectrometry techniques to determine ddA-TP and TFV-DP IC levels in HIV-infected patients cotreated with both drugs, in comparison with patients treated with just one of the two drugs. These measurements revealed no significant differences in IC levels of the corresponding triphosphates when ddI (250 mg, once a day [QD]) was coadministered with TDF (300 mg, QD) compared to ddI 400 mg (QD) administered without TDF, thus supporting the dose adaptation proposed for this combination. However, we observed that both ddA-TP and TFV-DP have very long IC half-lives, resulting in unusual IC pharmacokinetic profiles with no significant changes in triphosphate concentrations between two dosings. In the case of TFV-DP, this t(1/2) of elimination was roughly estimated to be 180 h (7.5 days). This characteristic is certainly interesting in terms of efficacy but could have some drawbacks in terms of virus resistance for patients discontinuing these drugs. Topics: Adenine; Anti-HIV Agents; Cell Count; Chromatography, Liquid; Cross-Sectional Studies; Didanosine; Half-Life; HIV Infections; HIV-1; Humans; Kinetics; Longitudinal Studies; Mass Spectrometry; Organophosphonates; Phosphorylation; Reference Standards; Tenofovir | 2005 |
Pharmacokinetics of didanosine and drug resistance mutations in infants exposed to zidovudine during gestation or postnatally and treated with didanosine or zidovudine in the first three months of life.
There are limited numbers of drugs that are available in formulations that are appropriate for neonates and few studies assessing resistance among infants born to human immunodeficiency virus (HIV)-infected women.. Pharmacokinetics and tolerance of didanosine (ddI) were determined for infants < or =120 days of age. Infants received at least 24 hours of zidovudine (ZDV) treatment, followed by a single ddI dose and pharmacokinetic sampling. The target area under the concentration-time curve (AUC) was between 2.5 and 5.0 microM . hour. Toxicity and drug resistance mutations were assessed at baseline and follow-up times.. The initial ddI pharmacokinetic dosing of 50 mg/m for infants >28 days of age achieved a median AUC0-infinity of 2.8 microM . hour. For infants < or =28 days of age, the target AUC was achieved after dose escalation from 25 mg/m (median AUC0-infinity, 1.4 microM . hour) to 50 mg/m (median AUC0-infinity, 5.40 microM . hour). At baseline, 25% of infected infants had drug resistance mutations (9 of 44 to ZDV and 2 of 44 to ddI). Resistance mutations were present for 29% of infants (5 of 17 infants) with in utero ZDV exposure and 25% (8 of 32 infants) with prior ZDV treatment. The most common ZDV mutation noted at baseline was the T215Y/F (n = 7) mutation; 2 of these infants also had the M41L mutation, which is associated with high level ZDV resistance. No prior exposure was noted for the 2 infants with ddI resistance, which indicates possible perinatal transmission of ddI-resistant virus to these infants.. A dose of 50 mg/m is the appropriate ddI dose for infants <120 days of age and is a safe treatment for newborns when used in combination with ZDV. Genotypic resistance occurs frequently among infected infants exposed to ZDV during gestation or postnatally, which suggests that resistance testing should be considered for infants with newly diagnosed HIV infection. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Male; Mutation; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Zidovudine | 2005 |
Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency.
The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Didanosine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; HIV; HIV Infections; Humans; Hydroxyurea; Male; RNA, Viral; Stavudine; Viral Load; Viremia | 2005 |
Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms.
The hydroxyurea-didanosine combination has been shown to limit immune activation (a major pathogenic component of HIV/AIDS) and suppress viral load by both antiviral and cytostatic ('virostatic') activities. Virostatics action represent a novel approach to attack HIV/AIDS from multiple directions; however, the use of these drugs is limited by the lack of understanding of their dose-dependent mechanism of action and by fear of pancreatic toxicity, even though a large review of ACTG studies has shown that hydroxyurea does not increase the incidence of pancreatitis.. In vitro cytostatic and cytotoxic activity, inhibition of viral replication and immune activation by pharmacologically attainable plasma concentrations of hydroxyurea (10-100 micromol/l) and didanosine (1-5 micromol/l) were analyzed by cell proliferation, viability, apoptosis and infection assays using peripheral blood mononuclear cells. In vivo, 600, 900 and 1200 mg daily doses of hydroxyurea in combination with standard doses of didanosine and stavudine were studied in 115 randomized chronically infected patients.. A cytostatic low (10 micromol/l) concentration of hydroxyurea inhibited cell proliferation and HIV replication in vitro. A gradual switch from cytostatic to cytotoxic effects was observed by increasing hydroxyurea concentration to 50-100 micromol/l, predicting that lower doses of hydroxyurea would be less toxic and more potent in vivo. The clinical results confirmed that 600 mg hydroxyurea was better tolerated, had fewer side effects and was more potent in suppressing HIV replication than the higher doses.. A bimodal, dose-dependent, cytostatic-cytotoxic switch is an immune-based mechanism explaining the apparent paradox that lowering the dose of hydroxyurea to 600 mg daily induces maximal antiviral suppression in HIV-infected patients. Topics: Anti-HIV Agents; Apoptosis; Cell Proliferation; Cells, Cultured; Didanosine; Dose-Response Relationship, Drug; Drug Combinations; HIV Infections; Humans; Hydroxyurea; Maximum Tolerated Dose; Nucleic Acid Synthesis Inhibitors; Pancreatic Diseases; Viral Load; Virus Replication | 2005 |
Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial.
To compare the safety and efficacy of two once-daily antiretroviral regimens containing lamivudine (3TC) or tenofovir disoproxil fumarate (TDF), each administered with didanosine (ddI) and efavirenz (EFV) as initial therapy to HIV-1-infected subjects.. Single centre, randomized (1: 1), open-label study in antiretroviral-naive, HIV-infected adults. Subjects commenced either 3TC/ddI/EFV (3TC group) or TDF/ddI/EFV (TDF group). Safety, Medication Event Monitoring System (MEMScap) and plasma EFV concentration monitoring was performed over the study period. Comparisons between groups were assessed using chi test and linear regression analysis was used to assess the relationship between EFV concentrations and virological response.. Seventy-seven subjects were enrolled prior to recruitment being suspended, 36 to the 3TC group and 41 to the TDF group. Intention-to-treat analysis in which last observation carried forward (LOCF) found the mean viral log10 load [95% confidence interval (CI)] at weeks 4 and 12 to be 2.67 (2.47-2.87) and 1.83 (1.74-1.92) for the 3TC group and 2.75 (2.45-3.05) and 2.28 (1.96-2.6) for the TDF group (P = 0.013). Emergence of resistance occurred in five of 41 (12.2%) subjects in the TDF group up to week 12 compared with none of 36 in the 3TC group, (P < 0.05); these five subjects shared similar baseline characteristics (CD4+ cell counts < 200 x 10 cells/l and HIV-1 RNA > 100,000 copies/ml). Despite MEMScap monitoring showing > 99% adherence in all subjects, among the five failures, three had low EFV concentrations.. TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 x 10 cells/l and viral load > 100,000 copies/ml. Treatment failure with resistance was not attributable to baseline resistance, efavirenz exposure or poor adherence. Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphonates; Oxazines; Tenofovir; Treatment Failure | 2005 |
Comparison of tests and procedures to build clinically relevant genotypic scores: application to the Jaguar study.
To compare non-parametric tests and procedures of selection in building clinically validated genotypic scores.. In the Jaguar study, 111 patients on a stable antiretroviral regimen experiencing virological failure were randomized in the didanosine (ddI) arm to receive ddI for 4 weeks in addition to their current combination therapy.. The virological response was HIV-1 RNA reduction from baseline to week 4. The univariate impact of each mutation associated with resistance to ddI on virological response was quantified by comparing reduction in plasma HIV-1 RNA in patients with or without the specific mutation, using a Wilcoxon-Mann-Whitney test. The next step was to select the combination of mutations most strongly associated with the virological response. Two procedures and two tests were compared using either the set of resistance mutations or the set of resistance mutations and mutations providing a better virological response. The Kruskal-Wallis and the Jonckheere test for ordered alternatives were compared in order to build a genotypic score using the two distinct procedures.. Eight mutations were associated with a reduced virological response to ddI: M41L, D67N, T69D, L74V, V1181, L210W, T215Y/F and K219Q/E and two mutations with a better virological response: K70R and M184V/I. The Jonckheere-Terpstra test for trend provided the combination of mutations (M41L+T69D-K70R+L74V-M184V /I+T215Y/F+ K219A/E) that were the most predictive for the week 4 virological response, that is, leading to the lowest P value. The 'removing' procedure, starting from a set of mutations retained and removing mutations one by one to find the best combination, provides lower P values than the 'adding' procedure starting with a single mutation and adding mutations one by one. Whatever the set of mutations and the procedure used, the Jonckheere-Terpstra test selects combinations of mutations leading to lower P values than the Kruskal-Wallis test.. The Jonckheere-Terpstra test for trend is recommended for building a genotypic score when compared with the Kruskal-Wallis. The choice of the selection procedure is discussed here and may be dependent on the objective of the score. Topics: Anti-HIV Agents; Data Interpretation, Statistical; Didanosine; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; HIV Infections; HIV-1; Humans; Mutation; RNA, Viral; Selection, Genetic | 2005 |
Compromised immunologic recovery in treatment-experienced patients with HIV infection receiving both tenofovir disoproxil fumarate and didanosine in the TORO studies.
The effect of therapy with a combination of tenofovir and full-dose didanosine on increases in CD4+ cell count was examined in 2 large trials of treatment-experienced patients with human immunodeficiency virus (HIV) infection (the T-20 versus Optimized Regimen Only [TORO] 1 and 2 clinical trials). Individuals receiving both agents showed little additional increase in CD4+ cell count after week 8 of therapy, whereas those receiving 1 or neither of the agents had continuous increases over a 48-week period. Topics: Adenine; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Peptide Fragments; Tenofovir; Time Factors; Viral Load | 2005 |
Efficacy and safety of once-daily combination therapy with didanosine, lamivudine and nevirapine in antiretroviral-naive HIV-infected patients.
Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection.. This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis.. Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10log10 copies/ml, and mean CD4 cell count was 262 cells/microl. At month 12, 67% (95% CI: 56-78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/microl. The treatment was more effective in patients with baseline CD4 counts >100 cells/microl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol.. A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Nevirapine; Pilot Projects; RNA, Viral; Spain | 2005 |
Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors.
Nucleoside reverse transcriptase inhibitors (NRTIs) suppress human immunodeficiency virus (HIV) replication, but are often associated with mitochondrial toxicity. Although well studied outside of the central nervous system, no investigation has examined the effects of these drugs on brain mitochondria of individuals living with HIV. The authors used proton magnetic resonance spectroscopy to evaluate NRTI-related changes in brain mitochondria. N-acetylaspartate (NAA; sensitive to alterations in mitochondrial integrity) was measured in frontal lobe white and gray matter of 18 HIV+ individuals taking didanosine and/or stavudine (two NRTIs likely to cause mitochondrial toxicity), 14 HIV+ individuals taking zidovudine and lamivudine, 16 HIV+ individuals not currently taking antiretrovirals, and 17 HIV- controls. The HIV+ groups were comparable on demographic measures, estimates of illness severity, and estimated length of HIV infection. Those taking didanosine and/or stavudine had a significant 11.4% decrease in concentrations of frontal white matter NAA compared to HIV- controls, whereas NAA levels of the other HIV+ groups were intermediate. Group differences in metabolites were not found in frontal gray matter. Lower levels of frontal white matter NAA were associated with longer periods of didanosine and/or stavudine treatment (r = -.41, P = .06). Levels of NAA were not related to length of zidovudine/lamivudine treatment (r = -.04, P = .44). Furthermore, taking more than one of stavudine, didanosine, and abacavir increased the likelihood of having reduced NAA. The results are consistent with previous studies finding HIV-related changes in neuronal integrity. However, because NRTIs can injure mitochondria, we propose that the observed reductions in NAA in individuals taking didanosine and/or stavudine may be the result of depleted brain mitochondria and/or alterations in cellular respiration. Measurement of brain metabolites sensitive to impairments in energy metabolism, including NAA, may aid in early detection of subclinical NRTI-mediated mitochondrial toxicity. Topics: Adult; Aspartic Acid; Brain; Cell Respiration; Didanosine; Female; HIV Infections; Humans; Lamivudine; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Zidovudine | 2005 |
Seminal reservoirs during an HIV type 1 eradication trial.
Despite dramatic reduction of the levels of human immunodeficiency virus type I (HIV-1) virions in blood and seminal plasma of infected patients, highly active antiretroviral therapy (HAART) does not eradicate HIV-1. Three patients, with less than 50 copies/ml of plasma viral RNA, were enrolled in this eradication protocol. Didanosine (DDI) and hydroxyurea (HU) were added to their baseline HAART and after a month of therapy, low dose OKT3, followed by a 2-week course of interleukin 2 (IL-2), was administrated. All antiretroviral therapy was then interrupted and the three patients developed viral rebound in the peripheral blood. The V3 loop region of the HIV-1 gp120 from cell-free viral RNA and proviral DNA in blood and seminal compartments was sequenced in one patient. The two major viral isolates in semen cells were macrophage- tropic (R5) and dual-tropic (R5X4), and these isolates were also present in the PBMCs. Six months after the viral rebound, we demonstrated a shift toward dual tropism in semen cell-associated HIV-1 proviral DNA, with the first appearance of a T-lymphotropic (X4) provirus solely in this compartment. The virus responsible for the blood plasma viral rebound was never found in the semen microenvironment. This study suggests viral compartmentalization of the semen microenvironment after an intensification and stimulatory HIV-1 eradication protocol, with evidence of viral evolution. Topics: Amino Acid Sequence; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; DNA, Viral; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Hydroxyurea; Immunosuppressive Agents; Interleukin-2; Male; Molecular Sequence Data; Muromonab-CD3; Nucleic Acid Synthesis Inhibitors; Peptide Fragments; Phylogeny; Proviruses; RNA, Viral; Semen; Sequence Alignment; Treatment Outcome; Viremia; Withholding Treatment | 2005 |
Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403.
Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children. We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an NRTI, protease inhibitors +/- a nonnucleoside reverse transcription inhibitor (NNRTI).. This was a phase II, randomized, multicenter study. Forty-one children and youths between 5 months and 21 years with prior NRTI and no prior NNRTI or protease inhibitor experience received either nelfinavir (NFV) 30 mg/kg twice daily (bid), ritonavir (RTV) 400 mg/m bid and buffered didanosine (ddI) 240 mg/m daily (arm A) or NFV 50-55 mg/kg bid, nevirapine (NVP) 120 mg/m bid and stavudine (d4T) 1 mg/kg bid (arm B). Patients were evaluated clinically for 48 weeks after initiation of therapy. Intensive pharmacokinetic sampling occurred after 4 weeks of therapy.. : The proportion of children with HIV-1 RNA < or =400 copies/mL and on randomized treatment at 48 weeks was 65% among children assigned NFV + RTV + ddI versus 28% among those assigned NFV + NVP + d4T (P = 0.039). No significant difference in median CD4% change from baseline to week 48 was found (3% versus 1%). No significant differences in safety or tolerability between children randomized to NFV + RTV + ddI versus NFV + NVP + d4T were identified. However, a trend toward a higher rate of permanent discontinuation of study treatment was noted among children assigned to NFV + NVP + d4T compared with NFV + RTV + ddI [7 of 20 (35%) versus 2 of 21 (10%); P = 0.12]. NFV pharmacokinetic measurements were not statistically different between the treatment groups, yet exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV. The pharmacokinetics for NVP, RTV and d4T were similar to those of previously reported data.. : Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containing NFV + NVP + d4T. Differences in tolerability between the 2 treatment groups were not identified. Systemic exposure of these drugs was similar to that reported in other HIV-infected children and adults. Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Didanosine; Female; HIV Infections; HIV-1; Humans; Infant; Male; Nelfinavir; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Treatment Outcome | 2005 |
Once-daily regimen of saquinavir, ritonavir, didanosine, and lamivudine in HIV-infected patients with standard tuberculosis therapy (TBQD Study).
To assess the efficacy and safety of a once-daily regimen with didanosine, lamivudine, saquinavir, and low-dose ritonavir in antiretroviral (ARV)-naive patients with tuberculosis treated with rifampin and the influence of rifampin on plasma trough concentration (Ctrough) of saquinavir.. Single-arm, prospective, multicenter, open-label pilot study, including 32 adult ARV-naive subjects with HIV infection and tuberculosis under standard treatment that included rifampin (600 mg q.d.) and isoniazid (300 mg q.d.). After 2 months of tuberculosis treatment, patients were started on once-daily ARV therapy, consisting of didanosine, lamivudine, ritonavir (200 mg), and saquinavir soft gel capsules (1600 mg). HIV RNA level, CD4 cell count, clinical and laboratory toxicity, and saquinavir Ctrough during and after antituberculosis therapy were analyzed.. After 48 weeks of follow-up, 20 of 32 patients (62.5%; 95% CI: 45.8% to 79.2%) in the intent-to-treat population and 20 of 28 (71.4%; 95% CI: 54.4% to 88.4%) in the on-treatment population had an HIV RNA level <50 copies/mL. Treatment tolerance was acceptable in all patients except for 2 with biologic hepatic toxicity leading to discontinuation. Seven patients had virologic failure. In 10 patients (36%), saquinavir Ctrough was <0.05 microg/mL during tuberculosis therapy and 5 of them had virologic failure. The median saquinavir Ctrough was 44% lower (interquartile range: 19% to 71%) with coadministration of rifampin than without.. The combination of didanosine, lamivudine, saquinavir, and ritonavir may be a useful treatment regimen for patients with tuberculosis in whom a once-daily protease inhibitor-containing regimen is considered indicated. Nevertheless, on the basis of pharmacokinetic profile the dose of 1600/200 mg of saquinavir/ritonavir cannot be recommended. Further studies with higher doses of saquinavir (2000 mg) boosted with ritonavir are warranted. Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Pilot Projects; Ritonavir; Saquinavir; Spain; Treatment Outcome; Tuberculosis | 2005 |
Simplification therapy with once-daily didanosine, tenofovir and efavirenz in HIV-1-infected adults with viral suppression receiving a more complex antiretroviral regimen: final results of the EFADITE trial.
High pill burden and side effects often impact on the long-term success of highly active antiretroviral therapy (HAART), which has led clinicians to search for more convenient regimens.. A prospective, multicentre, open, comparative study in which HIV-1-infected patients on HAART and with plasma HIV-1 RNA <50 copies/ml for longer than 6 months were switched to tenofovir, didanosine and efavirenz (QD arm) or remained on the same treatment regimen (control arm). Patients with grade 4 toxicities or plasma HIV-1 RNA values repeatedly >1000 copies/ml discontinued the study.. A total of 390 patients were included in the trial (309 in the QD arm and 81 in the control arm). The main baseline characteristics were well balanced between groups. In the QD arm, 41% of patients received high (standard) didanosine doses and 59% received reduced doses. At 12 months, plasma HIV-1 RNA <400 copies/ml was attained in 66% of QD patients and 73% of controls in the intent-to-treat (ITT) analysis (P=NS). However, the number of individuals with HIV-1 RNA <400 copies/ml in the QD arm was 56% versus 71% when comparing the use of high versus low didanosine doses (P=0.007). Treatment discontinuation occurred in 87 QD cases (28%) and 17 controls (21%). Twenty QD individuals (6.5%) and 2 controls (2.5%) discontinued because of virological failure (P=NS). The median CD4+ cell count change at 12 months was -26 and +27 cells/microl in QD patients and controls, respectively (P=0.001). In individuals who attained HIV-1 RNA <400 copies/ml, CD4+ cell changes were -25 and +15 cells/microl in QD patients and controls, respectively (P=0.001). Moreover, CD4+ cell declines in the QD arm were significantly greater in patients taking high versus low didanosine doses (-59 versus -15 cells/microl; P=0.04). The lipid profile improved significantly in the QD arm, particularly in patients who were on protease inhibitors prior to simplification.. Simplification to didanosine-tenofovir-efavirenz provides a virological suppression rate at 12 months similar to that seen in patients who do not change therapy, as long as low didanosine doses are administered. Decreases in CD4+ cell levels in patients in the QD arm (especially decreases seen with high didanosine doses) and dyslipidaemias along with less convenient pill burden and schedules in controls were the main long-term concerns for each option. Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Dose-Response Relationship, Drug; HIV Infections; HIV-1; Humans; Male; Middle Aged; Odds Ratio; Organophosphonates; Oxazines; Prospective Studies; RNA, Viral; Tenofovir; Treatment Outcome | 2005 |
Mutations linked to drug resistance, human immunodeficiency virus type 1 biologic phenotype and their association with disease progression in children receiving nucleoside reverse transcriptase inhibitors.
Few data are available concerning the impact of antiretroviral resistance in response to antiviral therapy in children. We evaluated the development of antiretroviral genotypic resistance and clinical outcome in a subgroup of children involved in a prospective antiretroviral therapy trial (Pediatric AIDS Clinical Trials Group Protocol 152).. We studied 26 matched case/control pairs. A case was defined as having clinical disease progression during the study period; controls did not have disease progression. Cases and controls were matched by age and CD4+ cell count at baseline. Matched pairs received treatment with zidovudine (9 pairs), didanosine (12 pairs) or combined therapy (5 pairs). Multiple codons of the reverse transcriptase coding region (41, 67, 70, 74, 151, 184, 210, 215 and 219) were analyzed. Patients were evaluated for CD4+ cell count, HIV-1 viral load and HIV-1 biologic phenotype at baseline and clinical endpoint.. The presence of mutations associated with resistance after nucleoside antiretroviral therapy (P = 0.039) and syncytium-inducing phenotype (P = 0.031), were significantly associated with increased risk of clinical disease progression. The mean difference in HIV-1 RNA levels between cases and their matched controls after nucleoside antiretroviral therapy was 0.77 log10 copies/ml higher for cases (P = 0.003). The median difference between cases and controls for CD4+ cell count after nucleoside antiretroviral therapy was 349 cells/mm3 lower for cases (P < 0.001).. In this small prospective study of HIV-infected children, mutations in the reverse transcriptase coding region, syncytium-inducing viral phenotype, higher HIV-1 RNA load and lower CD4+ cell count were significantly correlated with increased risk of HIV clinical disease progression. Topics: Case-Control Studies; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Infant; Male; Mutation; Pharmacogenetics; Phenotype; Polymerase Chain Reaction; Probability; Prospective Studies; Reference Values; Reverse Transcriptase Inhibitors; RNA, Viral; Statistics, Nonparametric; Viral Load; Zidovudine | 2004 |
A randomized trial to investigate the recycling of stavudine and didanosine with and without hydroxyurea in salvage therapy (RESTART).
Treatment failure during highly active antiretroviral therapy (HAART) is ultimately common and associated with the development of resistance mutations to both the specific drug in question and cross-resistance to other available treatment options. In heavily pre-treated patients, the recycling of antiretroviral agents that have been utilized previously may, however, be associated with antiviral efficacy. We therefore conducted an investigation into the concept of recycling stavudine (d4T, Zerit) and didanosine (ddI, Videx) with and without hydroxyurea, in the management of heavily pre-treated HIV-1 infected individuals requiring salvage therapy (RESTART).. We randomized 21 individuals with treatment failure to receive stavudine and didanosine or stavudine, didanosine and hydroxyurea, for 12 weeks prior to optimizing therapy. Viral load, immunological parameters, genotypic information and the virtual phenotypes were obtained at baseline and at the end of the study.. Significant decreases in viral loads were observed in both groups during a 12 week study period (P = 0.04), the addition of hydroxyurea conferring no additional benefit. This was not predicted by information from genotypes and virtual phenotypes, and these did not reveal sensitive or specific phenotypic cut-offs for those individuals who responded to recycling.. Salvage therapy with didanosine and stavudine can decrease viral loads in heavily pre-treated individuals. Genotypic and virtual phenotype profiles provide little additional information in this setting. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV-1; Humans; Hydroxyurea; Male; Middle Aged; Nucleic Acid Synthesis Inhibitors; Phenotype; Salvage Therapy; Stavudine; Treatment Outcome; Viral Load | 2004 |
Pharmacokinetics of emtricitabine, didanosine and efavirenz administered once-daily for the treatment of HIV-infected adults (pharmacokinetic substudy of the ANRS 091 trial).
This study was conducted to investigate the pharmacokinetics of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a once-daily combination.. Nine antiretroviral-naïve HIV-infected adults who received FTC [200 mg once a day (q.d.)], ddI (400 mg q.d. if > or =60 kg; 250 mg q.d. if <60 kg) and EFV (600 mg q.d.) were studied. The following pharmacokinetic (PK) parameters were determined over 24 h at steady-state after 4 weeks of treatment: area under the plasma concentration vs. time curve (AUC(0-24 h)), maximum (Cmax) and minimum (Cmin) plasma concentrations, time to reach Cmax (Tmax), and the elimination half-life (t(1/2)). EFV plasma concentrations were also measured during follow-up.. Median PK parameters for FTC, ddI and EFV, respectively, were as follows. AUC(0-24 h): 7.2, 7.0 and 36.4 h x mg/L; Cmax: 1.8, 2.6 and 2.5 mg/L; Cmin: 0.04, <0.01 and 1.0 mg/L; Tmax: 1.8, 1.1 and 2.5 h; t(1/2): 7.4, 2.3, and 23.7 h. EFV plasma concentrations measured 10-13 h postdosing were higher during follow-up than during the PK study (2.57 vs. 1.19 mg/L, P<0.01).. The simultaneous administration of FTC, ddI and EFV did not affect the PK parameters of FTC when compared to historical controls. EFV Cmax and Cmin were lower than expected, but the data may have been slightly underestimated in this study. High ddI AUC and Cmax were measured in these patients, and further studies are warranted to confirm this finding. Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Male; Middle Aged; Oxazines; Prospective Studies; Treatment Outcome | 2004 |
Efavirenz induces a striking and generalized increase of HDL-cholesterol in HIV-infected patients.
Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cholesterol, HDL; Cyclopropanes; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Lipoproteins; Magnetic Resonance Spectroscopy; Male; Multivariate Analysis; Oxazines; Reverse Transcriptase Inhibitors; Stavudine | 2004 |
Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome.
To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age.. A multicentre, phase I/II, non-randomized, open-label study (PENTA 7).. Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated.. Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations.. Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required. Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Male; Nelfinavir; Prospective Studies; RNA, Viral; Stavudine; Treatment Outcome; Viral Load | 2004 |
A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection.
We previously demonstrated that short-cycle structured intermittent therapy (SIT; 7 days without therapy followed by 7 days with antiretroviral therapy [ART]) with a ritonavir-boosted, indinavir-based, twice-daily regimen maintained suppression of plasma HIV viremia while reducing serum levels of lipids. Adherence to such a regimen may be problematic for certain patients.. Eight patients with a history of receiving combination ART that maintained suppression of plasma HIV RNA to <50 copies/mL received a once-daily SIT regimen of didanosine, lamivudine, and efavirenz.. For 7 patients, suppression of plasma HIV RNA to <50 copies/mL was maintained for 60-84 weeks. Four patients with adequate samples had no evidence for an increase in plasma viremia for up to 72 weeks, by use of an assay with a limit of detection of <1 copy/mL. The lack of rebound viremia may be the result of the persistence of efavirenz in plasma on day 7 of the no-therapy period, as was detected in 7 of 7 patients. There was no significant change in CD4(+) T cell counts or serum hepatic transaminase or lipid levels.. A once-daily short-cycle SIT regimen maintained suppression of plasma HIV RNA while preserving CD4(+) T cell counts. Such a regimen may have importance in resource-limited settings where the monetary cost of continuous ART is prohibitive. Topics: Alanine Transaminase; Alkynes; Anti-HIV Agents; Aspartate Aminotransferases; Benzoxazines; Cholesterol; Cyclopropanes; Didanosine; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Polymerase Chain Reaction; RNA, Viral; Triglycerides | 2004 |
Three-year durability of dual-nucleoside versus triple-nucleoside therapy in a Thai population with HIV infection.
We compared the long-term immunologic and virologic efficacy of the dual- and triple-nucleoside therapy for HIV infection. This was a retrospective analysis of 2 randomized clinical trials in antiretroviral-naive patients. In the dual-nucleoside group, 15 started with didanosine (ddI) monotherapy and then added stavudine (d4T) after 24 weeks, 63 started with various doses of d4T and ddI, and 53 started with zidovudine (ZDV) and lamivudine (3TC). In the triple-nucleoside group, 53 started with ZDV, 3TC, and ddI. After 48 weeks, patients who were not failing were randomized to immediate (before treatment failure) versus delayed (at the time of virologic failure) switching from ddI and d4T to ZDV and 3TC or vice versa and from ZDV, 3TC, and ddI to d4T, 3TC, and abacavir (ABC). Failure was defined as a plasma HIV-1 RNA level>or=1 log10 above nadir or >or=10,000 copies/mL when nadir was <500 copies/mL. Patients failing therapy before week 48 received the new treatment as in the immediate switching group. Hydroxyurea was added to the last treatment regimen if patients failed after week 96. CD4 count and plasma HIV-1 RNA level (branched DNA assay with a cutoff point of 50 copies/mL) at week 144 were analyzed by intention to treat. Compared with the dual-nucleoside group, the triple-nucleoside group had a higher proportion of patients with <50 copies/mL at 144 weeks (60% vs. 18%; P<0.001), higher median CD4 count (388 cells/microL vs. 346 cells/microL; P=0.018), and longer duration of response, defined as the time from onset of viral suppression (<500 copies/mL) to the time of treatment failure (the first of 2 consecutive HIV-1 RNA measurements >500 copies/mL never followed by 2 consecutive visits showing suppressible viremia to <500 copies/mL) or discontinuation from the study (144 weeks vs. 104 weeks; P=0.002). Multivariate regression analyses showed that significant predictors for treatment success, defined as a plasma viral load <50 copies/mL at week 144, were asymptomatic clinical status at enrollment, a baseline plasma viral load Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Retrospective Studies; RNA, Viral; Stavudine; Thailand; Time Factors; Zidovudine | 2004 |
A pilot study of once-daily antiretroviral therapy integrated with tuberculosis directly observed therapy in a resource-limited setting.
To determine the feasibility and effectiveness of integrating highly active antiretroviral therapy (HAART) into existing tuberculosis directly observed therapy (TB/DOT) programs, we performed a pilot study in an urban TB clinic in South Africa. Patients with smear-positive pulmonary TB were offered HIV counseling and testing. Twenty HIV-positive patients received once-daily didanosine (400 mg) plus lamivudine (300 mg) plus efavirenz (600 mg) administered concomitantly with standard TB therapy Monday to Friday and self-administered on weekends. After completing TB therapy, patients were referred to an HIV clinic for continued treatment. At baseline, patients had a mean CD4 count of 230 cells/mm(3) (range: 24-499 cells/mm(3)) and a mean viral load of 5.75 log(10) (range: 3.81-7.53 log(10)). Seventeen completed combined standard TB and HIV therapy; 16 of 20 (80%) patients enrolled and 15 of 17 (88%) patients completing standard TB therapy achieved a viral load <50 copies/mL and mean CD4 count increase of 148 cells/mm(3). TB was cured in 17 of 20 (85%) enrolled patients and 17 of 19 (89%) patients with drug-sensitive TB. Treatment was well tolerated, with minimal gastrointestinal, hepatic, skin, or neurologic toxicity. The project was well accepted and integrated into the daily TB clinic functions. This pilot study demonstrates that TB/DOT programs can be feasible and effective sites for HIV identification and the introduction and monitoring of a once-daily HAART regimen in resource-limited settings. Topics: Administration, Oral; Adolescent; Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; Costs and Cost Analysis; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Outpatient Clinics, Hospital; Oxazines; Pilot Projects; South Africa; Treatment Outcome; Tuberculosis; Urban Population | 2004 |
Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial.
Emtricitabine is a new, once-daily nucleoside reverse transcriptase inhibitor (NRTI) with potent activity against human immunodeficiency virus (HIV).. To assess the efficacy and safety of emtricitabine as compared with stavudine when used with a background regimen of didanosine and efavirenz.. Randomized, double-blind, double-dummy study conducted at 101 research clinics in North America, Latin America, and Europe. The first patient was enrolled on August 21, 2000; no investigator or patient was unblinded until the last patient randomized completed the week 48 visit on October 24, 2002. Analyses were based on data collected in a double-blind setting with a median follow-up of 60 weeks. Patients were 571 antiretroviral-naive, HIV-1-infected adults aged 18 years or older with viral load levels greater than or equal to 5000 copies/mL.. Receipt of either 200 mg of emtricitabine once daily (plus stavudine placebo twice daily) (n = 286) or stavudine at standard doses twice daily (plus emtricitabine placebo once daily) (n = 285) plus open-label didanosine and efavirenz, once daily.. Persistent virological response, defined as achieving and maintaining viral load at or below the limit of assay quantification (< or =400 or 50 copies/mL).. At the interim analysis on June 14, 2002, when the last patient randomized completed 24 weeks of double-blind treatment (median follow-up time of 42 weeks), patients in the emtricitabine group had a higher probability of a persistent virological response < or =50 copies/mL vs the stavudine group (85% vs 76%, P =.005). This was associated with a higher mean CD4 cell count change from baseline for the emtricitabine group (156 cells/ microL vs 119 cells/microL, P =.01 [of note, there was no statistical difference at 48 weeks [P =.15], although a sensitivity analysis, using an intent-to-treat population with the last CD4 cell count observation carried forward to week 48 showed a difference [P =.02]]). The independent data and safety monitoring board recommended offering open-label emtricitabine based on the interim analysis. The probability of persistent virological response < or =50 copies/mL through week 60 was 76% for the emtricitabine group vs 54% for the stavudine group (P<.001). The probability of virological failure through week 60 was 4% in the emtricitabine group and 12% in the stavudine group (P<.001). Patients in the stavudine group had a greater probability of an adverse event that led to study drug discontinuation through week 60 than did those in the emtricitabine group (15% vs 7%, P =.005).. Once-daily emtricitabine appeared to demonstrate greater virological efficacy, durability of response, and tolerability compared with twice-daily stavudine when used with once-daily didanosine and efavirenz. Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Deoxycytidine; Didanosine; Double-Blind Method; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Stavudine; Viral Load | 2004 |
Safety and efficacy of once-daily didanosine, tenofovir and nevirapine as a simplification antiretroviral approach.
To assess the efficacy and safety of a once-daily antiretroviral regimen in HAART-experienced subjects with long-lasting viral suppression.. One-hundred-and-sixty-nine patients with chronically suppressed viral load (limit of detection <50 copies/ml) were recruited. Based on patient willingness to simplify treatment, 84 of them continued receiving their usual treatment (BID Group) and 85 switched to once-daily didanosine/tenofovir/nevirapine (QD Group) in a non-randomized fashion.. At week 48, the proportion of patients with viral suppression in the QD and in the BID Group, respectively, was 97 vs 100% in the per-protocol analysis (P = 0.497), and 76 vs 86% for the intention-to-treat analysis (P = 0.176). Nevertheless, CD4 count decreased in the QD Group, with a mean decline of 95 cells/mm3 (95% CI: 45-145). Twelve subjects in the QD Group (14%) discontinued treatment due to adverse events, mainly nevirapine-related hepatitis (6%). No significant differences regarding the rate of acute pancreatitis or peripheral neuropathy were observed between both groups. A significant improvement in the lipid profile was only seen in the QD Group. High levels of adherence were observed in both groups during follow-up, as well as a good quality of life. At week 48, a reduction in effort to take medication (P < or = 0.001) and an increment in the satisfaction with the treatment (P < 0.001) was only seen in the QD group. No differences were observed in median nevirapine trough levels between patients on twice-daily nevirapine at baseline (4820 ng/ml) and subjects in the QD Group (6090 ng/ml, P = 0.30).. Treatment simplification to a once-daily antiretroviral regimen based on didanosine, tenofovir and nevirapine may be a valid approach in HIV-infected subjects with long-lasting viral suppression. Combination of standard doses of didanosine and tenofovir may have contributed to the CD4 cell decline observed with this QD regimen. Topics: Adenine; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Chemical and Drug Induced Liver Injury; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipids; Male; Nevirapine; Organophosphonates; Pancreatitis; Patient Compliance; Quality of Life; RNA, Viral; Tenofovir | 2004 |
Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment.
Gynaecomastia has been described in HIV-infected men undergoing highly active antiretroviral therapy (HAART). However, there are insufficient data on the relationship between gynaecomastia and any specific antiretroviral drug and hormone abnormality.. To assess the frequency of gynaecomastia in HIV-infected men receiving HAART and its association with antiretroviral drugs and hormone abnormalities.. We carried out a prospective study of 1304 HIV-infected men undergoing HAART. In addition, we included a case (with gynaecomastia)-control (without gynaecomastia) analysis in the second part of this study. Cases and controls were matched according to age, HIV infection CDC clinical category, HCV infection, the date of study and the physician responsible for the patient. Patients bearing known causes of gynaecomastia were excluded. We analysed epidemiological, clinical, haematological and immunological characteristics and the use and duration of the antiretroviral therapy. In 13 cases and 13 controls a sexual hormone profile was carried out.. A total of 30 (2.3%) HIV-infected men presented with gynaecomastia of unexplained cause. In 22 (73%) of these individuals, gynaecomastia completely resolved after a median time of 9 months (range: 5-22 months). The percentage of individuals who were receiving efavirenz and didanosine at the time of the study was higher among patients with gynaecomastia [57% vs 17% (P=0.004) and 50% vs 13% (P=0.003), respectively]. Plasma total testosterone, free testosterone index and bioavailable testosterone levels were lower in patients with gynaecomastia, whereas plasma free testosterone levels were not significantly different in either population.. Gynaecomastia is not uncommon in HIV-infected men undergoing HAART and it is usually transient. Efavirenz and didanosine treatment are associated with the emergence of gynaecomastia. An underlying hypoandrogenism seems to contribute to the emergence of this disorder in these patients. Topics: Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; Didanosine; Gynecomastia; HIV Infections; Humans; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; Testosterone; Triglycerides | 2004 |
Upregulatory mechanisms compensate for mitochondrial DNA depletion in asymptomatic individuals receiving stavudine plus didanosine.
Nucleoside analogue use is often related to mitochondrial DNA (mtDNA) depletion, but mitochondrial function is preserved in most asymptomatic patients. We determined whether homeostatic mechanisms are able to compensate for this mtDNA depletion in patients receiving stavudine plus didanosine (d4T + ddI), an antiretroviral combination with great in vitro and in vivo capacity to decrease mtDNA. We included 28 asymptomatic HIV-infected individuals: 17 subjects (cases) on a first-line antiretroviral regimen consisting of d4T + ddI as the nucleoside backbone plus nevirapine or nelfinavir for at least 6 months (mean: 16 +/- 8 months) and 11 naive subjects (controls). We assessed the following in peripheral blood mononuclear cells: mitochondrial mass by citrate synthase activity, mtDNA content by real-time polymerase chain reaction, cytochrome c oxidase subunit II (COX-II) expression by Western blot analysis, and COX activity by spectrophotometry. The mitochondrial mass and mtDNA content of cases decreased when compared with controls, whether normalized per cell or per mitochondrion. Conversely, COX-II expression and COX activity were similar in cases and controls. COX-II expression was constant and independent of the mtDNA content, whereas it was closely related to COX activity. We concluded that treatment with dd4T + ddI is associated with decreased mitochondrial mass and mtDNA content but that COX-II expression and COX activity remain unaltered. These data suggest that upregulatory transcriptional or posttranscriptional mechanisms compensate for mtDNA depletion caused by d4T + ddI before profound mtDNA depletion occurs. Topics: Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Electron Transport Complex IV; Female; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Transcription, Genetic; Up-Regulation | 2004 |
Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307.
We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Hydroxyurea; Male; Nucleic Acid Synthesis Inhibitors; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load | 2004 |
Mitochondrial effects of a 24-week course of pegylated-interferon plus ribavirin in asymptomatic HCV/HIV co-infected patients on long-term treatment with didanosine, stavudine or both.
It has been suggested that the addition of ribavirin (RBV) as a part of the treatment for chronic hepatitis C virus (HCV) in HIV co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function.. Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HCV/HIV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their current antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus pegylated interferon (PEG-IFN) alpha-2b therapy (HCV-treated group).. We assessed peripheral blood mononuclear cells mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy.. Times on ddI or d4T exposure were 194 +/- 54.9 and 131 +/- 66.5 weeks in the HCV-treated and control groups, respectively. There were no differences either in mtDNA content, the enzyme activity of MRC complexes or clinical parameters at baseline. Throughout the study, mitochondrial measurements remained stable within groups and without differences when we compared HCV-treated and control groups.. In our study, the addition of RBV and PEG-IFN during a 24-week period in HCV/HIV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop. Topics: Adult; Anti-HIV Agents; Antiviral Agents; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Female; Hepatitis C, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Mitochondria; Polyethylene Glycols; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin; Stavudine; Time Factors | 2004 |
Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects.
Three dose levels of the protease inhibitor (PI) atazanavir (200, 400, and 500 mg once daily) were compared with nelfinavir (750 mg three times daily) when given both as monotherapy and in combination with didanosine and stavudine in 420 antiretroviral-naive subjects infected with HIV-1. Subjects received monotherapy for 2 weeks, followed by combination therapy for 46 weeks. After 48 weeks, mean change from baseline in HIV RNA (-2.57 to -2.33 log 10 copies/mL), the proportion of subjects with HIV RNA <400 copies/mL (56%-64%) and <50 copies/mL (28%-42%), and mean increases in CD4 cell count (185-221 cells/mm 3) were comparable across treatment groups. Diarrhea was two to three times more common in the nelfinavir group (61% of subjects) than in the atazanavir groups (23%-30% of subjects, <.0001 versus nelfinavir), and jaundice occurred only in atazanavir-treated subjects (6%, 6%, and 12% in the 200-, 400-, and 500-mg groups, respectively) ( <.03 for all atazanavir regimens vs. nelfinavir). Mean percent change from baseline in fasting low-density lipoprotein (LDL) cholesterol was significantly less in the atazanavir groups (-7% to 4%) than in the nelfinavir group (31%) ( <.0001). In conclusion, once-daily atazanavir is a potent, safe, and well tolerated PI that rapidly and durably suppresses HIV RNA and durably increases CD4 cell count in antiretroviral-naive subjects. Through 48 weeks, atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, or fasting triglycerides. In comparison, nelfinavir was associated with prompt, marked, and sustained elevations in these parameters of a magnitude that suggests they are clinically relevant. Topics: Adult; Atazanavir Sulfate; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lipids; Nelfinavir; Oligopeptides; Pyridines; RNA, Viral; Stavudine; Time Factors; Viral Load | 2003 |
Pharmacokinetics of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1.
In children younger than 2 years of age vertically infected with HIV-1, the recommended pediatric dosing regimen for nelfinavir (20 to 30 mg/kg three times a day) provides insufficient drug exposure. This study was conducted to determine the steady state pharmacokinetics of nelfinavir and its active metabolite, M8, in this population.. Fourteen infants (2.3 to 8.5 months) underwent 18 intensive pharmacokinetic studies of nelfinavir and M8 at steady state. Nelfinavir and M8 concentrations were measured by high performance liquid chromatography coupled with mass spectrometry, and individual pharmacokinetic values were determined.. A mean nelfinavir daily dose of 135.7 +/- 18.8 mg/kg (twice or three times a day) resulted in median C(min), C(max), area under the plasma concentration-time curve (AUC(0-24 h)) and CL/ for nelfinavir of 0.627 mg/l, 2.39 mg/l, 30.6 mg*h/l and 4.2 liters/h/kg, respectively. When normalized for a daily dose of nelfinavir of 150 mg/kg/day, 16.7% of C(max) and 27.8% of AUC(0-24 h) values were below the tenth percentile for adult values.. During the first year of life, nelfinavir requirement is much higher than in older children and adults to obtain similar drug exposure. The mechanisms underlying such differences may involve higher first past metabolism and/or drug interactions or might be related to feeding conditions. Topics: Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Male; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine | 2003 |
Predictive factors and selection of thymidine analogue mutations by nucleoside reverse transcriptase inhibitors according to initial regimen received.
Thymidine analogue mutations were determined and compared in patients who received zidovudine monotherapy and added didanosine or zalcitabine, and in patients who started with one of these dual nucleoside combinations. Although patients who started in the era of zidovudine monotherapy had a longer duration of therapy compared with the other group, there was no statistical difference in the number of mutations between the two groups. However, thymidine analogue mutations were more frequent in patients who added didanosine to zidovudine monotherapy compared with those who added zalcitabine. Patients who started with a dual nucleoside combination developed 215Y/F first, followed by 215Y/F+41L, then 215Y/F+41L+210W, then 215Y/F+67N+70R+41L or 219Q/E, and then 215Y/F+41L+67N+70R+219Q/E. Patients who started with zidovudine monotherapy had a different pathway with the mutation at codon 70 appearing first, followed by 215Y/F+70R or 210W, then 215Y/F+41L+210W, then 215Y/F+67N+70R+219Q/E, and then 215Y/F+41L+67N+70R+210W. Medication adherence was associated with the number of mutations in both groups of patients. Two distinct mutational patterns were noted. The first pattern involved mutations at codons 41, 210 and 215, while the second involved mutations at codons 67, 70 and 219. Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Predictive Value of Tests; Reverse Transcriptase Inhibitors; Selection, Genetic; Thymidine; Zalcitabine; Zidovudine | 2003 |
K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine.
Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Denmark; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Genome, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutation; Phenotype; Reverse Transcriptase Inhibitors; Salvage Therapy; Stavudine; Time Factors; Treatment Failure | 2003 |
Hydroxyurea in combination with didanosine and stavudine in antiretroviral-experienced HIV-infected subjects with a review of the literature.
The safety and efficacy of hydroxyurea with didanosine in combination with stavudine in nucleoside reverse-transcriptase inhibitor (NRTI)-experienced patients was investigated. Entry criteria included HIV-1 infected, NRTI-experienced adults, with CD4(+) counts 50-550 cells/mm(3) and viral loads >or=12,500 copies/mL. Subjects were treated with didanosine 200 mg twice a day (BID), stavudine 40 mg BID, and hydroxyurea 1000 mg daily for 16 weeks. Thirty-one HIV-1 subjects with mean bDNA viral load 1x10(5) log(10) copies/mL and mean CD4(+) T-cell counts of 231 cells/mm(3) were enrolled. A 1.3 log(10) decrease in mean viral load was seen at 12 weeks of therapy. Prior didanosine use resulted in a more rapid response to therapy compared with prior zidovudine use. Side effects consisting of neutropenia, pancreatitis, and peripheral neuropathy occurred in four subjects and resolved upon withdrawal of therapy. This non-randomized study in subjects with a mean CD4(+) T-cell count of 230 cells/mm(3) demonstrates the antiviral activity of hydroxyurea+didanosine and stavudine. Toxicities related to therapy need to be followed closely. The results support the need for a randomized, prospective study to determine the safety and efficacy of hydroxyurea plus didanosine in antiretroviral-experienced patients with CD4(+) cell counts below 300 cells/mm(3). Topics: Adult; Anti-HIV Agents; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Hydroxyurea; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Viral Load; Zidovudine | 2003 |
Feeding risk cut for HIV-infected women.
Topics: Anti-HIV Agents; Breast Feeding; Didanosine; Female; HIV Infections; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Risk Factors; Rwanda; Uganda; Zidovudine | 2003 |
Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients.
Virologic outcome among 104 lamivudine (3TC)-experienced individuals infected with human immunodeficiency virus type 1 who switched to a didanosine (ddI)-containing triple- or quadruple-drug regimen was compared with those who continued receiving a 3TC-containing regimen. A significantly increased independent risk of virologic failure was associated with continuing a 3TC-containing regimen. In addition, most patients for whom the ddI-containing regimen failed lost the M184V/I mutation. These results show that ddI continues to provide activity against viruses with the M184V/I mutation and suggest that the presence of the M184V/I mutation should not preclude the use of ddI in nucleoside-experienced patients. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Proportional Hazards Models; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load | 2003 |
Nucleoside analogue mutations and Q151M in HIV-1 subtype A/E infection treated with nucleoside reverse transcriptase inhibitors.
To investigate genotypic drug resistance in HIV-1 subtype A/E infection associated with failure of double/triple-nucleoside reverse transcriptase (RT) inhibitor therapy.. Patients from HIV-NAT 002 [stavudine (d4T)/didanosine (ddI) dose reduction study] and HIV-NAT 003 (zidovudine (ZDV)/lamivudine (3TC) versus ZDV/3TC/ddI) whose HIV-1 RNA was > 1000 copies/ml at week 48 and/or week 96 were tested for genotypic resistance. In both studies, after 48 weeks, patients were switched to the other dual or triple-nucleoside RT inhibitor (NRTI) either according to randomization or to the occurrence of virological failure.. Resistance mutations found in the d4T/ddI, ZDV/3TC, and ZDV/3TC/ddI groups: none at baseline; at week 48, nucleoside analogue mutations (NAM), 2/17 (12%), 2/10 (20%), and 1/8; Q151M complex, 3/17 (18%), 0%, and 0%; M184V, 0%, 10/10 (P < 0.001), 3/8; V75T, 3/17 (18%), 0%, and 0%; L74V, 3/7 (18%), 0%, and 0%, respectively. At week 96, among the switchers, i.e., group A d4T/ddI to ZDV/3TC, group B ZDV/3TC to d4T/ddI, and group C ZDV/3TC/ddI to d4T/3TC/abacavir: NAM, 12/21 (57%), 4/7 and 1/3; Q151M, 4/21 (19%), 0% and 1/3, respectively. Interestingly, four or more NAM were observed in a higher proportion in group A (4/17 versus none in the others).. Multi-NRTI resistance (NAM and Q151M) and M184V (only in 3TC failure) are commonly found in HIV-1 subtype A/E infection associated with NRTI failure. Suboptimal d4T/ddI therapy led to a high incidence of V75T and L74V mutations. Switching from d4T/ddI to ZDV/3TC may be associated with a higher incidence of four or more NAM. Thus, suboptimal and dual NRTI therapy is not recommended for global application. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Multiple; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 2003 |
Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine.
Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear.. Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks.. At baseline, the median CD4 cell count was 161 x 106 cells/l (range, 0-920) and the HIV RNA was 5.0 log10 copies/ml (range, 2.7-6.7). At 48 weeks, 43% in the A/S/D arm had a HIV RNA < or = 20 copies/ml, compared with 69% in the N/N arm (P < 0.01) and 62% in the R/S arm (P < 0.05). In a multivariate analysis, the A/S/D arm had an odds ratio of obtaining a viral load of < or = 20 copies/ml at week 48 of 0.25 [95% confidence interval (CI) 0.10-0.59] versus N/N and 0.53 (95% CI, 0.33-0.83) versus R/S. The A/S/D arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms 8%.. The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended. Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Male; Middle Aged; Nelfinavir; Nervous System Diseases; Nevirapine; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Treatment Outcome | 2003 |
Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial.
Scheduled treatment interruptions are being evaluated in an effort to decrease costs and side effects of highly active antiretroviral therapy (HAART). A schedule of 1 week on and 1 week off therapy offers the promise of 50% less drug exposure with continuously undetectable HIV RNA concentration.. In the Staccato study 600 patients on successful HAART were to be randomized to either continued therapy, CD4-guided therapy, or one week on, one week off therapy. A scheduled preliminary analysis evaluated effectiveness in the 1-week-on-1-week-off arm.. Of 36 evaluable patients, 19 (53%) had two successive HIV RNA concentrations > 500 copies/ml at the end of the week off therapy, and were classified as virological failure. Most of those who failed took didanosine, stavudine, saquinavir, and ritonavir (11 patients). In these patients, there was no evidence of mutations suggestive of drug resistance, and plasma saquinavir levels were within the expected range. Two of three patients failing on triple nucleotides had drug resistance mutations, but nonetheless responded to reintroduction of triple nucleotide therapy. One of two patients taking nevirapine, and one of eight taking efavirenz, also failed. Both had resistance mutations at the time of failure, but not at baseline.. The 1-week-on-1-week-off schedule, as tested in the Staccato study, showed an unacceptably high failure rate and was therefore terminated. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Administration Schedule; Drug Resistance, Viral; Genes, Viral; Genotype; HIV Infections; Humans; Mutation; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Treatment Failure | 2003 |
Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection.
The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies.. This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen.. A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression.. The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study. Topics: Adult; Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Oxazines; RNA, Viral; Stavudine; Time Factors; Treatment Failure; Zidovudine | 2003 |
Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection.
It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens.. In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir.. A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21).. There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice. Topics: Adult; Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Nelfinavir; Oxazines; Stavudine; Time Factors; Treatment Failure; Zidovudine | 2003 |
L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine.
Apoptosis is critical to the progression of human immunodeficiency virus-1 (HIV-1) infection. It appears reasonable that antiretroviral therapies may not achieve a full control of the infection in the absence of an impact on apoptosis. We assigned 20 asymptomatic HIV-infected subjects with advanced immunodeficiency to receive either zidovudine (AZT), and didanosine (DDI) or the same regimen plus L-carnitine, a known antiapoptotic drug, for 7 months. Immunologic and virologic parameters were measured at baseline and after 15, 60, 120, and 210 days of treatment. We assessed on each time point the following: (a) the frequency of peripheral blood apoptotic CD4 and CD8 lymphocytes, CD4 and CD8 cells with disrupted mitochondrial membrane potential, and CD4 and CD8 cells undergoing oxidant stress; (b) the expression of the molecular markers of apoptosis Fas and caspase-1; and (c) the expression of p35/cdk-5 regulatory subunit that is involved in regulating cell survival and apoptosis. Absolute CD4 and CD8 counts and plasma viremia were also measured. Apoptotic CD4 and CD8 cells, lymphocytes with disrupted mitochondrial membrane potential, and lymphocytes undergoing oxidant stress were greatly reduced in subjects treated with AZT and DDI plus L-carnitine compared with those who did not receive L-carnitine. Fas and caspase-1 were down-expressed and p35 over-expressed in lymphocytes from patients of the L-carnitine group. No difference was found in CD4 and CD8 counts and viremia between the groups. No toxicity of L-carnitine was recognized. The addition of L-carnitine is safe and allows apoptosis and oxidant stress to be greatly reduced in lymphocytes from subjects treated with AZT and DDI. Topics: Anti-HIV Agents; Apoptosis; Carnitine; Didanosine; Drug Therapy, Combination; fas Receptor; Flow Cytometry; HIV Infections; HIV-1; Humans; Hydrogen Peroxide; Male; Membrane Potentials; Mitochondria; Oxidants; Oxidative Stress; Phenotype; Reverse Transcriptase Inhibitors; Superoxides; T-Lymphocytes; Zidovudine | 2002 |
Once-daily quadruple-drug therapy with adefovir dipivoxil, Lamivudine, Didanosine, and efavirenz in treatment-naive human immunodeficiency virus type 1-infected patients.
A 48-week open-label study of 11 antiretroviral-naive, human immunodeficiency virus type 1 (HIV-1)-infected adults evaluated once-daily treatment with adefovir dipivoxil, lamivudine, didanosine, and efavirenz. At baseline, the median plasma HIV-1 RNA level was 4.99 log(10) copies/mL, and the median CD4 cell count was 471 cells/mm(3). At 24 and 48 weeks after initiation of treatment, median HIV-1 RNA levels decreased from baseline by 4.77 and 4.99 log(10) copies/mL, respectively, and median CD4 cell counts increased by 135 and 177 cells/mm(3), respectively. The regimen was generally well tolerated. No patients withdrew from the study because of adverse events. However, 7 patients developed adefovir-related nephrotoxicity after >/=20 weeks of treatment; this resolved without sequelae after adefovir was discontinued. Overall adherence was 85%. Once-daily quadruple-drug therapy with adefovir, lamivudine, didanosine, and efavirenz provides pronounced and durable suppression of HIV-1 RNA and elevation of CD4 cell counts over the course of 48 weeks, with generally good tolerability and adherence. Topics: Adenine; Adult; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Kidney Diseases; Lamivudine; Male; Organophosphonates; Oxazines; Pulse Therapy, Drug; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome | 2002 |
Antiviral activity of enteric-coated didanosine, stavudine, and nelfinavir versus zidovudine plus lamivudine and nelfinavir.
To assess and compare the activity and safety of capsules containing enteric-coated beadlets of didanosine given once daily with stavudine and nelfinavir with that of a standard reference triple drug regimen of zidovudine plus lamivudine and nelfinavir.. Multinational, 49-site, prospective, open-label, randomized, two-arm comparison study.. HIV-infected subjects with limited or no previous antiretroviral therapy who had plasma HIV RNA levels of >or=2000 copies/mL and CD4 cell counts of >or=200/mm3 (511 were randomized to treatment groups, and 352 completed the study).. Triple antiretroviral therapy for 48 weeks: didanosine EC (400 mg once daily), stavudine (40 mg twice daily), and nelfinavir (750 mg three times daily) or a twice-daily coformulation of zidovudine (300 mg) plus lamivudine (150 mg) and nelfinavir (750 mg three times daily).. Proportion of subjects with HIV RNA levels of <400 copies/mL at week 48 based on an "intent-to-treat, missing = treatment failure" analysis.. The two treatment groups were similar in the proportion of treatment responders (i.e., HIV RNA level of <400 copies/mL), with 54% of subjects in the didanosine EC and zidovudine plus lamivudine treatment groups responding at week 48. Results of other analyses supported those of the primary analysis. The two study regimens were associated with similar numbers of adverse events.. The antiviral efficacy of a triple combination regimen containing once-daily didanosine EC is similar to that of a reference triple combination regimen. Topics: Adolescent; Adult; Anti-HIV Agents; Child; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nelfinavir; Stavudine; Tablets, Enteric-Coated | 2002 |
Evidence of immune reconstitution in antiretroviral drug-experienced patients with advanced HIV disease.
Highly active antiretroviral therapy (HAART) of HIV disease is associated with effective virologic control, immune reconstitution, and clinical improvements. This study addresses the potential for improvements in lymphocyte phenotype and virologic responses of HIV-infected persons with extensive experience with dual nucleoside reverse transcriptase (NRTI) treatment and advanced HIV disease after a change to a potent antiretroviral therapy (NRTI + protease inhibitor). The majority of participants achieved virologic success. There was a median rise in CD4+ lymphocytes of 99 cells/mm(3) by 48 weeks, because of an increase in memory CD4+ cells at 4 and 16 weeks, followed by a later increase in naive CD4+ cells between weeks 16 and 48. The proportion of activated, DR+ CD38+ CD8+ lymphocytes decreased during the 48 weeks of follow-up. The immunologic findings (increased memory and naive T cells and reduced activation levels) were significantly improved in participants with persistent suppression of viral replication over the 48 weeks of the study. Baseline HIV RNA copy number was lower (median, 14,784 copies/ml) in persons who responded virologically than in those not suppressing viral replication (median, 49,454 copies/ml). CD4+ cell counts above the median (125/mm(3)) at time 0 for the participants, was the only baseline immunologic marker significantly associated with viral suppression at week 48. Participants older than 40 years of age demonstrated less immunologic recovery. The results of the study show that patients with extensive experience with NRTIs respond both virologically and immunologically during the first 48 weeks of therapy with a potent antiretroviral regimen. Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cyclopropanes; Didanosine; Dideoxynucleosides; Double-Blind Method; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine | 2002 |
Higher rate of toxicity with no increased efficacy when hydroxyurea is added to a regimen of stavudine plus didanosine and nevirapine in primary HIV infection.
Twenty-four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy-five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention-to-treat (ITT) and on-treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p >.1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p <.05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Hydroxyurea; Male; Middle Aged; Nevirapine; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Viremia | 2002 |
Dose-escalating study of the safety and pharmacokinetics of nelfinavir in HIV-exposed neonates.
The pharmacokinetics of nelfinavir (NFV) in neonates younger than 4 weeks of age was assessed. Three cohorts of HIV-exposed neonates were enrolled in cohorts to receive 15, 30, and 45 mg of NFV/kg twice daily in combination with stavudine and didanosine for 4 weeks after birth. Trough NFV concentrations (C(min)) were measured at 1 and 7 days of age. Intensive pharmacokinetic evaluations were performed at 14 and 28 days of age. The median NFV C(min) values in the 15 mg/kg (6 patients), 30 mg/kg (5), and 45 mg/kg (11) cohorts at 1, 7, 14, and 28 days of age were 0.19, 1.21, 0.51, and 0.33; 1.02, 3.18, 0.73, and 0.55; and 0.67, 3.21, 0.70, and 0.73 mg/L, respectively. The median area under the plasma concentration-versus-time curve values over 12 hours in the three cohorts at 14 and 28 days of age were 14.4 and 8.7, 19.4 and 15.8, and 23.4 and 18.5 (h. mg)/L, respectively. No serious adverse events were observed. In conclusion, the systemic exposure of NFV decreased after 7 days of age, possibly because of hepatic enzyme maturation, autoinduction of NFV metabolism, and/or changes in NFV absorption. The highly variable systemic exposure observed in the study indicates that therapeutic drug monitoring seems warranted to ensure adequate NFV dosing in this population. Topics: Adult; Anti-HIV Agents; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Infant, Newborn; Nelfinavir; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome | 2002 |
Bioequivalence of two formulations of didanosine, encapsulated enteric-coated beads and buffered tablet, in healthy volunteers and HIV-infected subjects.
Didanosine is an acid labile drug and hence has been given with buffering agents. To avoid the need for concurrent administration with antacids, an encapsulated enteric-coated bead formulation of didanosine was developed. The objective of this study was to assess the bioequivalence of the encapsulated enteric-coated beads compared to the buffered tablet. Two separate open-label, randomized, two-way crossover studies were conducted, one in healthy subjects and the other in HIV-infected subjects (with CD4 cell counts > 200 cells/mm3). All subjects received a 400-mg dose of the buffered tablet (reference formulation) and the encapsulated enteric-coated beads (test formulation). Blood samples were collected over 12 hours, and plasma levels of didanosine were determined using a validated assay. The 90% confidence interval (CI) of the ratio of the geometric means of log-transformed Cmax and AUCinfinity values were used to assess bioequivalence between the two formulations using the equivalence interval of 0.80 and 1.25. In healthy volunteers (n = 46), the point estimate and 90% CI of the ratios of Cmax and AUCinfinity values were 0.58 (0.52, 0.64) and 1.02 (0.95, 1.01), respectively. In HIV-infected subjects (n = 30), the point estimate and 90% CI of the ratios of Cmax and AUCinfinity values were 0.64 (0.56, 0.72) and 0.95 (0.86, 1.06), respectively. Median t(max) value increased significantly from 0.67 hours for the buffered tablet in both studies to 2.33 hours (in healthy subjects) or 2.0 hours (in HIV-infected subjects) for the enteric-coated beads. The mean half-life of didanosine was similar between treatments and ranged between 1.60 and 1.70 hours across healthy and HIV-infected subjects. It was concluded that the encapsulated enteric-coated bead formulation of didanosine is equivalent to the buffered tablet in the extent of exposure but differs in the rate of absorption. The pharmacokinetic profile of the enteric formulation appears to be similar in healthy and HIV-infected subjects. Topics: Administration, Oral; Adolescent; Adult; Anti-HIV Agents; Area Under Curve; Capsules; Cross-Over Studies; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Tablets, Enteric-Coated; Therapeutic Equivalency | 2002 |
If taken 1 hour before indinavir (IDV), didanosine does not affect IDV exposure, despite persistent buffering effects.
Concurrent administration of indinavir and didanosine significantly reduces the level of exposure to indinavir, but it is unclear how soon after didanosine administration indinavir may be given safely. We compared indinavir pharmacokinetics and gastric pH in 12 human immunodeficiency virus-positive patients by use of 800 mg of indinavir alone versus 800 mg of indinavir administered 1 h after didanosine administration. Median gastric pH was significantly higher when indinavir was taken after didanosine administration; however, no significant difference in the maximum concentration in plasma or the area under the concentration-time curve from time zero to 8 h was observed. Indinavir may be taken with a light meal 1 h following the administration of 400 mg of didanosine. Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Area Under Curve; Didanosine; Drug Interactions; Gastric Acid; HIV Infections; HIV-1; Humans; Indinavir; Middle Aged | 2001 |
Virologic and CD4 cell response to zidovudine or zidovudine and lamivudine following didanosine treatment of human immunodeficiency virus infection.
To optimize nucleoside reverse transcriptase inhibitor (nRTI) antiretroviral therapy, 137 subjects who had been treated with didanosine monotherapy for more than 3 years in the AIDS Clinical Trials Group (ACTG) 175 study were randomized to zidovudine and didanosine (dual therapy) or zidovudine, didanosine, and lamivudine (triple therapy). Evaluation of early (8 week) change in HIV plasma RNA demonstrated that addition of lamivudine and zidovudine provided significantly greater virologic suppression compared to the addition of zidovudine alone (mean decrease of 1.27 vs. 0.74 log(10) copies/ml, n = 108, p = 0.007). Both dual and triple therapy provided significant long-term decreases (from study entry to mean at Weeks 40 and 48) in HIV plasma RNA: 0.62 and 0.86 log(10) copies/ml, respectively (n = 110). However, the difference between treatments was not significant (p = 0.16). At 48 weeks, 26% of subjects starting study treatment had <500 copies/ml of plasma HIV RNA. The CD4 count response was greater at 4 weeks for triple versus dual therapy: a mean increase of 51 vs. 12 CD4 cells/ml(3) (n = 126, p = 0.039). The difference at Weeks 40 and 48 was not significant (a 22 cell increase vs. a 1 cell decrease, n = 129, p = 0.41). Zidovudine and didanosine treatment, with or without lamivudine, was well tolerated and only 2 of 137 (1.5%) of study participants developed an AIDS-defining event over 48 weeks. Topics: Adult; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zidovudine | 2001 |
Lack of an effect of azithromycin on the disposition of zidovudine and dideoxyinosine in HIV-infected patients.
Two studies were conducted in HIV-infected subjects to assess the potential for azithromycin to interact with zidovudine and dideoxyinosine. Both studies used 12 subjects. The zidovudine study dosed subjects with 1200 mg/day of azithromycin (n = 7) (later changed to 600 mg/day [n = 5]) for Days 8 to 21 of a 21-day course of 100 mg, five times/day of zidovudine. Subjects treated with 200 mg of dideoxyinosine twice daily for 21 days received 1200 mg of azithromycin or an equivalent amount of placebo/day for Days 8 to 21. Antiretroviral plasma and urine sampling were conducted on Days 1, 7, and 21 for zidovudine and on Days 7 and 21 for dideoxyinosine. Peripheral mononuclear cells were also collected for quantitation of phosphorylated zidovudine. Azithromycin had no significant impact on the Cmax and AUC of zidovudine, although it significantly decreased the zidovudine tmax by 44% and increased the intracellular exposure to phosphorylated zidovudine by 110%. Azithromycin had no significant effect on dideoxyinosine pharmacokinetics. Based on the results of these studies, it is concluded that azithromycin may be safely coadministered with both zidovudine and dideoxyinosine. Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Anti-HIV Agents; Azithromycin; Didanosine; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Zidovudine | 2001 |
Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection.
Since psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS and death independently of the immune status, there is urgent need for a neurological therapeutic rationale.. The therapeutic efficacy of nucleoside analogues with different abilities to penetrate into the cerebrospinal fluid was assessed in 410 HIV-1-seropositive patients using the results of detailed fine motor tests, which detect minor motor deficits. Patients were selected who showed pathological psychomotor slowing as signs of central nervous system (CNS) dysfunction before therapy onset and who were then treated only with nucleoside analogues for at least 6 months.. Both zidovudine and didanosine improve CNS function to an equal degree when given as monotherapy. Adding a second nucleoside analogue (didanosine, lamivudine, zalcitabine) to zidovudine does not further improve psychomotor performance. However, adding a second nucleoside after a period of zidovudine monotherapy does result in a second but less remarkable therapeutic effect. Combinations containing stavudine are as effective as those including zidovudine when given as first antiretroviral treatment. Furthermore, stavudine effectively improves motor performance even after pretreatment with zidovudine. Topics: Adult; Anti-HIV Agents; Central Nervous System Diseases; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Seropositivity; HIV-1; Humans; Lamivudine; Male; Middle Aged; Motor Skills; Stavudine; Zalcitabine; Zidovudine | 2001 |
An open-label randomized trial to evaluate different therapeutic strategies of combination therapy in HIV-1 infection: design, rationale, and methods of the initio trial.
This article discusses the design of an ongoing open-label, randomized trial comparing three strategies of initial and subsequent HIV therapy in terms of long-term immunological and virological effect. The three treatment arms are (1) didanosine (ddI) plus stavudine (d4T) plus efavirenz (EFV) followed by zidovudine (ZDV) plus lamivudine (3TC) plus abacavir (ABC) plus nelfinavir (NFV); (2) ddI plus d4T plus NFV followed by ZDV plus 3TC plus ABC plus EFV; (3) ddI plus d4T plus EFV plus NFV followed by ZDV plus 3TC plus ABC plus saquinavir plus ritonavir. The primary objective is to determine whether it is best to start with a protease inhibitor (PI)-containing regimen, a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI)-containing regimen, or with a regimen containing both a PI and an NNRTI. The aim is to recruit over 1000 patients followed for at least 3 years. The entry criteria are broad with no restriction on stage of disease, CD4 count, or HIV viral load. The criteria for therapeutic failure determining change of treatment are not defined and are left to the clinicians, but randomization is stratified by country and by the current criteria used for changing treatment. We describe the rationale behind various aspects of the design and discuss the complexities involved in undertaking such a large trial in HIV-infected patients from 180 clinical sites in 17 countries. Control Clin Trials 2001;22:160-175 Topics: Adult; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Patient Selection; Randomized Controlled Trials as Topic; Research Design; Ritonavir; Sample Size; Saquinavir; Stavudine; Zidovudine | 2001 |
A randomized, open-label, comparative trial of zidovudine plus lamivudine versus zidovudine plus lamivudine plus didanosine in antiretroviral-naive HIV-1-infected Thai patients.
To assess the efficacy and tolerability of a triple nucleoside reverse transcriptase inhibitor combination of zidovudine, lamivudine, and didanosine therapy.. A randomized open-label trial.. Antiretroviral-naive HIV-infected patients with CD4+ cell counts of 100 to 500 cells/microl.. A total of 106 patients were randomly assigned to 300 mg of zidovudine (200 mg for body weight <60 kg) twice daily plus 150 mg of lamivudine twice daily plus 200 mg of didanosine (125 mg for body weight <60 kg) twice daily (n = 53) or to zidovudine plus lamivudine (n = 53) for 48 weeks.. Degree and duration of reduction of HIV-1 RNA load and increase in CD4+ cell counts from baseline and development of drug-related toxicities.. At 48 weeks, triple drug therapy showed greater declines in plasma HIV-RNA levels from the beginning of treatment than double drug therapy (1.86 vs. 1.15 log10 copies/ml, respectively; p <.001). The proportions of patients with HIV-RNA <50 copies/ml in an intention-to-treat analysis were 54.7% (29 of 53 patients) and 11.3% (6 of 53 patients) in the triple and double drug therapy, respectively (p =.001). There was no significant difference in increase of CD4 count.. Triple drug therapy with zidovudine, lamivudine, and didanosine was significantly more effective in inducing sustained immunologic and virologic responses than the double combination of zidovudine and lamivudine. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Thailand; Treatment Outcome; Zidovudine | 2001 |
High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals.
To explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial.. The elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine, zidovudine and didanosine in 51 antiretroviral-naive HIV-1-infected patients. The relationships between the value of k, the time to reach an undetectable HIV-1 RNA concentration in plasma (< 20 copies/ml) and the success of therapy after 52 weeks of treatment as dependent variables and the exposure to nevirapine, baseline HIV-1 RNA and baseline CD4 cell count as independent variables, were explored using linear regression analyses, proportional hazard models and logistic analyses, respectively.. The value of k for HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P = 0.011) and the baseline HIV-1 RNA (P = 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P = 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P < 0.02).. A high exposure to nevirapine (in a twice daily regimen) is significantly associated with improved virological response in the short as well as in the long term. These findings suggest that optimization of nevirapine concentration might be used as a tool to improve virological outcome in (antiretroviral-naive) patients treated with nevirapine. Topics: Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Nevirapine; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome; Zidovudine | 2001 |
Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine.
To evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents.. All patients were enrolled in a double-blind controlled randomized trial (the INCAS study) and were selected for detailed resistance studies based on specimen availability and virologic response.. Within the three study groups (zidovudine/nevirapine, zidovudine/didanosine or zidovudine/nevirapine/didanosine), 16, 19 and 24 patients, respectively, had evaluable baseline isolates and remained in the study > 24 weeks. Phenotypic resistance to all three drugs was evaluated using the VIRCO recombinant virus assay. Genotypic sequencing was done on selected specimens from patients receiving zidovudine/nevirapine/didanosine.. After 24 weeks, all available isolates taken from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients receiving triple therapy carried such isolates at 30--60 weeks. At 24 weeks, zidovudine resistance developed in 4/40 isolates but was more frequent after 30--60 weeks, especially in patients on two drugs. The degree of zidovudine resistance (rise in concentration required for 50% inhibition) appeared lower in the triple therapy group compared with zidovudine/didanosine (P = 0.0004). All nevirapine-resistant isolates that were sequenced carried at least one mutation associated with resistance, most often K103N and/or Y181C.. The use of highly active drug therapies may be associated with a beneficial effect on the development of antiretroviral drug resistance. The characteristics of virologic suppression that must be maintained to avoid resistance are currently being studied in hypothesis-driven clinical trials. Topics: Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV Infections; HIV-1; Humans; Mutation; Nevirapine; Phenotype; Reverse Transcriptase Inhibitors; Zidovudine | 2001 |
Comparison of genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 isolates from patients treated with stavudine and didanosine or zidovudine and lamivudine.
Sequencing of reverse-transcriptase genes and recombinant virus assays were performed on paired isolates from antiretroviral drug-naive patients randomized to stavudine and didanosine (group 1; n = 21) or zidovudine and lamivudine (group 2; n = 21) at baseline and after > or = 12 months of follow-up. The T215Y mutation emerged in 13 (61.9%) and 2 (9.5%) isolates in groups 1 and 2, respectively (P < .0001). Furthermore, in group 1, mutations associated with multidideoxynucleoside resistance were selected in 3 isolates. In group 2, all isolates carried the M184V mutation. The median fold changes in susceptibilities to zidovudine, stavudine, and lamivudine were 16.4 and 1, 2.2 and 0.6, and 4.5 and > 38 in groups 1 and 2, respectively (P < .0001, all comparisons). These results suggest that the combination of stavudine and didanosine is associated more frequently with the emergence of zidovudine resistance and a decrease in susceptibility to stavudine than the combination of zidovudine and lamivudine. Topics: Adult; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Microbial Sensitivity Tests; Phenotype; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 2001 |
HIV-1 induction-maintenance at the lymph node level: the "Apollo-97" Study.
To assess the effects of five-drug combination therapy on HIV-1 load in lymph nodes and subsequent maintenance with four and three drugs.. Ten pharmacotherapeutically naive patients received a combination of zidovudine, lamivudine, didanosine, ritonavir, and saquinavir for 24 weeks, then zidovudine, lamivudine, didanosine, and saquinavir for the next 24 weeks, and finally zidovudine, lamivudine, and saquinavir for the last 24 weeks. HIV-1 RNA in lymph nodes was measured using quantitative polymerase chain reaction (PCR) at baseline, after 12, 24, 48, and 78 weeks. Plasma HIV-1 RNA, proviral DNA in peripheral blood mononuclear cells (PBMCs), circulating lymphocyte subsets, and protease inhibitor levels in blood were also regularly measured. Genotypic resistance was assessed in the different compartments in 2 patients who were failed by therapy.. HIV-1 RNA decreased in lymph nodes in 9 patients and was stable in 1 despite initial control of plasma replication <20 copies/ml in each patient. Lymph node levels rebounded in 1 patient at week 72 as a result of lack of adherence and remained stable in the 8 others despite maintenance regimens. This represents a mean drop of -3.17 log in lymph nodes for the 8 patients maintaining undetectable viremia at 72 weeks. In the patient with stable lymph node viral RNA, selection of the M184V mutation was demonstrated at this level before detection in plasma and low blood saquinavir levels were found throughout the study. Continuous improvements in immune parameters were observed in all cases, although PBMC proviral DNA levels either showed a continuous decrease or stabilized to a plateau.. More complex regimens do not perform better in lymph nodes than classic triple therapy. The persistence of HIV-1 RNA in lymph nodes could be related with cellular resistance mechanisms rather than an insufficient potency of the regimens. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biopsy; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; France; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lymph Nodes; Lymphocyte Subsets; Lymphocytes; Male; Polymerase Chain Reaction; Ritonavir; RNA, Viral; Saquinavir; Time Factors; Viral Load; Viremia; Virus Replication | 2001 |
Potential adverse effects of structured therapeutic interruptions on the pool of HIV-infected cells.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Disease Progression; HIV Infections; HIV-1; Humans; Lamivudine; Lymphocyte Count; Morbidity; Prognosis; Ritonavir; RNA, Viral; Saquinavir; Viral Load; Zidovudine | 2001 |
Pharmacokinetics of stavudine and didanosine coadministered with nelfinavir in human immunodeficiency virus-exposed neonates.
We evaluated the pharmacokinetics of stavudine (d4T) and didanosine (ddI) in neonates. Eight neonates born to human immunodeficiency virus-infected mothers were enrolled to receive 1 mg of d4T per kg of body weight twice daily and 100 mg of ddI per m(2) once daily in combination with nelfinavir for 4 weeks after birth. Pharmacokinetic evaluations were performed at 14 and 28 days of age. For d4T, on days 14 and 28, the median areas under the concentration-time curves from 0 to 12 h (AUC(0-12)s) were 1,866 and 1,603, ng x h/ml, respectively, and the median peak concentrations (C(max)s) were 463 and 507 ng/ml, respectively. For ddI, on days 14 and 28, the median AUC(0-10)s were 1,573 and 1,562 h x ng/ml, respectively, and the median C(max)s were 627 and 687 ng/ml, respectively. Systemic levels of exposure to d4T were comparable to those seen in children, suggesting that the pediatric dose of 1 mg/kg twice daily is appropriate for neonates at 2 to 4 weeks of age. Levels of exposure to ddI were modestly higher than those seen in children. Whether this observation warrants a reduction of the ddI dose in neonates is unclear. Topics: Anti-HIV Agents; Area Under Curve; Didanosine; DNA, Viral; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Infant; Infant, Newborn; Nelfinavir; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; Stavudine | 2001 |
Evidence for prolonged clinical benefit from initial combination antiretroviral therapy: Delta extended follow-up.
The findings from therapeutic trials in HIV infection with surrogate endpoints based on laboratory markers are only partially relevant for clinical decisions on treatment. Although the collection of clinical follow-up data from such a trial would be relatively straightforward, this rarely occurs. An important reason for this may be the perception that such data have little value because the number of participants remaining on their original allocated therapy has usually fallen substantially.. Delta was an international, multicentre trial in which 3207 HIV infected individuals were randomly allocated to treatment with zidovudine (ZDV) alone, ZDV combined with didanosine (ddI) or ZDV combined with zalcitabine (ddC). Although the trial closed in September 1995, information on vital status, AIDS events, treatment changes and CD4 counts was still collected every 12 months until at least March 1997. This has allowed analyses of the longer term clinical effect of treatment.. The median follow-up to date of death or last known vital status was 43 months (10th percentile 18 months; 90th percentile 55 months). The proportion of participants remaining on their allocated treatment fell steadily over time; by 4 years after trial entry, 3% remained on ZDV, 20% on ZDV + ddI and 21% on ZDV + ddC. Changes mainly involved the stopping, addition or switching of a nucleoside reverse transcriptase inhibitor (NRTIs). There was little use of protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) before the third year of the trial. Between the third and fourth years, regimens included a drug from one of these classes for approximately 17% of person-time in all treatment groups. Relative to ZDV monotherapy, the beneficial effects of combination therapy on mortality and disease progression rates increased significantly with time since randomization. The maximum effects on mortality were observed between 2 and 3 years, with a 48% reduction for ZDV + ddI and a 26% reduction for ZDV + ddC. These rates were observed when the original allocated treatment was received 42% and 47% of the time in the ZDV + ddI and ZDV + ddC groups, respectively. The mean CD4 count remained significantly higher (approximately 50 cells/microL) in the combination therapy groups 4 years after randomization, suggesting a projection of a clinical benefit beyond this time point.. The sustained clinical effect of the initial allocation to combination therapy, particularly ZDV + ddI, was remarkable in light of the convergence of drug regimens actually received across the three treatment groups. Interpretation of this finding is not straightforward. One of the possible explanations is that the effectiveness of ddI and ddC is diminished if first used later in infection or with greater prior exposure to ZDV, although the data do not clearly support either hypothesis. This analysis highlights the value of long-term clinical follow-up of therapeutic trials in HIV infection, which should be considered in the planning of all new studies. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; International Cooperation; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Survival Analysis; Treatment Outcome; Zalcitabine; Zidovudine | 2001 |
Low risk of pancreatitis in HIV-infected patients on hydroxyurea plus didanosine.
Topics: Anti-HIV Agents; Didanosine; HIV Infections; HIV-1; Humans; Hydroxyurea; Incidence; Pancreatitis; Reverse Transcriptase Inhibitors | 2001 |
A randomized study of the safety and antiretroviral activity of hydroxyurea combined with didanosine in persons infected with human immunodeficiency virus type 1. American Foundation for AIDS Research Community-Based Clinical Trials Network.
This randomized open-label trial of human immunodeficiency virus type 1-infected persons compared safety and efficacy for 38 patients receiving hydroxyurea/didanosine combination therapy with findings in 42 persons given didanosine monotherapy for 12 weeks, followed by 12 weeks of hydroxyurea/didanosine combination therapy for all patients. Week 12 on-treatment group comparisons showed a mean decrease in virus load between hydroxyurea/didanosine versus didanosine groups of -0.93 versus -0.74 log10 copies/mL (P=.20); a higher percentage of the hydroxyurea/didanosine group below the assay's detection limit (500 copies/mL), 29% versus 7% (P=.017); and median change in CD4 cells for the hydroxyurea/didanosine versus didanosine group of 0 versus 43 cells/mm3 (P=.045), although median change in CD4 percentage was similar (0.9% vs. 1.2%, P=.64). Week 24 virus load reductions and CD4 cell changes were similar in both groups. Intent-to-treat and on-treatment analyses showed similar results. The hydroxyurea/didanosine combination was well tolerated. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Hydroxyurea; Male; Nucleic Acid Synthesis Inhibitors; Reverse Transcriptase Inhibitors; Viral Load | 2000 |
Cellular proviral HIV-DNA decline and viral isolation in naïve subjects with <5000 copies/ml of HIV-RNA and >500 x 10(6)/l CD4 cells treated with highly active antiretroviral therapy.
To evaluate the decay rate of cellular proviral HIV-DNA and viral replication in patients receiving highly active antiretroviral therapy (HAART) in the very early phase of infection.. Thirty-four patients treated with HAART and retrospectively selected for progressive decline of plasma viraemia up to undetectable levels (< 20 copies/ml), were stratified according to CD4+ cell count and plasma viraemia at base line: > 500 x 10(6) cells/l with < 5000 copies/ml (group 1) or with > 5000 copies/ml (group 2), > 5000 copies/ml with 300-500 x 10(6) cells/l (group 3) or with < 300 x 10(6) cells/l (group 4). Plasma HIV-RNA and proviral HIV-DNA were analysed at baseline and after 1, 2, 3, 6, 9 and 12 months of treatment.. After 1 year of treatment, a significant decrease of proviral DNA titre was observed in all patients and a decrease > 1 log was achieved in 24 of 29 subjects of the first three groups. The more pronounced decay of HIV-DNA (half-life 28 weeks) up to < 50 HIV-DNA copies/10(6) CD4+ cells was detected in patients of group 1. At the year's endpoint, five patients (four in group 1 and one in group 2) had < 20 HIV-DNA copies. However, HIV strains sensitive to antiretroviral drugs were isolated from peripheral lymphocytes of 16 out of 34 patients.. In patients with undetectable plasma viraemia after 1 year of HAART, the highest reduction of proviral DNA up to < 50 copies/10(6) CD4+ cells was obtained only in subjects in the early asymptomatic phase of infection. Nevertheless, a replication-competent virus can be detected in all phases of antiretroviral therapy. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Proviruses; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Stavudine; Viremia | 2000 |
Pharmacologic characteristics of indinavir, didanosine, and stavudine in human immunodeficiency virus-infected children receiving combination therapy.
The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m(2) every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of > or =0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m(2); nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean +/- standard deviation) were the following: oral clearance, 1.4 +/- 0.5 liters/h/kg; half-life, 1.1 +/- 0.43 h; and trough concentration, 0. 29 +/- 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV. Topics: Anti-HIV Agents; Area Under Curve; Child; Chromatography, High Pressure Liquid; Didanosine; Drug Therapy, Combination; Half-Life; HIV Infections; Humans; Indinavir; Spectrophotometry, Ultraviolet; Stavudine; Time Factors | 2000 |
Relationship between CD4 count, viral burden, and quality of life over time in HIV-1-infected patients.
Although surrogate markers such as CD4 counts and viral burden (HIV-1 RNA) are predictive of AIDS-related disease progression, little is known about the relationship between changes in surrogate markers and health-related quality of life (HRQOL) outcomes. This study investigated how changes in CD4/mm3 and viral burden (RNA copies/mL) are related to changes in HRQOL as indexed by the Medical Outcomes Study HIV Health Survey (MOS-HIV-30).. Subjects were HIV-1-infected patients with CD4 counts <300/mm3 enrolled in a double-blind, randomized clinical trial of delavirdine. As part of the clinical protocol, patients completed the MOS-HIV-30, from which the Physical Health (PHS) and Mental Health (MHS) summary scores were used for analyses. HRQOL and surrogate marker data assessed up to 2 years after randomization were analyzed for a total of 1,112 patients.. Individual patients' initial status (intercepts) and rates of change (slopes) over time for log CD4, log RNA, PHS, and MHS were estimated with the use of empirical Bayes. Early response to treatment correlated with HRQOL better for RNA than for CD4. However, the relationship between weekly change and HRQOL was stronger for CD4 than for RNA.. Surrogate markers are significantly associated with HRQOL outcomes. Improvements in HRQOL over time are associated with lower initial viral load and with increases in CD4 counts. Limitations concerning the restricted variability of the change scores are addressed. Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Delavirdine; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; Health Status Indicators; HIV Infections; HIV-1; Humans; Male; Middle Aged; Quality of Life; RNA, Viral; Viral Load | 2000 |
Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study Team.
The effect of food on didanosine bioavailability and interpatient pharmacokinetic variability was examined in children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150 mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n = 39) and high (n = 38) dosing groups were not significantly different, but intersubject variability was substantial. The fraction absorbed was higher while fasting than with food (0.27+/-0.13 versus 0.19+/-0.09, p < 0.0001); the zero order absorption rate was faster (0.48+/-0.31 versus 0.76+/-0.72 hr, p = 0.003); and the plasma half-life was shorter (0.93+/-0.43 versus 1.39+/-0.65 hr, p < 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming rate limiting for elimination, resulting in similar areas under the concentration-time curves (normalized to 100 mg/m2) when fasted (853.9+/-465.8 microg/liter-hr) versus fed (796.3+/-367.5 microg/liter x hr). Oral clearances during fasting (152.5+/-81.7 liters/hr/m2) and fed states (163.6+/-99.3 liters/hr/m2) were similar, but these values in children are substantially higher than previously reported for adults. The systemic exposure (i.e., AUC) of didanosine was highly variable in children but similar in the presence and absence of food. Administration of didanosine with food in children may be permissible if total systemic exposure rather than maximum plasma concentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacokinetic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infected children. Topics: Administration, Oral; Adolescent; Area Under Curve; Biological Availability; Child; Child, Preschool; Didanosine; Double-Blind Method; Fasting; Female; Food; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Male; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors | 2000 |
A randomized, controlled, phase II trial comparing escalating doses of subcutaneous interleukin-2 plus antiretrovirals versus antiretrovirals alone in human immunodeficiency virus-infected patients with CD4+ cell counts >/=350/mm3.
A total of 73 patients with baseline CD4+ cell counts >/=350 cells/mm3 who were receiving combination antiretroviral therapy (ART) were randomized to receive subcutaneous interleukin-2 (IL-2; n=36) in addition to ART or to continue ART alone (n=37). Subcutaneous IL-2 was delivered at 1 of 3 doses (1.5 million international units ¿MIU, 4.5 MIU, and 7.5 MIU per dose) by twice-daily injection for 5 consecutive days every 8 weeks. After 24 weeks, the time-weighted mean change from baseline CD4+ cell count was 210 cells/mm3 for recipients of subcutaneous IL-2, compared with 29 cells/mm3 for recipients of ART alone (P<.001). There were no significant differences between treatment groups for measures of plasma human immunodeficiency virus RNA (P=.851). Subcutaneous IL-2 delivered at doses of 4.5 MIU and 7.5 MIU resulted in significant increases in CD4+ cell count (P=.006 and P<.001, respectively), compared with that seen in control patients. These changes were not significant in the 1.5 MIU dose group compared with that in the control patients (P=.105). Side effects that occurred from subcutaneous IL-2 administration were generally low grade, of short duration, and readily managed in an outpatient environment. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Didanosine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Injections, Subcutaneous; Interleukin-2; Lamivudine; Lymphocyte Count; Male; Nelfinavir; Nevirapine; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Zalcitabine; Zidovudine | 2000 |
Mutations in the reverse transcriptase gene of HIV type 1 from subjects after stavudine-didanosine dual therapy.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Genes, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Stavudine | 2000 |
Dual nucleoside regimens in nonadvanced HIV infection: prospective follow-up of 130 patients, Aquitaine Cohort, 1996 to 1998. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA).
To describe the response to combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) initiated early in the course of HIV infection under routine circumstances and to research prognostic factors indicating good virologic response.. Patients of the Aquitaine Cohort, a hospital-based open cohort that had been recruiting since 1987 in five public hospitals of the Aquitaine region in southwestern France.. Prospective cohort study of antiretroviral-naive patients with CD4+ cell counts >0.350 x 10(9)/L who started dual NRTI therapy between January 1996 and June 1997. Intent-to-treat analysis and multivariate logistic regression were used with data collected up to March 31, 1998.. In this study, 130 patients were enrolled with a median follow-up of 14 months. At the time of first prescription, 79% were in U. S. Centers for Disease Control and Prevention (CDC) group A, 16% in group B, and 5% in group C; median CD4+ cell count was 0.466 x 10(9)/L and median HIV RNA level was 4.52 log10 copies/ml. The two main combinations used were zidovudine (AZT) plus zalcitabine (ddC; 38%) and AZT plus didanosine (ddI; 37%). At week 52, median CD4+ and HIV RNA responses were, respectively, +80 cells and -1.6 log; the proportions of patients with HIV RNA level <5000 and <500 copies/ml were 70% and 45%, respectively, and 96% of the patients had a CD4+ cell count >0.350 x 10(9)/L at that time. At their last follow-up, 3 patients had reached been diagnosed with full-blown AIDS and the AIDS-free survival probability at 1 year was 98.2% (95% confidence interval [CI], 93.1-99.6); 1 death had occurred. The only significant variable associated with an undetectable HIV RNA level at 1 year was a lower HIV RNA level at the first prescription of dual therapy.. Our data indicate that dual nucleoside combinations could be a therapeutic option for patients diagnosed and observed during follow-up in the early course of HIV infection. Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Multivariate Analysis; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Zalcitabine; Zidovudine | 2000 |
Effect of two different combinations of antiretrovirals (AZT+ddI and AZT+3TC) on cytokine production and apoptosis in asymptomatic HIV infection.
Nineteen HIV-seropositive antiretroviral therapy-naive and asymptomatic individuals (200-500 CD4/microl) were enrolled in a prospective study aimed at analyzing the immunologic and virologic effects of two different combinations of nucleoside reverse transcriptase inhibitors (AZT+ddI and AZT+3TC), and randomly assigned to one of the treatment group. Immunologic (CD4 and CD8 counts, mitogen-stimulated cytokine production, unstimulated and mitogen-stimulated apoptosis) and virologic (HIV viral load) determinations were performed pre-therapy and 15, 30, 90, 200 and 360 days after initiation of therapy. Results showed that the two combinations had comparable effects on increasing CD4 counts and the CD4/CD8 ratio and in reducing HIV viral load. In contrast, AZT+3TC was more efficient in improving interleukin-2 (IL-2) and interferon gamma (IFNgamma) production as well as the type 1/type 2 cytokine ratio and in down modulating the susceptibility of peripheral blood mononuclear cells to in vitro mitogen-stimulated apoptotic cell death. These data suggest that the combination of AZT+3TC has a stronger effect on potentially beneficial immune parameters (IL-2 production; reduction of apoptosis) than the one between AZT+ddI. The combination of AZT+3TC could be more advantageous in the therapy of HIV infection even when used in association with a protease inhibitor. Topics: Anti-HIV Agents; Apoptosis; CD4 Lymphocyte Count; CD4-CD8 Ratio; Cytokines; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Leukocytes, Mononuclear; Prospective Studies; Reverse Transcriptase Inhibitors; Th1 Cells; Viremia; Zidovudine | 2000 |
A randomised, open-label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and indinavir for previously untreated HIV-1 infection: the OzCombo1 study.
Highly active antiretroviral therapy (HAART) including two nucleoside analogues and a potent protease inhibitor is standard of care initial therapy for HIV-infected adults. The best-tolerated and most potent initial HAART regimen is unknown and was investigated in this study.. One hundred and nine HIV-infected adults with no prior antiretroviral therapy, and CD4 lymphocyte counts < 500 x 10(6) cells/l or plasma HIV RNA > 30,000 copies/ml were randomized to zidovudine-lamivudine-indinavir (ZDV-3TC-IDV), stavudine-lamivudine-indinavir (d4T-3TC-IDV) or stavudine-didanosine-indinavir (d4T-ddI-IDV) for 52 weeks. The primary endpoints were plasma HIV RNA and drug-related adverse events. Other assessments were overall safety, adherence and adverse events, CD4 lymphocyte counts, cutaneous delayed type hypersensitivity (DTH) responses and quality of life (Euroqol).. Only 58% patients had HIV RNA < 50 copies/ml plasma at 12 months, with no significant difference between the three regimes (P = 0.34). Drug-related adverse events sufficiently severe to warrant drug discontinuation were less common (P = 0.06) in patients receiving d4T-3TC-IDV (18%) than in those receiving ZDV-3TC-IDV (34%) or d4T-ddI-IDV (41%). The percentages of patients who remained on their assigned therapy with plasma HIV RNA < 50 copies/ml at 52 weeks were 60% with d4T-3TC-IDV, 53% with ZDV-3TC-IDV and 35% with d4T-ddI-IDV. Virological failure at 52 weeks was more likely in those whose adherence was estimated to be < 100% in the first 4 weeks of therapy (P = 0.02), but not in those who developed grade 3 or 4 drug-related adverse events. At 52 weeks, the mean CD4 lymphocyte count increase was 200 x 10(6) cells/l with only 7% of patients having counts lower than at baseline; DTH responses improved but remained clinically impaired in most patients. Quality of life improved significantly in all groups.. Initial HAART regimens including IDV failed to suppress plasma HIV RNA to < 50 copies/ml in > 40% patients after only 12 months of therapy although there was significant overall improvement immunologically and in quality of life. The type of dual nucleoside combination used was less important in predicting virological failure than was imperfect adherence early in therapy. Consideration should be given to modifying a HAART regimen relatively early in non-adherent patients. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Australia; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Stavudine; Viral Load; Zidovudine | 2000 |
Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. German Ritonavir/Indinavir Study Group.
To evaluate the virological efficacy and safety of quadruple therapy with two nucleoside analogues and ritonavir (400 mg twice daily) plus indinavir (400 mg twice daily) combination in antiretroviral therapy-naive patients.. An open-label, uncontrolled multicentre trial. Antiretroviral therapy-naive patients (n = 90) with high median baseline HIV RNA levels of 220,000 copies/ml (range, 36,000-2,943,000 copies/ml) and median CD4 cell count of 189 x 10(6)/l (range, 4-656 x 10(6)/l) were started on a twice daily regimen of either zidovudine/lamivudine (49%), stavudine/lamivudine (38%) or stavudine/didanosine (13%) plus ritonavir 400 mg twice daily and indinavir 400 mg twice daily combination therapy. CD4 cell counts and HIV RNA were determined at weeks 0, 4, 8, 12, 16, 20, and 24. Statistical analysis was performed on treatment as well as intent-to-treat, where missing values were accounted for as failure.. In the intent-to-treat analysis at week 24, the proportion of patients with HIV RNA of < 500 copies/ml, and < 80 copies/ml was 86.7% and 71.1%, respectively. In the on-treatment analysis at week 24, 80.0% of patients had undetectable viral load in the ultrasensitive assay (< 80 copies/ml; n = 80). The quadruple therapy was well tolerated except for mild diarrhoea, initial nausea and increased triglyceride levels. Treatment was stopped in seven (7.7%) patients because of adverse events and three (3.3%) were lost to follow-up.. Our preliminary data suggest that the protease inhibitor combination ritonavir/indinavir plus double nucleoside therapy appears to be effective and safe in short-term treatment (up to 24 weeks). Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Black People; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Female; Germany; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Stavudine; Time Factors; White People | 2000 |
The CCR5Delta32 allele slows disease progression of human immunodeficiency virus-1-infected children receiving antiretroviral treatment.
The role of the CCR5Delta32 allele in human immunodeficiency virus (HIV)-1-related disease progression was analyzed for 457 antiretroviral-naïve children who had participated in the Pediatric AIDS Clinical Trials Group 152 study, which demonstrated that didanosine (ddI) or zidovudine + ddI treatments were superior to zidovudine alone. The CCR5Delta32 allele was detected at an overall frequency of 6.1% (28/457). At study entry, heterozygote children (wild type [wt]/Delta32) had higher baseline median CD4(+) counts/mm(3) than wt/wt children had (1035 vs. 835 cells/mm(3); P=. 043), higher mean weight-for-age Z scores (-0.15 vs. -0.84; P=.01), and a trend toward less cortical atrophy (P=.059). During antiretroviral treatment and study follow-up, there was a trend toward less disease progression and death among heterozygote children than among wt/wt children (P=.056; relative hazard, 0.28; 95% confidence interval, 0.07-1.13) independent of the antiretroviral treatment to which they were randomized. Topics: Alleles; Anti-HIV Agents; Child, Preschool; Clinical Trials as Topic; Didanosine; Disease Progression; Disease-Free Survival; Ethnicity; Gene Frequency; HIV Infections; HIV-1; Humans; Racial Groups; Receptors, CCR5; Sequence Deletion; Zidovudine | 2000 |
Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients.
The safety and efficacy of a once-daily regimen that combines emtricitabine, didanosine, and efavirenz was studied among 40 previously untreated human immunodeficiency virus (HIV)-infected patients. The median plasma HIV RNA level was 4.77 log(10) copies/mL at baseline and decreased by a median of 3.5 log(10) copies/mL at 24 weeks, with 98% and 93% of patients achieving plasma HIV RNA levels <400 and <50 copies/mL, respectively. The median CD4 cell count was 373 cells/microL at baseline and increased by a median of 159 cells/microL at week 24. The most common treatment-related adverse events were mild to moderate central nervous system symptoms (73% of patients), diarrhea (33%), rashes (10%), and biochemical abnormalities. Adverse reactions led to permanent drug discontinuation in only 1 patient. The once-daily combination therapy of emtricitabine, didanosine, and efavirenz was safe and demonstrated strong antiviral and immunologic effects that lasted for the 24-week period of the study. Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Didanosine; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Male; Oxazines; Pilot Projects; RNA, Viral | 2000 |
A randomized, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naive, HIV-infected Thai patients.
To evaluate the safety and efficacy of four different regimens of didanosine (ddI) + stavudine (d4T) in HIV-infected Thais.. Prospective, open-label, randomized study.. Patients were randomized to four regimens of high and low doses of ddI and d4T or to ddI alone. D4T was added to the ddI-alone arm after week 24. The duration of study was 48 weeks.. Seventy-eight patients were randomized (mean CD4 cell count, 255 x 10(6)/l; mean plasma HIV-1 RNA; 4.3 log10 copies/ml). In the intent-to-treat analysis, 78% of patients in the pooled combination arms and 20% of the patients in the ddI alone arm (to which d4T was added after 24 weeks) showed plasma HIV-1 RNA < 500 copies/ml at week 24 (P < 0.001), and 59% versus 53% at week 48, respectively. In addition, the proportion of patients with < 50 HIV-1 RNA copies/ml was 13% versus 7% at week 24 (P = 0.5) and 17% versus 20% at week 48 respectively. At week 24, median CD4 cell count increases from baseline were 101 x 10(6)/l in the pooled combination versus 76 x 10(6)/l in the ddI alone arm (P = 0.78). Logistic regression modeling suggested a correlation between receiving high dose ddI and achieving HIV-1 RNA < 500 copies/ml at week 48 (P = 0.07).. The d4T/ddI combination was superior to ddI alone in producing HIV-1 viral suppression. At week 48, > 60% of patients treated with this combination reached HIV-1 RNA levels < 500 copies/ml. Receiving high dose ddI but not d4T may correlate with a better viral suppression. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Prospective Studies; RNA, Viral; Safety; Stavudine; Thailand | 2000 |
Plasma HIV-1 copy number and in vitro infectivity of plasma prior to and during combination antiretroviral treatment.
Some studies on untreated patients have shown a general correlation between plasma HIV copy number and plasma infectivity in in vitro models. Recent observations also indicate that HIV-RNA level is an important predictor of perinatal transmission and may also have a role in heterosexual transmission. To further analyse the correlation between HIV viral load and plasma infectivity, we studied the relationship between HIV-1 plasma copy number and plasma infectivity prior to and during treatment with antiretroviral combination regimens in HIV-1 infected adults. Plasma infectivity was assessed in vitro by coculture of plasma from HIV-positive patients with PHA-stimulated fresh PBMC from uninfected donors. A positive plasma isolation, in almost all cases (43/45) and irrespective of treatment status, was associated with an HIV viral load higher than 100000 copies per ml, with higher plasma HIV-1 RNA values in isolation-positive samples compared with isolation-negative samples (median values, 710000 vs. 37500 copies per ml, respectively). SI and NSI strains had similarly high viral load values (470000 vs. 790000 copies per ml), but CD4 counts were lower in the SI phenotype group. Our data indicate that low levels of viral load are only exceptionally associated with isolation from plasma in the in vitro model we used. This observation confirms indirectly the presence of an association between viral load and infectivity. The requisite of a high plasma viral load in order to obtain infectivity (i.e. positivity of HIV isolation from plasma) also seems maintained under antiretroviral treatment, adding confidence in the conclusion that reductions in viral load translate into reduction of plasma infectivity. Due to the extreme complexity of factors determining transmission, a very prudent interpretation of the results is essential when information from experimental studies has to be transferred to clinical situations requiring assessment of risks or clinical decisions. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; Giant Cells; HIV Infections; HIV-1; Humans; Nevirapine; RNA, Viral; Viral Load; Zidovudine | 2000 |
A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).
Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients.. Randomized, open-label.. Fourteen HIV Clinical Research Centers.. Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml.. Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV.. The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared.. In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms.. The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment. Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Reverse Transcriptase Inhibitors; Stavudine; Thymidine; Viral Load; Zidovudine | 2000 |
Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team.
To prospectively examine differences in baseline characteristics and study outcomes between HIV-infected women and men during a clinical trial of nucleoside analogue therapy.. ACTG 175 randomized HIV-infected patients with CD4+ counts between 200 and 500 cells/mm3 to one of four nucleoside analogue regimens: zidovudine (ZDV), didanosine (ddI), ZDV + ddI, or ZDV + zalcitabine (ddC). Differences in time to first dose modification, voluntary withdrawal, development of toxicity and symptomatology, and AIDS progression were compared by gender.. The study included 438 women and 2029 men. Baseline values of HIV RNA plasma concentrations were significantly lower for women (0.3 log10) than men in a subset of patients in whom assays were taken and this difference persisted after adjustment for CD4+ count. Women reported reducing dosage and discontinue ddI-containing regimens more frequently than men did; adjustment for weight did not completely explain this difference. Women were at lower risk than men for progression to a study endpoint (19% of women versus 24% of men; p <.0001). Among those antiretroviral-naive study subjects receiving ZDV, men were four times more likely to progress to a study endpoint than women.. Differences in pretreatment characteristics and on study experiences were demonstrated between women and men enrolled in this clinical trial. The suggestion of a gender difference in response to ZDV monotherapy by antiretroviral-naive study subjects and the lower baseline values for HIV RNA in women compared with those in men provides evidence for gender differences in the relationship between virus replication, CD4+ decline, and responses to nucleoside analogue therapy. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Female; HIV Infections; Humans; Liver; Male; Nucleosides; Prospective Studies; Sex Characteristics; Zalcitabine; Zidovudine | 2000 |
Effect of lamivudine in HIV-infected persons with prior exposure to zidovudine/didanosine or zidovudine/zalcitabine.
Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p < 0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zalcitabine; Zidovudine | 2000 |
Didanosine dosed once daily is equivalent to twice daily dosing for patients on double or triple combination antiretroviral therapy. The AI454-147 Team.
To compare the antiviral activity, effect on CD4 cell count, and tolerability of didanosine (ddI) administered once daily and twice daily in HIV-1-infected patients receiving ddI with stavudine or zidovudine, with or without a protease inhibitor. The study was designed to demonstrate that once-daily dosing of ddI was not inferior to twice-daily dosing.. Randomized, open-label, multicenter, two-arm study.. 121 HIV-1-infected adults on a stable regimen including ddI (twice daily) during the previous 3 months with a stable viral load <10,000 copies/ml started therapy. Of these, 62 were randomized to switch to a combination that included ddI once daily and 59 to continue with ddI twice daily. The ddI dose was 400 mg/day (250 mg/day if body weight was <60 kg). The primary efficacy analysis compared the time-averaged difference (TAD) between the two treatment regimens in change from baseline log10 plasma HIV-1 RNA levels over 24 weeks of therapy, with an equivalence margin between the two treatment groups of <0.5 log10 copies/ml.. At week 24, the mean plasma HIV-1 RNA level had increased by 0.31 and 0.17 log10 copies/ml in the ddI once-daily and ddI twice-daily groups, respectively. The time-averaged difference between the two groups in change from baseline plasma HIV-1 RNA levels over 24 weeks was (0.05 log10 copies/ml (95% confidence interval, -0.21 to +0.12 log10 copies/ml), indicating that the antiviral activity of ddI once daily is similar to that of ddI twice daily. After 24 weeks of treatment, changes from baseline in CD4 cell counts were similar in the two groups. Both regimens were generally well-tolerated.. Once-daily and twice-daily ddI are equally effective at reducing plasma HIV-1 RNA levels when used in a combination regimen with stavudine or zidovudine, with or without a protease inhibitor. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Zidovudine | 2000 |
Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.
In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200-500 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained > 200 x 10(6) cells/l. We report results after 24 months.. Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P< 0.02), fatigue (22 versus 7%, P< 0.01), and nausea or vomiting (26 versus 9%, P< 0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir.. HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens. Topics: Anti-HIV Agents; Diarrhea; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; Follow-Up Studies; HIV Infections; HIV-1; Humans; Hydroxyurea; Nausea; Peripheral Nervous System Diseases; Stavudine | 2000 |
Patterns of lymphotropic herpesvirus viraemia in HIV-infected patients with Kaposi's sarcoma treated with highly active antiretroviral therapy and liposomal daunorubicin.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Daunorubicin; Didanosine; Drug Therapy, Combination; Herpesvirus 8, Human; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Sarcoma, Kaposi; Stavudine; Viremia | 2000 |
Comparison of twice-daily stavudine plus once- or twice-daily didanosine and nevirapine in early stages of HIV infection: the scan study.
To evaluate the safety and effectiveness of once-daily didanosine and nevirapine plus twice-daily stavudine versus twice-daily administration of all three drugs.. This open-label, randomized, multicentre study enrolled 94 antiretroviral-naive patients with chronic HIV infection, CD4+ cell counts > 500 x 10(6) cells/l, and viral loads > 5000 copies/ml. Patients were treated with either 40 mg stavudine (twice daily) plus 400 mg didanosine (once daily) and 400 mg nevirapine (once daily) or 40 mg stavudine (twice daily) plus 200 mg didanosine (twice daily) and 200 mg nevirapine (twice daily).. After 12 months, 68% of patients who received twice-daily didanosine and nevirapine had viral loads < 200 copies/ml in the intention-to-treat and 79% in the on-treatment analysis, respectively. The corresponding values for patients treated with didanosine and nevirapine, taken once-daily, were 73 and 85%. The percentages of patients in each group with viral loads < 5 copies/ml at 12 months were 40% (once daily ) and 45% (twice daily) for the intention-to-treat analysis. Five of 11 patients (45%) with plasma viral loads < 5 copies/ml at 12 months had detectable virus in tonsillar tissue. Genotypic resistance to nevirapine was noted in seven of the 14 patients with detectable viral load at month 12. Mean changes in CD4+ cell counts for patients treated with stavudine plus once- or twice-daily didanosine and nevirapine were 154 and 132 x 10(6) cells/l, respectively. Treatment was interrupted due to adverse events in seven patients (8%) (four who received once-daily didanosine and nevirapine and three treated with twice-daily doses).. The combination of twice-daily stavudine plus once-daily didanosine and nevirapine was as safe and well tolerated as twice-daily administration of all three agents. Both regimens were equally effective in reducing viral loads and in increasing CD4+ cell counts. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Nevirapine; Palatine Tonsil; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; T-Lymphocyte Subsets; Viral Load | 2000 |
Quality of life outcomes of combination zidovudine- didanosine-nevirapine and zidovudine-didanosine for antiretroviral-naive advanced HIV-infected patients.
To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanità 047 trial).. A 48-week randomized, double-blind trial.. Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health.. Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P< 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score.. Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions. Topics: Adult; Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Nevirapine; Quality of Life; Reverse Transcriptase Inhibitors; Treatment Outcome; Zidovudine | 2000 |
Frequency of cytokine-producing T cells in HIV-infected patients treated with stavudine, didanosine, and ritonavir.
To assess prospectively the influence of the control of viral replication on the frequency of cytokine-producing T cells, and to correlate these changes with immune activation, we conducted a 15-month follow-up study of IFN-gamma- and IL-2-producing CD4+ and CD8+ T cells at a single-cell level in 12 previously untreated patients receiving highly active antiretroviral therapy (HAART). At baseline we observed a strikingly high proportion of IFN-gamma-producing CD8+ T cells. The treatment-induced decrease in the proportion of IFN-gamma-producing CD8+ T cells ran parallel to the decrease in HLA-DR+ and CD38+CD8+ T cell subsets and was associated with the reduction in HIV RNA level. IL-2-producing cells were mainly CD4+. As a consequence of CD4+ T cell loss, the number of IL-2-producing CD4+ T cells was lower in patients than in control subjects (52 vs. 171 cells/microl), but the proportion of these cells was unchanged (22.4 vs. 19.3). During therapy the proportion of CD4+ IL-2-producing cells was initially stable and then fell markedly at month 5, followed by a gradual return to previous values. The reduction in viral load was associated with the fall in the proportion of CD4+ activated subsets. Intracellular cytokine assays are a new approach to the assessment of T cell function in HIV infection. Our results suggest that the functional capacity of CD4+ T cells is probably less severely altered than previously thought on the basis of conventional assays. CD8+ T cells exhibit an increased capacity to produce IFN-gamma that is associated with an increase in activation marker expression. These alterations decrease partially and in parallel under treatment. Topics: Adult; Anti-HIV Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Didanosine; Drug Therapy, Combination; Female; Flow Cytometry; Follow-Up Studies; HIV Infections; HIV-1; Humans; Interferon-gamma; Interleukin-2; Male; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Stavudine; T-Lymphocyte Subsets; Viral Load | 2000 |
The VIRGO study: nevirapine, didanosine and stavudine combination therapy in antiretroviral-naive HIV-1-infected adults.
The virological and immunological efficacy of the triple regimen containing nevirapine (once or twice daily), didanosine (once daily) and stavudine, in antiretroviral-naive patients infected with HIV-1, was evaluated in an open-label, prospective, non-randomized, multi-centre, 52-week study. The first 60 patients (VIRGO I) received nevirapine as the standard dose, 200 mg twice daily; the subsequent 40 patients (VIRGO II) received nevirapine at a dose of 400 mg once daily. All patients received 400 mg of didanosine once daily and 40 mg of stavudine twice daily, adjusted for body weight. At baseline, the median CD4 cell count and plasma viral load (pVL) were 414 cells/mm3 and 4.59 log10 copies/ml in VIRGO I, and 412 cells/mm3 and 4.87 log10 copies/ml in VIRGO II. Using an intent-to-treat, 'non-completer equals failure', analysis, 78% (95% CI, 68-88%) of patients in VIRGO I and 68% (95% CI, 53-83%) of those in VIRGO II had a pVL <500 copies/ml at 24 weeks; the proportions achieving a pVL of <50 copies/ml were 62% (95% CI, 50-74%) and 50% (95% CI, 35-65%), respectively. The week 24 median CD4 cell count increase was 168 cells/mm3 (VIRGO I) and 139 cells/mm3 (VIRGO II). At week 52, 39/45 (87%) of VIRGO I patients had pVL <500 copies/ml and 30/45 (67%) <50 copies/ml. Of the 100 patients, 44 experienced grade 2 to 4 adverse events; 20 permanently discontinued study medication because of an adverse event. Combination therapy with the three reverse transcriptase (RT) inhibitors stavudine, once-daily didanosine and either once- or twice-daily nevirapine could be considered as an alternative option for first-line antiretroviral therapy. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Prospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome | 2000 |
Use of hydroxyurea in heavily pretreated patients with HIV infection.
This study was designed to assess the potential benefit of hydroxyurea (HU) on virological and immunological markers in heavily pretreated human immunodeficiency virus (HIV)-infected patients. A total of 118 patients received hydroxyurea as treatment added to their current antiviral therapy ('add' group), or as treatment added together with a switched nucleoside reverse transcriptase inhibitor or protease inhibitor or with the introduction of an additional antiviral agent ('add and switch' group). Efficacy of HU was also compared among patients receiving didanosine- and non-didanosine-containing regimens. Results showed that HU was not associated with a significant decline in plasma HIV-1 RNA, and no significant difference in plasma HIV-1 RNA changes was noted between patients who did and did not receive didanosine. The absolute number of CD4 cells, but not the CD4 percentage, declined significantly from baseline. Significantly more grade 3-4 neutropenia occurred among patients receiving HU combined with zidovudine, although the discontinuation rate for haematological toxicity was similar in zidovudine- and non-zidovudine-treated patients. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; Female; HIV Infections; HIV-1; Humans; Hydroxyurea; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome | 1999 |
Results of the ALBI trial: a randomized comparison of stavudine/didanosine, zidovudine/lamivudine and alternating treatment in antiretroviral-naive patients.
In the ALBI trial, 151 antiretroviral-naive patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 10,000 to 100,000 copies/ml and CD4 cell counts > or = 200 cells/mm3 received 24 weeks of treatment with stavudine/didanosine (n=51), zidovudine/lamivudine (n=51) or stavudine/didanosine for 12 weeks followed by zidovudine/lamivudine (n=49). Baseline plasma HIV-1 RNA and CD4 cell counts were comparable in the treatment groups. The mean decrease in plasma HIV-1 RNA at 24 weeks in the stavudine/didanosine group (2.26 log10) was significantly greater than that in either the zidovudine/lamivudine group (1.26 log10) or the alternating treatment group (1.58 log10) (P<0.0001 for both). Proportions of patients with plasma HIV-1 RNA level <500 copies/ml (91% vs 42% and 60%) and <50 copies/ml (47% versus 4% and 9%) were significantly greater in the stavudine/didanosine group (P<0.001 for pairwise comparisons). Stavudine/didanosine was associated with a mean increase in CD4 cell count (124 cells/mm3) significantly greater than that in the zidovudine/lamivudine group (62 cells/mm3, P<0.01) and comparable to that in the alternating group (118 cells/mm3). All study regimens were well tolerated. These findings, indicating superiority of stavudine/didanosine over zidovudine/lamivudine in virological and immunological response over 24 weeks, suggest that the combination should be considered as a basis for highly active antiretroviral therapy. Topics: Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine | 1999 |
Stavudine, didanosine and nevirapine in antiretroviral-naive HIV-1-infected patients.
In an ongoing, open-label, non-comparative study, the safety and efficacy of nevirapine/stavudine/didanosine were evaluated in 100 antiretroviral-naive adults with CD4 cell counts > or = 200 cells/mm3 and plasma HIV-1 RNA (pVL) > or = 5000 copies/ml. Sixty patients received nevirapine twice daily (VIRGO I) and 40 received nevirapine once daily (VIRGO II); all patients received didanosine once a day. After median follow-ups of 44 weeks in VIRGO I and 30 weeks in VIRGO II, the following virological results were observed (ongoing study): an intent-to-treat, non-completer equals failure analysis at week 24 showed the proportions of patients with pVL <500 copies/ml were 78% in VIRGO I (60% <50 copies/ml) and 75% in VIRGO II. An on-treatment analysis at week 52 showed 80% of patients with a pVL <500 copies/ml and 59% with <50 copies/ml in VIRGO I. The mean CD4 cell count increase was +171 cells/mm3 at week 24 and +218 cells/mm3 at week 52 in VIRGO I and +158 cells/mm3 at week 24 in VIRGO II. Cutaneous rash (grades 1 to 3) occurred in 24% of patients leading to nevirapine discontinuation in eight of 24 patients. Five other patients discontinued therapy during the first 24 weeks because of hepatic cytolysis, peripheral neuropathy or biological pancreatitis. The nevirapine/stavudine/didanosine combination is a convenient and safe regimen, with rapid and potent immunological and antiviral effects sustained over 12 months. Topics: Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viral Load | 1999 |
Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators.
The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL, VSS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of VSS. The average individual oral CL, VSS, and V of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and VSS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (FTRIPLE = 1.05 and FDOUBLE = 1 by definition), but the F of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters. Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Models, Biological; Nevirapine; Zidovudine | 1999 |
Virologic and immunologic response to nucleoside reverse-transcriptase inhibitor therapy among human immunodeficiency virus-infected infants and children.
Plasma human immunodeficiency virus RNA and CD4 lymphocyte response to nucleoside reverse-transcriptase therapy were evaluated in a large, comparative pediatric trial. Both baseline values and changes in the two laboratory markers over time correlated well with clinical outcome and possessed independent predictive value. In comparison of RNA reduction from baseline between the dideoxyinosine (ddI) and zidovudine+ddI therapeutic arms, marginal superiority of the combination arm was not correlated with an observed clinical benefit. Despite the size of this trial and the significantly higher rate of clinical end points in the zidovudine monotherapy group, attempts to establish surrogacy for plasma RNA were difficult. Nevertheless, plasma RNA and CD4 lymphocyte count together possess strong clinical predictive power and are valuable tools for both the clinician and the evaluation of new therapies. Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; Humans; Infant; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Zidovudine | 1999 |
Lack of absorption of didanosine after rectal administration in human immunodeficiency virus-infected patients.
The feasibility of rectal administration of didanosine (DDI) was studied in six human immunodeficiency virus-infected patients. After oral intake of a DDI solution (100 mg/m2 of body surface area) combined with an antacid (Maalox), pharmacokinetic parametric values were in accordance with previously published data; the mean +/- standard deviation for terminal half-life was 59.5 +/- 15.0 min, that for peak concentration was 5.2 +/- 3.9 mumol/liter, and that for the area under the time-concentration curve (AUC) was 494 +/- 412 min.mumol/liter. After rectal administration of a similarly prepared DDI solution (100 mg/m2 of body surface area), plasma DDI levels were below the detection limit (0.1 mumol/liter) at all time points in five of the six patients, and in the remaining patient the AUC after rectal application was only 5% of that after oral administration. We conclude that oral administration of DDI cannot be easily replaced by rectal application. Topics: Administration, Rectal; Adolescent; Adult; Anti-HIV Agents; Area Under Curve; Child; Didanosine; Half-Life; HIV Infections; Humans; Intestinal Absorption; Male; Middle Aged | 1999 |
An evaluation of HIV RNA and CD4 cell count as surrogates for clinical outcome. Delta Coordinating Committee and Virology Group.
To evaluate the role of viral load, as measured by HIV-1 RNA, and CD4 cell counts as surrogates for clinical outcome using the data from the Delta trial.. A total of 1280 participants (40% of the 3207 participants in the Delta trial) with baseline and at least one other serum sample stored at -70 degrees C were included in the extended virology study, of whom 411 were allocated to zidovudine (ZDV) alone, 439 to ZDV plus didanosine (ddl) and 430 to ZDV plus zalcitabine (ddC). The extent to which changes in HIV or CD4 cell levels up to week 32 can explain the benefit of combination therapy was investigated by fitting these marker levels in addition to allocated treatment to Cox proportional hazards models for time to death and to disease progression.. RNA at baseline and changes at weeks 8, 16 and 32 were independent and highly significant predictors of disease progression or death. The hazard of progression was increased fourfold (P < 0.0004) for each log10 higher baseline RNA and was reduced by 43% (P = 0.004) and by 38% (P = 0.002) for each log10 reduction at weeks 8 and 16, respectively. Compared with ZDV monotherapy, the progression rate was reduced by 43% (P = 0.0001) by ZDV plus ddl and by 36% (P = 0.001) by ZDV plus ddC. After adjusting for RNA up to week 16, however, there was a highly significant treatment effect favouring ZDV monotherapy, which was not explained by RNA: the adjusted progression rates were 66% higher (P = 0.005) for ZDV plus ddl and 67% higher (P = 0.004) for ZDV plus ddC compared with ZDV alone. In contrast, after adjusting for CD4 to week 16 there remained a significant treatment effect favouring combination therapy: compared with ZDV monotherapy, the progression rate was reduced by 29% (P < 0.0001) by ZDV plus ddl and 12% (P = 0.1) by ZDV plus ddC. Adjustment for both RNA and CD4 to week 16 resulted in a relative increase in the hazard of progression (49% (P = 0.04) for ZDV plus ddl and 37% (P = 0.09) for ZDV plus ddC) not explained by the two markers combined.. Clinical benefit from combinations of ZDV plus ddl or ZDV plus ddC was underestimated by CD4 cell counts and overestimated by RNA levels and by the two markers combined. Neither HIV RNA levels nor CD4 cell counts appear to be complete surrogates for clinical outcome. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine | 1999 |
HIV-1 RNA response to antiretroviral treatment in 1280 participants in the Delta Trial: an extended virology study.
To assess changes in HIV RNA and their relationship to disease progression.. Delta was a randomized double-blind trial comparing zidovudine (ZDV) monotherapy with ZDV plus didanosine (ddI) or ZDV plus zalcitabine (ddC). Participants had AIDS (with CD4 cell counts above 50 x 10(6)/l), AIDS-related complex, or were asymptomatic with CD4 cell counts below 350 x 10(6)/l. The trial included both ZDV-naive and ZDV-experienced participants.. A total of 1280 participants in the Delta trial whose serum samples had been stored at -70 degrees C and who had a minimum of one sample taken before the start of treatment and at least one later sample.. HIV-1 RNA quantification was performed using the nucleic acid sequence-based amplification HIV-1 RNA quantitative assay with a cut-off of 800 copies/ml.. Reductions in HIV RNA by treatment group were consistent with the clinical results; in ZDV-naive participants the maximum median fall occurred at 4 weeks for all three groups (ZDV, 0.54 log10 copies/ml; ZDV-ddI, 1.38 log10 copies/ml; ZDV-ddC, 1.31 log10 copies/ml). On average the reductions were smaller in ZDV-experienced participants but the difference between the monotherapy and combination arms was very similar in ZDV-naive and experienced participants. Baseline HIV RNA levels, adjusted for CD4 cell counts were highly predictive of time to virological response (HIV RNA < 800 copies/ml); HIV RNA nadirs achieved were predictive of survival. Viral load rebound following response was independent of treatment group and previous ZDV therapy.. Virological changes in response to treatment are of value in assessing prognosis and the activity of new therapies; in particular, there is a strong association between the minimum HIV RNA achieved in the first 16 weeks and subsequent clinical response. CD4 cell counts are independently predictive of response. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; Predictive Value of Tests; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load; Zalcitabine; Zidovudine | 1999 |
Combination therapy with stavudine (d4T) plus didanosine (ddI) in children with human immunodeficiency virus infection. The Pediatric AIDS Clinical Trials Group 327 Team.
To evaluate the safety, tolerance, and antiviral activity of combination therapy with stavudine (d4T) plus didanosine (ddI) in symptomatic human immunodeficiency virus (HIV)-infected children.. The study enrolled HIV-infected children who successfully completed Pediatric AIDS Clinical Trials Group (PACTG) protocol 240 (d4T versus zidovudine [ZDV] monotherapy) without disease progression or who had received ZDV monotherapy by prescription for at least the preceding 6 months. Children who had received d4T monotherapy in PACTG 240 were assigned to treatment with d4T plus ddI (arm 1). Children who had received ZDV monotherapy in PACTG 240 or by prescription were randomized in a double-blind manner to treatment with either d4T alone (arm 2) or d4T plus ddI (arm 3). Patients were followed for 48 weeks each.. A total of 108 children were enrolled. The mean age was 5.0 years (range, 1. 6 to 11.5 years), with mean baseline plasma HIV RNA concentration and CD4(+) lymphocyte count of 4.6 log10 copies/mL (range, 2.6 to 5. 9 log10 copies/mL) and 819 cells/microL (range, 8 to 3431 cells/microL), respectively. Both d4T monotherapy and d4T plus ddI combination therapy were well-tolerated, with 96 (89%) patients completing 48 weeks of study treatment. Plasma HIV RNA concentrations showed larger average declines in arm 3 compared with arm 2 at study week 12 (0.49 vs 0.18 log10 copies/mL, respectively); these average declines were maintained through week 48 (0.51 vs 0.17 log10 copies/mL, respectively). Fewer than 8% of the patients in any of the treatment arms had plasma HIV RNA concentrations below the limit of quantification (200 copies/mL) at any time point.. Combination therapy with d4T plus ddI is safe and well-tolerated in HIV-infected children, producing durable, but incomplete, suppression of virus replication. This combination of nucleoside antiretroviral agents may provide a valuable backbone to protease inhibitor-containing treatment regimens for HIV-infected children. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infant; Male; RNA, Viral; Statistics, Nonparametric; Stavudine | 1999 |
Recombinant human gamma interferon in human immunodeficiency virus-infected children: safety, CD4(+)-lymphocyte count, viral load, and neutrophil function (AIDS Clinical Trials Group Protocol 211).
Nineteen children with human immunodeficiency virus (HIV) infection were treated with recombinant human gamma interferon (rIFN-gamma) (50 microg/m2 subcutaneously three times each week during weeks 1 through 12 and 100 microg/m2 subcutaneously three times each week during weeks 13 through 24) in a phase I/II clinical trial. All children continued to receive previously prescribed therapy with oral zidovudine or didanosine. Children were assessed clinically and with laboratory studies during 24 weeks of study treatment and for 12 weeks after completion of rIFN-gamma therapy. In general, rIFN-gamma therapy was well tolerated. There were two clinical or laboratory adverse events thought to be possibly or probably study drug associated. One child developed acute pancreatitis; another child developed granulocytopenia. Median CD4(+)-lymphocyte counts and plasma HIV RNA concentrations did not change significantly during therapy. In vitro neutrophil bactericidal activity against Staphylococcus aureus and superoxide production were not significantly affected by rIFN-gamma therapy. We conclude that rIFN-gamma therapy in HIV-infected children receiving single-agent antiretroviral therapy is safe and does not produce consistent changes in CD4(+)-lymphocyte count, plasma HIV RNA concentration, or in vitro neutrophil function. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Interferon-gamma; Male; Neutrophils; Recombinant Proteins; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine | 1999 |
Immunoreconstitution after ritonavir therapy in children with human immunodeficiency virus infection involves multiple lymphocyte lineages.
To evaluate lymphocyte reconstitution after protease inhibitor therapy in children with human immunodeficiency virus (HIV) infection.. Forty-four HIV-infected children receiving ritonavir monotherapy followed by the addition of zidovudine and didanosine were evaluated during a phase I/II clinical trial. The cohort had a median age of 6.8 years and advanced disease (57% Centers for Disease Control and Prevention stage C, 73% immune stage 3) and was naive to protease inhibitor therapy.. After 4 weeks of therapy, there was a significant increase in CD4(+) and CD8(+) T cells. CD4(+) T cells continued to increase, whereas CD8(+) T cells returned to baseline by 24 weeks. Unexpectedly, there was a significant increase in B cells. Changes in CD4(+) T-cell subsets revealed an initial increase in CD4(+) CD45RO T cells followed by a sustained increase in CD4(+) CD45RA T cells. Children <6 years of age had the highest increase in all lymphocyte populations. Significant improvement in CD4(+) T-cell counts was observed even in those children whose viral burden returned to pre-therapy levels.. Early increases in lymphocytes after ritonavir therapy are a result of recirculation, as shown by increases in B cells and CD4(+) CD45RO and CD8(+) T cells. Children exhibited a high potential to reconstitute CD4(+) CD45RA T cells even with advanced disease and incomplete viral suppression. Topics: Adolescent; Anti-HIV Agents; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Immunophenotyping; Infant; Leukocyte Common Antigens; Lymphocyte Subsets; Ritonavir; Viral Load; Zidovudine | 1999 |
Immune restoration by combination of a cytostatic drug (hydroxyurea) and anti-HIV drugs (didanosine and indinavir).
Cell activation is essential for HIV infection. CD4+ T lymphocyte activation allows virus replication and CD8+ T lymphocyte activation may contribute to pathogenesis. We combined hydroxyurea, a cytostatic drug that inhibits cell activation and proliferation, with two drugs that inhibit HIV (didanosine and indinavir), to block the "cell activation-virus production-pathogenesis" cycle. HIV was strongly suppressed in treated patients, and the average CD4 count increased to 224/mm3. Compared with a matched group of patients who had declined antiretroviral treatment, treated patients had a significantly lower proportion of activated CD8+ T lymphocytes and a significantly higher number of naive CD8+ and CD4+ T lymphocytes. The proliferative responses to allogeneic and influenza virus antigens were increased in treated patients, and a defect in CD3-zeta expression, the signaling chain of the T cell receptor complex, was reversed. The use of a cytostatic drug was not detrimental to the immune system; on the contrary, the combination of antiviral and cytostatic treatment improved all of the immune parameters tested. Topics: Anti-HIV Agents; CD3 Complex; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Indinavir; Lymphocyte Activation; Nucleic Acid Synthesis Inhibitors; Reverse Transcriptase Inhibitors; Viremia | 1999 |
[Response of fetal macrophages in the placenta of pregnant HIV-positive patients with and without antiretroviral treatment].
We studied the cellular answer of placentary macrophages in pregnant women seropositive to the virus of human immunodefficiency (VIH-1) treated with zidovudina (AZT) and didanosine (ddl). Twenty eight pregnant women were studies; there were four groups of seven patients each: The control group; the group with seropositive women without treatment; the group given AZT, and the group that recieved AZT and ddl. Placentary specimens were obtained immediately after delivery. One hundred and fifty chorionic vellosities of cells. The control group showed an average of 26 Hofbauer cells; the seropositive women without antiretroviral treatment, was 115; the patients who received only AZT, the average was 65; and the ones who received a combine therapy AZT and ddl, cellular average was 44. There were no differences in the weight of the products in all the groups, nor congenital malformations in the newborns. The use of medication antiretroviral suppress viral replication, and so, there is a significant answer in the amount and size of Hofbauer cells. The administration of two medicaments is more effective in the cellular immune answer. Topics: Antiviral Agents; Didanosine; Female; HIV Infections; HIV Seropositivity; Humans; Macrophages; Pregnancy; Pregnancy Complications, Infectious; Retroviridae; Zidovudine | 1999 |
Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group.
Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients.. 94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56.. CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p<0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups.. Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Didanosine; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infusions, Intravenous; Injections, Subcutaneous; Interleukin-2; Male; Time Factors; Zidovudine | 1999 |
The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus.
A total of 151 previously untreated patients infected with human immunodeficiency virus type 1 (HIV-1) with CD4 cell counts >/=200/microL and plasma HIV-1 RNA levels of 10,000-100,000 copies/mL were randomly assigned to 24 weeks of open-labeled stavudine plus didanosine (group 1), zidovudine plus lamivudine (group 2), or stavudine plus didanosine followed by zidovudine plus lamivudine (group 3). The mean decrease in HIV-1 RNA level was greater in group 1 (2.26 log10 copies/mL) than in groups 2 (1.26 log10 copies/mL) or 3 (1.58 log10 copies/mL; P<.0001). The mean increase in CD4 cell counts was greater in groups 1 (124 cells/microL) and 3 (118 cells/microL) than in group 2 (62 cells/microL; P=.02). All regimens were generally well tolerated. The combination of stavudine plus didanosine reduced plasma HIV-1 RNA concentrations and increased CD4 cell counts more effectively than did the combination of zidovudine plus lamivudine or the regimen alternating both combinations. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viremia; Zidovudine | 1999 |
Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Invest
To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T).. Randomized, placebo-controlled, partially double-blinded multicenter study.. Adult AIDS Clinical Trials Units.. Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l.. Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms.. The reduction in plasma HIV-1 RNA level at weeks 24 and 48.. Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb.. 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Viral Load; Zidovudine | 1999 |
Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team.
To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Delavirdine; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Safety; Zidovudine | 1999 |
Preliminary evaluation of human immunodeficiency virus type 1 (HIV-1) immunogen in children with HIV-1 infection.
The safety and preliminary activity of human immunodeficiency virus type 1 (HIV-1) immunogen were evaluated in 10 HIV-1-infected children with disease stage N1,2 or A1,2. Multiple inoculations of 2. 5 or 10 units (U) of HIV-1 immunogen were safe and well tolerated without an acceleration of disease progression. When antiretroviral agents were coadministered, the 10 U dose appeared to be associated with more sustained reduction in plasma HIV-1 RNA than the 2.5 U dose (median log10 HIV-1 RNA at month 18, 3.07 vs. 4.01 copies/mL in 10 U [n=4] vs. 2.5 U [n=3], respectively; P=.034). Levels of regulated-on-activation, normal T cell-expressed and -secreted chemokine produced from HIV-1 immunogen-stimulated lymphocytes in vitro were increased in the children who had HIV-1 immunogen-specific antibody responses (P<.02) and appeared to be inversely correlated with levels of plasma HIV-1 RNA (P<.01). These preliminary data warrant larger studies to determine the effectiveness of adjunctive therapy with HIV-1 immunogen in children with HIV-1 infection. Topics: Adolescent; AIDS Vaccines; Anti-HIV Agents; Child; Child, Preschool; Combined Modality Therapy; Didanosine; Dose-Response Relationship, Drug; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Infant; Male; RNA, Viral; Safety; Time Factors; Zidovudine | 1999 |
Cell-associated HIV-1 RNA in blood as indicator of virus load in lymph nodes. The Swiss HIV Cohort Study.
We have developed sensitive assays for viremia and cell-associated human immunodeficiency virus type 1 (HIV-1) RNA and DNA to assess the predictive value of virological parameters determined in blood for virus load in lymph nodes (LNs). Eighteen patients were included; 13 received stavudine/didanosine/hydroxyurea and 5 stavudine/didanosine, and all had viremia <500 copies/mL for >3 months. At the time of LN biopsy (median, 10 months), the median viremia was 2.09 log copies/mL (range, <0.70-3.34). Cell-associated HIV-1 RNA and DNA were detectable in blood and LNs of all patients. The median cell-associated RNA and DNA were 2.16 log copies/106 cells and 2.60 log copies/106 cells in blood versus 4.31 log RNA copies/106 cells and 3.26 log DNA copies/106 cells in LNs. Regression analysis shows that, in treated patients with sustained low viremia, cell-associated RNA and DNA in blood are better predictors of virus load in LNs than viremia. Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Lymph Nodes; RNA, Viral; Stavudine; Viral Load | 1999 |
Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy.
Efavirenz, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, is a promising addition to the antiretroviral armamentarium. Efavirenz levels and HIV-1 RNA levels were measured in cerebrospinal fluid (CSF) and plasma of 10 HIV-1-infected patients taking efavirenz, 600 mg daily, in combination with other antiretroviral medications. Efavirenz was detected in the CSF at a mean concentration of 35.1 nM (range, 6. 6-58.9 nM), which was above the IC95 for wild-type HIV-1. The mean CSF-to-plasma ratio was 0.61% (range, 0.26%-0.99%). CSF HIV-1 RNA levels were ascertained in 9 of the patients; all were <400 copies/mL after a mean of 26 weeks on therapy. Eight of the 9 patients had no detectable virus in plasma. These results indicate that efavirenz is present in the CSF at low levels and is effective in suppressing CSF viral levels when used in combination therapy. Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Oxazines; Viral Load; Zidovudine | 1999 |
Virological and immunological responses to once-daily dosing of didanosine in combination with stavudine. AI454-143 Team.
To compare the antiviral activity of once-daily didanosine (ddI) and twice-daily ddI in combination with stavudine (d4T).. Randomized, double-blind, multicenter study.. Twenty-one sites in the United States.. Eighty-seven antiretroviral-naive, HIV-1-infected adults with baseline plasma HIV RNA counts of > or = 10,000 copies/ml and CD4 cell counts of > or = 100 cells/mm3 started study therapy.. Patients received once-daily ddI or twice-daily ddI, each combined with twice-daily d4T.. Plasma HIV-1 RNA levels, CD4 cell counts, and adverse events were regularly monitored. The primary efficacy analysis used was the time-averaged difference (TAD) between treatment regimens in change from baseline plasma HIV-1 RNA levels over the first 12 weeks of therapy.. At week 12, median log10 HIV-1 RNA changes were -1.83 log10 copies/ml in the once-daily ddI/d4T group and -1.80 log10 copies/ml in the twice-daily ddI/d4T group, and 18 out of 44 patients (41%) and 17 out of 43 patients (40%), respectively, had HIV-1 RNA levels below 400 copies/ml. Similar results were seen at week 24. The TAD between the two treatment groups (once-daily ddI/d4T minus twice-daily ddI/d4T) in change from baseline plasma HIV RNA levels over the first 12 weeks was 0.14 log10 copies/ml (95% CI: -0.11, 0.40). At week 12, subjects averaged an increase in CD4 cell count of over 140 cells/mm3. The TAD between the two treatment groups in change from baseline CD4 cell counts over the first 12 weeks was 2 cells/mm3 (95% CI: -40, 45).. Once-daily ddI plus d4T and twice-daily ddI plus d4T were similarly effective in reducing plasma HIV-1 RNA levels and increasing CD4 cell counts over 12-24 weeks of therapy. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome | 1999 |
Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team.
To compare the impact of three different nucleoside reverse transcriptase inhibitor regimens, zidovudine (ZDV) monotherapy, didanosine (ddI) monotherapy, and ZDV plus ddI combination therapy, on central nervous system (CNS) outcomes in symptomatic human immunodeficiency virus (HIV)-infected children.. Serial neurologic examinations, neurocognitive tests, and brain growth assessments (head circumference measurements and head computed tomography or magnetic resonance imaging studies) were performed in 831 infants and children who participated in a randomized double-blind clinical trial of nucleoside reverse transcriptase inhibitors. The Pediatric AIDS Clinical Trials Group study 152 conducted between 1991 and 1995 enrolled antiretroviral therapy-naive children. Subjects were stratified by age (3 to <30 months of age or 30 months to 18 years of age) and randomized in equal proportions to the three treatment groups.. Combination ZDV and ddI therapy was superior to either ZDV or ddI monotherapy for most of the CNS outcomes evaluated. Treatment differences were observed within both age strata. ZDV monotherapy showed a modest statistically significant improvement in cognitive performance compared with ddI monotherapy during the initial 24 weeks, but for subsequent protection against CNS deterioration no clear difference was observed between the two monotherapy arms.. Combination therapy with ZDV and ddI was more effective than either of the two monotherapies against CNS manifestations of human immunodeficiency virus disease. The results of this study did not indicate a long-term beneficial effect for ZDV monotherapy compared with ddI monotherapy. Topics: Adolescent; Analysis of Variance; Anti-HIV Agents; Brain; Central Nervous System Diseases; Child; Child, Preschool; Cognition; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Intelligence Tests; Male; Motor Skills; Reverse Transcriptase Inhibitors; Zidovudine | 1999 |
Long-term effects of antiretroviral combination therapy on HIV type 1 DNA levels.
HIV-1 RNA and DNA levels were measured in 58 patients, of whom 37 and 11, respectively, received triple or double combination therapy. At baseline, strong correlations were found between the number of HIV-1 DNA copies per 106 CD4+ cells, the plasma HIV-1 RNA levels, and the isolation rate of HIV-1 from blood cells. In comparison with HIV-1 RNA, a much slower decline in HIV-1 DNA levels was seen, which probably represents a long lifetime of provirus-bearing CD4+ cells. In 10 untreated patients, the proviral load was stable. In patients receiving triple therapy, a significant decline in HIV-1 DNA was seen independent of whether the proviral load was expressed as copies per 106 CD4+ cells or as copies per milliliter of blood. In contrast, a decline was seen only when the proviral load was expressed as copies per 10(6) CD4+ cells in patients given two drugs. The difference between the two patient categories is likely to be due to a more frequent infection of CD4+ cells during therapy in the patients with double therapy. Interpretation of changes in HIV-1 DNA levels is thus dependent on how the proviral burden is expressed. Further studies should evaluate whether changes in HIV-1 DNA load can be used as markers of viral replication during efficient antiretroviral combination therapy. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Data Interpretation, Statistical; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Polymerase Chain Reaction; RNA, Viral; Stavudine; Time Factors; Zidovudine | 1999 |
Rapid detection of the HIV type 1 reverse transcriptase codon T215Y by reverse transcription-polymerase chain reaction with fluorogenic probes.
Early detection of viral mutations, particularly those mutations associated with cross-resistance to antiretroviral drugs, is critical both for understanding the mechanism of drug resistance and for the clinical management of patients infected with HIV-1. One of the frequently observed mutations in the HIV-1 reverse transcriptase (RT)-coding region is ACC --> TAC at codon 215, resulting in a change of wild-type threonine (T) to tyrosine (Y); this mutation has been associated with decreased phenotypic susceptibility to zidovudine (ZDV). We describe a technique for the detection of the T215Y mutation using reverse transcription-polymerase chain reaction (RT-PCR) amplification of viral sequences and a 5' nuclease assay requiring fluorogenic probes. In addition to detecting the presence of the ACC --> TAC mutation at codon 215, this assay provides an increased ability to detect low levels of mutant species in a mixed population, relative to conventional sequencing. Further advantages of this technique include the rapid and high-throughput nature of the assay, the accuracy of the assay relative to conventional DNA sequencing, and the convenience of combining RT-PCR virus amplification with the allelic discrimination assay, without the need for purification of PCR products. Topics: Anti-HIV Agents; Child; Child, Preschool; Codon; Didanosine; DNA Mutational Analysis; Drug Resistance, Microbial; Drug Resistance, Multiple; Fluorescent Dyes; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Point Mutation; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Zidovudine | 1999 |
Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children.
In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HIV-infected previously treatment-naive children taking triple therapy.. sixteen HIV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load.. No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log10 (range, 1.4-4.2 log10) was achieved over a period of 12 months in both groups. Viral load < 500 copies/ml was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 x 10(6) to 850 x 10(6) cells/l after 3 months and was maintained at 813 x 10(6) cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients.. Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HIV-infected children compared with studies combining two nucleoside analogues. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Lamivudine; Male; Nelfinavir; Prospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Viral Load; Zidovudine | 1999 |
Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus--infected pregnant women and their neonates: an AIDS clinical trials group study.
Didanosine (ddI) pharmacokinetics in antepartum and postpartum human immunodeficiency virus (HIV)-infected women and their neonates were studied. HIV-infected pregnant women received an intravenous (iv) ddI infusion (1.6 mg/kg/h) or an oral dose (200 mg bid or 125 mg bid) at 31 weeks antepartum and 6 weeks postpartum. Blood samples were obtained regularly up to 6 or 8 h after drug administration. The same oral dose of ddI (bid) was administered until labor began. Then, ddI was infused iv until delivery. An oral pharmacokinetic study (60 mg/m2) was conducted in infants at day 1 and at week 6 after birth. Plasma concentrations of ddI were measured by radioimmunoassay. After iv ddI administration, only the maternal plasma clearance was found to be significantly increased antepartum (1028+/-231 mL/min) versus postpartum (707+/-213 mL/min). No pharmacokinetic parameters after oral administration were significantly affected by pregnancy. The pharmacokinetics of ddI in the neonates were highly variable. We conclude that the oral ddI dose need not be adjusted during pregnancy. Topics: Anti-HIV Agents; Didanosine; Female; Fetal Blood; Half-Life; HIV Infections; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Infectious | 1999 |
Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.
The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication. Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; RNA, Viral; Stavudine; Viral Load; Virus Replication; Weight Gain | 1999 |
Once-daily administration of didanosine in combination with stavudine in antiretroviral-naive patients. The STADI Group.
Topics: Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Patient Compliance; Peripheral Nervous System Diseases; RNA, Viral; Stavudine | 1999 |
Mutations conferring resistance to zidovudine diminish the antiviral effect of stavudine plus didanosine.
This study evaluated the influence of zidovudine (ZDV) resistance mutations on the antiviral effect of the combination of stavudine (D4T) plus didanosine (ddI) in patients treated previously with ZDV plus zalcitabine (ddC). Twenty patients who had been treated with ZDV plus ddC for a median duration of 11 months (range, 7-42 months) were switched to D4T (40 mg twice a day [BID]) + ddI (200 mg BID) in an open pilot study lasting 6 months. The CDC classes were A (n = 10) and B (n = 10). The median baseline CD4 count was 285/mm(3) and the median baseline plasma virus RNA (Amplicor HIV Monitor RT-PCR assay) was 4.6 log copies/ml. Population-based sequence analysis detected mutations associated with resistance to reverse transcriptase (RT) inhibitors in the RT domain of virus RNA from baseline plasma samples in 13/20 (65%) patients. Twelve patients had mutations associated with zidovudine resistance (3 T215Y - M41L - L210W; 3 T215Y - M41L; 2 T215Y - L210W; 3 T215Y; 1 K70R) and 1 patient had a multi-dideoxynucleoside resistance mutation (QI5IM). Patients with a resistance mutation had a significantly lower RNA suppression after 3 and 6 months (median RNA reduction -0.5 log and -0.1 log) than the remaining patients (-1.6 log and -2 log). Fifty percent of patients with wild-type viruses had undetectable plasma RNA after 24 weeks of D4T plus ddI therapy, whereas all those with mutated viruses had HIV RNA concentration > 3 log copies/ml at week 24 (P <.05). Our finding may have implications when deciding on a second line therapy with three or four drugs that includes two new nucleoside analogues. Cross-resistance between nucleoside analogues deserves maximal attention to ensure optimal antiretroviral therapy and design algorithms for antiretroviral management based on genotypic antiretroviral resistance testing. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Mutation; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Zidovudine | 1999 |
Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir.
Current treatments for human immunodeficiency virus (HIV) require uninterrupted drug administration because they are unable to reconstitute the immune response and do not affect the viral reservoir. Ten patients were treated during acute HIV infection before complete Western blot (WB) seroconversion with the combination of hydroxyurea, didanosine, and indinavir. This treatment was associated with the normalization of some immune parameters and functions. No loss of naive CD4 T lymphocytes was observed, and recovery of up to 35% of naive CD8 T lymphocytes occurred in several weeks. A vigorous HIV-specific T helper response (stimulation index >8) was observed in 7 of 8 patients treated before complete WB seroconversion but in only 1 of 5 controls treated after seroconversion. In addition, a limited latent viral reservoir (<0.02-0.5 infectious units/106 cells) was documented in quiescent peripheral blood lymphocytes after treatment initiated before complete WB seroconversion. Topics: Anti-HIV Agents; Blotting, Western; CD4 Lymphocyte Count; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Flow Cytometry; HIV Antibodies; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Indinavir; Lymphocyte Activation; Viral Load | 1999 |
Combined antiviral therapy reduces HIV-1 plasma load and improves CD4 counts but does not interfere with ongoing lymphocyte apoptosis.
The progression of HIV-1 disease appears associated with an unregulated Fas-mediated apoptosis of lymphocytes that involves the activation of ICE protease and ceramide generation and antiviral therapy may not be fully effective in the absence of a relevant impact on apoptosis. Six drug-naive HIV-1-infected symptomless patients with advanced immunodeficiency were treated with combined AZT and ddl for 4 months; plasma HIV-1 RNA levels, the counts of CD4 cells, CD4 and CD8 apoptotic lymphocytes, Fas-positive cells and ICE-positive cells, and intracellular ceramide levels were measured at base-line and after 7, 45 and 120 days of treatment. There was a prompt reduction in plasma viremia and a secondary increase in CD4 counts, but the treatment had no impact on apoptotic CD4 and CD8 lymphocytes, Fas-positive cells and ICE-positive cells, and on the intracellular levels of ceramide. A discrepancy exists between the positive impact of combined AZT and ddl treatment on plasma viral load and CD4 counts and the lack of any effect on the process of lymphocyte apoptosis. We suggest to use the measurement of apoptotic lymphocytes as a surrogate marker to predict, in combination with viral load and CD4 counts, a large proportion of the clinical effect of antiviral therapy. Topics: Adult; Anti-HIV Agents; Apoptosis; Caspase 1; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Ceramides; Didanosine; Drug Therapy, Combination; fas Receptor; HIV Infections; HIV-1; Humans; Male; Mitochondria; Viral Load; Viremia; Zidovudine | 1999 |
A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study.
Most current guidelines state that antiretroviral therapy should be considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml and CD4 cells > 500 x 10(6) cells/l. However, there is increasing concern about whether this is the optimal point to begin treatment or whether it is better to delay the initiation to more advanced stages.. To study the immunological and virological benefits of starting antiretroviral therapy at these early stages.. A total of 161 HIV-infected asymptomatic patients with CD4 cell count > 500 x 10(6) cells/l and viral load > 10000 copies/ml were randomly assigned to one of five treatment groups: no treatment, twice daily zidovudine and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and didanosine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice daily three-drug regimen with stavudine and lamivudine and ritonavir. The endpoints were progression to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10(6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load > 0.5 log10 copies/ml above baseline, or to AIDS or death. In various substudies, the lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to mitogens and cytomegalovirus, and HIV-1 specific antigens and other immunophenotypic markers were also analysed.. Progression rates to study endpoints within 1 year were greater in the control group (31%) than in all groups receiving antiretroviral therapy pooled together (5%; estimated hazard ratio 7.41; 95% confidence interval 5.72-74.55; P < 0.001). The peak mean viral load decrease was greater in the three-drug group when compared with any of the three groups with a two-drug regimen (2.32, 1.65, 1.72 and 1.84, respectively; P < or = 0.001). At 1 year, viral load remained below 20 copies/ml in 30 out of 33 patients in the three-drug group (91%) and in only eight out of 94 patients (9%) in two-drug groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x 10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the three-drug group regimen had to change the therapy as a result of adverse events. Substudies were performed in 60 patients recruited at two sites. Tonsillar tissue HIV RNA was measured in seven patients (two in the two-drug groups and five in the three-drug group) in whom plasma HIV RNA was < 20 copies/ml at 1 year. It was 15151 and 133333 copies/mg tissue in the two patients from the two-drug group, < 40 copies/mg tissue in four patients in the three-drug group, and 485 copies/mg in one patient in the three-drug group. At 1 year there was a mean increase of 4.21+/-2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48+/-3.36% in the two-drug groups (P = 0.01), and 19.87+/-3.64 in the three-drug group (P = 0.001 and P = 0.05, for comparisons with control group and two-drug groups, respectively). Although proliferative responses to cytomegalovirus antigens were significantly greater in those receiving antiretroviral therapy, response to HIV-1 p24 antigen was not detected in any patient in either treatment group.. This study supports the recommendation to start antiretroviral therapy with a three-drug combination during very early stages of HIV-1 disease, at least if viral load is above a cut-off point (10000 copies/ml in our study). The risk of progression was sevenfold higher in non-treated patients at 8 months of follow-up. Some immune system parameters improved toward normal values after 1 year of antiretroviral therapy, but the proliferative response of CD4 T lymphocytes against the p24 HIV-1 antigen was not recovered. Therapeutic approaches with more potent, better-tolerated and more convenient regimens will increasingly favour early intervention with antiretroviral t Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Palatine Tonsil; Ritonavir; RNA, Viral; Spain; Stavudine; Viremia; Zalcitabine; Zidovudine | 1999 |
Comparison of once and twice daily dosing of didanosine in combination with stavudine for the treatment of HIV-1 infection. AI 454-146 Team.
To compare the antiviral activity, safety and tolerability of didanosine dosed once and twice daily when administered in combination with stavudine dosed twice daily in human immunodeficiency virus type 1 (HIV-1)-infected individuals with little or no previous exposure to antiretroviral drugs.. Comparative, multicentre, randomized, open-label, short-term study.. Eighty-four HIV-1-infected adults with qualifying baseline CD4 cell counts of 200 to 500 cells/mm3 were included in the study. Of these, 43 patients received once daily didanosine plus twice daily stavudine (group A) and 41 subjects received twice daily didanosine plus twice daily stavudine (group B). The primary efficacy analysis used was the time-averaged difference (TAD) between treatment regimens of variations in plasma HIV-1 RNA levels from baseline over the first 12 weeks of therapy. Plasma HIV-1 RNA levels, CD4 cell counts and adverse events were monitored.. At week 12, median HIV-1 RNA variations were -1.18 log10 copies/ml in group A and -0.88 log10 copies/ml in group B. For patients who were followed up to week 24, median variations of HIV-1 RNA levels from baseline were -1.21 log10 copies/ml in group A and -0.78 log10 copies/ml in group B. The TAD between the two treatment groups for variations from baseline plasma HIV-1 RNA levels over the first 12 weeks was 0.10 log10 copies/ml (95% confidence interval, -0.19 to 0.40), indicating equivalence.. Once daily didanosine plus twice daily stavudine and twice daily didanosine plus twice daily stavudine are equally effective in reducing plasma HIV-1 RNA levels and increasing CD4 cell counts. Both regimens are safe and well tolerated. Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Factors; RNA, Viral; Stavudine | 1999 |
Meta-analysis of two randomized controlled trials comparing combined zidovudine and didanosine therapy with combined zidovudine, didanosine, and nevirapine therapy in patients with HIV. INCAS study team.
To extend the range of CD4 counts in which a plasma viral load nadir (pVL) <20 copies/ml was known to be predictive of the duration of virologic response. To determine whether baseline pVL is predictive of virologic response during the study periods.. A meta-analysis was conducted of the original individual patient data from two randomized controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP).. In total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects on triple therapy with baseline pVL <100,000 copies/ml were more likely to achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml (OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir <20 copies/ml and between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26), respectively, compared with patients with a pVL nadir >400 copies/ml.. We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression. Topics: Adult; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis; Nevirapine; Proportional Hazards Models; Viral Load; Zidovudine | 1999 |
The safety profile and antiviral activity of the combination of stavudine, didanosine, and nelfinavir in patients with HIV infection.
We assessed the safety profile, tolerability, and antiviral effect of 12 weeks of triple combination therapy with stavudine (d4T), didanosine (ddI), and nelfinavir in patients who had not previously received therapy with d4T, ddI, or a protease inhibitor. We also assessed the effect of the buffered tablet formulation of ddI on the pharmacokinetics of nelfinavir. The study had a single-arm, open-label design and enrolled patients aged > or =18 years who had HIV infection and > or =10,000 plasma HIV RNA copies/mL. Patients received the full recommended doses of oral d4T, ddI, and nelfinavir. Efficacy was assessed in terms of change from baseline in plasma HIV RNA and CD4+ cell counts, as well as in terms of the proportion of patients achieving HIV RNA levels <400 copies/mL. The first 10 patients enrolled in the study were included in a substudy to determine the effects of the buffered tablet formulation of ddI on the pharmacokinetic profile of nelfinavir. A dose of ddI was given 1 hour before nelfinavir, after which the maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve (AUC) of nelfinavir were determined. A total of 22 patients entered the trial, of whom 1 (5%) had AIDS, 12 (55%) had symptomatic HIV infection, and 9 (41%) were asymptomatic. The median baseline CD4+ cell count was 315 cells/microL (range, 70-709 cells/microL), and the median plasma viral load was 4.8 log10 copies/mL (range, 4.0-5.6 log10 copies/mL). ddI had no clinically significant effects on the plasma pharmacokinetics of nelfinavir. At the end of 12 weeks of treatment, the mean (+/- SE) decrease in plasma viral load was 1.36+/-0.24 log10 copies/mL, and 8 of 16 patients (50%) achieved plasma HIV RNA levels <400 copies/mL; the mean (+/- SE) increase in CD4+ cell count was 111.4+/-31.7 cells/microL. Patients who were judged to be compliant with antiretroviral therapy (ie, who missed <7 days of all 3 study drugs during 12 weeks of treatment) experienced mean decreases in viral load exceeding 2.0 log10 copies/mL, and 6 of 7 patients achieved HIV RNA levels <400 copies/mL after 12 weeks of therapy. Although 95% of patients reported an adverse event of grade 1 or higher, only 1 patient experienced a grade 3 or 4 adverse event (maculopapular rash) related to nelfinavir. As reflected in the Cmax, Tmax, and AUC, administration of ddI 1 hour before nelfinavir did not influence the pharmacokinetic profile of the protease inhibitor. Triple drug thera Topics: Administration, Oral; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Nelfinavir; RNA, Viral; Safety; Stavudine; Treatment Outcome; Viral Load | 1999 |
Interleukin-2 in combination with zidovudine and didanosine is able to maintain high levels of CD4 cells and undetectable HIV viraemia.
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Interleukin-2; Leukocyte Common Antigens; Male; Pilot Projects; RNA, Viral; Viremia; Zidovudine | 1998 |
A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection.
Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects.. HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m given every 12 hours) were evaluated in two age groups (2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks.. A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m for the 24-week period.. The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine. Topics: Administration, Oral; Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Male; Ritonavir; Viral Load; Zidovudine | 1998 |
Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects.
The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddI), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T-lymphocyte count > or =100 cells/microl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in Cmax and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6% and 19.5%, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0% and 114.6%; and for ddI administered simultaneously with ganciclovir, 107.9% and 107.1%, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir Cmax and AUC(0-8) when coadministered with AZT. Mean increases in Cmax and AUC(0-8) of oral ganciclovir averaged 40.1% and 52.5%, respectively, when coadministered with probenecid, but decreased by 22.1% and 22.7%, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir Cmax or AUC(0-8) when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19% when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI c Topics: Administration, Oral; Adult; Anti-HIV Agents; Antiviral Agents; Area Under Curve; Didanosine; Drug Interactions; Female; Ganciclovir; Half-Life; HIV Infections; Humans; Male; Probenecid; Renal Agents; Zidovudine | 1998 |
Changes in virologic markers as predictors of CD4 cell decline and progression of disease in human immunodeficiency virus type 1-infected adults treated with nucleosides. AIDS Clinical Trials Group Protocol 175 Team.
The associations of CD4 cell count, plasma human immunodeficiency virus (HIV) type 1 RNA, infectious HIV titer in peripheral blood mononuclear cells, immune complex-disrupted (ICD) p24 antigen, and MT-2 assays with measures of disease progression after drug treatment were assessed in a subset of patients enrolled in AIDS Clinical Trials Group Study 175. Baseline plasma RNA levels and changes in RNA values at weeks 8 or 56 were more important predictors of disease progression than were baseline or changes in CD4 cell counts. Each 10-fold lower HIV RNA concentration at baseline and each 10-fold decrease in HIV RNA between baseline and week 8 was associated with increases of 49-61 CD4 cells/mm3 at weeks 56 and 104. In multivariate analyses, neither baseline values nor changes in infectious HIV titer nor ICD p24 antigen concentrations were associated with long-term changes in CD4 cell count. Plasma HIV-1 RNA appears to be the best predictor of long-term CD4 cell count responses and disease progression. Topics: Adult; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Disease Progression; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Multivariate Analysis; Prognosis; Reverse Transcriptase Inhibitors; RNA, Viral; Zalcitabine; Zidovudine | 1998 |
Antiviral effect of double and triple drug combinations amongst HIV-infected adults: lessons from the implementation of viral load-driven antiretroviral therapy.
To study the antiviral effect and predictors of response to two- and three-drug regimens amongst antiretroviral-naive individuals using an intent-to-treat analysis.. Suppression of plasma viral load to < 500 copies/ml.. A total of 420 (264 double drug, 156 triple drug) individuals in a province-wide treatment programme were studied.. A decrease in plasma viral load to < 500 copies/ml was documented in 197 (47%) subjects. This was independently associated with a lower baseline plasma viral load (odds ratio, 3.67; 95% confidence interval, 2.13-6.30) and initiation onto a three-drug regimen (odds ratio, 3.86; 95% confidence interval, 2.24-6.66). Median plasma viral load failed to reach < 500 copies/ml and in fact rebounded in the two-drug group. In contrast, 91 (58%) subjects receiving three drugs reached < 500 copies/ml during the study period.. These results support the use of powerful triple drug regimens as initial therapy in HIV-infected individuals. Topics: Adult; Anti-HIV Agents; Cohort Studies; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Multivariate Analysis; Stavudine; Viral Load; Zalcitabine; Zidovudine | 1998 |
The effects of lamivudine treatment on HIV-1 disease progression are highly correlated with plasma HIV-1 RNA and CD4 cell count.
To determine the value of plasma HIV-1 RNA and CD4 cell count as predictors of the clinical benefit of antiretroviral treatment.. The CAESAR (Canada, Australia, Europe, South Africa) trial randomized 1840 patients [inclusion CD4 cell count, 25-250 x 10(6)/l] to add either placebo, lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline treatments (zidovudine, zidovudine-didanosine or zidovudine-zalcitabine) for 1 year.. This analysis included 487 patients with data on CD4 cell count and HIV-1 RNA after 12-20 weeks of treatment and subsequent follow-up for clinical progression.. The correlation between 12-20-week change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the placebo group was used to predict the clinical benefit of the 3TC-containing arms of the trial, given their effects on CD4 cell count and HIV-1 RNA.. After 12-20 weeks of treatment, HIV-1 RNA fell by 0.37 log10 copies/ml in the 3TC arms versus a rise of 0.05 log10 copies/ml in the placebo arm. The 12-20-week CD4 cell count rose by 35 x 10(6)/l in the 3TC arm versus a fall of 8 x 10(6)/l in the placebo arm. After 12-20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10 at 12-20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.87] and a rise in CD4 cell count of 50 x 10(6)/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33-0.73). Using the model from the placebo arm, the rises in CD4 cell count and reductions in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to AIDS or death. The observed clinical benefit was a 57% reduction in progression for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26-0.71).. Rises in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the clinical benefit of 3TC in the CAESAR trial. Topics: Acetamides; Acetophenones; Acquired Immunodeficiency Syndrome; Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; RNA, Viral; Treatment Outcome; Viral Load; Zalcitabine; Zidovudine | 1998 |
A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study.
Current guidelines recommend that individuals infected with the human immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral agents to achieve sustained suppression of viral replication as measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission of the disease. However, until recently, many drug combinations have not led to sustained suppression of HIV-1 RNA.. To compare the virologic effects of various combinations of nevirapine, didanosine, and zidovudine.. Double-blind, controlled, randomized trial.. University-affiliated ambulatory research clinics in Italy, the Netherlands, Canada and Australia (INCAS).. Antiretroviral therapy-naive adults free of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and 0.60x10(9)/L (200-600/microL).. Patients received zidovudine plus nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine plus nevirapine.. Plasma HIV-1 RNA.. Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.001). Viral amplification was attempted in 59 patients at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus could be amplified, resistance to nevirapine was found in all 11 patients receiving zidovudine plus nevirapine and in all 5 patients receiving triple drug therapy. Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08).. Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; RNA, Viral; Viral Load; Zidovudine | 1998 |
A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddI) in children infected with the human immunodeficiency virus.
Twelve children infected with the human immunodeficiency virus were treated orally with indinavir, stavudine, plus didanosine for 12 to 48 weeks. Therapy was limited in some cases by nonadherence, intolerance, toxicity, and virologic failure. Marked increases in CD4+ lymphocyte counts and decreases in plasma human immunodeficiency virus RNA concentrations suggest that the regimen has potent antiviral activity. Topics: Administration, Oral; Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Chromatography, High Pressure Liquid; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Male; Pilot Projects; RNA, Viral; Stavudine | 1998 |
Relationship between didanosine exposure and surrogate marker response in human immunodeficiency virus-infected outpatients.
We used information available from routine clinic visits to characterize the pharmacokinetics of didanosine in 82 human immunodeficiency virus-infected patients. A total of 271 blood samples were collected for the measurement of didanosine concentrations in plasma (mean +/- standard deviation [SD], 3.30 +/- 2.21 samples/patient). Bayesian estimates of didanosine oral clearance (CL[oral]) were obtained for these patients by the POSTHOC option within the NONMEM software package. Population priors from a previous NONMEM analysis of didanosine pharmacokinetics were used. The mean +/- SD CL(oral) was 132 +/- 27.7 liters/h, which agrees reasonably well with estimates obtained from previous pharmacokinetic studies of didanosine. Estimates of individual didanosine exposure were then used to consider potential relationships between drug exposure and surrogate marker response over a 6-month period. No correlations were found between the didanosine area under the concentration-time curve from 0 to 6 months and the absolute CD4 cell count (r = 0.305; 0.1 < P < 0.2), weight response (r = 0.0857; P > 0.4), or percentage of CD4 lymphocytes (r = 0.0559; P > 0.4). Future efforts to characterize didanosine exposure in outpatients by random sampling methods should involve more directed efforts to limit residual variability in the data. Topics: Adult; Aged; Antiviral Agents; Area Under Curve; Biomarkers; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis | 1998 |
[Efficacy of combining zidovudine plus didanosine in patients with and without previous exposure to zidovudine].
The virologic and immunologic efficacy of the combination of zidovudine (ZDV) and didanosine (DDI) was examined in 27 HIV-infected patients.. 27 HIV-infected patients, 15 of whom were naive for antiretroviral drugs. The remaining 12 subjects had been exposed to ZDV for at least 16 weeks. Mean plasma viral load was of 4.7 logs and 4.5 logs, respectively. All patients had less than 350 x 10(6)/l CD4+ T lymphocytes at baseline.. Significant reductions in viremia (> 0.5 logs) were seen at the first and third months, respectively, in 71.4% and 64.3% of naive patients. In contrast, it occurred only in 10% and 0%, respectively, of pre-treated patients. Moreover, the CD4 count only increased significantly (> 15%) in naive individuals. Changes in serum p24 antigenemia were not significant in both groups neither at the first nor at the third months of began therapy.. The antiviral efficacy of the ZDV plus DDI combination is limited and transient in patients with advanced HIV disease, and disappears in subjects already exposed to ZDV. Topics: Adult; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Viral Load; Zidovudine | 1998 |
A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study.
To explore the short-term effects on surrogate markers for HIV progression of didanosine (ddl) plus stavudine (d4T), with or without hydroxyurea.. Randomized, double-blinded, prospective study.. Swiss HIV Cohort Study.. A total of 144 patients (75% antiretroviral-naive) were studied (mean baseline HIV-1 RNA, 4.53 log10 copies/ml; mean CD4 cell count, 370 x 10(6)/l).. Patients received ddl (200 mg twice daily) plus d4T (40 mg twice daily), with additional hydroxyurea (500 mg twice daily) or placebo.. The primary endpoint was a reduction of viraemia below 200 copies/ml after 12 weeks. At that time, patients who did not reach the primary endpoint were withdrawn in the hydroxyurea arm, whereas patients in the placebo group had the option of adding hydroxyurea to ddl and d4T. All patients were followed until week 24.. After 12 weeks, 54% of the patients randomized to hydroxyurea had viraemia below 200 copies/ml, compared with 28% on placebo (P < 0.001). Using an ultrasensitive assay with a limit of detection of 20 copies/ml, 19% of patients receiving hydroxyurea had viraemia levels below 20 copies/ml, compared with 8% on placebo (P = 0.05). Mean decrease in HIV-1 RNA was 2.3 and 1.7 log10 copies/ml for hydroxyurea and placebo groups, respectively (P = 0.001). Hydroxyurea was found to induce lymphopenia (-124 x 10(6)/l). Increase in CD4 cell counts was +28 x 10(6)/l during hydroxyurea treatment compared with +107 x 10(6)/l on placebo (P = 0.001).. Hydroxyurea improved the antiviral activity of d4T and ddl over a 12-week period, but was associated with a smaller increase in CD4 cell counts due to hydroxyurea-induced lymphopenia. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Didanosine; Double-Blind Method; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Middle Aged; Prospective Studies; RNA, Viral; Stavudine; Switzerland; Viremia | 1998 |
An open-label pilot study of the efficacy and tolerability of once-daily didanosine versus twice-daily didanosine.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; HIV Infections; Humans; Male; Pilot Projects; Viral Load | 1998 |
Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV-infected patients.
The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddI's systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically. Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir | 1998 |
Cellular proviral HIV type 1 DNA load persists after long-term RT-inhibitor therapy in HIV type 1 infected persons.
In a set of 42 antiretroviral naive HIV-1 infected persons who were treated with either Zidovudine (AZT) monotherapy, or a combination of AZT + ddC (Zalcitabine) or AZT + ddI (Didanosine), the HIV-1 DNA load was measured by competitive polymerase chain reaction (PCR) and related to the HIV-1 RNA load in plasma, the CD4+ counts and to clinical markers. The question was whether a reduction in the cellular HIV-1 DNA level contributes to clinical benefit, as predicted by a lasting response in HIV-1 RNA levels in plasma. No significant decline relative to baseline in HIV-1 DNA load was found in the AZT monotherapy arm. In this arm the differences from baseline for both HIV-1 RNA load and CD4+ T cell counts were small and transient. In both combination therapy arms, the maximum mean decline in HIV-1 DNA load was 0.6 log and it never differed significantly from baseline. This is in contrast to plasma HIV-1 RNA load that declined earlier and steeper (mean of 1.5 and 1.9 log for AZT + ddC and AZT + ddI, respectively) and that remained significantly below baseline for 80 weeks. Although 9 of 42 (32%) of the patients under combination therapy had prolonged decreased plasma RNA levels, the proviral HIV-1 DNA remained present in the cells throughout the total follow-up of 144 weeks. In conclusion, combination therapy showed better laboratory parameter responses than AZT monotherapy, in agreement with the clinical data. The HIV-1 DNA sequences did not disappear in any of the patients, heralding renewed active infection after cessation of therapy. Topics: Anti-HIV Agents; Base Sequence; Didanosine; DNA Primers; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Proviruses; Reverse Transcriptase Inhibitors; Viral Load; Zalcitabine; Zidovudine | 1998 |
Predictive factors influencing peak viral load drop in response to nucleoside reverse transcriptase inhibitors in antiretroviral-naive HIV-1-infected patients.
Therapy with two nucleoside reverse transcriptase inhibitors (NRTI), the backbone of triple combinations, is still widely used in early stages of HIV-1 disease. However, factors influencing virologic response need to be further analyzed, to test the hypothesis that the reduction of plasma RNA viremia with NRTI may be greater in patients with higher baseline viral load (BVL) and to analyze the predictive factors of viral load drop below detection (200 HIV RNA copies/ml of plasma). Selected for the study were 169 HIV-1-infected antiretroviral therapy-naive patients with CD4+ T-lymphocyte counts ranging from 6 to 1040/microl coming from three randomized studies comparing the efficacy of monotherapy (zidovudine [ZDV], 250 mg every 12 hours; N=40) versus two-drug therapy consisting of ZDV (250 mg every 12 hours) with dideoxycytidine (ddC, 0.75 mg every 8 hours) or didanosine (ddI, 200 mg every 12 hours; N=129). Viral load was measured at 1, 3, and 6 months by polymerase chain reaction (PCR). A linear regression model was used to analyze the relation between BVL and the peak reduction of plasma RNA viremia. The variables included in a logistic regression model to determine the likelihood of VLs dropping below detection levels were age, gender, risk group for HIV-1 infection, baseline CD4+ lymphocyte count, BVL, clinical status (AIDS versus non-AIDS), HIV-1 phenotype (syncytium-inducing [SI] versus non-syncytium-inducing [NSI]) and type of treatment (monotherapy versus double therapy). The peak reduction of VL was related to baseline level following a linear model in both monotherapy and double-therapy regimens. In the subgroup of patients treated with two NRTIs, the regression line that fitted best with the data was log10 (peak reduction)=1.8-0.36 log10 (BVL) (F=23.5; p < .0001). This indicates that for every increase of 1 log10 of BVL, the peak reduction would be of 0.64 log10 greater. Forty-nine (29%) of the 169 patients dropped to <200 copies/ml. The likelihood of dropping below detection level was significantly greater in those receiving double therapy versus monotherapy (odds ratio [OR]=16.1; 95% confidence interval [CI], 2-128), in those with baseline CD4+ lymphocyte count >350/microl (OR=2.28; 95% CI, 1.1-4.9) and in those with BVL <10,000 HIV-1 RNA copies/ml (OR= 2.25; 95% CI, 1.1-6.1). None of the 13 patients with an SI phenotype at baseline dropped below detection levels. The reduction of VL in response to two NRTIs was greater in those patients with Topics: Adult; Analysis of Variance; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; Giant Cells; HIV Infections; HIV-1; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Phenotype; Probability; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors; Viral Load; Zalcitabine; Zidovudine | 1998 |
Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy.
Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml.. Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment.. One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir < or = (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir < or = 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001).. Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection. Topics: Anti-HIV Agents; Australia; Canada; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Italy; Netherlands; Nevirapine; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine | 1998 |
A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team.
The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 300 assessed the clinical efficacy and safety of combination zidovudine/lamivudine (ZDV/3TC) compared with either didanosine (ddI) alone or combination ZDV/ddI.. Children with symptomatic human immunodeficiency virus (HIV) infection, 6 weeks through 15 years of age, were stratified according to age and randomly assigned to receive ddI, ZDV/3TC, or ZDV/ddI. The primary endpoint was time to first progression of HIV disease or death. Enrollment in the ZDV/ddI arm stopped after 11 months on the basis of results of PACTG Protocol 152, but blinded follow-up continued.. For the 471 children who could be evaluated, the median age was 2.7 years, median CD4 cell count was 699 cells/mm3, and median log10 HIV RNA was 5.1/mL. Median follow-up was 9.4 months. Patients receiving ZDV/3TC had a lower risk of HIV disease progression or death than those receiving ddI alone (15 vs 38 failures, P = .0006) and a lower risk of death (3 vs 15 deaths, P = .0039). Weight and height growth rates, CD4+ cell counts, and RNA concentrations showed results favoring ZDV/3TC. For patients concurrently randomized to all 3 treatment arms, both ZDV/3TC and ZDV/ddI recipients had lower risk of HIV disease progression than those who received ddI alone (P = .0026 and P = .0045).. Combination therapy with either ZDV/3TC or ZDV/ddI was superior, as determined by clinical and laboratory measures, to monotherapy with ddI. Topics: Adolescent; Anti-HIV Agents; CD4 Antigens; Child; Child, Preschool; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Male; Neurodegenerative Diseases; Polymerase Chain Reaction; RNA, Viral; Survival Rate; Zidovudine | 1998 |
A randomized double-blind trial of the addition of lamivudine or matching placebo to current nucleoside analogue reverse transcriptase inhibitor therapy in HIV-infected children: the PENTA-4 trial. Paediatric European Network for Treatment of AIDS.
To evaluate the toxicity, tolerability and effect on laboratory markers of adding lamivudine (3TC) to nucleoside analogue reverse transcriptase inhibitors (NRTI) in children with HIV-1 infection.. Randomized double-blind trial.. HIV-1-infected children on stable NRTI therapy were randomized to receive 3TC syrup or tablets (4 mg/kg twice daily) or matching placebo in addition to existing therapy. Endpoints were serious adverse events, and changes in CD4 cell count and plasma HIV-1 RNA. Analyses were on an intention-to-treat basis.. A total of 162 (81 on 3TC, 81 on placebo) children [median age, 6.5 years; interquartile range (IQR), 4.1-10.1 years] were included. At randomization, 52 were receiving zidovudine (ZDV), 39 didanosine (ddl), 54 ZDV-ddl and 17 ZDV-zalcitabine (ddC); 32 (20%) had AIDS; median CD4 cell count was 328 x 10(6)/I (IQR, 127-696 x 10(6)/l), and median HIV-1 RNA was 4.9 log10 copies/ml (IQR, 4.3-5.4 log10 copies/ml). Median follow-up was 40 weeks (IQR, 29-49 weeks) and 76% of follow-up was on blinded therapy for both 3TC and placebo groups. There were 11 serious adverse events in the blinded phase [two clinical (both placebo) and nine laboratory (five 3TC, four placebo)], five (two 3TC, three placebo) resulting in stopping trial drug. At 24 weeks, the CD4 cell count was greater in the 3TC group by a median of 47 x 10(6)/l and HIV-1 RNA was lower by 0.30 log10 copies/ml (P = 0.03 and 0.002, respectively, versus the placebo group). The difference in reduction in HIV-1 RNA up to 24 weeks, as measured by area under the curve minus baseline, between 3TC and placebo groups was 0.38 log10 copies/ml (95% confidence interval, 0.12-0.65) greater in children taking ZDV-containing regimens at baseline, compared with those on ddl monotherapy (P = 0.005), after adjusting for other factors at baseline. Thirteen children developed new AIDS events (six on 3TC, four on placebo) of whom three died (all placebo).. The addition of 3TC to current NRTI therapy in children was safe and well-tolerated. There was evidence that treatment changes in HIV-1 RNA viral load were greater in children taking regimens that included ZDV. Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome; Viral Load; Zalcitabine; Zidovudine | 1998 |
Individual prognoses of long-term responses to antiretroviral treatment based on virological, immunological and pharmacological parameters measured during the first week under therapy.
To predict long-term (12 weeks or longer) virological responses to antiretroviral treatment from measurements made during the first few days on therapy.. Forty-one HIV-1-infected children were treated with ritonavir for 12 weeks followed by triple drug combination treatment, and the kinetics of virus decay in plasma, ritonavir concentration and CD4 cell counts were measured. A robust multivariate pattern recognition method was used for prediction of the longterm virological responses.. The virus decay rate constants calculated from measurements of plasma viral RNA concentrations on the first, second, third, fourth and seventh day on therapy, the drug concentrations in the plasma on day seven, and the pretreatment levels of viral RNA and CD4 cell counts, correlated with long-term levels of plasma HIV-1 RNA. The combination of these parameters contained sufficient information for correct and robust prediction of the long-term response in 88% of the treated children. The predictions of individual responses were stable as demonstrated by a cross-validation analysis, which was highly statistically significant (r=0.87) and specific.. These results demonstrate that multiple parameters determine the response to antiretroviral therapy and offer a very early measure of individual long-term responses, suggesting that treatment could be optimized after few days of therapy. Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Prognosis; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load; Zidovudine | 1998 |
Efficacy and safety of stavudine and didanosine combination therapy in antiretroviral-experienced patients.
To assess the efficacy, tolerance, and safety of combination antiretroviral therapy with didanosine and stavudine in HIV-infected patients with CD4+ cell counts > 100 x 10(6)/l and HIV plasma RNA > 10(4) copies/ml previously treated with other antiretroviral agents for at least 3 months.. In this open, multicentre, non-randomized, Phase II pilot study, adult patients were administered didanosine (200 mg twice daily) plus stavudine (40 mg twice daily) for 6 months. Patients for whom the first regimen had led to undetectable HIV RNA levels were offered a second 6-month course of treatment; those who had achieved insufficient immunological and virological gains in the first 6 months were given a new combination.. Primary evaluation of efficacy was based on viral load measured by branched DNA second-generation testing (lower limit of detection, 500 copies/ml) and CD4+ cell counts; secondary evaluations included AIDS-defining events and clinical side-effects.. Sixty-five patients with median prior antiretroviral therapy of 24 months (65 with zidovudine, 29 with zalcitabine) were included in the study. At baseline, median CD4+ cell count was 198 x 10(6)/l and median plasma HIV RNA was 80000 copies/ml (4.9 log10 copies/ml). In this heavily pretreated population, an increase in the mean CD4+ cell count was observed (+70 x 10(6)/l at 24 weeks). In addition, rapid and prolonged antiviral activity was seen, with a mean maximal decrease of 1.1 log10 copies/ml at week 4, a mean decrease of 0.89 log10 copies/ml at week 24, and a plasma RNA viraemia < 500 copies/ml achieved in 14% of patients at week 24.. Combination therapy with stavudine and didanosine is safe and leads to a sustained antiviral effect, even in patients with prolonged prior antiretroviral exposure and low CD4+ cell counts. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Pilot Projects; Reverse Transcriptase Inhibitors; Stavudine; Viral Load | 1998 |
A trial comparing nucleoside monotherapy with sequential therapy with 3 drugs in HIV-infected patients.
53 HIV-positive patients, 66% of them zidovudine-experienced, were randomized to receive monotherapy with zidovudine or sequential therapy with zidovudine, didanosine and zalcitabine. Clinical end points, CD4 cell count change, and analysis abnormalities showed better results with sequential therapy. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors; Treatment Outcome; Zalcitabine; Zidovudine | 1998 |
Pharmacokinetics, safety and anti-human immunodeficiency virus (HIV) activity of hydroxyurea in combination with didanosine.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Hydroxyurea; Male; Middle Aged; Nucleic Acid Synthesis Inhibitors | 1998 |
Comparison of the plasma pharmacokinetics and renal clearance of didanosine during once and twice daily dosing in HIV-1 infected individuals.
To compare the plasma pharmacokinetics of didanosine during once daily (qd) and twice daily (bid) dosing.. Open-label, randomized, cross-over study.. HIV-1 infected patients who used didanosine were randomized to either a qd or a bid dosing regimen of didanosine. The total daily dose of didanosine was identical in both regimens. Seven days after the start of the study, the pharmacokinetic profile of didanosine in plasma and urine was assessed during an 8-h period. The next day, the patient was switched to the opposite dosing regimen, and after another 7 days, the study was concluded by again assessing the plasma and urine pharmacokinetics of didanosine during 8 h.. A total of 19 patients completed the study. The pharmacokinetics of didanosine in plasma (with maximum plasma concentration adjusted for dose) and urine were not significantly different in the qd and bid dosing regimen (P > 0.28 for all parameters).. We conclude that qd dosing of didanosine leads to a similar exposure in plasma as bid dosing (using the same total daily dose). Since qd dosing may lead to improved compliance of patients to regimens containing didanosine, these results provide a rationale for prescribing didanosine in a qd regimen, and is reassuring when we realize that the drug is being administered in a qd dosing regimen on a large scale in clinical practice. Topics: Adult; Cross-Over Studies; Didanosine; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Structure | 1998 |
Zidovudine therapy and HIV type 1 mutations in children with symptomatic HIV type 1 infection: effect of switching to didanosine or zidovudine plus didanosine therapy. Italian Multicenter Study Group on HIV Mutations in Children.
Type and prevalence of zidovudine (ZDV) resistance mutations in HIV-1-infected children in clinically stable condition and on ZDV monotherapy were analyzed to evaluate the effect of switching to didanosine (ddI) monotherapy or to ZDV plus ddI on the pattern of mutations and on the clinical outcome. Monthly clinical and laboratory controls for HIV-1 infection status were performed; at enrollment and every 4 to 6 months after treatment randomization mutant proviral sequences were evaluated in all the children, whereas viral burden was performed only in a small subgroup of patients randomly selected in each of the three treatment groups. ZDV resistance-associated proviral DNA mutations were defined as low-level resistance (LLR) mutations or medium/high-level resistance (MHLR) mutations; clinical outcome was considered as stable or deteriorating. Results showed that at entry into the study the duration of ZDV therapy was significantly correlated with the presence of mutations, and that the level of resistance given by mutations was associated with the severity both of symptoms and immunodeficiency. After randomization to treatment, in patients with mutations that confer LLR a better clinical outcome with ddI monotherapy than with ZDV plus ddI and ZDV alone was observed in the subsequent 6 months, whereas in patients with mutations that confer MHLR no significant difference among the three treatment groups was found. Data showed also that levels of viral burden at the time of changing therapy are related to clinical outcome if measured by plasma viral load. These results suggest that genotypic resistance assays, together with viral load, may prove useful for rational treatment decisions both at the start of therapy and with failure. Topics: Anti-HIV Agents; Base Sequence; Child; Codon; Didanosine; DNA Primers; Drug Therapy, Combination; Genotype; HIV Infections; HIV-1; Humans; Mutation; Reverse Transcriptase Inhibitors; Zidovudine | 1998 |
Nevirapine/didanosine/lamivudine once daily in HIV-1-infected intravenous drug users.
Human immunodeficiency virus (HIV)-infected, active intravenous drug users received once-daily therapy consisting of a combination of didanosine (2',3'-dideoxyinosine or DDI), lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine or 3TC] and nevirapine. Preliminary results for the first 24 weeks show that the regimen provides potent immunological and antiviral effects. Topics: Adult; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Methadone; Nevirapine; Pilot Projects; Prospective Studies; Substance Abuse, Intravenous; Viral Load | 1998 |
Stavudine plus didanosine and nevirapine in antiretroviral-naive HIV-infected adults: preliminary safety and efficacy results. VIRGO Study Team.
The objective of this open-label trial is to evaluate the virological and immunological effects of triple therapy with stavudine (40 mg twice daily if > or = 60 kg, 30 mg twice daily if < 60 kg)/didanosine (400 mg once daily if > or = 60 kg, 300 mg once daily if < 60 kg)/nevirapine (200 mg daily from day 1 to 14, then 200 mg twice daily) in 60 antiretroviral-naive HIV-infected adults with CD4 cell counts > or = 200 cells/mm3 and plasma HIV RNA > or = 5000 copies/ml. At present, 59 patients have begun receiving the trial regimen. Characteristics of patients at baseline were as follows: 46 men/13 women, CDC stage A, 75%; mean CD4 cell count, 429 cells/mm3; mean HIV RNA, 4.6 log10 copies/ml). Mean decrease of viral load was -1.9 log10 at week 4 (n = 39), -1.9 log10 at week 16 (n = 20), with HIV RNA below the detectable level (< 500 copies/ml) in 62% of patients at week 4 and 85% at week 16. Mean CD4 cell count increase was +118 cells/mm3 at week 4. Cutaneous intolerance occurred within the first 4 weeks in 11/59 (19%) patients after a mean of 14 days (range, 3-24 days) and led to nevirapine discontinuation in 3/11 patients. Preliminary results of this ongoing trial show that combination therapy with stavudine/didanosine/nevirapine is a convenient (seven pills in two daily intakes) triple-therapy regimen with rapid immunological and antiviral effects. Rash, frequent in the first weeks of therapy, usually can be managed without stopping nevirapine. Long-term suppression of plasma HIV RNA with this combination needs to be confirmed but may support use of nevirapine as a component of first-line anti-HIV therapy along with two nucleosides. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Male; Nevirapine; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine | 1998 |
Ongoing open-label trials of triple therapy with stavudine and lamivudine or stavudine and didanosine plus nelfinavir.
The VZN and ZEN studies are non-comparative trials assessing triple combination therapy comprising thymidine and non-thymidine analogue nucleoside reverse transcriptase inhibitors plus a protease inhibitor. Preliminary data are available for the VZN study and recruitment for the ZEN study is underway. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; Stavudine | 1998 |
Didanosine plus stavudine with or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Swiss HIV Cohort Study.
A total of 144 human immunodeficiency virus (HIV)-infected patients (mean CD4 cell count, 367 cells/mm3) were included in a double-blind placebo-controlled trial testing the efficacy on surrogate markers of HIV progression of the combination didanosine (2',3'-dideoxyinosine or DDI) plus stavudine (2',3'-didehydro-2',3'-dideoxythymidine or D4T) with or without hydroxyurea. The primary end point was a reduction of HIV RNA levels to below 200 copies/ml after 12 weeks of treatment. The results showed that the triple combination was associated with a more profound decrease in HIV RNA with an increased proportion of patients with viraemia < 200 copies/ml. This effect persisted for the majority of the patients after a 48 week follow-up. In contrast, the increase in CD4 cell counts was less in patients treated with hydroxyurea because of lymphopenia, and adverse events were more frequent in hydroxyurea-treated patients. In conclusion, the addition of hydroxyurea consistently improved the antiviral activity of the didanosine/stavudine combination over a 48 week follow-up. Increased toxicity and decreased effect on CD4 cell counts might inspire caution. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Synergism; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV-1; Humans; Hydroxyurea; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine | 1998 |
Hydroxyurea for HIV infection.
Hydroxyurea, an inhibitor of DNA synthesis, is used to treat HIV infection. By inhibiting ribonucleotide reductase, hydroxyurea depletes the pool of deoxynucleoside triphosphates, particularly dATP, available for DNA synthesis. Hydroxyurea may be a candidate for use with nucleoside analogs, particularly ddI. Hydroxyurea's use in treating HIV infection with and without ddI, with ddI and without d4T, and with ddI plus a protease inhibitor are discussed. Studies using hydroxyurea with ddI and d4T have shown clinical promise and could be a viable antiretroviral strategy in some patients, especially in countries with limited resources. A regimen containing hydroxyurea, ddI, and a protease inhibitor could be used in aggressive initial or salvage antiretroviral therapy. It is also possible that during acute HIV infection, hydroxyurea's cytostatic properties could contribute to the ultimate preservation of normal immunologic function. Hydroxyurea's dosage level is still uncertain; 500 mg twice daily has been used most often. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; DNA Replication; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Stavudine; Viral Load | 1998 |
Hydroxyurea in HIV therapy.
A 1993 presentation described the role of hydroxyurea in inhibiting HIV replication in peripheral blood mononuclear cells and macrophages as well as a synergistic effect with ddI. How hydroxyurea works and its ability to overcome resistance are discussed, including its effectiveness in stabilizing and improving CD4 counts and viral load levels over a 28-week period. A table presents 12-week study results on nucleoside therapy with hydroxyurea or placebo. Concluding comments discuss hydroxyurea's role in rebuilding the immunity system and its side effects. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Mutation; Placebos; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Viral Load; Virus Replication | 1998 |
Maintaining a low viral load with Nevirapine?
A study called INCAS enrolled 150 treatment-naive subjects. Half of the subjects had CD4+ counts of 370 and a viral load of about 32,000 copies. Subjects were divided into groups that received AZT and Nevirapine, ddI and Nevirapine, or AZT with ddI and Nevirapine. Researchers monitored the subjects for 1 year. Results indicated that subjects who received the triple drug combination had fewer complications and infections. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine | 1998 |
A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV trials network protocol 080.
To assess the in vivo short-term antiretroviral effect of hydroxyurea in human immunodeficiency virus (HIV)-infected persons chronically treated with didanosine (ddI), 26 patients with CD4 cell counts between 100 and 350 were enrolled in a 12-week, open-label pilot study and randomly assigned to receive 500 or 1000 mg/day hydroxyurea. Clinical status, laboratory toxicities, CD4 lymphocyte count, and HIV RNA plasma virus load were assessed weekly. Median declines from baseline of 0.02 and 0.63 log10 HIV-1 RNA copies/mL of plasma were observed for the 500- and 1000-mg/day groups, respectively (P = .02). CD4 cell counts did not change significantly with the addition of hydroxyurea; however, a small but statistically significant decrease in counts was observed during the washout phase. Both doses of hydroxyurea were well-tolerated. These results demonstrate a substantial decrease in plasma virus load when 1000 mg of hydroxyurea is administered over 1 month as adjunctive therapy to ddI among HIV-infected persons with 100-350 CD4 cells/mm3. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Hydroxyurea; Male; Middle Aged; Pilot Projects; RNA, Viral | 1997 |
Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years.
The genetic mechanisms of human immunodeficiency virus type 1 (HIV-1) resistance to dideoxyinosine (ddI) in vivo have been described based on data from primary HIV-1 isolates. To better define the spectrum of HIV-1 reverse transcriptase (RT) changes occurring during ddI therapy, we determined the genotype and ddI susceptibility of the RT gene of HIV RNA isolated from the plasma of 23 patients who had received 1 to 2 years (mean, 87 +/- 16 weeks) of ddI monotherapy. Population-based sequencing of plasma virus showed that 12 of 23 (52%) patients developed known ddI resistance mutations: L74V (7 patients), K65R (2 patients), L74V with M184V (3 patients), and L74V with K65R (1 patient). Five patients developed one or more known zidovudine resistance mutations (at codons 41, 67, 70, 215, and/or 219) during the study. Other amino acid substitutions were found, but only S68G and L210W occurred in more than one patient. Studies of sensitivity to ddI were performed on population-based recombinant-virus stocks generated by homologous recombination between a plasmid containing an HXB2 clone with the RT gene deleted and RT-PCR products of the RT genes from patients' plasma RNA. The sequences of the virus stocks produced by this procedure were typically identical to the sequence of the input PCR product from plasma RNA. Both an MT-2 cell-based culture assay and a cell-free virion-associated RT inhibition assay showed that viruses possessing an L74V and/or M184V mutation or a K65R mutation had reduced sensitivity to ddI. Viruses without these specific mutations had no change in sensitivity to ddI. The results presented here show that the spectrum of RT mutations in a population of patients on ddI monotherapy is more complex than previously described. The development of multiple mutational patterns, including those that confer resistance to other nucleoside analogs, highlights the complexity of using the currently available nucleoside analogs for antiretroviral therapy. Topics: Anti-HIV Agents; Didanosine; Double-Blind Method; Drug Resistance, Microbial; Genotype; HIV Infections; HIV Reverse Transcriptase; Humans; Mutation; Polymerase Chain Reaction; Recombinant Proteins; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine | 1997 |
Phase I dose-escalation pharmacokinetics of AZT-P-ddI (IVX-E-59) in patients with human immunodeficiency virus.
3'-Azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI, IVX-E-59, Scriptene) is a heterodimer composed of one molecule of 3'-azido-3'-deoxythymidine (zidovudine or AZT) and one molecule of 2',3'-dideoxyinosine (didanosine or ddI) linked through their 5' positions by a phosphate bond. AZT-P-ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT-P-ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3. Isotopic preparations of (14C)-AZT-P-(3H)-ddI were administered intravenously (50 mg and 100 mg) to eight patients; 1 month later these patients were crossed over to oral administration (100 mg and 200 mg). A second group of patients (n = 4) received only a 450-mg oral dose of AZT-P-ddI. Plasma levels of unchanged AZT-P-ddI after intravenous infusion declined rapidly and were undetectable 0.75 hours after the end of infusion, whereas the parent compound was not detected after oral administration, indicative of a very rapid metabolism. The parent entity was enzymatically cleaved in vivo yielding the two constituent drugs AZT and ddI, which were subsequently subjected to their respective pharmacokinetic and metabolic processes. The beta-glucuronide derivative of AZT (GAZT) represented the major metabolite of AZT, but there were no detectable levels of the toxic metabolite 3'-amino-3'-deoxythymidine (AMT). A major and previously unrecognized in vivo metabolite of ddI, referred as ddI-M, was detected in plasma and urine. Analysis by high-field proton nuclear magnetic resonance and mass spectrometry led to the identification of ddI-M as being R(-)-dihydro-5-(hydroxymethyl)-2(3H)-furanone. The formation of AZT and ddI metabolites was increased after oral administration of AZT-P-ddI compared with the intravenous infusion, with an area under the concentration-time curve (AUC) ratio of metabolite to AZT and metabolite to ddI being 7.7 and 5.7 (oral) and 3.8 and 1.1 (intravenous), respectively. The newly identified ddI-M exhibited sustained plasma levels for extended time periods with an apparent elimination half-life (t1/2) of approximately 10 hours after oral administration of AZT-P-ddI. Recovery of radioactivity associated with 3H and 14C in urine was essentially complete within 48 hours after oral and intravenous administration of AZT-P-ddI. The oral bioavailability of AZT (64.7-67.3%) and ddI (33.6-42.9% Topics: Administration, Oral; Adult; Anti-HIV Agents; Biological Availability; Didanosine; Dideoxynucleotides; HIV Infections; Humans; Infusions, Intravenous; Male; Zidovudine | 1997 |
Italian multicentre study of didanosine compassionate use in advanced HIV infection. Italian BMS-906 Study Group.
The aim of the present study, a multicentre trial of didanosine (ddI) compassionate use, was to identify factors associated with a better outcome in patients given ddI monotherapy. Enrolled were 1047 HIV-positive patients intolerant of and/or unresponsive to zidovudine (ZDV) therapy, with CD4+ cell counts of < 200/microliter or AIDS. Didanosine was given at a dose of 250 mg b.i.d. (patients > or = 60 kg) or 167 mg b.i.d. (patients < 60 kg). Clinical examinations and laboratory tests were performed every two months. Endpoints included death, the occurrence of a new AIDS-defining disease, or permanent discontinuation of ddI for a severe adverse event. At entry, the median CD41 cell count was 47/microliter and the median duration of prior ZDV treatment 19 months; 446 patients (43%) were classified as having AIDS. Severe toxicity occurred in 143 subjects (14%); the frequency of pancreatitis was very low (0.2%). The benefit in terms of CD4+ cell counts was greater for patients whose counts exceeded 100/microliter at entry and remained at this level until month 12 in those patients still receiving treatment. Death and/or new AIDS-defining events were observed in 374 cases (36%) over a median follow-up of eight months. AIDS dementia was observed in 11 patients (1%). Multivariate analysis of survival without disease progression showed that the factors associated with a worse outcome include the severity of immunodepression, a diagnosis of AIDS at entry, and a history of both intolerance of and clinical resistance to ZDV. Surprisingly, the patients who had received previous prolonged treatment with ZDV had a better outcome. In conclusion, severely immunodepressed patients previously administered long-term monotherapy may receive a short-term benefit from being switched to another antiretroviral drug. Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; AIDS Dementia Complex; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Resistance, Microbial; Female; HIV Infections; Humans; Immunocompromised Host; Italy; Male; Middle Aged; Multivariate Analysis; Pancreatitis; Treatment Outcome; Zidovudine | 1997 |
Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection.
A combination of zidovudine, didanosine, and lamivudine was used to treat 10 patients with primary human immunodeficiency virus type 1 (HIV-1) infection 5-28 days after the onset of symptoms. When therapy began, the mean plasma HIV-1 RNA level was 5.31 +/- 0.33 log10 copies/mL and the mean CD4 T cell count was 630 +/- 112 x 10(6)/L. The plasma HIV-1 RNA level decreased rapidly, and levels dropped below the cutoff in each case after 108 +/- 32 days. Lymph nodes from 5 patients were biopsied before therapy and during follow-up. Infectious HIV-1 could not be cultivated from any lymph node mononuclear cells taken on day 90, and HIV-1 RNA was at very low levels in lymph nodes after 1 year. In some cases, waning of the antibody response to HIV-1 was shown by Western blot after several months of undetectable plasma RNA. These data demonstrate that triple-drug therapy has a potent antiviral effect during primary HIV-1 infection. Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4-CD8 Ratio; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lymphocytes; Male; Pilot Projects; Proviruses; RNA, Viral; Zidovudine | 1997 |
Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection.
In infants and children with maternally acquired human immunodeficiency virus type 1 (HIV-1) infection, treatment with a single antiretroviral agent has limited efficacy. We evaluated the safety and efficacy of a three-drug regimen in a small group of maternally infected infants.. Zidovudine, didanosine, and nevirapine were administered in combination orally to eight infants 2 to 16 months of age. The efficacy of antiretroviral treatment was evaluated by serial measurements of plasma HIV-1 RNA, quantitative plasma cultures, and quantitative cultures of peripheral-blood mononuclear cells.. The three-drug regimen was well tolerated, without clinically important adverse events. Within four weeks, there were reductions in plasma levels of HIV-1 RNA of at least 96 percent (1.5 log) in seven of the eight study patients. Over the 6-month study period, replication of HIV-1 was controlled in two infants who began therapy at 2 1/2 months of age. Plasma RNA levels were reduced by 0.5 to 1.5 log in five of the other six infants.. Although further observations are needed, it appears that in infants with maternally acquired HIV-1 infection, combined treatment with zidovudine, didanosine, and nevirapine is well tolerated and has sustained efficacy against HIV-1. Topics: Administration, Oral; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Male; Nevirapine; Pyridines; RNA, Viral; Viral Load; Zidovudine | 1997 |
Additive or sequential nucleoside analogue therapy compared with continued zidovudine monotherapy in human immunodeficiency virus-infected patients with advanced disease does not prolong survival: an observational study.
To study the effect of sequential or additive use of zalcitabine or didanosine on survival in 308 human immunodeficiency virus-infected patients with advanced disease treated with zidovudine, an observational study using time-dependent Cox proportional hazards models was done. Changing to sequential or additive therapy was based on deterioration of a patient's health status, a significant drop in CD4 cell count, or intolerance for zidovudine. The median CD4 cell count at baseline was 110 x 10(6)/L; 42% of patients had AIDS. The median count before a change in therapy was 50 x 10(6)/L. Additive or sequential treatment was associated with an increased risk for death (relative hazard, 1.59; 95% confidence interval [CI], 1.01-2.49; and 1.58; 95% CI, 1.10-2.37, respectively). Adjustment of the models for prognostic factors failed to substantially affect this observation. Possibly the lack of benefit in this study is because patients switched therapy at advanced stages, whereas the switch may be more effective in early disease. Topics: Adult; Age Factors; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Middle Aged; Prognosis; Proportional Hazards Models; Survival Rate; Treatment Outcome; Zalcitabine; Zidovudine | 1997 |
Alternating treatment with didanosine and zidovudine versus either drug alone for the treatment of advanced HIV infection. The Alter Study. Nordic HIV Therapy Group.
The efficacy and safety of an alternating regime with zidovudine and didanosine versus treatment with either drug alone were investigated in a randomized, open, controlled trial, 552 patients with advanced HIV infection, 47% of whom had received prior treatment with zidovudine, were enrolled. The patients were randomly assigned to zidovudine 600 mg/day, didanosine 400 mg/day or 4-week alternations with the 2 drugs in the same dose. The study had a median length of follow-up of 88 weeks. In the overall analyses, time to death (p = 0.48) and time to death or new AIDA event (0.80) were equally distributed between the 3 treatment groups. In the subgroup of patients with a CD4 count < 100 x 10(6)/l the survival was longer in the alternating arm (p < 0.005) primarily because of differences among zidovudine naive patients. The alternating regime was better tolerated than the 2 monotherapies, with a longer time to dose reduction or withdrawal owing to side effects (p < 0.001). Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Zidovudine | 1997 |
Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team.
Zidovudine has been the drug of choice for the initial treatment of symptomatic children infected with the human immunodeficiency virus (HIV). This trial was designed to assess the efficacy and safety of treatment with zidovudine alone as compared with either didanosine alone or combination therapy with zidovudine plus didanosine.. In this multicenter, double-blind study, symptomatic HIV-infected children 3 months through 18 years of age were stratified according to age (<30 months or > or =30 months) and randomly assigned to receive zidovudine, didanosine, or zidovudine plus didanosine. The primary end point was length of time to death or to progression of HIV disease.. Of the 831 children who could be evaluated, 92 percent had never received antiretroviral therapy and 90 percent had acquired HIV perinatally. An interim analysis (median follow-up, 23 months) showed a significantly higher risk of HIV-disease progression or death in patients receiving zidovudine alone than in those receiving combination therapy (relative risk, 0.61; 95 percent confidence interval, 0.42 to 0.88; P=0.007). The study arm with zidovudine alone was stopped and unblinded; the other two treatment arms were continued. At the end of the study, didanosine alone had an efficacy similar to that of zidovudine plus didanosine (median follow-up, 32 months) (relative risk of disease progression or death, 0.98; 95 percent confidence interval, 0.70 to 1.37; P=0.91). A significantly lower risk of anemia or neutropenia was seen in patients receiving didanosine alone (P=0.036).. In symptomatic HIV-infected children, treatment with either didanosine alone or zidovudine plus didanosine was more effective than treatment with zidovudine alone. The efficacy of didanosine alone was similar to that of the combination therapy and was associated with less hematologic toxicity. Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Therapy, Combination; Female; HIV Core Protein p24; HIV Infections; Humans; Infant; Male; Treatment Outcome; Zidovudine | 1997 |
A randomized trial (ISS 902) of didanosine versus zidovudine in previously untreated patients with mildly symptomatic human immunodeficiency virus infection.
In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred. Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Body Weight; CD4 Lymphocyte Count; Didanosine; Disease Progression; Female; HIV Core Protein p24; HIV Infections; Humans; Male; Risk; Zidovudine | 1997 |
No therapeutic advantage from didanosine (ddI) and hydroxyurea versus ddI alone in patients with HIV infection.
Topics: CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; RNA, Viral; Treatment Outcome; Viremia; Zidovudine | 1997 |
HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. The National Virology Groups. Delta Virology Working Group and Coordinating Committee.
The Delta trial showed that combination therapy (zidovudine plus didanosine and zidovudine plus zalcitabine) substantially lengthened life and reduced disease progression compared with zidovudine monotherapy. We did a nested virological study in three countries (France, the Netherlands, and the UK) to investigate changes in markers for viral load and antiretroviral-drug resistance during therapy.. 240 zidovudine-naive HIV-1-infected patients were randomly assigned zidovudine only (n = 87), zidovudine plus didanosine (n = 80), or zidovudine plus zalcitabine (n = 73). Viral load in peripheral-blood mononuclear cells and plasma was measured by quantitative culture. Plasma HIV-1 RNA was measured by reverse-transcriptase PCR amplification, and serum p24 antigen by ELISA. Resistance to antiretroviral drugs was measured phenotypically by culture and genotypically by detection and quantification of drug-related point mutations in the pol gene. Analyses were done by intention to treat.. The reduction in viral load was greatest 4-12 weeks after the start of therapy and was most pronounced in the combination-therapy study groups (median reductions of RNA at 4 weeks 1.58, 1.28, and 0.49 log10 copies/mL for zidovudine plus didanosine, zidovudine plus zalcitabine, and zidovudine only, respectively). RNA levels at 8 weeks were predictive of disease progression and death after allowance for baseline values. At 48 weeks, the proportion of participants with phenotypic zidovudine resistance was similar in all three groups: didanosine and zalcitabine resistance were rare; zidovudine genomic resistance correlated with phenotypic resistance (r = 0.54, p < 0.0001) and developed earlier in the combined-therapy groups. However, participants in the zidovudine monotherapy group had higher circulating loads of resistant virus than those in the combined-therapy groups.. Combined antiretroviral therapy was more efficient at lowering virus load than monotherapy. Although zidovudine resistance was common in monotherapy and combined-therapy groups, circulating concentrations of resistant virus were substantially lower in the combination groups, which is likely to be a result of the continued antiviral activity of didanosine or zalcitabine. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Resistance, Microbial; Drug Therapy, Combination; Genes, pol; HIV Infections; HIV-1; Humans; Point Mutation; Prospective Studies; RNA, Viral; Viral Load; Zalcitabine; Zidovudine | 1997 |
Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy.
The pattern of mutations in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) strains that confer resistance to didanosine (ddI) was analyzed in 2 groups of patients receiving either ddI monotherapy or ddI plus hydroxyurea (HU) combination therapy. Twelve patients receiving combination therapy and 8 receiving monotherapy were tested. Combinations of ddI plus HU did not prevent the onset of mutations, which emerged in 50% of the patients in this group compared with 25% of the ddI monotherapy group. In addition, in 1 patient from the combination therapy arm, who had a limited response to the therapy, an unusual pattern of mutations was found: the insertion of 2 amino acids between residues 69 and 70, a region critical for resistance to nucleoside analogs. The higher efficacy of the combination of HU and ddI compared with that of ddI monotherapy cannot be attributed to a delayed or decreased onset of resistance to ddI. Topics: Anti-HIV Agents; Didanosine; DNA, Complementary; Drug Resistance, Microbial; Drug Therapy, Combination; Genes, pol; Genes, Viral; HIV Infections; HIV-1; Humans; Hydroxyurea; Mutagenesis, Insertional; Nucleic Acid Synthesis Inhibitors; Polymerase Chain Reaction; RNA, Viral; Sequence Alignment; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Viremia | 1997 |
Hydroxyurea and didanosine is a more potent combination than hydroxyurea and zidovudine.
The in vitro and in vivo antiviral activity of hydroxyurea in combination with either zidovudine or didanosine was evaluated in primary human peripheral mononuclear cells and in a cohort of 29 asymptomatic patients infected with HIV. In vitro, hydroxyurea alone did not significantly affect HIV replication, whereas the combination of hydroxyurea with didanosine was more effective than the combination of hydroxyurea with zidovudine. Our clinical results confirmed these studies. Patients were randomly assigned to five arms (zidovudine, hydroxyurea or didanosine monotherapy, or hydroxyurea in combination with either zidovudine or didanosine) to evaluate preliminary safety and efficacy. Bone-marrow toxicity occurred in two patients treated with zidovudine plus hydroxyurea, alopecia was reported in one patient treated with hydroxyurea monotherapy, and there were no toxic effects recorded in the remaining three groups. Plasma viraemia was not influenced by hydroxyurea monotherapy, and the hydroxyurea-zidovudine combination did not give any advantage over either zidovudine or didanosine monotherapy (0.3-0.5 log decrease in plasma viraemia). In contrast, a 1.1 log drop in plasma viraemia was observed in patients treated with hydroxyurea plus didanosine, this reduction was sustained throughout the 24-week course of the treatment. Combination therapy with hydroxyurea and didanosine exhibited statistically significant improvements compared with the other therapeutic approaches. Although further clinical trials are required, these results suggest that hydroxyurea in combination with didanosine might be an effective and well-tolerated, simple and affordable, treatment for HIV infection. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Hydroxyurea; Male; Middle Aged; Zidovudine | 1997 |
Once versus twice daily administration of didanosine in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine. The Italian Pediatric Collaborative Study Group on Didanosine.
The objective of this study was to compare the safety, tolerability and clinical response of once- versus twice-daily administration of didanosine given at a dosage of 270 mg/m2/day in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine monotherapy. We carried out a randomized, open-label multicentre trial. Didanosine was supplied in buffered tablets, which could be chewed or dispersed in liquid. The children were recruited from 16 paediatric departments participating in the Italian Register for HIV Infection in Children. A total of 53 children (median age 5.5 years) started trial treatment; 26 were given didanosine twice daily and 27 once daily; 85% had AIDS and 98% had clinically deteriorated while on zidovudine therapy. Similar safety and tolerability results were demonstrated for the two schemes of therapy. A total of 11 children (20.7%) required discontinuation of didanosine for severe adverse events (five children (19.2%) in the twice-daily group; six children (22.2%) in the once-daily group, log-rank P = 0.81). Severe hepatic toxicity was uncommon (5.6%) while mild to moderate hepatic dysfunction was demonstrated in about 17% of the participants, without any difference between the two groups. Haematological toxicity was common (about 40% of the children, 11 in the twice- and 19 in the once-daily group) but never severe. Clinical pancreatitis and retinal lesions were never demonstrated. There was no significant difference in progression to death or to a new opportunistic infection between the two treatment regimens (log-rank P = 0.54). The modification of surrogate efficacy parameters during the study period was similar in the two groups. However, weight gain was poorer in children treated once daily. This study suggests that the safety and tolerability of 270 mg/m2/day of didanosine given once daily is substantially similar to that of the traditionally recommended schedule of two divided doses. Owing to the small sample and to the severity of the clinical condition of the children enrolled, no definite conclusions on the comparative efficacy of the two regimens can be drawn. Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Administration Schedule; Female; HIV Infections; Humans; Infant; Male; Zidovudine | 1997 |
Final CESARE trial results show continued clinical and survival benefit.
Topics: Acetamides; Acetophenones; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Controlled Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Survival Rate; Zalcitabine; Zidovudine | 1997 |
Viramune triple combo reduces viral load below limit of detection.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Randomized Controlled Trials as Topic; Viral Load; Zidovudine | 1997 |
Major pediatric study stopped early: combination treatment better.
The National Institute of Allergy and Infectious Diseases (NIAID) stopped a clinical trial (ACTG 300) of more than 600 children because of obvious benefits of the combination of zidovudine (AZT) plus lamivudine (3TC) over didanosine (ddI) monotherapy in reducing disease progression. The children had symptomatic HIV disease with little or no experience with antiretrovirals. A third treatment using AZT plus ddI also did better than using ddI alone, although there is less information on this arm of the study. Topics: Anti-HIV Agents; Child; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Zidovudine | 1997 |
Combination therapies improve outlook for children with HIV disease.
Results of the ACTG 300 clinical trial show that infants and children with symptomatic HIV infection are treated more successfully when given AZT plus either 3TC or ddI, than with ddI alone. This combination can slow disease progression and reduce the risk of death. The most noticeable results were seen in patients under three years of age. Two protease inhibitors, nelfinavir and ritonavir, have also been approved for treating HIV infection in children, and are currently in combination trials. Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Infant; Lamivudine; Zidovudine | 1997 |
Response of CD4 lymphocytes and clinical consequences of treatment using ddI or ddC in patients with advanced HIV infection.
The value of CD4 lymphocyte counts as a surrogate marker in persons with advanced human immunodeficiency virus infection during antiretroviral treatment was assessed using longitudinal models and data from the Terry Beirn Community Programs for Clinical Research on AIDS didanosine/zalcitabine trial of 467 HIV-infected patients. Patients with AIDS or two CD4 counts of < or = 300 who fulfilled specific criteria for zidovudine intolerance or failure were randomized to receive either 500 mg didanosine (ddl) daily or 2.25 mg zalcitabine (ddC) per day. Absolute CD4 counts were recorded at study entry and at as many as four visits. Patients were followed for clinical disease progression and survival. At 2 months, the difference in mean CD4 count from baseline was +15.4 cells/mm3 in the ddI group but -1.3 cells/mm3 in the ddC group. Patients assigned to ddI had a greater chance of a CD4 response at 2 months than those on ddC, yet only those in the ddC group with a response showed significant improvement in progression of disease or survival compared with ddC nonresponders, ddI responders, and ddI nonresponders (p = 0.03). We conclude that a CD4 response does not necessarily correlate with improved outcome and is therefore not a useful surrogate marker in these patients. Topics: Antiviral Agents; Biomarkers; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Didanosine; Disease Progression; Follow-Up Studies; HIV Infections; HIV-1; Humans; Regression Analysis; Survival Rate; Treatment Outcome; Zalcitabine | 1996 |
Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial.
A nonrandomized trial was undertaken to evaluate the combination of didanosine and interferon-alpha (INF-alpha) in human immunodeficiency virus (HIV)-infected patients. Thirty-six volunteers with >200 x 10(6) CD4 cells/L received didanosine (one 100-, 250-, or 375-mg sachet twice daily) for at least 6 weeks, following which IFN-alpha (1, 5, 10, or 15 MU/day) was begun. Didanosine (one 375-mg sachet twice daily) was substituted for zidovudine in 14 additional patients who had received IFN-alpha and zidovudine for 7-45 months. Thirty-five patients completed the 34-week study. Clinical or chemical pancreatitis was the most common (6 patients) dose-limiting toxicity. CD4 cell counts increased with didanosine but declined following the addition of IFN-alpha; CD4 cell percents tended to increase and remain elevated. Thus, combination therapy with didanosine and IFN-alpha can be safely administered to patients with HIV infection. The clinical benefit of this combination therapy will require further evaluation. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Interferon-alpha; Male; Pancreatitis; Reverse Transcriptase Inhibitors; RNA, Viral | 1996 |
Combination therapy with ZDV + DDI versus ZDV + DDC in patients with progression of HIV-infection under treatment with ZDV.
HIV-seropositive patients (n = 67) who had tolerated zidovudine for at least 24 weeks and deteriorated clinically or immunologically within 12 weeks prior to study entry were allocated in an alternating manner to didanosine chewable tablets (400 mg/day) plus zidovudine (500 mg/day) or dideoxicytidine capsules (2.25 mg/day) plus zidovudine (500 mg/day). The combination of didanosine and zidovudine resulted in a more pronounced increase of CD4 cells over time compared to the combination of dideoxicytidine with zidovudine (p < 0.002). The increase of CD4 cells was almost exclusively due to patients with more than 100 CD4 cells/microliters. Clinical end points (death, AIDS-defining disease, CDC IV event) were less frequent under didanosine plus zidovudine but failed to reach statistical significance (p = 0.07). For didanosine plus zidovudine the median time on medication during study was shorter (63% vs. 100%, p < 0.05) and the number of patients discontinuing medication prematurely due to side effects was higher (59% vs. 30%, p < 0.02). The present study favors the combination of didanosine and zidovudine in patients deteriorating while receiving zidovudine for > 24 weeks in respect to the time course of the CD4 cells. In this small sized study, there seemed to be fewer clinical events in patients on the didanosine combination compared to the combination with dideoxicytidine; however, this trend failed to reach statistical significance and needs therefore to be substantiated by larger studies. However, the lower compliance of the patients may hamper the efficacy of didanosine. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Survival Analysis; Treatment Outcome; Zalcitabine; Zidovudine | 1996 |
Impact of missing data due to dropouts on estimates of the treatment effect in a randomized trial of antiretroviral therapy for HIV-infected individuals. Canadian HIV Trials Network A002 Study Group.
To evaluate the impact of missing data due to nonrandom dropout on estimates of the effect of treatment on the CD4 count in a clinical trial of antiretroviral therapy for HIV infected individuals.. The effect of treatment on CD4 counts in a recent study of continued ZDV versus ddI in HIV-infected individuals was estimated from the observed data and after imputing missing CD4 counts for patients who dropped out of the study. Imputation methods studied were (a) carrying forward the last observed CD4 count, (b) predicting missing CD4 counts from regression models, and (c) assuming that CD4 counts of patients who dropped out declined at a rate of 100 cells per year.. Of the 245 patients enrolled in the study, 52% completed the planned 48 weeks of follow-up. Patients with lower CD4 counts were more likely to drop out of the study (RR = 1.77; p = 0.0001). Patients receiving ZDV had a greater tendency to drop out than patients receiving ddI (p = 0.07). Mean CD4 counts calculated after imputing missing data were lower than those obtained from the observed data at all follow-up times for both treatment groups. Imputing CD4 counts with regression models yielded higher estimates of the effect of treatment than were obtained using the observed data.. Missing outcome data due to dropouts can result in an underestimation of the treatment effect and overly optimistic statements about the outcome of participants on both treatment arms due to the selective dropout of participants with lower or decreasing CD4 counts. When there are significant dropout rates in randomized trials, imputation is a useful technique to assess the range of plausible values of the treatment effect. Topics: Antiviral Agents; Bias; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Data Interpretation, Statistical; Didanosine; Double-Blind Method; HIV Infections; Humans; Patient Dropouts; Randomized Controlled Trials as Topic; Reproducibility of Results; Treatment Outcome; Zidovudine | 1996 |
Patterns of opportunistic infections in patients with HIV infection.
The pattern of the development of opportunistic infections (OIs) in HIV-infected patients was evaluated, based on a cohort of 1,530 patients enrolled in two AIDS Clinical Trials Group anti-retroviral studies. We quantified the increase in risk of OIs associated with the occurrence of a previous OI. This assessment was based on the observed event rates of the more common AIDS-defining OIs: Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex (MAC), cytomegalovirus (CMV), and a systemic mycosis. Additionally, for each OI, we assessed the relative risks associated with a history of prior OIs, changes in CD4 levels, and baseline prognostic factors. We found that the occurrence of each of these OIs increased the risk of subsequent OIs, even after adjusting for the CD4 count. Specifically, the occurrence of PCP significantly increased the risk of MAC and CMV, and somewhat increased the risk of systemic mycoses. Diagnosis with MAC was associated with an increased risk of subsequent CMV, whereas the occurrence of CMV increased the risk of MAC. Finally, once patients were diagnosed with a systemic mycosis, they were at a somewhat increased risk of subsequently developing MAC or CMV. Although current practice for determining the timing and initiation of prophylactic therapies relies chiefly on CD4 count, the occurrence of specific AIDS-defining OIs in patients with HIV infection should also be taken into account in making decisions regarding prophylaxis strategies. Topics: Adult; AIDS-Related Opportunistic Infections; Antiviral Agents; CD4 Lymphocyte Count; Cohort Studies; Cytomegalovirus Infections; Didanosine; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; Mycobacterium avium-intracellulare Infection; Mycoses; Pneumonia, Pneumocystis; Prospective Studies; Retrospective Studies; Risk Factors; Survival Rate; Zidovudine | 1996 |
Changes in biologic phenotype of human immunodeficiency virus during treatment of patients with didanosine.
Progression to AIDS in patients harboring human immunodeficiency virus type-1 (HIV-1) isolates expressing a syncytium-inducing (SI) phenotype is faster than in those in whom the virus expresses a non-SI (NSI) phenotype. Zidovudine monotherapy does not appear to alter this outcome. To examine the role of didanosine (ddI) monotherapy in phenotype expression, HIV-1 isolates from 73 patients receiving ddI for up to 72 weeks were analyzed. After 12 weeks, the number of isolates expressing an NSI phenotype was 29% higher than at the start of treatment. Patients receiving high-dose ddI (375 mg twice daily) were significantly more likely to express the NSI phenotype at 12 weeks than patients who received low-dose ddI (100 mg twice daily), even after adjustment for phenotype and CD4 cell count at baseline, suggesting that ddI may be selective against the faster-replicating virus. ddI at 375 mg twice daily significantly increases the probability of an NSI phenotype over the short term in patients with advanced HIV disease. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Giant Cells; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Phenotype | 1996 |
Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protoco
To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine.. A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units.. 398 adults who had HIV-1 infection, had 350 or fewer CD4+ T lymphocytes/mm3, and had had more than 6 months of previous nucleoside therapy.. 1) Either nevirapine or placebo (200 mg/d for 2 weeks, then 400 mg/d thereafter) and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing > or = 60 kg).. CD4+ T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites.. After 48 weeks of study treatment the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% Cl, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (Cl, 0.05 to 0.59 log10 infectious units per million cells; P = 0.023), and a 0.25 log10 lower mean plasma HIV-1 RNA level (Cl, 0.03 to 0.48 log10 RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [Cl, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference.. Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens. Topics: Adult; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Erythema; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Prospective Studies; Pyridines; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine | 1996 |
Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group.
A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-1 RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Seropositivity; HIV-1; Humans; Male; Middle Aged; Phenotype; RNA, Viral; Zalcitabine; Zidovudine | 1996 |
Combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus infection: pharmacokinetic properties, safety, and immunologic and virologic effects.
To obtain preliminary information on the pharmacokinetic properties, tolerance, safety, and antiviral activity of combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus (HIV) infection.. Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (median CD4 + lymphocyte count at baseline, 42 cells/ microL; range, 8 to 553 cells/microL) were treated with stavudine (2 mg/kg per day in two divided doses) and didanosine (180 mg/m2 per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. All children had received stavudine alone for 19 to 33 months before the addition of didanosine to the treatment regimen. Children were assessed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter.. Analysis of stavudine and didanosine plasma half-life values, clearances, and area under the plasma concentration-versus-time curves revealed no obvious clinical pharmacokinetic interaction between the drugs through study week 12. Combination therapy was well tolerated, and there were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three children with baseline CD4 + lymphocyte counts greater than 50 cells/muL had greater than 20% increases in their counts within the first 12 weeks of therapy; CD4 + lymphocyte count increases were not observed in the other children. Plasma HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10 to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks 12 and 24, respectively.. Combination therapy with stavudine and didanosine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be confirmed, and the regimen's clinical efficacy should be examined, in controlled studies of HIV-infected children with less-advanced disease. Topics: Antiviral Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Pilot Projects; RNA, Viral; Stavudine | 1996 |
Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease.
We assessed the safety and surrogate markers' effect of acemannan as an adjunctive to antiretroviral therapy among patients with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI) in a randomized, double-blind, placebo-controlled trial of acemannan (400 mg orally four times daily). Eligible patients of either sex had CD4 counts of 50-300/microl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. P24 antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for HIV and ZDV pharmacokinetics were performed in a subset of patients. Sixty-three patients were randomized. All were males (mean age 39 years). The mean baseline CD4 counts were 165 and 147/microl in the placebo and acemannan groups, respectively; 90 percent of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDS-defining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were - 121 and - 120 cells per year in the placebo and acemannan groups, respectively ( p = 0.45), ACD4 from week 16 to 48 was 0 and - 61 cells per year in the acemannan and placebo groups (p = .11), respectively. There was no statistical difference between groups with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11 receiving placebo and 13 receiving acemannan, discontinued study therapy prematurely, none due to serious adverse reactions. Our results demonstrate that acemannan at an oral daily dose of 1600 mg does not prevent the decline in CD4 count characteristic of progressive HIV disease. Acemannan showed no significant effect on p24 antigen and quantitative virology. Acemannan was well tolerated and showed no significant pharmacokinetic interaction with ZDV. Topics: Administration, Oral; Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; HIV Infections; Humans; Male; Mannans; Pilot Projects; Safety; Zidovudine | 1996 |
[Comparative study of the placenta from HIV+ mothers. Ultrastructural analysis].
Perinatal vertical transmission has increased in all the world; it is considered that at the present time there are about one million of children with HIV. Variation goes from 12 to 40%, at different countries. During the last years antiretroviral drugs as AZT, ddI and others have been used to diminish the virus passage via transplacentary. Eighteen placentaes from HIV seropositive women, three corresponded to first trimester, and 15 to the third trimester of gestation; in four cases they were treated with AZT in weeks fourteen (two patients), 26 and 35 of gestation; and one patient received AZT and ddI at week 28. Control group was with ten normal placentaes. Ultraestructural analysis and immuno-peroxidase and immuno-oro with antibody anti gp 41, were done. Ultraestructurally there were different localizations of HIV virus, at sincitiotrophoblast, decidual cells and umbilical vessels (six cases). In 13 cases there was hyperplasia and hypertrophy of macrophages containing a great amount of lysosomes. In one case, where a girl was seropositive many viriones HIV, were identified in macrophages. With immuno-oro viral proteins were seen in cytoplasm an plasmatic membrane, in endothelium of fetal capillars and trophoblast. With immunoperoxidase, four cases were positive. Placentaes with antiretroviral treatment since week 14, trophoblast was more dense by philaments increment. Placentaes with treatment during the third trimester, showed normal morphology with slight increase of philaments. In the cases treated with AZT and ddI, there were not macrophages hyperplasia and hypertrophy, nor viral particles. It is concluded that in seropositive mothers without treatment, the virus may be present in any part of chorionic villi, and in patients with treatment, virus is not identified, but a viral proteins synthesis. Topics: Antiviral Agents; Didanosine; Female; HIV Infections; HIV Seropositivity; Humans; Infectious Disease Transmission, Vertical; Microscopy, Electron; Placenta; Pregnancy; Pregnancy Complications, Infectious; Zidovudine | 1996 |
Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Delta Coordinating Committee.
Because the benefits of zidovudine (AZT) in HIV-infected individuals are small and do not last long the Delta trial was designed to test whether combinations of zidovudine with didanosine (ddl) or zalcitabine (ddC) were more effective than AZT alone in extending survival and delaying disease progression.. The trial was randomised, double blind, and international. 3207 participants were allocated to either AZT (600 mg per day) alone (1055), AZT plus ddl (400 mg per day) (1080), or AZT plus ddC (2.25 mg per day) (1072). Participants either had symptoms of HIV disease (if AIDS, with a CD4 cell count of > 50 x 10(6)/L) or a CD4 count of less than 350 x 10(6)/L; 2124 had not had zidovudine before (Delta 1) and 1083 had for at least 3 months (Delta 2).. Over a median follow-up of 30 months, 699 participants died, and 936 of the 2765 without AIDS at entry developed AIDS or died. In participants who had not had AZT before, both combination regimens had substantial benefits in terms of survival (regardless of disease stage at entry); a relative reduction in mortality of 42%, compared to AZT alone (95% Cl 25% to 55%), for AZT plus ddl and of 32% (95% Cl 22% to 47%) for AZT plus ddC. In participants who had had AZT before, the addition of ddl improved survival (p = 0.05; relative reduction 23% [95% Cl 0% to 41%]) but there was no direct evidence of benefit from the addition of ddC (p = 0.47; relative reduction 9% [95% Cl--17% to 29%]). The overall difference in survival between the treatment groups was significant (p < 0.0001; a relative reduction in mortality, compared to AZT alone, of 33% (95% Cl 20% to 44%) for AZT plus ddl and 21% (95% Cl 6% to 34%) for AZT plus ddC). Benefit in terms of disease progression was seen mainly in participants not previously treated with AZT and overall. There was no unexpected toxicity from the combination treatments.. Initiation of treatment with combinations of AZT plus ddl or ddC prolongs life and delays disease progression compared with AZT alone. The addition of ddl to participants already treated with AZT also improves survival, although the benefit appears less. Topics: Adolescent; Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Male; Survival Analysis; Zalcitabine; Zidovudine | 1996 |
Combination therapy with zidovudine, didanosine and saquinavir.
The goal of AIDS Clinical Trials Group (ACTG) Protocol 229 was to evaluate the shorter term (24 week) and longer term (48 week) safety and activity of the HIV-1 proteinase inhibitor saquinavir in combination with zalcitabine (ddC) and zidovudine (ZDV) versus saquinavir in combination with ZDV versus ddC in combination with ZDV. This study confirms and extends the conclusions from the first 24 weeks of this study and showed that in subjects with extensive prior antiretroviral experience, the triple combination of saquinavir, ddC and ZDV was well-tolerated, safe and remained superior to the other double drug regimens as measured by CD4+ cell counts, quantitative HIV-1 microculture and plasma HIV-1 RNA levels. Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Isoquinolines; Quinolines; Saquinavir; Zidovudine | 1996 |
D4T nucleoside combinations for HIV.
Topics: Adult; Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Stavudine; Zidovudine | 1996 |
Pilot clinical trial of the combination of hydroxyurea and didanosine in HIV-1 infected individuals.
Topics: Adult; Antineoplastic Agents; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; France; HIV Infections; HIV-1; Humans; Hydroxyurea; Leukocytes, Mononuclear; Male; Middle Aged; Pilot Projects; RNA, Viral | 1996 |
Effect of clarithromycin on the pharmacokinetics of 2',3'-dideoxyinosine in patients who are seropositive for human immunodeficiency virus.
Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-Bacterial Agents; Clarithromycin; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Middle Aged; Reverse Transcriptase Inhibitors | 1996 |
Development of resistance of zidovudine (ZDV) and didanosine (ddI) in HIV from patients in ZDV, ddI and alternating ZDV/ddI therapy.
To study development of phenotypic and genotypic resistance against zidovudine (ZDV) and didanosine (ddI) during 24 months of mono- and monthly alternating therapy.. Forty-six patients, not previously treated with antiretroviral drugs, were included in the study.. ZDV and ddI sensitivity were determined in a biological assay based on production of HIV antigen in cultures of CD4+ lymphocytes. The ZDV-associated mutations at codon 41 and 215, and the ddI-associated mutation at codon 74 of the reverse transcriptase (RT) gene were analysed using selective polymerase chain reaction on DNA from peripheral blood mononuclear cells. The biological phenotype [syncytium-inducing (SI)/non-SI(NSI)] of the viral isolates was assessed using a MT2 assay.. Of the patients, 82% in ZDV therapy and 73% in alternating therapy developed phenotypic resistant HIV [median inhibitory concentration (IC50) > 0.1 microM]. Patients treated for 1 year with ddI (monotherapy or alternating) had significant higher ddI IC50 values than patients in ZDV monotherapy. During ZDV and alternating therapy, 67 and 75% of the patients, respectively, developed mutations in RT codon 41, whereas 83 and 75%, respectively, developed mutations in codon 215. In patients treated with ddI, 60% developed mutations in codon 74, whereas none of the patients in either alternating ZDV/ddI or ZDV therapy developed this mutation. Forty-six per cent of the patients had SI HIV at start of therapy. Four patients switched from SI to NSI during either ZDV, ddI or alternating therapy. Faster development of resistance was associated with the SI phenotype.. No difference in either phenotypic ZDV or ddI resistance, or genotypic ZDV resistance could be demonstrated during monotherapy or monthly alternating ZDV/ddI therapy, whereas genotypic ddI resistance (mutation in RT codon 74) only were detected in patients in ddI monotherapy. In addition, we found that development of phenotypic and genotypic resistance was faster in patients harbouring SI isolates, and that switches from SI to NSI during therapy was independent of the type of therapy. Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cells, Cultured; Didanosine; Drug Resistance; HIV Infections; HIV-1; Humans; Mutation; Zidovudine | 1996 |
Effects of cytokines on antiviral pharmacokinetics: an alternative approach to assessment of drug interactions using bioequivalence guidelines.
The effects of cytokines on the pharmacokinetics of nucleoside analogs were evaluated in two separate studies using zidovudine in combination with interleukin-2 and didanosine in combination with alpha interferon. In each study, drug interactions were evaluated by using both a standard method (Student's t test) and bioequivalence testing. Serial blood samples were collected from human immunodeficiency virus-infected patients prior to and during cytokine therapy for determination of nucleoside analog concentrations. Concentrations were fit separately to a two-compartment model by using the iterative two-stage approach to population analysis. No alterations in area under the curve or oral clearance were observed for either drug during combination therapy. In general, there was good agreement between statistical methods for determining if antiviral pharmacokinetic parameters were altered by concomitant cytokine therapy. However, large individual changes in the maximum concentration of zidovudine in serum were detected by bioequivalence testing but no difference was found by Student's t test. For didanosine, significant but clinically irrelevant decreases determined by standard hypothesis testing were seen for both the volume of the central compartment (1.91 to 1.86 liters) and the absorption rate constant (0.79 to 0.73 h-1) in the presence of alpha interferon. No interaction was noted for these parameters by using bioequivalence guidelines. Bioequivalence testing may provide an alternative approach to assessment of drug interactions. Interleukin-2 and alpha interferon do not alter the pharmacokinetics of zidovudine and didanosine, respectively. Topics: Adult; Antiviral Agents; Cytokines; Didanosine; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Interferon-alpha; Interleukin-2; Male; Reference Standards; Reference Values; Therapeutic Equivalency; Zidovudine | 1996 |
Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients.
Delavirdine mesylate (DLV) is a potent nonnucleoside reverse transcriptase inhibitor with activity specific for human immunodeficiency virus type 1. In the present phase I/II study we evaluated the safety, toxicity, pharmacokinetics, and antiretroviral activities of two-drug and three-drug combinations of DLV and conventional doses of nucleoside analogs compared with those of both DLV monotherapy and two-drug nucleoside analog therapy. A total of 85 human immunodeficiency virus type 1 infected patients with CD4 counts of 100 to 300 cells per mm3 were enrolled in two periods: in the first period patients were randomized to receive either zidovudine (ZDV) plus didanosine (group 1) or ZDV plus didanosine plus escalating doses (400 to 1,200 mg/day) of DLV (group 2). In the second period, patients were randomized to receive either 1,200 mg of DLV alone per day (group 3) or ZDV plus 1,200 mg of DLV per day (group 4). DLV demonstrated good oral bioavailability at all five doses tested. The major toxicity was a transient mild rash which appeared in 44% of all DLV recipients. Overall, group 2 patients demonstrated more sustained improvements in CD4 counts, percent CD4 cells, branched DNA levels, p24 antigen levels, and virus titers in plasma than group 1, 3, or 4 patients. The magnitude of the response correlated with the intensity of prior nucleoside analog treatment, the non-syncytium-inducing or syncytium-inducing viral phenotype at baseline, and the presence of a wild-type codon at amino acid position 215 in the baseline reverse transcriptase genotype. Despite a transient rash, DLV therapy was well tolerated. Combination therapy with DLV and nucleoside analogs appears promising, with the three-drug combination appearing to be more potent that either two-drug combinations or monotherapy. Topics: Adult; Anti-HIV Agents; Biological Availability; Delavirdine; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indoles; Male; Middle Aged; Piperazines; Reverse Transcriptase Inhibitors; Zidovudine | 1996 |
A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team.
This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter.. We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death.. Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment.. Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter. Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Proportional Hazards Models; Treatment Outcome; Zidovudine | 1996 |
The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team.
We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175.. The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype.. After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome.. Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis; Phenotype; Proportional Hazards Models; RNA, Viral; Treatment Outcome; Virus Replication; Zidovudine | 1996 |
The Alpha trial: European/Australian randomized double-blind trial of two doses of didanosine in zidovudine-intolerant patients with symptomatic HIV disease. Alpha International Coordinating Committee.
To compare the efficacy and toxicity of two doses of didanosine (ddI) in patients with symptomatic HIV disease who are intolerant of zidovudine (ZDV).. The Alpha trial is a randomized double-blind multicentre trial of two doses of ddI. ddI was given as one buffered sachet twice daily in doses adjusted for weight: 750 mg per day for patients > or = 60 kg in the higher-dose group, and 200 per day for the lower-dose group.. Patients (n = 1775; 907 higher-dose, 868 lower-dose) from nine European countries and Australia were randomized and started trial treatment. Sixty per cent had AIDS, 65% had CD4 cell counts < 50 x 10(6)/l and 55% had received ZDV for more than 12 months. Follow-up was to death or 30 September 1992, and only 33 patients (20 higher-dose, 13 lower-dose) had been lost to follow-up for at least 3 months at that time. The longest follow-up was 28.5 months and the mean (SD) was 12.4 (6.9) months. There was no significant difference in survival between the groups: 67% of patients in each group died, the median survival being 13.0 months in the higher-dose and 12.5 in the lower-dose groups, a difference of about 0.5 months (95% confidence interval, -0.9 to 2.0; log-rank P = 0.7). There was also no significant difference in progression to AIDS or death, development of HIV encephalopathy or death, or development of new AIDS events or death. There were small (but statistically significant) differences in the changes in CD4 cell count and in p24 antigen levels between the groups, with greater increases in CD4 and greater decreases in p24 in the higher-dose group. There were also clear differences in adverse events: pancreatitis developed more frequently in the higher-dose group, 66 patients compared to nine patients in the lower-dose group, of whom 37 and six, respectively, were classified as definite cases. Nine cases (seven higher-dose, two lower-dose) were reported to have died because of or with pancreatitis. Peripheral neuropathy, abnormal liver function and dry mouth were also reported more often in the higher-dose group.. The Alpha trial is not able to provide direct evidence for the clinical efficacy of ddI. There was no significant difference between the two doses in mortality or disease progression. However, the higher dose was more toxic. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Tolerance; Female; HIV Core Protein p24; HIV Infections; Humans; Male; Pancreatitis; Zidovudine | 1996 |
Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections.
Atevirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 and is currently in phase II clinical trials. Atevirdine is most soluble at a pH of < 2, and therefore, normal gastric acidity is most likely necessary for optimal bioavailability. Because of the rapid development of resistance in vitro, atevirdine is being evaluated in combination with didanosine and/or zidovudine in both two- and three-drug combination regimens. To examine the influence of concurrent didanosine (buffered tablet formulation) on the disposition of atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of didanosine and atevirdine when each drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of didanosine and atevirdine significantly reduced the maximum concentration of atevirdine in serum from 3.45 +/- 2.8 to 0.854 +/- 0.33 microM (P = 0.004). Likewise, the mean atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 +/- 2.2 microM.h (P = 0.004) relative to a value of 11.3 +/- 4.8 microM.h for atevirdine alone. Atevirdine had no statistically significant effect on the pharmacokinetic parameters of didanosine. Concurrent administration of single doses of atevirdine and didanosine resulted in a markedly lower maximum concentration of atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both atevirdine and didanosine should be designed so that their administration times are separated. Since the duration of the buffering effect of didanosine formulations is unknown, atevirdine should be given prior to didanosine. Topics: Adolescent; Adult; Antiviral Agents; Cross-Over Studies; Didanosine; Drug Interactions; Female; Half-Life; HIV Infections; HIV-1; Humans; Intestinal Absorption; Male; Middle Aged; Piperazines | 1996 |
Viral load, CD4 percentage, and delayed-type hypersensitivity in subjects receiving the HIV-1 immunogen and antiviral drug therapy.
Two trials of subjects inoculated with the inactivated, gp120-depleted HIV-1 Immunogen are reported. In one study, in which 19 subjects received ZDV and 8 subjects received ddI, treatment with the HIV-1 Immunogen did not affect the pharmacokinetic parameters of the antiviral drugs. In another study, 65 subjects who were previously immunized with the HIV-1 Immunogen over a mean period of 4.0 years (range, 1.2-5.4 years) received inoculations at 0 and 6 months. At some point during this 48-week study, 72% of the subjects (47/65) were receiving antiviral drug therapy. The HIV-1 DNA load in CD4 cells and CD4 percentage were found to be stable over the 48-week period. Delayed-type hypersensitivity to HIV-1 antigens increased after two inoculations with the HIV-1 Immunogen. In these two trials, no serious treatment-related adverse events were documented in the subjects. The two studies presented herein are the first to suggest that an immune-based therapy such as the HIV-1 Immunogen can be combined safely with antiviral drugs, supporting further study to evaluate the clinical utility of this approach. Topics: AIDS Vaccines; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Envelope Protein gp120; HIV Infections; Hypersensitivity, Delayed; Immunotherapy, Active; Viral Load; Zidovudine | 1996 |
Intrathecal immunoactivation in patients with HIV-1 infection is reduced by zidovudine but not by didanosine.
The effect of zidovudine and didanosine on the cerebrospinal fluid (CSF) concentrations of neopterin was studied in 12 patients with human immunodeficiency virus type-1 (HIV-1) infection 3-12 months after initiation of antiretroviral therapy. Ten treatment periods on zidovudine and 7 on didanosine were analysed. The CSF concentrations of neopterin decreased by 63% (from 29.6 to 12.9 nmol/l, p < 0.01) during zidovudine but increased by 15% (from 22.6 to 25.9 nmol/l, not significant during didanosine treatment. The CSF monocytic cell count decreased during zidovudine but increased during didanosine treatment. The results suggest that zidovudine but not didanosine reduces intrathecal immunoactivation during HIV-1 infection. Topics: Adult; Aged; Anti-HIV Agents; Biopterins; Didanosine; HIV Infections; HIV-1; Humans; Immunoglobulin G; Middle Aged; Neopterin; Zidovudine | 1996 |
A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team.
A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy. Topics: Adult; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Interactions; Drug Therapy, Combination; Female; Genetic Variation; Giant Cells; HIV Infections; HIV-1; Humans; Male; Middle Aged; Ribavirin; RNA, Viral; Viremia | 1996 |
CD8+ lymphocyte responses to antiretroviral therapy of HIV infection.
CD8+ T lymphocytes may mediate important host responses to human immunodeficiency virus (HIV) infection by human leukocyte antigen (HLA)-restricted cytotoxicity and production of soluble HIV suppressor factors. CD8+ lymphocytes are also important for the suppression of many latent pathogens responsible for opportunistic disease in HIV-infected patients. There has been no systematic analysis of the responses of CD8+ lymphocyte counts to antiretroviral therapy. We compared CD8+ lymphocyte responses in seven trials of nucleoside or non-nucleoside analog reverse transcriptase inhibitors and in two trials of ritonavir, a HIV protease inhibitor. Nucleoside analog and non-nucleoside analog reverse transcriptase inhibitor monotherapy resulted in no substantial changes in CD8+ counts relative to baseline or placebo. Combination nucleoside analog therapy resulted in variable peak responses (-145 to +240 cells/mm3), which remained significantly above baseline for 0 to 12 weeks. In contrast, ritonavir monotherapy caused a peak increase of 892 CD8+ cells/mm3, which remained significantly above baseline for 32 weeks. There was a significant correlation (Rs 0.61, p = 0.01) between the peak CD4+ cell and CD8+ responses to each therapy, but no significant correlation between the peak viral load responses and peak CD8+ cell responses. These findings suggest that the greater CD8+ response seen with ritonavir may be due to its specific inhibition of HIV protease and also that the CD8+ response is dependent on new CD4+ cell production. The CD8+ lymphocyte proliferation observed with protease inhibitor therapy could result in improved suppression of HIV replication by the immune system and should be confirmed in a prospective trial comparing protease inhibitors with both nucleoside and non-nucleoside analog therapies. Topics: Acetamides; Acetophenones; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Lamivudine; Lymphocyte Count; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load; Zalcitabine; Zidovudine | 1996 |
Should we embrace new drugs with open arms? Experience from a community-based, open-arm, randomized clinical trial of combination antiretroviral therapy in advanced HIV disease.
The effect of an open arm in the enrollment to a randomized clinical trial comparing zidovudine (ZDV) plus didanosine (ddI) versus ZDV plus zalcitabine (ddC) was assessed. HIV-infected individuals were eligible to participate in this protocol if they were ddI and ddC naive, had CD4 counts of 50-350/mm3, and were residents of the province of British Columbia. Participating individuals could choose between open-label ZDV/ddI, ZDV/ddC, or randomization to open-label ZDV/ddI or ZDV/ ddC. Study drugs were made available free of charge for all participants through a centralized drug distribution system. There is no other source of these drugs in the province. Primary care physicians were required to renew the patient's prescription every 2 months. Enrollment was initiated in November 1992 and was closed in March 1994 when the randomized arm of the protocol met the predetermined target sample size of 120 evaluable participants. A total of 582 patients received combination therapy in the province through this protocol: 138 (28%) enrolled in the randomized arm and 444 (76%) in the open arm. In the latter group, 320 (72%) were initially prescribed ZDV/ddI and 124 (28%) were prescribed ZDV/ddC. The enrollment rate was strikingly higher in the open arm, with 168 patients enrolled in the first 2 months compared with 138 patients enrolled in the randomized arm over 17 months. Of the 78 study physicians, 69 enrolled patients in the open arm and 23 enrolled patients in the randomized arm of the study. Experienced physicians were more likely to refer patients for randomization (p = 0.025). No statistically significant differences were observed between patients enrolled in either study arm. Our results illustrate the challenge posed to recruitment into clinical trials by the coexistence of an open arm. This is despite the noncoercive, open-label and community-based nature of our randomized protocol and the high priority given to it by a variety of local and national organizations. It is clear that an increased commitment by all interested parties will be required if randomized clinical trials are to be carried out with coexistent open arms. Topics: Adult; Anti-HIV Agents; British Columbia; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Patient Selection; Practice Patterns, Physicians'; Prospective Studies; Zalcitabine; Zidovudine | 1996 |
A pilot case-control study of zidovudine compared with zidovudine plus didanosine in patients with advanced HIV-1 disease and no previous experience with antiretrovirals.
Although zidovudine (ZDV) is effective in HIV-1-infected patients, the duration of its efficacy may be short when treatment is started in advanced HIV disease. This pilot prospective case-control study was designed to evaluate the combination of ZDV plus didanosine [ddI] compared with ZDV monotherapy as an initial therapeutic strategy. 'Control' patients (ZDV monotherapy) were matched with 'case' patients (ZDV plus ddI combination therapy) according to the presence or absence of AIDS-defining criteria at entry and CD4 cell count. The case patient group consisted of 35 consecutive HIV-1-infected individuals with < or = 300 CD4 cells/mm3, no previous experience of antiretroviral therapy and who accepted treatment with a combination of ZDV plus ddI. The control patient group consisted of 35 consecutive patients with similar characteristics, but who preferred to start treatment with ZDV alone. Control patients received 250 mg ZDV bid and case patients received ZDV at the same dose plus ddI (200 mg bid). Primary study endpoints were virological (serum HIV-1 RNA) and immunological (CD4 cell count) responses. Viral phenotype (syncytium-inducing (SI) or non-syncytium-inducing (NSI)), development of mutations at codons 215, 41 and 74 and clinical progression (new AIDS-defining event or death) were also assessed. Virological and CD4 cell count responses were significantly greater and more sustained in the group treated with ZDV plus ddI than in the control group, with peak responses of -1.2 +/- 0.7 log10 versus -0.3 +/- 0.4 log10 at 1 month (P = 0.0003) and 61 +/- 52 cells/mm3 versus 19 +/- 25 cells/mm3 at 2 months (P = 0.001), respectively. In both groups the percentage of patients developing a mutation at codon 215 was around 80 per cent at 12 months. A mutation at codon 74 was detected in 30 per cent of case patients at 12 months. Five case patients (14 per cent) versus 12 control patients (34 per cent) showed signs of clinical progression (P = 0.09). In a multivariate model, clinical progression was significantly associated with a baseline Topics: Adult; Anti-HIV Agents; Case-Control Studies; CD4 Lymphocyte Count; Codon; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Multivariate Analysis; Mutation; Nausea; Neutropenia; Pilot Projects; RNA, Viral; Survival Analysis; Zidovudine | 1996 |
The impact of zidovudine compared with didanosine on health status and functioning in persons with advanced HIV infection and a varying duration of prior zidovudine therapy. AIDS Clinical Trials Group 116/117 Study Group.
The objective of this study was to compare the effects of zidovudine and didanosine on health-related quality of life in persons with advanced HIV infection and varying duration of prior zidovudine exposure. It was designed as a substudy nested in two similar placebo-controlled active-control-arm randomized trials, using sites of the AIDS Clinical Trials Group participating in the randomized trials of zidovudine versus didanosine (ACTG 116 and 117). The patients comprised 356 participants enrolled in ACTG 116 and 117. All had HIV infection and either a CD4 count of <200 cells/mm3, or a CD4 count of <300 cells/mm3 plus symptoms of HIV disease. Participants were randomized equally within strata defined by duration of prior zidovudine therapy, to receive didanosine sachets at a dose of 500 mg daily (334 mg in subjects weighing <60 kg) or 750 mg daily (500 mg in subjects weighting <60 kg) plus inactive capsules resembling zidovudine, or to receive zidovudine capsules at a dose of 600 mg daily plus inactive sachets resembling didanosine. The main outcome measures were self-reported health-related quality of life, healthcare utilization, disability, work and symptom impact. The results showed no differences in reported symptom impact or healthcare utilization, and most measures of disability were similar. In the group with more than 8 weeks of prior zidovudine therapy, several of the health status scale scores for ongoing participants were significantly better for didanosine recipients, but average differences were small. Use of several different approaches to combining health status and survival showed no differences in the overall quality-time experiences between the treatment groups. Individuals taking zidovudine, low-dose didanosine and high-dose didanosine experienced 33, 34 and 35 weeks, respectively, in at least the typical health state if they had fewer than 8 weeks of previous zidovudine therapy, and had 23, 23 and 26 weeks, respectively, if they had more than 8 weeks previous use of zidovudine. Results did not differ when data were analysed within strata ofpatients who had any versus no prior exposure to zidovudine, or AIDS versus non-AIDS status. In conclusion, functional status and health-related quality of life were substantially similar among persons receiving either zidovudine or didanosine, regardless of the duration of prior zidovudine treatment. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Male; Severity of Illness Index; Sickness Impact Profile; Survival Analysis; Time Factors; Treatment Outcome; Zidovudine | 1996 |
d4T plus ddI antiviral results.
Ninety-two volunteers participated in a d4T plus ddI study, with randomization to one of five different dose combination arms. All participants received some of each drug, but since the trial is ongoing, assignments are still blinded, so dose-response information on antiviral activity is not yet available. Volunteers had no previous HIV therapy. Preliminary data show a median viral load decrease of about 1.2 logs and a median CD4 increase of about 60 to 80. These increases appear to be sustained for at least a year. Reasons for volunteers exiting the study did not appear to be dose-related. Another study reports positive antiviral activity using the d4T plus ddI combination. Topics: CD4 Lymphocyte Count; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; Humans; Stavudine | 1996 |
Hydroxyurea continues to show promise.
Human trial data on hydroxyurea, presented at the Third Conference on Human Retroviruses and Opportunistic Infections, confirm the early positive impression that the drug made in earlier trials. Hydroxyurea and related compounds act by restricting cellular pathways by which new DNA nucleotides are made. These gene-creating building blocks are taken up by the HIV enzyme, reverse transcriptase, as HIV infects new cells. Initial experiments by the National Cancer Institute (NCI) show that HIV-1 inhibition was still seen several weeks after treatment was stopped. Rapidity of rebound in present human trials indicates that continued viral suppression may not occur after withdrawal of hydroxyurea, at least in populations with advanced HIV infections and high CD4 turnover. No serious toxicities were reported. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Placebos | 1996 |
Antiretroviral combination treatment prolongs life in people with HIV/AIDS.
Results of ACTG 175 and Delta, large multicenter studies comparing combinations of nucleoside antiretroviral drugs with monotherapy, are reported. ACTG 175 enrolled 2,500 HIV-infected patients (1,000 subjects were AZT naive) over a 3-year period and randomized them to one of four drug regimens: AZT plus ddC, AZT plus ddI, AZT alone, or ddI alone. In moderately immunocompromised patients, the best results are obtained with either combination, or with ddI alone. In patients already on AZT, it is better to add or switch to ddI than to continue AZT monotherapy. The Delta trial enrolled 3,300 subjects and studied the same combinations as in ACTG 175 and AZT monotherapy, but did not study ddI monotherapy. Patients receiving combination therapy did better than those receiving AZT alone. AZT-experienced patients, regardless of the treatment received, experienced similar rates of progression to AIDS or death. This study was ceased prematurely due to the high rate of deaths in AZT-naive subjects receiving AZT alone compared to combination therapies. Other drug combination studies, such as AZT combined with 3TC, show superiority to AZT monotherapy in decreasing viral load and increasing CD4 counts, but do not correlate the results with clinical benefit. Other issues discussed include development and use of non-nucleoside reverse transcriptase inhibitors, studies involving HIV protease inhibitors, and the development of resistance and cross-resistance to various classes of antiviral agents. Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1996 |
CPCRA 007: preliminary results of combination antiretroviral study.
Preliminary data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) showed that in patients with no prior use of zidovudine (AZT), combination therapy was more effective than AZT alone for slowing clinical progression and improving survival. Sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), CPCRA 007 assessed the safety and efficacy of combination therapy--AZT plus didanosine (ddI) or AZT plus zalcitabine (ddC)-- as compared to AZT monotherapy in HIV-infected people. Volunteers who previously had an AIDS-defining condition or fewer than 200 CD4+ T cells per cubic millimeter (mm3) of blood were admitted to the study. The results also showed that combination therapy (AZT plus ddI or AZT plus ddC) provided modest benefits in slowing disease progression and reducing the rate of death compared to AZT alone. The findings of CPCRA 007 are similar to the Delta trial (a European-Australian collaborative study) and the NIAID-supported AIDS Clinical Trials Group (ACTG) 175. NIAID researchers are now working with sponsors of the Delta trial to analyze data from all three studies. For enrollment information, individuals may contact the AIDS Clinical Trials Information Service. Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine | 1996 |
Antiretrovirals plus immunomodulators: didanosine/interferon-alpha combination shows promise.
Researchers at the National Institute of Allergy and Infectious Diseases' (NIAID) Clinical Center intramural AIDS program safely administered didanosine (ddI) and interferon-alpha (IFN-alpha) to selected patients for more than 4 years. The study enrolled 36 asymptomatic patients, divided into 12 groups. Each of the groups received 1 of 3 doses of ddI for 6 weeks and 1 of 4 subcutaneous doses of IFN-alpha for an additional 28 weeks. A 13th group included 14 patients who had previously received IFN-alpha plus AZT for 7 to 45 months. The study showed that the maximal tolerated dose for long-term combination therapy is a 250 mg ddI sachet twice daily and 5 MU/day for IFN-alpha. Researchers noted an increase in CD4+ T cell counts and percentages during therapy with ddI alone. After administration of IFN-alpha, the CD4+ T cell percentages remained elevated while the counts decreased slightly. Researchers saw a decrease in the number of copies of HIV RNA per mL of blood after administration of IFN-alpha. Topics: Adjuvants, Immunologic; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV; HIV Core Protein p24; HIV Infections; Humans; Interferon-alpha; RNA, Viral | 1996 |
Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. The AIDS Clinical Trials Group 143 Virology Team.
Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/microL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient > 10-fold reductions in HIV RNA: 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/microL; P = .006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P = .01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P = .02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 in > or = 4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy. Topics: Amino Acid Sequence; Base Sequence; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Codon; Didanosine; DNA Primers; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; RNA, Viral; Zidovudine | 1995 |
Insights from monitoring the CPCRA didanosine/zalcitabine trial. Terry Beirn Community Programs for Clinical Research on AIDS.
The design, conduct, and analysis of clinical trials that evaluate the safety and efficacy of treatment interventions in patients with HIV infection provide many scientific challenges. A recently completed randomized trial of didanosine (ddI) and zalcitabine (ddC), sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), is an especially valuable resource for illustrating these challenging issues and for providing insights into how they might be properly addressed. Establishing equivalence of treatment effects on clinical efficacy end points is illustrated through the use of the confidence interval approach. The striking changes in treatment efficacy results that occurred during the course of the CPCRA trial provide important insights into how a data and safety monitoring board can reduce the risk of inappropriate early study termination. The trial also provides valuable insights into how treatment effects should be assessed, revealing inconsistencies between effects on the CD4 surrogate end point and effects on primary clinical efficacy end points and showing the incompleteness of the standardly employed definition of AIDS progression. Finally, the results of this ddI/ddC trial are used to examine the role of covariate adjustment. Topics: Antiviral Agents; Biomarkers; CD4 Lymphocyte Count; Confidence Intervals; Didanosine; Disease Progression; Drug Monitoring; HIV Infections; Humans; National Institutes of Health (U.S.); Prognosis; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; United States; Zalcitabine | 1995 |
A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team.
Ro 24-7429, a Tat antagonist, dosed at 75, 150, or 300 mg/day, was compared with nucleoside analogue (zidovudine or didanosine) for 12 weeks in 96 human immunodeficiency virus (HIV)-infected patients to assess safety and activity. The primary adverse effect of Ro 24-7429 was rash, which necessitated treatment discontinuation in 6 of 71 patients. Nucleoside analogue treatment produced an average increase in CD4 cell count of 28 cells/mm3 at week 8 versus a decrease of 27 cells/mm3 in recipients of Ro 24-7429 (P < .001). Serum HIV p24 antigen levels decreased by an average of 111 pg/mL in nucleoside recipients at week 8 compared with an increase of 41 pg/mL in recipients of Ro 24-7429 (P = .007). Nucleoside-treated patients had a mean 0.66 log10 reduction in infectious peripheral blood mononuclear cells, while Ro 24-7429 recipients had a mean 0.02 log10 reduction (P = .02). No dose-response relationships were observed in the Ro 24-7429 groups. In this study, Ro 24-7429 treatment showed no evidence of antiviral activity. Topics: Adult; Antiviral Agents; Benzodiazepines; CD4 Lymphocyte Count; Didanosine; Dose-Response Relationship, Drug; Female; Gene Products, tat; HIV Core Protein p24; HIV Infections; Humans; Male; Middle Aged; Pyrroles; tat Gene Products, Human Immunodeficiency Virus; Time Factors; Zidovudine | 1995 |
Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.
Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue. Topics: Adult; Didanosine; DNA, Viral; Female; HIV Infections; HIV-1; Humans; Lymph Nodes; Lymphocytes; Male; Time Factors; Viremia; Zidovudine | 1995 |
Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in children with HIV infection.
The pharmacokinetics of zidovudine (ZDV) and dideoxyinosine (ddI) were investigated following administration alone and in combination to children with symptomatic HIV disease. The children were studied on three separate occasions and received ZDV 200 mg m-2, ddI 100 mg m2 or a combination of ZDV 200 mg m-2 plus ddI 100 mg m-2. The administration of ddI did not significantly alter ZDV pharmacokinetics. The area under the curve (AUC) was 14.2 +/- 4.9 and 15.8 +/- 7.2 mumol l-1 h and elimination half-life (t1/2, z) was 1.4 +/- 0.4 and 1.2 +/- 0.2 h in the absence and presence of ddI respectively. The peak concentration (Cmax), time to peak (tmax) and apparent oral clearance (CL/F) were also unchanged. The administration of ZDV had no significant effect on ddI Cmax, tmax, t1/2,z, or CL/F, however the AUC was reduced by 19% (5.9 +/- 2.9 to 4.8 +/- 2.7 mumol l-1 h; P < 0.05). This study suggests that ZDV and ddI may be co-administered to children with symptomatic HIV disease without concern of a clinically relevant pharmacokinetic drug interaction. Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Didanosine; Drug Interactions; Drug Therapy, Combination; Half-Life; HIV Infections; Humans; Male; Radioimmunoassay; Zidovudine | 1995 |
Didanosine compared with continued zidovudine therapy for HIV-infected patients with 200 to 500 CD4 cells/mm3. A double-blind, randomized, controlled trial. Canadian HIV Trials Network Protocol 002 Study Group.
To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm3.. Double-blind, randomized controlled trial.. 10 Canadian university-affiliated specialty clinics.. 246 patients were assigned to receive standard doses of either zidovudine or didanosine.. The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death.. 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm3. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < or = 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 microM) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05).. In clinically stable patients with 200 to 500 CD4 cells/mm3 who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated. Topics: Adult; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Resistance, Microbial; Female; HIV Infections; Humans; Male; Prospective Studies; Zidovudine | 1995 |
Randomized study of didanosine monotherapy and combination therapy with zidovudine in hemophilic and nonhemophilic subjects with asymptomatic human immunodeficiency virus-1 infection. AIDS Clinical Trial Groups.
To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients. Topics: Adult; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Didanosine; Drug Therapy, Combination; Female; Hemophilia A; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Male; Safety; Treatment Outcome; Viremia; Zidovudine | 1995 |
Human immunodeficiency virus type 1 (HIV-1) viremia changes and development of drug-related mutations in patients with symptomatic HIV-1 infection receiving alternating or simultaneous zidovudine and didanosine therapy.
The changes in viremia levels and the development of drug-related mutations were examined in 26 patients with symptomatic human immunodeficiency virus type 1 (HIV-1) infection participating in a randomized trial comparing alternating (A) and simultaneous (S) regimens of zidovudine and didanosine therapy. Patients on both arms had significant reduction in serum RNA copies from baseline throughout the 2 years of study. Significant differences between the two arms were demonstrated over the first 2-3 months of therapy. Analyses with nested polymerase chain reaction revealed that the emergence of the didanosine-related position 74 Leu-->Val mutation was significantly blocked in both regimens, while the zidovudine-related mutation at codon 215 was not affected. Determination of the overall durability of the antiviremic effect of the A and S regimens of zidovudine and didanosine and clinical implications of the results require further research. Topics: Adult; Base Sequence; CD4 Lymphocyte Count; Codon; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genes, pol; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; RNA, Viral; Viremia; Zidovudine | 1995 |
Five-year follow-up of a phase I study of didanosine in patients with advanced human immunodeficiency virus infection.
Starting in 1988, 72 patients with advanced human immunodeficiency virus (HIV) infection were enrolled in a phase I study of didanosine at the National Cancer Institute. Beginning in 1992, patients with decreases in CD4 cell counts could switch to a combination of zidovudine and didanosine. The estimated median survival for all patients was 28 months (95% confidence interval, 23-46). However, for patients whose entry CD4 cell counts were 100-300/mm3, the estimated 4-year survival was 80%. Baseline CD4 and CD8 cell counts, hemoglobin, lymphocytes, sedimentation rates, diagnosis of AIDS, and fever were significant predictors of overall survival. Principal toxicities were pancreatitis and peripheral neuropathy; no new toxicities were seen with extended didanosine treatment that had not been observed in shorter-term studies. This 5-year follow-up shows that didanosine can be tolerated for > 4 years in some patients with advanced HIV infection and may have particular long-term utility in patients with moderately advanced immunosuppression. Topics: Adult; CD4 Lymphocyte Count; Didanosine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Male; Middle Aged; Survival Rate; Zidovudine | 1995 |
A phase I evaluation of concomitant rifabutin and didanosine in symptomatic HIV-infected patients.
It has been suggested that didanosine (ddI) may undergo hepatic metabolism. Rifabutin is an inducer of drug metabolism. Fifteen human immunodeficiency virus-infected patients whose conditions were stabilized on twice-daily doses of ddI participated in a Phase I, open-label, pharmacokinetic and safety drug interaction study between rifabutin and ddI. Twelve patients completed the study. All patients received their regular ddI dose (167-375 mg) on day 1. On days 2-13 they received once-daily rifabutin (600 mg, three patients; 300 mg, nine patients) with their regular twice-daily ddI regimen. On days 14-16 they received rifabutin alone. Serial blood and urine samples were collected for 12 h on day 1 and for 24 h on days 13 and 16, and safety evaluations were made throughout the study. Average day 1/day 13 ddI pharmacokinetic ratios and 95% confidence interval values for Cmax, AUC0-infinity, Cls/F, and t 1/2, lambda z were 1.17 (0.96-1.38), 1.13 (0.99-1.27), 0.91 (0.81-1.01), and 0.97 (0.79-1.15), respectively (p > 0.05 for all comparisons; paired t test). A 20% difference in AUC0-infinity could be detected with 90% power. Also, there were no significant changes in laboratory values or electrocardiograms, or in rifabutin pharmacokinetic parameters when the two agents were coadministered. Based on the safety and pharmacokinetic assessments, rifabutin did not appear to interact with ddI. Topics: Adult; Biological Availability; Didanosine; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Rifabutin | 1995 |
Human immunodeficiency virus type 1 quantitative cell microculture as a measure of antiviral efficacy in a multicenter clinical trial.
A quantitative cell microculture assay (QMC) was used to measure the human immunodeficiency virus type 1 (HIV-1) peripheral blood mononuclear cell (PBMC)-associated titer in 109 subjects rolled in an open-label phase I/II study of didanosine monotherapy or combination therapy with zidovudine. The titer was inversely correlated with CD4+ cell count at baseline (r = .37, P = .001). After 12 weeks of therapy, subjects showed a significant decreases in virus titer and those with the highest baseline virus titers had the greatest increase in CD4+ cell number (r = .430, P = .002). The QMC assay was more sensitive (98%) for assessing the antiretroviral effect of therapy than was immune complex-dissociated HIV p24 antigen (32%) or plasma culture (3.4%). Estimated sample sizes for phase I/II clinical trials were derived using the within-subject QMC SD of .72 log10 infectious units per 10(6) PMBC. Topics: CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Treatment Outcome; Virus Cultivation; Zidovudine | 1995 |
Something better than zidovudine for children.
Topics: Adolescent; Child; Child, Preschool; Didanosine; Double-Blind Method; Drug Therapy, Combination; HIV Infections; Humans; Infant; Zidovudine | 1995 |
Pharmacokinetics of zidovudine and didanosine during combination therapy.
While the combination of zidovudine and didanosine is used in HIV-infected patients with more advanced disease, the possibility of a pharmacokinetic interaction between these two drugs remains controversial. Zidovudine doses of 50, 100, and 200 mg, combined with 67, 167, and 250 mg of didanosine were evaluated in 11 asymptomatic HIV-infected patients after receiving 24 weeks of combination therapy in AIDS Clinical Trials Group protocol 143. The pharmacokinetic parameters of zidovudine and didanosine were similar to those obtained with each drug given as monotherapy in other previously published studies. The renal clearance and urinary recovery of glucuronidated zidovudine was reduced when zidovudine was given in combination with didanosine, possibly due to competition for renal tubular secretion. These data suggest that no clinically important pharmacokinetic interaction occurs when zidovudine and didanosine are given together. Topics: Adult; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Zidovudine | 1995 |
Tolerance of a triple combination therapy with zidovudine, didanosine and interferon-alpha in seven HIV-infected patients.
Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Interferon-alpha; Zidovudine | 1995 |
A phase II controlled study of a combination of the immune modulator, lentinan, with didanosine (ddI) in HIV patients with CD4 cells of 200-500/mm3.
This study was carried out to assess the safety and efficacy of a combination of lentinan, an immune modulator, and didanosine (ddI) in a controlled study in HIV positive patients with CD4 levels of 200-500 cells/mm3. Didanosine was administered to HIV patients at doses of 400 mg/day (po) for six weeks (bid), then 2 mg of lentinan i.v. was added per week for 24-80 weeks. A control group (20%) received ddI only. A total of 107 patients were enrolled at three sites, and 88 patients started the ddI/lentinan phase. The combination caused significant increases in CD4 levels up to 38 weeks, whereas ddI alone was significant at the 5% level at 14 weeks. Based on these data, lentinan qualifies as a participant in future multi-drug studies in HIV. Topics: Adjuvants, Immunologic; Adult; CD4 Antigens; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Lentinan; Male; Middle Aged | 1995 |
AZT: pediatric study changed after worse monotherapy survival.
The AZT arm of a pediatric study (ACTG 152) was halted early after the AZT-treated group showed worse survival than those in at least one of the comparison treatment groups. The double-blind study treated patients with either AZT alone, AZT with ddI, or ddI alone. The study is continuing with ddI and the AZT/ddI combination. The AZT monotherapy results were unexpected and the reasons are currently unknown. One question of interest is the effect of age on the outcomes. It is believed age-related analysis will be important for developing treatment recommendations for children of different ages, for understanding what this result may mean in terms of treating adults, and for guidance about when and how adult data can reliably be used to guide treatment for children. Topics: Adolescent; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Infant; Survival Analysis; Zidovudine | 1995 |
Major study shows AZT monotherapy inferior.
A major government study has found that AZT alone is inferior to AZT plus ddI or AZT plus ddC combination therapy, or to ddI therapy alone, in patients starting with a CD4 count between 200 and 500. Over 2,000 patients were enrolled in a randomized trial that lasted two years. Patients who did not do well on the therapy were switched to a different study. Results of the study were analyzed differently for patients that had previously taken antivirals as opposed to those that were antiretroviral-naive. AZT alone performed worse than combinations in both of these groups. Selected patients also had results analyzed in terms of change in viral load; AZT alone proved to be the least effective in lowering viral load when compared to the combinations. Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; Humans; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine | 1995 |
New double vs. triple antiviral combination study, CD4 200-500, no prior treatment.
A clinical trial, protocol ICC-002, is comparing three anti-HIV treatment regimens: 1) AZT and ddI; 2) AZT, ddI, and 3TC; and 3) AZT, ddI, and nevirapine (an experimental non-nucleoside reverse transcriptase inhibitor). The Inter-Company Collaboration for AIDS Drug Development will enroll 225 participants with CD4 counts between 200 and 500, who have not previously used antiretrovirals. The study will compare the effects of these treatments on viral load, CD4 count, and other disease progression markers. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Nevirapine; Pyridines; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1995 |
Virus sidesteps convergent therapy.
The ambiguous results from ACTG 241, a federally funded clinical trial, may mark the end for the convergent combination therapy. The study enrolled volunteers with CD4 counts between 50 and 350 who had received at least six months of nucleoside analog therapy. They were randomized to take either a combination of AZT, ddi and nevirapine or AZT/ddI therapy. Although convergent combination therapy initially made a difference, the final difference in HIV load was not statistically significant. A small difference in absolute CD4 counts (30 cells or so) did not affect the incidence of new symptoms or death. Those on convergent therapy fared worse in terms of disease progression and clinical endpoints. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Pyridines; Zidovudine | 1995 |
Effects of two formats of informed consent on knowledge amongst persons with advanced HIV disease in a clinical trial of didanosine.
To determine subjects' perception of the purpose of informed consent, 113 subjects were recruited from a dose-controlled clinical trial of didanosine (ddI). Subjects were surveyed regarding how they made decisions regarding their medical care in general, about how they obtained information about this trial in particular, and several aspects of the informed consent procedure. Subjects were then randomly allocated to receive information about the trial by either a written only format or a written and verbal format 1 week before commencement of the trial. An eight-item instrument assessed knowledge of ddI prior to and subsequent to receiving information. Most subjects obtained information about HIV-related issues from their specialist (70%) or general (51%) medical practitioner. A large proportion of subjects (88%) reported that they believed their specialist medical practitioner always acted in their best interest. The majority of subjects (79%) believed that subjects should be allowed the choice between participating in the clinical trial and receiving the drug outside the trial mechanism. Of the subjects, 96% believed that informed consent was necessary in clinical trials; however, their opinions of the purpose of informed consent varied widely. Although they signed the informed consent, 44% of the subjects stated that they did not understand 'all' of the information that was provided. We found that the provision of information by written mode alone, or written and verbal modes were both associated with significant increases in knowledge levels and that there was a significant interaction in the degree of change between the two methods, with the written plus verbal method showing the most improvement over time. There was an interaction between degree of improvement in knowledge of didanosine in subjects who received written information versus those who received written and verbal knowledge and time (pre- versus post-consent) and a significant main effect for time. All subjects were relatively well-informed about the drug and stated that specialist and general medical practitioners were their major source of knowledge for all aspects of their HIV health care. Topics: Adult; Comprehension; Consent Forms; Didanosine; Educational Measurement; HIV Infections; Humans; Informed Consent; Middle Aged; Patient Education as Topic; Research Subjects; Therapeutic Human Experimentation | 1994 |
Expanded distribution of an investigational drug in parallel with ongoing controlled clinical trials: the didanosine model.
The purpose of the didanosine Expanded Access Program was to provide a needed antiretroviral agent to individuals who were unable to tolerate other therapy for human immunodeficiency virus infection or in whom such therapy was failing. The logistics of establishing this program are described, and the results of on-site auditing that confirmed the validity of the data obtained through this program are presented. Topics: Didanosine; Drug Tolerance; Drugs, Investigational; Health Services Accessibility; HIV Infections; Humans; Medication Systems; Models, Biological; United States; United States Food and Drug Administration | 1994 |
Rates and risk factors for adverse events associated with didanosine in the expanded access program.
The didanosine Expanded Access Program was the largest AIDS treatment program to prospectively evaluate the safety of an antiretroviral agent among patients with advanced human immunodeficiency virus (HIV) disease in whom therapy with zidovudine was failing. A total of 21,198 patients who had infections refractory to zidovudine or who were intolerant of the drug received didanosine as a buffered powder for oral solution (sachet), with total daily doses of 6.6-10 mg/kg; the median CD4 lymphocyte count was 0.04 x 10(9)/L for this population. At the currently recommended dose (6.6-8.29 mg/[kg.d]), 6-month estimated rates of pancreatitis ranged from 1.2% for patients with AIDS-related complex (ARC) and CD4 lymphocyte counts of > or = 0.1 x 10(9)/L to 6.7% for patients with AIDS and CD4 lymphocyte counts of < 0.05 x 10(9)/L. Laboratory toxicities of World Health Organization grades 3 and 4 developed in fewer than 4% of patients entering the study with normal baseline values; the sole exception was leukopenia, which was documented in 8% of these patients. The results of this program demonstrated that patients with CD4 lymphocyte counts of < 0.10 x 10(9)/L or with a diagnosis of AIDS (defined by the 1987 classification system of the Centers for Disease Control and Prevention) were less tolerant of didanosine and significantly more likely to develop adverse clinical reactions and myelosuppression than other patients. Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; CD4 Lymphocyte Count; Child; Didanosine; Drugs, Investigational; Female; Health Services Accessibility; HIV Infections; Humans; Male; Medication Systems; Middle Aged; Pancreatitis; Prospective Studies; Risk Factors | 1994 |
A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection.
A randomized pilot study comparing alternating and simultaneous regimens of zidovudine and didanosine (ddl) was conducted in 41 patients with AIDS or symptomatic human immunodeficiency virus (HIV) infection. Patients on each regimen received the same overall amounts of zidovudine and didanosine over time. CD4 cell counts in patients on the simultaneous regimen reached a maximum (mean +/- SE) of 108 +/- 16/mm3 above baseline (two-tailed P < or = .0001) and were significantly higher than in patients on the alternating regimen at all time points during weeks 6-45. At 54 weeks, the CD4 cell counts in the patients on the simultaneous regimen were still 40 +/- 19/mm3 above baseline. Patients on the simultaneous regimen also had significantly greater weight gain. While toxicities were generally mild and comparable between the regimens, 1 patient on the simultaneous regimen died of pancreatitis and lactic acidosis. Thus, simultaneous therapy provided more sustained elevations in CD4 cells than alternating therapy over 1 year and may be worth exploring in larger controlled trials. Topics: Administration, Oral; Adolescent; Adult; AIDS-Related Opportunistic Infections; beta 2-Microglobulin; Body Weight; CD4-Positive T-Lymphocytes; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Core Protein p24; HIV Infections; Humans; Leukocyte Count; Male; Middle Aged; Pancreatitis; Pilot Projects; Zidovudine | 1994 |
A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. The Terry Beirn Community Programs for Clinical Research on AIDS.
Both didanosine and zalcitabine are commonly used to treat patients with human immunodeficiency virus (HIV) infection who cannot tolerate zidovudine treatment or who have had disease progression despite it. The relative efficacy and safety of these second-line therapies are not well defined.. In this multicenter, open-label trial we randomly assigned 467 patients who previously received zidovudine and had 300 or fewer CD4 cells per cubic millimeter or a diagnosis of the acquired immunodeficiency syndrome (AIDS) to treatment with either didanosine (500 mg per day) or zalcitabine (2.25 mg per day).. After a median follow-up of 16 months, disease progression or death occurred in 157 of 230 patients assigned to didanosine and 152 of 237 patients assigned to zalcitabine, for a relative risk of 0.93 for the zalcitabine group as compared with the didanosine group (P = 0.56), which decreased to 0.84 (P = 0.15) after adjustment for the CD4 count, Karnofsky score, and presence of AIDS at base line. There were 100 deaths in the didanosine group and 88 in the zalcitabine group, for a relative risk of 0.78 (P = 0.09) and an adjusted relative risk of 0.63 (P = 0.003). A majority of patients in each group (66 percent) had at least one adverse event during treatment (153 patients taking didanosine and 157 taking zalcitabine). Peripheral neuropathy and stomatitis occurred more often with zalcitabine and diarrhea and abdominal pain more frequently with didanosine.. For patients with HIV infection who have not responded to treatment with zidovudine, zalcitabine is at least as efficacious as didanosine in delaying disease progression and death. Topics: Acquired Immunodeficiency Syndrome; Adult; CD4-Positive T-Lymphocytes; Didanosine; Female; Follow-Up Studies; HIV Infections; Humans; Leukocyte Count; Male; Risk; Zalcitabine; Zidovudine | 1994 |
Zidovudine and didanosine combination therapy in children with human immunodeficiency virus infection.
Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy.. We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m2 every 6 hours and doses of didanosine ranging from 90 to 180 mg/m2 every 12 hours.. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/m2 every 6 hours orally and didanosine ranging from 90 to 180 mg/m2 every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/mm3 (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/mm3 (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to < 31 pg/mL (p < .001). The geometric mean titer of HIV in plasma decreased from 83.1 to 2.7 tissue culture infectious doses/mL (P = .001).. The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent therapy. Potent in vivo antiviral activity was observed. Combination therapy with nucleoside analogues may be an important approach to optimizing the use of these agents in the treatment of HIV infection. Topics: Adolescent; Adult; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Leukocyte Count; Male; Treatment Outcome; Zidovudine | 1994 |
A phase II study of effect of addition of trichosanthin to zidovudine in patients with HIV disease and failing antiretroviral agents.
Patients infected with HIV, including those with AIDS-related complex and AIDS, and failing treatment with antiretroviral agents such as zidovudine, have been evaluated following addition of trichosanthin to the antiretroviral agent regimen. This ribosomal inhibitory protein is specifically cytotoxic for HIV-infected macrophages and lymphocytes. Ninety-three patients were treated with trichosanthin, using a schedule of weekly, then monthly, intravenous injections of 1.2 mg of drug in combination with antiretroviral agents, usually zidovudine. Side effects included myalgias, fevers, mild elevation in liver function tests, and mild-moderate anaphylactic reactions, which respond well to therapy with steroids and/or benedryl. Reversible mental status changes were noted in two patients, both receiving concomitant therapy with ddI. Clinical responses to trichosanthin treatment were monitored primarily by changes in laboratory parameters, particularly levels of CD4+ T lymphocytes. In the total population evaluated for efficacy (85 patients) there was a significant increase in CD4+ cell levels after initiation of trichosanthin therapy. A second analysis performed on 72 patients measured the rate of change of CD4+ cells during therapy, using an "area under the curve" analysis. During therapy there was a median increase of 1.2 cells/mm3/month. In patients in the top 25th percentile, this increase was greater than 8.4 cells/mm3/month. In 59 of the 72 patients, responses could also be monitored by comparing the rate of loss of CD4+ cell levels on antiretroviral agents (zidovudine or ddI) alone, during the year prior to initiation of trichosanthin, to the rate of change when trichosanthin was added to the treatment regimen. During the period before trichosanthin treatment (311 +/- 11.7 days) the median loss of CD4+ cells was 6.91 cells/mm3/month. Addition of trichosanthin to the treatment regimen resulted in a median gain of 1.1 CD4+ cells/mm3/month. Topics: Adolescent; Adult; Aged; CD4-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Leukocyte Count; Liver; Male; Middle Aged; Trichosanthin; Zidovudine | 1994 |
Clinical and pharmacokinetic evaluation of long-term therapy with didanosine in children with HIV infection.
Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine.. Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 10(9) cells/L, received oral didanosine at doses between 20 mg/m2 to 180 mg/m2 every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients.. Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months; range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by > or = .05 x 10(9) cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x 10(9) cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration.. Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment. Topics: Adolescent; CD4 Antigens; Child; Child, Preschool; Didanosine; Disease Progression; Female; HIV Infections; Humans; Infant; Male; Treatment Outcome | 1994 |
Antiretroviral therapy is associated with a decrease in unintegrated HIV-1 DNA in pediatric patients.
Good markers for monitoring the efficacy of antiretroviral therapy in children do not currently exist. This study examined the effect of antiretroviral therapy on human immunodeficiency virus (HIV-1) unintegrated DNA (uDNA), integrated DNA (iDNA), percent uDNA, immune complex dissociated (ICD) p24 antigenemia, and plasma viral titer. Seven children were followed at therapy initiation and at approximately 3- and 10-month intervals. HIV-1 uDNA was detected in all children prior to start of therapy (average percent uDNA, 43%). At 3 months, the percent HIV uDNA decreased in all patients to an average of 18% (p = 0.01) and at 10 months decreased to an average of 1%. In contrast, the amount of HIV iDNA was relatively constant after initiation of therapy. ICD HIV p24 antigen was detected in all patients prior to therapy (average, 538 pg/ml). Over the study period, the ICD p24 antigen level decreased in three patients and remained relatively unchanged in four patients. Plasma cultures of HIV-1 were positive in only one of the seven patients prior to therapy. Among the methods evaluated, measurement of uDNA was the only parameter which reliable decreased after initiation of nucleoside therapy. Topics: CD4 Lymphocyte Count; Child, Preschool; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Infant; Leukocytes, Mononuclear; Male; Polymerase Chain Reaction; Viremia; Zidovudine | 1994 |
Pharmacokinetic evaluation of the combination of zidovudine and didanosine in children with human immunodeficiency virus infection.
As part of a phase I/II trial in children infected with human immunodeficiency virus, we studied the pharmacokinetics of zidovudine and didanosine administered as single agents and in combination. Zidovudine (60 to 180 mg/m2 per dose) was given orally every 6 hours, and didanosine (60 to 180 mg/m2 per dose) every 12 hours. Pharmacokinetic samples were obtained from 54 patients and the area under the plasma concentration-time curve (AUC) was estimated by means of a previously defined limited sampling strategy. Follow-up blood samples were obtained after 4 and 12 weeks of treatment. The mean AUC for zidovudine ranged from 4.8 mumol.hr per liter at 60 mg/m2 to 11.0 mumol.hr per liter at the 180 mg/m2 level, and increased in proportion to the dose. The mean AUC for didanosine ranged from 2.8 mumol.hr per liter (60 mg/m2) to 8.0 mumol.hr per liter (180 mg/m2), with a wide interpatient variability. The AUCs of zidovudine and didanosine remained unchanged when the agents were administered in combination. There was no significant change in the AUCs of either drug after 4 and 12 weeks in comparison with those on day 3 of therapy. However, there was greater interpatient and intrapatient variability with didanosine than with zidovudine. These observations have implications for the future utility of therapeutic drug monitoring with these agents. Topics: Adolescent; Adult; Child; Child, Preschool; Didanosine; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Male; Zidovudine | 1994 |
Sexual dysfunction in advanced HIV disease.
Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Complex; Didanosine; Erectile Dysfunction; HIV Infections; Homosexuality; Humans; Male; Quality of Life; Sexual Dysfunctions, Psychological | 1994 |
Uric acid and didanosine compliance in AIDS clinical trials: an analysis of AIDS Clinical Trials Group protocols 116A and 116B/117.
An analysis is presented that promotes the use of uric acid levels as an indicator of patients didanosine (ddI) use. Logistic regression techniques were used on data from two test groups that best represent patients entered on ACTG protocols 116A and 116B/117. Two classification functions resulted that are based on serial uric acid measurements and were used to classify patients to one of two groups: those treated with zidovudine (ZDV) and those treated with ddI. These functions correctly classified well over 70% of the patients in each of these two studies. Implications of these results with respect to the assessment of ddI compliance and limitations in the use of these classification functions are discussed. Topics: Adult; Clinical Protocols; Cohort Studies; Didanosine; Double-Blind Method; Female; HIV Infections; Humans; Male; Patient Compliance; Sensitivity and Specificity; Uric Acid; Zidovudine | 1993 |
Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection.
To assess safety, pharmacokinetics, and in-vivo virologic activity of five different combination regimens of zidovudine and didanosine compared with zidovudine alone in patients with human immunodeficiency virus type 1 (HIV-1) infection.. Open-label, partially randomized, dose-ranging study.. University-affiliated, medical center clinics.. A total of 69 patients with HIV-1 infection, CD4+ cell counts fewer than 400 cells/mm3, and fewer than 121 days of previous zidovudine treatment.. Fifty-five patients received combination therapy with zidovudine and didanosine, and 14 received zidovudine therapy alone (600 mg/d). Daily dosages in milligrams of zidovudine and didanosine, respectively, in the five combination groups were 150 and 90 mg, 300 and 334 mg, 600 and 334 mg, 300 and 500 mg, and 600 and 500 mg.. CD4+ cell counts, HIV-1 RNA titers in plasma, and toxic effects.. The combination regimens were associated with higher and more sustained increases in CD4+ cells than zidovudine alone, even after adjustment for initial CD4+ counts and previous zidovudine therapy (P < 0.001). The median increase in CD4+ cell counts was 166 cells/mm3 with combination therapy and 77 cells/mm3 with zidovudine alone (P = 0.001) and did not differ statistically among the five combination regimens. Human immunodeficiency virus type 1 RNA titers in plasma decreased in 15 (83%) of 18 combination-therapy recipients compared with 2 of 7 zidovudine-alone recipients (P = 0.017). No pharmacokinetic interactions were seen between zidovudine and didanosine. Toxicity rates were low among all treatment groups. A greater decrease in hemoglobin levels was seen with the regimen using zidovudine alone (-8 g/L) compared with combination regimens using the same zidovudine dose (-1.5 g/L, P = 0.03).. Combination therapy with zidovudine and didanosine produced larger and more sustained increases in CD4+ cell counts, more frequent decreases in plasma HIV-1 RNA titers, and more stable hematologic status than zidovudine therapy alone. The effects of this combination on the progression of HIV disease merit further study, to provide information about clinical outcome, because this was a relatively small study based on surrogate markers of HIV-1 infection. Topics: Adult; CD4 Antigens; Cell Count; Didanosine; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; RNA, Viral; Zidovudine | 1993 |
Longitudinal analysis of responses to oral didanosine therapy following zidovudine therapy in advanced infection with human immunodeficiency virus.
The effect on immunologic and virological parameters of up to 24 weeks of therapy with didanosine at daily oral doses of < or = 12.5 mg/(kg.d) was studied retrospectively in 69 patients with advanced disease due to human immunodeficiency virus--i.e., AIDS or advanced AIDS-related complex--who had previously been treated with zidovudine. Patients entered the study with a low CD4 cell count (median, 39/microL) and with evidence of an ongoing depression of bone marrow function. Didanosine therapy was associated with a significant increase in CD4 counts and a prolonged decrease in serum levels of p24 antigen relative to baseline. These changes were more pronounced in the population with baseline CD4 counts of > or = 100/microL. A beneficial effect of didanosine therapy on hematologic parameters was observed in these patients, with increases during therapy of hemoglobin levels as well as white blood cell, granulocyte, and platelet counts. These responses were maximal at weeks 16-20. Further investigations are needed to establish the clinical correlates of these observations. Topics: Administration, Oral; Adult; Blood Cell Count; Didanosine; Female; Hemoglobins; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Zidovudine | 1993 |
Long-term follow-up of didanosine administered orally twice daily to patients with advanced human immunodeficiency virus infection and hematologic intolerance of zidovudine.
This phase 1 trial was conducted to evaluate the safety and tolerance of didanosine (ddI) in subjects with AIDS or AIDS-related complex (ARC) who previously had demonstrated hematologic intolerance of zidovudine. Thirty subjects, 21 with AIDS and nine with ARC, were enrolled. Initially, didanosine was administered orally twice daily for a total daily dose of either 750 mg or 1,500 mg. Subsequently, the dosage for those receiving 1,500 mg/d was reduced to a maximum of 750 mg/d (375 mg twice daily) when data from this and other phase 1 studies showed that the dosage of 1,500 mg/d (750 mg twice daily) was associated with an unacceptable risk of developing neuropathy. The subjects were studied for 46 weeks (mean time; range, 7-122 weeks). The dose-limiting toxic effect observed was peripheral neuropathy, which occurred in eight patients. Other significant toxic effects included pancreatitis in three patients and xerostomia in eleven. In general, didanosine was well tolerated from a hematologic standpoint by the majority of patients during prolonged administration. Topics: Administration, Oral; Adult; Didanosine; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; HIV Infections; Humans; Male; Middle Aged; Zidovudine | 1993 |
New developments in the clinical use of didanosine.
Didanosine (ddI) is a purine analogue that demonstrates in vitro anti-human immunodeficiency virus (HIV) activity, effects on the surrogate markers CD4+ T-lymphocytes and p24 antigen, and has adequate oral bio-availability. Recently, 500 mg/day of ddI in sachet form demonstrated clinical effectiveness compared with zidovudine (ZDV) for delaying HIV disease progression in patients with AIDS or AIDS related complex (ARC) and less than 300 CD4+ T-lymphocytes, or asymptomatic individuals with less than 200 CD4+ T-lymphocytes. All patients tolerated a minimum of 16 weeks of prior ZDV treatment. ddI treatment was associated with an increase in serum amylase and pancreatitis, however, there was no significant difference in the incidence of pancreatitis between the 500 mg ddI and ZDV groups. There was significantly more hematologic toxicity associated with ZDV and no difference between ddI and ZDV groups with respect to peripheral neuropathy. ddI is presently available in tablet form with 125% the bioavailability of the sachet form of ddI; therefore, the 500-mg sachet formulation corresponds to a 400-mg daily tablet dose of ddI. Future studies of ddI will involve ddI's effects on antiretroviral naive patients and the potential of combining ddI with other agents. Topics: Didanosine; Dose-Response Relationship, Drug; HIV Infections; Humans | 1993 |
Randomized study of two doses of didanosine in children infected with human immunodeficiency virus.
2'3'-Dideoxyinosine (didanosine) is a nucleoside analog active in vitro against human immunodeficiency virus. Few data are available regarding its use for the treatment of children. In a single-center, randomized, open-label trial, we compared two dosages of didanosine (120 vs 270 mg/m2 per day) for at least 6 months in 34 children infected with human immunodeficiency virus who had become resistant to or were intolerant of zidovudine. Serum levels of didanosine 1 hour after administration were significantly different in the two groups and remained stable with time. There was a significant reduction in human immunodeficiency virus-p24 antigenemia and quantitative cellular viremia with time but no difference between the two groups. The intensity of the biologic response, however, was significantly higher in the patients who had more than 50 CD4+ cells 10(6)/L at inclusion. No pancreatic or neurologic toxic effects were observed. In five children, liver function abnormalities developed that are unusual in this setting, and the death of one child from unexplained hepatocellular failure suggests that didanosine may be hepatotoxic. Three of these five children had preexisting liver disease. Although no definite conclusion can be made as to the optimal dose, there were no major differences between the two administration schedules in terms of biologic effects and tolerability. Topics: Adolescent; Child; Child, Preschool; Didanosine; Female; HIV; HIV Core Protein p24; HIV Infections; Humans; Infant; Male; Viremia | 1993 |
Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A phase I trial.
To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV).. Open-label, phase I study.. Two university hospitals. Patients were studied in both inpatient and outpatient settings.. Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis.. Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined.. CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state.. Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant.. The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less. Topics: Administration, Oral; CD4-Positive T-Lymphocytes; Didanosine; Dose-Response Relationship, Drug; Drug Evaluation; HIV Core Protein p24; HIV Infections; Humans; Infusions, Intravenous; Leukocyte Count; Models, Biological | 1992 |
A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group.
Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine.. This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine.. There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group.. Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease. Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; CD4-Positive T-Lymphocytes; Didanosine; Double-Blind Method; Female; HIV Core Protein p24; HIV Infections; Humans; Leukocyte Count; Male; Patient Compliance; Survival Rate; Zidovudine | 1992 |
Didanosine for zidovudine-intolerant patients with HIV disease.
Topics: Didanosine; Europe; HIV Infections; HIV-1; Humans; Survival Rate; Zidovudine | 1992 |
Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection.
Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse transcriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations. In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in 1 study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity. Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest. Topics: Acquired Immunodeficiency Syndrome; Didanosine; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans | 1992 |
[Didanosine as an alternative for HIV infection. AIDS--disease progression].
Topics: Didanosine; Dose-Response Relationship, Drug; HIV; HIV Infections; Humans; Virus Replication | 1992 |
Changes in T-helper cell function in human immunodeficiency virus-infected children during didanosine therapy as a measure of antiretroviral activity.
Didanosine has shown activity against the human immunodeficiency virus (HIV) in both children and adults. We prospectively assessed T-helper cell (Th) function as determined by in vitro interleukin-2 (IL-2) production in response to a panel of T-cell stimuli in 22 HIV-infected children before and during didanosine therapy and we correlated the incidence of opportunistic and recurrent bacterial infections with changes in p24 antigen and CD4 counts. Didanosine (270, 360, or 540 mg/m2/d) was administered orally for periods ranging from 8 to 40 weeks (mean, 24 weeks). Five of six asymptomatic patients (Centers for Disease Control P-1) compared with 6 of 16 symptomatic (P-2) patients exhibited improved Th function (greater than threefold increase in IL-2 production to at least 2 of the 4 stimuli) during therapy. Of 12 patients without infections during therapy, 9 (75%) showed improvement in Th function, compared with only 2 of 10 patients with infections (P = .03). Notably, the incidence of infections was not correlated with improvements in CD4 count or decreases in p24 antigen. Improvement in Th function during didanosine therapy is correlated with decreased incidence of infections. Assessment of Th function may provide an additional measurement of immunologic response to antiretroviral therapy. Topics: Adolescent; Adult; Cells, Cultured; Child; Child, Preschool; Didanosine; Female; Follow-Up Studies; HIV Infections; Humans; Infant; Interleukin-2; Male; Reference Values; T-Lymphocytes, Helper-Inducer | 1992 |
Nucleoside therapy for HIV infection--some answers, many questions.
Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Didanosine; HIV Infections; Humans; Zidovudine | 1992 |
Clinical pharmacology of 2',3'-dideoxyinosine in human immunodeficiency virus-infected children.
The pharmacokinetics of intravenous and oral 2',3'-dideoxyinosine (ddI) and the relationships between pharmacokinetic parameters and measures of response were studied in 48 human immunodeficiency virus-infected children. Disappearance of ddI from plasma after the intravenous dose was rapid and biexponential, with half-lives of 12 min and 1.0 h and a total clearance of 510 +/- 180 ml/min/m2. After oral administration, ddI absorption was limited and variable (mean bioavailability, 19% +/- 17%). A plasma ddI concentration-response relationship was observed for both decline in viral p24 antigen levels and improvement in intelligence quotient score. A limited sampling model was developed that accurately predicts the area under the ddI plasma concentration-time curve from one to three plasma samples. Although this pharmacokinetic study was done in children, the results also have relevance to adults and suggest that individualization of dose and schedule through therapeutic drug monitoring may be necessary to achieve optimal response. Topics: Absorption; Administration, Oral; Adolescent; Child; Child, Preschool; Didanosine; Drug Evaluation; Female; Follow-Up Studies; Half-Life; HIV Infections; Humans; Infant; Infusions, Intravenous; Male | 1992 |
Retinal toxicity in human immunodeficiency virus-infected children treated with 2',3'-dideoxyinosine.
To assess the safety and antiretroviral activity of 2',3'-dideoxyinosine, we enrolled 43 children with symptomatic (Centers for Disease Control class P-2) human immunodeficiency virus infection in a Phase I-II study and monitored them prospectively for the development of ocular complications secondary to HIV infection or drug toxicity. Follow-up ranged from 12 to 103 weeks with a median follow-up of 71 weeks. Three of 43 children (7.0%) developed peripheral atrophy of the retinal pigment epithelium during treatment with 2',3'-dideoxyinosine. The two children with the most severe retinal atrophy were enrolled in the study at the highest dosage studied (540 mg/m2/day). In contrast to findings in children, no retinal atrophy in HIV-infected adults treated with 2',3'-dideoxyinosine has been evident to date. Topics: Atrophy; Child; Child, Preschool; Didanosine; Drug Evaluation; Electrooculography; Electroretinography; Female; Follow-Up Studies; Fundus Oculi; HIV Infections; HIV-1; Humans; Male; Pigment Epithelium of Eye; Prospective Studies; Retina; Retinal Diseases; Zidovudine | 1992 |
Dideoxyinosine in children with symptomatic human immunodeficiency virus infection.
2',3'-Dideoxyinosine (ddl) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddl showed evidence of antiretroviral activity with little hematologic toxicity.. We conducted a phase I-II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddl was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddl: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity.. After oral administration, ddl was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddl at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218 x 10(9) per liter (218 per cubic millimeter) at base line to 0.327 x 10(9) per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1 x 10(9) per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddl correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine.. Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddl indicates that bioavailability is an important consideration in the use of ddl to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity. Topics: Administration, Oral; Adolescent; Biological Availability; Brain Diseases; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Didanosine; Drug Evaluation; Female; Gene Products, gag; HIV Antigens; HIV Core Protein p24; HIV Infections; Humans; Infant; Intelligence; Leukocyte Count; Liver; Male; Pancreatitis; Viral Core Proteins | 1991 |
Chemotherapy of human immunodeficiency virus infections: current practice and future prospects.
As human immunodeficiency virus type 1 (HIV-1) has become better understood, numerous drugs have been developed that act at virus-specific sites. These are challenging our ability to evaluate them thoroughly and rapidly. Zidovudine (AZT) remains the mainstay of anti-HIV-1 drugs. Recent controlled trials indicate it should be used early in infection (in those with CD4 cell counts less than 500/mm3) and in lower doses (500-600 mg/day). Prolonged AZT treatment in patients with AIDS, however, is often associated with viral resistance. Newer reverse transcriptase-inhibiting nucleoside derivatives are currently in phase II-III clinical trials. Other HIV-1 replicative sites under attack in clinical studies include binding and entry of virus, envelope protein glycosylation, and viral assembly and release. Agents that target HIV-1 proteinase, integrase, ribonuclease H, and products of regulatory genes such as tat are under development. Combination therapies that target different viral replicative sites likely will allow use of individual agents below their toxic concentrations and help prevent drug resistance. Innovative programs for expanded access to experimental drugs are needed that will permit expeditious clinical trials, optimize the gathering of useful information, and permit the widest access to promising treatments. Topics: Animals; Antiviral Agents; Didanosine; DNA Nucleotidyltransferases; DNA Replication; Drug Therapy, Combination; Endopeptidases; HIV Infections; HIV-1; Humans; Integrases; RNA-Directed DNA Polymerase; Virus Replication; Zalcitabine; Zidovudine | 1990 |
Effects of antiretroviral dideoxynucleosides on polymorphonuclear leukocyte function.
Dideoxynucleosides (zidovudine[AZT], dideoxycytidine[ddC], and dideoxyinosine[ddI]) are promising new agents for the management of human immunodeficiency virus type 1 (HIV-1) infections. In light of recent data demonstrating defects in the polymorphonuclear leukocyte (PMN) bactericidal activity of HIV-1-infected patients and since many chemotherapeutic agents affect PMN function, we examined their effects on the function of PMNs from both healthy and HIV-1-infected individuals in vitro. AZT (0.1 to 25 microM), ddC (0.01 to 1 microM), and ddI (0.2 to 50 microM) had no effect on viability, chemotaxis to N-fromylmethionyl leucyl phenylalanine, phagocytosis of Candida albicans or Staphylococcus aureus, or superoxide production following stimulation by N-formylmethionyl leucyl phenylalanine. Killing of C. albicans was not affected by AZT but was enhanced by 0.1 and 1 microM ddc (a 1 microM, killing was 26.0 +/- 2.02% compared with 17.0 +/- 0.73% for controls: P = 0.006) and 0.2 to 50 microM ddI (at 10 microM, killing was 25.0 +/- 0.68% compared with 17.8 +/- 0.91% for controls; P = 0.002). Killing of S. aureus was unchanged by AZT and ddC but was significantly enhanced by ddI at 0.2 to 20 microM (at 2 microM, killing was 71.2 +/- 5.57% compared with 51.4 +/- 6.29% for controls; P = 0.0045). In addition, the preexisting defective bactericidal capacity of PMNs from HIV-1-infected patients was enhanced by ddI (P less than 0.025). Potential enhancement by these dideoxynucleosides of certain PMN functions of HIV-1-infected patients deserves further study. Topics: Cell Survival; Chemotaxis, Leukocyte; Didanosine; HIV Infections; HIV-1; Humans; Neutrophils; Phagocytosis; Superoxides; Zalcitabine; Zidovudine | 1990 |
Other Studies
653 other study(ies) available for didanosine and HIV-Infections
Article | Year |
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Long-term follow-up with multimodal imaging and functional testing in didanosine retinal toxicity.
Topics: Anti-HIV Agents; Didanosine; Eye Diseases; Follow-Up Studies; HIV Infections; Humans; Multimodal Imaging | 2023 |
Insulin resistance in people living with HIV is associated with exposure to thymidine analogues and/or didanosine and prior immunodeficiency.
As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance is a key determinant. In this study, we aimed to investigate risk factors associated with insulin resistance in PLWH.. We included well-treated PLWH without hepatitis co-infection, and with available fasting serum insulin and plasma glucose (n = 643) from the Copenhagen Comorbidity in HIV Infection Study. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the association between risk factors and high HOMA-IR in a logistic regression model adjusted for age, sex, abdominal obesity, smoking status, and origin. When including use of thymidine analogues and/or didanosine in the model, we also adjusted for time with HIV.. Insulin resistance in PLWH is associated with both use of thymidine analogues and/or didanosine and prior immunodeficiency suggesting that increased attention on blood glucose in these patients could be beneficial. Topics: Diabetes Mellitus, Type 2; Didanosine; Female; HIV Infections; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Abdominal; Thymidine | 2022 |
A Rare Case of Didanosine-Induced Mid-Peripheral Chorioretinal Atrophy Identified Incidentally 11 Years after the Drug Cessation.
Topics: Adult; Atrophy; Choroid Diseases; Didanosine; Emtricitabine; Female; HIV Infections; Humans; Hydroxychloroquine; Retinal Degeneration; Tenofovir; Tomography, Optical Coherence | 2022 |
Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls.
Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to estimate the prevalence and factors associated with liver fibrosis in PWH compared to population controls.. This was a cross-sectional cohort study comparing 342 PWH with 2190 population controls aged 50-70 years.Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were computed by logistic regression.. The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM. In multivariate analysis, elevated LSM was associated with HIV (aOR, 1.84 [95% CI, 1.17-2.88]; P < .01); higher age (per decade: aOR, 3.34 [95% CI, 1.81-6.18]; P < .01); alanine aminotransferase (ALT) (per 10 IU/L: aOR, 1.25 [95% CI, 1.05-1.49]; P < .01); body mass index (BMI) (per 1 kg/m2: aOR, 1.17 [95% CI, 1.05-1.29]; P < .01), and previous exposure to didanosine (per year: aOR, 2.26 [95% CI, 1.01-5.06]; P = .04).. The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM. Topics: Aged; Cross-Sectional Studies; Didanosine; Elasticity Imaging Techniques; Hepatitis, Viral, Human; HIV; HIV Infections; Humans; Liver; Liver Cirrhosis; Middle Aged; Population Control; Prevalence | 2021 |
Pericardial Adipose Tissue Volume Is Independently Associated With Human Immunodeficiency Virus Status and Prior Use of Stavudine, Didanosine, or Indinavir.
Increased pericardial adipose tissue is associated with higher risk of cardiovascular disease. We aimed to determine whether human immunodeficiency virus (HIV) status was independently associated with larger pericardial adipose tissue volume and to explore possible HIV-specific risk factors.. Persons with HIV (PWH) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study and matched 1:1 on age and sex to uninfected controls. Pericardial adipose tissue volume was measured using cardiac computed tomography.. A total of 587 PWH and 587 controls were included. Median age was 52 years, and 88% were male. Human immunodeficiency virus status was independently associated with 17 mL (95% confidence interval [CI], 10-23; P < .001) larger pericardial adipose tissue volume. Larger pericardial adipose tissue volume was associated with low CD4+ nadir and prior use of stavudine, didanosine, and indinavir. Among PWH without thymidine analogue or didanosine exposure, time since initiating combination antiretroviral treatment (per 5-year use) was associated with l6 mL (95% CI, -6 to -25; P = .002) lower pericardial adipose tissue volume.. Human immunodeficiency virus status was independently associated with larger pericardial adipose tissue volume. Severe immunodeficiency, stavudine, didanosine, and indinavir were associated with larger pericardial adipose tissue volume. Persons with HIV with prior exposure to these drugs may constitute a distinct cardiovascular risk population. Topics: Adipose Tissue; Adult; Anti-HIV Agents; Cardiovascular Diseases; Denmark; Didanosine; Female; Healthy Volunteers; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Pericardium; Risk Factors; Stavudine; Viral Load | 2020 |
Safety of in-utero antiretroviral exposure: neurologic outcomes in children who are HIV-exposed but uninfected.
To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.. Prospective cohort study of CHEU enrolled from 2007 to 2017.. We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.. Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4--7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94--2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09--3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11--4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07--4.87 and aRR = 2.02, 95% CI 1.01--4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75--7.84), which was observed consistently across several sensitivity analyses.. Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring. Topics: Abnormalities, Drug-Induced; Adult; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Treatment Outcome | 2020 |
Long-lasting alterations in adipose tissue density and adiponectin production in people living with HIV after thymidine analogues exposure.
Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CT-scan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation.. Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome).. prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [- 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]).. We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH. Topics: Adiponectin; Adipose Tissue; Adult; Anti-HIV Agents; Biomarkers; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Intra-Abdominal Fat; Longitudinal Studies; Male; Middle Aged; Subcutaneous Fat; Thymidine | 2019 |
Risk of cancer in children exposed to antiretroviral nucleoside analogues in utero: The french experience.
All nucleoside analogues for treating HIV infection, due to their capacity to integrate into and alter human DNA, are experimentally genotoxic to some extent. The long-term oncogenic risk after in utero exposure remains to be determined. Cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) was evaluated, by cross-checking against the National Cancer Registry, in the French perinatal study of children born to HIV Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Incidence; Infant; Infant, Newborn; Male; Maternal Exposure; Maternal-Fetal Exchange; Neoplasms; Nucleosides; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Reverse Transcriptase Inhibitors; Risk; Surveys and Questionnaires; Zidovudine | 2019 |
Metabolic events in HIV-infected patients using abacavir are associated with erythrocyte inosine triphosphatase activity.
Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5'-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients.. ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity <4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94C>A (rs1127354) and c.124 + 21A>C (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs.. In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34-7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype.. This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism. Topics: Adult; Aged; Diabetes Mellitus; Didanosine; Dideoxynucleosides; Erythrocytes; Female; Genotype; HIV Infections; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Pyrophosphatases; Reverse Transcriptase Inhibitors; Tenofovir | 2019 |
Prior exposure to thymidine analogs and didanosine is associated with long-lasting alterations in adipose tissue distribution and cardiovascular risk factors.
Thymidine analogs and didanosine (ddI) have been associated with redistribution of body fat from subcutaneous adipose tissue (SAT) to visceral adipose tissue (VAT), which, in turn, is a risk factor for cardiovascular disease. We explored differences in adipose tissue distribution between people living with HIV (PLWH) with prior exposure to thymidine analogs and/or ddI, without exposure, and uninfected controls and the association with cardiovascular disease risk factors.. In all, 761 PLWH from the Copenhagen Comorbidity in HIV Infection study, and 2283 age and sex-matched uninfected controls from the Copenhagen General Population Study were included. PLWH were stratified according to prior exposure to thymidine analogs and/or ddI. VAT and SAT were determined by abdominal computed tomography scan. Hypotheses were tested using regression analyses.. Exposure to thymidine analogs and/or ddI was associated with 21.6 cm larger VAT (13.8-29.3) compared to HIV infection without exposure. HIV-negative status was associated with similar VAT compared to HIV infection without exposure. Cumulative exposure to thymidine analogs and/or ddI [3.7 cm per year (2.3-5.1)], but not time since discontinuation [-1.1 cm per year (-3.4 to 1.1)], was associated with VAT. Prior exposure to thymidine analogs and/or ddI was associated with excess risk of hypertension [adjusted odds ratio (aOR) 1.62 (1.13-2.31)], hypercholesterolemia [aOR 1.49 (1.06-2.11)], and low high-density lipoprotein [aOR 1.40 (0.99-1.99)].. This study suggests a potentially irreversible and harmful association of thymidine analogs and ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low high-density lipoprotein found in PLWH with prior exposure to thymidine analogs and/or ddI, even years after treatment discontinuation. Topics: Adipose Tissue; Adult; Aged; Anti-HIV Agents; Cardiovascular Diseases; Denmark; Didanosine; Female; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Risk Factors; Thymidine | 2019 |
Epidemiology and factors associated with peripheral neuropathy among HIV infected patients in Gondar, Ethiopia: A cross-sectional study.
Antiretroviral therapy has surely increased the life expectancy of people living with HIV. However, long term complications like HIV associated sensory neuropathy has a negative impact on quality of life among people living with HIV (PLHIV). In Ethiopia, lack of data on magnitude of the burden and predictors of HIV associated sensory neuropathy in many resource limited setting has led to under diagnosis and eventually under management of HIV-SN. Hence, this study was set out to establish the burden of HIV-associated sensory neuropathy and, its association with demographic, health and clinical characteristics among people living with HIV in Ethiopia.. Cross-sectional study was conducted to assess the prevalence of HIV-associated sensory neuropathy and the associated factors among adult HIV patients at University of Gondar Teaching Hospital, Gondar, Ethiopia. Brief Peripheral Neuropathy Screening tool validated by AIDs Clinical trial group was used for screening HIV-associated sensory neuropathy. Data were analyzed descriptively and through uni- and multivariate logistic regression.. In total 359 adult PLHIV with a mean age of 36.5± 9.07 years participated, their median duration of HIV infection was 60 months (IQR 36-84) and their median CD4 count 143cells/μL (IQR 69.5-201.5). Age above 40 years, anti-tuberculosis regimen, tallness, and exposure to didanosine contained antiretroviral therapy were found to be associated with HIV-associated sensory neuropathy (AOR 1.82, 1.84, 1.98 and 4.33 respectively).. More than half of the HIV patients who attended HIV care clinic at University of Gondar hospital during the study period were found to present with peripheral sensory neuropathy. Higher age, tallness, TB medication, and didanosine in ART were significantly associated with HIV-SN as screened by effective diagnostic (BPNS) tool. Topics: Adult; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis; Peripheral Nervous System Diseases; Quality of Life | 2019 |
An association between K65R and HIV-1 subtype C viruses in patients treated with multiple NRTIs.
HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis.. We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs.. Subtype B patients ( n = 3410) were mostly MSM (78%) and those with subtype C ( n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P < 0.001).. Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Genetic Association Studies; Genotype; HIV Infections; HIV-1; Humans; Male; Multivariate Analysis; Mutation; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Stavudine; Tenofovir | 2017 |
New-onset diabetes in HIV-treated adults: predictors, long-term renal and cardiovascular outcomes.
To determine the incidence and risk factors for developing diabetes mellitus in a cohort of Thai HIV-infected patients on long-term combination antiretroviral therapy (cART).. Prospective study conducted between July 1996 and 30 April 2015.. A total of 1748 patients (60% men) who did not have diabetes mellitus prior to ART were assessed twice a year. Incident diabetes mellitus was defined as either having two consecutive fasting glucose levels more than 126 mg/dl, or reporting antidiabetes mellitus medication/diabetes mellitus diagnosis after starting cART. Incidence rates were calculated per 1000 person-year follow-up. Multivariate Cox regression was used to determine risk factors for the development of diabetes mellitus.. During a median follow-up of 9 years (16 274 person-year of follow-up), 123 patients developed new-onset diabetes mellitus, resulting in an incidence rate of 7.6 (95% confidence interval 6.3-9) per 1000 person-year of follow-up. From the multivariate models, age more than 35 years, male sex, BMI at least 25 kg/m, family history of diabetes, abnormal waist circumference, lipodystrophy and exposure to didanosine were significantly associated with incident diabetes mellitus. The diabetes mellitus group had higher mortality rate (8.1 vs. 4.1%, P = 0.04). A significantly higher proportion diabetes vs. nondiabetes patients developed cardiovascular and cerebrovascular complications (8.9 vs. 3.6%, P = 0.008) or chronic kidney disease stage III (estimated glomerular filtration rate <60 ml/min/1.73 m) (15.3 vs. 1.9%, P < 0.001) over total follow-up.. In addition to traditional risk factors, lipodystrophy and use of didanosine were strongly associated with development of incident diabetes. Given the higher rate of cardiovascular-cerebrovascular complications and chronic kidney disease among patients with diabetes mellitus, careful assessment and appropriate management of diabetes mellitus are essential. Topics: Adult; Antiretroviral Therapy, Highly Active; Asian People; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Didanosine; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Incidence; Male; Obesity, Abdominal; Proportional Hazards Models; Renal Insufficiency, Chronic; Reverse Transcriptase Inhibitors; Risk Factors; Thailand; Treatment Outcome | 2017 |
Effect of Antiretroviral Therapy on Bone and Renal Health in Young Adults Infected With HIV in Early Life.
HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from birth.. To prospectively evaluate renal and bone health in young adults with lifelong HIV and extensive ARV exposure.. Cross-sectional comparison of bone mineral density (BMD) by dual-energy X-ray absorptiometry, bone turnover, and renal function in young adults infected with HIV in early life (n = 65) to matched healthy controls (n = 23) and longitudinal evaluation (mean follow-up = 4.4 years) within a subset of the HIV cohort (n = 33).. Government outpatient research clinic.. Albumin/creatinine ratio, protein/creatinine ratio, anion gap, N-terminal telopeptides, and osteocalcin were significantly increased in persons with HIV compared with controls, whereas whole-body BMD and BMD z scores were lower. Within the HIV group, duration of tenofovir disoproxil fumarate (TDF) correlated with higher anion gap but did not correlate with bone parameters. Longer duration of didanosine and stavudine use correlated with lower BMD and BMD z scores. Longitudinal analyses revealed that BMD and bone metabolism significantly improved over time. No subject had an estimated glomerular filtration rate (eGFR) <60, but decline in eGFR correlated with increasing years of TDF exposure.. Subclinical markers of renal dysfunction were increased in HIV-infected young adults and associated with TDF exposure, whereas lower bone density was associated with didanosine and stavudine exposure. The tendency for improvement in markers of bone health over time and the availability of less toxic ARV alternatives may herald improvements in renal and bone health for perinatally infected patients in adulthood. Topics: Absorptiometry, Photon; Acid-Base Equilibrium; Adult; Age of Onset; Albuminuria; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Case-Control Studies; Creatinine; Cross-Sectional Studies; Didanosine; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Function Tests; Longitudinal Studies; Male; Osteocalcin; Prospective Studies; Proteinuria; Renal Insufficiency; Risk Factors; Stavudine; Tenofovir; Time Factors; Young Adult | 2017 |
A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects.
We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes; Cell Survival; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Receptors, CXCR4; Stavudine; T-Lymphocytes, Regulatory; Viral Load; Zalcitabine; Zidovudine | 2017 |
Prevalence of drug resistance mutations in HAART patients infected with HIV-1 CRF06_cpx in Estonia.
HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] + zidovudine [ZDV] vs. EFV + 3TC + ddI) among the HIV-1 CRF06_cpx infected subjects in Estonia. HIV-1 genomic RNA was sequenced; DRMs and amino acid substitutions were compared in 44 treatment naïve and 45 first-line NNRTI + 2 NRTI treatment failed patients consisting of EFV + 3TC + ZDV (n = 17) and EFV + 3TC + didanosine[ddI] (n = 21) therapy failed sub-populations. At least one DRM was found in 78% of treatment experienced patients. The most common NRTI mutations were M184V (80%), L74V (31%), L74I (17%), K219E (9%), and M184I (9%), NNRTI mutations were K103N (83%), P225H (14%), L100I (11%), and Y188L (11%), reflecting generally the similar pattern of DRMs to that seen in treatment failed subtype B viruses. Sub-population analysis revealed that EFV + 3TC + ddI failed patients had more DRMs compared to EFV + 3TC + ZDV failed patients, especially the ddI DRM L74IV and several additional NNRTI DRMs. Additionally, CRF06_cpx specific mutation E179V and substitutions R32K, K122E, and V200AE were also detected in treatment experienced population. After the failure of the first-line EFV + 3TC + ddI therapy HIV-1 CRF06_cpx viruses develop additional NRTI and NNRTI mutations compared to EFV + 3TC + ZDV regimen. Therefore the usage of EFV + 3TC + ddI in this subtype decreases the options for next regimens containing abacavir, and NNRTI class agents. Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Estonia; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Prevalence; Reverse Transcriptase Inhibitors; Zidovudine | 2016 |
Non-cirrhotic Portal Hypertension Associated with Didanosine and Streptococcus agalactiae Infection: A Case Report.
Non-Cirrhotic Portal Hypertension (NCPH) is a rare but potentially fatal liver disorder described in patients treated with anti-retroviral therapy for Human Immunodeficiency Virus (HIV). In particular, the most important predisposing factor to its development has been identified as prolonged exposure to Didanosine (ddI). The clinical entity of NCPH is characterized by an increase in portal pressure due to pre- or intra-hepatic causes, in absence of liver cirrhosis. However, the exact pathogenesis remains poorly understood, and due to its rarity, the diagnosis is often delayed.. We herein report a case in which ddI administration, with concomitant spontaneous bacterial peritonitis by Streptococcus agalactiae, has induced NCPH in a HIV male patient.. NPCH should be suspected when HIV patient with an history of ddI treatment presents liver decompensation. Topics: Antiviral Agents; Didanosine; HIV Infections; Humans; Hypertension, Portal; Male; Streptococcal Infections; Streptococcus agalactiae | 2016 |
Risk of cancer in children exposed to didanosine in utero.
Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine.. Updated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population.. A total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)].. There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class. Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; France; HIV Infections; Humans; Incidence; Infant; Infant, Newborn; Maternal-Fetal Exchange; Neoplasms; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Risk Assessment; Surveys and Questionnaires | 2016 |
Liver fibrosis in HIV-infected individuals on long-term antiretroviral therapy: associated with immune activation, immunodeficiency and prior use of didanosine.
It is unclear whether HIV infection is associated with liver fibrosis in the absence of chronic hepatitis B or C virus (HBV/HCV) coinfection. We compared prevalence of liver fibrosis, noninvasively assessed by the Fibrosis-4 (FIB-4) index, between HIV-infected patients and uninfected controls, and explored determinants of a higher FIB-4 score, indicative of more liver fibrosis.. FIB-4 was assessed in HIV-uninfected and HIV-1-infected, predominantly virologically suppressed participants of the AGEhIV Cohort Study without HBV and/or HCV coinfection, and aged at least 45. Using multivariable regression, we investigated associations between FIB-4 and HIV-status, HIV-disease characteristics, antiretroviral drugs and markers of microbial translocation and immune activation.. Prevalence of advanced liver fibrosis (FIB-4 ≥ 3.25) was low: 1.4% in HIV-infected and 1.0% in HIV-uninfected participants. After adjustment for age, sex, ethnicity, detectable anti-hepatitis B core/anti-HCV antibodies and excessive alcohol intake, HIV remained significantly associated with higher FIB-4 (+4.2%, P = 0.05). Prior exposure to didanosine, longer duration of a CD4 cell count below 500 cells/μl and a lower CD4 cell count at enrollment were each associated with a higher FIB-4. Markers of immune activation (soluble CD163, activated CD8 T-lymphocytes and regulatory T-lymphocytes) were associated with a higher FIB-4 in HIV-infected but not HIV-uninfected study participants.. HIV infection was independently associated with higher FIB-4 scores, indicating more advanced liver fibrosis, though the difference in FIB-4 scores between HIV-infected and HIV-uninfected was small. Higher levels of immune activation were associated with liver fibrosis in HIV-infected, even in the absence of HBV or HCV infection, but not in HIV-uninfected individuals. Topics: Aged; Anti-Retroviral Agents; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Liver Cirrhosis; Male; Middle Aged; Prevalence | 2016 |
Noncirrhotic Portal Hypertension in Perinatally HIV-infected Adolescents Treated With Didanosine-containing Antiretroviral Regimens in Childhood.
Noncirrhotic portal hypertension (NCPH) has been reported in HIV-infected adults. Antiretroviral drugs, as well as genetic and thrombophilic predisposition, have been suggested as possible etiologic factors.. Clinical data were collected from 6 HIV-infected patients attending the Infectious Diseases Departments at respectively Emma Children's Hospital Academic Medical Centre in Amsterdam, The Thai Red Cross AIDS Research Centre, Bangkok, Imperial College Healthcare NHS Trust, London who were diagnosed with NCPH. All underwent extensive blood analysis, liver ultrasound, liver elastography, esophagogastroduodenoscopy and percutaneous needle liver biopsy for histological evaluation.. We describe 6 perinatally HIV-infected adolescents, all female, who developed NCPH after prolonged exposure during childhood to a didanosine-containing antiretroviral regimen. Histology and electron microscopy showed periportal fibrosis and mitochondrial damage as key findings in their liver biopsies. One of these 6 patients required surgical intervention, the remainder have been managed conservatively to date.. Thus, symptomatic NCPH may present in adolescence after perinatally acquired HIV-1 infection. In this case series, risk factors included female sex and prolonged exposure to antiretroviral regimens that included the nucleoside-analogue didanosine in childhood. Topics: Adolescent; Adult; Anti-Retroviral Agents; Didanosine; Female; HIV Infections; Humans; Hypertension, Portal; Infectious Disease Transmission, Vertical; Liver; Young Adult | 2016 |
DIDANOSINE RETINAL TOXICITY.
To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature.. This was a multicenter, retrospective, observational case study from seven institutions. Medical records of patients who demonstrated well-demarcated severe midperipheral chorioretinal degeneration and who were previously treated with didanosine therapy were collected and the following information was reviewed: age, gender, medical history, detailed medication history including current and previous antiretroviral use, ocular and retinal examination findings, and multimodal imaging findings with optical coherence tomography, fundus photography, wide-field fundus autofluorescence, and wide-field fluorescein angiography. When available, findings with electrophysiology testing and automated perimetry were also collected and reviewed. A literature review was also performed to collect all reported cases of chorioretinal degeneration secondary to didanosine toxicity.. Nine patients were identified who had findings consistent with peripheral retinal toxicity secondary to didanosine use. Eight of the 9 patients were men, and the median age was 54 years at the time of presentation (mean: 55 years, range, 42-71 years). Snellen distance acuity ranged from 20/20 to 20/32. At least three of the cases in the series demonstrated progression of the peripheral retinal pigment epithelium and photoreceptor atrophy despite didanosine cessation. A review of the literature revealed 10 additional cases of didanosine toxicity. Seven of the 10 cases were in men (70%), and the average age was 26 years with a wide range (2-54 years). Chorioretinal findings were very similar to this cohort.. Herein, we report the largest series of nine cases of peripheral chorioretinal degeneration secondary to didanosine toxicity in adults. When combined with the cases in the literature, 19 cases of didanosine toxicity, 4 of which occurred in children, were collected and analyzed. Three of the new cases presented showed clear progression of degeneration despite didanosine cessation. Newer nucleoside reverse transcriptase inhibitors may potentiate mitochondrial DNA damage and lead to continued chorioretinal degeneration. Topics: Adult; Aged; Anti-HIV Agents; Choroid Diseases; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Retinal Degeneration; Retrospective Studies | 2016 |
A farewell to didanosine: harm reduction and cost savings by eliminating use of didanosine.
Didanosine (ddI) is a nucleoside reverse transcriptase inhibitor associated with adverse events and public health concerns which have diminished its place in HIV clinical practice, particularly in resource-rich settings. While international guidelines do not contain ddI-containing regimens in preferred first- or second-line antiretroviral therapy (ART), there is no guidance for management of patients currently on ddI. In 2012 at least 20 countries purchased a total of $1-2 million of ddI. Drug purchase data in that year show 3.2-10.3 times higher costs for ddI compared to lamivudine (3TC). Given issues of multiple toxicities, monitoring, drug interactions, inconvenience, and virologic efficacy, as well as cost and formulary concerns, national (including resource-limited setting) ART programmes should consider complete phase-out of ddI. Topics: Cost Savings; Didanosine; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Harm Reduction; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Treatment Outcome | 2015 |
Associations between lipodystrophy or antiretroviral medications and cirrhosis in patients with HIV infection or HIV/HCV coinfection.
Many HIV antiretroviral medications have been associated with chronic liver injury. HIV-infected patients frequently develop HIV and highly active antiretroviral treatment-associated lipodystrophy syndrome (HALS), characterized by accumulation of intra-abdominal fat, insulin resistance, and hepatic steatosis. We sought to determine whether long-term exposure to specific antiretroviral medications or the presence of HALS predispose HIV-infected patients to the development of cirrhosis.. HIV-infected patients with cirrhosis who received care in the Veterans Affairs Healthcare System nationally in 2009 were matched by hepatitis C virus (HCV) coinfection status and year of first visit for HIV to the Veterans Affairs Healthcare System with HIV-infected patients without cirrhosis in a 1 : 3 ratio.. Among HIV/HCV coinfected patients (593 with cirrhosis and 1591 matched controls), HALS was associated with a significantly increased risk for cirrhosis (adjusted odds ratio 1.6, 95% confidence interval 1.1-2.3), especially among Black patients (adjusted odds ratio 2.9, 95% confidence interval 1.6-5.2). In addition, among HIV/HCV coinfected patients, longer cumulative exposures to all antiretroviral medications, all nucleoside reverse transcriptase inhibitors, all protease inhibitors, and selected individual medications (didanosine, stavudine, and nelfinavir) were found to be significantly associated with cirrhosis. In contrast, among HIV-infected patients not coinfected with HCV (245 with cirrhosis and 658 matched controls), HALS or exposure to antiretroviral medications was found not to be significantly associated with cirrhosis, with the exception of didanosine.. HALS and cumulative exposure to nucleoside reverse transcriptase inhibitors and protease inhibitors, especially stavudine, didanosine, and nelfinavir, were found to be associated with the development of cirrhosis in HIV/HCV coinfected patients, but not in HIV-monoinfected patients. Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Case-Control Studies; Coinfection; Didanosine; Female; Hepatitis C; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Liver Cirrhosis; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Time Factors | 2015 |
Simultaneous determination of 2',3'-dideoxyinosine and the active metabolite, 2',3'-dideoxyadenosine-5'-triphosphate in human peripheral-blood mononuclear cell by HPLC-MS/MS and the application to cell pharmacokinetics.
A specific and reliable HPLC-MS/MS method was developed and validated for the simultaneous determination of 2',3'-dideoxyinosine (ddI) and the active metabolites, 2',3'-dideoxyadenosine-5'-triphosphate (ddA-TP) in human peripheral-blood mononuclear cell for the first time. The analytes were separated on a HILIC column (100mm×2.1mm, 1.7μm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source was used for detection. The cell homogenates sample was prepared by the solid phase extraction. The calibration curves were linear over a concentration range of 0.5-200.0ng/mL for ddI and 0.25-100.0ng/mL for ddA-TP. The intra-day and inter-day precision was less than 15% and the relative error (RE) were all within ±15%. The validated method was successfully applied to assess the disposition characteristics of ddI and support cell pharmacokinetics after the patients with AIDS were orally administrated with ddI and tenofovir disoproxyl fumarate (TDF). Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Deoxyadenine Nucleotides; Didanosine; Dideoxynucleotides; HIV Infections; Humans; Limit of Detection; Middle Aged; Reproducibility of Results; Tandem Mass Spectrometry | 2015 |
Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization.
Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed. Topics: Anti-HIV Agents; Catalytic Domain; Dose-Response Relationship, Drug; Drug Design; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Models, Molecular; Molecular Structure; Niacinamide; Protein Conformation; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured | 2014 |
In vitro comparative evaluation of monolayered multipolymeric films embedded with didanosine-loaded solid lipid nanoparticles: a potential buccal drug delivery system for ARV therapy.
Drug delivery via the buccal route has emerged as a promising alternative to oral drug delivery. Didanosine (DDI) undergoes rapid degradation in the gastrointestinal tract, has a short half-life and low oral bioavailability, making DDI a suitable candidate for buccal delivery. Recent developments in buccal drug delivery show an increased interest toward nano-enabled delivery systems. The advantages of buccal drug delivery can be combined with that of nanoparticulate delivery systems to provide a superior delivery system. The aim of this study was to design and evaluate the preparation of novel nano-enabled films for buccal delivery of DDI. Solid lipid nanoparticles (SLNs) were prepared via hot homogenization followed by ultrasonication and were characterized before being incorporated into nano-enabled monolayered multipolymeric films (MMFs). Glyceryl tripalmitate with Poloxamer 188 was identified as most suitable for the preparation of DDI-loaded SLNs. SLNs with desired particle size (PS) (201 nm), polydispersity index (PDI) (0.168) and zeta potential (-18.8 mV) were incorporated into MMFs and characterized. Conventional and nano-enabled MMFs were prepared via solvent casting/evaporation using Eudragit RS100 and hydroxypropyl methylcellulose. Drug release from the nano-enabled films was found to be faster (56% versus 20% in first hour). Conventional MMFs exhibited higher mucoadhesion and mechanical strength than nano-enabled MMFs. SLNs did not adversely affect the steady state flux (71.63 ± 13.54 µg/cm(2) h versus 74.39 ± 15.95 µg/cm(2) h) thereby confirming the potential transbuccal delivery of DDI using nano-enabled MMFs. Nano-enabled buccal films for delivery of DDI can be successfully prepared, and these physico-mechanical studies serve as a platform for future formulation optimization work in this emerging field. Topics: Adhesiveness; Administration, Buccal; Anti-HIV Agents; Chemistry, Pharmaceutical; Didanosine; Drug Delivery Systems; Elastic Modulus; HIV Infections; Humans; Lipids; Nanoparticles; Particle Size; Permeability; Poloxamer; Polymers; Tensile Strength; Triglycerides | 2014 |
High-level cross-resistance to didanosine observed in South African children failing an abacavir- or stavudine-based 1st-line regimen.
The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure.. A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.. Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).. Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens. Topics: Anti-HIV Agents; Base Sequence; Child; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; pol Gene Products, Human Immunodeficiency Virus; Sequence Analysis, DNA; South Africa; Statistics, Nonparametric; Stavudine | 2014 |
A case of non-cirrhotic portal hypertension associated with anti-retroviral therapy in a Japanese patient with human immunodeficiency virus infection.
The diagnosis of non-cirrhotic portal hypertension (NCPH), a rare but potentially life-threatening complication in human immunodeficiency virus (HIV)-positive individuals, often occurs only after the emergence of fatal manifestations such as bleeding of esophageal varices. We herein report a female Japanese HIV patient who developed NCPH approximately 4 years after discontinuation of 65 months of didanosine (ddI) administration. The patient presented with severe ascites, bloody bowel discharge, extreme abdominal swelling, and symptoms of portal hypertension but no sign of liver cirrhosis. Examination revealed esophageal varices, oozing-like bleeding from a wide part of the colon, significant atrophy of the right lobe of the liver, and arterio-portal shunting and recanalization from the left medial segment branch of the portal vein to a paraumbilical vein, but no visible obstruction of the main trunk of the portal vein. Treatment for esophageal varices consisted of coagulation therapy with argon plasma after enforcement by endoscopic sclerotherapy and oral administration of β-blockers for elevated portal blood pressure. The patient has not experienced gastrointestinal bleeding in the approximately 5 years since the diagnosis of NCPH. Reviewing this case suggests the importance of suspecting NCPH in HIV patients with liver dysfunction of unknown etiology with a history of ddI and other purine analogs use, as well as the importance of controlling portal hypertension and esophageal varices in the treatment of NCPH. Topics: Adult; Anti-Retroviral Agents; Didanosine; Female; HIV Infections; Humans; Hypertension, Portal; Liver Cirrhosis | 2014 |
Blepharoptosis and HAART related mitochondrial myopathy.
To report a case of blepharoptosis in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) with biopsy confirmed mitochondrial deletions consistent with HAART related myopathy.. A 51-year-old man with HIV demonstrated visually significant ptosis after being on HAART therapy for over 20 years.. Muscle tissue biopsy following blepharoplasty was analyzed and found to have significant mitochondrial deletions.. This patient represents a case of isolated ptosis consistent with acquired myopathy secondary to mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders. Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blepharoptosis; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA, Mitochondrial; HIV Infections; Humans; Male; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Oculomotor Muscles | 2014 |
Didanosine-associated retinal toxicity in adults infected with human immunodeficiency virus.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Corneal Dystrophies, Hereditary; Didanosine; Electroretinography; HIV Infections; Humans; Male; Middle Aged; Retina; Visual Acuity; Zidovudine | 2013 |
Scoring methods for building genotypic scores: an application to didanosine resistance in a large derivation set.
Several attempts have been made to determine HIV-1 resistance from genotype resistance testing. We compare scoring methods for building weighted genotyping scores and commonly used systems to determine whether the virus of a HIV-infected patient is resistant.. Three statistical methods (linear discriminant analysis, support vector machine and logistic regression) are used to determine the weight of mutations involved in HIV resistance. We compared these weighted scores with known interpretation systems (ANRS, REGA and Stanford HIV-db) to classify patients as resistant or not. Our methodology is illustrated on the Forum for Collaborative HIV Research didanosine database (N = 1453). The database was divided into four samples according to the country of enrolment (France, USA/Canada, Italy and Spain/UK/Switzerland). The total sample and the four country-based samples allow external validation (one sample is used to estimate a score and the other samples are used to validate it). We used the observed precision to compare the performance of newly derived scores with other interpretation systems. Our results show that newly derived scores performed better than or similar to existing interpretation systems, even with external validation sets. No difference was found between the three methods investigated. Our analysis identified four new mutations associated with didanosine resistance: D123S, Q207K, H208Y and K223Q.. We explored the potential of three statistical methods to construct weighted scores for didanosine resistance. Our proposed scores performed at least as well as already existing interpretation systems and previously unrecognized didanosine-resistance associated mutations were identified. This approach could be used for building scores of genotypic resistance to other antiretroviral drugs. Topics: Anti-HIV Agents; Canada; Databases, Factual; Didanosine; Drug Resistance, Viral; France; Genotype; HIV Infections; HIV-1; Humans; Italy; Models, Statistical; Mutation; Mutation Rate; Reproducibility of Results; Spain; Switzerland; United Kingdom; United States | 2013 |
Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.
Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs. Topics: 1-Deoxynojirimycin; Algorithms; Anti-HIV Agents; CCR5 Receptor Antagonists; Computer Simulation; Cyclohexanes; Databases, Chemical; Didanosine; Drug Design; Drug Discovery; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Maraviroc; Models, Molecular; Protein Interaction Mapping; Protein Interaction Maps; Receptors, CCR5; Triazoles | 2013 |
A woman with didanosine retinopathy and non-cirrhotic portal hypertension.
Topics: Didanosine; Female; HIV Infections; Humans; Hypertension, Portal; Liver; Middle Aged; Retina; Retinal Diseases; Reverse Transcriptase Inhibitors; Treatment Outcome | 2013 |
Pancreatic insufficiency in patients with HIV infection: role of didanosine questioned.
The aim of the study was to identify possible causes of pancreatic insufficiency in patients with HIV infection.. A retrospective analysis of 233 HIV-positive patients for whom faecal elastase measurement was available was performed to investigate potential associations with core demographic data, HIV infection characteristics, degree of immunosuppresion, exposure to antiretroviral therapy (ART), alcohol misuse, diabetes, hepatitis C virus (HCV) infection, triglyceride and cholesterol levels and symptomatology. The response to pancreatic enzyme replacement for patients with evidence of insufficiency was also evaluated.. Of 233 patients, 104 (45%) had evidence of pancreatic exocrine insufficiency (faecal elastase < 200 mcg/g). A positive association with exocrine pancreatic insufficiency was found for HCV infection (P = 0.007), previous or current HCV treatment (P = 0.003), alcohol misuse history (P = 0.006) and the presence of steatorrhoea (P = 0.03). There was no demonstrated association between exocrine pancreatic insufficiency and didanosine (ddI) exposure (P = 0.43) or stavudine (d4T) exposure (P = 0.62). Seventy-seven per cent of patients who were treated with pancreatic enzymatic supplementation reported a subjective improvement in symptoms.. Faecal elastase sampling should form part of the routine work-up for HIV-positive patients with chronic diarrhoea even in the absence of 'traditional' risk factors such as ddI exposure. In particular, if the patient has steatorrhoea, a history of alcohol exposure or their HCV serology is positive, they should be considered for investigation. Treatment with pancreatic enzyme supplementation appears to be effective in the treatment of chronic diarrhoea caused by pancreatic insufficiency in the majority of patients. Topics: Adult; Anti-HIV Agents; Didanosine; Exocrine Pancreatic Insufficiency; Feces; Female; HIV Infections; Humans; Male; Pancreatic Elastase; Retrospective Studies; Risk Factors; Stavudine; Steatorrhea; Viral Load | 2013 |
Impact of recommendation updates in well-controlled patients on nonrecommended antiretroviral therapies: the Swiss HIV cohort study.
HIV treatment recommendations are updated as clinical trials are published. Whether recommendations drive clinicians to change antiretroviral therapy in well-controlled patients is unexplored.. We selected patients with undetectable viral loads (VLs) on nonrecommended regimens containing double-boosted protease inhibitors (DBPIs), triple-nucleoside reverse transcriptase inhibitors (NRTIs), or didanosine (ddI) plus stavudine (d4T) at publication of the 2006 International AIDS Society recommendations. We compared demographic and clinical characteristics with those of control patients with undetectable VL not on these regimens and examined clinical outcome and reasons for treatment modification.. At inclusion, 104 patients were in the DBPI group, 436 in the triple-NRTI group, and 19 in the ddI/d4T group. By 2010, 28 (29%), 204 (52%), and 1 (5%) patient were still on DBPIs, triple-NRTIs, and ddI plus d4T, respectively. 'Physician decision,' excluding toxicity/virological failure, drove 30% of treatment changes. Predictors of recommendation nonobservance included female sex [adjusted odds ratio (aOR) 2.69, 95% confidence interval (CI) 1 to 7.26; P = 0.01] for DPBIs, and undetectable VL (aOR 3.53, 95% CI 1.6 to 7.8; P = 0.002) and lack of cardiovascular events (aOR 2.93, 95% CI 1.23 to 6.97; P = 0.02) for triple-NRTIs. All patients on DBPIs with documented diabetes or a cardiovascular event changed treatment. Recommendation observance resulted in lower cholesterol values in the DBPI group (P = 0.06), and more patients having undetectable VL (P = 0.02) in the triple-NRTI group.. The physician's decision is the main factor driving change from nonrecommended to recommended regimens, whereas virological suppression is associated with not switching. Positive clinical outcomes observed postswitch underline the importance of observing recommendations, even in well-controlled patients. Topics: Adult; Cardiovascular Diseases; Chi-Square Distribution; Cholesterol; Diabetes Complications; Didanosine; Drug Therapy, Combination; Female; Guideline Adherence; HIV Infections; HIV Protease Inhibitors; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Practice Guidelines as Topic; Practice Patterns, Physicians'; Retrospective Studies; Reverse Transcriptase Inhibitors; Sex Factors; Statistics, Nonparametric; Stavudine; Switzerland; Viral Load | 2013 |
Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients.
Noncirrhotic portal hypertension (NCPH) is a rare but potentially life-threatening complication in patients with human immunodeficiency virus (HIV). Cases of NCPH have been reported in HIV-negative individuals as result of treatment with thiopurines for leukemia or inflammatory bowel disease. Exposure to didanosine, which is also a purine analogue, predisposes to NCPH in the HIV setting. However, it is unclear why NCPH only develops in a small subset of didanosine-treated patients.. A multicenter, case-control study was conducted to investigate the role of pharmacogenomics in NCPH in HIV patients with prior didanosine exposure. Three controls were chosen for each case, adjusted for sex, age, CD4 counts, plasma HIV-RNA, and site. Tagging 36 single-nucleotide polymorphisms (SNPs) at enzymes involved in the purine metabolism (inosine triphosphatase, 5'-nucleotidase cytosolic-II, purine nucleoside phosphorylase and xanthine oxidase) was performed using SNPlex microarray technology.. Eighty individuals were examined; 22 with NCPH and 58 matched controls. Two SNPs at the 5'-nucleotidase gene were associated with NCPH: rs11191561 (48% CG/GG vs 17% CC; P=.003) and rs11598702 (40% CC/CT vs 9% TT; P=.003). SNPs at another 2 loci at the xanthine oxidase gene were also associated with NCPH: rs1429376 (71% AA vs 23% CC/AC; P=.015) and rs1594160 (71% AA vs 23% CC/AC; P=.015). There was a cumulative risk of NCPH for these 4 SNPs: 7%, 26%, 42%, 50%, and 100%, respectively, for 0, 1, 2, 3, or all SNPs (P=.001).. SNPs at the 5'-nucleotidase and xanthine oxidase genes influence the risk of NCPH in HIV patients treated with didanosine. Topics: 5'-Nucleotidase; Adult; Anti-HIV Agents; Case-Control Studies; Didanosine; Female; Genetic Association Studies; GPI-Linked Proteins; HIV Infections; Humans; Hypertension, Portal; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Risk; Xanthine Oxidase | 2013 |
An unusual cause of oesophageal variceal bleeding in a Chinese human immunodeficiency virus-infected patient.
Non-cirrhotic portal hypertension is an unusual but potentially serious liver disorder in human immunodeficiency virus-infected patients with prolonged exposure to didanosine. Due to its rarity, the diagnosis is often delayed. It is postulated that didanosine contributes to obliterative portal venopathy and causes portal hypertension. Affected patients may present with abnormal liver function or signs of portal hypertension, while the diagnosis usually depends on liver biopsy. We report a case of non-cirrhotic portal hypertension in a human immunodeficiency virus-infected patient. The reported histological features include nodular regenerative hyperplasia and hepatoportal sclerosis. Early recognition is important as timely management of severe portal hypertension may prevent potentially fatal gastro-intestinal bleeding. Topics: Anti-HIV Agents; Didanosine; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; HIV Infections; Humans; Hypertension, Portal; Male; Middle Aged; Severity of Illness Index; Time Factors | 2013 |
Fatal pancreatitis in simian immunodeficiency virus SIV(mac251)-infected macaques treated with 2',3'-dideoxyinosine and stavudine following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase blockade.
Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4⁺-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV(mac251) and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART. Topics: AIDS Vaccines; Animals; Anti-HIV Agents; CTLA-4 Antigen; Didanosine; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Macaca mulatta; Pancreatitis; Simian Immunodeficiency Virus; Stavudine; Tryptophan | 2012 |
Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment.
To evaluate the incidence and determinants of diabetes in a cohort of HIV-infected adults initiated with combination antiretroviral treatment (cART) in 1997-1999 and followed up to 2009.. Prospective study of 1046 patients at 47 French clinical sites.. Potential determinants of diabetes occurrence, defined by confirmed increased glycemia and/or initiation of antidiabetic treatment, were assessed by a proportional hazards model, including time-updated metabolic parameters and ART exposure.. Among the cohort, representing 7846 person-years of follow-up (PYFU), 54% received indinavir, 75% stavudine and 52% didanosine. Overall, 111 patients developed diabetes, with an incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women). Incidence peaked in 1999-2000 (23.2/1000 PYFU) and decreased thereafter. The incidence of diabetes was associated [adjusted hazard ratio (aHR), all P<0.02] with older age (hazard ratio = 2.13 when 40-49 years, hazard ratio = 3.63 when ≥50 years), overweight (hazard ratio = 1.91 for a BMI 25-29 kg/m(2), hazard ratio = 2.85 >30 kg/m(2)), waist-to-hip ratio (hazard ratio = 3.87 for ≥0.97 male/0.92 female), time-updated lipoatrophy (hazard ratio = 2.14) and short-term exposure to indinavir (0-1 year: hazard ratio = 2.53), stavudine (0-1 year: hazard ratio = 2.56, 1-2 years: hazard ratio = 2.65) or didanosine (2-3 years: hazard ratio = 3.16). Occurrence of diabetes was not associated with HIV-related markers, hepatitis C, hypertension or family history of diabetes. Insulin resistance was predictive for incident diabetes.. In this nationwide cohort, followed for 10 years after cART initiation, diabetes incidence peaked in 1990-2000, was markedly higher than that reported for European uninfected or other HIV-infected populations (4-6/1000 PYFU) and linked with age and adiposity. Adiposity and glycemic markers should be monitored in aging HIV-infected patients. Topics: Adiposity; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Mass Index; Cohort Studies; Diabetes Mellitus; Didanosine; Female; Follow-Up Studies; HIV Infections; Humans; Incidence; Indinavir; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Prospective Studies; Risk Factors; Stavudine; Waist-Hip Ratio | 2012 |
E17A mutation in HIV-1 Vpr confers resistance to didanosine in association with thymidine analog mutations.
HIV-1 accessory Vpr protein is involved in the reverse transcription process and has been shown to modulate the virus mutation rate. This process may play a role in the kinetics of appearance of drug resistance mutations under antiretroviral treatment.. Vpr sequences were analyzed from plasma viruses derived from 97 HIV-1-infected individuals failing antiretroviral treatment and 63 antiretroviral-naïve patients. Vpr genetic variability was analyzed for association with specific drug treatment and drug resistance mutations. Biological and virological experiments were employed to characterize a mutation in Vpr found to be associated with virological failure.. E17A mutation located in the first α-helix of Vpr was more prevalent in HAART-treated individuals compared to untreated individuals. E17A was associated with thymidine analog mutations (TAMs) in reverse transcriptase M41L, L210W and T215Y and with the use of didanosine in the patients' treatment histories. E17A had no impact on the biochemical and functional properties of Vpr, and did not affect kinetics of replication of wild-type or TAMs-containing viruses. However, its association with TAMs and the use of didanosine was consistent with phenotypic susceptibility assays showing a significant 3-fold decrease in didanosine susceptibility of viruses harboring Vpr E17A combined with TAMs compared to viruses harboring TAMs alone.. These findings highlight a novel role of Vpr in HIV-1 drug resistance. Vpr E17A confers resistance to didanosine when associated with TAMs. Whether Vpr E17A facilitates excision of didanosine is still to be determined. Topics: Adult; Aged; Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Female; Genes, vpr; HEK293 Cells; HeLa Cells; HIV Infections; HIV-1; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Sequence Data; Mutation; Polymorphism, Genetic; Protein Transport; Thymidine; Virus Replication; vpr Gene Products, Human Immunodeficiency Virus | 2012 |
Common inherited mitochondrial DNA mutations and nucleoside reverse transcriptase inhibitor-induced severe hyperlactataemia in HIV-infected adults: an exploratory study.
Genetic predisposition to dideoxynucleoside-induced mitochondrial dysfunction might be related to mitochondrial DNA (mtDNA) polymorphisms. Severe hyperlactataemia is probably the best model to assess such a predisposition.. For this exploratory study in White European and Black African HIV-infected adults, hypervariable region 1 of mtDNA samples from peripheral blood mononuclear cells or buccal smears of patients who have developed confirmed severe hyperlactataemia was sequenced. Additionally, 21 single nucleotide polymorphisms and a 9 bp deletion were genotyped to assign mtDNA haplogroups. Finally, entire mtDNA sequencing was performed in a subset of European samples. Samples were obtained from Black African cases and controls recruited from a single centre in Johannesburg, South Africa and from white European cases from Amsterdam, London and Zurich.. A total of 40 cases and 38 controls from Johannesburg were included. All of the cases and 33 controls were receiving stavudine-based therapy at the time of the index date (P=0.024). The distribution of mtDNA haplotypes was not different between cases and controls (P=0.137), and neither were the predicted haplogroups (P=0.751). In total, 11 of the 12 European cases were on stavudine and/or didanosine at the time of the event. No hypervariable region 1 haplotype was consistently found in the European cases. Sequencing of the entire mtDNA from three of these cases supported the absence of any shared mutations other than major alleles frequently seen in the mtDNA database.. We did not find an association between homoplasmic inherited mtDNA polymorphisms and severe hyperlactataemia. Our data do not support the existence of non-synonymous mtDNA mutations that explain an increased predisposition to dideoxynucleoside-induced mitochondrial dysfunction. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Black People; Case-Control Studies; Didanosine; DNA, Mitochondrial; Female; HIV Infections; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Mutation; Polymorphism, Single Nucleotide; Reverse Transcriptase Inhibitors; Sequence Deletion; Stavudine; White People; Zidovudine | 2012 |
Submicron-size biodegradable polymer-based didanosine particles for treating HIV at early stage: an in vitro study.
Human immunodeficiency viruses (HIV) hide themselves in macrophages at the early stage of infection. Delivering drug in a sustained manner from polymeric nanoparticles in those cells could control the disease effectively. The study was intended to develop poly(d,l-lactic-co-glycolic acid)-based nanoparticles containing didanosine and to observe their uptake by macrophages in vitro. Various physicochemical evaluations related to nanoparticles, such as drug-excipient interaction, surface morphology, particle size, zeta potential, polydispersity index, drug loading, in vitro drug release and nanoparticle-uptake by macrophages in vitro were determined. Homogenising speeds and drug-polymer ratio varied drug loading and polydispersity index of nanoparticles, providing sustained drug release. Dimethyl sulphoxide/polyethylene glycol improved drug loading predominantly. Nanoparticle-uptake by macrophages was concentration dependent. Experimental nanoparticles successfully transported didanosine to macrophages in vitro, suggesting reduction of dose, thus minimising toxicity and side effects. Developed nanoparticle may control HIV infection effectively at an early stage. Topics: Animals; Anti-HIV Agents; Cells, Cultured; Delayed-Action Preparations; Didanosine; Drug Evaluation, Preclinical; Female; HIV; HIV Infections; Humans; Lactic Acid; Macrophages, Peritoneal; Mice; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer | 2012 |
The role of nucleoside reverse transcriptase inhibitors usage in the incidence of hyperlactatemia and lactic acidosis in HIV/AIDS patients.
Hyperlactatemia and lactic acidosis (LA) are among the most dangerous and life-threatening side effect that occurs during therapy with some nucleoside reverse transcriptase inhibitors (NRTIs), mainly didanosine (ddI) and stavudine (d4T), also known as d-drugs. Therefore, we performed a prospective, follow-up study and aimed to examine the incidence rates (IR) and rate ratios (RR) of hyperlactatemia and LA for each NRTI. Three hundred and ninety-six HIV-patients were included in final analysis comprising 783.8 person-years of follow-up. Between 1st January 2000 and 1st January 2008, 19 cases of hyperlactatemia and 15 cases of LA were recorded. Between regimens with the significant impact for developing hyperlactatemia and LA the lowest IR was for didanosine (IR=2.87 per 100 person-years, 95%CI=0.45-9.25 and IR=4.31 per 100 person-years, 95%CI=1.07-13.91, respectively), and the highest for didanosine+stavudine (IR=10.17 per 100 person-years, 95%CI=1.02-19.76 and IR=7.39 per 100 person-years, 95%CI=1.02-13.05, respectively). Compared to didanosine alone the RR of hyperlactatemia was 2.67 (95%CI=1.11-12.52) for stavudine, and 4.06 (95%CI=1.31-15.48) for didanosine+stavudine. The RR of LA was 3.12 (95%CI=1.13-10.65) for stavudine, and 5.13 (95%CI=1.54-13.37) for didanosine+stavudine in comparison with didanosine alone. Other risk factors for AP were CD4 cell count less than 200 cells/mm³ and female sex. Our results suggest that the use of stavudine alone or in combination with didanosine should not be used as first-line therapy, especially in patients with CD4 cell count less than 200 cells/mm³ and females if other treatment options are available. Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Incidence; Lactic Acid; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Sex Factors; Stavudine | 2012 |
Didanosine (ddI) associates with increased liver fibrosis in adult HIV-HCV coinfected patients.
The role of exposure to antiretrovirals (ARV) and serum matrix metalloproteases (MMPs) on liver fibrosis (LF) progression in human immunodeficiency virus (HIV) mono or HIV- hepatitis C virus (HCV) coinfection is unclear. Thus, 213 Caucasian adult HIV-infected patients were studied, 111 of whom had HCV-coinfection and 68 were HCV-monoinfected. Patients with ethanol consumption >50 g/day, hepatitis B coinfection, non-infective liver diseases or HAART adherence <75% were excluded. LF was assessed by transient elastometry (TE, Fibroscan). Serum levels of MMPs (MMP -1,-2,-3,-8,-9,-10 and -13) and their tissue inhibitors (TIMP-1,-2 and -4) were measured by ELISA microarrays. Associations with LF were statistically analysed. Protease inhibitors, usually administered to patients with advanced LF were excluded from the analysis. Increased LF was significantly associated with d4T (P = 0.006) and didanosine (ddI) use (P = 0.007), months on d4T (P = 0.001) and on ARV (P = 0.025), duration of HIV (P < 0.0001) and HCV infections (P < 0.0001), higher HIV (P = 0.03) and HCV loads (P < 0.0001), presence of lipodystrophy (P = 0.02), male gender (P = 0.02), older age (P = 0.04), low nadir (P = 0.02) and current CD4(+) T-cells (P < 0.0001), low gain of CD4(+) T-cells after HAART (P = 0.01) and higher MMP-2 (P = 0.02) and TIMP-2 serum levels (P = 0.02). By logistic regression the only variables significantly associated with increased LF were: use of ddI (OR 8.77, 95% CI: 2.36-32.26; P = 0.005), male gender (OR 7.75, 95% CI: 2.33-25.64, P = 0.0008), HCV viral load (in log) (OR 3.53, 95% CI: 2.16-5.77; P < 0.0001) and age (in years) (OR 1.21, 95% CI: 1.09-1.34, P = 0.0003). We conclude that only higher HCV viral load, older age, male gender, and use of ddI associated independently with increased LF in our study. Topics: Adult; Age Factors; Anti-HIV Agents; Didanosine; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Male; Matrix Metalloproteinases; Microarray Analysis; Middle Aged; Risk Factors; Sex Factors; Tissue Inhibitor of Metalloproteinases; Viral Load | 2012 |
Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension.
Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection.. To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome.. All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case–control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed.. On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3–2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1–19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2–22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003).. HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation Topics: Adenine; Adult; Anti-HIV Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Hypertension, Portal; Liver; Male; Middle Aged; Multivariate Analysis; Netherlands; Organophosphonates; Risk Factors; Stavudine; Tenofovir; Young Adult | 2012 |
Risk of diabetes mellitus in persons with and without HIV: a Danish nationwide population-based cohort study.
In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals.. We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996-2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses.. In the period 1996-1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57-5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03-5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42-7.39). In the period 1999-2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72-1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21-0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine.. Native HIV-infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM. Topics: Adult; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Body Mass Index; Cohort Studies; Denmark; Diabetes Complications; Diabetes Mellitus; Didanosine; Female; HIV Infections; Humans; Incidence; Indinavir; Male; Middle Aged; Regression Analysis; Risk Factors; Saquinavir; Stavudine; Treatment Outcome | 2012 |
Arylazolylthioacetanilide. Part 8: Design, synthesis and biological evaluation of novel 2-(2-(2,4-dichlorophenyl)-2H-1,2,4-triazol-3-ylthio)-N-arylacetamides as potent HIV-1 inhibitors.
The development of novel HIV-1 NNRTIs offers the possibility of generating novel structures with increased potency. Based on the bioisosteric principle, a novel series of 2-(2-(2,4-dichlorophenyl)-2H-1,2,4-triazol-3-ylthio)-N-arylacetamide derivatives were designed, synthesized using a simple and efficient synthetic route, structurally confirmed by spectral analysis, evaluated for their anti-HIV activity in MT-4 cells and their inhibitory effect on HIV-1 RT. The results showed that some of the new compounds displayed low micromolar potency for inhibiting HIV-1 replication and promising activities against several selected resistant strains that confer resistance to current NNRTIs. However, all newly synthesized derivatives were not active against HIV-2 replication. Topics: Acetamides; Anti-HIV Agents; Cell Line; HIV Infections; HIV Reverse Transcriptase; HIV-1; HIV-2; Humans; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Triazoles; Virus Replication | 2011 |
Lipoatrophy of the footpad in HIV-treated patients is associated with increased PAI-1.
To describe lipoatrophy of the plantar pedis fat pads in human immunodeficiency virus (HIV) patients with or without long-term antiretroviral therapy (ART); to compare the characteristics of ART patients with and without plantar pedis lipoatrophy; and to examine the effects of HIV and metabolic/cardiovascular risk parameters and treatment history on plantar pedis lipoatrophy.. Participants included 134 patients who started protease inhibitors in antiretroviral therapy (ART) in 1996 and 49 treatment-naive patients, recruited in 2004. Participants were examined and graded for lipoatrophy of five body compartments including the plantar fat pads. Baseline HIV- and ART-related factors were documented together with follow-up metabolic/ cardiovascular risk parameters.. Plantar pedis lipoatrophy occurred more often among ART patients (60%) than among treatment-naive patients (12%; p < .001). ART patients with plantar lipoatrophy were older, had higher plasminogen activator inhibitor 1 (PAI-1) values, a higher prevalence of lipoatrophy in other body compartments, and longer stavudine and didanosine treatment history as compared to patients without plantar lipoatrophy. Multiple logistic regression modeling revealed that among the metabolic/cardiovascular parameters, increased PAI-1 was strongly and positively associated with plantar lipoatrophy. Among the treatment history parameters, didanosine was the strongest independent predictor for plantar lipoatrophy. Increased PAI-1 was not associated to lipoatrophy in any other location.. Plantar lipoatrophy is common among patients on long-term ART and, though often overlooked, may cause significant discomfort. The association to PAI-1, a well-known marker of increased cardiovascular risk, is intriguing and places further focus on the need for an active approach to evaluating and lowering cardiovascular risk factors in long-term HIV treatment. Topics: Adipose Tissue; Adult; Anti-HIV Agents; Atrophy; Cardiovascular Diseases; Cross-Sectional Studies; Didanosine; Foot; HIV Infections; Humans; Logistic Models; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Prevalence; Risk Factors; Stavudine | 2011 |
Risk factors for advanced liver fibrosis in HIV-infected individuals: role of antiretroviral drugs and insulin resistance.
Liver damage may result from multiple factors in HIV-infected patients. The availability of reliable noninvasive tools to measure liver fibrosis has permitted the screening of large patient populations. Cross-sectional study of all consecutive HIV outpatients who underwent examination by transient elastometry (FibroScan) at one HIV reference clinic during 2007. Advanced liver fibrosis (ALF) was defined as hepatic stiffness >9.5 kilopascals, which corresponds to Metavir stages F3-F4 in the liver biopsy. A total of 681 consecutive HIV-infected patients (64% injecting drug users; mean age 43; 78% male; 98% on antiretroviral therapy) had at least one valid FibroScan evaluation. ALF was diagnosed in 215 (32%) of them. In the univariate analysis, ALF was significantly associated with older age, low CD4 counts, chronic hepatitis C, past alcohol abuse, elevated ALT, high triglycerides, low cholesterol, high homeostasis model assessment (HOMA) index and exposure to didanosine and/or stavudine. In a multivariate model (OR, 95% CI), chronic hepatitis C (2.83, 1.57-5.08), past alcohol abuse (2.26, 1.37-3.74), exposure to didanosine and/or stavudine (1.85, 1.14-3.01), high HOMA index (1.25, 1.04-1.51), older age (1.09, 1.05-1.14) and elevated ALT (1.04, 1.03-1.06) remained as independently associated with ALF. Therefore, in addition to chronic hepatitis C and alcohol abuse, insulin resistance and/or exposure to dideoxy-nucleosides may contribute to ALF in HIV-infected patients. Topics: Adult; Anti-HIV Agents; Antiviral Agents; Cross-Sectional Studies; Didanosine; Female; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Insulin Resistance; Liver Cirrhosis; Male; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine | 2011 |
The role of nucleoside and nucleotide analogues in nodular regenerative hyperplasia in HIV-infected patients: a case control study.
Nodular regenerative hyperplasia (NRH) leading to non-cirrhotic portal hypertension has been described in HIV-infected patients and has been linked to didanosine. The relation between NRH and other antiretrovirals remains unclear.. A case-control study was performed in 13 patients with NRH and 78 controls matched for time of inclusion, baseline CD4, and duration of follow-up. Univariate and multivariate conditional logistic regression analyses were performed.. Control patients and patients with NRH were similar at baseline regarding demographics and biological data with the exception of older age for patients with NRH (43.9 vs. 33.5 years, p=0.044). At the time of NRH diagnosis, cases had a lower CD4 count (327 vs. 468/mm(3), p=0.013), a similar CD4 percentage (24 vs. 26.2%, p=0.7), a lower platelet count (169 vs. 228 giga/L, p=0.003) and a higher AST level (33 vs. 26 IU/L, p=0.001) than controls. Univariate analysis demonstrated that patients with NRH had been exposed longer than controls to didanosine, stavudine, tenofovir, didanosine+stavudine, and didanosine+tenofovir. The age at baseline [OR 2.2 (1.0-5.0) per 10 years, p=0.053] and didanosine+stavudine cumulative exposure [OR 3.7 (1.4-10.2) per year, p=0.011] were independently associated with NRH. The age at baseline [OR 2.3 (1.0-5.3) per 10 years, p=0.045], cumulative exposure to didanosine [OR 1.4 (1.1-1.9) per year, p=0.023] and to tenofovir [OR 1.7 (1.0-2.8) per year, p=0.04] were independently associated with NRH when didanosine+stavudine exposure was excluded from the model.. NRH in HIV-infected patients seems strongly related to age and the cumulative exposure to didanosine+stavudine, didanosine, and stavudine. Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Case-Control Studies; Didanosine; Female; HIV Infections; Humans; Hyperplasia; Hypertension, Portal; Liver; Liver Regeneration; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir | 2011 |
The development of hepatoportal sclerosis and portal hypertension due to didanosine use in HIV.
Hepatoportal sclerosis (HPS) is one of several entities known to cause noncirrhotic portal hypertension. To date, its etiology is unknown. There have been increasing reports of HPS occurring in patients with human immunodeficiency virus (HIV), and the US Food and Drug Administration (FDA) recently issued an advisory regarding the development of noncirrhotic portal hypertension in association with didanosine (ddI) use. We report on a patient with HIV who had taken ddI for 4 years and who developed portal hypertension. Histopathological review of paired liver biopsies showed an initial drug hepatotoxicity, microvascular liver injury, and the presence of HPS. Despite cessation of ddI, the latter biopsy showed resolution of the drug-induced injury, but it also showed progression of the HPS. The patient's portal hypertension also progressed suggestive of an unremitting vascular injury. This case demonstrates the development of HPS resulting from a drug-induced microvascular injury. The paired biopsies demonstrate that the initial vascular injury may disappear but that the portal hypertension and HPS progress. Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Hypertension, Portal; Liver; Male; Middle Aged; Portal System; Sclerosis | 2011 |
Impact of NRTIs on lipid levels among a large HIV-infected cohort initiating antiretroviral therapy in clinical care.
to assess the associations between nucleoside reverse transcriptase inhibitors (NRTIs) and change in lipid levels among a large cohort of HIV-infected patients in routine clinical care initiating their first potent antiretroviral regimen.. longitudinal observational cohort study from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort.. we used generalized estimating equations to examine the association between NRTIs and lipids accounting for within-patient correlations between repeated measures and key clinical and demographic characteristics including other antiretroviral medications.. among 2267 individuals who started their first antiretroviral regimen, tenofovir with emtricitabine or lamivudine was associated with lower levels for total cholesterol, low-density lipoprotein (LDL), triglycerides, non-high-density lipoprotein (HDL), and HDL, compared with other NRTI pairs in adjusted analyses. LDL levels were highest among patients receiving didanosine/lamivudine. Triglyceride levels were highest in stavudine/lamivudine users. HDL levels were highest among patients receiving didanosine/stavudine. Hepatitis C infection and younger age were also associated with lower lipid levels.. we found clinically important heterogeneity within the NRTI class of antiretroviral medications regarding their effect on lipid levels over time. Although the lipid profile of tenofovir with emtricitabine or lamivudine appeared to be less pro-atherogenic in this large longitudinal study of HIV-infected patients in routine clinical care, there was no association with beneficial HDL levels. In general, the change in lipid levels associated with most antiretroviral agents, particularly those NRTI combinations currently in common use, are relatively modest. Additional studies are needed to understand the long-term implications of these findings on cardiovascular disease risk. Topics: Adult; Antiretroviral Therapy, Highly Active; Cohort Studies; Didanosine; Dyslipidemias; Female; HIV Infections; HIV-1; Humans; Lamivudine; Longitudinal Studies; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Assessment; Risk Factors; Stavudine | 2011 |
Predictors for the emergence of the 2 multi-nucleoside/nucleotide resistance mutations 69 insertion and Q151M and their impact on clinical outcome in the Swiss HIV cohort study.
The 69 insertion and Q151M mutations are multi-nucleoside/nucleotide resistance mutations (MNR). The prevalence among 4078 antiretroviral therapy (ART)-experienced individuals was <1.3%. Combined ART fully prevented MNR in subtype B infections. Case-control studies were performed to identify risk factors. Control subjects were patients with ≥ 3 thymidine-analogue mutations. The 69 insertion study (27 control subjects, 14 case patients) identified didanosine exposure as a risk (odds ratio, 5.0 per year; P = .019), whereas the Q151M study (which included 44 control subjects and 25 case patients) detected no associations. Following detection, individuals with Q151M tended to have lower suppression rates and higher mortality rates, relative to control subjects. Additional studies are needed to verify these findings in non-subtype B infections. Topics: Anti-HIV Agents; Anti-Retroviral Agents; Case-Control Studies; Cause of Death; Cohort Studies; Didanosine; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Logistic Models; Mutation; Risk Factors; Switzerland; Treatment Outcome | 2011 |
[Protective role of antiretroviral treatment in the impairment of renal function in a cohort of human immunodeficiency virus patients].
To assess changes in renal function in a cohort of patients infected with the human immunodeficiency virus (HIV) and describe which factors are associated with deterioration.. This was a prospective transversal study. The follow-up period was 12 months. Data were collected at baseline and one year including the glomerular filtration rate (GFR). We analyzed epidemiological data, comorbidities, CD4 lymphocytes, viral load, and AIDS status.. A total of 365 patients. Three hundred and thirteen (85%) were under highly active antiretroviral therapy (HAART); the median CD4 was 606 ± 314 and the CV was undetectable in 85%. At 1-year, we found a mean deterioration in the GFR of 9.7 ml/h. Eighty patients (21.8%) had a fall in GFR > 10 ml/h, while in 20 patients (5.8%) it was > 30 ml/h. An association was found regarding age, treatment with didanosine (DDI) and males (OR 1.89 95% CI 1.3 to 4.08, OR 2.3 95% CI 1.9 to 23 and OR 3.47 95% CI 1.6 to 14.20 respectively). We found a protective role of being under HAART (OR 0.54, 95% CI, 0.25 to 0.8).. There was a protective role of HAART in the deterioration of GFR of patients with HIV infection. Male gender, age and use of DDI were associated with worsening renal function. Tenofovir and protease inhibitors were not associated with further deterioration of renal function. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cross-Sectional Studies; Didanosine; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Prospective Studies; Viral Load | 2011 |
Combination anti-HIV therapy with the self-assemblies of an asymmetric bolaamphiphilic zidovudine/didanosine prodrug.
Combination anti-HIV therapy is important for AIDS treatment. A bolaamphiphilic prodrug, zidovudine-phosphoryl-deoxycholyl didanosine (ZPDD), was synthesized, combining zidovudine (AZT) and didanosine (ddI) in one molecule. As one lipid derivative of nucleosides, ZPDD showed special solubility with free soluble in chloroform and tetrahydrofuran but was slightly soluble in cyclohexane. The amphiphilicity of ZPDD was shown according to the monolayers at the air-water interface. ZPDD self-assembled to the spherical vesicles in water with 174 nm in size and -31.3 mV of zeta potential. The stability of assemblies depended on pH because the phosphoryl zidovudine group could release hydrogen ions. ZPDD was rapidly degraded to AZT in the plasma and tissues of mice. ZPDD self-assemblies had high anti-HIV activity in vitro with the half effective concentration (EC₅₀) of 5 nM. ZPDD self-assemblies may be targeting macrophages since ZPDD was found in macrophage-rich tissues in vivo and rapidly released AZT in the targeted tissues after intravenous administration to mice. The bioavailability of ZPDD was 90.5% and 30.8% for the intraperitoneal and oral administrations compared with the venous route. The self-assemblies of bolaamphiphilic prodrugs could simultaneously deliver two types of drugs to targeted tissues and would become a promising nanomedicine. Topics: Animals; Anti-HIV Agents; Cell Line; Cell Survival; Chromatography, High Pressure Liquid; Didanosine; HIV Infections; Humans; Mice; Prodrugs; Zidovudine | 2011 |
A new nanomedicine based on didanosine glycerolipidic prodrug enhances the long term accumulation of drug in a HIV sanctuary.
New nanomedicines could improve drug accumulation in HIV sanctuaries and ameliorate their antiretroviral efficiency. In this view, we propose herein a combined strategy based on a biomimetic prodrug of ddI and its formulation in well-characterized lipid nanoobjects. The glycerolipidic prodrug of ddI (ProddINP) has been synthesized and its bulk structure was characterized. An appropriate formulation of this prodrug has been designed using a rational approach combining different physicochemical techniques. The high incorporation ratio of the prodrug into dipalmitoylphosphatidylcholine (DPPC) bilayers was determined by DSC. Then two liposome preparation methods were compared, with respect to size, incorporation yield and molecular/supramolecular organization of vesicles. The best liposomal formulation of ProddINP has been checked to keep intact the anti-HIV activity of ddI. This formulation was finally compared to ddI after oral route in rat. The animal experiments evidenced the increase of ddI blood half life (3-fold) and its enhanced accumulation as prodrug form at 24h in numerous organs and especially intestine after administration of ProddINP in comparison with free drug. Finally, the tested liposomal formulation of ProddINP seems to be a promising approach to eradicate HIV infection from intestinal sanctuaries where the virus can concentrate. Topics: 1,2-Dipalmitoylphosphatidylcholine; Administration, Oral; Animals; Anti-HIV Agents; Didanosine; Drug Carriers; Drug Compounding; Drug Delivery Systems; Freeze Drying; HIV; HIV Infections; Humans; Leukocytes, Mononuclear; Liposomes; Nanostructures; Particle Size; Prodrugs; Rats; Rats, Wistar; Time Factors | 2011 |
Treatment switches during pregnancy among HIV-positive women on antiretroviral therapy at conception.
To describe antiretroviral therapy (ART) use and clinical status, at start of and during pregnancy, for HIV-positive women receiving ART at conception, including the proportion conceiving on drugs (efavirenz and didanosine) not recommended for use in early pregnancy.. Women with a pregnancy resulting in a live-birth after 1995 (n = 1537) were identified in an observational cohort of patients receiving HIV care at 12 clinics in the UK by matching records with national pregnancy data. Treatment and clinical data were analysed for 375 women conceiving on ART, including logistic regression to identify factors associated with changing regimen during pregnancy.. Of the 375 women on ART, 39 (10%) conceived on dual therapy, 306 (82%) on triple therapy and 30 (8%) on more than three drugs. In total, 116 (31%) women conceived on a regimen containing efavirenz or didanosine (69 efavirenz, 54 didanosine, seven both). Overall, 38% (143) changed regimen during pregnancy, of whom 44% (n = 51) had a detectable viral load around that time. Detectable viral load was associated with increased risk of regimen change [adjusted odds ratio 2.97, 95% confidence interval (CI) (1.70-5.19)], while women on efavirenz at conception were three times more likely to switch than women on other drugs [3.40, (1.84-6.25)]. Regimen switching was also associated with year at conception [0.89, (0.83-0.96)].. These findings reinforce the need for careful consideration of ART use among women planning or likely to have a pregnancy in order to reduce viral load before pregnancy and avoid drugs not recommended for early antenatal use. Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; Fertilization; HIV Infections; Humans; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Risk Factors; United Kingdom; Viral Load; Young Adult | 2011 |
Non-cirrhotic portal hypertension in HIV-infected individuals.
Non-cirrhotic portal hypertension (NCPH) has been associated with didanosine (ddI) exposure. We aimed to determine the number of individuals with NCPH within our cohort and define their characteristics. We identified individuals within our cohort with NCPH and performed a retrospective case note review. Cumulative antiretroviral therapy (ART) use was calculated and a statistical analysis performed to compare exposure to the rest of the clinic cohort for the same time period. Where available, data was collated on FibroScan®, echocardiography and coagulation profile. Seventeen patients were identified. Upper gastrointestinal bleeding was the most common presenting feature. Liver biopsy showed mild portal or periportal fibrosis in 13 (81%) and four with features of nodular regenerative hyperplasia. There was significantly greater exposure to ddl in this group (59.5 months) compared to the rest of the HIV cohort (21.1 months) P = <0.001. Eleven subjects has a liver elastography performed, six (55%) had a result greater than 9.6 kPa (consistent with greater than F2 disease by Metavir scoring). Echocardiography was performed in seven patients: four met criteria for pulmonary hypertension. This is consistent with other cohorts demonstrating an association between the didanosine exposure and NCPH. Our data also suggest an increased risk of pulmonary hypertension. Topics: Adult; Anti-HIV Agents; Cohort Studies; Didanosine; Female; Gastrointestinal Hemorrhage; HIV Infections; Humans; Hypertension, Portal; Hypertension, Pulmonary; Male; Middle Aged; Retrospective Studies; Statistics, Nonparametric | 2011 |
Impact of HAART exposure and associated lipodystrophy on advanced liver fibrosis in HIV/HCV-coinfected patients.
The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness ≥9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1-3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1-3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2-3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0-2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0-1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided. Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Didanosine; Female; Hepatitis C; HIV Infections; Humans; Insulin Resistance; Lipodystrophy; Liver Cirrhosis; Male; Middle Aged; Mitochondria; Sex Factors; Stavudine | 2011 |
High prevalence of distal sensory polyneuropathy in antiretroviral-treated and untreated people with HIV in Tanzania.
To describe the prevalence of distal sensory polyneuropathy (DSP), a complication of both advanced HIV disease and of antiretroviral therapy (ART), amongst Tanzanians with HIV, on and off ART (including stavudine) with CD4 counts above and below 200 cells/μl.. We recruited participants attending ART clinic into four groups: >6 months ART exposure and (i) CD4 < 200 cells/μl or (ii) CD4 > 200 cells/μl (ART/CD4 < 200 and ART/CD4 > 200, respectively); ART-naïve and (iii) CD4 < 200 cells/μl or iv)CD4 > 200 cells/μl (noART/CD4 < 200 and noART/CD4 > 200, respectively). Primary outcome was DSP, as defined by presence of at least one symptom and one sign.. Of 326 evaluable participants, 81 (32 men, median age 38 years, median CD4 142 cells/μl) were enrolled in the ART/CD4 < 200 group, 78 (17 men, median age 37 years, median CD4 345 cells/μl) in ART/CD4 > 200, 81 (30 men, median age 37 years, median CD4 128 cells/μl) in noART/CD4 < 200 and 86 (22 men, median age 33 years, median CD4 446 cells/μl) in noART/CD4 > 200. Numbness was the most commonly reported symptom. DSP prevalence ranged from 43.2% in ART/CD4 < 200 to 20.9% in noART/CD4 > 200. DSP was more common among men (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.2-3.3) and older participants (aOR 2.7, 95% CI 1.1-6.2 for age 40 + vs. <30 years).. Distal sensory polyneuropathy is common amongst those attending this clinic, even those with no ART exposure and a CD4 count above 200 cells/μl. Stavudine and didanosine expose HIV-infected patients to an additional avoidable risk of DSP. Access to non-neurotoxic ART regimes as well as earlier HIV diagnosis and initiation of ART is needed. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Hypesthesia; Male; Middle Aged; Pain; Peripheral Nervous System; Polyneuropathies; Prevalence; Stavudine; Tanzania | 2011 |
Optimizing antiretroviral product selection: a sample approach to improving patient outcomes, saving money, and scaling-up health services in developing countries.
Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings. Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Developing Countries; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Health Planning; Health Services; HIV Infections; Humans; Lamivudine; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome | 2011 |
The value of screening HIV-infected individuals for didanosine-related liver disease?
Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Liver Diseases; Mass Screening | 2011 |
Abacavir, didanosine and tenofovir do not induce inflammatory, apoptotic or oxidative stress genes in coronary endothelial cells.
The use of abacavir and didanosine in HAART has been associated with an increased risk of myocardial infarction in HIV-infected patients. The aim of this study was to address the development of endothelial dysfunction in cultivated coronary artery endothelial cells (HCAECs) in response to abacavir, didanosine and tenofovir. We examined the impact of these drugs on the expression levels of the proinflammatory, oxidative stress and apoptosis regulating genes in HCAECs.. We tested gene and protein expression changes in HCAECs in response to abacavir, didanosine and tenofovir using quantitative real-time reverse transciptase PCR, FACS and ELISA. The assessed genes/proteins included the proinflammatory molecules VCAM-1, ICAM-1, MCP-1, RANTES and IL-6. In addition, we assessed the gene expression of the intracellular reactive oxygen producing NADPH oxidase subunit gp91(PHOX) and the apoptosis regulating molecules Bcl-2 and BAD.. Exposure of HCAECs to abacavir, didanosine and tenofovir resulted in no statistically significant changes in any of the tested genes/proteins at any time point or at any concentration.. We found no evidence that abacavir, didanosine or tenofovir had direct in vitro effects on coronary endothelial cell gene transcription and protein expression of the selected mediators. If abacavir or didanosine increase cardiovascular risk, it is likely not through the direct endothelial activation pathways tested in these experiments. However, further studies are needed to completely exclude the toxicity of abacavir or didanosine on endothelial cells. Topics: Adenine; Anti-HIV Agents; Apoptosis; Cardiovascular Diseases; Cell Adhesion Molecules; Coronary Vessels; Cytokines; Didanosine; Dideoxynucleosides; Endothelial Cells; Gene Expression; Gene Expression Profiling; HIV Infections; HIV-1; Humans; Inflammation; NADPH Oxidases; Organophosphonates; Oxidative Stress; Primary Cell Culture; Proto-Oncogene Proteins; Tenofovir | 2011 |
[Regenerative nodular hyperplasia in HIV].
Nodular regenerative hyperplasia of the liver is a rare condition. We describe here the case of a patient with HIV who presented with a clinical syndrome of portal hypertension. After multiple evaluations the diagnosis was recognized by the histology. The findings were attributed to the prolonged use of didanosine. Topics: Adult; Anti-HIV Agents; Didanosine; Female; Focal Nodular Hyperplasia; HIV Infections; Humans; Hypertension, Portal | 2011 |
Nodular regenerative hyperplasia of the liver associated with didanosine persists for years even after its interruption.
The authors describe an HIV-positive patient with nodular regenerative hyperplasia of the liver with non-cirrhotic portal hypertension. Despite stopping the culprit drug, didanosine, the radiologic changes persisted for years. When evaluating liver pathologies, antiretroviral drugs must be included in the differential diagnosis, even when they have been stopped years ago. Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Hyperplasia; Hypertension, Portal; Liver; Male; Middle Aged; Radiography; Time Factors | 2011 |
Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors. Topics: Adenine; Anti-HIV Agents; Cell Survival; Cells, Cultured; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Macrophages; Nucleosides; Nucleotides; Organophosphonates; Tenofovir | 2010 |
Anti-HIV and antiplasmodial activity of original flavonoid derivatives.
In our search for potent anti-HIV and antiplasmodial agents, novel series of flavonoid derivatives and their chalcone intermediates were synthesized and evaluated for inhibition of HIV multiplication and antiproliferative activity on Plasmodium falciparum parasites. Chalcones exhibited a more selective antiplasmodial activity than flavonoids. Methoxyflavone 7e was the only one compound active in both P. falciparum and HIV-1 whereas aminomethoxyflavones showed activity against HIV-2. Para substitution on the B ring seemed to increase HIV-2 potency. Topics: Anti-HIV Agents; Antimalarials; Cell Line; Cell Survival; Flavonoids; HIV; HIV Infections; Humans; Malaria, Falciparum; Plasmodium falciparum | 2010 |
High rates of survival, immune reconstitution, and virologic suppression on second-line antiretroviral therapy in South Africa.
To determine rates of survival, viral suppression, and immunologic change after 1 year on second-line antiretroviral therapy, we conducted a cohort study among 328 patients initiated on zidovudine, didanosine, and lopinavir/ritonavir. All patients who switched to standard second-line therapy at a large urban public-sector clinic in Johannesburg, South Africa, were included. A year after initiating second-line therapy 243/313 [78%; 95% confidence interval (CI) 73%-82%], subjects were alive and in care. Further, 203/262 (77%; 95% CI: 72%-82%) had a suppressed viral load by 1 year. Mean CD4 gain by 12 months was 133 cells/microL (95% CI: 106-160). Patients on second-line therapy had a small decreased likelihood of being alive and in care by 1 year [hazard ratio (HR) 0.84; 95% CI: 0.73-0.97] as time-matched comparisons on first-line antiretroviral therapy (ART). Patients switched before 2 viral loads >1000 (HR 1.68; 95% CI: 1.08-2.61), and those switched for reasons not related to noncompliance with first-line (HR 1.83; 95% CI: 1.14-2.93) were more likely to achieve virologic suppression by 1 year on second-line ART. As rates of treatment failure over the first year on second-line therapy were low, provision of second-line treatment to patients who fail their first-line ART should be considered a high priority in resource-poor settings. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; South Africa; Survival Analysis; Treatment Outcome; Viral Load; Zidovudine | 2010 |
Development of a didanosine genotypic resistance interpretation system based on large derivation and validation datasets.
To assess the genotypic determinants of the virological response to didanosine (ddI) in HIV-infected patients.. The Forum database on ddI was randomly divided into a derivation set (n = 1000) and a validation set (n = 453). Linear regression models and bootstrap sampling were used to select resistance mutations and to estimate their resistance scores. Linear regression models, accounted for the censoring of viral load measurements due to assay lower limits, of the week 8 reduction in viral load from baseline were adjusted for baseline viral load, the exact number of weeks between baseline and the week 8 viral load measurements, and the Stanford genotypic sensitivity score.. The ddI resistance mutations and their resistance scores based on the derivation set were as follows: M41L (score of 14), T69D (24), D123S (40), T139M (54), I180V (53), M184V (-12), V189I (55), Q207K (37), L210W (25), and T215Y (eight). The total score is obtained by adding the individual scores. Viruses with scores of 19 or less, 20-59, and 60 or more are considered sensitive, intermediate, and resistant, respectively. In the validation set, respectively, 58.7, 36.9, and 4.4% of viruses were predicted to be sensitive, intermediate, and resistant to ddI. The observed viral load reductions at week 8 were, respectively, 1.51 log10 copies/ml [interquartile range (IQR) 1.26-1.76] (P = 0.0001 versus resistant), 1.11 (0.94-1.30) (P = 0.0077 versus sensitive), and 0.46 (0.32-0.74) (P = 0.0079 versus intermediate).. We developed a genotypic resistance score for didanosine including four mutations never previously used. Topics: Adult; Algorithms; Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Linear Models; Male; Middle Aged; Mutation; RNA, Viral; Viral Load | 2010 |
Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting; an attractive route against infections caused by AIDS viruses.
The primary aim of this study was to investigate intranasal (i.n.) administration as a potential route to enhance systemic and brain delivery of didanosine (ddI). A further aim was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the systemic and brain targeting efficiency of ddI following i.n. administration. Didanosine-loaded chitosan nanoparticles, were prepared through ionotropic gelation of chitosan with tripolyphosphonate anions, and characterized in terms of their size, drug loading, and in vitro release. The nanoparticles were administered i.n. to rats, compared to i.n. and intravenous (i.v.) administration of ddI in solution. The concentrations of ddI in blood, CSF, and brain tissues were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). The brain/plasma, olfactory bulb/plasma and CSF/plasma concentration ratios were significantly higher (P < 0.05) after i.n. administration of ddI nanoparticles or solution than those after i.v. administration of didanosine aqueous solution. The ratio of ddI concentration values of the nanoparticles to the solution at 180 min post-i.n. dosing was 2.1 and 1.9 in CSF and brain, respectively. Thus, both the i.n. route of administration and formulation of ddI in chitosan nanoparticles increased delivery of ddI to CSF and brain. Topics: Administration, Intranasal; Animals; Brain; Chitosan; Chromatography, Liquid; Didanosine; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; HIV Infections; Male; Mass Spectrometry; Microscopy, Electron, Transmission; Nanoparticles; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors | 2010 |
Semiparametric analysis of recurrent events: artificial censoring, truncation, pairwise estimation and inference.
The analysis of recurrent failure time data from longitudinal studies can be complicated by the presence of dependent censoring. There has been a substantive literature that has developed based on an artificial censoring device. We explore in this article the connection between this class of methods with truncated data structures. In addition, a new procedure is developed for estimation and inference in a joint model for recurrent events and dependent censoring. Estimation proceeds using a mixed U-statistic based estimating function approach. New resampling-based methods for variance estimation and model checking are also described. The methods are illustrated by application to data from an HIV clinical trial as with a limited simulation study. Topics: AIDS-Related Opportunistic Infections; Computer Simulation; Data Interpretation, Statistical; Didanosine; HIV Infections; Humans; Kaplan-Meier Estimate; Models, Statistical; Recurrence; Zalcitabine | 2010 |
Another milestone in minimizing risks to mothers exposed to single-dose nevirapine for prevention of vertical transmission of HIV-1 to infants: what next?
Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Mutation, Missense; Nevirapine; Pregnancy; Zidovudine | 2010 |
Efficacy and safety of 1-month postpartum zidovudine-didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine.
Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine (sdNVP) would prevent the selection of nevirapine-resistance mutations.. HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, sdNVP during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received sdNVP in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations.. The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm3 (interquartile range [IQR], 322-549 cells/mm3), the median HIV load was 3.45 log10 copies/mL (IQR, 2.79-4.00 log10 copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major NNRTI resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls (P < .001).. A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of NNRTI resistance mutations. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Ligase Chain Reaction; Mutation, Missense; Nevirapine; Postpartum Period; Pregnancy; RNA, Viral; Sequence Analysis, DNA; Viral Load; Young Adult; Zidovudine | 2010 |
Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings.
Liver disease of unknown cause in HIV-infected persons is rare but increasingly being reported. Noncirrhotic portal hypertension is the main feature in a subset of these patients, in whom gastrointestinal bleeding is the most frequent and potentially life-threatening clinical presentation.. We describe the epidemiological, clinical and histological features of 12 HIV-positive individuals presenting with noncirrhotic portal hypertension.. An interpretable liver biopsy was available in 11, and cirrhosis was absent in all patients. Three patients had nodular regenerative hyperplasia of the liver, whereas eight showed morphological features previously described as 'hepatoportal sclerosis'. In four of the later group, a distinctive lesion was noted characterized by massive absence of portal veins along with focal fibrous obliteration of small portal veins. All patients had been treated with didanosine for long periods and inflammatory and thrombotic processes hypothetically triggered by this purine analogue in the hepatic microvasculature might result in this form of obliterative portal venopathy.. Noncirrhotic portal hypertension is a rare but unique entity presenting in HIV-positive individuals generally with prior prolonged exposure to didanosine, which shows an obliteration of portal veins as the most distinctive histological finding in the liver. Topics: Adult; Anti-Retroviral Agents; Didanosine; Female; Gastrointestinal Hemorrhage; HIV Infections; Humans; Hypertension, Portal; Liver Diseases; Male; Middle Aged | 2010 |
Recent FDA approvals and changes.
Topics: Adenine; Adolescent; Adult; Anti-HIV Agents; Child; Delayed-Action Preparations; Didanosine; Drug Approval; Drug Labeling; HIV Infections; Humans; Organophosphonates; Randomized Controlled Trials as Topic; Tenofovir; United States; United States Food and Drug Administration | 2010 |
Breast enlargement in an HIV-infected man on combined antiretroviral therapy: what if it was carcinoma?
We describe a case of an HIV-infected man on effective combined antiretroviral therapy, presenting with bilateral gynaecomastia revealing breast carcinoma. Gynaecomastia was first considered to be related to efavirenz and/or didanosine. Although breast carcinoma is rare among HIV-infected men, it should be considered as a potential cause of breast enlargement. Topics: Alkynes; Benzoxazines; Breast Neoplasms, Male; Carcinoma, Intraductal, Noninfiltrating; Cyclopropanes; Didanosine; Drug Therapy, Combination; Gynecomastia; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors | 2010 |
Clonal resistance analyses of HIV type-1 after failure of therapy with didanosine, lamivudine and tenofovir.
The rapid failure of initial therapy with combinations of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that exclude zidovudine has not been fully explained by standard virus population analyses of HIV type-1 (HIV-1) drug resistance. We therefore investigated HIV-1 genotype and phenotype at the single genome level in samples from patients on a failing regimen of tenofovir (TNV), didanosine (ddI) and lamivudine (3TC).. Single genome sequencing was performed on 9 failure samples containing both K65R and M184V mutations by standard genotype, either as wild-type/mutant mixtures (6/9) or as mutant only (3/9). Recombinant clones with different combinations of observed mutations were generated and tested for NRTI susceptibility.. Of the 204 single genome sequences analysed, 50% were K65R/M184V double mutants, 38% were M184V single mutants, 10% were M184I single mutants and only 1% (2 sequences) were K65R single mutants. Phenotypic testing of recombinant clones showed a significant increase in resistance for double mutants: mean fold resistance to abacavir, ddI and TNV was 6.5, 4.3 and 1.6 for K65R/M184V double mutants versus 2.5, 1.9 and 0.6 for M184V single mutants, respectively (P<0.001).. Mutants with K65R and M184V linked on the same genome were the most common HIV-1 variants in samples analysed from patients failing TNV, ddI and 3TC with both mutations detected by standard genotype. The double mutant exhibited reduced susceptibility to all three NRTIs in the regimen. This resistant phenotype, resulting from just two linked point mutations, likely contributes to rapid failure of NRTI combinations that exclude zidovudine. Topics: Adenine; Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Genome, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Organophosphonates; Phenotype; Recombination, Genetic; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Tenofovir; Treatment Failure | 2010 |
Open letter to Lamberto Andreotti, Chief Executive Officer, Bristol-Myers Squibb.
Topics: Africa South of the Sahara; Anti-HIV Agents; Developing Countries; Didanosine; Drug Industry; France; HIV Infections; Humans; Infant | 2010 |
Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients.
To determine maraviroc (MVC) concentrations in cerebrospinal fluid (CSF) in HIV-infected patients.. Twelve CCR5+ HIV-1 adult antiretroviral-experienced patients receiving MVC-containing regimens for at least 1 month were enrolled. Both CSF and blood samples were taken around 12 hours after the last MVC dose. liquid chromatography tandem mass spectrometry was used to determine MVC concentrations, and HIV-1 viral load was determined by real-time polymerase chain reaction, (LOD, 40 copies/mL).. Twelve blood and 12 CSF samples were collected. Median CD4 count was 281(120-759) cells per microliter, and median HIV-1 viral load was <40 copies per milliliter. Median time on MVC was 13.5 weeks (4-60). Nucleoside analogues (tenofovir/didanosine) were given in only 1 case. Median MVC concentrations in plasma were 124.75 (7.3-517) ng/mL. In all except one, CSF sample-receiving an erroneous MVC dose while taking concomitantly nevirapine-MVC concentrations [2.58 (<0.5-7.22) ng/mL] were within the EC(90) range (0.06-10.70). Median MVC CSF: plasma ratio was 0.022 (0.004-0.17), and when the free MVC plasma concentration was used, 0.094 (2.58-27.44). CSF viral load was <40 copies per milliliter in all 9 patients with undetectable plasma viral load.. MVC achieves concentrations within the EC(90) range in CSF. All patients with undetectable plasma viral load although receiving nucleoside-sparing regimens including new drugs showed viral suppression in CSF. Topics: Adenine; Adult; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Chromatography, Liquid; Cyclohexanes; Didanosine; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Organophosphonates; Polymerase Chain Reaction; Tandem Mass Spectrometry; Tenofovir; Triazoles; Viral Load | 2010 |
Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine.
Unexpected cases of severe liver disease in HIV-infected patients have been reported and an association with didanosine (ddI) has been suggested. Transient elastography (TE) might detect patients harbouring such a condition. Our objective was to search for the presence of abnormal liver stiffness (LS) in a cohort of HIV-infected patients without HBV or HCV coinfection and to assess the related factors.. A cross-sectional prospective study was conducted. LS was assessed by TE in 258 HIV-infected patients without HBV or HCV coinfection and with no evidence of acute hepatotoxicity or other origins of liver disease. LS values > or =7.2 kPa were considered abnormal. Multivariate analyses were performed to identify factors associated with abnormal LS.. Abnormal LS was observed in 29 (11.2%) patients. A total of 18 (16.4%) patients previously treated with ddI and 11 (7.4%) of those who never received ddI had LS values > or =7.2 kPa (P=0.02). The prevalence of abnormal LS was higher in patients previously treated with abacavir than in those who had never received abacavir (15 [21.7%] versus 14 [7.4%]; P=0.001). After multivariate analyses, age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.002-1.1; P=0.004) alcohol intake >50 g/day (AOR 7.2, 95% CI 2.6-19.7; P<0.0001), CD4(+) T-cell count <200 cells/ml (AOR 3.4, 95% CI 1.06-11.007; P=0.03), time on ddI treatment (AOR 1.31, 95% CI 1.12-1.52; P=0.001) and previous abacavir exposure (AOR 3.01, 95% CI 1.18-7.67; P=0.02) were independently associated with abnormal LS.. The prevalence of abnormal LS in HIV-infected patients without HBV or HCV coinfection is substantial. Long-term exposure to ddI is a major cause of liver damage in these patients. Topics: Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Elasticity; Elasticity Imaging Techniques; Female; HIV Infections; Humans; Liver; Liver Diseases; Male; Middle Aged; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors | 2010 |
Genotypic and phenotypic cross-drug resistance of harboring drug-resistant HIV type 1 subtype B' strains from former blood donors in central Chinese provinces.
The objective of this study was to assess the patterns of genotypic and phenotypic resistance in a population of blood donor patients infected with HIV-1 subtype B' (Thai B', a clade of HIV-1 B) from central China, previously treated and harboring NRTI and NNRTI resistance mutations, with the purpose of designing effective therapeutic regimens. The HIV-1 pol genes from 65 patients were sequenced and estimated for drug resistance while the viruses isolated from the patients were used to analyze the phenotype based on the TZM-bl cell line. All the HIV-1 strains harboring one or more drug resistance mutations to HIV-1 RTIs possessed high cross-resistance to EFV (100%) and DLV (92%), as well as to ABC (84%) and TDF (77%), which are much higher than both FTC and 3TC (42%). There were more thymidine analog mutation (TAM)-associated mutations in the AZT/ddI/NVP group (62.5%) than in the d4T/ddI/NVP group (32.65%). A phenotypic assay showed high concordance between genotypic and phenotypic cross-resistance. This study showed there was a high level of cross-drug resistance to HIV-1 RTIs among Chinese AIDS patients harboring resistant strains, and there is also a high prevalence of primary resistance to 3TC, suggesting that one important recommendation should be the realization of genotypes in all naive patients due to the high prevalence of NRTI and NNRTI mutations. Topics: Adult; Anti-HIV Agents; Blood Donors; China; Didanosine; Drug Resistance, Multiple, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Mutation; Phenotype; pol Gene Products, Human Immunodeficiency Virus; RNA, Viral; Sequence Analysis, RNA; Stavudine; Zidovudine | 2010 |
Bristol-Myers Squibb clarification on didanosine supply.
Topics: Anti-HIV Agents; Didanosine; Drug Industry; HIV Infections; Humans; Pediatrics; Tablets | 2010 |
Human immunodeficiency virus type 1 isolates with the reverse transcriptase (RT) mutation Q145M retain nucleoside and nonnucleoside RT inhibitor susceptibility.
Q145M, a mutation in a conserved human immunodeficiency virus type 1 reverse transcriptase (RT) region, was reported to decrease susceptibility to multiple RT inhibitors. We report that Q145M and other Q145 mutations do not emerge with RT inhibitors nor decrease RT inhibitor susceptibility. Q145M should not, therefore, be considered an RT inhibitor resistance mutation. Topics: Amino Acid Sequence; Anti-HIV Agents; Drug Resistance, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Nucleosides; Phenotype; Reverse Transcriptase Inhibitors | 2009 |
Anti-human immunodeficiency virus activity, cross-resistance, cytotoxicity, and intracellular pharmacology of the 3'-azido-2',3'-dideoxypurine nucleosides.
Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3'-azido-2',3'-dideoxypurine nucleosides (ADPNs) 3'-azido-2',3'-dideoxyadenosine (3'-azido-ddA) and 3'-azido-2',3'-dideoxyguanosine (3'-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC50s] range from 0.19 to 2.1 microM for 3'-azido-ddG and from 0.36 to 10 microM for 3'-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3'-azido-ddA and 3'-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC50 change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC50 change of <3.5-fold). In addition, 3'-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3'-azido-ddG is efficiently phosphorylated to 3'-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection. Topics: Anti-HIV Agents; Cell Line, Tumor; Cell Survival; Cells, Cultured; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Molecular Structure; Reverse Transcriptase Inhibitors | 2009 |
Sensitivity of phenotypic susceptibility analyses for nonthymidine nucleoside analogues conferred by K65R or M184V in mixtures with wild-type HIV-1.
Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques. Topics: Adenine; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Organophosphonates; Phenotype; Plasmids; Tenofovir; Viral Load | 2009 |
Highly active antiretroviral therapy-associated ptosis in patients with human immunodeficiency virus.
Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blepharoptosis; Carbamates; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Oculomotor Muscles; Organophosphates; Organophosphonates; Sulfonamides; Tenofovir | 2009 |
Emergence of primary NNRTI resistance mutations without antiretroviral selective pressure in a HAART-treated child.
The use of antiretrovirals (ARV) during pregnancy has drastically reduced the rate of the human immunodeficiency virus perinatal transmission (MTCT). As a consequence of widespread ARV use, transmission of drug resistant strains from mothers to their babies is increasing. Ultra-sensitive PCR techniques have permitted the quantification of minority viral populations, but little is known about the transmission of drug-resistant HIV-1 minority population in the setting of MTCT.. We describe the case of a female child born to an HIV-infected mother, which had not taken any ARV during the pregnancy. The child's first genotype demonstrated a minor non-nucleoside reverse transcriptase inhibitor (K101E), and during her treatment with reverse transcriptase and protease inhibitors full resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) emerged (G190A). Phenotypic/genotypic analysis of variant quasispecies through yeast TyHRT assay was conducted to characterize minority resistant viral strains circulating in both mother and child. Maximum likelihood and Bayesian MCMC phylogenetic analyses were performed with samples from the pair to assess genetic relatedness among minor viral strains. The analysis showed that the child received a minor NNRTI resistant variant, containing the mutation K101E that was present in less than 1% of the mother's quasispecies. Phylogenetic analyses have suggested common ancestry between the mother's virus strain carrying K101E with the viral sequences from the child.. This is the first documentation of MTCT of a minority resistant strain of HIV-1. The transmission of minor resistant variants carries the threat of emergence of multi-drug primary mutations without identified specific selective pressures. Topics: Adult; Antiretroviral Therapy, Highly Active; Didanosine; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Mutation, Missense; Nelfinavir; Phylogeny; Point Mutation; Pregnancy; Pregnancy Complications, Infectious; Selection, Genetic; Zidovudine | 2009 |
Proximal tubular dysfunction associated with tenofovir and didanosine causing Fanconi syndrome and diabetes insipidus: a report of 3 cases.
We report 3 cases of patients with HIV/AIDS in whom Fanconi syndrome and nephrogenic diabetes insipidus developed secondary to use of an antiretroviral regimen containing tenofovir disoproxil fumarate and didanosine. These patients presented with a history of polydipsia, polyuria, weight loss, anorexia, and wasting. Interestingly, 1 patient was not taking protease inhibitors. This response is a well-documented yet uncommon complication of tenofovir use in the HIV population. We recommend continued monitoring for renal toxicity when using NRTI combination of tenofovir and didanosine. Topics: Adenine; Adult; Anti-HIV Agents; Diabetes Insipidus; Didanosine; Drug Therapy, Combination; Fanconi Syndrome; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir | 2009 |
Editorial comment: tenofovir nephrotoxicity--the disconnect between clinical trials and real-world practice.
Topics: Adenine; Anti-HIV Agents; Clinical Trials as Topic; Diabetes Insipidus; Didanosine; Drug Therapy, Combination; Fanconi Syndrome; HIV Infections; Humans; Kidney Function Tests; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Risk Factors; Tenofovir | 2009 |
CXCR3 activation by lentivirus infection suppresses neuronal autophagy: neuroprotective effects of antiretroviral therapy.
Previous studies have implicated CXCL12 in the neuropathogenesis of HIV infection. Proteolysis of CXCL12 generates a neurotoxic molecule, CXCL12(5-67), which engages and activates CXCR3, in addition to exhibiting increased expression in the brains of patients with HIV-associated dementia (HAD). Herein, we investigated CXCR3-mediated neuronal injury, particularly, its contribution to autophagy suppression and the concomitant effects of antiretroviral therapy using human brain samples and models of HIV neuropathogenesis. Neurons in the brains of HAD patients and feline immunodeficiency virus (FIV)-infected animals, as well as cultured human neurons, expressed CXCR3, which was modulated in a ligand-specific manner. Exposure of human neurons to CXCL12(5-67) caused a reduction in the autophagy-associated molecule LC3 (P<0.05) and neuronal survival (P<0.05), which recapitulated findings in FIV- and HIV-infected brains (P<0.05). Oral didanosine (ddI) treatment of FIV-infected animals reduced neurobehavioral abnormalities in conjunction with diminished plasma viral load (P<0.05). F4/80 transcript abundance and CXCL12(5-67) immunoreactivity were reduced with restored neuronal LC3 expression in the brains of FIV-infected animals after ddI treatment (P<0.05). ddI treatment also prevented microglial activation and depletion of synaptic proteins in the cortex of FIV-infected animals (P<0.05). These findings indicate that the beneficial effects of ddI might be a consequence of a reduced systemic viral burden and concurrent leukocyte activation, leading to diminished neuroinflammation with preservation of neuronal autophagy by regulating CXCR3 activation. Topics: Animals; Anti-HIV Agents; Autophagy; Brain; Cats; Didanosine; Feline Acquired Immunodeficiency Syndrome; HIV Infections; Humans; Lentivirus Infections; Neurons; Neuroprotective Agents; Receptors, CXCR3 | 2009 |
Long-term suppressive therapy for pulmonary aspergilloma in an immunocompromised man with AIDS. Is it always necessary?
Aspergillus infections are rare opportunistic infections in the course of AIDS and they mostly present as invasive pulmonary disease. Owing to the prolonged survival of profoundly immunocompromised patients with AIDS, invasive pulmonary aspergillosis is being reported with increased frequency. However, although pulmonary aspergilloma has been well described in immunocompetent patients, it has been rarely reported in AIDS patients. The treatment for pulmonary aspergilloma remains challenging and often needs lifelong treatment to minimize fatal haemoptysis, which can occur in up to 25%, and progression to secondary invasive aspergillosis. We report a case of pulmonary aspergilloma in a severely immunocompromised patient with AIDS who stopped taking systemic antifungal treatment in April 1998 and remained well with little progression of invasive aspergillosis up until March 2002 when he died of acute pancreatitis related to a drug interaction of didanosine and tenofovir. Topics: Adenine; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antifungal Agents; Aspergillosis; Didanosine; Drug Administration Schedule; Drug Interactions; Fatal Outcome; HIV Infections; Humans; Immunocompromised Host; Lung Diseases, Fungal; Male; Middle Aged; Organophosphonates; Pancreatitis; Radiography; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome | 2009 |
Ophthalmoplegia and ptosis: mitochondrial toxicity in patients receiving HIV therapy.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blepharoptosis; Didanosine; DNA, Mitochondrial; Genetic Predisposition to Disease; HIV Infections; Humans; Lipodystrophy; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Mutation; Oculomotor Muscles; Ophthalmoplegia; Ophthalmoplegia, Chronic Progressive External; Recovery of Function; Risk Factors; Time | 2009 |
Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study.
Noncirrhotic portal hypertension (NCPH) is a newly described life-threatening liver disease of unknown cause in human immunodeficiency virus (HIV)-infected persons. Postulated pathogenesis includes prolonged exposure to antiretroviral therapy, particularly didanosine.. We performed a nested case-control study including 15 patients with NCPH and 75 matched control subjects of the Swiss HIV Cohort Study to investigate risk factors for the development of NCPH. Matching criteria were similar duration of HIV infection, absence of viral hepatitis, and follow-up to at least the date of NCPH diagnosis in the respective case.. All 15 case patients had endoscopically documented esophageal varices and absence of liver cirrhosis on biopsies; 4 died because of hepatic complications. At NCPH diagnosis, case patients and control subjects were similar concerning sex; race; Centers for Disease Control and Prevention stage; HIV-RNA level; CD4 cell count nadir; and lipids and lipodystrophy. Differences were found in age (conditional logistic regression odds ratio [OR] for 10 years older, 2.9; 95% confidence interval [CI], 1.4-6.1); homosexuality (OR, 4.5; 95% CI, 1.2-17); current CD4 cell count <200 cells/microL (OR, 34.3; 95% CI, 4.3-277); diabetes mellitus (OR, 8.8; 95% CI, 1.6-49); alanine aminotransferase level higher than normal (OR, 13.0; 95% CI, 2.7-63); alkaline phosphatase higher than normal (OR, 18.3; 95% CI, 4.0-85); and platelets lower than normal (OR, 20.5; 95% CI, 2.4-178). Cumulative exposure to antiretroviral therapy (OR per year, 1.3; 95% CI, 1.0-1.6), nucleoside reverse-transcriptase inhibitor (OR, 1.3; 95% CI, 1.1-1.7), didanosine (OR, 3.4; 95% CI, 1.5-8.1), ritonavir (OR, 1.4; 95% CI, 1.0-1.9), and nelfinavir (OR, 1.4; 95% CI, 1.0-1.9) were longer in case patients. Exposure to nonnucleoside reverse-transcriptase inhibitor and other protease inhibitors were not different between groups. In bivariable models, only the association of NCPH with didanosine exposure was robust; other covariables were not independent risk factors.. We found a strong association between prolonged exposure to didanosine and the development of NCPH. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Case-Control Studies; Didanosine; Female; HIV Infections; Humans; Hypertension, Portal; Male; Middle Aged | 2009 |
Conserved T cell and natural killer cell function in treatment-experienced adults receiving tenofovir plus didanosine as nucleoside reverse transcription inhibitor backbone.
Anti-retroviral treatment (ART) usually results in efficient control of virus replication and in immune reconstitution. Among potential adverse effects, impairment of immune responses in terms of CD4(+) T cell counts has been attributed to some ART regimens, as with didanosine-tenofovir. We studied the functional integrity of adaptive and innate immunity during didanosine-tenofovir-containing ART. Two groups of extensively pretreated patients completing at least 48 weeks of ART containing either lamivudine-didanosine (n = 21) or tenofovir-didanosine (n = 25) were identified. In addition to standard clinical immune and virological parameters, we performed a flow cytometric analysis of natural killer (NK) cells, of memory and naive CD4(+) T cells and of T cell receptor alphabeta(+) T cells co-expressing inhibitory NK receptors. Functional analysis consisted in specific and total interferon-gamma production by NK cells and of recall antigen proliferation of peripheral blood mononuclear cells. Comparable clinical immunological reconstitution and virological control were confirmed in the two groups of patients in the absence of clinically relevant adverse effects. The proportion of CD4(+)CD45RA(+) T cells and of functionally inhibited killer immunoglobulin-like receptor T cell receptor alphabeta(+) cells, the proliferation to recall antigens as well as NK cell phenotype and function as determined by interferon-gamma production in patients treated with tenofovir-didanosine were comparable to those treated with a different regimen. Thus, no differences in functional innate or adaptive immune reconstitution are detected in drug-experienced human immunodeficiency virus-infected patients on tenofovir-didanosine nucleoside reverse transcription inhibitor regimens. Topics: Adenine; Adult; CD4 Lymphocyte Count; Cell Proliferation; Didanosine; Drug Therapy, Combination; Flow Cytometry; Fluorescent Antibody Technique; Follow-Up Studies; HIV Infections; HIV-1; Humans; Immunologic Memory; Immunophenotyping; Interferon-gamma; Killer Cells, Natural; Lamivudine; Logistic Models; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Statistics, Nonparametric; T-Lymphocytes; Tenofovir | 2009 |
Highly active antiretroviral HIV therapy-associated fatal lactic acidosis: quantitative and qualitative mitochondrial DNA lesions with mitochondrial dysfunction in multiple organs.
Topics: Acidosis, Lactic; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; DNA, Mitochondrial; Fatal Outcome; HIV Infections; HIV-1; Humans; Male; Middle Aged; Stavudine | 2008 |
[Evaluation of antiretroviral therapy in HIV-infected adults in the Department of Haematology, University Hospital of Brazzavllle, Congo].
A retrospective study was conducted during 32 months; from 1 May 2003 to 30 December 2005 in haematology department. The objective of the study was to assess the effectiveness of the anti retroviral therapy 157 patients receiving antiretroviral treatment for at least a twelve month-period and presenting AIDS symptoms based on revised CDC criteria were included. The average number of initial T4 lymphocytes is 133/mm3 (extremes 1 and 385) and the initial plasmatic average viral load, quantified in 96 patients is 214,000 copies (extreme 30,000 et 999,000) The initial antiretroviral combinations were as follows: ZDV or D4T + LMV + NVP (59.2%); ZDV or D4T + LMV + EFV (28.7%), ZDV or D4T + LMV + IDNV (8.9%); ZDV or D4T + DDI + NVP (3.2%). The results of the study are: observance rate during the first 12 months (84%), antiretroviral therapy taken irregularly (10.8%), early submission of therapy (5.2%), weight gain after 24 months: +18 kgs, clinical response globally positive. The immune response is characterised by an average increase of 353/mm3 of CD4 after 24 months. Among 96 patients tested, the plasmatic viral load was undetectable in 71% of cases after a 12 month-follow up. Mild adverse drug effects have been noticed, represented by cutaneous and nervous toxicity anaemia and digestive disorders due to indinavir These therapeutic results confirm the importance of the antiretroviral therapy in the improvement of the quality of life of HIV/AIDS patients but a concern remains on the possible drug resistance still not documented. Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Congo; Cyclopropanes; Didanosine; Drug Evaluation; Drug Therapy, Combination; Female; Hematology; HIV Infections; Hospital Departments; Hospitals, University; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Retrospective Studies; Stavudine; Treatment Outcome; Viral Load; Zidovudine | 2008 |
Initiatives for developing and comparing genotype interpretation systems: external validation of existing systems for didanosine against virological response.
This study was performed to investigate the concordance between commonly used human immunodeficiency virus type 1 (HIV-1) drug resistance interpretation systems for didanosine (ddI) and their ability to predict responses at weeks 8 and 24.. The study included drug-experienced HIV-infected patients who had viral loads >500 copies/mL and who underwent a genotypic resistance test when beginning a ddI-containing therapy. The interpretations of the level of resistance to ddI were compared for the 6 interpretation systems. Linear and logistic regression were used to assess their ability to predict responses for weeks 8 and 24, respectively.. The 1453 patients had a median viral load of 4.3 log10 copies/mL, and 31% were preexposed to ddI. Complete concordance was found for 19% of samples, partial discordance for 49%, and complete discordance for 32%. The median viral load reduction at week 8 was 1.36 log10 copies/mL, and 56% of patients had viral loads > 400 copies/mL at week 24. At week 8, all systems correctly predicted a greater viral load reduction in patients with susceptible viruses than in those with resistant viruses, but only the Stanford system was able to discriminate between patients with resistant, intermediately resistant, and susceptible viruses. No systems predicted virological response correctly at week 24.. Our results show the need for standardized methods to establish genotypic interpretation systems. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Viral Load | 2008 |
The A62V and S68G mutations in HIV-1 reverse transcriptase partially restore the replication defect associated with the K65R mutation.
The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase can be selected by abacavir, didanosine, tenofovir, and stavudine in vivo resulting in reduced susceptibility to these drugs and decreased viral replication capacity. In clinical isolates, K65R is frequently accompanied by the A62V and S68G reverse transcriptase mutations.. The role of A62V and S68G in combination with K65R was investigated using phenotypic, viral growth competition, pre-steady-state kinetic, and excision analyses.. Addition of A62V and S68G to K65R caused no significant change in human immunodeficiency virus type 1 resistance to abacavir, didanosine, tenofovir, or stavudine but partially restored the replication defect of virus containing K65R. The triple mutant K65R+A62V+S68G still showed some replication defect compared with wild-type virus. Pre-steady-state kinetic analysis demonstrated that K65R resulted in a decreased rate of incorporation (kpol) for all natural dNTPs, which were partially restored to wild-type levels by addition of A62V and S68G. When added to K65R and S68G, the A62V mutation seemed to restore adenosine triphosphate-mediated excision of tenofovir to wild-type levels.. A62V and S68G serve as partial compensatory mutations for the K65R mutation in reverse transcriptase by improving the viral replication capacity, which is likely due to increased incorporation efficiency of the natural substrates. Topics: Adenine; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Organophosphonates; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Virus Replication | 2008 |
Noncirrhotic portal hypertension in patients with human immunodeficiency virus-1 infection.
Noncirrhotic portal hypertension (NCPH) is unusual in North American patients. This study characterized patients with NCPH and human immunodeficiency virus-1 (HIV-1) infection to identify potential risk factors for this association.. Eleven consecutive patients from our urban hepatology clinic with HIV-1 infection and NCPH were the subject of this series. Case histories, including medication lists and laboratory data, were analyzed.. Age at diagnosis was 51 +/- 7 years. CD4 count was 303 +/- 185 cells/mL, and HIV viral load was <75 copies/mL in 9 patients. Didanosine was the only medication taken by all patients; 10 each had taken lamivudine and zidovudine. In the 10 patients tested, 8 had at least 1 thrombophilic abnormality; 6 were deficient in protein S, and 2 had multiple abnormalities. Nodular regenerative hyperplasia was observed in all 11 and portal venulopathy in 5 patients. All patients had esophageal varices; 3 developed variceal bleeding. Six patients had ascites; 2 required transjugular intrahepatic portal systemic shunt.. Exposure to didanosine and/or a hypercoagulable tendency might predispose patients infected with HIV-1 to vascular changes resulting in NCPH. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; HIV-1; Humans; Hypertension, Portal; Lamivudine; Male; Middle Aged; Risk Factors; Thrombophilia; Viral Load; Zidovudine | 2008 |
FDA notifications. Large study suggests heart attack risk from use of abacavir or didanosine.
Topics: Didanosine; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors; United States; United States Food and Drug Administration | 2008 |
Abacavir and increased risk of myocardial infarction.
Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Endothelium, Vascular; HIV Infections; Humans; Myocardial Infarction; Nucleotidases | 2008 |
Two-year outcomes of children on non-nucleoside reverse transcriptase inhibitor and protease inhibitor regimens in a South African pediatric antiretroviral program.
Few data exist on the efficacy of the limited regimens for children with HIV, which are available in sub-Saharan Africa.. Retrospective cohort study to evaluate the clinical and laboratory outcomes of 391 children who received protease inhibitor (PI) or non-nucleoside reverse transcription inhibitor (nNRTI)-containing highly active antiretroviral regimens (HAART) from a Cape Town clinic. Endpoints included CD4% and count, viral loads, weight-for-age Z score (WAZ), survival, drug changes, and loss to follow-up over 24 months. A generalized estimating equation population-averaged model was used to identify associations with virological suppression, and a log-rank test explored associations with survival.. Overall, this cohort achieved a sustained doubling of median CD4% from baseline, steady increase of median WAZ, and survival of 91%, despite only 49% virologic suppression at 24 months. However, when analyzed according to regimen, PI-containing regimens had better virologic suppression at all time points. There were no differences in immunologic and growth endpoints between regimens or in survival. In a multivariate model predicting virologic suppression at any duration up to 24 months and adjusting for baseline CD4%, regimen, age, baseline WAZ, duration of HAART, and year of HAART initiation, nNRTI-based regimens (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.19-0.77) and length of time on HAART were inversely associated with virologic suppression. Age (OR: 1.23 per year; 95% CI: 1.09-1.39) was positively associated with virologic suppression.. The benefits of HAART are substantial in this setting, although PI regimens achieved greater virologic suppression than nNRTIs. Further exploration of regimens and dosing of antiretrovirals for children in these settings is needed. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Cohort Studies; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lamivudine; Lopinavir; Male; Multivariate Analysis; Pyrimidinones; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; South Africa; Stavudine; Treatment Outcome; Zidovudine | 2008 |
Bullous skin eruption in an HIV patient during antiretroviral drugs therapy.
Dermo-epidermal blistering is an uncommon presentation of adverse drug reactions. Several drugs are associated to such eruptions, but review of current knowledge does not list antiretroviral drugs. A 37-year-old Caucasian HIV-positive woman presented with a 6-week history of diffuse annular blistering affecting the trunk and limbs. Lesions appeared both on erythematous and normal-appearing skin. The patient was in treatment with antiretroviral (lamivudine + didanosine + nelfinavir) for 2 years. A history of previous adverse reactions to betalactams, nonsteroidal anti-inflammatory drugs, and a nevirapine-induced hepatitis was also referred. Histopathology showed a dermo-epidermal blister; direct immunofluorescence was positive for IgG, C3c at the basement membrane zone; enzyme-linked immunosorbent assay was positive for BP180 antigen. Oral prednisone 1 mg/kg daily for 20 days led to poor improvement. Discontinuation of the antiretrovirals was followed by a rapid healing. Blisters reappeared at first re-introduction essay 1 month later. Awareness of iatrogenic dermo-epidermal blistering is necessary to suspect the diagnosis and avoid long-term immunosuppressant treatment. Complete spontaneous recovery after withdrawal of the responsible drug and relapse at rechallenge are the main criteria for the diagnosis. Factors related to the state of the HIV infection, and/or immunodeficiency may have contributed in precipitating the reaction in the present authors' case. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Eruptions; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Nelfinavir; Skin Diseases, Vesiculobullous | 2008 |
Pediatric efficacy supplement for Videx EC.
Topics: Adolescent; Anti-HIV Agents; Body Weight; Child; Child, Preschool; Delayed-Action Preparations; Didanosine; Dosage Forms; Drug Approval; Drug Labeling; HIV Infections; Humans; Infant; Infant, Newborn; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration | 2008 |
FDA notifications. Generic didanosine approved by FDA.
Topics: Didanosine; Drugs, Generic; HIV Infections; Humans; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration | 2008 |
The role of antiretroviral therapy in the incidence of pancreatitis in HIV-positive individuals in the EuroSIDA study.
This study investigated the incidence of pancreatitis and its association with antiretroviral therapy (ART), focussing on stavudine and didanosine.. EuroSIDA has collected information on pancreatitis since Summer 2001. All identified cases have been verified by the coordinating centre. Individuals were followed from June 2001 or the date of entry into EuroSIDA (whichever occurred later) until a diagnosis of pancreatitis or the last study visit. Factors associated with pancreatitis were investigated using Poisson regression. Cumulative lengths of exposure to didanosine without stavudine, stavudine without didanosine, stavudine with didanosine, and other ART were time-updated variables. Treatment variables were fitted with a 6-month time lag.. There were 43 (nine presumptive) pancreatic events in 9678 individuals during 33 742 person-years (incidence 1.27/1000 person-years). The incidence among those with no, 2 or less and over 2 years' exposure to ART including stavudine and didanosine was 1.24, 1.73 and 0.78/1000 person-years, respectively. In multivariable analysis, higher baseline CD4 cell counts were associated with a decreased risk of pancreatitis. There was no evidence of an association of pancreatitis with cumulative exposure to didanosine and stavudine, didanosine without stavudine, stavudine without didanosine, or other ART.. We observed a low overall rate of pancreatitis in the years 2001-2006, and did not find an association of an increased incidence of pancreatitis with cumulative exposure to antiretroviral agents generally, and to didanosine and stavudine in particular. Topics: Adult; Anti-Retroviral Agents; Argentina; Case-Control Studies; CD4-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Europe; Female; HIV; HIV Infections; Humans; Incidence; Israel; Lymphopenia; Male; Middle Aged; Pancreatitis; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine | 2008 |
Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.
Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients.. We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals.. Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir).. There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation. Topics: Adult; Aged; Aged, 80 and over; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Poisson Distribution; Reverse Transcriptase Inhibitors; Risk Factors | 2008 |
Changing patterns in HIV reverse transcriptase resistance mutations after availability of tenofovir.
Assessment of 1177 human immunodeficiency virus (HIV) resistance genotypes at an HIV/AIDS clinic showed a decrease in the incidence of the K65R mutation, from 15.2% of isolates during the period 2002-2004 to 2.7% of isolates during the period 2005-2006 (P < .001), despite elevated and stable rates of tenofovir use. A reduction in the rate of coadministration of didanosine (from 41.6% of patients in 2004 to 0.8% of patients in 2006; P < .001) largely explained this observation. Topics: Adenine; Anti-HIV Agents; Didanosine; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Tenofovir | 2008 |
Heart attack risk with abacavir and didanosine.
Topics: Anti-HIV Agents; Australia; Didanosine; Dideoxynucleosides; Europe; Heart Diseases; HIV Infections; HIV-1; Humans; Myocardial Infarction; North America; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors | 2008 |
Partial immunological and mitochondrial recovery after reducing didanosine doses in patients on didanosine and tenofovir-based regimens.
Tenofovir disoproxil fumarate (TDF) has a safe toxicity profile; however, administration together with didanosine (ddl) increases ddl levels causing mitochondrial damage and CD4+ T-cell decline. We assessed whether a simple reduction of the ddl dose in patients receiving ddl (400 mg/day) and TDF could revert this side effect.. Immunological and mitochondrial changes were analysed in 20 patients at baseline, after 14 months of receiving ddl (400 mg/day), TDF (300 mg/day) and nevirapine (NVP; 400 mg/day) and 14 months after a ddl dose reduction to 250 mg/day. Immunological analyses measured CD4+ and CD8+ T-cell counts and mitochondrial studies in peripheral blood mononuclear cells assessed mitochondrial DNA content by quantitative real-time PCR, cytochrome c oxidase (COX) activity by spectrophotometry and mitochondrial protein synthesis (COX-II versus beta-actin or COX-IV expression) by western blot.. Treatment with TDF, ddl (400 mg/day) and NVP for 14 months produced significant decreases in mitochondrial parameters and CD4+ T-cell counts. The reduction in ddl dose resulted in mitochondrial DNA recovery; however, the remaining mitochondrial parameters remained significantly decreased. Levels of CD4+ T-cells were partially restored in 35% of patients. Subjects presenting a significant reduction in CD4+ T-cells during the high ddl dose period showed greater mitochondrial impairment in this stage and better mitochondrial and immunological recovery after drug reduction.. Administration of high ddl doses together with TDF was associated with mitochondrial damage, which may explain the observed CD4+ T-cell decay. A reduction of the ddl dose led to mitochondrial DNA recovery, but was not sufficient to recover baseline CD4+ T-cell counts. Other mitochondrial toxicity in addition to DNA gamma-polymerase inhibition could be responsible for CD4+ T-cell toxicity. Topics: Adenine; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; Humans; Male; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir | 2008 |
Once-daily highly active antiretroviral therapy for HIV-infected children: safety and efficacy of an efavirenz-containing regimen.
To improve adherence and virologic suppression, we assessed the feasibility and effectiveness of a once-daily regimen of efavirenz with 3 nucleoside reverse transcriptase inhibitors as first-line or second-line highly active antiretroviral therapy in a cohort of HIV-1-infected children.. HIV-1-infected children naive to efavirenz were treated with a combination of efavirenz, abacavir, didanosine, and lamivudine in an observational, prospective, single-center study. Virologic failure-free survival was assessed with Kaplan-Meier analysis. The CD4+ T-cell increase was estimated by using a generalized linear model incorporating repeated measurements.. Thirty-six children received the study medication for a median of 69 weeks. Virologic failure-free survival rates were 76% and 67% after 48 weeks and 96 weeks, respectively. No significant difference was found in efficacy between first-line and second-line highly active antiretroviral therapy. All children receiving highly active antiretroviral therapy showed a sustained CD4+ T-cell increase, irrespective of virologic suppression. Growth rates improved with highly active antiretroviral therapy. Study medication administration was stopped for 14 children, mostly because of nonadherence (4 cases) or virologic rebound (5 cases) and because of adverse events (unrelated death and grade 2 liver toxicity) in 2 cases. Lipid abnormalities and abacavir-related hypersensitivity were not observed.. For the first time, once-daily highly active antiretroviral therapy is demonstrated to be a safe, convenient, and potent antiretroviral regimen for HIV-1-infected children. Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child Development; Child, Preschool; Cholesterol; Cohort Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Oxazines; Patient Compliance; Prospective Studies; Treatment Outcome | 2007 |
CD4+ cell count decline despite HIV suppression: a probable didanosine-valganciclovir interaction.
To describe a case of significant CD4+ cell decline despite complete viral suppression in an HIV-positive patient receiving didanosine and valganciclovir.. A 68-year-old woman diagnosed with HIV and cytomegalovirus (CMV) enteritis (CD4+ cell count 22 cells/mm(3), viral load 88,898 [4.95 log] copies/mL) was treated with valganciclovir and began lamivudine, didanosine, and lopinavir/ritonavir. Three months later, her viral load was less than 50 copies/mL and CD4+ cell count was 317 cells/mm(3). Over the next 9 months, her viral load remained suppressed, but the CD4+ cell count declined to 83 cells/mm(3) and she experienced ongoing symptoms of didanosine toxicity. Didanosine was replaced with abacavir, leading to a complete CD4+ cell recovery and resolution of symptoms.. Paradoxical declines in CD4+ cell counts have been reported in HIV-infected patients virally suppressed on tenofovir/didanosine regimens, presumably via inhibition of purine nucleoside phosphorylase (PNP) by tenofovir and enhancement of didanosine toxicity. Ganciclovir and its prodrug valganciclovir also inhibit PNP and increase didanosine concentrations; thus, a similar immunological effect with this combination is possible. This hypothesis is consistent with observations from a historic multicenter CMV retinitis study, where a negative CD4+ cell response was observed in patients receiving ganciclovir, while those treated with foscarnet experienced a CD4+ cell increase and a mortality advantage. Of the subjects who received any type of nucleoside therapy during this study, didanosine use was proportionally higher in the ganciclovir arm versus the foscarnet arm. According to the Naranjo probability scale, our patient experienced a probable adverse reaction associated with the combination of didanosine and valganciclovir.. Patients receiving didanosine-containing highly active antiretroviral therapy and ganciclovir or valganciclovir for treatment of CMV infection should be monitored for didanosine toxicity and unexpected CD4+ cell loss or failure of CD4+ cell recovery. Reduction of didanosine dosage or substitution with an alternative antiretroviral may be necessary. Topics: Aged; Antiviral Agents; CD4 Lymphocyte Count; Cytomegalovirus Infections; Didanosine; Drug Interactions; Female; Ganciclovir; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Valganciclovir | 2007 |
[Sustained spontaneous remission of chronic hepatitis C coinfection in HIV].
Topics: Adult; Anti-HIV Agents; Didanosine; Female; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Remission, Spontaneous; Viremia; Zidovudine | 2007 |
CD4+ T cell evolution and predictors of its trend before and after tenofovir/didanosine backbone in the presence of sustained undetectable HIV plasma viral load.
Tenofovir with full-dose didanosine has been associated with paradoxical CD4 + T cell decrease despite virological suppression. We investigated whether tenofovir plus didanosine at a weight-adjusted dosage could be responsible for such an effect, and factors associated with CD4 + T cell count evolution under this combination.. This was a prospective observational multicohort study (Italian MASTER and Spanish Hospital Carlos III HIV cohorts). Patients with HIV plasma viral load suppression for >/= 6 months who switched to an antiretroviral combination including tenofovir plus didanosine were studied, as long as virological success was maintained. CD4 + T cell count variations over time (slopes) were compared before and after switching to tenofovir plus didanosine using linear mixed models and segmented regression analysis.. Annual time-weighted CD4 + T cell count slope did not change significantly after the prescription of tenofovir plus didanosine: it was 14 cells/mm(3) [95% confidence interval (CI) - 7 to 35] from month - 24 to month - 12, 12 cells/mm(3) (95% CI - 14 to 38) from month - 12 to the time of switching, 30 cells/mm(3) (95% CI 5-55) from switching to month + 12 and 15 cells/mm(3) (95% CI - 8 to 39) from month + 12 to month + 24 after switching to tenofovir plus didanosine. No significant change in the slope of the segment after the switch to tenofovir plus didanosine-containing regimens when compared with the segment preceding the intervention was found (CD4 + T cell count slope change: 24 cells/mm(3); 95% CI - 10 to 58). Similar results were obtained using CD4 + T cell percentage over total lymphocytes. The significant independent predictors of lower CD4 + T cell count slope were older age (P = 0.006), lower nadir CD4 + T cell count (P < 0.001) and positive hepatitis C virus antibody (P = 0.03). Moreover, reduced estimated creatinine clearance was an additional independent predictor of lower CD4 + T cell count slope (P = 0.02), but only after excluding nadir CD4 + T cell count.. Tenofovir plus didanosine (weight-adjusted dosage) was not associated with paradoxical CD4 + T cell decrease in our patients maintaining undetectable HIV plasma viral load for a maximum of 24 months after switching. Several factors could explain variability in CD4 + T cell count evolution in these patients. Topics: Adenine; Adult; Aging; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Italy; Male; Middle Aged; Organophosphonates; Risk Factors; Sex Characteristics; Tenofovir; Treatment Outcome; Viral Load | 2007 |
Possible allergic cross-reaction to didanosine and tenofovir in an HIV-1-infected woman.
Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Hypersensitivity; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Organophosphonates; Tenofovir | 2007 |
Association of serum lipid levels with HIV serostatus, specific antiretroviral agents, and treatment regimens.
The effects of HIV infection, highly active antiretroviral therapy (HAART), and specific antiretroviral agents on lipoproteins in women are not well described.. In a cross-sectional substudy of the Women's Interagency HIV Study with 623 HIV-negative and 1556 HIV-positive women (636 untreated, 419 on non-protease inhibitor [PI] HAART, and 501 on PI-containing HAART), we performed multivariate analyses of associations among fasting lipoprotein levels, HIV infection, and HAART.. Untreated HIV-positive women had lower high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TGs) but not lower low-density lipoprotein cholesterol (LDL-C) than HIV-negative women and were the most likely to have unfavorable HDL-C by National Cholesterol Education Program (NCEP) guidelines. PI HAART users had higher LDL-C than untreated HIV-infected women (107 vs. 100 mg/dL, P = 0.0006) and were the most likely to have unfavorable LDL-C and TGs by NCEP guidelines. HIV-negative women and non-PI HAART users had similar HDL-C levels (55 and 53 mg/dL, respectively), which were higher than those in untreated HIV-infected women and PI HAART users (42 and 49 mg/dL, respectively; P < 0.001 for all). Lamivudine, didanosine, nevirapine, and efavirenz were independently associated with higher HDL-C (P < 0.001 for all). Ritonavir, indinavir/ritonavir, and nelfinavir were associated with higher LDL-C (P < 0.01 for all). Stavudine, abacavir, and all ritonavir-containing regimens were associated with higher TGs (P < 0.05 for all), and tenofovir was associated with lower TGs (P = 0.009).. A dyslipidemic pattern was associated with HIV infection itself, was more severe in users of PI-containing HAART, but was not present in women taking non-PI HAART. Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Black People; Cholesterol; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Fasting; Female; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV Seropositivity; HIV-1; Humans; Indinavir; Lamivudine; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Multivariate Analysis; Nelfinavir; Nevirapine; Organophosphonates; Ritonavir; Stavudine; Tenofovir; Triglycerides; United States; White People | 2007 |
Virologic characterization of HIV type 1 with a codon 70 deletion in reverse transcriptase.
We identified a deletion at codon 70 (Delta70) of HIV-1 reverse transcriptase (RT) occurring together with L74V and Q151M mutations in a sample from a tenofovir (TFV)- and abacavir (ABC)-treated patient with extensive prior antiretroviral treatment. To investigate the characteristics of this mutant, we studied the drug susceptibility, relative infectivity, and fitness of viruses carrying Delta70 and associated RT mutations. The Delta70, L74V, and Q151M mutations were introduced into Hxb2 RT by site-directed mutagenesis and expressed in HIV-1 recombinants. The Delta70 mutation increased resistance to lamivudine and emtricitabine alone and in combination with various resistance mutations and augmented resistance to ABC and didanosine when present together with L74V. A recombinant virus expressing RT from the original clinical viral sample (Delta70-PRT) exhibited greater fitness than one in which the deletion had been repaired (K70-PRT). The Delta70 mutation also increased fitness of Hxb2 wild-type and 74V and Q151M mutants. Recombinants carrying Delta70-PRT showed greater relative infectivity in the presence of ABC (but not TFV) compared with K70-PRT recombinants. These results show that Delta70 enhances resistance to certain purine and pyrimidine analogues and contributes to multinucleoside resistance in the appropriate viral genetic background. Topics: Adenine; Antiviral Agents; Cell Line, Transformed; Codon; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Emtricitabine; HeLa Cells; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Organophosphonates; Point Mutation; Reassortant Viruses; Reverse Transcriptase Inhibitors; Tenofovir | 2007 |
Amprenavir and didanosine are associated with declining kidney function among patients receiving tenofovir.
To examine the effect of antiretroviral agents and clinical factors on the development of tenofovir-associated kidney dysfunction.. Observational cohort study of HIV-infected patients receiving tenofovir in an HIV clinic population. Patients' kidney function prior to initiating and while receiving tenofovir was evaluated in relation to other antiretroviral medications and demographic and clinical characteristics. Decline in kidney function was assessed by the glomerular filtration rate (GFR) as estimated by the Cockcroft-Gault (CG) equation, which incorporates weight. Logistic regression analysis was used to examine factors associated with GFR of > 90, 60-90, 30-60, and < 30 ml/min per 1.73 m(2) while on tenofovir. Secondary analyses used the simplified Modification of Diet in Renal Disease (MDRD) equation.. Among the 445 patients initiating tenofovir, 51 (11%) developed a decline in kidney function. In multivariate analysis, there was a significant association between decline in kidney function and concurrent use of amprenavir [odds ratio (OR) 3.6; P = 0.045] and didanosine (OR, 3.1; P = 0.006), age over 50 years (OR, 4.4; P = 0.03), and lower baseline weight (OR, 0.95/kg; P < 0.001). Patients identified with kidney dysfunction by the MDRD equation did not fully overlap with those identified by the CG equation.. Didanosine and amprenavir use, increased age, and lower baseline weight were significantly associated with risk for kidney dysfunction among patients receiving tenofovir. GFR results using the MDRD equation were inconsistent with those using CG, which highlights the impact of including weight in the estimation of GFR among HIV-infected patients. Topics: Adenine; Adult; Age Factors; Analysis of Variance; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Weight; Carbamates; Creatinine; Didanosine; Drug Interactions; Female; Furans; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Kidney; Linear Models; Male; Middle Aged; Organophosphonates; Sulfonamides; Tenofovir; Time Factors | 2007 |
Response to Mallet et al., 'Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients'.
Topics: Adult; Anti-Retroviral Agents; Didanosine; Esophageal and Gastric Varices; HIV Infections; HIV-1; Humans; Hyperplasia; Hypertension, Portal; Liver; Liver Diseases; Liver Regeneration; Middle Aged | 2007 |
Nodular regenerative hyperplasia: a new serious antiretroviral drugs side effect?
Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Didanosine; Female; HIV Infections; HIV-1; Humans; Hyperplasia; Liver; Liver Diseases; Liver Regeneration; Middle Aged; Nevirapine; Zidovudine | 2007 |
FDA notifications. FDA grants approval for generic didanosine for oral solution.
Topics: Administration, Oral; Didanosine; Dideoxynucleosides; Drugs, Generic; HIV Infections; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration | 2007 |
Adverse events experienced by three children taking tenofovir and didanosine in combination.
Topics: Adenine; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Male; Organophosphonates; Tenofovir; Viral Load | 2007 |
The reverse transcriptase 67N 70R 215Y genotype is the predominant TAM pathway associated with virologic failure among HIV type 1C-infected adults treated with ZDV/ddI-containing HAART in southern Africa.
HIV-1C has become the dominant HIV-1 subtype in the global AIDS epidemic. Historically, the evolution of drug-resistant mutations was characterized primarily among antiretroviral (ARV)-treated HIV-1B infections. Whereas the non-B viruses are susceptible to the currently used ARVs, some differences between HIV-1 subtypes in response to ARV regimens have been reported. We analyzed the profile of ARV-associated mutations in HIV-1C infection treated with ZDV/ddI-containing regimens in an open-label, randomized 3 x 2 x 2 factorial study comparing ZDV/3TC vs. ZDV/ddI vs. d4T/3TC and EFV vs. NVP regimens in drug-naive adults in Botswana. The overall rate of virologic failure in the ZDV/ddI-containing arms was 14%. We addressed the development of NRTI-associated mutations in 23 virologically failed patients in the ZDV/ddI-containing arms. The 67N 70R 215Y genotype with wild-type amino acids at codon positions 41 and 210 was a dominant pattern of NRTI-associated mutations at the time of virologic failure. The mutation T215Y was the first step in the evolution of the 67N 70R 215Y genotype and was followed by mutations K70R and D67N. Representing a mixture of TAM-1 (41L/210W/215Y) and TAM-2 (67N/70R/215F /219Q) pathways, the 67N 70R 215Y genotype with wild-type amino acids at codon positions 41, 210, and 219 is a unique TAM pathway that is rarely seen in HIV-1B infection. Although limited by relatively small numbers, our data suggest that the 67N 70R 215Y genotype may be the HIV-1C-specific response to the first-line ZDV/ddI-containing regimen at the time of virologic failure. The presence of the 67N 70R 215Y genotype with wild-type amino acids at codon positions 41, 210, and 219 in HIV-1C infection suggests that the evolution of ARV-associated mutations and TAM pathways might be unique in non-B HIV-1 subtypes treated with particular ARV regimens. Topics: Africa, Southern; Antiretroviral Therapy, Highly Active; Didanosine; Drug Resistance, Multiple, Viral; Evolution, Molecular; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Molecular Sequence Data; Mutation; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Thymidine; Treatment Failure; Zidovudine | 2007 |
Nucleoside reverse-transcriptase inhibitor dosing errors in an outpatient HIV clinic in the electronic medical record era.
Information on antiretroviral dosing errors among health care providers for outpatient human immunodeficiency virus (HIV)-infected patients is lacking. We evaluated factors associated with nucleoside reverse-transcriptase inhibitor dosing errors in a university-based HIV clinic using an electronic medical record. Overall, older age, minority race or ethnicity, and didanosine use were related to such errors. Impaired renal function was more common in older patients and racial or ethnic minorities and, in conjunction with fixed-dose combination drugs, contributed to the higher rates of errors in nucleoside reverse-transcriptase inhibitor dosing. Understanding the factors related to nucleoside reverse-transcriptase inhibitor dosing errors is an important step in the building of preventive tools. Topics: Adult; Age Factors; Cohort Studies; Didanosine; Drug Combinations; Drug Prescriptions; Ethnicity; Female; HIV Infections; Hospitals, University; Humans; Internship and Residency; Kidney Failure, Chronic; Male; Medical Audit; Medical Records Systems, Computerized; Medication Errors; Nurse Practitioners; Outpatient Clinics, Hospital; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors | 2007 |
Semen quality and drug concentrations in seminal plasma of patients using a didanosine or didanosine plus tenofovir containing antiretroviral regimen.
Data on the concentrations of didanosine (ddI) and tenofovir (TFV) in seminal plasma are sparse. Subtherapeutic drug concentrations within the lumen of the male genital tract may have implications for selection and transmission of drug-resistant HIV strains. On the other hand, sufficient penetration of these drugs into the male genital tract has potential toxic effects on the spermatozoa and their precursors. In the current study, the authors obtained paired semen and blood samples at variable time points after drug intake from 30 HIV-1-infected patients using a ddI (n = 15) or ddI + TFV (n = 15) containing an antiretroviral regimen. Didanosine and TFV concentrations were measured in seminal and blood plasma and semen quality was assessed. Both ddI and TFV penetrated well into seminal plasma. Whereas blood plasma ddI concentrations dropped to near or below the lower limit of quantification of 0.017 microg/mL 9 hours after drug intake, the ddI concentration in seminal plasma remained detectable during the whole dosing interval with a median of 0.20 and 0.21 microg/mL in the ddI and ddI + TFV groups, respectively. Tenofovir was detectable during the whole dosing interval in both blood and seminal plasma with a median concentration of 0.12 and 0.25 microg/mL, respectively, and a median seminal-to-blood-plasma ratio of 3.3. Semen quality was within the normal range according to the criteria of the World Health Organization, except for the percentage of progressively motile sperm, which was low in both groups of patients. The authors conclude that ddI and TFV penetrate well into seminal plasma and that the reduced sperm motility deserves further study. Topics: Adenine; Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Semen; Sperm Motility; Spermatozoa; Tenofovir | 2007 |
Presence of M184I/V in minor HIV-1 populations of patients with lamivudine and/or didanosine treatment failure.
The aim of the study was to investigate the presence of M184I/V in minor HIV-1 populations of patients who failed lamivudine (3TC) and/or didanosine (ddI) treatment.. Fourteen 3TC-experienced patients who, after switching therapy to a ddI regimen, had a new failure without M184I/V in the major viral population were included in the study. Ninety plasma samples were analysed by direct sequencing and selective real-time polymerase chain reaction (SPCR), which detects GTG/GTA and ATA mutants down to 1 and 0.2% of the population, respectively.. In five samples, SPCR detected resistant virus when direct sequencing detected wild-type M184. In patients with mixed viral populations at sequencing, the median proportion of mutants detected by SPCR was 30%. SPCRGTG reactivity dominated, while SPCRATA reactivity only was uncommon. M184I/V disappeared in patients in whom 3TC was stopped but ddI continued. Ten patients with ddI failure had no M184I/V.. Minor HIV-1 strains may harbour M184I/V in patients failing ddI therapy, despite direct sequencing showing wild-type virus. Although M184I/V may reduce the genetic barrier of ddI for mutations such as K65R and L74V, the lack of re-emergence of M184I/V in the minor quasispecies of most patients who failed ddI suggests that M184I/V was not a preferred route to ddI resistance in our patient population. Topics: Adult; Aged; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; RNA-Directed DNA Polymerase; Treatment Failure; Viral Load | 2007 |
Efficacy and safety of a once daily regimen with efavirenz, lamivudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study.
The combination of didanosine (ddI) and lamivudine (3TC) is attractive considering its low cost, potency, tolerability, and convenience (once daily administration), but it is not recommended as first-line therapy for HIV infection. A prospective, multicenter, open, comparative trial was conducted in HIV-infected, antiretroviral-naive persons in Spain who begun a QD regimen with efavirenz (EFV), 3TC, plus ddI, the latter with or without food. A total of 103 patients were recruited in the study. Median baseline CD4 count was 229 cells/microl and plasma HIV-RNA was 4.9 logs copies/ml. In an intent-to-treat analysis, 78 (75.8%) had undetectable viremia at week 48 of therapy, without significant differences when comparing patients on and without fasting ddI (75% vs. 76.6%, respectively). The mean CD4 increase was of 199 cells/microl, with no significant differences between groups. Overall, 29 adverse events were recorded in 23 patients, the majority associated with neuropsychiatric symptoms of EFV. Treatment was discontinued in 10 (9.7%) patients due to adverse events. Virological failure was recognized in only six patients, four taking ddI with and two without food (p = 0.3). Drug resistance mutations were recognised in four of them. Plasma ddI concentrations did not differ significantly between groups. Mitochondrial DNA within peripheral blood mononuclear cells tended to increase in most subjects over 48 weeks of therapy regardless of treatment group. A QD regimen with ddI, 3TC, and EFV shows potency and tolerance similar to that reported using other currently recommended regimens in drug-naive HIV-infected patients. Its efficacy does not seem to be compromised when ddI is administered with food. Therefore, this regimen merits further investigation in larger comparative trials. Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Administration Schedule; Female; Food; HIV; HIV Infections; Humans; Lamivudine; Male; Spain; Viral Load | 2007 |
Economic impact of antiretroviral therapy prescription decisions in the context of rapid scaling-up of access to treatment: lessons from Mexico.
Mexico started scaling-up access to antiretroviral treatment in the late 1990s. Even though the Mexican Health System enrolled patients at impressive speed, in the initial years important aspects of the quality of care were overlooked.. To describe antiretroviral prescribing and adherence practices in Mexico during initial scaling-up of antiretroviral treatment in comparison to national treatment guidelines and to estimate the associated economic cost.. Eleven public sector hospitals provided detailed patient chart data. Monthly observations formed the basis of scenarios aligned by calendar month and by month before and after initiation of triple therapy. The scenarios varied by extent of prescription refill, adherence levels, and compliance with national treatment guidelines.. Antiretroviral therapy prescription practices were largely inconsistent with published guidelines. Non-recommended combinations were prescribed to between 54 and 79% patients-months per year. Additionally, more than 50% of patients experienced four to 13 changes in treatment. Modeling of the economic impact of treatment practices showed that it would have been possible to effectively treat the same number of patients at the same or lower cost per patient.. In addition to dispensing drugs, countries scaling-up antiretroviral therapy must find ways to ensure consistent drug supply, appropriate prescription practices and effective levels of adherence. Failing to do so will seriously reduce treatment effectiveness, greatly increasing the cost per unit of health benefit. With very low levels of effective adherence patients may even be harmed and the spread of multi-drug resistant virus facilitated. Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Drug Prescriptions; Health Care Costs; Health Services Accessibility; HIV Infections; HIV Protease Inhibitors; Humans; Mexico; Oxazines; Patient Compliance; Practice Guidelines as Topic; Saquinavir; Zidovudine | 2006 |
A simplified weight-based method for pediatric drug dosing for zidovudine and didanosine in resource-limited settings.
Zidovudine and didanosine are antiretroviral drugs used for human immunodeficiency virus (HIV)-infected children with dose recommendations based on body surface area calculations. Although weight and height can both be measured, it may be impractical to expect providers in resource-limited settings to estimate accurately body surface area.. We developed an antiretroviral dosing chart based on authoritative sources for brand name drugs in weight bands (ie, 5-6.9, 7-9.9, 10-11.9, 12-14.9, 15-16.9, 17-19.9, 20-24.9, 25-29.9, 30-34.9 and 35-40 kg) to assist proper dosing of antiretrovirals for HIV-infected children in resource-limited settings. For drugs dosed by body surface area, we estimated likely weights and heights for age using standardized US growth charts for girls from which doses in weight bands were calculated. For this analysis, we calculated the difference between weight-based doses and body surface area-based doses for zidovudine 10 mg/mL oral solution, zidovudine 100-mg capsules, and didanosine 25, 50 and 100-mg chewable tablets using actual heights and weights from HIV-infected children in Africa and Romania.. We used 1752 observations from 826 HIV-infected children (48% girls) from 9 countries. A total of 454 observations were in children <20 kg and 1298 > or =20 kg. For those <20 kg, the median difference of the weight-based dose as compared with the body surface area-based dose for zidovudine solution was -6.4% (range, -22.6, +13.7), zidovudine capsules +3.1% (range, -38.8, +44.7), didanosine chewable tablets +0.7% (range, -24.4, +22.5); for those > or =20 kg for zidovudine solution was 0.0% (range, -16.4, +11.8), zidovudine capsules +7.6% (range, -16.4, +36.9) and didanosine chewable tablets +1.2% (range, -16.4, +14.1). The dose precision for children <20 versus > or =20 kg was different for zidovudine solution (P < 0.001) and zidovudine capsules (P < 0.001), but not didanosine chewable tablets. The frequency that weight-based dose was more than 20% less than the body surface area-based dose for those <20 kg was 1.3% for zidovudine solution, 27.2% for zidovudine capsules and 4.9% for didanosine chewable tablets. For those > or =20 kg, the weight-based dose was never more than 20% less than the body surface area-based dose.. Dosing zidovudine and didanosine by weight band provides reasonably precise dosing as compared with body surface area-based doses. However, use of zidovudine capsules in children <20 kg results in under dosing by >20% in many instances. Didanosine chewable tablets allow for higher dosing precision compared with zidovudine capsules because of increased flexibility in the dosage form. Solid dosage forms of antiretroviral medications designed specifically for children are urgently needed. Topics: Adolescent; Anti-HIV Agents; Body Surface Area; Body Weight; Child; Child, Preschool; Didanosine; Dosage Forms; Female; HIV Infections; Humans; Infant; Male; Zidovudine | 2006 |
Longitudinal study on mitochondrial effects of didanosine-tenofovir combination.
Tenofovir disoproxil fumarate (TDF) has been reported to be free of adverse effects on mitochondria. We evaluate the effects of the introduction of TDF in a didanosine (ddI)-based highly active antiretroviral therapy (HAART) on mitochondrial DNA (mtDNA) content, mitochondrial mass (MM), and cytochrome c oxidase (COX) activity of the oxidative phosphorylation (OXPHOS) system over a 12-month period. Forty-four asymptomatic HIV patients with undetectable viral load receiving a ddI-based HAART were recruited and switched to ddI plus TDF (ddI + TDF) and nevirapine (n = 22) or maintained with the same baseline ddIbased HAART scheme (n = 22). Peripheral blood mononuclear cells were obtained at 0, 6, and 12 months. COX activity and MM were determined by spectrophotometry and the mtDNA content by quantitative realtime PCR. The mtDNA content showed a progressive decrease over the 12-month period of the study for the two groups with respect to baseline, with such a decrease statistically significant only in the ddI + TDF group (55% decrease, p < 0.001). In addition, the decrease of mtDNA content over time was statistically different between both groups (p < 0.001). Consistently, MM and COX activity decreased significantly at 12 months with respect to baseline only in the ddI < TDF group (28% decrease for MM, p < 0.05; 47% decrease for COX activity, p < 0.001). We conclude that switching to a HAART regimen containing ddI + TDF is associated with evolutive mitochondrial damage expressed as mtDNA depletion, loss of MM, and decrease in COX efficiency. The particular relevance of either ddI, TDF, or any interaction between them in such a mitochondrial dysfunction remains to be established. Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Electron Transport Complex IV; HIV Infections; HIV-1; Humans; Longitudinal Studies; Organophosphonates; Oxidative Phosphorylation; Prospective Studies; Retrospective Studies; Tenofovir | 2006 |
An additive/subtractive genotypic score as a determinant of the virological response to didanosine in HIV-1 infected patients.
To assess the genotypic determinants of the virological response (VR) to didanosine (ddI) in nucleoside reverse transcriptase inhibitors (NRTI)-experienced patients.. Human immunodeficiency virus type 1 (HIV-1) genotype was determined at baseline in 74 ddI-naive-patients with baseline viral load >500 copies/ml and receiving ddI as part of a new regimen. VR was defined as a plasma HIV-1 RNA <50 copies/ml after three months on ddI. NRTI resistance mutations associated with higher or lower frequencies of VR with a p-value<0.25 were retained in different sets of mutations, where the mutations associated with a worse VR were added, whereas the mutations associated with a better VR were subtracted. The most significant mutation scores were then studied in a multivariate analysis.. Changes at three codons (M41L, L210W, T215Y/F/D/C/E) were associated with a worse VR and three mutations (K70R, M184V, K219Q) with a better VR. The strongest association with the VR was obtained with the score M41L+L210W+T215Y/F/D/C/E-K70R-K219Q. The score was independently associated with the VR in the multivariate analysis.. Taking into account the mutations associated with a better VR may improve genotypic resistance algorithms. Our results are of interest for the management of antiretroviral therapy in NRTI-experienced patients. Topics: Algorithms; Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Multivariate Analysis; Mutation; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load | 2006 |
Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy.
Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddl), their concurrent use was also investigated.. Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV-,n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddl, 10 of those once at unadjusted ddl dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests.. Kidney mtDNA levels were different among the three groups (P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0-12.1]) than in HIV- ones (14.3 [6.0-16.5], P=0.014), but not lower than HIV+/TDF- controls (6.4 [2.8-11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddl- and TDF+/ddl+ (P=0.005), with concurrent TDF/ddl use associated with lower mtDNA (2.1 [1.9-5.5], n=12) than TDF+/ddl- (13.8 [7.5-16.4], n=9, P=0.003). No TDF-/ddl+ biopsies were available. In regression analyses, only HIV infection (P=0.03), and TDF/ddl use (P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together (P<0.001) but not more so in TDF+/ddl+ biopsies than TDF+/ddl- ones (P=0.67).. Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddl therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddl may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddl when used in conjunction with TDF. Topics: Adenine; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biopsy; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Female; HIV Infections; Humans; Kidney; Male; Microscopy, Electron; Middle Aged; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome | 2006 |
Suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir.
The combination of nucleos(t)ide analogues (NAs) is essential for the design of effective antiretroviral regimens. Although there are currently many options for the selection of such drug backbones, not all combinations display optimal results. As the number of these compounds has increased, it has become clear that the concomitant administration of certain NAs should be avoided due to high rates of toxicity and/or greater risk of virological failure. As an example, the combination of didanosine and tenofovir has recently been associated with a paradoxical depletion of CD4+ T cells in the face of complete viral suppression. Interference between the pathways leading to the intracellular activation of didanosine and tenofovir, and their blocking of the purine nucleoside phosphorylase, seems to explain this phenomenon. Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Didanosine; Drug Interactions; HIV Infections; Humans; Mitochondria; Organophosphonates; Purine-Nucleoside Phosphorylase; Tenofovir | 2006 |
Didanosine-induced retinopathy in adults can be reversible.
Topics: Anti-HIV Agents; Didanosine; Electroretinography; HIV Infections; Humans; Male; Middle Aged; Retinal Diseases | 2006 |
Virological response to HIV-1 nucleoside/nucleotide reverse transcriptase inhibitors-based, tenofovir DF-including regimens in the ANRS Aquitaine Cohort.
HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTI)-only based, comprising tenofovir DF(TDF) have been shown to lead to high rates of virological failures (VF), mainly in patients on first-line combination therapy. We wished to investigate the virological response to these regimens in a large cohort of antiretroviral (ARV)-treated patients.. Patients followed-up in the Aquitaine Cohort in 2001-2003 and who had received NRTI-based, TDF-including regimens for at least 3 months were included. The VF was defined as: (i) a decrease in plasma HIV-1 RNA <0.5 log(10)copies/ml between M0 and M3; or (ii) a plasma HIV-1 RNA >50 copies/ml at M3 in patients with plasma HIV-1 RNA <50 copies/ml at M0. The baseline RT genotype was determined in a subgroup of patients.. Within 121 patients (95% ARV-experienced) who received either lamivudine (3TC)/didanosine (DDI)/TDF (n=48), or abacavir (ABC)/3TC/TDF (n=14), or 3TC/zidovudine (ZDV)/TDF (n=27), or 3TC/ZDV/ABC/TDF (n=20), or DDI/ABC/TDF (n=12), the ABC/3TC/TDF and DDI/ABC/TDF combinations were associated with the highest frequencies of VF. In contrast the use of ZDV was related to a better virological response. The baseline RT genotype was also predictive of the virological outcome.. NRTI-based, TDF-including therapies can lead to high rates of VF both in ARV-naïve and in ARV-experienced patients. Our data strongly suggest the interest of associating ZDV and TDF in these regimens. Topics: Adenine; Cohort Studies; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; France; HIV Infections; HIV Reverse Transcriptase; HIV-1; Hospitals, University; Humans; Lamivudine; Mutation; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Species Specificity; Tenofovir; Treatment Outcome; Viral Load; Zidovudine | 2006 |
Penetration of didanosine in semen of HIV-1-infected men.
The disposition of antiretroviral agents into genital tissue and fluids is one of the factors implicated in the control of viral replication within the male genital tract and should be an objective of highly active antiretroviral therapy. We have investigated didanosine penetration in seminal plasma of 16 HIV-infected patients.. A total of 16 patients on didanosine (200 mg every 12 h or 400 mg once daily) participated in the pharmacokinetic study. After the didanosine morning dose, peripheral blood plasma and semen plasma were collected within the intervals 0-4, 4-8 and 8-12 h in the twice-daily regimen and 0-4, 4-12 and 12-24 h in the once-daily regimen.. Within each sampling time interval didanosine concentrations in seminal plasma were higher than in blood. The interquartile range of concentrations in seminal plasma was 292-1217 ng/mL, compared with 50-150 ng/mL in blood plasma. Didanosine could be detected in 14 of the 16 semen samples analysed and in 8 of the 16 blood samples.. We have demonstrated that didanosine penetrates into the seminal plasma in higher concentrations than in blood plasma. Topics: Adult; Anti-HIV Agents; Didanosine; HIV Infections; HIV-1; Humans; Male; Middle Aged; Semen | 2006 |
Real-time nucleic acid sequence-based amplification assay to quantify changes in mitochondrial DNA concentrations in cell cultures and blood cells from HIV-infected patients receiving antiviral therapy.
To study the clinical relevance of changes in mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells (PBMCs) attributable to HIV infection and/or combination antiretroviral therapy (cART), a high-throughput molecular assay to quantify mtDNA is required.. We developed a quantitative real-time duplex nucleic acid sequence-based amplification assay in which both mtDNA and nuclear DNA are simultaneously amplified in 1 tube. The assay could accurately quantify mtDNA in a range of 15-1500 copies of mtDNA per 2 genomic copies with an intrarun variation of 11% and an interrun variation of 16%. We compared this real-time assay with the lactate/pyruvate ratios in fibroblasts incubated with glucose and exposed to zalcitabine. Additionally, we studied the effects of platelet contamination and the in vivo effects of cART on mtDNA in PBMCs from a small group of patients.. Decreases in mtDNA preceded the increase in lactate/pyruvate ratios and vice versa when zalcitabine was eliminated from the culture. Platelets affected the mtDNA in PBMCs if >5 platelets per PBMC were present. Within 12 weeks, mtDNA increased and remained increased in PBMCs from patients on continuous treatment with zidovudine/lamivudine/indinavir therapy (P = 0.03), but increased if patients were switched to stavudine/didanosine therapy (P = 0.008).. After drug exposure, the mtDNA assay can detect changes in mtDNA concentrations in cell lines and PBMCs, when properly controlled for platelet effects, earlier than traditional assays. Topics: Anti-HIV Agents; Base Sequence; Blood Platelets; Cell Nucleus; Cells, Cultured; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Feasibility Studies; Fibroblasts; HIV Infections; Humans; Indinavir; Lactic Acid; Lamivudine; Leukocytes, Mononuclear; Nucleic Acid Amplification Techniques; Pyruvic Acid; Stavudine; Zalcitabine | 2006 |
Short-term safety and tolerability of didanosine combined with high- versus low-dose tenofovir disproxil fumarate in ambulatory HIV-1-infected persons.
Coadministration of didanosine (ddI) and tenofovir (TDF) results in increased ddI serum concentrations, which may lead to increased risk of ddI-associated toxicities. To evaluate the safety and tolerability of ddI/TDF, we performed a retrospective cohort analysis of patients seen in the HIV Outpatient Study, an ongoing dynamic cohort study of HIV-infected persons in clinical care. Study subjects were those who received at least 14 days of combined ddI/TDF before October 2003. Of 260 subjects who received ddI/TDF-based antiretroviral therapy, 155 (60%) received high-dose ddI (400 mg daily dose) and 105 (40%) received low-dose ddI (100-250 mg daily). Forty-two of the high-dose ddI recipients were later switched to low-dose ddI. The median time of observation for those on high-dose ddI only was 5 months, high-dose ddI switched to low-dose ddI was 16 months, and low-dose ddI only was 5 months (p < 0.05). Discontinuations because of toxicity were more frequent on high-dose ddI regimens (34/155, 22%) than on low-dose ddI regimens (9/105, 9%) (unadjusted odds ratio [OR(unadj)] 3.0, 95% confidence interval [95% CI] 1.30-7.09; p = 0.007). Among subjects without preexisting peripheral neuropathy, 12 (12%) of 101 subjects ever on high-dose ddI regimens had treatment-emergent peripheral neuropathy compared to 2 (4%) of 55 subjects on low-dose ddI regimens (OR(unadj) 3.57; 95% CI, 0.72-24.1; p = 0.14). Among patients without a history of pancreatitis, 6 (4%) of 153 subjects developed pancreatitis after starting high-dose ddI regimens, compared to none of the 103 subjects on low-dose ddI regimens (OR(adj) and 95% CIs undefined; p = 0.08). Severe laboratory abnormalities of creatinine, phosphorous, and bicarbonate were not different between the groups. A summary variable for any event--discontinuation for toxicity, treatment- emergent adverse event or abnormal laboratory values--indicated that 44 (28%) of 155 of those on high-dose ddI versus 13 (12%) of 105 on low-dose ddI developed any event (OR(unadj) 2.81; 95% CI, 1.36-5.86; p = 0.004). In conclusion, high-dose ddI/TDF-based therapy was more frequently associated with drug-related toxicity, adverse events, and treatment discontinuation than low-dose ddI/TDF regimens; low-dose ddI with TDF was generally well tolerated in these HIV-infected persons. Topics: Adenine; Adult; Anti-HIV Agents; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Organophosphonates; Retrospective Studies; Tenofovir | 2006 |
Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir.
The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination. Topics: Adenine; Adult; Anti-HIV Agents; Blood Glucose; Didanosine; Drug Therapy, Combination; Fasting; Female; Follow-Up Studies; HIV Infections; Humans; Hyperglycemia; Linear Models; Male; Organophosphonates; Retrospective Studies; Risk Factors; RNA, Viral; Tenofovir; Time Factors; Treatment Outcome; Virus Replication | 2006 |
Severe liver disease associated with prolonged exposure to antiretroviral drugs.
Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals.. Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status.. CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population.. CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Ascites; Budd-Chiari Syndrome; Case-Control Studies; Didanosine; Female; Hemorrhage; HIV Infections; Humans; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Nevirapine; Spain; Stavudine; Time Factors; Transaminases | 2006 |
Comment on: suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir.
Topics: Adenine; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; HIV Infections; Humans; Organophosphonates; Purine-Nucleoside Phosphorylase; Tenofovir | 2006 |
Virologic and immunologic efficacy of the tenofovir/didanosine/lamivudine regimen.
Topics: Adenine; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir | 2006 |
Nephrotoxicity in a child with perinatal HIV on tenofovir, didanosine and lopinavir/ritonavir.
Tenofovir-related tubule damage characterized by Fanconi syndrome, renal insufficiency and nephrogenic diabetes insipidus has been reported in the adult HIV-infected population. To our knowledge there has been no reported case of such complications in the pediatric population. We report the case of a 12-year-old perinatally HIV-infected African-American girl who developed nephrogenic diabetes insipidus, renal insufficiency and Fanconi-like syndrome while taking tenofovir (Viread) in combination with lopinavir-ritonavir (Kaletra) and didanosine (Videx). Topics: Adenine; Anti-HIV Agents; Child; Diabetes Insipidus, Nephrogenic; Didanosine; Drug Therapy, Combination; Fanconi Syndrome; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Kidney; Kidney Diseases; Lopinavir; Organophosphonates; Pregnancy; Pregnancy Complications; Pyrimidinones; Ritonavir; Tenofovir | 2006 |
Distal sensory polyneuropathy in HIV-positive patients in the HAART era: an entity underestimated by clinical examination.
The aim of this study was to determine the prevalence of distal sensory polyneuropathy (DSP) in our HIV-positive patients under highly active antiretroviral therapy (HAART) and to investigate correlations with clinical, laboratory and demographic factors. One hundred consecutive HIV-positive patients underwent clinical and electrophysiological evaluation for DSP. Correlations with HIV stage, CD4 count, nadir CD4 count, viral load (VL), disease duration, age, sex and type of antiretrovirals were examined. Thirty-six percent of the patients had DSP (13% clinical, 23% subclinical diagnosed by electrophysiology). The prevalence of DSP was affected in a statistically significant manner by the diagnosis of AIDS (P = 0.00033), age (P = 0.0102), nadir CD4 count (P = 0.0087) and exposure to two neurotoxic antiretrovirals (P = 0.0189). Advanced HIV stage, sex, time from diagnosis, current CD4 count and VL did not seem to affect the prevalence of DSP. Clinical examination plus electrophysiology reveals that DSP affects 36% of patients under HAART, although subclinical in 2/3 of cases. Age, severe prior immunosuppression and the combined use of zalcitabine (ddC), stavudine (d4T) and didanosine (ddI) are important risk factors. Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Electrophysiology; Female; HIV Infections; Humans; Male; Middle Aged; Polyneuropathies; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Zalcitabine | 2006 |
Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C.
HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that alpha-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using alpha-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of alpha-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, alpha-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Calpha (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis. Topics: alpha-Tocopherol; Animals; Antioxidants; Atherosclerosis; CD36 Antigens; Cholesterol; Didanosine; Enzyme Activation; HIV Infections; HIV Protease Inhibitors; Humans; Macrophages; Mice; Mice, Knockout; Protein Kinase C-alpha; Receptors, LDL; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Ubiquitin | 2006 |
Hypokalemia in HIV patients on tenofovir.
Although adverse events in HIV patients taking tenofovir are relatively rare, postmarketing reports of nephrotoxicity have alerted physicians to other potentially serious outcomes. We present a series of 40 patients who developed hypokalemia associated with tenofovir. Identified risk factors included concomitant ritonavir or didanosine use, a lower weight and longer duration of tenofovir use. Recovery or improvement was seen in the majority of patients (66%) after the discontinuation of tenofovir; however, four deaths occurred. The associated consequences of tenofovir-related hypokalemia may be profound and life-threatening. Topics: Adenine; Adolescent; Adult; Body Weight; Child; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypokalemia; Kidney Diseases; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Tenofovir; Time Factors | 2006 |
Immunological and virological effects of structured treatment interruptions following exposure to hydroxyurea plus didanosine.
Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8+ responses to different HIV peptide pools and 23% of them had CD4+ responses to Gag and/or Env. The level of CD8+ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8+ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8+ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU. Topics: ADP-ribosyl Cyclase 1; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chi-Square Distribution; Didanosine; Drug Therapy, Combination; Female; Gene Products, nef; HIV Infections; Humans; Hydroxyurea; Immunity, Cellular; Lymphocyte Activation; Male; Middle Aged; nef Gene Products, Human Immunodeficiency Virus; Regression Analysis; RNA, Viral | 2006 |
Antiretroviral activity of didanosine in patients with different clusters of reverse transcriptase mutations.
Patterns of mutations associated with didanosine (ddI) resistance are still a controversial issue. The correlation between different clusters of reverse transcriptase mutations with the short-term virological activity of ddI when added to a failing regimen was examined in 40 patients. The median fall in plasma viral load at week 4 was 0.67 log10 copies/ml. There was good correlation between the median fall in plasma HIV RNA levels and the number of nucleoside-associated (P = 0.0152) or thymidine-associated (P = 0.0142) mutations. In conclusion, ddI retained substantial antiretroviral activity when the number of nucleoside-associated or thymidine-associated mutations was less than four. Topics: Didanosine; HIV Infections; HIV Reverse Transcriptase; Humans; Mutation; Nucleosides; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Thymidine; Treatment Outcome; Viral Load | 2006 |
High prevalence of the K65R mutation in human immunodeficiency virus type 1 subtype C isolates from infected patients in Botswana treated with didanosine-based regimens.
We analyzed the reverse transcriptase genotypes of human immunodeficiency virus type 1 subtype C viruses isolated from 23 patients in Botswana treated with didanosine-based regimens. The K65R mutation was selected either alone or together with the Q151M, S68G, or F116Y substitution in viruses from seven such individuals. The results of in vitro passage experiments were consistent with an apparent increased propensity of subtype C viruses to develop the K65R substitution. Topics: Anti-HIV Agents; Botswana; Didanosine; HIV Infections; HIV-1; Humans; Mutation; Prevalence | 2006 |
Establishment of a rodent model of HIV-associated sensory neuropathy.
Human immunodeficiency virus (HIV)-associated sensory neuropathy (SN) is the most common neurological complication of HIV infection in the current highly active antiretroviral therapy era. The painful sensory neuropathy is associated with the use of dideoxynucleoside antiretrovirals, and its development limits the choice of antiretroviral drugs in affected patients. There are presently no effective therapies for HIV-SN, and moreover there has been no robust animal model of HIV-SN in which candidate therapeutic agents can be tested. In this paper, we show that we have established a rodent model of HIV-SN by oral administration of a dideoxynucleoside drug, didanosine, to transgenic mice expressing the HIV coat protein gp120 under a GFAP promoter. The neuropathy in these rodents is characterized by distal degeneration of unmyelinated sensory axons, similar to the "dying back" pattern of C-fiber loss seen in patients with HIV-SN. This model will be useful in examining mechanisms of distal axonal degeneration and testing potential neuroprotective compounds that may prevent development of the sensory neuropathy. Topics: Animals; Anti-Retroviral Agents; Didanosine; Disease Models, Animal; HIV Infections; HIV-1; Mice; Mice, Transgenic; Peripheral Nervous System Diseases | 2006 |
Administration of efavirenz (600 mg/day) with rifampicin results in highly variable levels but excellent clinical outcomes in patients treated for tuberculosis and HIV.
Pharmacokinetic interactions between rifampicin and antiretroviral therapy (ART), including efavirenz, are problematic and need to be better defined to determine proper dose and to be correlated with short-term and long-term clinical outcomes.. Consenting patients with smear-positive pulmonary TB and HIV received once daily didanosine + lamivudine + efavirenz (600 mg), with rifampicin-containing TB regimen by directly observed therapy and self-administration at TB therapy completion. Trough efavirenz levels were measured by HPLC at 1, 2, 4 and 6 months while on rifampicin and after discontinuation. HIV and TB outcomes were monitored.. Twenty African patients were enrolled [15 female, mean age 31 years, baseline weight 59.4 kg (range 45-97), viral load 5.75 log10 copies/mL and CD4 230 cells/mm3]. Seventy-two efavirenz concentrations were available from 19 patients (58 on, 14 after rifampicin). The geometric mean efavirenz concentration was 1730 ng/mL (range 354-27,179) on and 1377 ng/mL (range 572-3975) off rifampicin (P = 0.55). Inter-subject variability in efavirenz concentrations was greater on rifampicin (CV 157% versus 58% off) with relatively consistent intra-subject variation over time (median CV 24%). Over half of patients had efavirenz concentrations above or below the expected therapeutic range (1000-4000 ng/mL). Efavirenz levels were not predicted by weight or gender and were not associated with HIV clinical outcomes. Overall 80% of patients had non-detectable viral loads at 6 months and 65% at 21 months with a cumulative CD4 cell increase of 196 cells/mm3.. In this longitudinal study, despite wide variability in plasma efavirenz concentrations during rifampicin administration, excellent clinical outcomes were obtained. In African patients treated for HIV and TB, our data support the routine use of efavirenz at 600 mg/day when receiving rifampicin. Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Longitudinal Studies; Male; Oxazines; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Viral Load | 2006 |
Severity of the toxicity associated with combinations that include didanosine plus stavudine in HIV-infected experienced patients.
The combination of didanosine (ddI) and stavudine (d4T) is no longer recommended as a first-line treatment because of toxicity, but it may be useful in experienced patients.. Retrospective chart review of experienced patients on ddI plus d4T was conducted at a single institution, recording the development of adverse events as well as their severity and action taken. The risk of developing severe toxicities was estimated by Kaplan-Meier analysis.. A total of 616 patients were on ddI plus d4T for a median time of 12 months (interquartile range: 5.0-24.7 months). Among them, 213 (34.6%) had AIDS, 161 (27.4%) had CD4 counts <200 cells/mm, and 503 (81.2%) had >2 previous treatment failures. Adverse events related to ddI plus d4T were recorded in 136 patients (22.1%), which were mild to moderate in 118 (19.1%) patients and severe in 18 (2.9%) patients. The mean times to development of severe and nonsevere adverse events were 72 (95% confidence interval [CI]: 70 to 75) weeks and 52 (95% CI: 48 to 55) weeks, respectively. The probability of developing severe adverse events was related to the nadir CD4 count, with higher risk in patients with <200 cells/mm (log rank test, P = 0.045).. Multiexperienced patients treated with combinations, including ddI plus d4T, frequently develop drug-related toxicity, but these events are rarely severe. Thus, these drugs can still be considered a valid option for salvage regimens. Topics: Adult; Cohort Studies; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Retrospective Studies; Stavudine | 2006 |
Hepatic steatosis and ddI, d4T use.
Topics: Biopsy; Didanosine; Fatty Liver; Hepatitis C; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine | 2006 |
Adherence strategies. FDA approves ddI generic version.
Topics: Didanosine; Drug Approval; HIV Infections; Humans; Patient Compliance; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration | 2006 |
Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography.
A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength of 260 nm. The assay was validated over the concentration range of 0.015-5 mg/l for all five NRTIs. The average accuracies for the assay were 92-102%, inter- and intra-day coefficients of variation (CV) were <2.5% and extraction recoveries were higher than 97%. This method proved to be simple, accurate and precise, and is currently in use in our laboratory for the quantitative analysis of NRTIs in plasma. Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Didanosine; Dideoxynucleosides; Drug Stability; HIV; HIV Infections; Humans; Lamivudine; Quality Control; Reproducibility of Results; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Stavudine; Zidovudine | 2005 |
Prolonged treatment interruption in chronic HIV infection: a new strategy?
The introduction of highly active antiretroviral therapy in 1995 dramatically decreased AIDS-related events and deaths rates; however, the enthusiasm among the medical and social community was soon limited by the growing incidence of various side-effects that often greatly limited patients' quality of life. The second problem caused by such a complex treatment consisted of sub-optimal adherence, with a consequent higher risk of the development of drug resistance. Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Chronic Disease; Cohort Studies; Didanosine; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine | 2005 |
Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine.
A 50% rate of early virological failure associated with the selection of resistance mutations was seen in a group of 14 antiretroviral-naive adults who initiated highly active antiretroviral therapy with tenofovir and didanosine plus efavirenz or nevirapine. At month 6, the mutations detected were K65R, L74V, L100I, K103N/R/T, Y181C and G190E/Q/S. These results argue against the use of tenofovir plus didanosine in HIV-infected antiretroviral-naive adults even when the third drug is a non-nucleoside reverse transcriptase inhibitor. Topics: Adenine; Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir | 2005 |
Pancreatic exocrine insufficiency in HIV-positive patients.
We describe the management of a cohort of eight HIV-positive patients on antiretroviral medication with evidence of pancreatic insufficiency consisting of chronic diarrhoea and a low faecal elastase measurement.. Twenty-two patients with chronic diarrhoea for whom a faecal elastase measurement was available were identified retrospectively. We compared baseline demographic characteristics, antiretroviral treatment and symptoms of steatorrhea between patients with evidence of pancreatic insufficiency, i.e. a low faecal elastase measurement of <200 microg/g (cases), and patients with evidence of normal pancreatic function, i.e. a normal faecal elastase measurement of >200 microg/g (controls). We describe the management of the patients with evidence of pancreatic insufficiency.. Of the 22 patients, eight had evidence of pancreatic insufficiency, i.e. a low faecal elastase measurement. Comparing cases with controls, cases were more likely to have symptoms of steatorrhea (P=0.03) or to have lost weight (P=0.02). Cases were also significantly more likely to have taken didanosine (ddI) as part of their antiretroviral treatment when their symptoms started. Seven cases were treated with oral pancreatic supplements and all had symptomatic improvement of their diarrhoea. One patient stopped treatment with oral pancreatic supplements because of side effects without a relapse of symptoms; he had also stopped zalcitabine (ddC).. We believe that measurement of faecal elastase to detect pancreatic insufficiency should be part of the standard investigation of HIV-positive patients with chronic diarrhoea alongside assessment for other causes of diarrhoea. Faecal elastase measurements should be requested, in particular, in all patients with diarrhoea and weight loss, or symptoms of steatorrhea, and in those on treatment with an antiretroviral regime containing ddI. If the faecal elastase level is low, a switch of antiretroviral medication to a nonddI/ddC-containing regime should be considered and treatment with oral pancreatic enzyme therapy should be instituted. Topics: Adult; Anti-HIV Agents; Biomarkers; Chronic Disease; Clinical Enzyme Tests; Diarrhea; Didanosine; Exocrine Pancreatic Insufficiency; Feces; HIV Infections; Humans; Male; Pancreatic Elastase; Pancreatic Extracts; Retrospective Studies; Steatorrhea | 2005 |
Meeting notes from ICAAC. Tenofovir + ddI: a combination to avoid.
Topics: Adenine; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load | 2005 |
Selection of a rare resistance profile in an HIV-1-infected patient exhibiting a failure to an antiretroviral regimen including tenofovir DF.
The human immunodeficiency virus type 1 (HIV-1) resistance profile, K65R, K70E and M184V, on reverse transcriptase gene was associated with the virologic rebound consecutively to the switch of lopinavir/r to tenofovir DF in a stable regimen with nucleoside backbone of abacavir, lamivudine and didanosine. The high selective pressure on the same resistance pathway was probably associated with the loss of antiviral potency, even in well-controlled patient. Topics: Adenine; Adult; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Gabon; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lopinavir; Microbial Sensitivity Tests; Mutation; Organophosphonates; Pyrimidinones; Tenofovir; Viral Load | 2005 |
Serum neopterin, an immune activation marker, independently predicts disease progression in advanced HIV-1 infection.
CD4+ T lymphocyte (CD4) counts and plasma human immunodeficiency virus (HIV) type 1 RNA concentrations predict clinical outcome in HIV-1 infection. Our objective was to assess the independent prognostic value for disease progression of soluble markers of immune system activation.. This retrospective marker-validation study utilized previously obtained clinical and laboratory data, including CD4+ cell counts, and made use of stored frozen serum samples to assay for levels of beta2-microglobulin, neopterin, endogenous interferon, triglycerides, interleukin-6, soluble tumor necrosis factor- alpha receptor II, and HIV-1 RNA, and to determine HIV genotypic reverse-transcriptase inhibitor resistance. The 152 patients who participated in this study represented a subsample of participants in AIDS Clinical Trials Group (ACTG) 116B/117, a randomized trial that demonstrated the clinical benefit of didanosine over zidovudine monotherapy in persons with advanced HIV-1 infection. Marker data were analyzed in relation to protocol-defined clinical disease progression, using Cox proportional hazards models.. The median duration of follow-up was 344 days. Elevated baseline values for neopterin (P=.0009), endogenous interferon (P=.00039) and interleukin-6 (P=.0007) were each associated with greater subsequent risk of clinical disease progression. In a head-to-head comparison that was adjusted for CD4+ cell count (P=.0165) and HIV-1 RNA level (P=.1220), we found that elevated values for neopterin (P=.0002) and, to a lesser extent, endogenous interferon (P=.0053) were the strongest predictors of increased risk of clinical disease progression 6 months later.. Soluble markers of immune activation add prognostic information to CD4 counts and viral load for risk of disease progression in advanced HIV-1 infection. The robust performance of neopterin, an inexpensive and reliably measured serum marker, supports its potential suitability for patient monitoring, particularly in resource-limited settings. Topics: Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; Didanosine; Disease Progression; Dose-Response Relationship, Drug; Female; HIV Infections; Humans; Interferons; Interleukin-6; Male; Neopterin; Predictive Value of Tests; Risk Factors; Zidovudine | 2005 |
Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy.
NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion. Determinants of cellular mtDNA copy number from HIV-infected patients receiving HAART and HIV-seronegative controls were investigated from subcutaneous fat samples, and relation with antiretroviral regimen was studied.. HIV-infected patients receiving HAART (n = 50), HIV-infected patients not currently under HAART regimen (n = 2) and HIV-seronegative controls (n = 9) of similar age and BMI were enrolled prospectively when undergoing Coleman's lipostructure for correction of facial lipoatrophy or plastic surgery, respectively. After centrifugation, abdominal fat tissue was collected and stored at -80 degrees C. MtDNA analysis was blindly performed after a total DNA extraction from adipose tissue, followed by a real-time PCR quantification. The log of mtDNA copies/cell in adipose tissue [log(DNA)] was compared between groups by means of analysis of variance.. The log(DNA) in adipose tissue of HIV-infected patients was significantly lower than in the HIV-seronegative control group (P < 0.0001). In HIV-infected patients, log(DNA) was significantly reduced in the 50 NRTI-treated patients (P < 0.01), but not when considering mtDNA level according to the use of PI or NNRTI in current HAART regimen. In NRTI-treated patients, only stavudine (n = 20) and didanosine (n=14) were significantly and independently associated with reduced mtDNA level (P < 0.0001 and <0.05, respectively). Currently stavudine or didanosine-treated patients had a significant reduced mtDNA level compared to past users (P < 0.0001 and <0.05, respectively). Other clinical, biological, and immuno-virological variables than NRTI did not correlate significantly to adipocyte mtDNA level.. This study supports that current treatment by NRTI is a main determinant of mtDNA depletion in adipose tissue of HIV-seropositive patients with peripheral fat wasting. Stavudine or didanosine current intake is significantly associated with mtDNA depletion in vivo, that could be reversible after the discontinuation of these molecules, when considering mtDNA level according to current use versus past use of these molecules. Topics: Adipose Tissue; Adolescent; Adult; Aged; Anti-HIV Agents; Didanosine; DNA, Mitochondrial; Female; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine | 2005 |
[Toxic epidermal necrolysis associated with abacavir].
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Stevens-Johnson Syndrome | 2005 |
Generic didanosine gets approved.
Topics: Anti-HIV Agents; Didanosine; Drug Approval; Drugs, Generic; HIV Infections; Humans; United States | 2005 |
The influence of the M184V mutation in HIV-1 reverse transcriptase on the virological outcome of highly active antiretroviral therapy regimens with or without didanosine.
In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddl). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddl- and non-ddl-containing regimens in the presence or absence of the M184V mutation.. Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddl-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by 'real phenotype' resistance test results.. Amongst patients on ddl-containing HAART, median fold changes in phenotypic susceptibility to ddl were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddl, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddl-containing HAART than in those on HAART without ddl (P<0.05).. While the M184V did increase the fold resistance of HIV to ddl, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Mutation; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Treatment Outcome | 2005 |
Fanconi syndrome associated with didanosine therapy.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Fanconi Syndrome; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors | 2005 |
The durability of virological success of tenofovir and didanosine dosed at either 400 or 250 mg once daily.
Tenofovir (TDF) co-administered with didanosine (ddI) 400 mg increases ddI plasma concentrations by up to 60%, raising concerns over toxicity. To limit this interaction, the dosage of ddI may be reduced to 250 mg once daily when co-prescribed with TDF. In this clinical cohort, highly active antiretroviral therapy regimens containing TDF and ddI 250 mg were significantly better tolerated than combinations with TDF and ddI at a dose of 400 mg. Low-dose ddI 250 mg once daily plus TDF as part of antiretroviral therapy was effective. Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; HIV Infections; HIV-1; Humans; Organophosphonates; Retrospective Studies; Survival Rate; Tenofovir; Treatment Failure; Viral Load | 2005 |
A long-term survival case of small cell lung cancer in an HIV-infected patient.
We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection. Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed | 2005 |
[Efficacy of anti-HIV treatment and drug-resistance mutations in some parts of China].
To evaluate the Virologic and Immunologic efficacy of HAART on Chinese HIV/AIDS patients and to assess the impact of of HAART on drug resistance mutations.. Three cohorts of Liaoning, Jilin and Henan province received three different regimens for 6 months respectively. Regimen of Liaoning cohort comprised Efavirenz + Indinavir (EFV + IDV), regimen of Jilin cohort comprised Stavudine + Didanosine + Efavirenz (d4T + ddI + EFV) and regimen of Henan cohort comprised Stavudine + Didanosine + Nevirapine (d4T + ddI + NVP). Viral load, CD4(+) T cell count and drug resistance genotype were detected on the three cohorts before and after treatment. Partial HIV-1 pol genes encoding protease and 1 - 220 amino acid of reverse transcriptase were amplified by RT-PCR and then automatically sequenced. All sequences were compared with the data of Stanford HIV Drug Resistance Database to assess resistance mutations against reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs).. During observation of 6 months, viral suppression to undetectable level and Elevated CD4(+)T cell count efficacy were achieved on partial Chinese HIV/AIDS patients in each of the three different regimens, even in some patients with rather low CD4(+)T cell count baseline. Before HAART, no primary mutations against PIs and RTIs were detected on the three cohorts, except one patient in Liaoning cohort. But after HAART, drug resistance mutations against RTIs occurred on each of the three cohorts. K103N is the most common mutation against NNRTIs, which can cause high-level resistance to each of the available NNRTIs. Y181C is another common mutation occurred in Henan cohort, which causes crossing drug resistance and multi-drug resistance to NNRTIs. In addition, intermediate level and low level resistance against NRTIs caused by K65R and L74V can also be found, but less commonly.. Treatment naive Chinese HIV/AIDS patients were sensitive to HAART. Expected virologic and immunologic efficacy of HAART were achieved on Chinese HIV/AIDS patients, but after the introduce of HAART, the high prevalence of drug resistance mutations against NNRTIs and NRTIs, crossing drug resistance and multi-drug resistance reminded us to pay more attention to the drug resistance mutations detection, treatment standardization, and to avoid drugs wasting and prevent the prevalence of drug resistance strains. Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Nevirapine; Oxazines; Stavudine; Viral Load | 2005 |
Risk factors for CD4 lymphopenia in patients treated with a tenofovir/didanosine high dose-containing highly active antiretroviral therapy regimen.
In this study, the dynamics of CD4 cell depletion during tenofovir/didanosine co-administration were analysed. Ninety-five HIV-positive patients were followed for 562 days, and 37 lost at least 50 CD4 cells, with a median delay of 274 days. Cox analysis showed that the CD4 cell decrease was associated with a duration of treatment by didanosine of more than 853 days and a didanosine dose of more than 5.50 mg/kg. Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Didanosine; Female; HIV Infections; Humans; Lymphopenia; Male; Organophosphonates; Risk Factors; Tenofovir | 2005 |
HAART with didanosine once versus twice daily: adherence and efficacy.
Highly active antiretroviral therapy (HAART) containing didanosine taken twice daily was compared with HAART containing didanosine taken once daily in terms of adherence and efficacy.. This was a self-controlled prospective cohort study, carried out in a tertiary level hospital. A total of 49 HIV-infected patients were included. They were prescribed HAART according to guidelines. After six months taking HAART containing didanosine twice daily, patients continued with the same regimen of HAART although once daily. Thereafter they were followed up for a further nine months. Adherence and virological efficacy were assessed at three-month intervals, for a total of six times, in every patient.. Overall, adherence was poor, with only 19 patients (39%) showing adequate adherence for all six visits. Adequate adherence was observed in 29 patients (59%) three months before didanosine switching, and in 37 patients (75%) three months after didanosine switching (P=0.034). Pooled HIV RNA results of the first three visits were higher than the same results of the last three visits (P=0.05).. Non-adherence is common among patients who take HAART. Simplification of regimens is useful to improve adherence and efficacy. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemistry, Pharmaceutical; Cohort Studies; Didanosine; Female; HIV Infections; Humans; Male; Patient Compliance; Prospective Studies | 2005 |
The L74V mutation in human immunodeficiency virus type 1 reverse transcriptase counteracts enhanced excision of zidovudine monophosphate associated with thymidine analog resistance mutations.
Thymidine analog mutations (TAMs) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) confer resistance to zidovudine (AZT) by increasing the rate of ATP-dependent phosphorolysis of the terminal nucleotide monophosphate (primer unblocking). By contrast, the L74V mutation, which confers resistance to didanosine, sensitizes HIV-1 to AZT and partially restores AZT susceptibility when present together with one or more TAMs. To compare rates of primer unblocking in RTs carrying different clusters of TAMs and to explore the biochemical mechanism by which L74V affects AZT susceptibility, ATP-mediated rescue of AZT-blocked DNA synthesis was assayed using a series of purified recombinant RTs. Rates of primer unblocking were higher in the 67N/70R/219Q RT than in the 41L/210W/215Y enzyme and were similar to rates observed with an RT carrying six TAMs (41L/67N/70R/210W/215Y/219Q). The presence of 74V in an otherwise wild-type RT reduced the rate of primer unblocking to a degree similar to that observed with the M184V mutation for lamivudine resistance, which also sensitizes HIV-1 to AZT. Introduction of 74V into RTs carrying TAMs partially counteracted the effect of TAMs on the rate of primer unblocking. The effect of 74V was less marked than that of the 184V mutation in the 67N/70R/219Q and 41L/210W/215Y RTs but similar in the RT carrying six TAMs. These results demonstrate that L74V enhances AZT susceptibility by reducing the extent of its removal by ATP-dependent phosphorolysis and provides further evidence for a common mechanism by which mutations conferring resistance to didanosine and lamivudine sensitize HIV-1 to AZT. Topics: Adenosine Triphosphate; Anti-HIV Agents; Base Sequence; Didanosine; DNA Primers; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutation; Reverse Transcriptase Inhibitors; Thymidine; Zidovudine | 2005 |
Discrepancy between blood and cerebral didanosine effects in HIV patients: a magnetic resonance spectroscopy study.
Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Retrospective Studies; Viral Load | 2005 |
Human immunodeficiency virus infection: personal experience in changes in head and neck manifestations due to recent antiretroviral therapies.
Both the incidence and prevalence of human immunodeficiency virus infection are increasing in the world. Diseases of ENT districts are more frequent in human immunodeficiency virus-infected patients and involve all the otolaryngological sites. The otorhinolaryngological manifestations in association with HIV infection are mainly atypical, so common in the clinical practice, really aspecific and very frequent in ENT daily routine (such as sinusitis, otitis, etc.) and, therefore, immunodeficiency may not be suspected. In other cases, ENT evidence is more peculiar or unusual, such as opportunistic infections, rare neoplasm and tumours with an unusual course, giving a very high suspect of a human immunodeficiency virus-related infection. The most frequent malignant neoplasm is Kaposi's Sarcoma which is extremely rare in non-human immunodeficiency virus-infected subjects; the second most frequent is non-Hodgkin's lymphoma with 50% in extranodal sites (oral and maxillary sinus). Following a review of the literature, modifications caused by current antiretroviral treatment on head and neck manifestations of human immunodeficiency virus infection have been evaluated. Highly active antiretroviral therapy is a new therapeutic strategy, based on poly-chemo-therapeutic schemes, providing simultaneously two or more anti-retroviral drugs. We have used highly active antiretroviral therapy in human immunodeficiency virus infection since 1997, substituting previous mono-chemotherapy based on Zidovudine or Didanosine alone. Highly active antiretroviral therapy is extremely efficient in reducing the viral load of human immunodeficiency virus and increasing CD4+ T-lymphocyte count. These biological effects are associated with an improvement in immune functions. To evaluate the effects of highly active antiretroviral therapy on otorhinolaryngological manifestations in human immunodeficiency virus infection, we performed a retrospective study on 470 adults, observed over 14 years (1989-2002) and constantly receiving the same treatment, with follow-up from 7 to 80 months. A total of 250 subjects underwent mono-antiretroviral chemotherapy (1989-1996), while 220 underwent highly active antiretroviral therapy (1997-2002). The results of the retrospective study showed that highly active antiretroviral therapy has greatly improved the control of the immune-deficiency (increasing the range of CD4+), reducing the number of otorhinolaryngological manifestations (also tumours). On the o Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Antigens; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Incidence; Lymphoma, Non-Hodgkin; Male; Prevalence; Pseudomonas Infections; Sarcoma, Kaposi; Zidovudine | 2005 |
The effect of long-term storage on measured plasma lactate concentrations and prospective lactate results from a multicenter trial of antiretroviral therapy.
Plasma lactate measurements are typically performed in real time, limiting their usefulness in multicenter or longitudinal studies. To determine the stability of lactate specimens, blood was drawn in sodium fluoride/potassium oxalate tubes from 13 volunteers before and after 5 min of handgrip exercise to intentionally increase lactate concentrations. Plasma was stored at -70 degrees C. Aliquots were assayed in real time and after 1, 3, 6, 9, 12, 18, and 24 months. Real-time lactate concentrations measured at baseline ranged from 0.52 to 2.23 mmol/L before and from 2.91 to 11.04 mmol/L after handgrip exercise. Using a linear mixed model, the estimated change from baseline at month 24 was 1.67% (95% confidence interval, -0.70% to 4.03%) for pre-exercise samples and 0.39% (95% CI, -1.13% to 1.91%) for post-exercise samples. Stored serial specimens from 232 HIV-infected subjects in a multicenter trial of antiretroviral therapy were also assayed centrally. Among those, median plasma lactate increased from baseline to 64 weeks by 0.4 mmol/L with zidovudine+lamivudine treatment and by 0.6 mmol/L with didanosine+stavudine (each p<0.001 from baseline; p=0.04 for difference between groups over time). When performed as in this study, frozen storage with central batch lactate analysis is appropriate for prospectively collected samples in multicenter trials. Topics: Acidosis, Lactic; Anti-HIV Agents; Blood Preservation; Blood Specimen Collection; Didanosine; HIV Infections; Humans; Lactates; Lamivudine; Multicenter Studies as Topic; Oxalates; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Sodium Fluoride; Specimen Handling; Stavudine; Time Factors; Zidovudine | 2005 |
High rate of virological failure in maintenance antiretroviral therapy with didanosine and tenofovir.
We evaluated the virological outcome of tenofovir plus didanosine-based regimens in 67 HIV-suppressed patients. After a median follow-up of 26 months (IQR 10.5-40.5), 12 (18%) discontinued the therapy because of virological failure. At virological failure 'de novo' selected mutations were identified in 11 of the 12 failing patients, including the K65R mutation in seven patients. These results argue against the use of tenofovir-didanosine not only in naive patients, but also in previously suppressed patients. Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Mutation; Organophosphonates; Tenofovir; Treatment Failure | 2005 |
Homo and heterodimers of ddI, d4T and AZT: influence of (5'-5') thiolcabonate-carbamate linkage on anti-HIV activity.
New homo and heterodimers of ddI, d4T and AZT with (5-5) thiolcarbonate-carbamate linkages have been prepared with the aim of testing them against wild type and NNRTI resistant HIV mutants. The prepared dimers showed a low activity in comparison to the parent drug. Topics: Anti-HIV Agents; Antiviral Agents; Carbamates; Didanosine; Dimerization; HIV; HIV Infections; Models, Chemical; Molecular Conformation; Mutation; Stavudine; Sulfhydryl Compounds; Zidovudine | 2005 |
Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir.
Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF.. To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent.. A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses.. CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups.. Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen. Topics: Adenine; Adult; CD4 Lymphocyte Count; Didanosine; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; Treatment Outcome | 2005 |
[Didanosine--stability as backbone drug].
Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Oxazines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors | 2005 |
Hepatitis C and didanosine: risk of lactic acidosis.
(1) In patients who are infected with both HIV and hepatitis C virus (HCV), treatment of hepatitis C slightly increases the risk of lactic acidosis associated with antiretroviral treatment, especially when the latter includes didanosine. (2) If a modification in antiretroviral treatment is needed and if treatment for hepatitis C is likely to be necessary, then it is best to avoid didanosine. However, systematic replacement of didanosine is not necessary, given the small magnitude of risk of lactic acidosis. (3) Fatigue, digestive problems, weight loss and dyspnea are signs of lactic acidosis. Topics: Acidosis, Lactic; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Comorbidity; Contraindications; Didanosine; Drug Interactions; Drug Therapy, Combination; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin | 2005 |
Should tenofovir ever be used in association with didanosine?
Topics: Adenine; Anti-HIV Agents; Contraindications; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure; Viral Load | 2005 |
Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors.
Most toxicities associated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) are thought to result from mitochondrial toxicity. These toxicities include peripheral neuropathy, pancreatitis, lactic acidosis, and peripheral lipoatrophy. Unfortunately, there are no validated laboratory markers for clinically assessing, let alone predicting, the onset of mitochondrial toxicity associated with NRTI therapy.. To provide preliminary evidence of the potential clinical utility of an assay which has been developed for quantifying mitochondrial DNA (mtDNA) in clinical samples from HIV-infected patients.. A single-tube duplex real-time DNA-nucleic acid sequence-based amplification (NASBA) assay (Mitox, Primagen, Amsterdam, the Netherlands) was used to quantify mtDNA in cryopreserved peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients during their prior participation in a randomized placebo-controlled trial comparing zidovudine (ZDV) monotherapy with combinations of ZDV plus either dideoxycytidine (ddC) or didanosine (ddI) (the Delta trial). Patients were antiretroviral naïve prior to entering the trial. Samples obtained during the initial 48 weeks of treatment were tested.. A significant decline of mtDNA, both in an intent-to-treat and in an as-treated analysis, was observed in patients treated with ZDV+ddC and ZDV+ddI, but not with ZDV alone, consistent with the results expected from the degree of mtDNA depletion described for each of these drugs in vitro.. This single-tube duplex real-time DNA-NASBA assay was shown to measure mtDNA accurately in PBMC. Treatment with a combination of two NRTIs was associated with greater reductions in mtDNA than obtained for ZDV monotherapy. The relevance of these results in predicting treatment toxicity requires further evaluation. Topics: Analysis of Variance; Anti-HIV Agents; Didanosine; DNA, Mitochondrial; Drug Combinations; HIV Infections; Humans; Mitochondrial Diseases; Reverse Transcriptase Inhibitors; Self-Sustained Sequence Replication; Sensitivity and Specificity; Zalcitabine; Zidovudine | 2004 |
Determination of ddATP levels in human immunodeficiency virus-infected patients treated with dideoxyinosine.
Clinical failures of the highly active antiretroviral therapy could result from inefficient intracellular concentrations of antiviral drugs. The determination of drug contents in target cells of each patient would be useful in clinical investigations and trials. The purpose of this work was to quantify the intracellular concentration of ddATP, the active metabolite of dideoxyinosine (ddI), in peripheral blood mononuclear cells (PBMCs) of human immunodeficiency virus (HIV)-infected patients treated with ddI. We have raised antibodies against ddA-citrate, a stable isostere of ddATP selected on the basis of its structural and electronic analogies with ddATP. The anti-ddA-citrate antibodies recognized ddATP and ddA with nanomolar affinities and cross-reacted neither with any of the nucleotide reverse transcriptase inhibitors used in HIV therapy nor with their phosphorylated metabolites. The three phosphorylated metabolites of ddI (ddAMP, ddADP, and ddATP) were purified by anion exchange chromatography and the amount of each metabolite was determined by radioimmunoassay with or without prior phosphatase treatment. The intracellular levels of the three ddI metabolites were measured both in an in vitro model and in PBMCs of HIV-infected patients under ddI treatment. The possibility to measure intracellular levels of ddATP from small blood samples of HIV-infected patients treated with ddI could be exploited to develop individual therapeutic monitoring. Topics: Anti-HIV Agents; Antibodies; Biotransformation; Chromatography, Ion Exchange; Deoxyadenine Nucleotides; Didanosine; Dideoxynucleotides; HIV Infections; Humans; Hydrolysis; In Vitro Techniques; Leukocyte Count; Models, Molecular; Neutrophils; Phosphorylation; Radioimmunoassay | 2004 |
Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine.
The "D drug" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the "non-D drugs" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation. Topics: Acidosis, Lactic; Adult; Cross-Sectional Studies; Didanosine; DNA, Mitochondrial; Female; Hepatitis C, Chronic; HIV Infections; Humans; Lactic Acid; Liver; Male; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine | 2004 |
The role of civil society in protecting public health over commercial interests: lessons from Thailand.
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Commerce; Didanosine; Drug Costs; Drug Industry; Health Services Accessibility; HIV Infections; Humans; Intellectual Property; Patents as Topic; Patient Rights; Public Health Administration; Thailand | 2004 |
Mitochondrial effects of antiretroviral therapies in asymptomatic patients.
A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear.. We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence.. Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups.. Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Base Sequence; Cross-Sectional Studies; Didanosine; DNA Primers; DNA, Mitochondrial; Female; HIV Infections; Humans; Lamivudine; Male; Mitochondria; Nelfinavir; Nevirapine; Polymerase Chain Reaction; Stavudine | 2004 |
High rate of didanosine-related mitochondrial toxicity in HIV/HCV-coinfected patients receiving ribavirin.
Nucleoside analogues may induce mitochondrial toxicity, particularly didanosine. Ribavirin increases didanosine exposure, which might be clinically relevant when coadministered in HIV/HCV-coinfected patients.. To evaluate, among 89 patients receiving highly active antiretroviral therapy (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial toxicity in those treated with concomitant ribavirin and didanosine (n=35, 39%).. From January 2000 to July 2002 longitudinal analysis of the incidence and clinical course of didanosine-related hyperamylasaemia, pancreatitis, hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using univariate and multivariate Cox's proportional hazards model.. Among 35 patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (> or = 10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18 patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients, respectively. Two patients (6%) with pancreatitis and severe lactic acidosis died; the other patients recovered uneventfully despite continuation of anti-HCV therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher baseline amylase levels (HR: 1.04, 95% CI: 1.02-1.06, P=0.001) and three nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73-16.24, P=0.003) were significantly associated to toxicity.. The coadministration of didanosine and ribavirin should be avoided in HIV/HCV-coinfected patients, due to a high rate of clinically significant toxicity, particularly in triple nucleoside-based HAART. Amylase levels should be strictly monitored, especially if elevated at baseline. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Didanosine; Female; Hepatitis C; HIV Infections; Humans; Incidence; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Proportional Hazards Models; Ribavirin | 2004 |
Interval-censored survival time data: confidence intervals for the non-parametric survivor function.
Survival data are described as interval censored when the failure time is not measured exactly but is known only to have occurred within a defined interval. In this paper, we describe and assess three methods for calculating pointwise confidence intervals for the non-parametric survivor function estimated from interval-censored data: the first based on the full information matrix, the second a modification of this approach involving deletion of rows and columns of the information matrix corresponding to zero estimates prior to inversion and the third based on likelihood ratio inference. In a simulation study the likelihood ratio method gave the most accurate confidence intervals with coverage consistently close to the nominal level of 95 per cent. Topics: Antiviral Agents; Computer Simulation; Confidence Intervals; Data Interpretation, Statistical; Didanosine; HIV Infections; Humans; RNA, Viral; Survival Analysis; Zidovudine | 2004 |
Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase.
Topics: Adenine; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Nucleosides; Nucleotides; Organophosphonates; Organophosphorus Compounds; Prevalence; Tenofovir | 2004 |
Tenofovir-related nephrotoxicity in HIV-infected patients.
Topics: Acute Kidney Injury; Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphonates; Organophosphorus Compounds; Oxazines; Tenofovir | 2004 |
Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients.
To determine the concentrations of intracellular active anabolites of stavudine (d4T) and didanosine (DDI) and their interpatient variability in HIV-infected patients and to explore relationships between plasma and intracellular forms.. This pilot study included 28 antiretroviral-naive HIV-infected patients who received d4T (40/30 mg twice daily), ddI (400/250 mg daily) and efavirenz (600 mg daily). After 6 months of therapy, 7 ml of blood was collected between 0.5 and 16.2 h and 2.5 and 28.5 h after the last dose of d4T and ddI, respectively. Plasma samples were obtained for the determination of d4T and ddI concentrations. Peripheral blood mononuclear cells were prepared for measuring intracellular d4T and ddI triphosphates (d4T-TP and ddA-TP, respectively).. d4T-TP and ddA-TP concentrations were above the limit of quantification in 25 of 26 compliant patients: median d4T-TP was 31 fmol/10(6) cells (range, 0-99) and median ddA-TP was 8 fmol/10(6) cells (range, 0-23). The half-life of d4T-TP was calculated as 7 h. Interpatient variability in d4T-TP and ddA-TP concentrations was 48% and 58%, respectively. A significant relationship was observed between plasma d4T and intracellular d4T-TP. No relation was found between ddI and ddA-TP. A linear relation was observed between the intracellular concentrations of d4T-TP and ddA-TP.. This is the first time that data have been obtained on intracellular concentrations of d4T-TP and ddA-TP, their intracellular pharmacokinetics and interpatient variability. Other similar studies with more patients are needed to enhance knowledge of the intracellular pharmacology of the nucleoside reverse transcriptase inhibitors. Topics: Anti-HIV Agents; Chromatography, Liquid; Didanosine; Dose-Response Relationship, Drug; Half-Life; HIV Infections; Humans; Intracellular Fluid; Leukocytes, Mononuclear; Mass Spectrometry; Phosphorylation; Pilot Projects; Plasma; Stavudine; Viral Load | 2004 |
EU issues warning about HAART regimen.
Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; European Union; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Patient Selection; Pilot Projects; Safety; Tenofovir; Treatment Failure; Viral Load | 2004 |
Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load.
We recently observed a significant CD4 cell count decline in patients receiving didanosine (ddI) 400 mg, tenofovir (TDF) and nevirapine (NVP), despite virological suppression.. We identified from our computerized patient database subjects who initiated combinations containing ddI and/or TDF for reasons other than virological failure, including simplification or intolerance. Changes in total, CD4+ and CD8+ lymphocyte counts since the initiation of therapy were analysed retrospectively. Plasma concentration of ddI was prospectively determined in eight of these patients receiving ddI 400 mg + TDF + NVP and 3 weeks after a ddI dosage reduction.. A total of 302 patients were studied. A significant decrease in CD4 and CD8 and in total lymphocyte counts was only seen in subjects receiving ddI standard dose + TDF-containing regimens, despite the maintenance of viral suppression. More than 50% of these patients showed a decline of more than 100 CD4 cells at 48 weeks. In contrast, subjects not receiving ddI + TDF together experienced the expected progressive increase in CD4 T-cell counts. Plasma levels of ddI were elevated in all patients receiving the standard ddI dose + TDF. DdI plasma levels significantly decreased when patients weighting > 60 kg reduced ddI dose to 250 mg, achieving similar levels to those generated by ddI 400 mg without TDF.. Co-administration of ddI at standard doses plus TDF appears to exert a deleterious effect on CD4 and CD8 counts. Although lymphocyte toxicity related to excessive ddI plasma levels could explain our findings, other mechanisms cannot be excluded. Pharmacokinetic data suggest ddI dose reduction when coadministered with TDF. Topics: Adenine; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Organophosphonates; Organophosphorus Compounds; Retrospective Studies; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load | 2004 |
Nucleoside analogues and mitochondrial toxicity.
An evaluation of the US Food and Drug Administration's Adverse Event Reporting System identified that patients coinfected with human immunodeficiency virus and chronic hepatitis C virus who were treated with a regimen of ribavirin and didanosine, with or without stavudine, were at increased risk for events associated with mitochondrial toxicity, including fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis. In response, the US product labels for didanosine and ribavirin have been revised to caution clinicians against coadministration of these drugs. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Mitochondria; Reverse Transcriptase Inhibitors; Ribavirin; Stavudine | 2004 |
Didanosine-associated toxicity: a predictable complication of therapy with tenofovir and didanosine?
Topics: Adenine; Adult; Anti-HIV Agents; Creatinine; Didanosine; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Kidney Diseases; Male; Middle Aged; Organophosphonates; Tenofovir | 2004 |
Distinct patterns of natural selection in the reverse transcriptase gene of HIV-1 in the presence and absence of antiretroviral therapy.
The emergence of human immunodeficiency virus (HIV) drug-resistant mutations during antiretroviral therapy is explained by either the preexistence of low-frequency-resistant strains before the start of therapy or by the selection of unsuppressed resistant strains during therapy. We used pairwise and maximum likelihood analyses of the ratio of nonsynonymous to synonymous substitutions per site (d(N)/d(S)) to study the extent of positive selection in the reverse transcriptase (RT) gene of HIV-1 from multiple data sets of drug-treated (117 sequences) and drug-naive patients (270 sequences). In the pairwise analysis, evidence for positive selection (d(N)/d(S) > 1) was only found in drug-treated individuals and in codons conferring drug resistance. By the maximum likelihood method, a positive selection at codons conferring drug resistance was only observed in patients receiving therapy, and although positive selection was detected in drug-naive patients, this was always at codons unrelated to drug resistance. We therefore document a striking difference in the process of allele fixation in drug resistance codons (RC) between populations of HIV-1-infected individuals naive to treatment and those receiving therapy. Furthermore, although mutations associated with drug resistance are sometimes found in drug-naive patients, we suggest that these are fixed because of linkage to sites experiencing immune escape. Finally, we show that compensatory changes are likely to be important in the development of HIV drug resistance by counter-acting the deleterious effects normally associated with drug resistance mutations. Topics: Amino Acid Sequence; Anti-HIV Agents; Base Sequence; Brazil; Codon; Didanosine; DNA, Viral; Drug Resistance, Viral; Evolution, Molecular; Genes, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Likelihood Functions; Molecular Sequence Data; Mutation; Phylogeny; Selection, Genetic | 2004 |
Nucleoside analogue use before and during highly active antiretroviral therapy and virus load rebound.
Patients who use nucleoside reverse-transcriptase inhibitors (NRTIs) before highly active antiretroviral therapy (HAART) have an increased rate of virus rebound. Study of rebound according to specific NRTIs used might inform which NRTIs retain activity once others have failed. We focused on 2280 patients who had received zidovudine and either didanosine or lamivudine before starting HAART, started HAART that included zidovudine with didanosine or lamivudine or stavudine with didanosine or lamivudine, and had virus loads <500 copies/mL within 24 weeks. In a Cox model, the relative hazard (RH) of virus rebound for having switched from zidovudine to stavudine (vs. retaining zidovudine) was 0.94 (95% confidence interval [CI], 0.77-1.15), which suggests little or no benefit in terms of reduced rebound rate. Having switched from didanosine to lamivudine, or vice versa, was associated with a reduced rebound rate (RH, 0.59 [95% CI, 0.48-0.73]), which suggests that these drugs retain appreciable activity after use of the other and of zidovudine. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Australia; Cohort Studies; Didanosine; Drug Administration Schedule; Europe; Female; HIV Infections; Humans; Lamivudine; Male; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Viral Load; Zidovudine | 2004 |
Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance.
To analyse the impact of the M184I/V mutation and individual thymidine-associated mutations (TAM) on nucleoside reverse transcriptase inhibitor (NRTI) phenotypic susceptibility and compare these results with those obtained using commercial and public algorithms.. An HIV genotypic/phenotypic database with over 27 000 samples was used to obtain the median fold change (5-95th percentile) in NRTI phenotypic susceptibility for viruses from patients containing individual TAM with or without the M184I or V mutation and for wild-type patient viruses.. The resulting data indicated that in vitro, individual TAM do not have an equivalent impact on NRTI resistance, with some individual TAM having little or no impact on NRTI resistance (e.g. M41L or K219Q/E/H/R). In the presence of the M184I/V mutation, re-sensitization to some drugs, including zidovudine, stavudine and tenofovir was observed despite the presence of a TAM. For didanosine and abacavir, the presence of the M184V mutation and a single TAM did not result in a fold-change increase associated with decreased drug susceptibility. Analysis of public and commercial algorithms revealed a lack of concordance regarding the impact of these mutations, and with the observed phenotypic data.. These analyses should assist in the creation of rules for genotypic drug resistance algorithms for a better reflection of the impact of individual TAM and also the impact of M184I/V on resistance. These data provide additional evidence that retaining lamivudine in those treatment regimens in which TAM can be selected may provide some therapeutic benefit by maintaining the M184V mutation. Topics: Adenine; Algorithms; Anti-HIV Agents; Databases, Genetic; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV; HIV Infections; Humans; Mutation; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Thymidine; Zalcitabine; Zidovudine | 2004 |
Tolerance of didanosine as enteric-coated capsules versus buffered tablets.
Topics: Adult; Anti-HIV Agents; Didanosine; Dosage Forms; Female; Gastrointestinal Diseases; HIV Infections; Humans; Male; Retrospective Studies | 2004 |
Fatal lactic acidosis associated with coadministration of didanosine and tenofovir disoproxil fumarate.
Lactic acidosis is an uncommon but potentially life-threatening adverse effect of didanosine. When given concomitantly with tenofovir disoproxil fumarate (DF), the area under the concentration-time curve of didanosine is increased by 48-60%. A 63-year-old man with human immunodeficiency virus (HIV) infection tolerated several didanosine-containing antiretroviral regimens. He developed generalized weakness, loss of appetite, weight loss, nausea, and vomiting 1.5 years after tenofovir DF was added to his didanosine-containing regimen. He was diagnosed with lactic acidosis and died after a 13-day hospital stay, when his lactate level increased to 189.7 mg/dl and his arterial blood gas pH value fell to 6.75. Health care providers should maintain a high index of suspicion for lactic acidosis in patients with HIV infection who receive didanosine and tenofovir DF concurrently. For patients receiving antiretroviral regimens containing this drug combination, it would be prudent to monitor lactate levels periodically. This is especially important when patients experience symptoms suggestive of lactic acidosis, such as weakness, abdominal pain, weight loss, nausea and vomiting, and shortness of breath. Topics: Acidosis, Lactic; Adenine; Anti-HIV Agents; Area Under Curve; Comorbidity; Didanosine; Drug Interactions; Fatal Outcome; Female; HIV Infections; Humans; Lactates; Male; Middle Aged; Organophosphonates; Organophosphorus Compounds; Tenofovir | 2004 |
Acute onset of pancreatitis with concomitant use of tenofovir and didanosine.
To report a case of pancreatitis associated with the combined use of didanosine and tenofovir.. A 51-year-old white man with HIV was initiated on antiretroviral therapy with didanosine 250 mg/day, tenofovir 300 mg/day, lamivudine 300 mg/day, stavudine 60 mg/day, and efavirenz 600 mg/day. Didanosine was prescribed at a reduced dosage due to the known interaction with tenofovir. Despite this dosage adjustment, the patient developed acute pancreatitis 10 weeks after antiretrovirals were initiated. Pancreatitis resolved spontaneously after antiretroviral discontinuation.. Our report of didanosine-induced pancreatitis secondary to concurrent use with tenofovir is the third reported case that utilized a reduced didanosine dosage. Five previous pancreatitis reports have been described using full-strength didanosine with tenofovir. The exact mechanism of action for this interaction is unknown. Utilizing the Naranjo probability scale to assess causality, a possible adverse drug reaction was determined.. Tenofovir and didanosine may be used cautiously in antiretroviral combination therapy. Reduced didanosine dosage (250 mg) should be used to reduce serum didanosine concentrations and subsequent toxicities. Practitioners should be aware that a significant drug interaction with resulting pancreatitis may occur even when a reduced dosage is prescribed. Topics: Acute Disease; Adenine; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Pancreatitis; Tenofovir | 2004 |
Resveratrol glucuronides as the metabolites of resveratrol in humans: characterization, synthesis, and anti-HIV activity.
Resveratrol is a natural product with diverse biological activities. We have previously reported that resveratrol possesses potent synergistic inhibitory activity against human immunodeficiency virus (HIV)-1 infection in combination with nucleoside analogs (Heredia et al. 2000. J Acquir Immune Defic Syndr 25:246-255). As a part of our program in developing resveratrol as a component for anti-HIV chemotherapy, we describe in this article the characterization, chemical synthesis, and biological effects of the human metabolites of resveratrol. We found that resveratrol was metabolized in humans into two metabolites, which were characterized as resveratrol-3-O- and 4'-O-glucuronides. For further biological studies, we reported two simple, alternative methods for the synthesis of the metabolites. The cytotoxic and antiviral activities of resveratrol and its metabolites were compared in cell culture experiments using human peripheral blood mononuclear cells. Whereas resveratrol was cytotoxic at > or =30 microM, no cytotoxicity was observed for the metabolites at concentrations as high as 300 microM. However, resveratrol showed strong synergistic anti-HIV activity with didanosine at 10 microM, but no synergistic effects were observed for either of the metabolites at up to 300 microM. Nevertheless, the in vitro activity of the metabolites (resveratrol glucuronides) may not necessarily reflect their in vivo function, given the fact that the ubiquitously existing human beta-glucuronidase could convert the metabolites back to resveratrol locally or systematically in vivo. The present studies have implications for future development of resveratrol and/or its derivatives as a chemotherapeutic agent. Topics: Administration, Oral; Anti-HIV Agents; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Didanosine; Dose-Response Relationship, Drug; Drug Synergism; Glucuronides; HIV Infections; Humans; Hydrolysis; Leukocytes, Mononuclear; Resveratrol; Stilbenes; Structure-Activity Relationship; Time Factors | 2004 |
Correlation between rules-based interpretation and virtual phenotype interpretation of HIV-1 genotypes for predicting drug resistance in HIV-infected individuals.
Drug resistance testing provides useful information for managing HIV-infected patients. Phenotyping could add complementary information to genotyping and occasionally be more useful, although is less available to clinicians. Large paired geno-pheno databases have allowed the prediction of phenotypes from genotypes. However, the accuracy of these virtual phenotypes (vPT) in a clinical setting has not been well assessed yet. We analyzed the concordance between vPT and interpreted genotype (GT) in 105 samples belonging to treatment-experienced HIV-infected patients. A high concordance was seen when examining both non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) (r = 0.95 either), while it was lower for nucleoside analogs (r = 0.79). The drugs with lower concordance were abacavir (71.1%), tenofovir (71.5%) and didanosine (71.9%). In 20% of specimens (21/105), the vPT did not provide results for all approved drugs. These were mainly samples with a high number of drug resistance mutations or rare genotypes, which seem to be underepresented in the VircoNET database. Overall, there is good correlation between vPT/GT, especially for PI and NNRTI. The inclusion of additional sequences in the VircoNET database, mainly those derived from heavily treatment-experienced patients and/or from patients failing the most recently approved drugs might improve its performance. Topics: Adenine; Amino Acid Substitution; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; Nucleosides; Organophosphonates; Phenotype; Protease Inhibitors; Reverse Transcriptase Inhibitors; Tenofovir | 2004 |
Enhanced HIV-specific immune responses in chronically HIV-infected patients receiving didanosine plus hydroxyurea.
The role of hydroxyurea (HU) in the treatment of HIV infection remains controversial. HU potentiates didanosine (ddI) antiviral activity and might exert immunomodulatory effects.. Immunologic parameters were examined in HIV-infected patients enrolled in a simplification trial in which ddI-HU was provided to subjects who had been on complete virus suppression under highly active antiretroviral therapy (HAART) for longer than 6 months. A total of 84 of these patients showed plasma viraemia repeatedly below 5000 HIV-RNA copies/ml, and were the main study population. A group of 22 patients who continued on HAART and another of 22 drug-naive HIV-positive individuals were taken as controls.. At 12 months, the levels of naive and memory T-cell subsets were similar in patients on ddI-HU and under HAART, whereas immune activation tended to be lower in the former group. The frequency of HIV-specific CD8+ T cells (CTL) directed against 125 peptides derived from Gag, Pol, Env, Nef and HIV regulatory proteins was similar among patients on ddI-HU and untreated controls, and significantly higher than in patients under HAART. This higher CTL response in patients on ddI-HU was seen even when considering only subjects with undetectable viral load. HIV-specific CD4+ T-cell responses were absent in almost all patients on HAART, whereas they were present in up to 19% of patients on ddI-HU.. Treatment with ddI-HU provides higher levels of HIV-specific CD8+ and CD4+ T-cell responses than standard triple drug regimens. Thus, hydroxyurea might exert a beneficial immunomodulatory effect in HIV infection. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Case-Control Studies; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cross-Sectional Studies; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV-1; Humans; Hydroxyurea; Immunophenotyping; Interferon-gamma; Nucleic Acid Synthesis Inhibitors; Receptors, Antigen, T-Cell; RNA, Viral; Viral Load | 2004 |
Gynecomastia and potent antiretroviral therapy.
Topics: Adult; Anti-HIV Agents; Case-Control Studies; Didanosine; Female; Gynecomastia; HIV Infections; HIV-1; Humans; Male; Stavudine | 2004 |
[Confirmed NRTI remains an important therapy option. Didanosine effective despite multiple resistance to NRTIs].
Topics: Didanosine; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load | 2004 |
Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals.
Exposure to nucleoside analogues in fetal or early life has been associated with rare clinically significant mitochondrial toxic effects, mainly neurologic symptoms. Lactate (LA) measurements have been used to monitor nucleoside-related mitochondrial toxicity. Our aim was to determine the prevalence, clinical evolution, and risk factors for hyperlactatemia in our cohort of human immunodeficiency virus (HIV)-uninfected children who were exposed to antiretrovirals.. We conducted a prospective observational study of 127 HIV-uninfected infants who were born to HIV-infected women. Clinical symptoms suggesting mitochondrial dysfunction were analyzed in routine follow-up, and LA and alanine plasma levels were obtained at 6 weeks, 3 months, 6 months, and 12 months in all patients. Elevated alanine levels, together with hyperlactatemia, suggest chronic mitochondrial injury.. Most (85%) women received highly active antiretroviral therapy (HAART) during pregnancy (mean duration: 31 weeks) and zidovudine during labor (93%). Most (96%) children received zidovudine alone. Hyperlactatemia with hyperalaninemia was detected in 63 children in at least 1 of the measurements. Mean LA levels were significantly higher in children who were exposed to nucleoside analogue reverse transcriptase inhibitors than in control subjects (2.88 vs 1.61 at 6 weeks, 2.78 vs 1.49 at 3 months, 1.89 vs 1.39 at 6 months, and 1.71 vs 1.24 at 12 months; peak levels: 8.06, 10.1, 7.28, and 4.48 mmol/L, respectively). In 44 patients, LA levels progressed spontaneously to normality within the first year of life. Three girls presented a slight and self-limited delay in psychomotor development, with LA peak levels of 7.3, 4.0, and 4.6 mmol/L. Only the gestational use of didanosine was associated with a higher risk of hyperlactatemia.. In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue-induced toxicity affected neurologic development. Topics: Alanine; Antiretroviral Therapy, Highly Active; Didanosine; Female; HIV Infections; HIV Seronegativity; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lactic Acid; Logistic Models; Male; Mitochondria; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Reverse Transcriptase Inhibitors; Zidovudine | 2004 |
Tenofovir: new indication. For first-line antiretroviral therapy: wait and see.
(1) First-line antiretroviral combinations generally include, in addition to a protease inhibitor or a non nucleoside reverse transcriptase inhibitor, two nucleoside reverse transcriptase inhibitors, namely zidovudine + didanosine, stavudine + lamivudine, or zidovudine + lamivudine. (2) Tenofovir disoproxil (referred to simply as tenofovir below) is a nucleotide HIV reverse transcriptase inhibitor. Previously recommended for second-line treatment in case of virological failure, it is now approved for first-line therapy in adults. (3) This licence extension is based on a double-blind trial comparing tenofovir + lamivudine + efavirenz with stavudine + lamivudine + efavirenz in 602 patients. After 96 weeks, three-quarters of patients had undetectable viral load (<50 copies/ml), and there was no statistically significant difference among the groups. (4) The number of serious adverse effects was similar in the two groups. Relative to the stavudine combinations, there were fewer reports of lipodystrophy (1% versus 12%), fewer peripheral neuropathies (3% versus 10%) and fewer prescriptions of lipid-lowering therapy (2% versus 10%) among patients taking tenofovir. Tenofovir seemed to have a worse effect on renal function and bone metabolism, however. (5) Tenofovir is taken only once a day, but so are didanosine and lamivudine. (6) In practice, there is not yet enough evidence to support the routine use of tenofovir in first-line antiretroviral combinations. Tenofovir is, however, an interesting alternative when stavudine is poorly tolerated. Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Controlled Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Zidovudine | 2004 |
Magnitude and duration of elevated gastric pH in patients infected with human immunodeficiency virus after administration of chewable, dispersible, buffered didanosine tablets.
To test the hypothesis that gastric pH would be elevated above pH 3.0 for at least 2 hours after administration of chewable, dispersible, buffered didanosine tablets. Doses tested were 200 mg (two 100-mg tablets) and 400 mg (two 200-mg tablets). We also sought to compare these doses with regard to maximum gastric pH (pHmax), time to pHmax (TpH-max), time that gastric pH exceeds 3.0 (TpH>3), and area under the gastric pH versus time curve for pH greater than 3.0 (AUCT>pH 3).. Prospective, parallel-group, dose-comparison, gastric pH study.. General Clinical Research Center, University of Michigan Hospitals, Ann Arbor, Michigan.. Nineteen patients infected with human immunodeficiency virus, aged 30-62 years, and receiving long-term didanosine therapy.. Patients underwent continuous gastric pH monitoring, using the Heidelberg capsule radiotelemetric pH monitoring device. After documentation of a fasting baseline gastric pH below 3.0, patients were given 180 ml of water (control phase), and gastric pH was allowed to return to baseline. After administration of a single, oral dose of didanosine 200 mg or 400 mg with 180 ml of water, gastric pH was recorded until pH remained below 3.0 for 10 minutes.. A mean pHmax of 8.6 (range 6.3-9.5) was achieved with a TpH-max of 4.1 minutes (range 1-12.0 min). Mean TpH>3 was 24.9 minutes (range 15-55 min), with an AUCT>pH 3 of 2.6 pH x min(-1) (range 1.2-6.9 pH x min(-1)). The two doses of didanosine tested did not differ significantly in mean gastric pH parameters.. After administration of chewable, dispersible, buffered didanosine tablets, 200 or 400 mg, the mean duration of elevated gastric pH (TpH>3) was less than 30 minutes, with a range of 15-55 minutes. Characterization of the magnitude and duration of elevated gastric pH may allow for earlier administration of other pH-sensitive drugs. The short duration of elevated gastric pH may help explain the wide variability in didanosine bioavailability observed clinically. Topics: Administration, Oral; Adult; Anti-HIV Agents; Area Under Curve; Buffers; Didanosine; Gastric Mucosa; HIV Infections; Humans; Hydrogen-Ion Concentration; Male; Mastication; Middle Aged; Prospective Studies; Tablets; Time Factors | 2004 |
Prevalence of toxoplasma encephalitis in AIDS patients treated with Didanosine hospitalised in a French infectious service.
In a previous work, we have showed in mice infected with an avirulent strain of Toxoplasma gondii and receiving a didanosine treatment, an important decrease of brain cysts. It is why, the purpose of this study was to investigate the effect of didanosine treatment on AIDS patients having developed Toxoplasma encephalitis. 60 patient reports were analyzed: 22 patients (group 1) did not received didanosine in their antiretroviral treatment and 38 (group 2) were treated with didanosine. The results showed that an antiretroviral therapy was prescribed for 93% of patients, 50% of them received only zidovudine and protease inhibitors were prescribed for 37%. The regimens given most frequently were those including zidovudine plus lamivudine or zidovudine plus indinavir. Among the group 1, 18% have had a relapse of Toxoplasma encephalitis. In the group 2, 37% of the patients suffered from one episode of TE while 16% have had two TE after the pause in their didanosine treatment, the maximum occurring between 4 and 24 months after the pause of didanosine. This study showed that didanosine seems to have an effect on cerebral cysts. Also, this work made a synthesis about the different treatment used in AIDS patients and the new molecules yet in development against T. gondii. Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Cohort Studies; Didanosine; Drug Therapy, Combination; Encephalitis; Female; France; HIV Infections; Hospitalization; Humans; Male; Middle Aged; Prevalence; Retrospective Studies; Reverse Transcriptase Inhibitors; Toxoplasmosis, Cerebral | 2004 |
Impact of a treatment including tenofovir plus didanosine on the selection of the 65R mutation in highly drug-experienced HIV-infected patients.
Data from 20 highly drug-experienced HIV-infected patients receiving tenofovir plus didanosine as part of a salvage regimen were analysed. At baseline, all but one patient harboured a virus bearing at least one nucleoside excision mutation (NEM); in 13 cases (65%) three or more NEM were detectable. After a median of 26 weeks of treatment, two patients (10%) selected the 65R mutation. These results support the hypothesis that NEM hinder the selection of this mutation. Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Databases, Genetic; Didanosine; DNA, Viral; Drug Resistance, Multiple, Viral; Gene Deletion; Genotype; HIV Infections; HIV-1; Humans; Mutation; Organophosphonates; Tenofovir | 2004 |
Warning on two specific 3-drug regimens: Viread + Didanosine + either Sustiva or Viramune.
Two more three-drug antiretroviral regimens have unexpectedly failed to control HIV in many patients. But some related regimens do seem to be working well. Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Organophosphonates; Oxazines; Tenofovir; United States; United States Food and Drug Administration | 2004 |
CD4 cell decline with didanosine and tenofovir and failure of triple nucleoside/nucleotide regimens may be related.
Topics: Adenine; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Lymphopenia; Organophosphonates; Purine-Nucleoside Phosphorylase; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure | 2004 |
Prevalence, risk factors and outcome of hyperlactataemia in HIV-infected patients.
We describe the prevalence, risk factors and outcome of hyperlactataemia (HL) in a cohort of 140 HIV-infected patients.. Patients were enrolled consecutively within a 3-month period (July to September 1999) and followed until 31 October 2000. One hundred and forty HIV-infected patients had venous plasma lactate levels measured. HL was defined at baseline by two consecutive lactate levels > 2.1 mmol/L (upper limit of normal). We compared baseline demographic characteristics, immuno-virological parameters, antiretroviral therapy and outcome between patients with HL (cases) or without HL (controls). We described the clinical features of patients with HL.. Among 129 patients included in the analysis, HL was found in 11 patients (8.5%), all of whom were receiving nucleoside reverse transcriptase inhibitors (NRTIs). Cases were more likely than controls to receive didanosine or stavudine (82% vs. 19%, P= 2.7 x 10(-6) and 82% vs. 48%, P= 0.03, respectively). Only 4/11 cases (36%) had symptoms consistent with HL. After a median follow-up of 15 months, lactate level returned to normal in all three patients who discontinued NRTIs, but in only 2/8 patients who did not (P = 0.06). Only one case experienced lactic acidosis and died during follow-up. Mortality rate was similar in cases and controls.. HL is associated with NRTI use, in particular didanosine and stavudine, and discontinuation of NRTIs seems to be associated with rapid resolution of HL. Lactic acidosis remains rare and the long-term outcome of patients with HL does not seem to be poorer than controls. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; Female; Follow-Up Studies; HIV Infections; Humans; Lactic Acid; Male; Middle Aged; Prevalence; Prognosis; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine | 2003 |
Symptomatic hyperlactatemia in an HIV-positive patient: a case report and discussion.
Prolonged exposure to highly active antiretroviral therapy may be associated with adverse effects related to mitochondrial toxicity, such as hyperlactatemia. We describe a case of symptomatic hyperlactatemia in an HIV-positive patient to illustrate the subtle clinical symptoms and abnormal laboratory test results associated with this condition. We also review the pathophysiology, prevalence, spectrum and management of disturbances in lactate homeostasis induced by nucleoside reverse transcriptase inhibitors. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; HIV Infections; Humans; Lactic Acid; Male; Reverse Transcriptase Inhibitors; Stavudine | 2003 |
Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy.
Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; Female; HIV Infections; HIV-1; Humans; Pregnancy; Pregnancy Complications, Infectious; Stavudine | 2003 |
New questions about an old combination--ddI + d4T.
For the last several years, the combination of ddI (didanosine, Videx) and d4T (stavudine, Zerit) as a backbone of three-drug therapy has been popular both in treatment and in research. Together, the two nucleoside analog reverse transcriptase inhibitor (NARTI) drugs offered relatively high strength and fairly simple use. Despite this, some researchers have long questioned the wisdom of the combination as it violates one of the key rules of combining drugs: combine only drugs with different side effect profiles. Both drugs are associated with the development of peripheral neuropathy and pancreatitis. Pancreatitis is more commonly seen with ddI and neuropathy with d4T, but both occur to a significant degree with each drug and to a higher degree than was seen with other drugs of their class. However, few if any studies were run comparing the ddI/d4T combination to alternatives such as AZT/3TC (Combivir) or even 3TC/d4T. Both ddI and d4T come from the same company, Bristol Myers Squibb. Topics: Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 2003 |
Acute hepatic failure and lactate acidosis associated with antiretroviral treatment for HIV.
Severe hepatotoxicity is a rare but potentially life-threatening side effect of antiretroviral therapy. In this case report we describe an HIV-positive patient who was admitted to our clinic with evidence of severe acute pancreatitis 18 months after the introduction of antiretroviral treatment, which included stavudine and didanosine. Shortly afterwards, she developed lactate acidosis and acute hepatic failure associated with renal failure. Renal support (hemofiltration) was required for three days. The patient subsequently developed grade III encephalopathy, as well as a large pleural effusion and ascites. Although the reported outcome of patients with liver failure due to antiretroviral treatment is poor, with a high mortality rate, our patient fully recovered after intensive supportive care and cessation of the antiretroviral agents. Liver biopsy revealed microvesicular steatosis and giant mitochondria, which are the typical hallmarks of mitochondrial damage, the presumed mechanism of antiretroviral drug toxicity. More than three years later the patient has an excellent clinical status with a stable HIV infection and no need for antiretroviral treatment. This case report indicates the need for increased awareness of the potential hepatotoxicity of an antiretroviral therapy, as severe side effects may occur more frequently with increasing use of such treatment. Topics: Acidosis, Lactic; Acute Disease; Adult; Anti-HIV Agents; Biopsy; Critical Care; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Liver; Liver Failure; Pancreatitis; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography; Zidovudine | 2003 |
Didanosine, interferon-alfa and ribavirin: a highly synergistic combination with potential activity against HIV-1 and hepatitis C virus.
To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-alpha), and ribavirin for potential synergy in inhibition of HIV-1 replication in vitro.. Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1(IIIB) or the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-alpha, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC(50)) for the various drugs in replicate assays. Analysis of combined effects was performed using both the median effect principle (CalcuSyn, Biosoft) and three-dimensional modelling (MacSynergy II).. The triple combination was highly synergistic against HIV-1 in vitro with combination indices < 1. The mean IC(50) was reduced from 6.85 to 0.90 micromol/l (P < 0.001) for ddI and from 6.58 to 1.00 micromol/l (P < 0.001) for IFN-alpha. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-alpha resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77-191] with 5 U IFN-alpha and 214.92 (95% CL, 116-314) with 10 U. This supporting the observation that the majority of the synergistic activity was derived from the combination of ddI and ribavirin, with IFN-alpha providing additional additive suppression.. This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study to determine if can be safely administered in the clinical setting. Topics: Anti-HIV Agents; Cells, Cultured; Didanosine; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Drug Synergism; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Interferon-alpha; Ribavirin; Virus Replication | 2003 |
Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) nephrotoxicity in rats.
Zidovudine (AZT) and didanosine (ddI) are antiretroviral drugs widely used in AIDS patients. Hypokalemia and hypomagnesemia are frequently encountered in AIDS patients using AZT and/or ddI.. To verify the effects of AZT and ddI on rat renal function submitted to normal diet, low potassium diet and magnesium-free diet.. Glomerular filtration rate and renal hemodynamic were measured in Wistar rats submitted to a normal or a potassium-depleted diet. The animals were given AZT, ddI for 15 days. Six groups of rats were studied: normal diet, normal diet + AZT, normal diet + ddI, low K diet, low K diet + AZT and low K diet + ddI. Three additional groups of rats submitted to magnesium depletion for 15 days were also studied: magnesium-free diet, magnesium-free diet + AZT and magnesium-free diet + ddI.. AZT and didanosine did not modify renal function of rats on a normal diet. However, in hypokalemic rats, both drugs produced a decrease in glomerular filtration rate and in renal blood flow consequent to renal vasoconstriction and associated with alterations in tubular function (characterized by an increased fractional excretion of sodium). Hypomagnesemia induced a decrease in glomerular filtration rate and in renal blood flow only in AZT-treated rats.. Our data suggest that hypokalemia predisposes to AZT and ddI nephrotoxicity, while hypomagnesemia predisposes only to AZT nephrotoxicity. Thus, chronic AZT and ddI administration may produce acute renal failure in AIDS patients with hypokalemia and/or hypomagnesemia. Serum K and Mg levels should be carefully monitored in these patients. Topics: Acute Kidney Injury; Animals; Anti-HIV Agents; Didanosine; Diet; Disease Models, Animal; HIV Infections; Hypokalemia; Magnesium; Male; Rats; Rats, Wistar; Risk Factors; Zidovudine | 2003 |
Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: a case-control study.
A case-control study was undertaken to determine risk factors for lactic acidosis in human immunodeficiency virus-infected patients treated with nucleoside reverse-transcriptase inhibitors (NRTIs). From May 1996 to June 2000, 9 patients with lactic acidosis (defined as a plasma lactic acid level of >5 mM and plasma pH of <7.38) were identified. Control patients were randomly selected from among a large cohort of patients who initiated a dual NRTI regimen in 1996 or after. Two factors were associated with an increased risk of lactic acidosis: first, a creatinine clearance of <70 mL/min before lactic acidosis (OR, 15.8 [range, 3.0-86.5], P<10(-4)), and, second, a low nadir CD4+ T lymphocyte count before the inception of NRTI therapy (OR, 8.4 [range, 1.2-infinity], P=.03). The total cumulative exposure to NRTIs was not associated with an increased risk of lactic acidosis, nor was the cumulative exposure to any of the 4 NRTIs studied. According to these results, monitoring of creatinine clearance, especially in patients with a low nadir CD4+ T lymphocyte count, could lead to modifications in antiretroviral therapy in order to diminish the risk of occurrence of lactic acidosis. Topics: Acidosis, Lactic; Adult; Case-Control Studies; Didanosine; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine | 2003 |
[Observational study on the efficacy of the application of two classical regimens of triple antiretroviral therapy].
To compare the temporal evolution of viral load and CD4 parameters in two cohorts of HIV infected patients enrolled in classical triple antiretroviral regimens.. Retrospective, observational, descriptive study of the proportions of patients reaching undetectable levels of viral load (VL) as well as the time necessary to get it. The two cohorts were as follows: 91 HIV patients on triple therapy with zidovudine plus lamivudine and indinavir (cohort A) versus 80 HIV patients with Stavudine plus Didanosine and Indinavir (cohort B).. The evolution of the patients in terms of percentages who reach undetectable VL was similar in the two therapeutic cohorts (75.8%for cohort A vs 73.8% for cohort B) along the duration of the study (four years). However, the mean time period needed to reach undetectable VL was different, 209 days (IC 95% 175-243 days) for patients in zidovudine plus lamivudine and indinavir and 330 days (IC 95% 263-396 days) for stavudine plus didanosine and indinavir regimen. The immunological status observed in the patients when reaching his first undetectable VL was significantly different. The proportion of patients with CD4 cells counts >200/mm3 in cohort A was 83.1% while for patients from cohort B was 65.4% (p=0.032).. This observational study from clinical settings seems demonstrate similar efficacy to reach undetectable VL with both classical triple antiretroviral therapies evaluated but a shorter delay of time to reach that virological situation for zidovudine plus lamivudine and indinavir regimen is reported. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Didanosine; Drug Evaluation; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Retrospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Treatment Outcome; Viral Load; Zidovudine | 2003 |
Pancreatitis in an HIV-infected person on a tenofovir, didanosine and stavudine containing highly active antiretroviral treatment.
Topics: Adenine; Adult; Antiretroviral Therapy, Highly Active; Didanosine; Drug Interactions; Female; HIV Infections; Humans; Organophosphonates; Organophosphorus Compounds; Pancreatitis; Ritonavir; Stavudine; Tenofovir | 2003 |
Incidence of liver toxicity in hiv-infected patients receiving isolated dual nucleoside analogue antitretroviral therapy.
Topics: Adult; Alanine Transaminase; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Incidence; Liver; Male; Middle Aged; Stavudine | 2003 |
Fatal lactic acidosis and mimicking Guillain-Barré syndrome in an adolescent with human immunodeficiency virus infection.
We report a case of antiretroviral therapy-related fatal lactic acidosis occurring in a vertically infected HIV-positive 17-year-old patient. While receiving antiretroviral therapy with stavudine, didanosine, tenofovir and amprenavir, the patient developed severe acidosis and rapid neuromuscular and respiratory failure mimicking Guillain-Barré syndrome. Topics: Acidosis, Lactic; Adenine; Adolescent; Antiretroviral Therapy, Highly Active; Carbamates; Diagnosis, Differential; Didanosine; Disease Progression; Drug Therapy, Combination; Fatal Outcome; Female; Furans; Guillain-Barre Syndrome; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Organophosphonates; Organophosphorus Compounds; Risk Assessment; Severity of Illness Index; Stavudine; Sulfonamides; Tenofovir | 2003 |
Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy.
Pancreatitis and lactic acidosis are severe and life-threatening adverse events associated with nucleoside analogue antiretroviral therapy used to treat HIV infection. The drug from this class most commonly associated with these adverse events is stavudine, although zidovudine and didanosine have also been implicated. Ribavirin is a nucleoside analogue used in combination with interferon alfa to treat hepatitis C. Because of similar mechanisms of action, the combination of these 2 drugs could potentially increase such toxicity. A case of fatal lactic acidosis and pancreatitis is described in an HIV-infected patient coinfected wtih hepatitis C on a didanosine-containing antiretroviral regimen after treatment of hepatitis C was initiated with ribavirin and pegylated interferon alfa-2b. Extreme caution should be exercised when didanosine and ribavirin are used concomitantly because of the increased risk of mitochondrial toxicity and the syndrome of severe metabolic acidosis with elevated lactic acid levels. Topics: Acidosis, Lactic; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Synergism; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Pancreatitis; Recombinant Proteins; Ribavirin; Risk Factors; Viral Load | 2003 |
Semiparametric regression analysis of longitudinal data with informative drop-outs.
Informative drop-out arises in longitudinal studies when the subject's follow-up time depends on the unobserved values of the response variable. We specify a semiparametric linear regression model for the repeatedly measured response variable and an accelerated failure time model for the time to informative drop-out. The error terms from the two models are assumed to have a common, but completely arbitrary joint distribution. Using a rank-based estimator for the accelerated failure time model and an artificial censoring device, we construct an asymptotically unbiased estimating function for the linear regression model. The resultant estimator is shown to be consistent and asymptotically normal. A resampling scheme is developed to estimate the limiting covariance matrix. Extensive simulation studies demonstrate that the proposed methods are suitable for practical use. Illustrations with data taken from two AIDS clinical trials are provided. Topics: Child; Clinical Trials as Topic; Computer Simulation; Didanosine; HIV Infections; Humans; Longitudinal Studies; Models, Statistical; Numerical Analysis, Computer-Assisted; Patient Dropouts; Regression Analysis; Time Factors; Zidovudine | 2003 |
Pancreatitis with didanosine and tenofovir disoproxil fumarate [corrected].
Pancreatitis occurs in up to 7% of patients infected with human immunodeficiency virus who are treated with standard doses of didanosine. Tenofovir disoproxil fumarate increases the plasma levels of didanosine and, thus, the combination of these agents may increase the risk of pancreatitis. Four cases of pancreatitis that occurred during administration of this drug combination are examined, including 1 that resulted in death. Topics: Adenine; Adult; Didanosine; Drug Interactions; Fatal Outcome; Female; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Organophosphorus Compounds; Pancreatitis; Tenofovir | 2003 |
Matched case-control study to evaluate risk factors for hyperlactataemia in HIV patients on antiretroviral therapy.
Lactic acidosis is a life-threatening event during antiretroviral therapy (ART). Hyperlactataemia may be a prelude to acidosis. Our database study suggested that female gender, intercurrent illness and didanosine (ddI)-based regimens may increase risk of lactic acidosis. The aim of this matched case-control study was to identify risk factors for hyperlactataemia requiring screening.. Cases were defined as patients with two consecutive lactate samples > or =3.5 mmol/L taken more than 1 week apart. Cases were matched to two controls on gender, use of ddI and total duration of therapy using a 6-month window on either side. Controls never had raised lactate >2.5 mmol/L. A conditional logistic regression analysis using the PHREG procedure in SAS (SAS Institute Inc, Cary, NC) was performed with a discreet logistic model stratified by matching variables.. Twenty-one cases were matched to 42 controls. In the univariate model, current use of stavudine (d4T), total cholesterol >5.3 mmol/L and glucose levels > or =5.2 mmol/L gave increased likelihood of persistent hyperlactataemia. The multivariate model showed current use of d4T to be a significant independent predictor of persistent hyperlactataemia.. The results of this case-control study indicate that, when controlling for ddI use, d4T use is an additional risk factor for hyperlactataemia. Topics: Acidosis, Lactic; Anti-HIV Agents; Case-Control Studies; Didanosine; Female; HIV Infections; Humans; Lactic Acid; Male; Multivariate Analysis; Risk Factors; Sex Factors; Stavudine | 2003 |
Fatal lactic acidosis during antiretroviral therapy.
To describe the first pediatric case of fatal lactic acidosis in an antiretroviral-treated child with human immunodeficiency virus (HIV) infection.. Case report.. Pediatric intensive care unit.. A patient with fatal antiretroviral therapy-associated type B lactic acidosis.. None.. We report the case of a 5-yr-old girl with HIV infection, receiving ritonavir, stavudine, and didanosine, who presented with a 10-day history of nausea and vomiting. Severe lactic acidosis was found. Her clinical condition worsened, with progressive increase in serum lactate, despite aggressive supportive therapy, including intravenous alkali and continuous arteriovenous hemodiafiltration.. Fatal lactic acidosis is a complication of antiretroviral therapy in pediatric HIV patients, which has not been previously reported in children. Early recognition of mitochondrial dysfunction in these patients could prevent the development of fatal lactic acidosis. Topics: Acidosis, Lactic; Child, Preschool; Didanosine; Fatal Outcome; Female; HIV Infections; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine | 2003 |
Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis.
To evaluate the safety and efficacy of rechallenging patients who have recovered from nucleoside reverse transcriptase inhibitor (NRTI)-induced symptomatic hyperlactatemia or lactic acidosis with alternative NRTI-containing regimens.. Data in this case series was collected from patients followed at the UCSD Owen Clinic from July 1998 through September 2002. Cases of symptomatic hyperlactatemia were HIV-infected adults receiving NRTI who had symptoms compatible with hyperlactatemia and two lactates > 2 times the upper normal limit. Lactic acidosis was defined as lactate > 5 mmol/l with bicarbonate < 20 mmol/l. The suspected offending NRTI in the prior regimen were replaced with other NRTI thought to have equivalent antiviral potency but less mitochondrial toxicity.. Ten patients diagnosed with symptomatic hyperlactatemia and two with lactic acidosis were later restarted on antiretrovirals that included new NRTI. The NRTI that patients were receiving when symptomatic hyperlactatemia or lactic acidosis was diagnosed included stavudine and lamivudine (n = 6), stavudine and didanosine (n = 4), and stavudine and abacavir (n = 2). The median (range) peak lactate was 5.4 (4.7-19.1) mmol/l. Five patients were rechallenged with abacavir and lamivudine, five with zidovudine, abacavir and lamivudine, and two with zidovudine and lamivudine. Among the 12 patients contributing over 22 years of cumulative reexposure to NRTI-containing therapy, one developed symptomatic hyperlactatemia again yielding a recurrence rate of 45.5 cases/1000 patient-years. Virologic control was maintained in all patients.. This data supports the strategy that in cases of symptomatic hyperlactatemia or lactic acidosis in which the toxicity is associated with stavudine, didanosine or both, it is safe and efficacious to reintroduce NRTI that are less potent inhibitors of mitochondria. Topics: Acidosis, Lactic; Adult; Alanine Transaminase; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Zidovudine | 2003 |
[A short-term trial of Didanosine, stavudine, and nevirapine combination therapy for human immunodeficiency virus infection].
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Stavudine | 2003 |
HIV biological variability unveiled: frequent isolations and chimeric receptors reveal unprecedented variation of coreceptor use.
To follow the evolution of coreceptor use in HIV-1-infected individuals with varying rates of disease progression.. The coreceptor use of 278 sequential HIV-1 isolates from 23 individuals was tested by infection of two human cell lines, U87.CD4 and GHOST(3), expressing CD4 and CCR1, CCR2b, CCR3, CCR5, CXCR4, CXCR6 or BOB. Differences in coreceptor use were further dissected by testing chimeric coreceptors constructed by exchanging successively larger parts of CCR5 for corresponding regions of CXCR4.. Three patterns of coreceptor use were distinguished: no evolution, evolution to CXCR4 use, and fluctuation. No evolution with stable CCR5 use (R5 phenotype) was linked to slow progression over 8-10 years in four patients. CXCR4-using virus was present from the onset (five patients) or appeared during clinical progression in all other patients, while taking zidovudine or didanosine monotherapy. The fluctuating pattern of coreceptor use, defined as reappearance of virus with R5 phenotype, was observed in five patients and, interestingly, followed initiation of highly active antiretroviral therapy in three of these. Monotropic R5 or X4 viruses were more selective in chimeric receptor use than R5X4 or multitropic viruses. Most importantly, the efficiency of chimeric receptor use increased over time.. The increase in efficiency of chimeric receptor use allows a new interpretation of evolution of HIV-1 coreceptor use. Evolution could be a continuous process that may lead to changes in the way a coreceptor is used, with the potential of profound alteration in signalling at that receptor. Topics: Adult; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cell Line; Didanosine; Disease Progression; Evolution, Molecular; Genetic Variation; HIV Infections; HIV-1; Humans; Male; Phenotype; Receptors, CCR5; Receptors, CXCR4; Receptors, HIV; Recombinant Fusion Proteins; Virus Replication; Zidovudine | 2003 |
Didanosine-ribavirin combination: synergistic combination in vitro, but high potential risk of toxicity in vivo.
Topics: Anti-HIV Agents; Antiviral Agents; Didanosine; Drug Synergism; Drug Therapy, Combination; Hepatitis C; HIV Infections; HIV-1; Humans; Interferon-gamma; Ribavirin | 2003 |
Nevirapine plus efavirenz plus didanosine: a simple, safe, and effective once-daily regimen for patients with HIV infection.
Conventional highly active antiretroviral therapy (HAART) regimens used to treat human immunodeficiency virus (HIV) infection typically use nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because PI-based regimens are associated with significant long-term toxicity and adherence difficulty, there is a need for novel regimens that maximize combination treatment options. This 12-month, observational, cohort study evaluated the efficacy, safety, and tolerability of a novel three-drug HAART regimen. Drug treatment consisted of nevirapine (NVP), efavirenz (EFV), and didanosine (ddl). Twenty-six treatment-naive and -experienced HIV-1+ men and women were included in the study. Assessment consisted of CD4+ cell count, plasma HIV-1 RNA load, and adverse effects of study medications. After one year of therapy, 11/12 treatment-naive subjects (92%) and 8/9 treatment-experienced subjects (89%) had viral loads < 400 copies/mL. Both groups also had an excellent immune response. At one year, there was a mean increase of 438 CD4+ cells/mm3 among treatment-naive subjects and 367 cells/mm3 among treatment-experienced subjects. Treatment-limiting adverse effects occurred in 3/15 treatment-naive (20%) and 2/11 treatment-experienced (18%) subjects. These preliminary data suggest that the combination of NVP, EFV, and ddl is simple, safe, and effective. Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Didanosine; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Oxazines; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome | 2003 |
Efficacy and safety of ritonavir/indinavir 100/400 mg twice daily in combination with two nucleoside analogues in antiretroviral treatment-naive HIV-infected individuals.
To evaluate the efficacy and tolerability of indinavir/ritonavir (IDV/RTV) 400/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors in antiretroviral-naive patients.. Antiviral therapy-naive patients with plasma HIV-1 RNA > 5000 copies/ml were enrolled in this pilot, single-arm study. CD4 cell count and viral load were evaluated at weeks (W) 4, 12, 24 and every 3 months until W48. The primary end-point was the percentage (%) of patients with viral load < 400 copies/ml at W48. Intent-to-treat (ITT) (missing values or change in treatment equalled failure) and on-treatment (OT) analyses were performed.. Forty patients were enrolled. Baseline median viral load was 5.36 log10 copies/ml, median CD4 count was 84 cells/mm3. At W48 by ITT analysis, the % patients with viral load < 400 copies/ml was 65% (95% CI: 48-79) and 50% (95% CI: 35-65) with viral load < 50 copies/ml, and 96% (26/27) (95% CI: 89-100) and 74% (95% CI: 57-91], respectively, by OT analysis. The median decrease in viral load at W48 was -3.83 log10 copies/ml (-0.1; -5.19) and the median increase in CD4 was +167 cells/mm3 (6-474 cell/mm3). At W4 (34/40), the median IDV C(min) was 500 ng/ml (range 5-8100) with 91% of patients with an adequate IDV C(min) > 150 ng/ml. Ten patients discontinued the study treatment before W48: adverse events (eight), patient's will (one) and simplification of therapy (one). Three patients were lost to follow-up. Only one virological failure occurred and was associated with poor compliance and sub-optimal concentrations of IDV/RTV.. IDV/RTV 400/100 mg twice daily is an effective and safe first-line antiretroviral therapy. The simplicity and the low cost of IDV/RTV is of major interest particularly in countries with limited resources. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Ritonavir; Stavudine; Zidovudine | 2003 |
High rate of virologic failure with once-daily ddI/3TC/TDF.
Topics: Adenine; Didanosine; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load | 2003 |
French investigators warn of LPV/TDF/ddI interaction.
Topics: Adenine; CD4 Lymphocyte Count; Didanosine; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load | 2003 |
Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors.
To evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy.. Cross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Cox's proportional hazards model.. Patients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated > or = 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Cox's proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlactataemia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactataemia. Choice of thymidine analogue did not influence risk. Hyperlactataemia was associated with acid-base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis.. Screening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid-base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Lactic Acid; Longitudinal Studies; Male; Multivariate Analysis; Prospective Studies; Reproducibility of Results; Risk Factors; Sex Factors; Thymidine | 2002 |
[Mononucleosis syndrome with viro-immunologic parameters similar to those of a primary HIV-1 infection after interruption of highly effective anti-retroviral treatment].
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-CD8 Ratio; Depression; Didanosine; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infectious Mononucleosis; Male; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Treatment Refusal; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load; Viremia; Zalcitabine; Zidovudine | 2002 |
[Cytomegalovirus retinitis after highly active antiretroviral therapy: a case report].
An HIV infected patient with cytomegalovirus retinitis with a CD4 lymphocyte count of 498 cells/mm3 after a good response to highly active antiretroviral therapy is described.. Some aspects of the immune system after highly active antiretroviral therapy remain unknown. CD4 T lymphocyte count might not be a good marker to identify some patients at risk of developing cytomegalovirus retinitis after this therapy. Topics: Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Cytomegalovirus Retinitis; Didanosine; Ganciclovir; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Retinal Hemorrhage; Reverse Transcriptase Inhibitors; Risk; Saquinavir; Stavudine; Substance Abuse, Intravenous; Zidovudine | 2002 |
Phenotypic and genotypic HIV-1 drug resistance assays provide complementary information.
To determine the extent to which genotype (GT) or phenotype (PT) methods provide HIV-1 drug resistance information that is overlapping or complementary, both tests were performed on 1378 patient plasma samples. Discordance, defined as determination of reduced susceptibility measured by PT but sensitivity by GT (PT-R/GT-S), or vice versa (PT-S/GT-R), was common: 83, 62, 43, and 28% of samples with evidence of drug resistance had at least 1, 2, 3, or 4 drugs discordant, respectively. Three types of discordance were observed: PT-R/GT-S, and PT-S/GT-R with or without the presence of mixtures at resistance-associated positions (25%, 34%, and 41% of all discordance, respectively). After accounting for mixtures, results for didanosine (30%), zalcitabine (18%), tenofovir (17%), abacavir (14%), lamivudine (12%), and amprenavir (11%) were discordant in >or= 10% of samples. PT-S/GT-R results were most common for didanosine and zalcitabine, whereas PT-R/GT-S results were most common for lamivudine and amprenavir. PT provided quantitative assessment of the degree of reduced susceptibility and identified reduced susceptibility (PT-R/GT-S) or normal susceptibility (PT-S/GT-R) that was not recognized by the GT interpretation algorithm. GT provided valuable information when mixtures were present and minor populations of drug resistant virus were not detected by phenotyping (PT-S/GT-R results). This demonstrates the complementary nature of information provided by PT and GT tests and suggests that their combined use can provide additional clinically-relevant information. Topics: Adenine; Anti-HIV Agents; Carbamates; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir; Zalcitabine | 2002 |
Significant differences between plasma HIV-1 RNA assays in HIV-1 subtype E infected patients treated with antiretroviral therapy.
A total of 72 HIV-1 infected Thai patients treated with didanosine (ddI) or stavudine (d4T) plus ddI at the time of interim analysis were analyzed. Sixty patients (83%) carried subtype E documented by HIV-1 V3 serotyping. HIV-1 RNA levels were measured using three commercial viral load assays. At baseline (n = 57), Quantiplex 2.0 and NucliSens 2.0 showed mean log10 HIV-1 RNA of 0.7 log10 or 5 fold lower than Amplicor 1.5 (mean 4.29 versus 5.0 log10, respectively, p < 0.001). At week 20 of treatment (n = 29), HIV-1 RNA levels were detected in 55.2%, 31%, and 33.5% of subjects tested by Amplicor 1.5, Quantiplex 2.0, and NucliSens 2.0, respectively.. plasma HIV-1 RNA analyses showed comparable values with Quantiplex 2.0 and NucliSens 2.0 assays. In contrast, Amplicor 1.5 resulted in approximately 5 folds higher HIV-1 RNA levels and a 25% higher rate of detection of plasma HIV-1 RNA as compared to the other two assays. As the current goal of therapy is to suppress plasma viral load below the detection limit of the assays, the significant differences between the assays may influence antiretroviral efficacy evaluation and management. Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Branched DNA Signal Amplification Assay; Cohort Studies; Didanosine; Female; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Prospective Studies; RNA, Viral; Self-Sustained Sequence Replication; Serotyping; Stavudine; Thailand; Treatment Outcome | 2002 |
Single-dose pharmacokinetics of enteric-coated didanosine in HIV-infected children.
Didanosine remains a cornerstone nucleoside analogue for the treatment of HIV infection. A potential problem with the buffered formulations of didanosine is the likelihood of interactions with other drugs that require an acidic pH for absorption or can be chelated by cations in the buffer. An encapsulated enteric-coated (EC) bead formulation of didanosine has been approved and is routinely used as an alternative to the chewable/dispersible buffered tablet formulation. The objective of this study was to evaluate the single-dose pharmacokinetics of didanosine EC at 240 mg/m2 in 10 HIV-infected children. Didanosine EC was administered at time 0 on an empty stomach with no other concomitant medications. Blood samples were collected at pre-dose, 0.5, 1, 2, 4, 8 and 12 h post-dose. Didanosine was measured in plasma using radioimmunoassay. Ten subjects completed the intensive pharmacokinetic evaluation; data are available for eight participants. Plasma concentrations of didanosine following EC administration were analysed using non-compartmental methods. Median (range) AUCinfinity, Cmax, Tmax and CL/F for didanosine following EC administration were 2385 (1291, 3966) ng x h/ml, 854 (300, 1799) ng/ml, 3.0 (1.0, 8.1) h and 3.3 (2.7-6.4) l/h/kg, respectively. Results from this study indicate that the didanosine Cmax is decreased and Tmax is prolonged, but total exposure of didanosine in plasma following didanosine EC administration appears similar to previous data collected in HIV-infected children following buffered didanosine administration. Topics: Anti-HIV Agents; Area Under Curve; Chemistry, Pharmaceutical; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Male; Tablets, Enteric-Coated | 2002 |
New warning for ddI.
Topics: Anti-HIV Agents; Antiviral Agents; Didanosine; Drug Interactions; Drug Labeling; Hepatitis C; HIV Infections; Humans; Ribavirin | 2002 |
Lymphocytes proliferate in blood and lymph nodes following interleukin-2 therapy in addition to highly active antiretroviral therapy.
Substantial redistribution of lymphocytes occurs upon the initiation of highly active antiretroviral therapy (HAART) and immune-based HIV therapies.. To evaluate the relative contribution of apoptosis and proliferation to changes in lymphocyte populations in peripheral blood and lymph node resulting from interleukin-2 (IL-2) therapy in patients receiving stable HAART.. Lymphocyte apoptosis was analyzed on various subtypes using fluorescence activated cell sorting with an annexin-V antibody in peripheral blood and by the TUNEL (terminal uridine nucleotide end labelling) method in corresponding lymph node sections. Lymphocyte proliferation was evaluated using an antibody against the cell cycle-associated marker Ki-67 (MIB-1) in peripheral blood and lymph nodes.. A transient increase in apoptosis was seen in peripheral blood and lymph nodes during a cycle of subcutaneous IL-2. A pronounced proliferative effect of IL-2 (from 6.4% of total lymphocytes in patients only treated with HAART to 23.4% in those treated with HAART + IL-2) was detected in peripheral blood, affecting the CD4, CD8 and CD16/56 subsets to a similar extent. Remarkably, the proliferative effect also occurred in lymphoid tissues. While the lymph node structure gradually disintegrated over 24 months in some individuals, the amount of proliferating lymphocytes, including CD4 cells, B cells and follicular dendritic cells, greatly increased upon IL-2, while HIV RNA load in lymph nodes remained unaffected.. These results show that IL-2 leads to lymphocyte proliferation in peripheral blood and lymph nodes without an impact on viral load in lymphoid tissue. These results have important implications for attempts to reconstitute the immune system in HIV disease. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Apoptosis; B-Lymphocytes; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cell Division; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunotherapy; Interleukin-2; Lymph Nodes; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; T-Lymphocytes; Zidovudine | 2002 |
Acanthosis nigricans: a new manifestation of insulin resistance in patients receiving treatment with protease inhibitors.
Topics: Acanthosis Nigricans; Adult; Diabetes Mellitus; Didanosine; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Male; Ritonavir; Zidovudine | 2002 |
Resistance to antiretroviral treatment in Gabon: need for implementation of guidelines on antiretroviral therapy use and HIV-1 drug resistance monitoring in developing countries.
The protease and reverse transcriptase (RT) genes were studied in antiretroviral (ARV)-experienced and drug-naive HIV-1-infected individuals in Libreville, Gabon. We have shown, although on a limited number of samples that in 58% (11/19) of the patients, with a mean of 17.7 months of ARV drug experience, major mutations inevitably inducing resistances to ARV drugs were present. Resistance was mainly observed to the NRTIs (nucleoside analogue RT inhibitors). This high prevalence may reflect inappropriate ARV drug use. In order to avoid the rapid emergence of resistant viruses on a large scale in the developing world, it is important that the infrastructures necessary to monitor ARV treatment are also rapidly implemented in these countries and that clinicans are trained in the appropriate use of ARV drugs. A continuous surveillance of the circulation of ARV drug-resistant viruses must be organized to guide ARV treatment strategies and policies. Topics: Anti-HIV Agents; Developing Countries; Didanosine; Drug Resistance, Viral; Gabon; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Population Surveillance; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 2002 |
The dangers of inferring treatment effects from observational data: a case study in HIV infection.
Several recent articles have implicitly questioned the need for randomized controlled trials, based on a comparison of treatment effects from observational studies and related randomized controlled trials. We present here a counterexample of a comparison of two antiretroviral drugs used in the treatment of HIV infection, in which the observational analysis gave a potentially misleading result. Examples such as this emphasize the need to regard randomized controlled trials as the primary mechanism for assessing therapeutic efficacy. Topics: Adult; Anti-HIV Agents; Data Interpretation, Statistical; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Observation; Randomized Controlled Trials as Topic; Selection Bias; Zalcitabine; Zidovudine | 2002 |
Impact of missing data due to selective dropouts in cohort studies and clinical trials.
Many cohort studies and clinical trials use repeated measurements of laboratory markers to track disease progression and to evaluate new therapies. A major problem in the analysis of such studies is that marker data are censored in some patients owing to withdrawal, loss to follow-up, or death. The objective of this paper is to evaluate the impact of selective dropouts attributable to death or disease progression on the estimates of marker change among different groups.. Data on CD4 cell count in human immunodeficiency virus 1-infected individuals from a clinical trial and a cohort study are used to illustrate this problem and a possible solution. Simulation studies are also presented.. When the rate of dropout is greater in subjects whose marker status is declining rapidly, commonly used methods, like random effects models, that ignore informative dropouts lead to overoptimistic statements about the marker trends in all compared groups, because subjects with steeper marker drops tend to have shorter follow-up times and hence are weighted less in the estimation of the group rate of the average marker decline.. The potential biases attributable to incomplete data require greater recognition in longitudinal studies. Sensitivity analyses to assess the effect of dropouts are important. Topics: Adolescent; Adult; Bias; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Data Interpretation, Statistical; Didanosine; Hemophilia A; HIV Infections; Humans; Infant; Least-Squares Analysis; Longitudinal Studies; Middle Aged; Models, Theoretical; Patient Dropouts; Randomized Controlled Trials as Topic | 2002 |
Hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for HIV-1.
Most people who have HIV-1 and live in less-developed countries cannot afford standard combination antiretroviral therapy, and more economical approaches to treatment are therefore needed. We treated 22 patients who were infected with HIV-1 (viral load < 100000 copies/mL and CD4 count >150 cells/microL) with hydroxychloroquine (200 mg), hydroxycarbamide (hydroxyurea) (500 mg), and didanosine (125-200 mg), taken twice daily. Treatment was well tolerated, with few serious adverse events. Viral load showed a sustained decrease of 1 3 log, and CD4 count was maintained (percentage increase; 2 9%) over 48 weeks in the 16 evaluable patients. This new combination of drugs could be suitable for countries that have restricted resources, but should first be further investigated. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; Female; HIV Infections; HIV-1; Humans; Hydroxychloroquine; Hydroxyurea; Male; Pilot Projects; Treatment Outcome; Viral Load | 2002 |
Side effects. FDA issues warning about d4T and ddI during pregnancy.
Topics: Didanosine; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration | 2001 |
d4T plus ddI: warning for pregnant women.
New data suggests that pregnant women may be at increased risk of lactic acidosis from the combination of d4T and ddI. Topics: Acidosis, Lactic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine | 2001 |
Drug Points: pancreatitis associated with hydroxyurea in combination with didanosine.
Topics: Acute Disease; Adult; Anti-HIV Agents; Didanosine; Drug Combinations; HIV Infections; Humans; Hydroxyurea; Male; Nucleic Acid Synthesis Inhibitors; Pancreatitis | 2001 |
Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco PEP Study.
The feasibility of providing postexposure prophylaxis (PEP) after sexual or injection drug use exposures to human immunodeficiency virus (HIV) was evaluated. PEP was provided within 72 h to individuals with exposures from partners known to have or to be at risk for HIV infection. PEP consisted of 4 weeks of antiretroviral medications and individually tailored risk-reduction and medication-adherence counseling. Among 401 participants seeking PEP, sexual exposures were most common (94%; n=375). Among sexual exposures, receptive (40%) and insertive (27%) anal intercourse were the most common sexual acts. The median time from exposure to treatment was 33 h. Ninety-seven percent of participants were treated exclusively with dual reverse-transcriptase inhibitors, and 78% completed the 4-week treatment. Six months after the exposure, no participant developed HIV antibodies, although a second PEP course for a subsequent exposure was provided to 12%. PEP, after nonoccupational HIV exposure, is feasible for persons at risk for HIV infection. Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Contact Tracing; Counseling; Didanosine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Patient Compliance; Reverse Transcriptase Inhibitors; Risk Factors; Risk-Taking; Sexually Transmitted Diseases, Viral; Substance Abuse, Intravenous; Time Factors; Zidovudine | 2001 |
Treatment interruption after one year of triple nucleoside analogue therapy for primary HIV infection.
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Time Factors; Viral Load; Zidovudine | 2001 |
[Bilateral hip necrosis, corticoids, and human immunodeficiency virus protease inhibitors].
Topics: Aged; Antiretroviral Therapy, Highly Active; Dexamethasone; Didanosine; Femur Head Necrosis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Prednisone; Zidovudine | 2001 |
Dynamics of seminal plasma HIV-1 decline after antiretroviral treatment.
Topics: Alkynes; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzoxazines; Cyclopropanes; Didanosine; Environmental Monitoring; HIV Infections; HIV-1; Humans; Hydroxyurea; Lamivudine; Male; Oxazines; Semen; Time Factors; Viral Load | 2001 |
Bristol-Myers warns of AIDS drugs' use.
Topics: Acidosis, Lactic; Anti-HIV Agents; Didanosine; Drug Industry; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Stavudine | 2001 |
Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs.
Pancreatitis is a known adverse effect of the nucleoside reverse transcriptase inhibitors, particularly didanosine. Hydroxyurea has been used to potentiate the antiviral efficacy of didanosine, but recently there has been concern that severe and even fatal pancreatitis may be more likely to occur when hydroxyurea is used in combination with didanosine. We investigated the incidence of pancreatitis in patients using nucleoside analogues with or without hydroxyurea.. Data were obtained from patients followed longitudinally on the Johns Hopkins HIV Clinic. Incidence rates of pancreatitis were calculated for each antiretroviral regimen that included zidovudine, stavudine, didanosine (+ hydroxyurea), and didanosine + stavudine (+ hydroxyurea). Poisson regression was used to compare the relative rate of pancreatitis for each regimen adjusting for other covariates.. A total of 2613 patients received at least one of the nucleoside reverse transcriptase inhibitor-containing regimens. There were 33 cases of pancreatitis. The crude incidence rate of pancreatitis ranged from 0.18 cases per 100 person-years on therapy for zidovudine to 6.25 cases per 100 person-years for didanosine + hydroxyurea. Compared to didanosine alone, and adjusting for CD4 cell count and other variables, the relative risk (RR) of pancreatitis was 8.56 [95% confidence interval) CI, 1.85-35.59] for didanosine + hydroxyurea, and 2.35 (95% CI, 0.46-11.89) for didanosine + stavudine + hydroxyurea. For any use of hydroxyurea, the RR = 4.01 (95% CI, 1.02-15.89). Other risk factors for pancreatitis included a CD4 cell count < 200 x 106 cells/l, female sex, and a history of pancreatitis.. Our data show that the risk of pancreatitis is four-fold higher when hydroxyurea is used. The use of hydroxyurea with didanosine should probably be discouraged if other treatment options are available. Topics: Adult; Amylases; Anti-HIV Agents; Didanosine; Female; HIV Infections; HIV-1; Humans; Hydroxyurea; Incidence; Lipase; Longitudinal Studies; Male; Pancreatitis; Reverse Transcriptase Inhibitors; Stavudine; United States; Zidovudine | 2001 |
Smaller amounts of antiretroviral drugs are needed when combined with an active ribozyme against HIV-1.
We have tested for combined anti-HIV-1 effects of a hammerhead ribozyme and antiretroviral drugs and the possibility of reducing the drug burden of patients on highly active antiretroviral therapy (HAART). The antiretroviral compounds used represent the three groups in HAART: nucleoside analogue reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors. A human T cell line (HUT78), stably expressing a hammerhead ribozyme targeted to nef (hhRz.nef(9016-9029)), was infected with HIV-1(SF2) in the presence of a single drug. The combined effects on HIV-1 replication were measured by p24 antigen determinations over a 2-week period. In the presence of the ribozyme, smaller amounts of antiretroviral drugs were required to reduce the HIV-1 p24 levels equally as much as when only drugs were present. The results support a strategy of combining ribozyme gene therapy with HAART to improve the long-term outcome of anti-HIV-1 therapy. Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cell Line; Cyclopropanes; Didanosine; Dose-Response Relationship, Drug; Enzyme Inhibitors; HIV Core Protein p24; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Oxazines; Protease Inhibitors; Reverse Transcriptase Inhibitors; RNA, Catalytic; T-Lymphocytes; Time Factors | 2001 |
Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia.
Acute hepatitis with lactic acidosis is a life-threatening but reversible toxic effect on mitochondria of HIV-1 nucleoside-analogue treatment. We report fatal portal hypertension, liver failure, and persistent mitochondrial dysfunction in a man aged 65 years with HIV-1 infection who had recovered from nucleoside-analogue-induced acute hepatitis and lactic acidaemia more than 18 months previously. We believe that symptom free patients who receive nucleoside-analogue therapy should have hepatic function constantly monitored, especially those with past or present lactic acidaemia. Topics: Acute Disease; Aged; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Didanosine; Fatal Outcome; Fatty Liver; HIV Infections; HIV-1; Humans; Hypertension, Portal; Male; Mitochondria, Liver; Stavudine; Zidovudine | 2001 |
Differing reverse transcriptase mutation patterns in individuals experiencing viral rebound on first-line regimens with stavudine/didanosine and stavudine/lamivudine.
Topics: Anti-HIV Agents; Didanosine; DNA Mutational Analysis; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Stavudine | 2001 |
[Didanosine as a capsule. A reliable drug in a new dosage form].
Ten years ago, the first clinical trial on the tolerability and efficacy of didanosine (ddl) was initiated in German therapeutic centers. At that time, AIDS patients in an advanced stage of the disease who failed to respond to monotherapy with AZT, were treated with ddl. However, the form of presentation of ddl, namely buffered powder, was poorly tolerated. In the meantime, galenical improvements have been made. Today, treatment with ddl is possible at a daily dose of one EC (enteric-coated) capsule. Given this in this form, the substance is highly effective, and the absorption of indinavir, ciprofloxacin, and ketoconazole is in no way impaired. Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Patient Compliance; Tablets, Enteric-Coated | 2001 |
Choosing which nuke to use first.
Topics: Didanosine; Dideoxynucleosides; Drug Administration Schedule; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 2001 |
Gynaecomastia in a male patient during stavudine and didanosine treatment for HIV infection.
We report a case of gynaecomastia developed in a HIV-seropositive man, associated with a severe lipodystrophy. We hypothesize the responsibility of stavudine and didanosine in the development of these 2 complications. If many reports suggest that the protease inhibitors may promote gynaecomastia, long-term nucleoside analogue therapy may also cause this side effect. Topics: Adult; Anti-HIV Agents; Didanosine; Gynecomastia; HIV Infections; HIV Seropositivity; Humans; Lipodystrophy; Male; Stavudine | 2001 |
[Symptomatic hyperlactemia in patients infected with the human immunodeficiency virus treated with nucleoside analogs].
Topics: Adult; Anti-HIV Agents; Didanosine; Female; HIV Infections; HIV Reverse Transcriptase; Humans; Lactic Acid; Lamivudine; Male; Reverse Transcriptase Inhibitors; Zidovudine | 2001 |
Antiretroviral-induced hepatic steatosis and lactic acidosis: case report and review of the literature.
As the prevalence of human immunodeficiency virus (HIV) infection continues to rise the clinician is encountered with a diagnostic challenge. Nonsurgical diseases such as acute colitis or enteritis can appear similar to such true surgical emergencies as abscess, perforation, or mesenteric ischemia. We report a case of fulminant hepatic failure associated with didanosine and masquerading as a surgical abdomen and compare the clinical, biologic, histologic, and ultrastructural findings with reports described previously. This entity should be kept in mind when evaluating the acute abdomen in the HIV-positive patient. Topics: Abdomen, Acute; Acidosis, Lactic; Adult; Anti-HIV Agents; Diagnosis, Differential; Didanosine; Fatty Liver; Female; HIV Infections; Humans; Liver; Liver Failure | 2001 |
A pilot trial of indinavir, ritonavir, didanosine, and lamivudine in a once-daily four-drug regimen for HIV infection.
To evaluate the tolerance, pharmacokinetics, and virologic and immunologic outcomes of once-daily indinavir, ritonavir, didanosine, and lamivudine in HIV-seropositive individuals.. Open-label 24-week pilot study.. Ten HIV-seropositive subjects who were either antiretroviral-naive or minimally experienced with short-term single-or dual-nucleoside therapy provided informed consent and were enrolled. All subjects received didanosine (400 mg) 30 to 60 minutes before a meal followed by indinavir (1200 mg), ritonavir (400 mg), and lamivudine (300 mg) concurrent with the aforementioned meal.. Safety laboratory tests, including a complete blood cell count and amylase, lipase, liver transaminase, and nonfasting lipid monitoring as well as plasma HIV viral load and CD4+ lymphocyte count, were carried out at monthly intervals. Genotyping was performed at baseline. Pharmacokinetic studies for indinavir and ritonavir were performed at week 8.. Nine of 10 subjects completed 24 weeks of therapy. No subject demonstrated primary protease inhibitor mutations at baseline. Toxicities experienced by subjects were typically mild and consistent with those commonly reported for each of the medications, including two cases of hematuria. By week 24, median nonfasting cholesterol and triglyceride levels increased by 49% and 108%, respectively. Median baseline plasma HIV viral load and CD4+ lymphocyte count were 29,292 (4.47 log10) copies/ml and 224 cells/mm3, respectively. Eight of 10 subjects had a plasma HIV viral load of <50 copies/ml by week 12. The 2 subjects with a detectable HIV viral load reached <50 copies/ml by week 28. Median CD4+ lymphocyte counts increased by 193 cells/mm3 at week 24. Indinavir and ritonavir plasma concentrations remained above respective inhibitory and effective concentrations (IC95 and EC50) (uncorrected for protein binding) throughout the 24-hour dosing interval for 6 of 10 and 8 of 10 subjects, respectively.. Our pilot study demonstrates excellent virologic suppression despite low minimum protease inhibitor concentrations during a dosing interval in some patients and is supportive of further study. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cholesterol; Didanosine; Drug Evaluation; Drug Therapy, Combination; Genotype; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Pilot Projects; Ritonavir; Safety; Treatment Outcome; Triglycerides; Viral Load | 2001 |
HIV-1 multi-dideoxynucleoside resistance mutation (Q151M): prevalence, associated resistance mutations and response to antiretroviral salvage treatment.
The prevalence and clinical implications of the Q151M multidrug-resistance mutation gene (mut) to antiretroviral drugs in the HIV reverse transcriptase (RT) gene have not yet been fully explained. In the present study three out of 350 (0.85%) of HIV-infected patients who underwent a drug-resistance genotyping assay because of therapeutic failure showed the Q151M mut. All these patients had been previously treated with zidovudine in association with didanosine. One such patient failed to respond to all salvage regimens tried and was shown to harbour some of the characteristic mut associated with Q151M (77L and 116Y). Another two patients partially responded to salvage regimens, both virologically and immunologically, and harboured the M184V mut in the RT gene. The prevalence of Q151M mut in our group was less (0.85%) than in other studies, which ranged from 2 to 19%. The M184V mut seemed to confer some viro-immunological benefit when associated with the Q151M mutation, compared with the latter alone. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Reverse Transcriptase Inhibitors; Salvage Therapy; Treatment Failure; Viral Load; Zidovudine | 2001 |
Clinical and laboratory signs of mitochondrial dysfunction secondary to nucleoside analogue antiretroviral therapy are reversible.
During 27 months treatment with 400 mg didanosine and 80 mg stavudine daily but no protease inhibitor therapy, a 50-y-old HIV-positive woman gradually lost 13 kg in weight, her arms, legs and buttocks decreased in volume and she experienced fatigue and polyneuropathy. Laboratory tests showed slight increases in plasma lactate and liver enzyme levels. Eighteen months after withdrawal of antiretroviral drug, the patient was free of fatigue and polyneuropathy and had regained 7 kg in weight as well as most of the volume of her arms, legs and buttocks. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Female; HIV Infections; Humans; Middle Aged; Mitochondrial Diseases; Reverse Transcriptase Inhibitors; Stavudine | 2001 |
[HIV-HBV coinfection and the liver].
Topics: Biopsy; Didanosine; Drug Therapy, Combination; Hepatitis B; HIV Infections; Humans; Lamivudine; Liver Cirrhosis; Male; Middle Aged; Ritonavir; Saquinavir; Stavudine | 2001 |
Immunological and virological effects of long term IL-2 therapy in HIV-1-infected patients.
We report the long-term outcome of 27 HIV-infected patients treated for over 3 years with IL-2 and binucleoside analogues. These patients experienced a sustained increase in CD4 cells and a decrease of proviral DNA with infrequent IL-2 cycles. In three cases, virus could not be isolated from activated peripheral cells. A high frequency of HIV-1-specific memory CD4 T cells was found in the patients studied. IL-2 maintains specific effector cells and reduces the pool of infected cells in patients, albeit treated only with binucleosides. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Didanosine; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Immunologic Memory; Interleukin-2; Reverse Transcriptase Inhibitors; Time Factors; Zidovudine | 2001 |
Nucleoside analogue-induced fatal lactic acidosis in two HIV-infected patients in Singapore.
The introduction of antiretroviral therapy has led to a significant decrease in the mortality and morbidity associated with human immunodeficiency virus (HIV) infection. Nucleoside reverse transcriptase inhibitors (NRTI) have been widely used as part of the antiretroviral therapy against HIV. However, one recently recognised serious complication of NRTI is the development of lactic acidosis. We report two cases of fatal NRTI-induced lactic acidosis, which occurred within five months of each other. Both were being treated with didanosine (ddI) and stavudine (d4T). Physicians involved in the care of HIV patients should recognise and be alert to the possibility of this highly fatal complication. Topics: Acidosis, Lactic; Adult; Didanosine; Fatal Outcome; Female; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine | 2001 |
Liver failure after long-term nucleoside antiretroviral therapy.
Topics: Anti-HIV Agents; Didanosine; Fatal Outcome; HIV Infections; HIV-1; Humans; Liver Failure; Male; Middle Aged; Stavudine | 2001 |
Tolerability of enteric-coated didanosine capsules compared with didanosine tablets in adults with HIV infection.
A new enteric-coated (EC) didanosine (ddI) formulation (Videx EC; Bristol-Myers Squibb, Princeton, NJ, U.S.A.) may be better tolerated than the tablet form because it lacks the buffer component thought to be responsible for diarrhea and other gastrointestinal (GI) side effects.. To evaluate the frequency and magnitude of GI side effects (nausea, bloating, GI upset, diarrhea, abdominal cramps, gas [flatus]) before and after switching the formulation of ddI, in study subjects who were experiencing one or more GI symptom(s) of at least moderate severity.. A 6-week open label crossover study of current didanosine tablet users comparing daily symptom scores (7 point scale, 0 = absent to 6 = very severe) during weeks 1 to 2 (on tablets) to weeks 4 and 6 (on EC capsules). Formulation palatability and preference, lifestyle effects, and use of antidiarrheals or other medications for symptom relief were also assessed.. GI symptom scores (7-day means) on tablets were diarrhea 2.11, gas 2.00, bloating 1.23, abdominal cramps 0.74, GI upset 0.69, nausea 0.66. After switching to EC (week 4 and week 6), mean scores decreased for diarrhea (mean scores 0.99 week 4, 0.79 week 6), gas (0.95, 0.79), bloating (0.49, 0.32), abdominal cramps (0.21, 0.05), GI upset (0.16, 0.14), and nausea (0.32, 0.22). Severity of all GI symptoms was significantly reduced after 4 weeks on EC capsules ( p <.01 by paired t- test). Negative impact of side effects on routine activities was significantly reduced (41% on tablet vs. 7% on EC; p <.01). All 42 study subjects preferred the EC form.. According to patients' diary scores, switching to ddI in EC form significantly reduces nausea, bloating, GI upset, diarrhea, abdominal cramps, and gas for individuals who experienced GI side effects while taking the buffered tablet form. The striking tolerability advantages appear to support routine switching to EC for such patients and may suggest that widespread preferential selection of the EC form is appropriate to enhance didanosine tolerability and promote treatment adherence. Topics: Adult; Amylases; Anti-HIV Agents; Boston; Capsules; CD4 Lymphocyte Count; Cross-Over Studies; Diarrhea; Didanosine; Drug Tolerance; Female; HIV Infections; Humans; Male; Nausea; Patient Selection; Tablets | 2001 |
Impaired absorption of rifabutin by concomitant administration of didanosine.
Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotics, Antitubercular; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Intestinal Absorption; Male; Middle Aged; Mycobacterium Infections; Reverse Transcriptase Inhibitors; Rifabutin | 2001 |
Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study.
The prevalence, clinical presentation, and risk factors for hyperlactatemia among patients receiving antiretroviral therapy was determined during a 1-month period for patients in the Swiss HIV Cohort Study. Overall, 73 (8.3%) of 880 patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine (odds ratio, 2.7; 95% confidence interval, 1.5-4.8), as compared with patients who received zidovudine-based regimens. The risk increased with increasing time receiving stavudine with or without didanosine. The association between hyperlactatemia and stavudine with or without didanosine was not biased by these medications being more recently available and, therefore, being given preferentially to patients who had prolonged use of nucleoside analog reverse-transcriptase inhibitors. Hyperlactatemia was associated with lipoatrophy, hyperlipidemia, and hyperglycemia. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia. Determination of lactate levels may prove useful in the screening for mitochondrial toxicity. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Cohort Studies; Didanosine; Female; HIV Infections; Humans; Male; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Switzerland; Zidovudine | 2001 |
Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons.
Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, recently diagnosed HIV-1-infected persons, we identified a distinct group of viruses that have mutations at codon 215 of the reverse transcriptase (RT) gene that are different from either the wild-type (WT) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 215D/C/S and were found in 20 patients (3.3%). The 215D, 215C, and 215S mutations differ from 215Y by a 1-nt change compared with 2 nt for the WT T215 and likely represent revertants of 215Y. These viruses all were found to have WT susceptibility to AZT, and all replicated efficiently as WT HIV-1(T215). However, differences in fitness among HIV-1(215D), HIV-1(215C), and HIV-1(215S) were seen when RT backgrounds were changed, demonstrating a role of the RT background in the selection of these revertants. In vitro selection with AZT showed that HIV-1(215D) and HIV-1(215C) acquired 215Y more rapidly than did WT HIV-1(T215), likely reflecting the need for only 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutations at codon 215 replicate efficiently, have WT susceptibility, and are commonly found in treatment-naive persons. The increased ability for selecting resistance mutations defines this class of WT HIV-1 and highlights the higher potential of these viruses to compromise the efficacy of antiretroviral therapy. Topics: Anti-HIV Agents; Base Sequence; Didanosine; Dideoxynucleosides; DNA, Viral; Drug Resistance, Viral; Evolution, Molecular; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutagenesis; Recombination, Genetic; Reverse Transcriptase Inhibitors; Stavudine; Virus Replication; Zalcitabine; Zidovudine | 2001 |
Drugs for HIV infection.
Topics: Alkynes; Benzoxazines; Cyclopropanes; Delavirdine; Didanosine; Dose-Response Relationship, Drug; HIV Infections; HIV Protease Inhibitors; Humans; Nelfinavir; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Saquinavir; Stavudine; Zidovudine | 2001 |
Peripheral neuropathy during stavudine-didanosine antiretroviral therapy.
Peripheral neuropathy (PN) is among the most frequent side effects described with nucleoside reverse transcriptase inhibitors (NRTIs). We investigated the incidence, evolution and predictive factors of PN during stavudine (d4T)-didanosine (ddI) combination therapy in 65 HIV infected patients, previously treated with zidovudine and/or zalcitabine (ddC) for at least 3 months. A subset of 16 patients was referred for systematic electromyographic examination at weeks 0 and 24: six among the 16 exhibited nerve conduction abnormalities at day 0, probably related to previous ddC treatment in four of those and to HIV infection in the other two, with worsening of abnormalities in one patient at week 24. In total, seven of the 59 assessable patients (11.8%) exhibited grade 2-3 neuropathy, with a median time of occurrence of 17 weeks. Distal, symmetrical paraesthesias of the extremities were the first symptoms in all the patients; none had motor symptoms. In all the patients, PN resolved rapidly after stopping d4T. There were no statistically different parameters between the seven cases and the other 52 patients according to CD4 T cells, HIV RNA, Centers for Disease Control and Prevention (CDC) stage C or d4T daily dose. In our study, the d4T-ddI combination did not seem to increase the incidence of PN; risk factors for PN could not be identified, probably in part because of the low number of patients with PN. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Electromyography; Female; HIV Infections; Humans; Incidence; Male; Peripheral Nervous System Diseases; Pilot Projects; Reverse Transcriptase Inhibitors; Risk Factors; Safety; Stavudine; Treatment Outcome | 2001 |
New formulation of ddI approved in Canada--Videx EC.
Topics: Canada; Didanosine; Dosage Forms; Drug Approval; HIV Infections; Humans; Reverse Transcriptase Inhibitors | 2001 |
[Acute myocardial infarct in HIV-positive patients in treatment with protease inhibitors].
We report the case of a 40-year-old HIV-positive man, undergoing three-drug antiretroviral therapy for 2 years that included a protease inhibitor (ritonavir). The patient was admitted to our Coronary Care Unit with an acute anterior myocardial infarction. He smoked 20 cigarettes/day and had a family history of hypertension. At the time of hospitalization, triglyceride levels were found to be high (290 mg/dl). Metabolic alterations associated with the prolonged use of protease inhibitors, such as insulin resistance, dyslipidemia and lipodystrophy, have recently been described. This side effect may lead to premature coronary artery disease. Therefore it is mandatory to be aware that treatment with protease inhibitors in HIV-positive patients, despite survival prolongation and lowering of AIDS complications, may accelerate atherosclerosis and precipitate acute coronary events, especially in patients with pre-existing cardiovascular risk factors. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hypertriglyceridemia; Male; Myocardial Infarction; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine | 2001 |
Prevalence and genetic heterogeneity of the reverse transcriptase T69S-S-X insertion in pretreated HIV-infected patients.
The emergence of resistance to antiretroviral drugs represents one of the main reasons for treatment failure in HIV-infected persons. Resistance to multiple nucleoside analogues may result from rearrangements in the HIV pol gene, in particular one insertion of two amino acids at position 69. Herein, we examined the prevalence of this resistant genotype and its genetic heterogeneity in a group of 475 healthy pretreated HIV-positive subjects in Spain. Only 4 (0.8%) carried the codon 69 insertion. It was always found coupled to the T69S mutation. The extra amino acids were S-S in 2 subjects and S-G in the other 2. The presence of the insert was seen only in subjects previously exposed to AZT monotherapy for at least 6 months. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Viral; Genetic Heterogeneity; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Mutagenesis; Prevalence; Reverse Transcriptase Inhibitors; Spain; Zidovudine | 2001 |
Caution issued for HIV combination therapy with Zerit and Videx in pregnant women.
Topics: Acidosis, Lactic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine | 2001 |
Virological and immunological responses to a once-a-day antiretroviral regimen with didanosine, lamivudine and efavirenz.
Current antiretroviral drugs cannot eradicate HIV infections, and persons living with HIV are often faced with very demanding daily therapeutic schedules that can induce poor adherence. More conveniently dosed and patient-friendly regimens are needed. We investigated, in this 48-week pilot study, a once-a-day highly active antiretroviral therapy regimen of didanosine, lamivudine and efavirenz. Seventy-five consecutive antiretroviral-naive subjects were enrolled. Over the 48-week period, plasma HIV-RNA levels declined sharply, with a median decrease at the end of the observation time >3.4 log copies/ml. The proportion of patients achieving a plasma HIV-RNA level below the limit of detection (50 copies/ml) was 77% (intention to treat analysis) at the end of the study period. The mean CD4 cell count increased steadily over time from 251 to 459 cells/microl. Antiviral efficacy was similar in patients with a baseline HIV-RNA level above or below 100,000 copies/ml. However, patients with a baseline CD4 cell count <200 cells/microl showed a significantly worse virological response than that observed in patients with higher baseline CD4 counts. Overall 15 patients interrupted therapy. In four cases treatment interruption was due to lack of treatment response; three additional patients were lost to follow-up or withdrew informed consent. Eight patients stopped therapy because of adverse events. The once-daily combination of didanosine, lamivudine and efavirenz resulted in sustained viral suppression and was well-accepted by patients. This regimen may offer advantages in selected difficult-to-treat populations, allows directly observed therapy and can be a safe and effective alternative in antiretroviral-naive patients. These encouraging pilot results need to be confirmed in a comparative clinical trial. Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oxazines; Prospective Studies; RNA, Viral | 2001 |
Systematic review of combination antiretroviral therapy with didanosine plus hydroxyurea: a partial solution to Africa's HIV/AIDS problem?
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Reverse Transcriptase Inhibitors; Systematic Reviews as Topic; Treatment Outcome | 2001 |
[Drug combination therapy for children infected with HIV/AIDS--own experience].
Background antiretroviral therapy (HAART) for primary perinatal infection with three drugs is recommended because it provides the best opportunity to preserve immune function and delay disease progression. The aim of HAART is to maximally suppress viral replication, preferably to undetectable levels. We evaluated the safety and efficacy of a three drug regimen in a small group 7 of maternally infected and 1 probably nosocomial infected children from 1998.. Triple drug combination regimen the most often was composed of: either AZT + 3TC + NFV, ddi + d4T + NFV, or ddI + d4T + NVP. This therapy was monitored by serial measurements of peripheral-blood CD4, viral load (VL), biochemical parameters and clinical observation. Lately also genotyping resistance and phenotyping drug susceptibility were investigated in the patients with high > 5000 kopii/ml VI.. The three-drug regiment was well tolerated in 6/8 patients. Hematological abnormalities (severe anaemia after AZT) was noticed in 1 patient and hyperlipidemia in the second one (after Nelfinavir). 3TC resistance or genotyping mutations were observed in 4/8. These patients had low or undetectable VL during a long time, but lately after > 1 year therapy VL has risen. In all 8 patients clinical and immunological parameters are good, stabile. The opportunistic infections weren't observed.. Although further observations are needed., it appears that in HIV infected children combined treatment is well tolerated and has sustained efficacy against HIV. Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Didanosine; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lamivudine; Male; Nelfinavir; Poland; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Viral Load; Zidovudine | 2001 |
Human immunodeficiency virus 1 strains resistant to nucleoside inhibitors of reverse transcriptase in isolates from the Czech Republic as monitored by line probe assay and nucleotide sequencing.
The genetic resistance to nucleoside inhibitors of the reverse transcriptase (RT) of human immunodeficiency virus I (HIV-1) isolates in the Czech Republic was examined by a line probe assay (LiPA) and nucleotide sequencing. The results of LiPA analysis of 294 blood specimens obtained from 156 patients revealed a high incidence of mutations in the RT gene related to resistance to various drugs (67.3%) in various combinations. Mutations in RT gene (M41L, K70R and T215Y/F) conferring the resistance to zidovudine (ZDV) were most frequent (62.6%), that (M184V) responsible for the resistance to lamivudine (3TC) was less frequent (33.7%), while those linked to the resistance to dideoxyinosine (ddl) and dideoxyinosine together with dideoxycytidine (ddl/ddC) were rather rare (6.5% and 5.1%, respectively). LiPA gave a high rate of uninterpretable results due to codon hybridization failure, especially in HIV-1 isolates of non-B subtype. Thirty-two specimens were analyzed also by direct sequencing of a part of RT gene. The results obtained by LiPA and the sequencing were highly concordant for codons successfully analyzed by both methods, but the sequencing provided information also about the codons that could not be analyzed by LiPA. A high prevalence of resistant strains in the Czech Republic and their heterogeneity justifies a regular HIV-1 resistance testing. LiPA turned out as a fast, powerful and most reliable tool for such a purpose. However, due to an increasing diversity of HIV-1 strains circulating in the Czech Republic, LiPA cannot replace the nucleotide sequence analysis. Topics: Base Sequence; Codon; Czech Republic; Didanosine; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Molecular Probe Techniques; Molecular Sequence Data; Mutation; Phylogeny; Prevalence; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Zalcitabine; Zidovudine | 2001 |
Drugs for HIV infection.
Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Costs; Drug Therapy, Combination; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine | 2000 |
Functional reconstitution of thymopoiesis after human immunodeficiency virus infection.
We have utilized combination antiretroviral therapy following human immunodeficiency virus type 1-induced human CD4(+) thymocyte depletion in the SCID-hu mouse to examine the immune competence of reconstituting thymocytes which appear following administration of combination therapy. These cells express a normal distribution of T-cell receptor variable gene families and are responsive to costimulatory signals. These results suggest that normal thymic function may be restored following antiretroviral treatment. Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Disease Models, Animal; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mice; Mice, SCID; Receptors, Antigen, T-Cell, alpha-beta; Reverse Transcriptase Inhibitors; Thymus Gland; Zidovudine | 2000 |
Initiation of antiretroviral therapy during primary HIV-1 infection induces rapid stabilization of the T-cell receptor beta chain repertoire and reduces the level of T-cell oligoclonality.
Major T-cell receptor beta chain variable region (TCRBV) repertoire perturbations are temporally associated with the down-regulation of viremia during primary human immunodeficiency virus (HIV) infection and with oligoclonal expansion and clonal exhaustion of HIV-specific cytotoxic T lymphocytes (CTLs). To determine whether initiation of antiretroviral therapy (ART) or highly active antiretroviral therapy (HAART) during primary infection influences the dynamics of T-cell-mediated immune responses, the TCRBV repertoire was analyzed by semiquantitative polymerase chain reaction in serial blood samples obtained from 11 untreated and 11 ART-treated patients. Repertoire variations were evaluated longitudinally. Stabilization of the TCRBV repertoire was more consistently observed in treated as compared with untreated patients. Furthermore, the extent and the rapidity of stabilization were significantly different in treated versus untreated patients. TCRBV repertoire stabilization was positively correlated with the slope of HIV viremia in the treated group, suggesting an association between repertoire stabilization and virologic response to treatment. To test whether stabilization was associated with variations in the clonal complexity of T-cell populations, T-cell receptor (TCR) heteroduplex mobility shift assays (HMAs) were performed on sequential samples from 4 HAART-treated subjects. Densitometric analysis of HMA profiles showed a reduction in the number of TCR clonotypes in most TCRBV families and a significant decrease in the total number of clonotypes following 7 months of HAART. Furthermore, a biphasic decline in HIV-specific but not heterologous CTL clones was observed. This indicates that ART leads to a global reduction of CD8(+) T-cell oligoclonality and significantly modulates the mobilization of HIV-specific CTL during primary infection. (Blood. 2000;95:1743-1751) Topics: Acute Disease; Anti-HIV Agents; Clone Cells; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; Saquinavir; T-Lymphocytes, Cytotoxic; Viremia; Zidovudine | 2000 |
Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine.
To evaluate the phenotypic susceptibilities and genotypic resistance patterns to both didanosine and stavudine of baseline and follow-up HIV-1 isolate pairs, derived from antiretroviral naive subjects treated with this dual nucleoside combination.. Phenotypic drug susceptibility testing was performed in peripheral blood mononuclear cells on 34 viral isolate pairs derived from patients participating in the BMS AI-460 trial. Sequencing of the complete reverse transcriptase of 36 study isolate pairs, baseline and follow-up, was performed using standard dideoxy techniques.. The mean fold change in susceptibilities to didanosine was 1.6 (P= 0.278) and to stavudine 1.9 (P= 0.002, Wilcoxon's signed rank test). Mutations classically associated with zidovudine resistance were observed to emerge in 7 out of 36 isolates, T215Y/F (four), M41L +T215Y/F (two) and D67N (one). Other mutations observed included the A62V, V751, F77L, F116Y, Q151 M multinucleoside resistance complex (one), the Q151M mutation (two) and the rare V75T mutation (two). No mutations classically associated with didanosine exposure and resistance were observed. No relationship was evident between the emergence of zidovudine associated mutations and the level of phenotypic resistance to either stavudine or didanosine or between the emergence of zidovudine associated mutations and changes in plasma HIV RNA levels.. These comprehensive data demonstrate modest (< twofold) mean reductions in didanosine and stavudine susceptibilities at follow-up. The emergence of zidovudine associated mutations in this retroviral-naive population treated with combination didanosine and stavudine therapy is notable. Furthermore, the emergence of these mutations and of the Q151 M multinucleoside resistance complex raise concerns for potential nucleoside analog cross-resistance. The potential mechanisms driving the selection of the zidovudine associated mutations in the setting of didanosine and stavudine therapy and the relevance of these findings to current three and four drug regimens merit further evaluation. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Follow-Up Studies; Genotype; HIV Infections; HIV-1; Humans; Mutation; Phenotype; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; RNA, Viral; Stavudine; Viral Load; Zidovudine | 2000 |
Hydroxyurea plus didanosine as maintenance therapy after 1 year on highly active antiretroviral therapy.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; HIV Infections; Humans; Hydroxyurea; Palliative Care; Viremia | 2000 |
Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume.
Despite significant rises in total CD4 T cells, the process of immune reconstitution in adults with HIV infection treated with potent antiretroviral treatment results in a rather slow increase in phenotypically naive lymphocytes. In children more than in adults, thymic function may be at least partly restored when disease-induced immunosuppression is attenuated by pharmacological means.. Twenty-five vertically infected and antiretroviral-experienced [zidovudine (ZDV)/ZDV plus didanosine (ddl)] children were prospectively followed during 12 months of treatment with lamivudine (3TC), stavudine (d4T) and indinavir (IDV). The plasma HIV viral load and phenotypic and functional cellular immunity-defining parameters were examined. The relationship between the degree of immune reconstitution and thymus volume assessed by nuclear magnetic resonance was also examined.. An early and steep increase in CD45RA+62L+ T cells was observed in parallel with a sustained decrease in plasma HIV RNA levels and a significant rise in total CD4 T cells. This increase was significantly greater than that observed in CD4+CD45RO+ T cells. Analysis of the CD4 T cell receptor (TCR) beta repertoire and T helper function showed the ability to reconstitute families almost completely absent at baseline, and a substantial improvement of antigen-specific responses by peripheral blood lymphocytes. The rise in CD4 cells and in CD4+CD45RA+62L+ T cells was statistically associated with changes in thymus size observed over time.. These data suggest a relevant contribution of the thymus to reconstitution of the peripheral pool of T cells in vertically HIV-infected children treated with potent antiretroviral regimens. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Cohort Studies; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Organ Size; Reverse Transcriptase Inhibitors; Stavudine; Thymus Gland; Viral Load; Zidovudine | 2000 |
Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea.
Sensory neuropathy is a common adverse effect of the nucleoside analogue anti-retroviral drugs didanosine (ddl) and stauvudine (d4T). These drugs are increasingly being used in combination, and it is not currently known whether the incidence of neuropathy is higher with combination compared to individual drug use. It is also not known if hydroxyurea, used to potentiate the antiviral efficacy of these drugs, may also increase the risk of neuropathy. The purpose of this analysis is to investigate if the combination of ddl and d4T, with or without hydroxyurea, has a higher incidence of neuropathy than a single drug regimen.. Data were obtained from patients followed longitudinally by the Johns Hopkins AIDS Services. Incidence rates of development of neuropathy were calculated for each of five regimens: ddl (+/- hydroxyurea), ddl + d4T (+/- hydroxyurea), and d4T. Cox proportional hazard regression was used to compare the relative risk of neuropathy for each regimen adjusting for CD4 cell count, other drugs received, and time on therapy.. A total of 1116 patients received at least one of the five regimens. There were 117 cases of neuropathy. The crude incidence rate of neuropathy ranged from 6.8 cases per 100 person-years for ddl to 28.6 cases per 100 person-years for ddl + d4T + hydroxyurea. Compared with ddl alone, and adjusting for CD4 cell counts and other variables, the relative risk of neuropathy was 1.39 [95% confidence interval (CI): 0.84-2.32] for d4T alone, 2.35 (95% CI: 0.69-8.07) for ddl + hydroxyurea, 3.50 (95% CI: 1.81-6.77) for ddl + d4T, and 7.80 (95% CI: 3.92-15.5) for ddl + d4T + hydroxyurea.. Based on the data, the risk of neuropathy is additive or even synergistic for ddl + d4T + hydroxyurea compared with ddl or d4T alone. The combination of ddl + d4T also increases the risk of neuropathy but less than when hydroxyurea is included. Topics: Adult; Aged; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Hydroxyurea; Incidence; Male; Middle Aged; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors; Stavudine | 2000 |
Excess peripheral neuropathy in patients treated with hydroxyurea plus didanosine and stavudine for HIV infection.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors; Stavudine | 2000 |
Pancreatic warning for ddI.
Topics: Acute Disease; Anti-HIV Agents; Didanosine; HIV Infections; Humans; Pancreatitis | 2000 |
Autonomic neuropathy in patients with HIV: course, impact of disease stage, and medication.
The purpose of this article is to examine the prevalence, degree, and natural course of pupillary neuropathy (PANP), cardiovascular autonomic neuropathy (CANP), and sensorimotor neuropathy (SNP) and to study the impact of disease stage and medication on neuropathy in 61 consecutive patients with HIV. PANP, CANP, and SNP were assessed by standardized test procedures. Overall prevalence of PANP, CANP, and SNP were 66%, 15%, and 15%, respectively. The maximal pupillary area (pupillary measure, p <0.0001) and the lying-to-standing ratio (cardiovascular measure, p <0.0001) were abnormal as compared with control subjects. The changes in CD4+ T-lymphocytes and respiratory sinus arrhythmia percentile during 2 years of follow-up correlated significantly (r = 0.758, p = 0.007). Patients with CANP were more often in an advanced disease stage than patients without CANP (p = 0.004). SNP, but not PANP or CANP, was associated with the intake of the neuropathogenic drugs dideoxycytidine, dideoxyinosine, and 2',3' didehydro-2',3' dideoxythymidine (p <0.05). Autonomic and sensorimotor neuropathy are frequent in patients with HIV, and progression of CANP may put patients at risk for unexpected cardiorespiratory arrest. Topics: Adult; Aged; Anti-HIV Agents; Autonomic Nervous System Diseases; Brain Diseases; Cardiovascular System; Didanosine; Female; Follow-Up Studies; HIV Infections; Humans; Iris Diseases; Male; Middle Aged; Movement; Prevalence; Sensation; Stavudine; Zalcitabine | 2000 |
L-Carnitine as a treatment of life-threatening lactic acidosis induced by nucleoside analogues.
Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Carnitine; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Male; Reverse Transcriptase Inhibitors; Saquinavir; Stavudine | 2000 |
Bioavailability of once- and twice-daily regimens of didanosine in human immunodeficiency virus-infected children.
The bioavailability of didanosine at 180 mg/m(2) once daily was compared to that at 90 mg/m(2) twice daily in 24 children with advanced human immunodeficiency virus infection. Children were studied at steady state using optimal sampling and prior pharmacokinetic parameter estimates. Relative bioavailability was 0. 95 +/- 0.49, supporting the potential clinical adequacy of once-daily dosing. Topics: Anti-HIV Agents; Biological Availability; Child; Child, Preschool; Didanosine; HIV Infections; Humans | 2000 |
Baseline HIV type 1 genotypic resistance to a newly added nucleoside analog is predictive of virologic failure of the new therapy.
We evaluated the predictive value of baseline HIV-1 genotypic resistance mutations for failure of a nucleoside reverse transcriptase inhibitor (NRTI) containing therapy. The change in therapy of 88 HIV-1-infected patients was analyzed retrospectively, relating the genotypic resistance profile at baseline to the evolution of viral load and CD4+ T cell counts. Genotypic resistance at baseline and at 6 months was evaluated with the LiPA HIV-1 RT, which detects mutations at codons 41, 69, 70, 74, 184, and 215. At 1 to 3 months after change in therapy, patients without preexisting resistance mutations to the new drug (group S) had a significantly better evolution in viral load (reduction of 0.37 log(10)) compared with patients with known preexisting resistance mutation(s) (group R) (increase of 0.08 log(10)). This difference was particularly striking for patients with the baseline M184V mutation and whose treatment was modified by the addition of lamivudine. After 6 months the median difference in viral load evolution between the two groups increased to 0.61 log(10): the viral load of patients of group S was still 0.18 log(10) below baseline while patients of group R had an increase of 0.43 log(10) in viral load above baseline. Changes in CD4+ T cell counts were not significantly different. The evolution in viral load in HIV-1-infected patients with and without baseline resistance mutation(s) toward a newly added NRTI is significantly different at 1-3 months and at 6 months after changing or adding one NRTI. Topics: CD4 Lymphocyte Count; Didanosine; Drug Resistance, Microbial; Female; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Polymerase Chain Reaction; Predictive Value of Tests; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zalcitabine; Zidovudine | 2000 |
Decreased HIV-associated T cell apoptosis by HIV protease inhibitors.
Antiretroviral treatment of patients infected with HIV results in improvements in CD4+ T cell number. Emerging evidence suggests that some of the improvements in CD4+ T cell number that occur in response to protease inhibitor (PI) therapy may not be accounted for solely by enhanced viral suppression, implying that PI may directly affect T cell survival. Since HIV T cell depletion is associated with enhanced apoptosis, we analyzed the effect of PIs on T cell apoptosis. In vitro treatment of peripheral blood lymphocytes (PBLs) from HIV-infected but untreated patients with reverse transcriptase inhibitors (RTIs) does not alter apoptosis, whereas PI treatment rapidly reduces CD4+ and CD8+ T cell apoptosis. In contrast, PI treatment does not alter apoptosis in PBL blasts from HIV-negative patients, or in Jurkat T cells. Consistent with this observation, 8 days of PI therapy in HIV-infected patients does not significantly alter plasma viremia, yet results in significant inhibition of CD4+ and CD8+ T cell apoptosis. The inhibitory effects of PI on apoptosis have implications concerning the treatment of HIV and its pathogenesis. Topics: Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Didanosine; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; HIV-1; Humans; Jurkat Cells; Nelfinavir; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; T-Lymphocytes; Viral Load; Zidovudine | 2000 |
Convergent evolution of reverse transcriptase (RT) genes of human immunodeficiency virus type 1 subtypes E and B following nucleoside analogue RT inhibitor therapies.
Changes in the drug susceptibility, gene lineage, and deduced amino acid sequences of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) subtype E following 3'-azido-3'-deoxythymidine (AZT) monotherapy or AZT-2', 3'-dideoxyinosine combination therapy were examined with sequential virus isolates from a single family. The changes were compared to those reported for HIV-1 subtype B, revealing striking similarities in selected phenotype and amino acids independent of differences in the RT backbone sequences that constantly distinguish the two subtypes. Particularly, identical amino acid substitutions were present simultaneously at four different positions (D67N, K70R, T215F, and K219Q) for high-level AZT resistance. These data suggest that HIV-1 subtypes E and B evolve convergently at the phenotypic and amino acid levels when the nucleoside analogue RT inhibitors act as selective forces. Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Base Sequence; Didanosine; DNA, Viral; Drug Resistance, Microbial; Evolution, Molecular; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Molecular Sequence Data; Protein Structure, Secondary; Reverse Transcriptase Inhibitors; Zidovudine | 2000 |
Cutaneous side effects induced by indinavir.
HIV-protease inhibitors demonstrated such high efficacy in short-term studies that they have been approved by the FDA, even though possible toxicity still needs further investigation. In the period between January 1997 and August 1998, 101 patients, staying at San Patrignano Medical Centre (Italy), received an HIV protease inhibitor (indinavir) plus two nucleoside reverse transcriptase inhibitors (NRTI's) selected from the following: AZT, didanosine, zalcitabine, lamivudine or stavudine. Seventy-three patients were male, 28 female and their ages ranged from 25 to 60 years, with an average of 34. At the end of the study, 84 patients were suitable for evaluation, as the other 17 dropped out for various reasons. Forty-eight patients (57.1%) developed cheilitis, 34 (40.5%) experienced diffuse cutaneous dryness and pruritus, 10 (11.9%) developed asteatotic dermatitis on the trunk, arms and thighs and another 10 (11.9%) complained of scalp defluvium. A severe alopecia was observed in only 1 patient (1.2%), while 6 reported that their body hair had become fairer, thinner and shed considerably. Multiple pyogenic granulomas were observed in the toenails of 5 patients (5. 9%). Softening of the nail plate was noted in 5 subjects as well. A peripheral lipodystrophy syndrome was noted in 12 patients (14.3%). Among these, one patient only developed a "buffalo hump" and another had diffused lipomatosis. The temporal relationship between the taking of indinavir and the onset of such cutaneous effects was striking. This was confirmed by the regression of symptoms in those patients who later discontinued indinavir. The emerging side effects of protease inhibitors require a multidisciplinary team for adequate diagnosis and treatment. Cutaneous toxicity involving the patient's own body image has a peculiar influence on compliance to the treatment and the patient's quality of life. Topics: Adult; Alopecia; Didanosine; Drug Eruptions; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lipodystrophy; Male; Middle Aged; Pruritus; Pyoderma Gangrenosum; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Scalp Dermatoses; Skin; Stavudine; Zalcitabine; Zidovudine | 2000 |
Principles of treating HIV.
Topics: Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Protease Inhibitors; Randomized Controlled Trials as Topic; Stavudine; Treatment Failure; Viral Load | 2000 |
GEE with Gaussian estimation of the correlations when data are incomplete.
This paper considers a modification of generalized estimating equations (GEE) for handling missing binary response data. The proposed method uses Gaussian estimation of the correlation parameters, i.e., the estimating function that yields an estimate of the correlation parameters is obtained from the multivariate normal likelihood. The proposed method yields consistent estimates of the regression parameters when data are missing completely at random (MCAR). However, when data are missing at random (MAR), consistency may not hold. In a simulation study with repeated binary outcomes that are missing at random, the magnitude of the potential bias that can arise is examined. The results of the simulation study indicate that, when the working correlation matrix is correctly specified, the bias is almost negligible for the modified GEE. In the simulation study, the proposed modification of GEE is also compared to the standard GEE, multiple imputation, and weighted estimating equations approaches. Finally, the proposed method is illustrated using data from a longitudinal clinical trial comparing two therapeutic treatments, zidovudine (AZT) and didanosine (ddI), in patients with HIV. Topics: Anti-HIV Agents; Biometry; Computer Simulation; Controlled Clinical Trials as Topic; Didanosine; HIV Infections; Humans; Longitudinal Studies; Models, Statistical; Normal Distribution; Zidovudine | 2000 |
Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection.
Progressive subcutaneous fat wasting, fat accumulation, dyslipidaemia and insulin resistance in HIV-infected patients on antiretroviral therapy has been attributed to the long-term toxicity of HIV protease inhibitors (PI). More recently, fat wasting has been observed in patients who have never taken a PI, implicating an independent effect of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy.. To determine the relative contribution of NRTI and PI, as well as any other factors, to fat wasting in HIV-infected patients.. Longitudinal cohort study involving 277 participants of the Western Australian HIV Cohort Study.. The time to onset of clinically apparent fat wasting in patients receiving different antiretroviral regimens was compared using standardized clinical criteria. Regional fat measured by dual energy X-ray absorptiometry (DEXA) in 161 patients was also compared. The average rate of percentage fat reduction was estimated in 70 patients who had consecutive DEXA scans at approximately 6-monthly intervals. Multiple confounding factors were considered in the analyses.. Progressive subcutaneous fat wasting, indistinguishable from that described in PI-treated patients, does occur in PI-naive, NRTI-treated patients. In patients taking triple combination antiretroviral therapy, age (relative risk = 1.052 per year; P < 0.0001), white race (relative risk = 3.9; P = 0.023), longer duration of dual NRTI therapy prior to addition of PI (relative risk = 1.021 per month; P = 0.0046) and increased cumulative time on stavudine-containing regimens compared with time on zidovudine-containing regimens (relative risk = 1.085 per month; P < 0.0001) are associated with increased risk of fat wasting. Stavudine increases the risk of fat wasting by 265% per year compared with zidovudine. However PI therapy is associated with faster progression to clinically apparent wasting compared with dual NRTI therapy without PI. The results of DEXA scanning supports these clinical data and suggest a non-linear decline in fat over time.. NRTIs do have an independent contribution to fat wasting, but PI are the predominant influence and may act synergistically with NRTIs. NRTIs appear to predispose individuals to slowly progressive fat loss, which is markedly accelerated when a PI and NRTIs are combined. Of the NRTIs, stavudine leads to an earlier onset of clinically apparent fat wasting compared with zidovudine. Fat wasting associated with NRTI use may be a manifestation of mitochondrial toxicity, which may be exacerbated by PI use. Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Cohort Studies; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; HIV Wasting Syndrome; Humans; Lamivudine; Longitudinal Studies; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Time Factors; Zidovudine | 2000 |
Lactic acidosis and antiretroviral therapy: a case report and literature review.
Antiretrovirals, particularly nucleoside analogue reverse transcriptase inhibitors (RTIs) - DDI, 3TC and D4T, are widely used to effectively control human immunodeficiency virus (HIV) infection. These drugs have several adverse effects including anemia, peripheral neuropathy, pancreatitis and, on rare occasions, lactic acidosis. We describe the case of a 39 year old patient who had severe lactic acidosis after receiving stavudine (D4T) and didanosine (DDI) for an 8 month period. She had never manifested an opportunistic infection and presented a CD4 count of 378 cells/mm3 and an undetectable viral load (< 400 copies/ml). The purpose of the following report is to alert clinicians and infectious diseases specialists to the occurrence of lactic acidosis in asymptomatic HIV patients receiving antiretrovirals for long periods of time. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Female; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine | 2000 |
[Fatal lactic acidosis in a patient infected by HIV and treated with stavudine and didanosine].
We report a case of severe lactic acidosis in an human immunodeficiency virus (HIV)-infected patient treated with combination regimen of stavudine, didanosine and nevirapine. Antiretroviral nucleoside analogs are inhibitors of mitochondrial DNA polymerase gamma, resulting in the dysfunction of the mitochondrial respiratory chain. Despite symptomatic treatments and intravenous L-carnitine supplementation, lactic acidosis persisted, leading to multiorgan failure. The patient died 7 days after admission to the intensive care unit. Retrospective analysis of published cases showed neither specific nor predictive signs of outcome that is usually fatal, with no effective therapy to date. We therefore recommend determining blood lactate in patients with onset of unexplained general fatigue or digestive signs and to stop all antiretroviral treatments in the case of lactate increase. Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; DNA Polymerase gamma; DNA-Directed DNA Polymerase; Fatal Outcome; Female; HIV Infections; Humans; Mitochondria; Nucleic Acid Synthesis Inhibitors; Stavudine | 2000 |
Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC].
The heterosubstituted nucleoside analogue dOTC [( )-2'-deoxy-3'-oxa-4'-thiocytidine, BCH-10652] is a racemic compound structurally related to 3TC (lamivudine), but has the oxygen and sulphur in the furanosyl ring transposed. Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM). Investigation of the activity of dOTC and its enantiomers against laboratory strains of HIV-1 with defined resistance to 3TC, AZT (zidovudine), ddl (didanosine), PMEA (adefovir), nevirapine and saquinavir indicated that sensitivity was maintained (<3-fold change in EC50) in all cases, with the exception of HIV-1RF 3TC-resistant viruses. The degree of resistance recorded for dOTC (four- to sevenfold), (-)dOTC (five- to eightfold) and (+)dOTC (five- to >18-fold) against these M1841 or M184V mutants, was significantly less than that recorded for 3TC (>100-fold). In addition, the inhibitory effect of the compounds against clinical isolates of HIV-1 recovered from patients with suspected resistance to 3TC and AZT was investigated. Clinical isolates were genotyped using the Murex Line Probe Assay (LiPA) and subgrouped into wild-type, 3TC-resistant and dual 3TC/AZT-resistant, as well as undefined or mixed genotype populations. Compared with the mean EC50 values obtained with genotypically and phenotypically wild-type clinical isolates, the mean EC50 values calculated for isolates phenotypically resistant to 3TC or 3TC and AZT were only 2.6-, 1.6- and 8.2-fold higher for dOTC, (-)dOTC and (+)dOTC, respectively. When the rate of emergence of virus resistant to dOTC and its enantiomers in vitro was investigated, virus resistant to (+)dOTC was readily selected for (<10 passages), and a methionine (ATG) to isoleucine (ATA) amino acid change at codon 184 was identified. In contrast, virus resistant to dOTC and (-)dOTC took longer to appear (15-20 passages), with a methionine (ATG) to valine (GTG) amino acid change at position 184 identified in both cases. In addition, virus passaged 20 times in the presence of dOTC also had a partial lysine (AAA) to arginine (AGA) exchange at position 65. These viruses showed only low-level resistance to dOTC and its enantiomers, but were highly resistant to 3TC. The antiviral effects of dOTC in combination with the nucleoside RT inhibitors AZT, 3TC, d4T (stavudine) and ddl, the non-nucleoside RT inhibitor nevirapine Topics: Anti-HIV Agents; Cells, Cultured; Deoxycytidine; Didanosine; Drug Combinations; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Molecular Structure; Mutation; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; T-Lymphocytes; Thionucleosides; Zidovudine | 2000 |
Interaction of methadone with didanosine and stavudine.
For opiate-dependent injection drug users infected with HIV, methadone therapy may facilitate adherence to complex highly active antiretroviral therapy (HAART) regimens. Current HAART regimens include one or more nucleoside analogues. We investigated the effects of methadone on the pharmacokinetics of the tablet formulation of didanosine (ddI) and of stavudine (d4T) in 17 study subjects on stable methadone therapy and in 10 untreated controls. Methadone treatment reduced the measured areas under the time-concentration curve (AUC0-6) by 63% for ddI (p =.04) and by 25% for d4T (p =.005) and the extrapolated AUCs for the full dosing interval (AUC0-12) by 57% for ddI (p =.11) and by 23% for d4T (p =. 02). Peak drug concentrations (Cmax) were reduced by 66% (p =.007) and 44% (p =.001) for ddI and d4T, respectively. The effects on AUC and Cmax appeared to result primarily from decreases in bioavailability. Methadone also delayed drug absorption. Trough levels for methadone did not differ significantly from those in historical controls, suggesting that ddI and d4T did not substantially alter methadone disposition. The results suggest that larger doses of the tablet formulation or an alternate formulation may be needed when didanosine is given to study subjects treated with methadone. Topics: Administration, Oral; Adult; Chromatography, High Pressure Liquid; Didanosine; Drug Interactions; Female; HIV Infections; Humans; Male; Methadone; Middle Aged; Narcotics; Stavudine; Substance Abuse, Intravenous; Tablets | 2000 |
Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a multicenter cohort of HIV-1-infected Italian patients with virologic failure.
We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR. Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Amino Acid Sequence; Cohort Studies; Consensus Sequence; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Italy; Male; Middle Aged; Molecular Sequence Data; Multicenter Studies as Topic; Mutagenesis, Insertional; Mutation; Prevalence; Protease Inhibitors; Reverse Transcriptase Inhibitors; Zidovudine | 2000 |
Preliminary experience of adverse drug reactions, tolerability, and efficacy of a once-daily regimen of antiretroviral combination therapy.
Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hypercholesterolemia; Hypertriglyceridemia; Indinavir; Middle Aged; Nausea; Oxazines; Ritonavir | 2000 |
Antiviral resistance of biologic HIV-2 clones obtained from individuals on nucleoside reverse transcriptase inhibitor therapy.
To study phenotypic and genotypic resistance of HIV-2 against nucleoside reverse transcriptase inhibitors (NRTI).. Biologic HIV-2 clones were generated from 3 patients before and after initiation of antiretroviral therapy with zidovudine (AZT) in patient RH2-7, AZT and didanosine (ddI) in patient PH2-1, and after addition of lamivudine (3TC) to AZT monotherapy in patient RH2-5. The sensitivity to NRTI of the virus clones, as defined by the 50% inhibitory concentration (IC(50)), was determined in vitro. The predicted amino acid sequences of the reverse transcriptase proteins from these clones were determined.. Comparing the sensitivity of the biologic HIV-2 clones obtained after start of therapy with those from antiviral naive patients, resistance had developed to AZT (patients RH2-7 and RH2-5) and 3TC (patient PH2-1 and RH2-5). No resistance to AZT was observed in the biologic clone from PH2-1 obtained after start of therapy. The resistant clones from RH2-5 and PH2-1, but not RH2-7, contained amino acid mutations at positions where HIV-1 has been shown to mutate after AZT and 3TC treatment.. Phenotypic resistance of HIV-2 to nucleoside analogues, which developed in HIV-2-infected patients treated with NRTIs, was associated with genotypic changes. Some of the mutations at amino acid positions in the HIV-2 reverse transcriptase gene corresponded with those involved in HIV-1 resistance, although no conventional mutations associated with resistance to AZT were observed. Topics: Adult; Amino Acid Sequence; Consensus Sequence; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genes, Viral; Genotype; HIV Infections; HIV-2; Humans; Lamivudine; Male; Molecular Sequence Data; Phenotype; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Zidovudine | 2000 |
Nevirapine plus didanosine: once or twice daily combination?
Topics: Administration, Oral; Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine | 2000 |
Monotherapy in an era of combination therapy: is there a benefit? Experience in HIV-1-infected symptomatic South African children.
We investigated the benefit of treating HIV-1-infected children with monotherapy where resources are limited. A retrospective chart review was undertaken in 12 symptomatic HIV-1-infected children treated with zidovudine or didanosine for at least 2 months. The main outcome measure was the effect on hospitalization. Anti-retroviral therapy was commenced in nine children because of prolonged or frequent hospitalization. Of three whose primary indication was bleeding secondary to thrombocytopenia, two had been hospitalized owing to severe intercurrent illness. One child had failure to thrive and another encephalopathy. Monotherapy was considered beneficial in all cases. Median duration of follow-up was 6.5 (2-31) months. The hospitalization index (days in hospital before and after start of monotherapy, divided by the total number of days before and after start of monotherapy) decreased from a median of 0.115 prior to therapy to 0.037 on therapy (p = 0.045, Wilcoxon matched pairs test). This study presents observational data supporting the investigation of monotherapy in resource-poor countries. It was associated with a significant reduction in hospitalization and appeared to result in clinical improvement. Prolonged or frequent hospitalization might represent a novel indication for use because in our setting the cost of hospitalization could potentially provide a 12-month-old infant with monotherapy for 2 months. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; Health Care Rationing; HIV Infections; HIV-1; Hospitalization; Humans; Infant; Male; Retrospective Studies; Reverse Transcriptase Inhibitors; South Africa; Treatment Outcome; Zidovudine | 2000 |
Evidence for late stage compartmentalization of HIV-1 resistance mutations between lymph node and peripheral blood mononuclear cells.
To determine the overall distribution of drug-resistance mutations to nucleoside reverse transcriptase inhibitors of HIV strains recovered from the lymph nodes (LN) and peripheral blood mononuclear cell (PBMC) compartments of four HIV-infected patients receiving zidovudine and didanosine and to compare them with antiretroviral-naive patients.. Molecular comparison of major and minor HIV-1 env and pol region variants residing in LN and PBMC compartments.. Proviral DNA sequences were amplified by PCR from both PBMC and LN compartments, cloned into PGEM-T II Easy vector and sequenced. The clones were subjected to molecular and phylogenetic analysis.. Comparison of PBMC and LN-derived HIV-1 variants in the env V3 region showed that nucleotide and amino acid variability was a characteristic feature of LN-derived variants. In contrast, a majority of resistance mutations to reverse transcriptase inhibitors were localized in the PBMC compartment rather than in LN, which is thought to be a reservoir of HIV.. Distinct compartmentalization or independent evolution of pol and env gene variants between LN and PBMC could be due to the differential selection pressure imposed by the combination drug regimen, hence the bimodal distribution of resistance variants between LN and PBMC compartments. Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; Evolution, Molecular; Genes, env; Genes, pol; Genetic Variation; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Lymph Nodes; Male; Mutation; Peptide Fragments; Time Factors; Zidovudine | 2000 |
A genotypic analysis of patients receiving Zidovudine with either Lamivudine, Didanosine or Zalcitabine dual therapy using the LiPA point mutation assay to detect genotypic variation at codons 41, 69, 70, 74, 184 and 215.
The Murex-Innogenetics LiPA HIV-1 RT assay can be used to identify the presence of mutations of the reverse transcriptase gene at codons 41, 69, 70, 74, 184 and 215 of HIV-1, which have been shown to confer resistance to the nucleoside analogs Zidovudine (ZDV), Lamivudine (3TC), Didanosine (ddI) and Zalcitabine (ddC). The M184V mutation of the reverse transcriptase gene of HIV-1 has been associated with resistance to 3TC, ddC and ddI. This mutation has also been observed in patients receiving ZDV+ddC and ZDV+ddI. We used LiPA HIV-1 RT assay to identify the presence of either consensus methionine 184 or the mutant valine 184 with three groups of patients who were treated with ZDV/3TC, ZDV/ddI or ZDV/ddC combination therapy.. The aim of our study was to determine the viral genotype of patients who were considered to be failing therapy, by two ways: using sequencing and LiPA assays. In particular we were interested in establishing a possible correlation between these methods.. The study group consisted of a consecutive series of 33 patients with a treatment failure, 18 of whom received ZDV+3TC therapy, seven received ZDV+ddI and eight received ZDV+ddC therapy. We also examined a small cohort of seven seroconverters.. The M184V mutation was observed in 47.0% of patients receiving ZDV+3TC combination therapy but was not observed in either patient group receiving either ddI or ddC as co-therapy with ZDV. There was no evidence of the L74V mutation in our study group in either the ZDV/ddI or ZDV/ddC combination therapy group. We found the frequency of the K70R mutation to be higher in patients treated with ZDV/ddI (P=0.033) or ZDV/ddC (P=0.3) when compared with patients treated with ZDV/3TC.. The LiPA assay allowed for the rapid detection of wild type and amino acid variations at key positions conferring resistance to the most used antiviral RT inhibitors. This represented a rapid, quite sensitive, and simple genotyping test. For these reasons the LiPA assay proved to be useful in studying genetic resistance in large screenings, when key RT mutations could be useful in guiding an effective HIV-1 suppressing regimen. Topics: Anti-HIV Agents; Codon; Didanosine; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Genotype; HIV Infections; HIV Seropositivity; HIV-1; Humans; Lamivudine; Nucleic Acid Hybridization; Point Mutation; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Zalcitabine; Zidovudine | 2000 |
Pilot study of hydroxyurea in human immunodeficiency virus-infected children receiving didanosine and/or stavudine.
To evaluate the safety and antiviral and immunologic effects of hydroxyurea given with didanosine (ddI) and/or stavudine (d4T) to symptomatic HIV-infected children.. HIV-infected children with a history of long term nucleoside antiretroviral therapy were treated orally with hydroxyurea (initial dose, 10 to 20 mg/kg once daily; final dose, 30 mg/kg once daily), added to existing therapy that included ddI and/or d4T.. Sixteen children were enrolled (mean age, 6.7 years; range, 1.8 to 13.4 years). Antiretroviral therapy used with hydroxyurea included d4T/ddI (12), ddI (2), d4T (1) and d4T/lamivudine (1). Children received between 24 and 48 weeks of therapy, which was well-tolerated. Hydroxyurea was held temporarily during the first month of therapy in 4 cases because of neutropenia; all patients resumed hydroxyurea at full dosage without recurrence of neutropenia. No patient discontinued therapy permanently because of intolerance or toxicity. For the 13 children who completed 48 weeks of study treatment, the mean plasma HIV RNA concentration decreased from 4.6 log10 copies/ml at baseline to 4.2 log10 copies/ml at study Week 48 (P = 0.035, paired t test). Eight of these 13 children experienced a 0.5-log10 copies/ml or greater drop in HIV RNA concentration in the 48 weeks of study treatment. Appreciable changes in CD4+ lymphocyte percentage were not noted.. Hydroxyurea, added to existing therapy with ddI and/or d4T, was well-tolerated and safe in HIV-infected children. Evidence of antiviral activity was observed in some cases. Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; Female; HIV Infections; Humans; Hydroxyurea; Infant; Male; Pilot Projects; RNA, Viral; Stavudine | 2000 |
Combining iron chelators with the nucleoside analog didanosine in anti-HIV therapy.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Iron Chelating Agents | 2000 |
Suppression of maternal virus load with zidovudine, didanosine, and indinavir combination therapy prevents mother-to-fetus HIV transmission in macaques.
Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287 (10-103 infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287 infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+ T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV. Topics: Animals; Didanosine; Drug Therapy, Combination; Female; Fetus; HIV Antibodies; HIV Infections; HIV Protease Inhibitors; HIV-2; Indinavir; Infectious Disease Transmission, Vertical; Macaca nemestrina; Pregnancy; Reverse Transcriptase Inhibitors; T-Lymphocyte Subsets; Viral Load; Zidovudine | 2000 |
Long-term safety and antiretroviral activity of hydroxyurea and didanosine in HIV-infected patients.
Long-term safety, immunologic effects, and antiretroviral activity of hydroxyurea and didanosine were evaluated in this retrospective study. Some 65 HIV-1-infected patients (39 of whom were antiretroviral naive) were studied (mean baseline CD4 count, 362 cells/mm3; mean plasma HIV-1 RNA viral load, 4.8 log10 copies/ml). The mean treatment duration was 20 months. Overall tolerance was good: 15 patients interrupted treatment because of clinical or biologic side effects. Four patients experienced a category B event. Patients had a mean increase of 27 CD4 cell counts after 12 months, of 112 after 24 months and of 59 after 36 months. They had a mean 1. 03 log10 fall in HIV-1 RNA after 12 months, 1.59 log10 after 24 months, and 1.27 log10 after 36 months. After 12 months, 35% developed an HIV-1 RNA viral load <200 copies/ml, 53% after 24 months, and 36% after 36 months. Those whose viral load became undetectable after 12 months have significantly lower baseline RNA values (p =.03). Fourteen patients had a viral load <3.4 log10 copies/ml after 24 months of the double therapy. A prolonged viral load suppression can be achieved using a simple combination of two drugs that are inexpensive and well tolerated. Topics: Adult; Anti-HIV Agents; Blood Chemical Analysis; CD4 Lymphocyte Count; Didanosine; Drug Combinations; Female; Hematocrit; Hemoglobins; HIV Infections; HIV-1; Humans; Hydroxyurea; Lymphocyte Count; Male; Middle Aged; Platelet Count; Polymerase Chain Reaction; Retrospective Studies; RNA, Viral; Statistics, Nonparametric | 2000 |
Sustained responses to dual nucleoside therapy in women.
Topics: Adult; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Viral Load; Zidovudine | 2000 |
Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus-infected haemophiliacs.
We performed a pilot study to evaluate the factors associated with response to interferon (IFN) therapy for chronic hepatitis C (CHC) with human immunodeficiency virus (HIV) coinfected haemophiliacs. Seven haemophiliacs, coinfected with HIV and hepatitis C virus (HCV), received 9 mega-units (MU) of natural IFN-alpha daily during the first 2 weeks and then three times a week for 22 weeks, all injected subcutaneously. Six patients were receiving zidovudine (AZT) 600 mg day-1 and didanosine (ddI) 200 mg day(-1) during IFN therapy. This treatment was safe and well tolerated. Four patients had no detectable serum HCV-RNA at the end of therapy, but long-term, none of the seven patients achieved a sustained response, i.e. undetectable serum HCV-RNA with persistently normal serum alanine aminotransferase (ALT) 6 months after therapy. IFN did not affect CD4-positive cell counts. Most of our patients had high HCV-RNA loads and/or low CD4 counts, both unfavourable markers for IFN therapy. In conclusion, IFN therapy did not eradicate HCV from haemophiliacs coinfected with HIV. Topics: Adult; Anti-HIV Agents; Antiviral Agents; Didanosine; Hemophilia A; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Middle Aged; Pilot Projects; Treatment Outcome; Zidovudine | 2000 |
Phenotypic resistance pattern of HIV-1 isolates with zidovudine and/or multidrug resistance mutations after didanosine-stavudine combination therapy.
Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Phenotype; Reverse Transcriptase Inhibitors; Stavudine; Viral Load; Zidovudine | 2000 |
Protease inhibitor therapy in HIV-infected children.
We reviewed the short-term response to and safety of protease inhibitor (PI) therapy in HIV-infected children by performing a retrospective chart review of open-label PI containing combination therapy at two urban pediatric HIV centers. Seventy HIV-infected children received 101 PI containing antiretroviral therapy (ART) combinations. Main outcome measures were follow-up CD4 counts, viral loads, and patient or caregiver reported compliance. During follow-up, treatment with PI ART was associated with a mean maximal increase in CD4+ lymphocyte count of 454 x 10(6)/L and a mean maximal decrease in viral load of 1.76 log units. Of the 32 patients who achieved undetectable viral loads, 28 (87.5%) remained undetectable through a mean follow-up of 8.9 months. Patients who reported good compliance achieved a higher rate of response (92.6%) than those who reported poor compliance (61.5%). Of 14 changes made to a second PI because of treatment failure, 11 (78.6%) resulted in a positive response to the second regimen. Nineteen of 101 courses of PI therapy resulted in significant side effects, including renal complications in 8 of 21 patients treated with indinavir. PI ART was associated with substantial short-term improvement in immunological and virological parameters in this heavily pretreated cohort, with 40% of patients maintaining an undetectable viral load after 9 months of therapy. Patients who failed one PI regimen usually responded to a second regimen. There was a significant rate of side effects from PI treatment. Topics: Adolescent; Age Factors; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lamivudine; Male; Nelfinavir; Patient Compliance; Retrospective Studies; Stavudine; Treatment Outcome; Viral Load; Zidovudine | 2000 |
Detection of resistant mutations in the reverse transcriptase of HIV-1-infected children.
Topics: CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Infant; Male; Mutation; Reverse Transcriptase Inhibitors; Ritonavir; Viremia; Zidovudine | 2000 |
[Exanthema in a patient infected with the human immunodeficiency virus after starting antiretroviral treatment].
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Eruptions; HIV Infections; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Stevens-Johnson Syndrome | 2000 |
Leukocytopenia due to zidovudine- and nevirapine-containing regimens in elderly patients with HIV infection.
Topics: Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Therapy, Combination; Fatal Outcome; Granulocyte Colony-Stimulating Factor; HIV Infections; HIV-1; Humans; Leukopenia; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Zidovudine | 2000 |
Didanosine (Videx).
Topics: Didanosine; Drug Resistance, Microbial; HIV; HIV Infections; Humans; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors | 2000 |
A simple, once-daily dosing regimen for treating HIV-1 infection in intravenous drug users.
Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Nevirapine; Pilot Projects; Polymerase Chain Reaction; RNA, Viral; Substance Abuse, Intravenous; Treatment Refusal; Viral Load | 2000 |
Treatment of primary HIV infection: a pilot study of stavudine and didanosine plus nevirapine with or without hydroxyurea.
Treatment of primary human immunodeficiency virus (HIV) infection (PHI) may provide an opportunity to achieve a long lasting suppression of viral replication. Although there is growing evidence of the benefit of treating PHI, clinical data are still very limited. Special therapeutic considerations in this clinical setting include the prevalence of resistant viruses in the community, complexity of regimens and their long-term toxicity. In addition, adjunctive therapies aimed at exploring the role of immune modulation and intensification of antiretroviral therapy are becoming areas of great interest. In this regard, the role of hydroxyurea, a cytostatic agent that potentiates the antiviral effect of didanosine, and possibly of stavudine is being investigated. A pilot study to assess the antiviral effect of a combination of didanosine plus stavudine plus nevirapine with or without hydroxyurea in the treatment of PHI is currently under way. Preliminary results on 22 patients who completed at least 36 weeks of therapy suggest that the combination is safe, well tolerated and effective for the treatment of PHI. Topics: Acute Disease; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; HIV Infections; Humans; Hydroxyurea; Nevirapine; Pilot Projects; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome | 1999 |
Nevirapine, didanosine, and zidovudine for patients with HIV: the INCAS trial. Italy, Netherlands, Canada, and Australia.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Randomized Controlled Trials as Topic; Zidovudine | 1999 |
Nevirapine, didanosine, and zidovudine for patients with HIV: the INCAS trial. Italy, Netherlands, Canada, and Australia.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Randomized Controlled Trials as Topic; Viral Load; Zidovudine | 1999 |
Normal T-cell telomerase activity and upregulation in human immunodeficiency virus-1 infection.
In human immunodeficiency virus (HIV)-1 infection, decrease of telomere length is mainly found in CD8(+) T cells and not in CD4(+) T cells. Telomerase, a ribonucleoprotein enzyme that can synthesize telomeric sequence onto chromosomal ends, can compensate for telomere loss. Here, we investigated if telomerase activity could explain differential telomere loss of CD4(+) and CD8(+) T cells in HIV-1 infection. Telomerase activity was higher in CD8(+) than in CD4(+) T cells from HIV-infected patients, but still in the same range as in healthy controls, and upregulation after stimulation was comparable to normal. Telomerase activity in lymph node CD4(+) and CD8(+) T cells from HIV-infected patients was in the same range as that in CD4(+) and CD8(+) T cells from peripheral blood (PB) and was normal in unseparated bone marrow cells. Thus, our study did not provide evidence for compartmentalized elongation of telomeres in HIV infection. In patients treated with reverse transcriptase inhibitors, telomerase activity was inhibited, but this did not lead to accelerated loss of telomere length in vivo. Thus, differential telomere loss in CD4(+) and CD8(+) T cells in HIV-1 infection cannot be explained by telomerase activity. Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; Didanosine; Drug Therapy, Combination; Enzyme Induction; HIV Infections; HIV-1; Humans; Lymphoid Tissue; Reverse Transcriptase Inhibitors; Telomerase; Telomere; Up-Regulation; Zalcitabine; Zidovudine | 1999 |
Butyl nitrite-induced acrocyanosis in an HIV-infected patient.
Topics: Acrodermatitis; Adult; Cyanosis; Didanosine; HIV Infections; Humans; Male; Nitrites; Nose Diseases; Pentamidine; Substance-Related Disorders; Vasodilator Agents | 1999 |
Concomitant therapy with subcutaneous interleukin-2 and zidovudine plus didanosine in patients with early stage HIV infection.
A phase II study was performed to evaluate the feasibility and activity of subcutaneous (SC) interleukin-2 (IL-2) administration plus zidovudine (ZDV) and didanosine (ddI) in patients with early stage HIV infection. Between October 1995 and October 1996, 12 patients completed 6 cycles of the following scheduled therapy: ZDV plus ddI and SC self-administration of 6 mIU of IL-2 at days 1 to 5 and 8 to 12 of a 28-day cycle for a total of 6 cycles (24 weeks). After 6 cycles, patients received only ZDV plus ddI and they were observed up for an additional 24 weeks. Our schedule was well tolerated as an outpatient regimen and led to a significant elevation in CD4 count, which lasted for 24 weeks after the end of IL-2 therapy. Moreover, CD4/CD25, as well as CD4/CD45RO and CD4/CD45RA, cell levels were significantly increased at the end of the therapy and remained significantly elevated after 24 weeks. During the 6 cycles, HIV-associated viremia was significantly decreased and, accordingly, we observed a significant decline of proviral DNA in peripheral blood mononuclear cells (PBMCs). During follow-up, 10 of 12 treated patients continued to show levels of HIV-related viremia <500 copies/ml. Our results demonstrated that IL-2 and ZDV plus ddI is a well tolerated and effective therapy for patients with HIV in early stages of the disease. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; Humans; Injections, Subcutaneous; Interleukin-2; Leukocyte Common Antigens; Male; Pilot Projects; Receptors, Interleukin-2; Zidovudine | 1999 |
Analysis of amino insertion mutations in the fingers subdomain of HIV-1 reverse transcriptase.
In response to dideoxy inosine/hydroxyurea dual therapy, HIV-1 (human immunodeficiency virus type-1) variants were isolated that had a small amino acid insertion and flanking amino acid substitutions in the fingers subdomain of HIV-1. We have analyzed the reverse transcriptase variants for their effects on HIV-1 reverse transcriptase activity. The data suggests that the inserted amino acid residues are responsible for low-level resistance to the nucleoside analog ddITP, while the role of the flanking amino acid substitutions is to compensate for the deleterious effects of the insertion. Topics: Anti-HIV Agents; Deoxyadenine Nucleotides; Didanosine; Dideoxynucleotides; Drug Resistance, Microbial; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Kinetics; Mutagenesis, Insertional; Protein Conformation | 1999 |
Effect of didanosine, stavudine, and hydroxyurea therapy on apoptosis in CD45RA+ and CD45RO+ T lymphocyte subpopulations.
The effect of aggressive antiretroviral therapy on spontaneous apoptosis (AP) in CD4+ and CD8+ lymphocytes expressing CD45RO (memory cells) and CD45RA (naive cells) and their relationship to cellular activation and viral load were examined. Ten patients receiving simultaneous treatment with d4T, ddI, and HU were evaluated. Flow cytometric analysis showed significant levels of AP (measured by TUNEL assay) among memory and naive T cells and an enhanced expression of CD38 and HLA-DR activation markers. The percentage of apoptotic CD4+CD45RO+ and CD4+CD45RA+ cells decreased, respectively, from 34 +/- 3.3 and 29 +/- 3.6 prior to treatment to 20.5 +/- 4 and 22 +/- 3.8 at week 8 into therapy. The percentage of apoptotic CD8+CD45RO+ and CD8+CD45RA+ cells similarly decreased, respectively, from 20 +/- 2.5 and 24 +/- 3 prior to treatment to 14.5 +/- 2.7 and 16 +/- 3 at week 8 into treatment. The percentage of CD4+ cells expressing the activation markers CD38 and HLA-DR decreased from 27 +/- 6 to 13 +/- 2 and from 26 +/- 4 to 13.5 +/- 3, respectively. The percentage of CD8+ cells expressing either CD38 or HLA-DR fell from 22 +/- 3 to 10 +/- 2 for the former and from 39 +/- 5 to 22 +/- 4 for the latter. This was associated with a significant decrease in viral load (mean, 1.4 log10), and a decline in circulating plasma TNF-alpha and sIL-2R levels from 50.5 +/- 10 to 21 +/- 6 and 92.5 +/- 11 to 68 +/- 9, respectively. These data indicate that short-term therapy with ddI, d4T, and HU in combination diminished AP, immune activation, and partially restored naive and memory T cell subpopulations. Topics: Adult; Anti-HIV Agents; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Didanosine; Drug Therapy, Combination; Female; Flow Cytometry; HIV Infections; HIV-1; HLA-DR Antigens; Humans; Hydroxyurea; Immunologic Memory; Leukocyte Common Antigens; Lymphocyte Activation; Male; Middle Aged; Nucleic Acid Synthesis Inhibitors; Stavudine; T-Lymphocyte Subsets; Viral Load | 1999 |
Hepatic mitochondrial toxicity from nucleoside analog therapy.
Topics: Adult; Didanosine; HIV Infections; Humans; Male; Mitochondria, Liver; Stavudine | 1999 |
Patients with HIV-1 RNA below 1000 copies/ml after 48 weeks on dual nucleoside combination therapy. Delta Coordinating Committee.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome; Viral Load; Zalcitabine; Zidovudine | 1999 |
Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.
Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term.. In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy.. Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml).. Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery.. Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation. Topics: Adult; Aging; Anti-HIV Agents; Didanosine; Follow-Up Studies; HIV Infections; HIV-1; Humans; Immunologic Memory; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Time Factors; Zidovudine | 1999 |
Management of liver failure in a haemophilic patient co-infected with human immunodeficiency and hepatitis C viruses.
We present a case of liver failure in a haemophilic patient coinfected with transfusion acquired human immunodeficiency (HIV) and hepatitis C (HCV) viruses. The case illustrates the interaction of multiple viruses with accelerated progression to end stage liver disease and ultimately death. We report the impact on the patient management of two liver biopsies, which diagnosed an initial drug induced hepatitis and subsequently an atypical HCV related hepatitis. Topics: Anti-Bacterial Agents; Anti-HIV Agents; Clarithromycin; Didanosine; Hemophilia A; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver Failure, Acute; Male; Middle Aged; Zidovudine | 1999 |
Estimation and comparison of rates of change in longitudinal studies with informative drop-outs.
Many cohort studies and clinical trials have designs which involve repeated measurements of disease markers. One problem in such longitudinal studies, when the primary interest is to estimate and to compare the evolution of a disease marker, is that planned data are not collected because of missing data due to missing visits and/or withdrawal or attrition (for example, death). Several methods to analyse such data are available, provided that the data are missing at random. However, serious biases can occur when missingness is informative. In such cases, one needs to apply methods that simultaneously model the observed data and the missingness process. In this paper we consider the problem of estimation of the rate of change of a disease marker in longitudinal studies, in which some subjects drop out prematurely (informatively) due to attrition, while others experience a non-informative drop-out process (end of study, withdrawal). We propose a method which combines a linear random effects model for the underlying pattern of the marker with a log-normal survival model for the informative drop-out process. Joint estimates are obtained through the restricted iterative generalized least squares method which are equivalent to restricted maximum likelihood estimates. A nested EM algorithm is applied to deal with censored survival data. The advantages of this method are: it provides a unified approach to estimate all the model parameters; it can effectively deal with irregular data (that is, measured at irregular time points), a complicated covariance structure and a complex underlying profile of the response variable; it does not entail such complex computation as would be required to maximize the joint likelihood. The method is illustrated by modelling CD4 count data in a clinical trial in patients with advanced HIV infection while its performance is tested by simulation studies. Topics: Biomarkers; CD4 Lymphocyte Count; Clinical Trials as Topic; Cohort Studies; Computer Simulation; Didanosine; Disease Progression; HIV Infections; Humans; Likelihood Functions; Linear Models; Longitudinal Studies; Models, Statistical; Multivariate Analysis; Patient Dropouts; Reverse Transcriptase Inhibitors; Survival Analysis; Survival Rate | 1999 |
Reconstitution of human thymic implants is limited by human immunodeficiency virus breakthrough during antiretroviral therapy.
Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants depleted of CD4(+) cells can support renewed thymopoiesis derived from both endogenous and exogenous T-cell progenitors after combination antiretroviral therapy. However, successful production of new thymocytes occurs transiently. Possible explanations for the temporary nature of this thymic reconstitution include cessation of the thymic stromal support function, exhaustion of T-cell progenitors, and viral resurgence. Distinguishing between these processes is important for the development of therapeutic strategies aimed at reconstituting the CD4(+) T-cell compartment in HIV-1 infection. Using an HIV-1 strain engineered to express the murine HSA heat-stable antigen surface marker, we explored the relationship between HIV-1 expression and CD4(+) cell resurgence kinetics in HIV-1-depleted SCID-hu implants following drug therapy. Antiviral therapy significantly suppressed HIV-1 expression in double-positive (DP) CD4/CD8 thymocytes, and the eventual secondary decline of DP thymocytes following therapy was associated with renewed viral expression in this cell subset. Thymocytes derived from exogenous T-cell progenitors induced to differentiate in HIV-1-depleted, drug-treated thymic implants also became infected. These results indicate that in this model, suppression of viral replication occurs transiently and that, in spite of drug therapy, virus resurgence contributes to the transient nature of the renewed thymic function. Topics: Animals; Anti-HIV Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Disease Models, Animal; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kinetics; Lymphocyte Depletion; Mice; Mice, SCID; Reverse Transcriptase Inhibitors; Thymus Gland; Zidovudine | 1999 |
Changing cost of English HIV service provision 1996-1997. NPMS Steering Group. National Prospective Monitoring System.
The objectives of this study were to provide individual and population-based unit cost estimates of HIV treatment and care by stage of HIV infection for adults in England and estimate the financial impact of the use of combination antiretroviral therapy. Individual unit cost estimates were calculated, based on 1997 activity data, and linked to the number of diagnosed HIV-infected individuals using statutory medical services by clinical stage of HIV infection in England during 1997 to obtain population-based cost estimates; these were compared with 1996 estimates. Most clinical guidelines now recommend the use of 3 antiretroviral agents, but cost estimates for mono and dual therapy were included as baseline estimates. Baseline costs for treating AIDS patients with zidovudine (AZT) monotherapy were estimated at pound sterling 16,830 (95% CI 14,633-18,985) per patient-year which was substantially lower than the 1996 estimate; costs for asymptomatic individuals and people with symptomatic non-AIDS were pound sterling 4450 (95% CI 3521-5612) and pound sterling 7289 (95% CI 6169-8386) per respective patient-year which did not differ substantially from 1996. The total annual population cost estimate for HIV service provision amounted to pound sterling 128 million (95% CI pound sterling 109m to pound sterling 147m), if all patients with HIV disease were treated with AZT monotherapy only. For all eligible patients to be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to pound sterling 161m (95% CI pound sterling 141m to pound sterling 181m), while for triple therapy, annual estimated expenditure amounted to pound sterling 185m (95% CI pound sterling 165m to pound sterling 206m) when a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) was included or pound sterling 205m (95% CI pound sterling 186m to pound sterling 235m) when a protease inhibitor was included. Compared with 1996 population-based cost estimates, the estimates for monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy which included a NNRTI and by 9% if a protease inhibitor was used as part of a triple therapy regimen. Similarly, compared with 1996 estimates, the proportion of total costs attributable to treating asymptomatic individuals increased by 5% and 2-3% for people with symptomatic non-AIDS, while the proportion attributable for treating people with AIDS decre Topics: Adult; Anti-HIV Agents; Didanosine; Drug Costs; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Hospital Costs; Humans; Nevirapine; RNA-Directed DNA Polymerase; United Kingdom; Zalcitabine; Zidovudine | 1999 |
[A very, very short of breath HIV-infected patient].
Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Antimetabolites; Diagnosis, Differential; Didanosine; Dyspnea; HIV Infections; Humans; Liver; Male; Mitochondria, Liver; Reverse Transcriptase Inhibitors; Stavudine; Time Factors | 1999 |
[Lipodystrophy in a patient treated with stavudine and didanosine].
Topics: Adipose Tissue; Anti-HIV Agents; Didanosine; HIV Infections; HIV-1; Humans; Lipodystrophy; Male; Middle Aged; Stavudine | 1999 |
Acute pancreatitis with severe lactic acidosis in an HIV-infected patient on didanosine therapy.
Topics: Acidosis, Lactic; Acute Disease; Anti-HIV Agents; Didanosine; HIV Infections; Humans; Male; Middle Aged; Pancreatitis | 1999 |
Beneficial effect of highly active antiretroviral therapy (HAART) in reducing both HIV viral load and monoclonal gammopathy.
Topics: Adult; Anti-HIV Agents; B-Lymphocytes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lymphocyte Activation; Male; Paraproteinemias; Ritonavir; Viral Load; Zidovudine | 1999 |
Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy. STADI Group.
Assessment of genotypic changes in the reverse transcriptase gene of HIV-1 occurring in antiretroviral naive patients treated by stavudine plus didanosine combination therapy.. Sequence analysis (codons 1-230) was performed after amplification of the reverse transcriptase gene from plasma samples collected at baseline and at the end of treatment from 39 previously treatment-naive patients treated for 24-48 weeks.. At baseline, mutations associated with zidovudine resistance were detected in plasma from two patients: Asp67Asn/Lys219Gln and Leu210Trp. Among the 39 subjects, 18 (46%) developed mutations: one developed the Val75Thr/Ala mutation, four (10%) developed a Gln151Met multidrug-resistance mutation (MDR), associated in one of them with the Phe77Leu and the Phe116Tyr MDR mutations and 14 (36%) developed one or more zidovudine-specific mutations (Met41Leu, Asp67Asn, Lys70Arg, Leu210Trp, Thr215Tyr/Phe). The development of a Met41Leu zidovudine-specific mutation was associated with the development of a Gln151Met mutation in one patient. Other reverse transcriptase mutations known to confer resistance to nucleoside analogues were not detected. At inclusion, there was no statistical difference in HIV-1 load between patients who developed resistance mutations and those who did not. RNA HIV-1 load decrease was higher (P = 0.05) in patients who maintained a wild-type reverse transcriptase genotype (-2.22 log10 copies/ml) than in patients who developed resistance mutations (-1.14 log10 copies/ml).. Stavudine/didanosine combination therapy is associated with emergence of zidovudine-related resistance or MDR mutations in naive patients. These findings should be considered when optimizing salvage therapy for patients who have received a treatment including stavudine/didanosine combination. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; Humans; Mutation; Reverse Transcriptase Inhibitors; Stavudine; Viral Load; Zidovudine | 1999 |
Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.
Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Flow Cytometry; HIV Infections; HIV-1; Humans; Hydroxyurea; Immunophenotyping; Lymphocyte Activation; Nucleic Acid Synthesis Inhibitors; T-Lymphocytes; Viral Load; Virus Replication | 1999 |
Hydroxyurea reduces the 50% inhibitory concentration of didanosine in HIV-infected cells.
Topics: Anti-HIV Agents; Cells, Cultured; Didanosine; Drug Synergism; HIV Infections; HIV-1; Humans; Hydroxyurea; Inhibitory Concentration 50; Nucleic Acid Synthesis Inhibitors; T-Lymphocytes | 1999 |
Reaction times are faster in HIV-seropositive patients on antiretroviral therapy: A preliminary report.
We evaluated subclinical mental and motor slowing in 142 HIV-seropositive patients without dementia, using computerized simple and choice reaction time tasks and self-report measures of psychological distress. Patients on antiretroviral therapy at the time of testing (n = 79) had significantly faster choice reaction times (p < 0.05), indicating faster mental processing speed, than untreated patients (n = 63). These faster RTs could not be attributed to differences in age, education, risk factors, degree of immunosuppression, substance abuse history, peripheral neuropathy, or psychological distress. Reaction time tasks should be investigated further as potential outcome measures in clinical trials, particularly for subjects with few or no overt cognitive deficits. Topics: Adult; Anti-HIV Agents; Case-Control Studies; CD4 Lymphocyte Count; CD4-CD8 Ratio; Choice Behavior; Cognition; Cross-Sectional Studies; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Pilot Projects; Psychiatric Status Rating Scales; Psychomotor Performance; Reaction Time; Statistics, Nonparametric; Zalcitabine; Zidovudine | 1999 |
Highly active anti-retroviral therapy (HAART) is associated with a lower level of CD4+ T cell apoptosis in HIV-infected patients.
HAART may increase CD4+ T cell counts despite a persistently detectable HIV load. The impact of HAART on apoptosis, which may play a role in the disease process in HIV-infected patients, has not been extensively studied. We performed a study to compare the level of spontaneous T cell apoptosis and anti-retroviral treatments in a cohort of HIV-1-infected patients. Data were obtained from a computerized medical record. Quantification of apoptotic cells was by cytofluorometric technique. From November 1995 to December 1997 we studied T cell apoptosis in 112 HIV-infected patients. Forty patients were classified A, 36 B and 36 C. Thirty patients were naive and 82 received an anti-retroviral treatment, 49 including a protease inhibitor (PI). The median plasma viraemia determined in 63 patients was 3.6 (range 1.3-5.6) log10. The median apoptotic cell count was 22% (range 2-73%) and 12% (range 2-60%) for CD4+ and CD8+ T cells, respectively. We did not observe any correlation between the HIV viraemia and the level of apoptosis of T cell subsets. Patients with HAART showed a lower percentage of apoptotic CD4+ T cells only: 16% (range 2-61%) versus 25% (range 5-73%) for patients receiving two nucleoside analogues (P = 0.02). This effect was significant in stage A patients and remained observable during the whole course of HIV disease. In conclusion, HAART, without any relation to plasma viraemia, is able to reduce apoptosis of CD4+ T cells. Topics: Adult; Aged; Anti-HIV Agents; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Multivariate Analysis; Retrospective Studies; Stavudine; Viral Load; Zalcitabine; Zidovudine | 1999 |
Beneficial effects of protease inhibitors on body composition and energy expenditure: a comparison between HIV-infected and AIDS patients.
(i) To investigate whether protease inhibitor (PI) (nelfinavir)-containing highly active antiretroviral therapy (HAART) affects body composition differently in HIV-infected and AIDS patients without wasting syndrome. (ii) To delineate the changes in resting energy expenditure (REE) under PI therapy, and to determine whether sustained reductions in HIV RNA would decrease REE.. Prospective longitudinal cohort study with individually matched healthy controls.. Tertiary care centre at a University Hospital.. HIV-seropositive (n = 20) and AIDS patients (n = 17) with a plasma viral load of at least 10000 copies/ml and 37 healthy volunteers were enrolled. All participants were weight stable, free of acute opportunistic infections, and naive to PI therapy. Patients underwent testing of bioelectrical impedance analysis (BIA), indirect calorimetry and food intake, shortly before the initiation of HAART and 24 weeks thereafter.. Both patient groups gained weight, body mass index (BMI), and fat-free mass (FFM) (P < 0.05 versus baseline), whereas only AIDS patients gained fat mass. Increases were more pronounced in the AIDS group. REE was elevated compared with corresponding controls at baseline, and decreased similarly in HIV and in AIDS patients during PI therapy (P < 0.05). The reduction in the viral burden preceded the decrease in REE by several weeks.. Body composition and metabolic parameters improved during PI therapy in HIV-infected and AIDS patients without wasting. Although an early reduction in viral load as a result of HAART does not seem to influence REE directly, sustained viral load suppression may promote a decrease in energy expenditure. Topics: Acquired Immunodeficiency Syndrome; Adult; Basal Metabolism; Body Composition; Body Weight; Case-Control Studies; Cohort Studies; Didanosine; Energy Metabolism; Female; HIV Infections; HIV Protease Inhibitors; Humans; Longitudinal Studies; Male; Middle Aged; Nelfinavir; Prospective Studies; Stavudine; Viremia | 1999 |
Incidence and predictors of virologic failure of antiretroviral triple-drug therapy in a community-based cohort.
Highly active antiretroviral therapy fails to reach its recommended goal of sustained suppression of viral replication in a substantial proportion of patients. We analyzed incidence and predictors of virologic failure of the first regimen of a triple-drug combination therapy, including a protease inhibitor and two nucleoside analog reverse transcriptase inhibitors (NRTIs), in 274 HIV-infected patients. Long-term virologic response to combination therapy including salvage regimens was assessed 2.5 years after treatment initiation. During an initial observation period of up to 1.8 years (median, 0.8 years) 152 patients (55%) experienced sustained suppression of HIV-1 RNA to <500 copies/ml. Failure to reduce viral load to <500 copies/ml within 6 months (initial failure) was observed in 51 patients (19%). Independent risk factors for initial failure included higher baseline viral load; addition of a protease inhibitor to an unchanged NRTI regimen; use of saquinavir hard-gel capsules; and longer duration of prior NRTI treatment. Within a median of 7 months viral load rebound above 500 copies/ml occurred in 71 of 223 patients (32%) whose viral load had initially decreased below this threshold. In proportional hazard analysis none of the potential risk factors was significantly associated with viral load rebound. However, in 40 patients (56%) with viral load rebound, incomplete adherence to therapy or treatment interruptions preceded the rebound. Virologic outcome after 2.5 years correlated with initial response to the first regimen: viral load was <500 copies/ml in 88, 55, and 21% of patients with sustained suppression, viral load rebound, and initial failure, respectively. Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Didanosine; Disease Progression; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Incidence; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; RNA, Viral; Salvage Therapy; Saquinavir; Stavudine; Switzerland; Treatment Failure; Viral Load; Zalcitabine; Zidovudine | 1999 |
Improvement of onychomycosis without antifungal therapy after initiation of highly active anti-retroviral therapy (HAART) in an HIV-infected patient.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Indinavir; Male; Onychomycosis; Reverse Transcriptase Inhibitors; Stavudine; Syphilis | 1999 |
A novel genotype encoding a single amino acid insertion and five other substitutions between residues 64 and 74 of the HIV-1 reverse transcriptase confers high-level cross-resistance to nucleoside reverse transcriptase inhibitors. Abacavir CNA2007 Interna
We investigated HIV-1 reverse transcriptase (RT) polymorphisms of plasma isolates from 98 HIV-1-infected study subjects with >2 years of antiretroviral therapy who were failing their current protease inhibitor (PI)-containing regimen. In 1 patient, we detected a virus with a heavily mutated beta3-beta4 connecting loop of the HIV-1 RT fingers subdomain, consisting of a single aspartate codon insertion between positions 69 and 70 and five additional variations: 64N, K65, K66, 67G, 68Y, T69, Ins D, 70R, W71, R72, K73, 74I. Mutants with the recently described 2-aa insertions between codons 68 and 70 of RT were detected in another 3 patients. Among the four isolates with the 1- or 2-aa insertions, the novel genotype was the most refractory to therapy and displayed the highest level of phenotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Follow-up samples demonstrated that the novel mutant represents a stable genetic rearrangement and that the amino acid insertions can coexist with nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) mutations resulting in phenotypic resistance to both NRTIs and NNRTIs. An increasing number of HIV-1 isolates containing various insertions in the beta3-beta4 hairpin of the HIV-1 RT fingers subdomain appear to emerge after prolonged therapy with different NRTIs, and these polymorphisms can confer multiple drug resistance against NRTIs. Topics: Amino Acid Substitution; Codon; Cohort Studies; Didanosine; Drug Resistance, Microbial; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Phenotype; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Zalcitabine | 1999 |
[Perinatal co-infection with hepatitis B and HIV viruses--reciprocal effect of the disease and the treatment].
We report the case study of a 1-year-old girl who was perinatally infected with both hepatitis B (HBV) and HIV viruses. The clinical presentation and treatment are described. We examined the interaction between the 2 viruses and the possible effects of the interaction on the development of each virus and on treatment. Our findings demonstrate that combined HIV and HBV infections intensified deterioration, as the HBV liver disease aggravated the HIV infection. The medication of choice was Lamivudine, since it prevents the transcription of both viruses. Topics: Anti-HIV Agents; Didanosine; Female; Hepatitis B; HIV Infections; Humans; Infant; Ritonavir; Zidovudine | 1999 |
Interrupting HAART; Hydroxyurea; five+ drug therapy - report from the RIGHT Conference.
The issue of interrupting highly active antiretroviral therapy (HAART) was discussed in depth at a meeting of the Research Institute for Genetic and Human Therapy (RIGHT) in April. The U.S. AIDS Clinical Trials Group will begin a study (A5063) of how some people maintain undetectable viral loads after they stop taking their medications. The study is still in the planning stages and needs approval from the FDA and the National Institutes of Health before it can begin. Results of studies featuring hydroxyurea plus ddI and anti-HIV treatment using five or more drugs are also described. A full report of the conference is available on the National AIDS Treatment Advocacy Project's web site. Contact information is included. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Nucleic Acid Synthesis Inhibitors; Stavudine | 1999 |
Extended warning on Didanosine-related pancreatitis.
A new notice was distributed to health care providers cautioning of the increased risk of fatal and nonfatal pancreatitis for patients taking didanosine (Videx) from Bristol-Meyers Squibb. Several patients enrolled in the clinical trials died from pancreatitis. Any incidences of pancreatitis should be disclosed to Bristol-Meyers Squibb, and the FDA through MEDWATCH. Contact information is provided. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Indinavir; Nucleic Acid Synthesis Inhibitors; Pancreatitis; Stavudine | 1999 |
ddI, d4T, Hydroxyurea: new pancreatitis warning.
Physicians and researchers received a stronger warning from Bristol-Myers Squibb (BMS) this week about the risk of pancreatitis in patients taking ddI (Videx). The risk is higher if they are also taking d4T, with or without Hydroxyurea (Hydrea). There have been four deaths in recent clinical trials. Each of the four had CD4 counts greater than 500, viral loads below 200 copies, and were taking d4T. Two of the four were also enrolled in a study which included ddI, d4T, and Hydroxyurea, and three had known risk factors for pancreatitis. The new warning follows an October 27 letter from the FDA to BMS after an investigation found the drug company failed to disclose important safety information, and was promoting hydroxyurea for unapproved uses. The text of the warning letter, as well as a web site address for the full text of the FDA warning, is included. Topics: Anti-HIV Agents; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Nucleic Acid Synthesis Inhibitors; Pancreatitis; Stavudine; United States Food and Drug Administration | 1999 |
Hydroxychloroquine+ddI+Hydroxyurea antiretroviral trial, AIDS Research Alliance, Los Angeles.
A well-known malaria drug, Hydroxychloroquine, has shown some modest anti-HIV activity in laboratory and human studies, and volunteers are being recruited for a small phase I/II trial in Los Angeles. The drug will be studied in combination with ddI and Hydroxyurea, to determine if a less expensive and more tolerable regimen can be found. The study is sponsored by the AIDS Research Alliance (formerly Search Alliance) and funded by Bristol Myers. Sanofi will donate the Hydroxychloroquine. Study enrollment criteria and contact information are included. Topics: Anti-HIV Agents; Antimalarials; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxychloroquine; Hydroxyurea; Los Angeles; Nucleic Acid Synthesis Inhibitors; Patient Selection | 1999 |
ddI: FDA approves once-daily dosing. Food and Drug Administration.
The FDA approved a new ddI (Videx), manufactured by Bristol-Myers Squibb of Princeton, New Jersey. The formulation has been designed to be taken once a day. Restrictions on food and other medicines near the time of administration, make once a day use more feasible. This new type of dosing could improve adherence and help patients stay on their therapy longer. Topics: Administration, Oral; Anti-HIV Agents; Didanosine; Drug Approval; HIV Infections; Humans; United States Food and Drug Administration | 1999 |
New dosing of ddI (Videx) and Nelfinavir (Viracept) approved.
The Food and Drug Administration (FDA) approved once-daily dosing of a new 200mg formulation of Bristol-Myers Squibb's nucleoside analog, ddI. The new tablet will be available in December 1999. Two tablets of ddI must always be taken together to minimize gastric acid degradation. The FDA will require the drug company to warn patients of the increased risk of developing pancreatitis, sometimes observed in persons on ddI therapy. The FDA also approved a 1,250mg twice-daily dosing of nelfinavir, a protease inhibitor manufactured by Agouron Pharmaceuticals. Topics: Anti-HIV Agents; Didanosine; HIV Infections; HIV Protease Inhibitors; Humans; Nelfinavir; Pancreatitis; United States Food and Drug Administration | 1999 |
New anti-HIV drugs in development.
Updates are provided for new anti-HIV drugs currently in development. ABT-378, Tipranavir, and DMP-450 are among the new protease inhibitors discussed. Drugs from other classes that are discussed include emivirine (Coactinon, formerly MKC-442), FTC (emtricitabine, Coviracil), adefovir (Preveon), and pentafuside (T-20). A small study has found that women using Ritonavir (Norvir) may be at a greater risk for anemia (a decrease in red blood cells), caused by excessive menstrual bleeding or hypermenorrhea. New formulations of Ritonavir and ddI (Didanosine, Videx) are described. Topics: Adverse Drug Reaction Reporting Systems; Anti-HIV Agents; Capsules; Carbamates; Chemistry, Pharmaceutical; Didanosine; Drug Synergism; Drug Therapy, Combination; Drugs, Investigational; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Menorrhagia; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides | 1999 |
Severe hyperglycemia in an HIV clinic: preexisting versus drug-associated diabetes mellitus.
We determined the frequency and clinical nature of severe hyperglycemia in a university clinic for HIV-1-infected patients. The medical records of 1392 adult HIV-infected patients were reviewed for cases of severe hyperglycemia, defined as two or more serum glucose values >250 mg/dl or diabetes treatment during clinic care. Demographic information, family histories of diabetes mellitus, body weights, CD4+ lymphocyte counts, and use of corticosteroids, megestrol acetate, pentamidine, or didanosine were recorded for subjects meeting the case definition. Comparisons were made between preexisting diabetic (group 1) and incident hyperglycemic cases (group 2). Less than 2% of the total clinic population experienced severe hyperglycemia: 12 in group 1 and 13 in group 2. Group 2 had lower body weights (mean, 70.6 kg versus 90.0 kg; p < 0.05) and more advanced HIV disease (mean CD4 count, 79/mm3 versus 550/mm3; p < 0.05) than group 1. Group 2 cases had evidence of drug-associated hyperglycemia; four cases demonstrated hyperglycemia coinciding with large fluctuations in weight during megestrol therapy. Among megestrol recipients, cases did not differ from noncases in demographics, weight, or CD4 count. Severe hyperglycemia is uncommon in adult HIV-infected patients. Approximately one half of these patients have preexisting diabetic conditions; many of the remainder may have drug-induced hyperglycemia, especially as a result of corticosteroids or megestrol acetate. Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-HIV Agents; Diabetes Complications; Diabetes Mellitus; Didanosine; Female; HIV Infections; Humans; Hyperglycemia; Male; Megestrol Acetate; Middle Aged; Pentamidine; Retrospective Studies | 1998 |
Drug susceptibility of subtypes A,B,C,D, and E human immunodeficiency virus type 1 primary isolates.
We determined the susceptibility to antiviral drugs of clinical isolates of human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C, D, and E. Isolates from treated and untreated patients were tested for sensitivity to zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), nevirapine (NVP), foscarnet (PFA), and ritonavir (RNV). The susceptibility to these different drugs was broadly similar between the different subtypes of HIV-1. Isolates of subtype D showed a tendency toward slightly lower susceptibility to all the antiviral drugs, which could be related to the rapid growth characteristics of these isolates. Topics: Anti-HIV Agents; Cell Line, Transformed; Cells, Cultured; Didanosine; Foscarnet; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Leukocytes, Mononuclear; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine | 1998 |
Oligonucleotide ligation assay for detecting mutations in the human immunodeficiency virus type 1 pol gene that are associated with resistance to zidovudine, didanosine, and lamivudine.
This report describes the detection of mutations in the pol gene of human immunodeficiency virus type 1 associated with resistance to zidovudine, didanosine, and lamivudine by genotyping by an oligonucleotide ligation assay specific codons in the pol gene amplified by PCR. Our studies demonstrate the sensitivity, simplicity, and specificity of this genotyping system. Topics: Anti-HIV Agents; Codon; Didanosine; Drug Resistance, Microbial; Genes, pol; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Oligonucleotide Probes; Polymerase Chain Reaction; RNA, Viral; Sensitivity and Specificity; Sequence Analysis, DNA; Zidovudine | 1998 |
Effect of combined zidovudine and didanosine therapy in early asymptomatic primary HIV-1 infection.
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Polymerase Chain Reaction; Treatment Outcome; Zidovudine | 1998 |
Survival in 2367 zidovudine-treated patients according to use of other nucleoside analogue drugs. The EuroSIDA Study Group.
To evaluate survival according to use of different nucleoside drugs in a routine clinical setting, we studied a large group of zidovudine-treated patients seen in clinics across Europe. A total of 3128 subjects was recruited to the observational, prospective EuroSIDA study in May 1994. These were consecutive patients (up to a predefined limit) seen at outpatient clinics in 37 centers from 16 European countries and followed at 6-month intervals by use of standardized forms completed by clinicians at the respective centers. This report concerns 2367 subjects who began antiretroviral therapy with a regime that included zidovudine either before study entry or during the course of follow-up. Cox proportional hazards models were fitted, with use of other antiretroviral drugs, CD4 count, and date of development of AIDS fitted as time-dependent covariates. Survival times from start of therapy were left truncated at study entry to avoid survival bias. In addition to zidovudine, antiretroviral drugs used included didanosine (ddI) (n = 1119; median 1.6 years after starting zidovudine), dideoxycytidine (ddC) (n = 592; median 1.9 years after starting zidovudine), stavudine (d4T) (n = 241; median 2.9 years after starting zidovudine) and lamivudine (3TC) (n = 33 ; median 2.7 years after starting zidovudine). Of the 2367 patients, 613 died during follow-up. Overall, risk of death was reduced in those zidovudine-treated patients who began at least one other nucleoside analogue drug with or after taking zidovudine (relative hazard [RH], 0.61; 95% confidence interval [CI], 0.51-0.72, adjusting for CD4 count, development of AIDS, and age). Fitting each drug separately, there was a larger association with reduced mortality for starting 3TC (RH, 0.41; 95% CI, 0.28-0.62) than for starting ddl (RH, 0.79; 95% CI, 0.67-0.93), ddC (RH, 0.74; 95% CI, 0.59-0.92) or d4T (RH, 0.67; 95% CI, 0.49-0.91). These results suggest that the beneficial effect of nucleoside combination therapy identified in controlled trials can be seen in routine clinical practice. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Didanosine; Dideoxynucleosides; Disease Progression; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Stavudine; Survival Analysis; Zalcitabine; Zidovudine | 1998 |
Combination therapy for HIV: the effect on inpatient activity, morbidity and mortality of a cohort of patients.
We set out to quantify the changes in HIV-related morbidity and mortality associated with the clinical use of antiretroviral therapy via prospectively collected patient-related events (admissions, bed days, deaths, WHO stage 3 and 4 events and drug costs) on all HIV patients known to the Regional Infectious Disease Unit (RIDU) from 1 January 1987 to 31 December 1996. The introduction of zidovudine monotherapy in 1987 for those with AIDS was associated with a subsequent decline of inpatient activity for 2 years: in 1989 there was a 23% reduction in bed days but only a 6% reduction in admissions. A further dramatic decline of patient-related events in those with AIDS was noted during 1996 following the introduction of combination therapy, a 39% reduction in admissions, 44% reduction in bed days, 54% reduction in stage 4 events, 33% reduction in WHO stage 3 events and 40% reduction in the death rate. Reductions were also observed for patients without AIDS including a 42% reduction in the rate of patients developing AIDS. Similar reductions were noted when the patients were classified by immunological instead of clinical status although data for 1997 suggest an increase in patient-related activity for those with CD4 counts >200 cells/microl possibly as a result of low levels of anti-HIV therapy. The introduction of combination therapy for HIV has to date led to a minimum saving of one inpatient bed per 100 patient years which helped defray the cost of combination therapy. Although we cannot imply causality from an observational study, dramatic reductions in patient-related activity were associated with the introduction of combination therapy into clinical practice. The ultimate extent and duration of this effect cannot as yet be predicted and caution is required since similar reductions were noted with zidovudine therapy which were unfortunately time limited. Topics: Anti-HIV Agents; Cohort Studies; Cost Savings; Costs and Cost Analysis; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Prospective Studies; Zalcitabine; Zidovudine | 1998 |
Multiple imputation for early stopping of a complex clinical trial.
It is desirable to have procedures available for stopping a clinical trial early if there appears to be no treatment effect. Conditional power procedures allow for early stopping in favor of the null hypothesis if the probability of rejecting H0 at the planned end of the trial given the current data and a value of the parameter of interest is below some threshold level. Lan, Simon, and Halperin (1982, Communications in Statistics C1, 207-219) proposed a stochastic curtailment procedure that calculates the conditional power under the alternative hypothesis. Alternatively, predictive power procedures incorporate information from the observed data by averaging the conditional power over the posterior distribution of the parameter. For complex problems in which explicit evaluation of conditional power is not possible, we propose treating the problem of projecting the outcome of a trial given the current data as a missing data problem. We then complete the data using multiple imputation and thus eliminate the need for explicit calculation of conditional power. We apply this method to AIDS Clinical Trials Group (ACTG) protocol 118 and to several simulated clinical trials. Topics: Anti-HIV Agents; Biometry; Clinical Trials as Topic; Didanosine; HIV Infections; Humans; Linear Models; Proportional Hazards Models; Survival Analysis; Time Factors; Treatment Outcome | 1998 |
[Combined antiretroviral therapy for prevention of vertical HIV-1 transmission].
A 25-year old woman with rapid HIV disease progression had been receiving zidovudine (ZDV) for two years, when she became pregnant. She had a high viral load and carried out zidovudine-resistant viral strains. For these reasons, and with the main objective to maximally reduce viremia, the association of DDI to ZDV was introduced a few weeks before delivery. The virological follow-up for one year has confirmed the lack of HIV infection in the child. Combined antiretroviral therapy during the last weeks of pregnancy might be considered for the prevention of vertical transmission of HIV in cases of high risk of newborn infection, without adding relevant toxicity. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Zidovudine | 1998 |
Virus burden in lymph nodes and blood of subjects with primary human immunodeficiency virus type 1 infection on bitherapy.
At present, it is not known whether undetectable plasma viremia corresponds to an absence of human immunodeficiency virus type 1 (HIV-1) replication in lymphoid tissues. This issue has been explored in 11 subjects with primary HIV-1 infection treated with zidovudine plus didanosine by evaluating virologic markers in blood and lymphoid tissues 9-18 months after initiation of treatment. These markers include plasma viremia, measured with a sensitive assay with a detection limit of 20 HIV-1 RNA copies/mL, infectious virus titers and proviral DNA in lymph node mononuclear cells, and HIV-1 RNA in lymphoid tissue. Five subjects had plasma viremia <20 copies/mL and showed no evidence of viral replication in lymphoid tissue. Six subjects had both detectable plasma viremia and evidence of HIV-1 RNA in lymphoid tissue. The results indicate that absence of detectable HIV RNA in lymphoid tissue is associated with viremia levels of HIV-1 RNA <20 copies/mL. Topics: Adenoids; Adult; Anti-HIV Agents; CD4-CD8 Ratio; Dendritic Cells; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lymph Nodes; Male; Middle Aged; Palatine Tonsil; Proviruses; Reverse Transcriptase Inhibitors; Viral Load; Virus Replication; Zidovudine | 1998 |
Emergence of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 variants, viral sequence variation, and disease progression in patients receiving antiretroviral chemotherapy.
A set of five reverse transcriptase mutations, which include Q151M, is known to confer multi-dideoxynucleoside resistance (MDR) in human immunodeficiency virus type 1 (HIV-1). MDR mutations were found in 6 (17%) HIV-1 isolates from 36 patients, most of whom were receiving long-term combination therapy. Q151M was among the first of the substitutions to appear. Additional substitutions were observed, although none were common among all 6 patients. Certain zidovudine-related mutations were not observed together with the MDR mutations, indicating possible enzymatic constraint. During chemotherapy, the HIV-1 RNA levels in the 6 patients initially decreased and then rose. Initially, CD4 cell counts also responded favorably but were near or below baseline beyond 40 months of therapy. Such loss of clinical benefits appeared to coincide with the appearance of the MDR mutations. A common background genotype was not observed among HIV-1 isolates with or without MDR. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Didanosine; Dideoxynucleosides; Disease Progression; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Genetic Variation; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Point Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; Zalcitabine; Zidovudine | 1998 |
Human immunodeficiency virus proviral DNA from peripheral blood and lymph nodes demonstrates concordant resistance mutations to zidovudine (codon 215) and didanosine (codon 74). Division of AIDS Treatment Research Initiative 003 Study Group.
Genotypes that confer drug resistance were evaluated in human immunodeficiency virus (HIV) proviral DNA obtained from peripheral blood mononuclear cells (PBMC) and lymphoid tissue at baseline and after 8 weeks of therapy with zidovudine alone or in combination with didanosine from 22 patients (8 zidovudine-naive and 14 zidovudine-experienced). There was evidence of zidovudine resistance at codon 215 in 27.3% (6/22) of patients. All 20 patients evaluable for codon 74 (site of didanosine resistance) had virus that remained wild type during the 8-week study period. When HIV proviral DNA from PBMC was compared with that from lymphoid tissue, 94.7% (18/19) of evaluable samples were concordant at codon 215 at baseline, while 85.7% (12/14) were concordant at week 8. Resistance in PBMC (but not in lymphoid tissue) developed in 1 of 8 zidovudine-naive patients; an increased proportion of resistant strains in PBMC (but not in lymphoid tissue) was observed in 2 of 14 zidovudine-experienced patients. These results suggest high concordance for drug resistance mutations in HIV proviral DNA from blood and lymph node tissue. Topics: Adult; Anti-HIV Agents; Codon; Didanosine; DNA, Viral; Drug Resistance, Microbial; Drug Resistance, Multiple; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Lymph Nodes; Male; Point Mutation; Proviruses; Reverse Transcriptase Inhibitors; Zidovudine | 1998 |
Induction-maintenance antiretroviral therapy: proof of concept.
To investigate the concept of aggressive initial combination therapy followed by reduction to a less demanding maintenance regimen with respect to its potential for sustaining viral suppression.. Durable viral suppression to < 20 HIV RNA copies/ml plasma was achieved with zidovudine-nevirapine-didanosine (ZDV-NVP-ddl) therapy. Potential for sustained antiviral response was explored for patients who began with ZDV-NVP-ddl and subsequently interrupted ddl.. Antiretroviral-naive patients were treated with ZDV-NVP, ZDV-ddl, or ZDV-NVP-ddl. Viral load was measured with the Amplicor assay (limit of quantification 400 copies/ml) and by the Ultra Direct assay (limit of quantification 20 copies/ml) when the Amplicor result was < 500 copies/ml. Treatment adherence for each drug was recorded, including all dose adjustments.. Five patients who had begun treatment with ZDV-NVP-ddl discontinued ddl for at least 6 weeks after achieving viral load levels below detection. All were documented to have sustained their viral load at < 20 copies/ml during the ddl interruption. Two patients permanently discontinued ddl, both with sustained viral load below detection for more than 1 year while treated with ZDV NVP. In contrast, no patient initially receiving ZDV-NVP was able to maintain viral load below detection for sustained periods; none had viral load below detection after week 12 of treatment.. After induction with ZDV-NVP-ddl, patients were able to sustain viral suppression with a regimen (ZDV NVP) that was only transiently effective as initial therapy. There was no evidence of virologic escape, even with the most sensitive measure of plasma viral load. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine | 1998 |
The M184V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT inhibitors.
To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patients.. A total of 255 samples from patients treated with lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and stavudine using a recombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold compared with wild-type (high-level resistance, > 10-fold). A genotypic analysis of plasma-derived reverse transcriptase coding regions was carried out in samples with cross-resistance.. The majority of samples displayed wild-type or greater than wild-type sensitivity to zalcitabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in samples with high ZDV resistance. There was no obvious correlation between cross-resistance and genotype; all but two samples were mutant at codon 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n=27) were four- to eightfold less sensitive to abacavir. There were no other genotypic changes in addition to M184V known to be associated with abacavir resistance.. Cross-resistance was not commonly observed in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavudine or combinations containing abacavir. Topics: Anti-HIV Agents; Cohort Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Methionine; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Valine; Zalcitabine; Zidovudine | 1998 |
Researchers report sustained suppression of HIV with nevirapine--didanosine--zidovudine.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Zidovudine | 1998 |
A mixed model for repeated dilution assays.
We propose a generalized linear mixed model to estimate and test marginal effects on titers repeatedly measured by serial dilution assays. The link is log-log and the titer is assumed to follow a gamma distribution. The parameters are estimated by generalized estimating equations. The marginal effects are tested by means of Wald and score tests, using the robust estimator of the variance. This approach avoids the problems arising from assays leading to nonestimable individual titers. Simulations were used to compare the Wald and score tests to Wilcoxon and Student t-tests. This method is applied to the comparison of the antiviral efficiency of three treatments against HIV. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; Humans; Models, Statistical; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Reproducibility of Results; Viral Load; Zalcitabine; Zidovudine | 1998 |
Prevalence of genotypic resistance to nucleoside analogues in antiretroviral-naive and antiretroviral-experienced HIV-infected patients in Spain.
To determine the prevalence of genotypic resistance to nucleoside analogues (NA) in a large group of HIV-infected individuals in Spain, some of whom had no previous treatment with antiretroviral drugs (antiretroviral-naive) and some of whom had such experience (antiretroviral-experienced).. Cross-sectional study in out-patient clinics in three reference hospitals for HIV/AIDS located in Barcelona, Madrid and Seville, Spain.. Primary mutant genotypes were examined in plasma HIV RNA collected from 150 antiretroviral-naive subjects, half in 1993 and the other half in 1997. Furthermore, drug resistance mutations were analysed in plasma collected from another 150 antiretroviral-experienced patients who had received 2 NA for longer than 1 year, either in sequence as monotherapy or as combination therapy. A line probe assay was used for recognizing mutations conferring resistance to zidovudine (ZDV), didanosine (ddI), zalcitabine (ddC), and lamivudine (3TC). A point-mutation nested-PCR assay was used for examining a codon 151 mutation associated with multiple drug resistance.. One or more mutations associated with primary resistance to NA were seen in 10 antiretroviral-naive (13.3%) patients in 1993 and in nine (12%) in 1997. In all but two cases, they were associated with ZDV resistance. In contrast, all but six (96%) of the antiretroviral-experienced subjects harboured drug-resistant mutant viruses. The codon 184 mutation (associated with resistance to 3TC) was detected in 92% of patients treated with 3TC, but also in 18% of those treated with only ddI or ddC. The codon 215 mutation was found in 67.3% of patients who had been exposed to ZDV; the codon 69 mutation was found in 15% of patients treated with ddC; and the codon 74 mutation was found in only 7.2% of patients treated with ddI. Finally, the codon 151 multidrug resistant mutation was found in four (2.7%) of 150 patients with a long-term exposure to NA.. Overall, the prevalence of drug-resistant HIV-1 genotypes was 12.7% in antiretroviral-naive patients, most of whom had ZDV-resistant mutants. There is no evidence of an increase during the last 5 years. However, multidrug-resistant HIV genotypes are currently circulating in Spain. Topics: Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Female; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Prevalence; Reverse Transcriptase Inhibitors; Spain; Zalcitabine; Zidovudine | 1998 |
Therapeutic advantage of hydroxyurea and didanosine combination therapy in patients previously treated with zidovudine.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Retrospective Studies; Reverse Transcriptase Inhibitors; Zidovudine | 1998 |
Deafness caused by didanosine.
Topics: Adult; Anti-HIV Agents; Deafness; Didanosine; HIV Infections; Humans; Male | 1998 |
HIV-1 suppression by early treatment with hydroxyurea, didanosine, and a protease inhibitor.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Indinavir; Male | 1998 |
Therapeutic and other interventions to reduce the risk of mother-to-child transmission of HIV-1 in Europe. The European Collaborative Study.
To document policies regarding the use of interventions to reduce risk of vertical transmission of human immunodeficiency virus (HIV) and assess the extent of changes since 1994.. A postal questionnaire survey and data from the European Collaborative Study (ECS), a prospective multi-centre cohort study.. Fifty-four obstetric centres in 16 European countries.. A questionnaire response from 54 obstetricians; 669 deliveries to HIV-infected women enrolled in the ECS from 1994 to 1997.. Use of zidovudine during pregnancy, at delivery and to the neonate; caesarean section delivery rates; vaginal lavage; avoidance of breastfeeding; vertical transmission rate.. Zidovudine therapy to reduce vertical transmission is now widespread in Europe and routine in all but one centre surveyed, although regimens vary. In 11 (26%) centres elective caesarean section is offered to all HIV-infected women and a further nine (21%) have a policy of routine vaginal lavage. In all centres HIV-infected women are advised to avoid breastfeeding. In the ECS there has been a significant temporal decline in the vertical transmission rate with an increase in zidovudine use. More than 90% of women in the ECS who were delivered in 1997 received one or more components of zidovudine therapy; the rate of vertical transmission is 9% where zidovudine has been used, compared with 15% without use of zidovudine.. Although the use of zidovudine to reduce vertical transmission is increasing in Europe and, with the avoidance of breastfeeding, is associated with a decline in vertical transmission, the success of these interventions will be limited by the uptake of antenatal screening. Topics: Adult; Anti-HIV Agents; Breast Feeding; Cesarean Section; Cohort Studies; Didanosine; Europe; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Prenatal Care; Prospective Studies; Risk Factors; Zidovudine | 1998 |
Comparison of the LiPA HIV-1 RT test, selective PCR and direct solid phase sequencing for the detection of HIV-1 drug resistance mutations.
The performance to detect drug resistance mutations in the reverse transcriptase gene of HIV-1 was compared for direct solid phase sequencing, selective polymerase chain reaction (PCR) using the amplification refractory mutation system (ARMS) and the new line probe assay (LIPA) HIV-1 RT. The three tests were undertaken on 50 plasma samples from 25 treatment-experienced patients under combination therapy with dideoxynucleoside analogues. LiPA HIV-1 RT gave interpretable results in 80 to 96% of the samples depending on the codon of interest. In 2% of the samples a failure to amplify resulted in uninterpretable results for sequencing. ARMS gave no result in seven samples (14%). Overall, there was a 73 to 100% concordance between the three methods. In this study, LiPA HIV-1 RT proved to be an accurate and reliable alternative to DNA sequencing for the detection of drug resistance mutations in patient samples. Topics: Anti-HIV Agents; Codon; Didanosine; DNA Probes; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Polymerase Chain Reaction; Sequence Analysis, DNA; Zalcitabine; Zidovudine | 1998 |
Changes in blood CD8+ lymphocyte activation status and plasma HIV RNA levels during antiretroviral therapy.
To analyse the relationship between CD8+ lymphocyte phenotype alterations and plasma HIV RNA levels in HIV-infected patients treated with the zidovudine-didanosine combination.. A total of 30 HIV-infected patients who had never received antiretroviral therapy and who were starting treatment with a combination of zidovudine and didanosine were prospectively studied. Multiparameter flow cytometric analysis of CD8+ lymphocytes and plasma HIV RNA determination were performed on day 0, day 15 and monthly from months 1 to 6.. Patients were divided into three categories according to the time-course of plasma HIV RNA levels. In 14 patients, an early and sustained fall in plasma HIV RNA to below the detection limit (500 copies/ml) was observed; in 10 patients, the fall was transient; in six patients, plasma HIV RNA was always detectable (non-responders). The mean CD4+ lymphocyte gain was 120 x 10(6)/l at month 6 in sustained and transient responders, and 55 x 10(6)/l in non-responders. A significant fall in the proportion of CD8+ lymphocytes with an activated phenotype was observed only in the two groups of responders, and was higher in the sustained responders (CD38+HLA-DR+, -56.8%; CD38+CD45RO+, -54.0%; HLA-DR+CD45RO+, -48.4%; CD38+CD28-, -47.3%).. A fall in the proportion of activated CD8+ lymphocytes is associated with the disappearance of HIV RNA from plasma during antiretroviral therapy. Undetectable plasma HIV RNA is not associated with a return to normal CD8+ lymphocyte activation status after 6 months of treatment, suggesting that viral replication persists in lymphoid tissues. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Immunophenotyping; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine | 1998 |
Rebound of plasma HIV viral load following prolonged suppression with combination therapy.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Time Factors; Viral Load; Zidovudine | 1998 |
Visceral leishmaniasis: a lingual presentation in a patient with HIV infection.
The term leishmaniasis covers a series of illnesses caused by the protozoan Leishmania; depending on the patient's immune response, the particular species of the protozoan, and the geography, the condition may manifest itself as cutaneous, mucocutaneous, or visceral disease. Visceral leishmaniasis has often been found as a co-infection associated with the human immunodeficiency virus, particularly in the region of the western Mediterranean. We report the case of an HIV-infected patient with a history of treated laryngeal leishmaniasis who subsequently appeared for treatment with a tumorous lesion on the dorsum of the tongue that was caused by Leishmania infection. Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antimony; Antiprotozoal Agents; Didanosine; HIV Infections; Humans; Laryngitis; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Spain; Tongue Diseases; Zidovudine | 1998 |
The sequential occurrence of pol 215 and pol 41 zidovudine resistance mutations is associated in an additive fashion with low CD4 cell counts and high plasma and cellular HIV viral load.
We report on a cross-sectional study of virological and immunological surrogate markers of HIV infection in 115 patients for whom a determination of the pol 215 and pol 41 zidovudine (ZDV) resistance mutations had been described between January 1995 and February 1996. The patients received ZDV alone or a combination of ZDV and zalcitabine or didanosine. A total of 55, 15 and 45 patients exhibited a wild (W), a mixed (MIX) or a mutant (M) genotype at codon pol 215, respectively; 85, 10 and 20 patients exhibited a W, a MIX or a M genotype at codon pol 41, respectively. Patients exhibiting the pol 215 M genotype had lower CD4 cells, higher plasma viral load and higher proviral burden than patients exhibiting the pol 215 W genotype. Patients who had variants exhibiting both pol 215 M and pol 41 M or MIX genotypes had significantly worsened surrogate marker values than patients having variants only carrying the pol 215 M genotype. These observations demonstrate that the two mutations additively associate with pejorative surrogate markers. Topics: Adult; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; Cross-Sectional Studies; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV-1; Humans; Longitudinal Studies; Male; Mutation; RNA, Viral; Viral Load; Zalcitabine; Zidovudine | 1998 |
Taste and smell complaints in HIV-infected patients.
To define the scope of taste and smell (chemosensory) complaints amongst HIV-infected persons in the study population; to evaluate the clinical factors associated with chemosensory complaints; and to determine the impact of chemosensory complaints on quality of life.. Cross-sectional survey.. Tertiary care university medical center clinic.. A total of 207 HIV-infected patients.. Chemosensory complaint score from taste and smell questionnaire and quality of life scores from the Medical Outcomes Study HIV Health Survey (MOS-HIV).. A total of 144 patients (70%) reported chemosensory complaints, 91 (44%) reported both taste and smell complaints, 47 (23%) reported only taste complaints, and six (3%) reported only smell complaints. Many patients complained that drugs interfered with their sense of taste, or that medications tasted bad. Higher chemosensory complaint scores were associated with a greater number of medications taken, tobacco use, and hay fever. Patients with chemosensory complaints had significantly lower scores in all domains of the MOS-HIV than those without complaints. Quality of life as measured by the MOS-HIV was lower in patients with chemosensory complaints even after controlling for number of AIDS diagnoses, number of medications, CD4 cell count, and HIV-1 viral load.. Chemosensory complaints were common in the patient population and were associated with a poor quality of life. Medications played an important role in chemosensory complaints. Measures to optimize taste and smell function may improve quality of life and medication adherence, and prevent complications such as inadequate oral intake, malnutrition, weight loss, and ultimately wasting. Topics: Adult; Aged; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Clarithromycin; Didanosine; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Quality of Life; Ritonavir; Smell; Surveys and Questionnaires; Taste; Trimethoprim, Sulfamethoxazole Drug Combination; Zidovudine | 1998 |
Resting energy expenditure and body composition in children with HIV infection.
The purpose of this study was to determine whether alterations in body composition, resting energy expenditure (REE), and dietary energy intake are associated with growth retardation in HIV-positive children. Body composition (deuterium oxide dilution, skinfold measurements), REE (indirect calorimetry), and energy intake (24-hour weighed food intake) were evaluated in three groups: HIV-positive with growth retardation (HIV+Gr), HIV-positive with normal growth (HIV+); and HIV-uninfected with normal growth (HIV-). Children were between 2 and 11 years of age, afebrile, and free from acute infection. Forty-two children (13 HIV+Gr, 19 HIV+, 10 HIV-) were studied. Lean body mass was significantly reduced in HIV+Gr compared with HIV- (p < .05), and fat mass was significantly reduced in HIV+Gr and HIV+ compared with HIV- (p < .05). The percentages of lean and fat mass were not significantly different between groups, suggesting that differences in lean and fat mass were proportional to differences in body size. Consistent with reduced lean body mass, mean REE was significantly lower in HIV+Gr compared with HIV- (p < .05). Differences in mean REE/kg of body weight or lean body mass between groups were not statistically significant. A significant negative correlation was found between REE (kcal/kg/day) and weight-for-age (p = .04), and a trend with height-for-age Z-score (p = .07). Mean energy intake was not significantly different between groups. This study suggests that lean and fat mass are proportionately reduced in HIV-positive children with growth retardation. Further studies are necessary to delineate the relationship between energy balance and growth in children with HIV infection. Topics: Adipose Tissue; Anthropometry; Anti-HIV Agents; Arm; Body Composition; Body Water; Child; Child Development; Child, Preschool; Didanosine; Energy Intake; Energy Metabolism; Female; Growth Disorders; HIV Infections; Humans; Male; Muscle Development; Muscle, Skeletal; Skinfold Thickness; Zidovudine | 1998 |
Comparison of the QUANTIPLEX HIV-1 RNA 2.0 assay with the AMPLICOR HIV-1 MONITOR 1.0 assay for quantitation of levels of human immunodeficiency virus type 1 RNA in plasma of patients receiving stavudine-didanosine combination therapy.
We compared the QUANTIPLEX HIV-1 RNA 2.0 assay with the AMPLICOR HIV-1 MONITOR 1.0 assay for quantitation of human immunodeficiency virus type 1 (HIV-1) RNA in plasma in the Stadi trail, which evaluated a stavudine plus didanosine combination therapy in 52 patients. HIV-1 RNA baseline values measured with AMPLICOR HIV-1 MONITOR 1.0 were significantly higher than those measured with QUANTIPLEX HIV-1 RNA 2.0, and decreases in HIV-1 RNA levels from baseline were also found to be significantly higher when measured with the AMPLICOR HIV-1 MONITOR 1.0 assay. The frequency of HIV-1 RNA levels below the lower limit of quantitation was significantly higher with QUANTIPLEX HIV-1 RNA 2.0 than with AMPLICOR HIV-1 MONITOR 1.0. Reanalysis of these results by an ultrasensitive procedure of AMPLICOR HIV-1 MONITOR 1.0 or by a modified version of the test that included additional primers adapted for non-B HIV-1 clades yielded greater differences between the QUANTIPLEX HIV-1 RNA 2.0 assay and the AMPLICOR HIV-1 MONITOR 1.0 assay. Our results indicate that a valid comparison of the virological efficacies obtained with different antiretroviral drug regimens requires the use of the same viral load quantitation procedure; further standardization between the different HIV-1 RNA quantitation kits is therefore needed. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Evaluation Studies as Topic; HIV Infections; HIV-1; Humans; RNA, Viral; Stavudine; Viremia; Virology | 1998 |
Antiretroviral treatment.
Topics: Anti-HIV Agents; Chloroquine; Developing Countries; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea | 1998 |
High incidence of nevirapine-associated rash in HIV-infected Chinese.
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; China; Didanosine; Drug Eruptions; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine | 1998 |
A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors.
While many point mutations in the HIV-1 reverse transcriptase (RT) confer resistance to antiretroviral drugs, inserts or deletions in this gene have not been previously characterized. In this report, 14 RT inhibitor-treated patients were found to have HIV-1 strains possessing a 6-basepair insert between codons 69 and 70 of the RT gene. Known drug resistance mutations were also observed in these strains, with T215Y appearing in all strains. Genotypic analysis indicated that the inserts had substantial nucleotide variability that resulted in relatively restricted sets of amino acid sequences. Linkage of patients' treatment histories with longitudinal sequencing data showed that insert strains appeared during drug regimens containing ddI or ddC, with prior or concurrent AZT treatment. Drug susceptibility tests of recombinant patient isolates showed reduced susceptibility to nearly all nucleoside RT inhibitors. Site- directed mutagenesis studies confirmed the role of the inserts alone in conferring reduced susceptibility to most RT inhibitors. The addition of AZT-associated drug resistance mutations further increased the range and magnitude of resistance. These results establish that inserts, like point mutations, are selected in vivo during antiretroviral therapy and provide resistance to multiple nucleoside analogs. Topics: Amino Acid Sequence; Anti-HIV Agents; Base Sequence; Cells, Cultured; Didanosine; Drug Resistance, Multiple; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutagenesis, Site-Directed; Mutation; Nucleosides; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1998 |
Estimates of the virological benefit of antiretroviral therapy are both assay- and analysis-dependent.
To assess the potential discrepancies in reported changes in plasma viral load (PVL) depending on how values below the detection limit of the assay are handled in the data analysis phase of a randomized controlled clinical trial.. Data from a recently completed clinical trial comparing combinations of zidovudine, didanosine and nevirapine were analysed. In this trial, PVL was measured using an assay with a lower quantification limit of 400 HIV-1 RNA copies/ml initially. All PVL values less than 500 copies/ml were retested with a more sensitive assay with a lower quantification limit of 20 copies/ml.. Several summary measures for assessing change in PVL were calculated using three different methods to adjust for PVL values less than the quantification limit of the assay. The differences between these measures were evaluated.. We found that the magnitude of the discrepancy between summary measures used to report changes in PVL depended on the proportion of subjects with PVL less than the quantification limit of the assay, how those observations were handled in the data analysis, and the relative difference between the quantification limits of the conventional and more sensitive assay.. The lack of consensus in reporting of PVL data in the literature makes the interpretation of published trial results difficult. In the absence of agreement on the most appropriate summary measure of PVL data, we recommend that all summaries include information on the quantification limit of the assay used, the proportion of observations at or below the quantification limit and how these observations were handled in the data analysis. Topics: Analysis of Variance; Anti-HIV Agents; Data Interpretation, Statistical; Didanosine; HIV Infections; HIV-1; Humans; Nevirapine; RNA, Viral; Statistics, Nonparametric; Time Factors; Viral Load; Zidovudine | 1998 |
[Observing in HIV infections].
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Patient Compliance; Physician-Patient Relations; Reverse Transcriptase Inhibitors; Time Factors; Zidovudine | 1998 |
Protease inhibitor-sparing regimen suppresses HIV.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine | 1998 |
Reevaluating initial therapy.
Numerous treatment options are available for antiretroviral-naive patients and the initial sequence of drugs prescribed for them can have consequences on future treatments. Physicians need to make wise decisions when prescribing medications to prevent the development of cross-resistance to other medications. Currently, d4T and AZT are common initial therapies. Results of the ACTG 306 trials, evaluating several combinations for both short-term and long-term effectiveness, are described. The choice of drugs for any treatment regimen must also consider convenience and tolerability. Whichever nucleoside analogs are chosen will frequently be combined with protease inhibitors or other drugs. Food restrictions, drug interactions, dosing requirements, and side effects may make a particular regimen less desirable. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; DNA, Viral; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Polymerase Chain Reaction; Stavudine; Viral Load; Zidovudine | 1998 |
Selected highlights on women and HIV from the 5th Conference on Retroviruses and Opportunistic Infections.
Many sessions at the 5th Conference on Retroviruses and Opportunistic Infections dealt specifically with HIV infection and treatment in women. Highlights are presented from several sessions, including indinavir blood levels at various points in the menstrual cycle, abnormal kidney function associated with women taking indinavir, abnormal pap smears in women with high viral load, the relationship between viral load and the increased risk of death in women, and the impact of ddI crossing the placenta in pregnant women. Information is given on each presentation, including clinical trial results, side effects, and impacts on disease progression. Topics: Anti-HIV Agents; Cervix Uteri; Chicago; Clinical Trials as Topic; Congresses as Topic; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Male; Maternal-Fetal Exchange; Menstrual Cycle; Papanicolaou Test; Papillomavirus Infections; Pregnancy; Risk Factors; RNA, Viral; Tumor Virus Infections; Vaginal Smears; Viral Load | 1998 |
Vertical transmission research at the Retrovirus Conference.
Researchers have seen a dramatic drop in mother-to-child HIV transmissions due to medical breakthroughs and the role of AZT. ACTG protocols 076 and 185 provided further information on the association between maternal viral load and vertical transmission. Dr. Lynne Mofenson of the National Institute of Child Health and Human Development at the National Institutes of Health followed treatment-naive and treatment-experienced pregnant women through a three-part AZT regimen. The regimen was administered during the last two-thirds of pregnancy, during delivery, and to the newborn for six weeks. The studies showed that transmission took place across all levels, however, the women taking AZT reduced vertical transmission by two-thirds at each viral load level. Dr. Mofensen concluded that reducing viral load to low levels in pregnant women receiving AZT treatment will further reduce transmission. Other studies presented at the 5th Conference on Retroviruses and Opportunistic Infections concluded that predicting HIV transmission based on maternal viral load is more accurate for groups of untreated, rather than treated, mothers. In Thailand, a short-course treatment alternative of administering AZT near the end of gestation and during delivery, but not to the newborn, showed a 51 percent reduction in the rate of transmission. Although not proven, it is assumed that this is the period when most transmission occurs. Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Resistance, Microbial; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Infectious; Viral Load; Zidovudine | 1998 |
Hydroxyurea for HIV?
The anticancer drug, hydroxyurea, can help certain anti-HIV drugs work better. Hydroxyurea's side effects, dosage requirements, and method of reducing HIV in the body are discussed. Results from several small studies of hydroxyurea indicate that the addition of hydroxyurea to ddI produces a stronger anti-HIV effect than ddI alone. Hydroxyurea may also help to increase T4 cell counts. It is uncertain how hydroxyurea combined with ddI will work in patients with low T4 cell counts and more advanced HIV. Resistance to hydroxyurea is not a problem since it works by affecting cells rather than by directly attacking HIV. Manufacturer contact information for patient assistance is provided. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Stavudine | 1998 |
Hydroxyurea - new observations.
Hydroxyurea obstructs HIV from reproducing, is effective when combined with nucleoside analogue reverse transcriptase inhibitors, and it is difficult for HIV to develop a resistance to it. The combination of Hydroxyurea and ddI may be effective in targeting the HIV virus that hides in resting cells. This is in contrast to most other anti-HIV drugs, which tend to target HIV in activated cells. Two studies are described that echo the benefits of combining Hydroxyurea with ddI. Another study employed the previous combination with Indinavir, and all participants achieved below 400 copies of HIV RNA. Observations of three individuals, who discontinued treatments subsequent to taking regimens including Hydroxyurea, indicate that they have maintained HIV RNA below the level of detection. These case studies are not necessarily a good representation of the people actually using Hydroxyurea. More research is necessary to determine the best way to utilize this drug. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Indinavir; Nucleic Acid Synthesis Inhibitors; Stavudine; Viral Load; Virus Replication | 1998 |
Is Hydroxyurea for real?
There continues to be questions about the safety and effectiveness of Hydroxyurea since rigorous clinical trials have just begun. The mechanisms of the drug are not fully understood, but may include inhibition of DNA synthesis, potentiation of nucleoside reverse transcriptase inhibitor activity, enhancement of nucleoside phosphorylation, compensation for resistance to ddI, and modulation of the immune system. A table compares the results of several recent trials of Hydroxyurea treatment in combination with antiretrovirals. There is a discussion of how well Hydroxyurea works with ddI, other nucleosides, and whether it is best used in salvage or first-time treatment. More studies of Hydroxyurea are needed. Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Nucleic Acid Synthesis Inhibitors; Phosphorylation; Salvage Therapy; Viral Load | 1998 |
Viral load--how low is best?
Antiviral therapy aims to suppress HIV to undetectable levels, and technology to measure these levels is constantly improved. Chiron 3 and similar tests can now detect viral loads as low as 50 copies. Viral load tests have also been valuable in assessing the effectiveness of antiviral drugs. An alliance of mathematicians and doctors have been trying to estimate the level of viral suppression needed to minimize the development of resistance. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine | 1998 |
The Delta trial.
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1997 |
Dideoxyinosine-induced pancreatitis in human immunodeficiency virus-infected children.
Dideoxyinosine (ddI) is a widely used antiretroviral agent in treatment of HIV infection. Pancreatitis is a serious side effect. Two cases are reported, one with rapid development of a pseudocyst. Topics: Amylases; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Fatty Liver; Female; HIV Infections; Humans; Lipase; Male; Pancreatic Pseudocyst; Pancreatitis | 1997 |
Focusing on the second phase of plasma HIV-1 RNA clearance.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Reverse Transcriptase Inhibitors; RNA, Viral; Virus Replication; Zidovudine | 1997 |
Treatment of late-state HIV infection.
Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Combinations; HIV Infections; Humans; Randomized Controlled Trials as Topic; Reproducibility of Results; Reverse Transcriptase Inhibitors; Treatment Outcome; Zalcitabine; Zidovudine | 1997 |
Effect of antiretroviral combination therapy (zidovudine/didanosine or zidovudine/lamivudine) on quantitative plasma human immunodeficiency virus-ribonucleic acid in children and adolescents infected with human immunodeficiency virus.
To assess human immunodeficiency virus (HIV) ribonucleic acid load in children and adolescents with HIV infection who are being treated with antiretroviral combination therapy.. Five patients whose disease progressed with their prior antiretroviral therapy had treatment regimens changed to zidovudine (ZDV)/didanosine (DDI) (group A), and the regimens of six patients were changed to ZDV/lamivudine (3TC) (group B). Patients were followed every 4 to 8 weeks for an average period of 8.6 months. Serial determinations of viral copy numbers and CD4 cells were performed.. In group A patients' mean relative changes in CD4 cells showed a 20% increase after 4 months (difference not significant (NS)) and a return to baseline after 8 months; in group B patients' mean relative increases of CD4 cells were 72% (p = 0.046) and 50% (NS), respectively. In group A mean relative viral load increased 21% (0.08 log10, NS) and 71% (0.23(10) log, NS), whereas in group B viral load decreased 22% (0.1 log10, NS) and 74% (0.58 log10, p = 0.03) after 4 and 8 months, respectively. After starting antiretroviral combination therapy in group A, there was a slight trend of a decreasing ratio of viral load per number of CD4 cells, whereas in group B this ratio significantly decreased, indicating a marked suppression of viral turnover with ZDV/3TC treatment.. In a small cohort of pediatric patients, combination therapy with ZDV/3TC was well tolerated and had a strong and sustained effect on the decrease of viral loads similar to results obtained in adults. In patients with ZDV/DDI therapy the reduction of viral load was less pronounced, but treatment groups A and B were not comparable for statistic evaluation. Topics: Adolescent; AIDS-Related Opportunistic Infections; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; RNA, Viral; Time Factors; Viral Load; Viremia; Zidovudine | 1997 |
HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine.
Previous studies have shown that the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase mutation Y181C, which confers high-level resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs), develops rarely during therapy with NNRTIs plus zidovudine. To determine whether didanosine (ddI) is also effective in preventing the emergence of Y181C, we analyzed delavirdine (DLV) susceptibilties and reverse transcriptase sequences of isolates obtained from patients enrolled in a pharmacokinetic study of DLV and ddI. Nine NNRTI-naive patients were evaluated. Seven received DLV/ddI and two received DLV/ddI/zidovudine. Median durations of prior zidovudine and ddI were 26 and 15 months, respectively. Isolates from eight of nine patients had a mutation(s) associated with nucleoside resistance at entry. After treatment with DLV and ddI alone, isolates from five of seven patients developed Y181C, four in combination with K103N. Thus, in this group of nucleoside-experienced patients, combination therapy with DLV/ddI did not prevent the emergence of Y181C. Topics: Adult; Anti-HIV Agents; Delavirdine; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indoles; Male; Mutation; Phenotype; Piperazines; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine | 1997 |
Potential role of dideoxyinosine and hydroxyurea combination in prophylaxis of HIV infection after accidental percutaneous exposure.
Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Hydroxyurea | 1997 |
Shedding of HIV-1 in semen during primary infection.
Topics: Anti-HIV Agents; Didanosine; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; RNA, Viral; Semen; Virus Shedding; Zidovudine | 1997 |
Analysis of repeated virological measurements based on cell dilution assays.
Virological measurement has become increasingly popular as an endpoint in the evaluation of new drugs to treat human immunodeficiency virus (HIV) diseases. A commonly used quantity to measure the viral load is the proportion of infected cells in a patient's blood. Although the literature suggests various patient-specific estimation procedures for such proportions based on a series of cell dilutions, the resulting estimates are highly unstable. Moreover, it seems inappropriate to use those estimates as raw data points to make inferences about the group differences in comparative studies. In this article, under a two-arm clinical trial setting, we propose semi-parametric methods to estimate the treatment difference with this particular quantity evaluated repeatedly over time. Our proposals are conceptually simple and implemented easily in practice. We also propose model checking techniques to examine the adequacy of the fitted model. Data from a recent trial conducted by the AIDS Clinical Trials Group to evaluate the relative merit of zidovudine (ZDV) and dideoxyinosine (ddI) illustrate the methods. Our analysis indicates that patients treated with high dose ddI tended to have significantly lower viral load than those treated with a low dose combination of ZDV and ddI. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Models, Statistical; Survival Analysis; Treatment Outcome; Viral Load; Zidovudine | 1997 |
Hearing loss and antiretroviral therapy in patients infected with HIV-1.
To explore the association between hearing loss and antiretroviral therapy in human immunodeficiency virus type 1 (HIV-1)-infected persons.. Case-control study.. University-based HIV clinic.. Volunteer sample of 99 HIV-infected patients.. Standardized interview focusing on risks for hearing loss, review of clinic pharmacy records, and hearing tests by portable audiometry.. Hearing loss, defined as threshold of more than a 25-dB hearing level at 4000 Hz in 1 or both ears.. Hearing loss was common, seen in 29 subjects (29%). It was significantly associated with age and history of ear infection and tended to be more common in subjects prescribed antiretroviral agents. An interaction existed between age and antiretroviral therapy; the association between hearing loss and antiretroviral therapy was significant for subjects aged 35 years or older, but not for subjects younger than 35 years. In subjects aged 35 years or older, this association remained significant using a multivariate model that included those variables found to have the greatest potential for confounding (odds ratio, 4.6; 95% confidence interval, 1.0-20.5; P = .05).. Hearing loss is common among HIV-infected individuals and is associated with antiretroviral therapy in those aged 35 years or older. Topics: Adult; Anti-HIV Agents; Didanosine; Female; Hearing Disorders; HIV Infections; HIV-1; Humans; Male; Middle Aged; Stavudine; Zidovudine | 1997 |
Antiretroviral effect of zidovudine-didanosine combination on blood and lymph nodes.
To evaluate the antiretroviral effect of a combination of zidovudine (ZDV) and didanosine (ddl) on plasma, peripheral blood mononuclear cells (PBMC) and lymph nodes after 24 weeks.. Eight patients naive of antiretroviral therapy were followed by monthly blood samples and two surgical lymph-node biopsies taken at baseline and after 24 weeks. CD4+ T cells were counted monthly by flow cytometry. Plasma HIV-1 RNA was measured monthly by polymerase chain reaction (PCR). Infectious cellular viraemia was measured monthly by a culture technique. Proviral DNA titres in PBMC were measured by endpoint dilution PCR at baseline and 24 weeks. Infectious HIV-1 and proviral DNA titres were measured in the lymph-node mononuclear cells (LNMC). The total HIV-1 RNA content of lymph nodes was measured by PCR. In some cases, phenotypic resistance to ZDV was measured, and codon 215 and 74 mutations in PBMC and LNMC were analysed.. A mean increase in CD4 cell count of 122 x 10(6)/l, a mean decrease in HIV-1 RNA of 1.47 log10 in plasma and a mean decrease in HIV-1 DNA titre of 0.63 log10 were found after 24 weeks of therapy. Nevertheless, there were no statistically significant changes in the mean infectious HIV-1 titre in PBMC and LNMC, in the HIV-1 DNA titre in LNMC or in the total lymph-node HIV-1 RNA burden at week 24. Phenotypic or genotypic markers of drug resistance were rarely found in PBMC at week 24, although they were detected in LNMC from some patients.. A discrepancy in the therapeutic effect can be observed between lymphoid organs and blood after 24 weeks of therapy with ZDV and ddl. This difference could be explained by the insufficient antiretroviral potency of this combination facing the significant viral burden present in lymph nodes. Development of drug resistance in this compartment prior to blood can be demonstrated in some cases, although other mechanisms remain to be investigated in future studies to explain this difference. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Lymph Nodes; Male; Viral Load; Zidovudine | 1997 |
HIV-associated primary pulmonary hypertension. A case control study. Swiss HIV Cohort Study.
To assess the clinical and echocardiographic time course, prognosis, and possible etiology of HIV-associated primary pulmonary hypertension (PPH), we prospectively followed all 19 patients in whom PPH was diagnosed in our centers. Women (12 cases) and injecting drug use (16 cases) predominated; the median CD4 lymphocytes count was 83/microliter (range, 1 to 740). Matched control subjects without PPH were identified within the Swiss HIV Cohort Study. Frozen serum samples of both groups were then reanalyzed for autoimmune parameters, neopterin, beta-2-microglobulin, and thyroid-stimulating hormone. The median follow up of the patients was 1.3 yr. Follow-up Doppler echocardiography was available in 13 patients. The RVSP-RAP pressure gradient decreased by 3.2 mm Hg for those six patients who received antiretroviral treatment but increased by 19.0 mm Hg for untreated patients (p = 0.026). PPH was the cause of eight of 17 deaths. The probability of surviving was significantly decreased in patients with PPH in comparison with the control subjects; the median survival was 1.3 versus 2.6 yr (p < 0.05). Patients with PPH had significantly higher anticardiolipin IgM, anti SS-B, and neopterin, but all other laboratory values did not differ between cases and control subjects. In conclusion, HIV-associated PPH contributed significantly to mortality. Antiretroviral treatment may exert a beneficial effect on the pressure gradient. A possible role of an autoimmune phenomenon in the pathogenesis could not be substantiated. Topics: Adult; Anti-HIV Agents; Antibodies, Anticardiolipin; Case-Control Studies; Didanosine; Echocardiography, Doppler; Enzyme-Linked Immunosorbent Assay; Female; HIV Infections; Humans; Hypertension, Pulmonary; Immunoglobulin M; Male; Prospective Studies; Survival Rate; Zidovudine | 1997 |
Phenotypic variations and switches in HIV isolated from the blood and the gastrointestinal tissues of patients with HIV-1 infection. HIV/GI Research Study Group.
The objective of this study was to determine the initial and subsequent phenotypes of HIV-1 isolated from the blood, duodenal, and colonic biopsies of 51 HIV-1 positive patients followed prospectively over 2 years. Blood and tissues were cocultured with stimulated peripheral blood monocytes, and HIV was analyzed for phenotypic expression of syncytia-induction (SI). A total of 45/51 patients had HIV-1 isolated from the blood and 35/51 had HIV isolated from gastrointestinal tract. In 12/45 patients SI-HIV-1 was isolated from the blood. In 6/12 patients the blood phenotype reverted to the NSI phenotype. SI phenotypes were also isolated from the colon and duodenum of 8/35 patients and reversion from SI to NSI virus phenotype was again observed in gut tissue of 3/8 patients. These results show that gastrointestinal tissues can harbor SI HIV phenotype. Discordant phenotypes can be found in tissue and blood of late-stage patients. Reversion of phenotypic SI expression to NSI may occur in patients receiving monotherapy as antiretroviral treatment. These results suggest that gastrointestinal tissues may act as a separate and distinct site involved in HIV replication and its associated pathogenesis. Topics: Biopsy; Didanosine; Digestive System; Female; Giant Cells; HIV; HIV Enteropathy; HIV Infections; Humans; Male; Mutation; Phenotype; Prospective Studies; Stavudine; Viral Load; Zidovudine | 1997 |
Long-term suppression of HIV-1 by hydroxyurea and didanosine.
Topics: Anti-HIV Agents; Didanosine; Drug Synergism; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Viral Load | 1997 |
Correlation between plasma HIV-1 RNA levels and the rate of immunologic decline.
To determine the influence of HIV-1 replication on immunologic decline and clinical outcome, we quantified the HIV-1 plasma viral load in 20 patients at different times over a mean period of 10.8 months. Quantitation was performed by branched DNA signal amplification (bDNA) and p24 antigenemia. Immunologic status was assessed through beta 2-microglobulin and CD4+ cell count determinations. CD4+ cell decline was expressed as a slope of the regression line constructed by the logarithms of CD4+ cell count observations. Mean values of plasma viral load were correlated with CD4+ cell decline and mean beta 2-microglobulin levels. Significant correlation was observed between plasma viral load quantified by the bDNA technique and CD4+ cell decline. No significant correlation was observed between plasma viral load quantified by p24 antigenemia and CD4+ cell decline. A significant correlation was observed between plasma viral load and beta 2-microglobulin levels. Immunologic decline was better predicted from HIV-1 RNA levels than from the CD4+ cell count. Significantly higher plasma viral load was observed in patients who had clinical progression of HIV-1 infection. Thus, HIV-1 plasma viral load quantified by a highly reliable technique such as bDNA showed that the immunologic decline is closely related to HIV-1 RNA replication. Topics: Anti-HIV Agents; beta 2-Microglobulin; CD4 Lymphocyte Count; Didanosine; Disease Progression; DNA, Viral; Drug Therapy, Combination; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Longitudinal Studies; RNA, Viral; Stavudine; Viral Load; Viremia; Virus Replication; Zalcitabine; Zidovudine | 1997 |
Quantification of HIV-1 viral load in lymphoid and blood cells: assessment during four-drug combination therapy.
To assess the antiretroviral effect of a combination of zidovudine, didanosine, lamivudine and saquinavir in plasma, peripheral blood mononuclear cells (PBMC) and lymph-node mononuclear cells (LNMC) after 8 weeks.. Ten HIV-1 antiretroviral therapy-naive patients were given a combination of oral zidovudine (200 mg three times daily), oral didanosine (200 twice a day), oral lamivudine (150 mg twice a day) and oral saquinavir (600 mg three times daily). HIV-1 plasma RNA was measured by quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR). Infectious HIV-1 in PBMC and LNMC was measured by a coculture technique. HIV-1 RNA in PBMC and LNMC was quantified by RT-PCR. Proviral DNA titres in PBMC and LNMC were measured by endpoint dilution PCR. CD4 T-cells were analysed by flow cytometry.. CD4 cell counts rose in all patients (mean increase of 125 +/- 71 CD4 cells x 10(6)/l) and the benefit was greater for patients with fewer than 350 CD4 cells x 10(6)/l (mean increase of 159 +/- 74 CD4 cells x 10(6)/l). Plasma HIV-1 RNA decreased exponentially in all patients (mean decrease of 3.1 log10 after 8 weeks with a mean half-life of 2.2 +/- 0.6 days). HIV-1 RNA showed a decrease of 3.07 log10 in PBMC and of 2.1 log10 in LNMC. The decrease in plasma HIV-1 RNA was consistently associated with the decrease in LNMC. These data were supported by a concomitant drop of HIV-1 infectious titres in PBMC (mean decrease of 1.41 log10) and in LNMC (mean decrease of 2.54 log).. These data show a significant antiretroviral effect of this four-drug combination in blood and lymphoid tissues. However, a greater decrease in HIV-1 RNA was observed in PBMC and in plasma than in lymph node cells. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Leukocytes, Mononuclear; Lymph Nodes; Male; Polymerase Chain Reaction; RNA, Viral; Saquinavir; Viral Load; Viremia; Zidovudine | 1997 |
Stable neurological function in subjects treated with 2'3'-dideoxyinosine.
AIDS Dementia Complex (ADC) is a frequent and devastating complication of HIV infection. There is evidence that zidovudine (ZDV) has an effect in alleviating the symptoms of ADC, and may have a role in its prevention. It is therefore important that new antiretroviral therapies be evaluated not only for the risk of neurologic side effects, but also for their relative efficacy to ZDV in the prevention of ADC. The present study reports the effects of 2'3'-dideoxyinosine (DDI, didanosine, Videx) therapy on neuropsychological performance in the context of several large clinical trials targeting advanced systemic HIV-1 infection. Subjects treated with DDI had stable neurologic performance in quantitative tests over a 1 year period and were similar to zidovudine treated subjects. Topics: Adult; AIDS Dementia Complex; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Follow-Up Studies; HIV Infections; Humans; Neuropsychological Tests; Zidovudine | 1997 |
The effect on human immunodeficiency virus type 1 RNA levels in cerebrospinal fluid after initiation of zidovudine or didanosine.
Human immunodeficiency virus type 1 (HIV-1) RNA, neopterin, and beta2-microglobulin levels were analyzed in cerebrospinal fluid (CSF) and serum before and 3-13 months after initiation of antiretroviral monotherapy in 16 HIV-1-infected persons. Twenty-one treatment periods, 13 after initiation of zidovudine and 8 after initiation of didanosine, were studied. During zidovudine treatment, CSF HIV RNA levels decreased by a mean of 1.05 log10 (-91%, P < .01), and CSF neopterin and beta2-microglobulin levels by 57% and 33%, respectively (P < .01). No reduction was seen during didanosine treatment in CSF HIV RNA (+0.13 log10, not significant), CSF neopterin, or beta2-microglobulin levels. Changes in CSF HIV RNA levels correlated with changes in CSF neopterin and beta2-microglobulin (r(s) = .81 and .83, respectively, P < .001). The decrease in HIV RNA was significantly larger in CSF than in serum following zidovudine treatment (P < .01). These data demonstrate that zidovudine is a potent reducer of central nervous system virus load, which may be important for long-term neuroprotection. Topics: Adult; Aged; Anti-HIV Agents; beta 2-Microglobulin; Biopterins; Didanosine; HIV Infections; HIV-1; Humans; Middle Aged; Neopterin; RNA, Viral; Viral Load; Zidovudine | 1997 |
Successful treatment of HIV-1-related, zidovudine resistant, thrombocytopenia with didanosine.
Topics: Adult; CD4 Lymphocyte Count; Didanosine; HIV Infections; Humans; Male; Platelet Count; Thrombocytopenia; Zidovudine | 1997 |
Xerostomia: a symptom which acts like a disease.
Topics: Acquired Immunodeficiency Syndrome; Aged; Anti-HIV Agents; Diagnosis, Differential; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Xerostomia | 1997 |
Downregulation of increased CD95 (APO-1/Fas) ligand in T cells from human immunodeficiency virus-type 1-infected children after antiretroviral therapy.
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Didanosine; Drug Therapy, Combination; Fas Ligand Protein; fas Receptor; Gene Expression Regulation; HIV Infections; HIV-1; Humans; Lamivudine; Membrane Glycoproteins; Reverse Transcriptase Inhibitors; RNA, Messenger; T-Lymphocytes; Time Factors; Transcription, Genetic; Zalcitabine; Zidovudine | 1997 |
Cure or control of HIV/AIDS?
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Models, Biological; Nevirapine; Pyridines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine | 1997 |
Monitoring antiretroviral activity using ICDp24 and CD4 counts in HIV infection.
The fluctuations of HIV-1 p24 antigen concentration have been monitored in the follow-up of 118 subjects in different clinical stages and compared to their CD4 cell count; 104 patients received antiretroviral therapy. Persistent (65%) or sporadic (28%) antigenaemia has been detected in most patients in different clinical stages. The variations of the p24 Ag level are significantly correlated with the CD4 cell count and therapy administration (P = 0.0001). In patients with relatively conserved immune function (CDC II and III), antiretroviral therapy shows the best efficacy and can be efficiently monitored by p24 and CD4 surrogate markers. The data here suggest that although the informative value of p24 Ag is not representative of an AIDS-defining event, it can be used as a short-term and relatively inexpensive virological marker of antiviral activity in vivo, to support the routine management of patients. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Follow-Up Studies; HIV Core Protein p24; HIV Infections; Humans; Zidovudine | 1997 |
Absence of viral rebound after treatment of HIV-infected patients with didanosine and hydroxycarbamide.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Nucleic Acid Synthesis Inhibitors; Time Factors; Viral Load | 1997 |
Human immunodeficiency virus type 1 dynamics in different lymphoid tissue compartments.
Human immunodeficiency virus type 1 (HIV-1) RNA was measured in total lymph node (LN) tissue and isolated LN mononuclear cells (LNMC) in sequential LN biopsy samples from 1 patient with primary HIV-1 infection and from 5 previously untreated patients with chronic disease. HIV-1 RNA levels were an average of 210-fold higher in total LN tissue compared with levels in LNMC, even during primary infection, when circulating antibodies were absent. After the patients were treated with a three- or four-drug regimen, total HIV-1 RNA decreased exponentially in total LN tissue and in LNMC (mean half-lives of 8.5 +/- 1.8 and 7.9 +/- 2.2 days, respectively). In addition, the evolution of the infectious virus in LNMC was analyzed for the 5 patients with chronic disease: Titers decreased, with a mean half-life of 7.5 +/- 2.3 days. Extracellular virions are the most important virus compartments in LNs; however, they exhibit the same dynamics as virions situated in LNMC, with a mean virus decay half-life of approximately 1 week. Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Leukocytes, Mononuclear; Lymphoid Tissue; Male; RNA, Viral; Zidovudine | 1997 |
2',3'-Dideoxyinosine-induced Mallory bodies in patients with HIV.
Didanosine (ddI) that inhibits the reverse transcriptase of human immunodeficiency virus (HIV) causes steatosis and fulminant hepatitis in some patients with HIV. We studied hepatic histopathologic changes with particular attention to ddI-induced Mallory body formation. Three liver biopsies were performed on three patients with HIV who were treated with ddI; an autopsy was performed on a patient with HIV who was also treated with ddI. All hepatic specimens were studied with a routine liver immunohistochemical panel including antibodies to ubiquitin and cytokeratin (CAM 5.2). Morphologically, all hepatic specimens showed focal to diffuse steatosis with a predominance of macrovesicular fatty change. Fibrosis was minimal in three cases. No secondary bacterial and fungal infections were noted. Single or clusters of "empty cells" were present, and some contained Mallory bodies validated by ubiquitin stain. Empty cells are hepatocytes that fail to stain positive for cytokeratin. The Mallory bodies were different from the others because they were randomly distributed and occurred in noncirrhotic hepatic tissue. In the autopsy specimen, the Mallory bodies had a centrilobular location with central fibrosis (central sclerosing hyaline necrosis). Topics: Adult; Anti-HIV Agents; Biopsy; Didanosine; Female; HIV Infections; Humans; Immunohistochemistry; Inclusion Bodies; Keratins; Liver; Male; Middle Aged; Pathology, Clinical; Ubiquitins | 1997 |
[Once-daily administration of didanosine in combination with anti-retroviral zidovudine in previously untreated patients].
25 HIV-infected antiretroviral-naive adults were included in a 24-week study to evaluate the efficacy and the tolerability of a zidovudine/didanosine combination therapy in which didanosine was administered once daily (200 mg if weight < 60 kg, 300 mg if weight > 60 kg) and zidovudine twice daily (500 mg/day if weight < 90 kg, 600 mg/day if weight > 90 kg). 5 patients discontinued their treatment early: 3 had poor compliance and 2 presented adverse events. Evaluation of treatment efficacy was based on CD4+ T cell enumeration and HIV RNA level quantitation in plasma (NASBA). Baseline values were 278 CD4+/mm3 and 5.42 log RNA copies/ml. Mean changes from baseline were +102 CD4+/mm3 and -2.14 log RNA copies/ml at week 8 and +156 CD4+/mm3 and -2.07 log RNA copies/ml at week 24. HIV RNA in plasma was lower than the detection limit (2.60 log RNA copies/ml) in 55% of patients at week 8 and in 30% at week 24. No major adverse events such as neuropathy or pancreatitis were observed. Once-daily administration of didanosine in combination with twice-daily administration of zidovudine is a well tolerated regimen that appears to be as effective ad the conventional zidovudine/didanosine combination regimen. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Male; Middle Aged; RNA, Viral; Zidovudine | 1997 |
Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy.
Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment. Topics: Animals; Antigens, CD; Antigens, CD34; Antiviral Agents; CD4-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Flow Cytometry; Hematopoietic Stem Cells; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lymphocyte Depletion; Methylurea Compounds; Mice; Mice, SCID; Polymerase Chain Reaction; Proviruses; Pyridines; T-Lymphocytes; Thymus Gland; Transplantation, Heterologous; Valine; Zidovudine | 1997 |
[Initial administration of a protease inhibitor delays the progression of AIDS by half time].
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Didanosine; Disease Progression; HIV Infections; HIV Protease Inhibitors; Humans; Time Factors; Zalcitabine; Zidovudine | 1997 |
Drugs for HIV infection.
Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Delavirdine; Diarrhea; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Virus Replication; Zalcitabine; Zidovudine | 1997 |
Selective inhibition of syncytium-inducing and nonsyncytium-inducing HIV-1 variants in individuals receiving didanosine or zidovudine, respectively.
By studying changes in the clonal composition of HIV-1 populations during the first weeks of zidovudine (ZDV) treatment before the development of ZDV resistance-conferring mutations, we demonstrated previously a selective inhibition of nonsyncytium-inducing (NSI) HIV-1, even when present as coexisting population in individuals also harboring syncytium-inducing (SI) HIV-1. In this study, we observed the opposite in individuals receiving didanosine (ddI) treatment. In these individuals (n = 7) a median -0.98 log change (range -1.55-0.08) in infectious cellular SI load was observed, whereas the coexisting NSI load was only minimally affected (median -0.15 log, range -1.27-0.50; P = 0.03). The virus phenotype-dependent treatment responses were independent of the clonal composition of HIV-1 populations at baseline. Individuals treated with a combination of ZDV and ddI revealed an equal decline of both NSI and SI infectious cellular load (n = 4; NSI: median -1.55 log, range -2.19 to -1.45; SI: median -1.47 log, range -1.81 to -0.86; P = 0.56). To test the hypothesis that the previously reported optimal activation of ZDV and ddI in activated and resting T cells, respectively, in combination with the differential T cell tropism of NSI and SI HIV-1 is the basis for the observed virus phenotype specific efficacy of nucleoside analogs, we studied the effect of treatment with a protease inhibitor that does not require intracellular activation. Individuals receiving ritonavir (n = 4) indeed showed equal declines in NSI and SI infectious cellular load (NSI: median -2.37 log, range -2.59 to -2.16; SI: median -2.82 log, range -3.14 to -2.50; P = 0.25). Our data suggest HIV-1 phenotype as an additional parameter in the design of optimal treatment regimens. Topics: Animals; Anti-HIV Agents; CD4 Lymphocyte Count; Cell Fusion; Didanosine; Giant Cells; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Mice; Ritonavir; RNA, Viral; Zidovudine | 1997 |
Safety and efficacy of two different triple drug combinations in which either lamivudine or didanosine were administered with stavudine plus indinavir.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome | 1997 |
Kinetics of tumor necrosis factor alpha and soluble TNFRII in HIV-infected patients treated with a triple combination of stavudine, didanosine, and hydroxyurea.
TNF-alpha is involved in the pathogenesis of HIV, and is known to enhance HIV replication in vitro. In this report the kinetics of plasma TNF-alpha and sTNFRII in patients receiving aggressive antiretroviral therapy and their relationship to HIV plasma RNA and CD4 cell counts were examined. Eleven patients participating in an open label study for assessment of safety, and of virological and immunological effects of simultaneous treatment with d4T, ddI, and HU, were evaluated. The CD4 cell count of the patients before treatment ranged from 65 to 374/mm3 and their HIV plasma RNA ranged from 1.9 x 10(4) to 3.7 x 10(5) copies/ml. The viral load in eight patients decreased significantly (mean, 1.9 log10). TNF-alpha and sTNFRII plasma levels pretreatment and at 8 weeks into therapy directly correlated with HIV plasma RNA. Pretreatment circulating TNF-alpha levels of 25-114 pg/ml (mean, 56 pg/ml) decreased by more than twofold in seven patients. The change in TNF-alpha levels inversely correlated with the change in absolute CD4 cell number. Detailed kinetics of TNF-alpha and sTNFRII measured at weeks 0, 1, 2, 4, 6, 8, and 12 paralleled those of HIV plasma RNA. A rapid decline in these soluble markers was always observed at week 1 together with the HIV plasma RNA response. Three patients maintained a high viral load as well as high TNF-alpha and sTNFRII. These data suggest that (1) combination therapy with d4T, ddI, and HU decreased viral load and circulating levels of TNF-alpha/sTNFRII; (2) an association exists between the TNF-alpha/sTNFRII and HIV viral load; and (3) TNF-alpha/sTNFRII might be a useful surrogate marker for predicting efficacy of antiretroviral therapy. Topics: Adult; Anti-HIV Agents; Antigens, CD; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Hydroxyurea; Kinetics; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Reverse Transcriptase Inhibitors; Solubility; Stavudine; Tumor Necrosis Factor-alpha; Viremia | 1997 |
Dideoxyinosine-associated Ofuji papuloerythroderma in an HIV-infected patient.
Topics: Acquired Immunodeficiency Syndrome; Adult; Dermatitis, Exfoliative; Didanosine; Drug Eruptions; Exanthema; Follow-Up Studies; HIV Infections; Humans; Male; PUVA Therapy; Skin Diseases, Papulosquamous | 1997 |
Zidovudine toxicity in uninfected healthcare workers. Italian Registry of Antiretroviral Prophylaxis.
To evaluate the toxicity of zidovudine (ZDV) prophylaxis in human immunodeficiency virus (HIV)-exposed healthcare workers (HCWs) in Italy, a national protocol for postexposure prophylaxis has been implemented and a national registry has been established. All Italian clinical centers licensed to dispense ZDV participate. As of December 1995, data from 674 individuals who received ZDV prophylaxis have been collected. In three cases ZDV was used in combination with either didanosine (DDI) or dideoxycytidine (DDC). In 556 cases (82%), the daily dose of ZDV was 1,000 mg/day; 21 HCWs (3%) were treated with 300-800 mg/day, and in 72 persons (11%) the dose was 1,200-3,000 mg/day. A total of 332 (49%) HCWs reported at least one adverse effect; 132 (20%) discontinued prophylaxis because of side effects (40% of those reporting side effects). Nausea was reported in 243 cases; other side effects included vomiting, gastric pain, diarrhea, asthenia, and headache. Most constitutional adverse effects were reported during the first week of prophylaxis. Grade 1 anemia (hemoglobin 9.5-11 g/dL) occurred in 10 cases (3%); in 2 cases, the neutrophil count decreased to <1,000 cells/mm3. A transient increase of serum alanine aminotransferase to three times the upper limit of normal was observed in 7 persons. All side effects were reversible after the prophylaxis was stopped. Among those reporting at least one side effect the mean duration of treatment was 22 days; for HCWs reporting hematologic or liver adverse effects the mean length of treatment was 34 days. A total of 351 HCWs (54.6%) ceased the treatment before the scheduled 1-month period. In the 132 persons who discontinued treatment because of side effects, the mean length of prophylaxis was 8 days. One HCW seroconverted after conjunctival exposure to blood. The short-term toxicity of ZDV prophylaxis is frequent, mild, dose related, and reversible. Further studies are needed to assess the risk of long-term sequelae of this treatment as well as of prophylaxis with combinations of antiretroviral drugs. Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Health Personnel; HIV Infections; Humans; Italy; Occupational Exposure; Registries; Retrospective Studies; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1997 |
Two studies suggest nevirapine benefit for children.
Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Nevirapine; Pregnancy; Pyridines; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine | 1997 |
ddI + d4T + IDV well tolerated in HIV-infected children.
Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Drug Combinations; HIV Infections; Humans; Indinavir; Stavudine | 1997 |
d4T and ddI shown to be safe and effective.
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Stavudine; Viral Load | 1997 |
Viramune triple therapy shows suppression of HIV after 1 year, 7 months.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Zidovudine | 1997 |
Dethroning AZT.
Several trials have found that AZT added little benefit when included in two drug regimens. Human tolerance to AZT and HIV's propensity for becoming resistant to AZT are major problems. AZT remains the most prescribed HIV therapy, particularly in combination with 3TC. A popular solution for patients failing or intolerant to AZT or AZT/3TC has been d4T/3TC. AZT is known to penetrate the blood/brain barrier, thus helping to prevent or treat AIDS-related dementia. Over time, however, studies show AZT/3TC and d4T/3TC were essentially equivalent and that both should be helpful for dementia. Another study using d4T/ddI showed reduction in viral loads by 80 to 90 percent at 24 weeks, accompanied by a CD4 rise of about 40, but with significant neurological adverse effects. Combining d4T/ddI with protease inhibitors presents problems, such as a complicated dosing schedule and harsh gastrointestinal side effects. Combining hydroxyurea with d4T/ddI appears to strengthen this combination's effects. One study showed that the combination of ddI and hydroxyurea was unable to prevent the emergence of mutations that confer ddI resistance; however, the mutants were still sensitive to standard doses of ddI in the presence of hydroxyurea. One other conference report presented results of a two-arm trial comparing DuPont Merck's new DMP 266 plus indinavir to indinavir alone for 24 weeks. At trial's end, viral loads were down 2.2 logs (99.4 percent) in the indinavir arm, and CD4 counts, initially averaging 224, were up about 100 cells in both groups. The results achieved with DMP 266/indinavir rival those achieved with indinavir plus AZT/3TC or any two nucleoside analogs. DMP 266 not only is potent, but is taken only once a day. Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Lamivudine; Oxazines; Stavudine; Viral Load; Zidovudine | 1997 |
NIAID researchers present new findings at retrovirus meeting. National Institute of Allergy and Infectious Diseases.
Research presented at the Third Conference on Retroviruses and Opportunistic Infections included reports on partial restoration of immune function and prolonged survival in people with HIV. Findings from several studies are highlighted. ACTG 315 suggests that potent new drug cocktails may partially restore immune system function. ACTG 193A demonstrates that three antiretrovirals are more effective than two for delaying disease progression and prolonging survival in individuals with advanced HIV disease. Other studies presented new findings on the HIV disease process and the complex interactions between the virus and the human immune system. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Chemokines; Clinical Trials as Topic; Clone Cells; Dendritic Cells; Didanosine; Disease Progression; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Interleukin-10; Killer Cells, Natural; Lamivudine; Male; Nevirapine; Pyridines; Receptors, Cytokine; Reverse Transcriptase Inhibitors; Ritonavir; Virus Replication; Zalcitabine; Zidovudine | 1997 |
Delavirdine (Rescriptor) approved.
The Food and Drug Administration (FDA) approved delavirdine (Rescriptor) for HIV-1 treatment in March. Delavirdine becomes the second non-nucleoside reverse transcriptase inhibitor approved; the first was nevirapine. The drug must be used in antiretroviral combinations because of resistance problems associated with using it alone. Delavirdine's primary side effect is skin rash, occasionally severe enough to cause permanent discontinuation of the treatment. The approval follows weak clinical data; further clinical testing is called for. Cost is relatively low at $2,250 annually. Topics: Anti-HIV Agents; Delavirdine; Didanosine; Drug Approval; Drug Costs; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indoles; Piperazines; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration; Zidovudine | 1997 |
Immune modulation with IL-2 and IL-12.
Scientists have identified a number of chemical messengers that play a fundamental role in directing the body's natural response to the invasion of organisms and pathogens in the human immune system. One group, cytokines, are an essential communications link between the cells of the immune system and the body. The decrease in immune function with HIV is apparent in both the amount of HIV detected and in the decline in CD4 cells. Levels of two cytokines, IL-12 and IL-2, appear to have a direct correlation to cellular immunity. Treatment with these two substances may strengthen immune function and decrease the pace of disease development. Recombinant forms have been developed as hopeful treatments for cancer, HIV, and other infectious diseases. Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cytokines; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Interleukin-12; Interleukin-2; Zidovudine | 1997 |
Combo therapy for children and adolescents.
A pediatric study showed combination anti-HIV treatment to be effective in children. In a comparison trial of AZT/3TC to ddI, AZT/3TC reduced the chance of disease progression by 70 percent and the risk of death by 80 percent. The study results indicate that children also should receive strong anti-HIV drug combinations. Six related studies are underway. To date, there are six anti-HIV drugs, three nucleoside analogs and two protease inhibitors, that are approved for use in children. Referrals can be made through the Network for study information. Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Clinical Trials as Topic; Didanosine; Disease Progression; Drug Therapy, Combination; HIV Infections; Humans; Infant; Lamivudine; Zidovudine | 1997 |
Update on nevirapine: quest for a niche.
Nevirapine received its initial Food and Drug Administration (FDA) approval based on its use in combination with nucleoside analogs. However, AIDS treatment standards changed shortly thereafter with the introduction of viral load testing and protease inhibitors. Nevirapine's use may change now, with its target audience being those patients who cannot tolerate or afford protease inhibitors or who have failed other drug regimens. A number of recent studies are described that tested the efficacy of nevirapine with other medications, its safety in HIV-infected infants and children, and the interactions between nevirapine and protease inhibitors. Drug specifications are included, covering indications, dosage, adverse reactions, interactions, and dietary restrictions. Topics: Adult; Anti-HIV Agents; Child; Clinical Trials as Topic; Didanosine; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Infant, Newborn; Nevirapine; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine | 1997 |
Ocular manifestations of AIDS.
Topics: Adolescent; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Antiviral Agents; CD4 Lymphocyte Count; Cytomegalovirus Retinitis; Didanosine; Ganciclovir; HIV Infections; Humans; Rifabutin; Uveitis; Visual Acuity | 1996 |
Population pharmacokinetics of didanosine in patients with human immunodeficiency virus infection.
Topics: Antiviral Agents; Demography; Didanosine; HIV Infections; Humans; Zidovudine | 1996 |
Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy.
Multidrug-resistant human immunodeficiency virus type 1 (HIV-1) strains with reverse transcriptase (RT) mutations at codons A62-->V, V75-->I, F77-->L, F116-->Y, and Q151-->M have been reported in patients receiving combination therapy with zidovudine (AZT) and didanosine (ddI). Infectious clones with each mutation alone, all five mutations together, and various combinations of mutations were created by site-directed mutagenesis. Mutation Q151-->M conferred partial resistance to AZT, ddI, zalcitibine, and stavudine, whereas a combination of four mutations conferred increased resistance to AZT, ddI, zalcitibine, and stavudine. The positions of residues 75, 77, and 151 in the three-dimensional crystal structure of HIV-1 RT suggest that these residues may affect the ability of the enzyme to discriminate between deoxynucleoside triphosphates and nucleoside analog RT inhibitors. Replication experiments showed that clones with mutation F77-->L but without V75-->I (HIV-1(77), HIV-1(77,151), and HIV-1(77,116,151) had attenuated growth compared with that of the original HIV-1NL4-3 strain and strains containing mutations at both positions 75 and 77 (HIV-1(75,77,151) and HIV-1(75,77,116,15)). Sequence analysis of viral RNA and proviral DNA from several patients indicated that RT mutations developed in a sequential and cumulative pattern over the course of a 2- to 4-year observation period. The present results suggest that drug resistance and viral replicative capacity both may play a role in selection of HIV-1 RT mutations. Topics: Animals; Antiviral Agents; Base Sequence; Cell Line; Didanosine; DNA Primers; DNA, Viral; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HeLa Cells; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Virus Replication; Zidovudine | 1996 |
[Combination therapy of HIV].
Topics: Antimetabolites; Antiviral Agents; Denmark; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors; Zalcitabine | 1996 |
Recognition of the highly conserved YMDD region in the human immunodeficiency virus type 1 reverse transcriptase by HLA-A2-restricted cytotoxic T lymphocytes from an asymptomatic long-term nonprogressor.
The human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT) is an important target for therapeutic intervention and for HIV-1-specific cytotoxic T lymphocytes (CTL). An HLA-A2-restricted CTL epitope containing the sequence YMDD, which is highly conserved among human and animal retroviruses and essential for function of the RNA-dependent DNA polymerase, is identified. The drug resistance mutation at RT amino acid 184 (M184V), associated with (-)-2'-deoxy-3'-thiacytidine (lamivudine), (-)-2'-deoxy-5-fluoro-3'-thiacytidine (FTC), and dideoxyinosine resistance, is located within this epitope and abolishes recognition by an established CTL response. This study demonstrates that the CTL response may target functionally relevant regions of the RT protein and suggests drug therapy may select for viral variants with altered susceptibility to established cellular immune responses. Topics: Amino Acid Sequence; Antiviral Agents; Base Sequence; Conserved Sequence; Deoxycytidine; Didanosine; DNA Primers; Drug Resistance, Microbial; Epitopes; HIV Infections; HIV Reverse Transcriptase; HIV-1; HLA-A2 Antigen; Humans; Lamivudine; Molecular Sequence Data; Oligopeptides; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; T-Lymphocytes, Cytotoxic; Zalcitabine | 1996 |
Managing HIV disease after Delta.
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Combinations; HIV Infections; Humans; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine | 1996 |
[Pancreatic disease in patients with HIV treated with didanosine (DDI)].
Pancreatic involvement has been studied in 70 HIV infected patients, in diverse stages, that were treated with didanosine (ddI), both as monotherapy or associated to zidovudine; 38% of patients presented adverse reaction that obliged to withdraw the medication: pancreatitis (4%), hyperamylasemia (21%) and abdominal pain and/or diarrhea (12%). The possible causes in presentation of adverse effects were evaluated: route of infection, stage of HIV infection, use of pentamidine or trimethoprim-sulfamethoxazole for preventing Pneumocystis carinii pneumonia, administration of ddI in monotherapy or in combined form with zidovudine, time of treatment and level of CD4 lymphocytes. The outcome of adverse effects is related significantly only with the most advanced stage of HIV infection. Topics: Acute Disease; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Pancreatic Diseases; Pancreatitis; Zidovudine | 1996 |
1-year follow-up of the use of hydroxycarbamide and didanosine in HIV infection.
Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Hydroxyurea; Time Factors | 1996 |
Adverse events from drug therapy for human immunodeficiency virus disease.
Drug therapies for patients with human immunodeficiency virus (HIV) infection are associated with adverse events that can potentially limit their effectiveness. We sought to quantify the incidence of these events in clinical practice and determine whether there were demographic and clinical differences in adverse event rates for these drugs.. We calculated specific and overall adverse event rates from use of zidovudine, didanosine, zalcitabine, cotrimoxazole, and dapsone in an observational urban cohort of 1,450 HIV-infected patients with a CD4+ count of 500 cells/mm3 or less. We compared adverse event rates by gender, race, age, injecting drug use, and CD4+ count.. Overall adverse event rates in order of incidence were dapsone, 16.2 per 100 person-years (PY); didanosine, 24.1 per 100 PY; zidovudine, 26.3 per 100 PY; cotrimoxazole, 26.3 per 100 PY; and zalcitabine, 37.0 per 100 PY. Rates increased significantly with decline in CD4+ count from > 200 to < 100 cells/mm3 for all drugs but dapsone. In addition, women were more likely than men to have an adverse event for didanosine (relative risk [RR] = 2.7, P = 0.03) and from cotrimoxazole (RR 1.5; P = 0.05). Whites were at greater risk than blacks for adverse events from cotrimoxazole (RR = 1.6, P = 0.03). Only 22 of 357 total events (6%) required hospitalization, and there were no deaths.. Adverse events from antiretroviral drugs and Pneumocystis carinii pneumonia prophylaxis that interrupt therapy are relatively common, although serious events requiring hospitalization are rare. Adverse event rates increase progressively with decline in CD4+ count. The gender and race of the patient modify the risk of adverse events for some drugs. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Dapsone; Didanosine; Female; HIV Infections; Humans; Male; Pneumonia, Pneumocystis; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Urban Health; Zalcitabine; Zidovudine | 1996 |
Didanosine (DDI) alone is now considered the first-line therapy for symptomatic children infected with the human immunodeficiency virus (HIV)
Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Clinical Trials as Topic; Didanosine; HIV Infections; Humans; Infant; Zidovudine | 1996 |
Human immunodeficiency virus type 1 kinetics in lymph nodes compared with plasma.
As lymphoid organs are the major reservoir of human immunodeficiency virus type 1 (HIV-1), the rates at which HIV-1 RNA decreases from the plasma and from a series of lymph node biopsies from 4 patients treated with a combination of zidovudine, didanosine, and lamivudine were measured. The concentrations of HIV-1 RNA in the plasma and in lymph nodes declined exponentially, with mean half-lives of 1.88 +/- 0.86 days for plasma and 6.01 +/- 3.44 days for lymph nodes. These data show that most of the HIV-1 in lymphoid organs is due to the infection of new cells and demonstrate that a triple-drug combination is able to target this compartment. Topics: Antiviral Agents; Biopsy; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Kinetics; Lamivudine; Lymph Nodes; RNA, Viral; Viremia; Zalcitabine; Zidovudine | 1996 |
Zidovudine resistance reverse transcriptase mutations during didanosine monotherapy.
Topics: Didanosine; Drug Resistance, Microbial; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Mutation; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Sequence Analysis; Zidovudine | 1996 |
MDL 74,968, a new acyclonucleotide analog: activity against human immunodeficiency virus in vitro and in the hu-PBL-SCID.beige mouse model of infection.
The novel acyclonucleotide derivative of guanine, 9-[2-methylidene-3-(phosphonomethoxy)propyl] guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken together, these promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection. Topics: Adenine; Animals; Antiviral Agents; Cell Line; Cells, Cultured; Didanosine; DNA, Viral; Guanine; HIV Infections; HIV-1; HIV-2; Humans; Male; Mice; Mice, SCID; Monocytes; Organophosphonates; Spleen; T-Lymphocytes; Zidovudine | 1996 |
Combination antiretroviral chemotherapy: a potential strategy in AIDS-related malignancy.
There has been considerable interest and controversy over the potential clinical role of combination antiretroviral therapy, primarily in the treatment of patients with established HIV infection. In order to model the hematologic toxicity of high-dose combination antiretroviral therapy, the HL60 myeloid leukemia cell line was exposed to zidovudine, dideoxycytidine and/or didanosine. The results suggest that the myelotoxicity of high-dose combination antiretroviral therapy may be controlled by using very brief periods of drug exposure. Brief intense antiretroviral therapy may offer a useful approach, particularly in the treatment of patients with AIDS-related neoplasms who are also receiving myelotoxic antineoplastic drugs. Topics: Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Cell Division; Didanosine; HIV Infections; HL-60 Cells; Humans; Zalcitabine; Zidovudine | 1996 |
Combination drug treatment benefits patients with HIV.
Topics: Antiviral Agents; Didanosine; Drug Combinations; HIV Infections; Humans; Zalcitabine; Zidovudine | 1996 |
Acquisition of syncytium-inducing HIV-1 strains during therapy with zidovudine alone or combined with alpha interferon or didanosine.
The effect of antiretroviral treatment on HIV-1 phenotype was studied in a group of 83 nucleoside-naive patients. These initially nonsyncytium-inducing HIV-1 positive patients were followed prospectively for their HIV-1 phenotype. Syncytium-inducing variants were detected by cocultivation of peripheral blood mononuclear cells with the MT-2 T-cell line. Overall, 16 of 83 (19%) patients underwent a shift to syncytium-inducing phenotype: 11 of 67 during zidovudine treatment, 3 of 10 during zidovudine plus alpha interferon treatment, and 2 of 6 under initial zidovudine plus didanosine therapy. The results of this study demonstrate that neither zidovudine therapy alone nor combined with interferon or didanosine prevents the acquisition of syncytium-inducing strains. Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; Giant Cells; HIV Infections; HIV-1; Humans; Interferon-alpha; Male; Phenotype; Prospective Studies; Zidovudine | 1996 |
Protection of human immunodeficiency virus encephalitis by a switch from zidovudine to didanosine.
Topics: Didanosine; Encephalitis, Viral; HIV Infections; Humans; Retrospective Studies; Zidovudine | 1996 |
Lack of muscle toxicity with didanosine (ddI). Clinical and experimental studies.
Currently, 2',3'-dideoxyinosine (ddI) is used in AIDS therapy. To investigate the possible myotoxicity of ddI in patients infected with human immunodeficiency virus (HIV), we examined the effect of ddI in vitro in tissue cultures of skeletal muscles of rats exposed to ddI at doses equivalent to plasma ddI levels obtained in the treatment of HIV patients. Control cultures were exposed to normal saline and zidovudine (AZT). After 4 weeks no changes were noted in the ddI and normal saline cultures, but AZT cultures showed abnormal accumulation of mitochondria. The creatine kinase values in culture supernatants were all normal. We also reviewed the clinical, nutritional and biological parameters, AZT and ddI dosage, and histochemical findings in muscle specimens of 14 HIV patients receiving ddI therapy. All patients had previously received AZT. The mean cumulative dose of ddI was 91.6 gm. Two patients had myalgia, 9 muscle atrophy, and 13 weakness. All patients were malnourished. Five patients had mitochondrial myopathy related to AZT, 4 had ddI-associated neuropathy and 2 patients had only selective type 2 fiber atrophy. One patient had necrotizing vasculitis, one had scattered necrotic fibers and type 2 fiber atrophy and 2 had a normal muscle biopsy. On the basis of the results, we have been unable to implicate ddI as a cause of skeletal myopathy. Topics: Adult; Animals; Anti-HIV Agents; Biopsy; Cells, Cultured; Didanosine; HIV Infections; Humans; Male; Middle Aged; Muscle, Skeletal; Rats; Rats, Wistar; Retrospective Studies | 1996 |
Comparison of virus burden in blood and sequential lymph node biopsy specimens from children infected with human immunodeficiency virus.
Lymph nodes serve as reservoirs for the replication of human immunodeficiency virus (HIV) type 1. Comparison of serial measurements of virus burden in lymph nodes and peripheral blood after a change in antiretroviral therapy may provide insights into pathogenic mechanisms and permit a more accurate assessment of a therapeutic response.. Nevirapine was added to the drug regiment of eight children with HIV infection treated with the combination of zidovudine and didanosine who had increasing levels of serum p24 antigen. Lymph node biopsies were performed at entry and after 12 weeks of therapy.. Neither CD4 counts nor p24 antigen level correlated with the degree of viremia as measured by ribonucleic acid copy numbers in plasma. Correlations were found between HIV DNA copy number in peripheral blood mononuclear cells and HIV DNA copy number in lymph nodes (p = 0.02), as well as between peripheral blood CD4 counts and lymph node architecture. The HIV signals in the lymph nodes conformed to the anatomic organization of apical light zones in the germinal centers; however, in more advanced disease stages, organized germinal centers disappeared as evidence by a decline in the extent of the follicular dendritic network.. Lymph node biopsies in this small number of HIV-infected children revealed a progressive loss of an organized architecture, especially of the follicular dendritic network. This correlated with a progressive loss of CD4+ cells but not with other measures of disease stage, including viral load, as measured by ribonucleic acid copy numbers. Topics: Antiviral Agents; Biopsy; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Core Protein p24; HIV Infections; HIV-1; Humans; In Situ Hybridization; Infant; Lymph Nodes; Male; Nevirapine; Pyridines; Viremia; Zidovudine | 1996 |
Therapy of HIV infections: problems and prospects.
Topics: Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Stavudine; Urban Health; Zalcitabine; Zidovudine | 1996 |
Kinetics of viral clearance in plasma, peripheral blood mononuclear cells and lymph nodes.
Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Leukocytes, Mononuclear; Lymph Nodes; Male; Plasma; RNA, Viral; Time Factors; Zidovudine | 1996 |
AZT-related mutation Lys70Arg in reverse transcriptase of human immunodeficiency virus type 1 confers decrease in susceptibility to ddATP in in vitro RT inhibition assay.
The genetic basis for didanosine (ddl) resistance in human immunodeficiency virus (HIV-1) has previously been shown to be commonly associated with a Leu to Val change at codon 74 in the HIV-1 RT gene. In this study sequential viral isolates were analyzed from five patients with prior zidovudine (AZT) use who received 6 to 16 months of ddl therapy. Following ddl therapy, viral isolates exhibited an increased AZT susceptibility and decreased ddl susceptibility. Sequence and nested PCR analysis of the HIV-1 RT gene revealed that two viral isolates contained the Leu to Val change at codon 74, and three other isolates with reduced susceptibility to ddl each contained changes at codons 65, 70, and 72. Site-directed mutagenesis was employed to insert specific mutations in RT gene of proviral clone pNL4-3. Analysis of virion-associated reverse transcriptase activity indicated that the Lys70Arg mutation resulted in an enzyme with 2- to 4-fold decreased susceptibility to ddATP. Statistical analysis of the inhibitory concentration for RT activity between pNL4-3 and mutant Lys70Arg viruses obtained in three independent RT inhibition assays was significant (P = 0.05) by student t test paired analysis. Drug susceptibility assays on the virus with Lys70Arg mutation showed a marginal decrease in susceptibility to ddl (1.5- to 2-fold) and about 4- to 6-fold decrease in susceptibility to AZT. Mutations Lys65Glu and Arg72Ser resulted in an impaired RT with greatly diminished functional RT activity. The AZT-associated Lys70Arg mutation results in an RT enzyme with decreased susceptibility to ddATP. Topics: Base Sequence; Didanosine; Drug Resistance, Microbial; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Polymerase Chain Reaction; Proviruses; Reverse Transcriptase Inhibitors; Zidovudine | 1996 |
Therapy for human immunodeficiency virus infection -- what have we learned?
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1996 |
Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry.
SID 791, a bicyclam inhibiting human immunodeficiency virus (HIV) replication in vitro by blocking virus entry into cells, is an effective inhibitor of virus production and of depletion of human CD4+ T cells in HIV type 1-infected SCID-hu Thy/Liv mice. Steady levels of 100 ng of SID 791 or higher per ml in plasma resulted in statistically significant inhibition of p24 antigen formation. Daily injections of SID 791 caused a dose-dependent decrease in viremia, and this inhibition could be potentiated by coadministration of zidovudine or didanose. The present study suggests that SID 791 alone or in combination with licensed antiviral agents may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. The SCID-hu Thy/Liv model in effect provides a rapid means of assessing the potential of compounds with novel modes of antiviral action, as well as the potential of antiviral drug combinations. Topics: Animals; Antiviral Agents; Benzylamines; CD4-CD8 Ratio; Chromatography, High Pressure Liquid; Cyclams; Didanosine; Drug Implants; Heterocyclic Compounds; HIV Infections; HIV-1; Injections, Subcutaneous; Mice; Mice, Inbred BALB C; Mice, SCID; Rats; Spectrophotometry, Ultraviolet; Virus Replication; Zidovudine | 1996 |
Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.
We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo. Topics: Animals; Antiviral Agents; Didanosine; DNA, Viral; Enzyme-Linked Immunosorbent Assay; Fetal Tissue Transplantation; Flow Cytometry; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Liver Transplantation; Lymphocyte Count; Mice; Mice, SCID; Neutrophils; Nevirapine; Polymerase Chain Reaction; Pyridines; Rats; T-Lymphocytes; Thymus Gland; Transplantation, Heterologous; Zidovudine | 1996 |
Reverse transcriptase genotype and antiretroviral susceptibility of human immunodeficiency virus isolates from patients with advanced disease treated with didanosine: correlation with virologic response and survival.
To identify correlates of virologic response and survival, the reverse transcriptase (RT) genotype and in vitro antiviral susceptibility of human immunodeficiency virus (HIV) isolates from 20 patients treated with didanosine were studied. Patients had advanced HIV disease and were intolerant to or had failed zidovudine. Neither RT genotype nor antiviral susceptibility testing, as determined by a peripheral blood mononuclear cell-based assay, correlated with a virologic response to didanosine, as determined previously by quantitative serum culture. Only one (8%) of 12 isolates obtained after 6-12 months of treatment showed mutation at codon 74 conferring didanosine resistance. Reversions were seen in three of five patients with pre-treatment zidovudine resistance mutations at codons 70, but in none of eight with mutations at codon 215. Pretreatment isolates encoding mutations at RT codon 215 or encoding codon 123 asp were associated with both significantly greater CD4 lymphocyte depletion and shorter survival. In this cohort of patients with advanced HIV disease, neither rapid emergence of didanosine resistance nor rapid reversion of zidovudine resistance was observed. To better understand the relationship between virologic response and in vitro susceptibility to didanosine, more precise tools may be needed. Topics: Anti-HIV Agents; Didanosine; Genotype; HIV; HIV Infections; Humans; Retroviridae Proteins; RNA-Directed DNA Polymerase; Survival | 1996 |
Increased plasma human immunodeficiency virus type 1 burden following antigenic challenge with pneumococcal vaccine.
Primary factors that influence virus burden during human immunodeficiency virus type 1 (HIV-1) disease progression remain a fundamental issue in pathogenesis. Because pneumococcal vaccine is routinely given to HIV-1-infected patients and replication of HIV-1 within CD4 T cells is dependent on the activation state of the cell, it was investigated whether the T cell activation that enhances the immune response to vaccines may also enhance HIV-1 replication. Vaccination of asymptomatic HIV-1-infected patients led to rapid and significant increases in virus burden in some patients. The magnitude of these increases correlated significantly with the extent of the antibody response to the vaccination. Thus, antigenic stimulation by vaccines designed to prevent secondary infections may promote HIV-1 replication in certain patients. These findings provide a window for examining HIV-1 pathogenesis and for determining the appropriate preventive measures against other diseases in HIV-1-infected persons. Topics: Adult; Anti-HIV Agents; Antibodies, Bacterial; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Disease Progression; DNA, Viral; HIV Infections; HIV-1; Humans; Immunoglobulin G; Influenza Vaccines; Lymphocyte Activation; Middle Aged; Pneumococcal Infections; Polysaccharides, Bacterial; Proviruses; Receptors, Interleukin-2; RNA, Viral; Time Factors; Vaccination; Vaccines; Viral Load; Zidovudine | 1996 |
Efficacy of a combined zidovudine plus didanosine therapy in one case of HIV-related thrombocytopenia non-responder to zidovudine alone or to anti-Rho immunoglobulin administration.
Topics: Acute-Phase Proteins; Adult; Anti-HIV Agents; Didanosine; Drug Resistance; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Immunoglobulins, Intravenous; Male; Thrombocytopenia; Zidovudine | 1996 |
[Nevirapine: a new principle of action against HIV].
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Child; Clinical Trials as Topic; Didanosine; Double-Blind Method; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infant, Newborn; Male; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Pyridines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Time Factors; Zidovudine | 1996 |
Resolution of HIV-associated cystic benign lymphoepithelial lesion of the parotid gland in a patient undergoing chemotherapy for non-Hodgkin's lymphoma.
Cystic benign lymphoepithelial lesion, a previously rare lesion of the parotid gland characterized by multiple cysts accompanied by marked lymphoid hyperplasia, is increasingly reported in patients with human immunodeficiency virus infection. The case of a 59-year-old man without identifiable risk factors for the acquired immunodeficiency syndrome is presented, in whom the development of cystic benign lymphoepithelial lesions led to the diagnosis of the underlying human immunodeficiency virus infection. The lymphoepithelial lesion remained unchanged for 8 years. When chemotherapy was instituted for abdominal non-Hodgkin's lymphoma all cystic lesions resolved completely. This previously undescribed phenomenon strongly supports the concept that the development of the cysts is secondary to the mechanical obstruction of salivary ducts caused by lymphoid hyperplasia and not due to true de novo cyst formation. Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Cyclophosphamide; Cysts; Didanosine; Doxorubicin; Fatal Outcome; HIV Infections; Humans; Hyperplasia; Lymphoma, Non-Hodgkin; Male; Middle Aged; Parotid Diseases; Prednisone; Vincristine; Zidovudine | 1996 |
[Efficacy of 2 combined drugs for HIV infected patients].
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Stavudine; Treatment Outcome | 1996 |
Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons.
To delineate the pharmacokinetic profile of the oral capsule formulation of ganciclovir, and determine whether oral ganciclovir has any pharmacokinetics interactions with zidovudine, didanosine or probenecid.. Serum and urine concentrations of ganciclovir, zidovudine and didanosine were measured. From these concentrations, standard pharmacokinetic parameters such as peak concentration, area under the curve (AUC), elimination half-life and renal clearance were determined.. The bioavailability of oral ganciclovir averages 6-9%. Inter- and intrasubject variability of AUC is low (coefficient of variation 21.8 and 12.6%, respectively). The steady-state AUCs achieved with oral ganciclovir (1000 mg three times daily or 500 mg six times daily) are approximately 70% of the AUC achieved with the daily maintenance dose of intravenous ganciclovir (5 mg/kg). Serum concentrations of ganciclovir are 20% higher when the oral formulation is administered with a high fat meal than when taken following an overnight fast. Serum concentrations of didanosine (200 mg every 12 h) are approximately doubled when taken in combination with oral ganciclovir (1000 mg every 8 h).. Although bioavailability of the oral formulation of ganciclovir is low, the serum concentrations are predictable, with low inter- and intrasubject variability in peak concentrations and AUC. The two oral regimens studied (500 mg six times daily or 1000 mg three times daily) have comparable bioavailability. Food has a beneficial effect of increasing serum concentrations. There is a potentially important pharmacokinetic interaction between oral ganciclovir and didanosine. Topics: Anti-HIV Agents; Antiviral Agents; Area Under Curve; Biological Availability; Clinical Trials as Topic; Didanosine; Drug Interactions; Drug Therapy, Combination; Ganciclovir; HIV Infections; Humans; Zidovudine | 1996 |
Treatment options for human immunodeficiency virus.
Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; Child; Didanosine; Drug Approval; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant, Newborn; Lamivudine; Male; Saquinavir; Stavudine; United States; United States Food and Drug Administration; Zalcitabine; Zidovudine | 1996 |
Antiretroviral drugs: new agents, new combinations line up against HIV.
Topics: Antiviral Agents; Australia; Didanosine; Drug Therapy, Combination; Europe; HIV; HIV Infections; Humans; Lamivudine; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; Thiazoles; United States; Valine; Zalcitabine; Zidovudine | 1996 |
Predictive value of codon 215 reverse transcriptase mutation on the efficacy of didanosine in HIV-infected, zidovudine-experienced patients.
We investigated whether or not mutations at codon 215 in the HIV reverse-transcriptase-encoding gene predicted a lower efficacy of didanosine therapy, as defined by survival of patients and change in CD4 cell counts in 121 HIV-infected, zidovudine-experienced patients. A trend for shorter survival, although not reaching significance, was observed for patients with HIV strains with the reverse transcriptase codon 215 mutation (P = 0.07), but this trend disappeared after adjustment for initial CD4 cell counts. During the first 3 months on didanosine therapy, the increase in CD4 cell counts was greater in patients who were wild type at codon 215 than in those with the mutation at codon 215 (P = 0.03). These data suggest that there was a better initial CD4 response to didanosine therapy in patients with HIV without the mutation at codon 215, but that this response did not translate into increased survival. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Codon; Didanosine; Female; HIV Infections; HIV Reverse Transcriptase; Humans; Male; Mutation; Retrospective Studies; Survival Rate; Zidovudine | 1996 |
A bend in the road--implications of ACTG 175 and Delta trials.
Topics: Anti-HIV Agents; Australia; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; Europe; HIV Infections; HIV-1; Humans; Survival Analysis; United States; Zalcitabine; Zidovudine | 1996 |
Triple therapy in previously untreated patients reduces viral load below limit of detection.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Pyridines; Viral Load; Zidovudine | 1996 |
Crixivan reduces viral load.
Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Viral Load; Zalcitabine; Zidovudine | 1996 |
Pancreatitis in children infected with human immunodeficiency virus.
The incidence of pancreatitis in HIV-infected children is not well known. Medical records of 42 children with HIV infection followed at Children's Hospital during a 6-year period were reviewed. Pancreatitis (elevated serum lipase levels) developed in 10 children (23.8%). Three children acquired HIV infection from vertical transmission and seven from contaminated blood products (hemophiliacs). Nine were severely immunosuppressed (CD4+ of < 100 cells/mm3). Lipase values were more often elevated than amylase values. The clinical course was protracted and severe in two children, one had four recurrences, and seven had only a single episode of pancreatitis lasting a few weeks. Opportunistic infections were present in four children and seven were receiving medications previously implicated as cause of pancreatitis. Discontinuation of dideoxynosine (ddI) in one child led to rapid resolution of pancreatitis, but continuation of medications in the other children did not alter the course. The etiology of pancreatitis may be multifactorial. Severe and prolonged clinical course is associated with advanced HIV infection. Determination of serum lipase is more useful than serum amylase for identifying those with pancreatitis. Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Amylases; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Infant; Lipase; Male; Pancreatitis | 1996 |
Merck protease inhibitor: more news from Retroviruses Conference.
Several reports on indinavir studies were delivered at the 1996 Conference on Retroviruses and Opportunistic Infections. Indinavir's effect on viral load when combined with AZT, 3TC, or ddI was studied. One ongoing study at the 16-week mark revealed undetectable viral load in 24 of 26 volunteers taking indinavir plus AZT plus 3TC, compared to 13 of 26 on indinavir alone. Median CD4 increases for the triple combination were 79 at 12 weeks and 146 at 24 weeks. A second study reported that 59 percent of the patients on the triple combination had an undetectable viral load, and the median CD4 increase was 90 at 24 weeks. Data on resistance to indinavir indicates that resistant viruses may become defective, causing less damage than the patient's original virus. Topics: CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Pyridines; Zalcitabine; Zidovudine | 1996 |
Pediatric treatment update.
The ACTG 152 study compared AZT monotherapy with ddI monotherapy in HIV-positive children, ranging in age from 3 months to 18 years. The Data Safety and Monitoring Board (DSMB) recommended that AZT monotherapy be discontinued based on survival and HIV disease progression. ACTG 152 opened in August 1991 and included 839 children. The trial assessed the efficacy of three antiretroviral drugs as first-line treatment. Only asymptomatic children with relatively normal laboratory values were excluded, so the trial was unusually broad. There were fewer toxicities associated with ddI monotherapy than ddI plus AZT. Final results clearly support the results of ACTG 175, which found that AZT alone is not the most effective first-line therapy. Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection occurring in HIV-positive children. However, CD4 cell counts are not an effective indicator of PCP risk until the children are twelve months old. In March 1994, the National Pediatric and Family HIV Resource Center, in conjunction with the Centers for Disease Control and Prevention (CDC), revised the guidelines for pediatric care. The new guidelines recommend that all HIV-positive infants, or those born to HIV-positive mothers, be started on prophylactic treatment at the age of one month. Topics: Adolescent; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Infant; Zidovudine | 1996 |
Update on other antivirals.
Data from recently announced virology studies show that monotherapy of any kind is not an adequate treatment for HIV disease. Preliminary results of AZT, ddI, ddC, and d4T and ddI combinations are examined, as are hydroxyurea and ddI combinations. Results show that combination therapies are having a positive effect on reducing viral load, reducing disease progression, and enhancing patient survivability. It is now believed that combination therapies that include a protease inhibitor are likely to become a recommended standard of care in the near future. Preliminary studies of two new drugs, BW-1592 (Glaxo Wellcome) and bis-POM PMEA (Gilead Sciences), are highlighted. Topics: Adenine; Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Organophosphonates; Stavudine; Zalcitabine; Zidovudine | 1996 |
More information on hydroxyurea.
Franco Lori, director of the Research Institute for Genetic and Human Therapy (RIGHT), explains the results of the clinical trial of ddI versus ddI and hydroxyurea. Hydroxyurea shows a capacity to induce sustained viral inhibition when used in combination with ddI. The only adverse effect reported was hair loss. Several of the studies and their findings are reported, and other planned studies are described. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; HIV Infections; HIV-1; Humans; Hydroxyurea | 1996 |
Nipping HIV in the bud.
HIV may be ultimately cleared in recently infected people with the use of antiviral treatments, according to a general practitioner from San Francisco. Newly infected patients have a homogenous virus population that should be susceptible to all the drugs being used. The initial test regimen, used on eight participants who now have undetectable viral loads, was AZT/3TC/ritonavir. Other researchers tested less potent combinations; many showed impressive results. A chart shows data from the protease inhibitor combination trials. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Lamivudine; Pyridines; Quinolines; Ritonavir; Saquinavir; Stavudine; Thiazoles; Valine; Virus Replication; Zalcitabine; Zidovudine | 1996 |
Antiviral roundup.
Data on nonnucleoside reverse transcriptase inhibitors presented at the Vancouver conference is provided. Unexpectedly strong antiretroviral effects were found for 1592U89 succinate, a guanosine nucleoside analog being developed by Glaxo Wellcome. Lobucavir, another guanosine nucleoside analog, apparently has activity against most herpes viruses. Clinical trial results on the ddI/d4T combination and the ddI/delavirdine combination are presented. Topics: CD4 Lymphocyte Count; Cohort Studies; Delavirdine; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indoles; Mutation; Piperazines; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Stavudine; Zidovudine | 1996 |
Top AIDS researchers' strategy for antiretroviral treatment.
The International AIDS Society developed clinical recommendations for antiretroviral therapy, including information on when to start treatment, what to change to, and the special considerations of postexposure prophylaxis and primary infection. The recommendations, published in the Journal of the American Medical Association, were discussed at the XI International Conference on AIDS in Vancouver. Panel members agreed that HIV RNA measurements are superior to CD4 counts in predicting the risk of clinical progression in asymptomatic patients. However, viral load measurements are most helpful when used in conjunction with CD4 counts in order to make both immediate and long-term treatment decisions. Until long-term clinical trials are complete, using a combination of two nucleoside analogues is recommended. Reasons for changing therapy include treatment failure, toxicity, and drug resistance. Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Patient Compliance; Practice Guidelines as Topic; RNA, Viral; Stavudine; Zalcitabine; Zidovudine | 1996 |
Nevirapine: new drug, new class, new questions.
The Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee recommended the accelerated approval of nevirapine, a nonnucleoside reverse transcriptase inhibitor. The recommendation was based on immunologic and virologic data obtained in several trials. Nevirapine must be given in combination with nucleoside analogs. Combining protease inhibitors with nevirapine is being considered, but more data on its safety is necessary. HIV becomes resistant to nevirapine, but curiously, some patients sustain their reduction in HIV RNA. Several adult nevirapine trials are summarized. Pediatric studies have shown interesting results, such as effective entry of the drug into both plasma and cerebrospinal fluid, decreased viral load, and antibody seroreversion. The primary side effect of nevirapine is rash, which may be fatal in some patients. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Child; Didanosine; Drug Approval; Drug Therapy, Combination; HIV; HIV Infections; Humans; Nevirapine; Pyridines; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration; Zidovudine | 1996 |
3TC: combination trial stopped early as clinical benefit shown.
The DSMB (data safety monitoring board) stopped a major trial of 3TC (lamivudine) when the ongoing study showed a significant reduction in the rates of death or disease progression when 3TC was added to other antiretroviral regimens. The trial was discontinued by unanimous consent. A separate pediatric trial is now underway, monitoring the effects of 3TC in delaying disease progression or death in children. Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Disease Progression; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Placebos; Treatment Failure; Zalcitabine; Zidovudine | 1996 |
ACTG 152: new insights into pediatric antiretroviral therapy.
Final results of the pediatric clinical trial, AIDS Clinical Trials Group (ACTG) 152, show that initial antiretroviral therapy with didanosine (ddI) alone slows disease progression in HIV-infected children as effectively as combination therapy with ddI and AZT. The trial, sponsored by the National Institutes of Health (NIH), enrolled 839 children ranging in age from 3 months to 18 years at 78 sites across the United States. The trial was organized into three treatment arms, with patients receiving either AZT alone, ddI alone, or ddI plus AZT. The AZT-only group was discontinued before the end of the study after analyses indicated the treatment was less effective than either of the ddI treatments and was associated with more side effects. The results of the two ddI arms showed that both treatments were effective in preventing or delaying such clinical outcomes as poor weight gain, developmental and neurologic problems, new or recurrent opportunistic infections, malignancy and death. Other AIDS antiretroviral therapies under study for use in children include various combinations of ddC, d4T, ddI and AZT. The NIAID Pediatric ACTG also supports other clinical trials for children with HIV infection, including a study comparing the efficacy of AZT plus 3TC to AZT plus ddI and to ddI alone. NIAID is also planning clinical trials of protease inhibitors in pediatric AIDS patients. Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Infant; Zidovudine | 1996 |
ddI plus d4T.
A study of 85 volunteers divided into 5 separate dosage groups found fairly good viral suppression from a combination of didanosine plus stavudine. A 1.3 log viral load reduction was sustained for at least 52 weeks when the 5 dose groups were pooled together. For the individual groups, reductions were 1.1 to 1.8 logs at 52 weeks. By the eighth week, average CD4 count increased by about 80, and this increase was sustained until at least week 52. Treatment was well tolerated with no dose-related adverse events. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans; Stavudine | 1996 |
Outdated yet out-of-reach: AIDS society treatment guidelines at the International Conference.
The AIDS Society Treatment Guidelines came under scrutiny at the XI International AIDS Conference in Vancouver in 1996. The review panel agreed that treatment needs to be initiated before irreversible immunologic damage occurs. The types of drugs to use for initial therapy (AZT plus ddC, AZT plus ddI, or AZT plus 3TC), when to change therapy, and when to stop antiretroviral therapy, were recommended by the panel. Other panel recommendations for treating acute or primary (new) infection, prevention of high-risk exposures, and vertical transmission are briefly outlined. Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Antiviral Agents; CD4 Lymphocyte Count; Decision Making; Didanosine; Drug Therapy, Combination; HIV; HIV Infections; Humans; Lamivudine; Practice Guidelines as Topic; Zalcitabine; Zidovudine | 1996 |
Nevirapine approved by FDA. Food and Drug Administration.
Nevirapine, the ninth approved anti-HIV drug, is the first of a new class of pharmaceuticals developed for HIV treatment. A non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine targets the same HIV enzyme as AZT, ddI, ddC, d4T and 3TC. A three-drug treatment including AZT and ddI was shown to be significantly better than an AZT/ddI combination in patients who had received no prior treatment. The drug has a long half-life, which means that it can be administered less often. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Approval; Drug Therapy, Combination; Female; HIV Infections; Infant, Newborn; Infectious Disease Transmission, Vertical; Nevirapine; Pregnancy; Pyridines; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration; Viral Load; Zidovudine | 1996 |
Drug combo safe for HIV-infected children.
A 6-month study of 8 children with advanced HIV infection shows that combination therapy with d4T and ddI is safe and well tolerated. The combination treatment caused no drug-associated clinical or laboratory adverse effects. Further studies are needed to determine the effectiveness of this treatment regimen in children with less advanced HIV infections. Topics: Antiviral Agents; CD4 Lymphocyte Count; Child; Didanosine; Drug Monitoring; Drug Therapy, Combination; HIV Infections; Humans; RNA, Viral; Stavudine | 1996 |
A patient's guide to protease inhibitors.
Dosage guidelines and side effects of three currently available protease inhibitors (saquinavir, ritonavir, indinavir) reveal very different patterns. Dosage regimens are as follows: saquinavir, 3 capsules every 8 hours with food; ritonavir, 6 capsules every 12 hours with food; and indinavir, 2 capsules every 8 hours on an empty stomach. Ritonavir has the severest side effects, including nausea, diarrhea, and initially, tingling feeling of the mouth, arms, or legs. The drugs work best when taken with well-studied medicines such as AZT, d4T, and ddI. Topics: Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Eating; Guidelines as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Saquinavir; Stavudine; Zidovudine | 1996 |
ddI and d4T plus protease inhibitors.
As a first-time regimen against HIV, treatment with zidovudine (AZT)/lamivudine (3TC) plus a protease inhibitor is not recommended. If resistance to 3TC develops, it could jeopardize the effectiveness of other subsequent drugs. In addition, peripheral neuropathy caused by didanosine (ddI), zalcitabine (ddC) or stavudine (d4T) is most commonly reported in late-stage AIDS patients, indicating that regimens including ddI, d4T, or ddC probably should be administered earlier in the course of disease. The relatively benign AZT/3TC combination should be reserved for more advanced patients. A recommended dosage schedule for ddI and d4T combined with indinavir is provided. Topics: Anti-HIV Agents; Didanosine; HIV Infections; Humans; Lamivudine; Stavudine; Zalcitabine; Zidovudine | 1996 |
FDA advisory committee deadlocks on delavirdine. Food and Drug Administration.
The Food and Drug Administration (FDA) Advisory Committee split on whether to grant accelerated approval to delavirdine, the nonnucleoside reverse transcriptor inhibitor from Pharmacia & Upjohn. The drug has variable effects on viral load and CD4 count when combined with AZT, ddI, or both. Several studies showed inconsistent results, and there are a number of drugs which should not be taken with delavirdine. Further studies are planned to see if the drug is safe and effective in triple or quadruple combinations; all members agreed that the drug should not be taken alone. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Delavirdine; Didanosine; Disease Progression; Drug Approval; Drug Industry; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indoles; Piperazines; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration; Viral Load; Zidovudine | 1996 |
Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 2. 6-Halo and 6-alkoxy prodrugs of 2'-beta-fluoro-2',3'-dideoxyinosine.
A series of 6-halo-(F-, Cl-, Br-, I-) and 6-alkoxy-(OMe-, OEt-) 9-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl) purines (F-ddN) have been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds, which contain lipophilic 6-substituents, were chosen as acid-stable prodrugs for the anti-HIV-active F-ddN, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) hypoxanthine (F-ddI), because of their potential to increase blood-brain-barrier penetration relative to F-ddI. All the new compounds were more lipophilic than the currently approved anti-AIDS drugs. Partition coefficient increases of 30- and 110-fold were achieved, relative to didanosine (ddI), for the 6-chloro- and 6-ethoxy analogues. 2'-Fluoro substitution abolished the pH 1, acid-catalyzed cleavage of the nucleoside glycosylic bond. However, pH 1, acid-catalyzed hydrolysis of the 6-fluoro substituent to produce F-ddI was observed to occur at a rate (t1/2 0.54 h) which was ca. 40-170 times faster than that of the other prodrugs. The utility of the F-ddNs as prodrugs for F-ddI depends upon their ability to act as substrates for adenosine deaminase. The relative rates of adenosine deaminase-catalyzed prodrug hydrolysis to F-ddI varied by a factor of > 25,000 with the 6-fluoro- and 6-ethoxy analogues reacting the fastest and slowest, respectively. All of the prodrugs possessed anti-HIV activity in the phytohemagglutinin-stimulated peripheral blood mononuclear cell test system and a qualitative correlation exists between prodrug anti-HIV activity and adenosine deaminase hydrolysis rates. Topics: Adenosine Deaminase; Antiviral Agents; Cells, Cultured; Didanosine; HIV Infections; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Prodrugs; Solubility | 1995 |
[Antiretroviral treatment against HIV].
Topics: Antiviral Agents; Didanosine; HIV Infections; Humans; Zalcitabine; Zidovudine | 1995 |
Combined drugs may be better than zidovudine alone for immunocompromised adults infected with HIV-1.
Topics: Adult; Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Immunocompromised Host; Treatment Outcome; Zalcitabine; Zidovudine | 1995 |
Genotypic evolution of HIV-1 isolates from patients after a switch of therapy from zidovudine to didanosine.
The existence of zidovudine (ZDV)-resistant and didanosine (ddI)-resistant human immunodeficiency-1 (HIV-1) variants mutated in the reverse transcriptase (RT) gene has been previously demonstrated. In this study, we tried to follow up the genotypic changes in the RT after the switch of therapy from ZDV to ddI. We studied HIV-1 isolates from 11 patients undergoing ddI therapy. Genotypic data were obtained with differential polymerase chain reaction (PCR) and with direct sequencing after PCR. The prevalence of ZDV resistance-related mutations showed a very slow decrease, particularly when patients had been treated with ZDV for a long time. The appearance of a mutation at codon 74 seemed to be independent of the presence or absence of ZDV resistance-related mutations. The broad genotypic heterogeneity of the isolates and the complexity of the evolution in one patient's isolates plead for large sequencing studies of the RT genome in new therapeutic approaches. Topics: Base Sequence; Biological Evolution; Didanosine; DNA Primers; DNA, Viral; Drug Resistance, Microbial; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Leukocytes, Mononuclear; Molecular Sequence Data; Mutation; Phenotype; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; Zidovudine | 1995 |
Comparison of selective polymerase chain reaction primers and differential probe hybridization of polymerase chain reaction products for determination of relative amounts of codon 215 mutant and wild-type HIV-1 populations.
A mutation at codon 215 of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) gene results in decreased sensitivity to zidovudine (ZDV). In order to follow changes in codon 215 mutant (MUT) and wild-type (WT) populations in the plasma of patients during therapy, two polymerase chain reaction (PCR) procedures were investigated. The first was a nested, selective PCR, wherein a first round with viral-specific primers was followed by a second round with allele-specific primers. Although the procedure is relatively sensitive, some samples in the first round of PCR could not be amplified. In mixing experiments, mispriming of the MUT primer made relative determination of quantities subjective and difficult. Differential hybridization of PCR product with probes specific for codon 215 MUT or WT sequences was also investigated. A probe directed to a highly conserved region of the RT gene in the amplified PCR product was used to determine the total amount of PCR product analyzed. Differential hybridization was linear and reproducible over several logs of MUT:WT ratios, and determination of a 1:100 ratio of MUT:WT was readily achieved. When applied to longitudinal samples from three patients, dramatic changes in each population were readily apparent. These changes were evaluated with regard to viral load. Topics: Base Sequence; Codon; Didanosine; DNA Primers; DNA Probes; DNA, Single-Stranded; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Nucleic Acid Hybridization; Point Mutation; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; RNA, Viral; Zidovudine | 1995 |
Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection.
Dideoxynucleosides induce a dose-related toxic neuropathy; however, there is a paucity of information on whether other risk factors influence the development of neuropathy. We reviewed the records of 103 patients at an AIDS Clinical Trials Unit who were taking didanosine and/or zalcitabine to determine the risk factors for dideoxynucleoside-induced toxic neuropathy. Most were homosexual or bisexual (85%) men with a mean age of 39 years. The median CD4+ lymphocyte count was 59 cells/mm3, and 35% had a previous diagnosis of AIDS. Toxic neuropathy was more common in patients taking zalcitabine compared with those taking didanosine (14 of 51 versus seven of 55, p = 0.08). In the patients who took zalcitabine, those who had a low baseline serum cobalamin level, a history of heavy ethanol consumption, or a history of symptoms of peripheral nerve dysfunction were more likely to develop a toxic neuropathy (10 of 14 versus 12 of 37, p = 0.01). Conversely, there were no factors associated with the development of didanosine-induced toxic neuropathy. Dideoxynucleoside-induced toxic neuropathy is a common problem that can be disabling but is usually reversible. A history of symptoms of peripheral nervous system disease, heavy ethanol consumption, or a low serum cobalamin level may be useful in distinguishing patients at higher risk of developing zalcitabine-induced toxic neuropathy. Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antiviral Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Peripheral Nervous System Diseases; Retrospective Studies; Risk Factors; Zalcitabine | 1995 |
Combination superior to zidovudine in Delta trial.
Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1995 |
Study shows two drugs are best for HIV infection.
Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1995 |
Perspectives in drug therapy of HIV infection.
Current key issues in the drug therapy of HIV infection include the timing of treatment initiation, the use of multiple-drug therapy and the duration of treatment. Although most clinicians agree that symptomatic HIV disease should be treated, there is no consensus as to whether patients should be treated before symptoms develop; the results of the Concorde trial failed to demonstrate any long term improvement in disease progression or survival when antiretroviral therapy was initiated in asymptomatic individuals rather than deferring it until the development of AIDS or ARC. However, combination therapy may prove to be the most effective long term option. In the future, monitoring viral load or viral resistance may be a useful aid in determining whether antiretroviral therapy should be stopped or changed, particularly if any clinical benefits are transient or if adverse effects persist. New antiretroviral therapies must be evaluated in terms of both risks (associated adverse effects) and benefits (increase in survival, delay in disease progression or improvement in quality of life). There is an urgent need to identify the best surrogate markers to permit more rapid evaluation of therapeutic strategies. Topics: Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Time Factors; Zidovudine | 1995 |
Quantitative molecular monitoring of human immunodeficiency virus type 1 activity during therapy with specific antiretroviral compounds.
Methods for the absolute quantitation of nucleic acids present in small amounts in biological samples (competitive PCR and competitive reverse transcription PCR) were applied to the direct monitoring of specific anti-human immunodeficiency virus type 1 (HIV-1) therapy. With these techniques, different parameters of HIV-1 activity (including genomic RNA copy numbers in plasma, proviral and late transcript copy numbers in peripheral blood lymphocytes, and mean transcriptional activity per each HIV-1 provirus) were monitored during therapy with azidothymidine or ddI. In most of these treated patients, a direct response to the antiretroviral compounds employed was detected during the first few weeks of treatment, as documented by a fast decrease of all molecular indexes of HIV-1 activity. However, residual viral replication (albeit at minimal levels) was documented during therapy in all subjects monitored in this study. In a minority of the patients under study (3 of 12), the drug-dependent viral inhibition was maintained throughout the observation time (213 to 791 days), but in 9 patients a rebound in viremia level was detected during therapy with competitive reverse transcription PCR. Sequencing analysis of a portion of the HIV-1 gene pol from cell-free virions showed that circulating viral variants bearing at least two mutations compatible with azidothymidine or ddI resistance were detectable in the patients who exhibited a rebound in cell-free HIV-1 genomic RNA copy numbers in plasma but not in one patient who maintained (for 455 days) lowered levels of viral load during ddI treatment. Topics: Amino Acid Sequence; Didanosine; DNA, Viral; Female; Genes, pol; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Male; Molecular Sequence Data; Mutagenesis; RNA, Viral; Sequence Analysis, DNA; Transcription, Genetic; Viremia; Zidovudine | 1995 |
[2',3'-Dideoxyinosine and pancreatic disease in HIV infection].
Topics: Didanosine; HIV Infections; HIV-1; Humans; Pancreatitis | 1995 |
Specific, sensitive, and rapid assay for human immunodeficiency virus type 1 pol mutations associated with resistance to zidovudine and didanosine.
The effectiveness of antiretroviral therapy may be limited by the development of human immunodeficiency virus type 1 (HIV-1) resistance. Monitoring for resistance will perhaps allow changes in therapy prior to deterioration in the patient's clinical or immunologic status. Our objective was to develop a rapid, specific, and sensitive genotypic assay for HIV-1 resistance to zidovudine (ZDV) and didanosine (ddI) which is simple to perform. In our assay the DNA of HIV-1 pol was amplified by PCR using two sets of nested oligonucleotide primers. Mutations of reverse transcriptase (RT) encoding amino acids (aa) 74 and 41, 70, and 215 which have been associated with HIV-1 resistance to ddI and ZDV, respectively, were detected with a ligase detection reaction (LDR) and indicated colorimetrically. The RT genotypes of 35 patient specimens (140 codons) blindly assessed for these mutations were in agreement by PCR-LDR and by dideoxynucleotide sequencing. To evaluate the limits of the assay, other specimens with mutations close to the ligation site were evaluated by PCR-LDR. The assay was sensitive and specific for all specimens except when mutations occurred within 2 bases on either side of the ligation site. In summary, this PCR-LDR assay specifically, sensitively, and rapidly detected pol mutations (RT aa 74, 41, 70, and 215) associated with HIV-1 resistance to ddI and ZDV. Topics: Base Sequence; Didanosine; DNA Ligases; DNA Primers; DNA Probes; DNA, Viral; Drug Resistance, Microbial; Evaluation Studies as Topic; Genes, pol; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Sensitivity and Specificity; Time Factors; Virology; Zidovudine | 1995 |
Treatment of children with HIV infection. PENTA (Paediatric European Network for Treatment of AIDS)
Topics: Child; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zidovudine | 1995 |
Determination of human immunodeficiency virus RNA in plasma and cellular viral DNA genotypic zidovudine resistance and viral load during zidovudine-didanosine combination therapy.
Eleven human immunodeficiency virus (HIV)-infected subjects on long-term zidovudine (ZDV) therapy had didanosine (ddI) added to their antiretroviral regimen. HIV RNA in plasma was quantitated by branched-DNA signal amplification assay. Peripheral blood mononuclear cell (PBMC) HIV viral DNA was quantitated by PCR. The relative amounts of wild-type (WT) sequence, ddI resistance-associated codon changes (reverse transcriptase [RT] gene codon 65 K-->R [RT K65R], RT 174V, RT I135K/T/V, and RT M184I/V), and ZDV resistance-associated codon change (RT T215Y/F) from HIV RNA in plasma and RT T215Y/F from PBMC viral DNA were determined by differential hybridization of PCR products from 10 of 11 subjects. All subjects had evidence of RT T215Y/F mutation in both RNA in plasma and PBMC DNA at baseline. Subjects with a mixture of WT and RT T215Y/F HIV RNA in plasma at baseline demonstrated a decline in RNA levels in plasma after the addition of ddI. However, after 6 months of ZDV-ddI therapy, WT HIV RNA in plasma was undetectable in all subjects who had demonstrated a mixture at baseline. Subjects with only RT T215Y/F RNA present in plasma at baseline remained so and demonstrated no decline in RNA levels in plasma. In all subjects, no significant changes in PBMC DNA viral load and RT T215Y/F or WT levels were seen. HIV RNA in plasma demonstrated a significantly higher RT T215Y/F mutant/WT ratio than that of PBMC viral DNA, both at baseline and after ZDV-ddI combination therapy in all subjects. No subjects developed mutations associated with ddI resistance at codons 65, 74, 135, and 184 during this study. This study suggests that determination of relative amounts of RT T215Y/F and WT species from HIV RNA in plasma at baseline may be predictive of virologic response during ZDV-ddI combination therapy. Topics: Base Sequence; Didanosine; DNA, Viral; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV; HIV Infections; Humans; Molecular Sequence Data; RNA, Viral; Zidovudine | 1995 |
Study of AZT effectiveness in treating HIV-infected children halted.
Topics: Adolescent; Child; Child, Preschool; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Infant; Treatment Outcome; Zidovudine | 1995 |
Community treatment of HIV-1: initial stage and asymptotic dynamics.
Treatment with antiviral drugs (zidovudine and ddI) has been reported to delay progression to AIDS, and may even possibly lower the infectiousness of the infectives. However, its effect on the community level is still uncertain. The latter is important since a successful community treatment program must meet both public health and individual health goals. Our study will focus on the effect of a community-wide treatment program initiated at the early stages of the disease as well as the long-term effect of the program. Using a simple mathematical model, we demonstrate that a community-wide treatment program could be instrumental in decreasing HIV incidence rate and eradicating the disease in the future if certain conditions on the parameters are met. On the other hand, when the above mentioned conditions on the parameters are not satisfied, we show that even if the treatment does improve survival in AIDS patients and decrease the rate at which HIV infection spreads in the community, it is still possible for the treatment program to have an adverse effect on the spread of AIDS in the population in the long run. Hence, a public health policy maker must exercise caution in order to design an effective treatment program for HIV/AIDS. Topics: Community Health Services; Didanosine; HIV Infections; HIV-1; Humans; Male; Mathematics; Models, Biological; Zidovudine | 1995 |
Early and prolonged decrease of viremia in HIV-1-infected patients treated with didanosine.
Fourteen patients previously treated with zidovudine were monitored for laboratory parameters and clinical events during 1 year after introduction of didanosine (ddI) monotherapy. Proviral human immunodeficiency virus type 1 (HIV-1) copy numbers (cell-associated DNA) and concentration of free virions (viremia) were determined using a semiquantitative polymerase chain reaction (PCR). High levels of circulating virus were detected in all patients (range, 17 to 5,934 x 10(3)/ml of serum). Within 4 weeks of therapy, a decrease of viremia (60 to 98%) was observed in nine patients. After 1 year of treatment, eight of these nine patients still had decreased viremia when proviral HIV DNA was decreased or stable, and CD4+ lymphocytes were stable or higher in seven of these eight patients. Antiviral effect was more pronounced in the six patients with CD4+ > 100/mm3 at entry, five of them belonging to the subgroup of the seven responding patients as compared to two of eight patients with CD4+ < 100/mm3. Clinical events in this small group were not statistically correlated with virologic parameters; however, responding patients had a tendency to stabilize or gain weight. This study suggests that measurement of viremia deserves further study as a marker of antiviral efficacy and might predict, even at 4 weeks, the beneficial potential of ddI. Topics: AIDS-Related Opportunistic Infections; CD4 Lymphocyte Count; Didanosine; DNA, Viral; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Polymerase Chain Reaction; Proviruses; RNA, Viral; Viremia; Virion; Zidovudine | 1995 |
In vivo inhibition of syncytium-inducing variants of HIV in patients treated with didanosine.
Topics: Acquired Immunodeficiency Syndrome; Didanosine; Giant Cells; HIV Infections; HIV-1; Humans; Phenotype; Prospective Studies; Zidovudine | 1995 |
Development of a human thymic organ culture model for the study of HIV pathogenesis.
The development of effective therapies for the treatment of AIDS would be facilitated by a better understanding of HIV pathogenesis in vivo. While some aspects of pathogenesis may be assessed by standard tissue culture assays, in vivo animal models may provide clues to other aspects of HIV-mediated progression toward AIDS. Current animal models include primate models for the study of simian immunodeficiency virus (SIV) and HIV, SCID-hu and hu-PBL SCID mouse models for the study of HIV, and feline models for the study of feline immunodeficiency virus (FIV). In general these models are costly and labor intensive. We have developed a simple human fetal thymic organ culture (TOC) system that is permissive for HIV infection and that exhibits pathology similar to that observed in vivo. A key feature of this system is the time-dependent destruction of thymocytes typified by the preferential loss of CD4-expressing cells. HIV-mediated thymocyte destruction occurs by a process involving programmed cell death. We have infected TOC with a panel of HIV isolates and found that the resulting viral replicative and pathogenic profiles are similar to those seen in the SCID-hu Thy/Liv mouse, yet different from profiles observed in standard PHA-blast tissue culture assays. In addition, we find that TOC may be used to assess efficacy of antiviral agents such as AZT (3'-azido-3'-deoxythymidine) and ddI (2',3'-dideoxyinosine) in blocking both viral replication and virus-induced pathology. These results indicate that this model is amenable to the systematic manipulation, analysis, and characterization of a variety of HIV virus isolates and antiviral therapies. Topics: Animals; Antiviral Agents; Apoptosis; Cats; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Didanosine; Drug Evaluation, Preclinical; Fetus; HIV Infections; HIV-1; Humans; Mice; Models, Biological; Organ Culture Techniques; Thymus Gland; Time Factors; Virus Replication; Zidovudine | 1995 |
Hydroxyurea and HIV-1 viraemia.
Topics: Acquired Immunodeficiency Syndrome; Didanosine; Drug Therapy, Combination; Enzyme Inhibitors; HIV Infections; HIV-1; Humans; Hydroxyurea; Viremia | 1995 |
Perforating granuloma annulare and HIV.
Topics: Adult; Antiviral Agents; Arm; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Didanosine; Female; Granuloma Annulare; HIV Infections; HIV Seropositivity; Humans; Leg Dermatoses | 1995 |
Factors associated with changes in the use of antiretroviral therapy by a cohort of homosexual men infected with human immunodeficiency virus type 1.
Changes in the use of antiretroviral drugs and factors associated with changes from monotherapy with zidovudine (ZDV) to other regimens were quantified in the Multicenter AIDS Cohort Study. Participants who had been receiving monotherapy with ZDV were categorized as (1) discontinuing ZDV monotherapy; (2) switching to disanosine (ddI), zalcitabine (ddC), or stavudine (d4T) monotherapy; (3) switching to combination therapy (ZDV with ddI, ddC, or d4T); or (4) continuing ZDV monotherapy. From 1990 to 1994, the percentage of participants using ZDV monotherapy decreased from 27% to 17% (among participants without AIDS) and from 60% to 17% (among those with AIDS). At the same time, the proportion of participants using combination therapy increased from zero to 8% (no AIDS) and from 8% to 26% (AIDS). Polychotomous logistic regression methods were used to identify the factors predicting changes from ZDV monotherapy. Among participants without AIDS, indicators of drug failure (such as a lower CD4 lymphocyte count or symptoms of human immunodeficiency virus type 1 infection) were predictive of the initiation of combination therapy, while among patients with AIDS they were predictive of a switch to an alternative monotherapy. A decrease in hemoglobin levels, a marker of ZDV toxicity, was predictive for all patients of a switch to other monotherapy. These data show that clinicians and patients are opting for more aggressive antiretroviral regiments and that changes in CD4 lymphocyte count and in the status of symptoms remain the primary guides for changes in therapy. Topics: Antiviral Agents; CD4 Lymphocyte Count; Cohort Studies; Didanosine; Drug Therapy, Combination; Drug Utilization; Follow-Up Studies; Hemoglobins; HIV Infections; HIV-1; Homosexuality, Male; Humans; Male; Multicenter Studies as Topic; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine | 1995 |
[Anti-retroviral monotherapy with nucleoside analogues].
Topics: Antiviral Agents; Didanosine; HIV Infections; Humans; Zalcitabine; Zidovudine | 1995 |
The data and safety monitoring board and acquired immune deficiency syndrome (AIDS) clinical trials.
The urgency of the Acquired immune deficiency syndrome (AIDS) epidemic has mandated that multiple therapeutic approaches be developed and that these approaches be evaluated through clinical trials. To oversee these trials, the National Institute of Allergy and Infectious Diseases (NIAID) has created three large clinical trial programs monitored by a Data and Safety Monitoring Board (DSMB). For each clinical trial, this Board uses a standardized approach employing contemporary biostatistical, medical, and ethical principles. The DSMB is responsible for reviewing interim data on clinical trial performance, treatment safety and efficacy, and overall study progress. If interim results provide convincing evidence of either excessive adverse effects or significant treatment benefit, the DSMB may recommend early termination of the trial to the NIAID and the study investigators. The responsibility, organization, and operating procedures of this DSMB are presented and illustrated through three clinical trials sponsored by NIAID and monitored by the Board. The rationale and operational model for the DSMB may be a useful example for the development of similar review processes in other HIV clinical trial settings. Topics: Advisory Committees; Anti-Infective Agents; Clinical Trials as Topic; Clinical Trials Data Monitoring Committees; Confidentiality; Conflict of Interest; Didanosine; Drug Evaluation; Federal Government; HIV Infections; Humans; National Institutes of Health (U.S.); Organizational Objectives; Professional Staff Committees; Pyrimethamine; Reverse Transcriptase Inhibitors; Risk Assessment; Toxoplasmosis, Cerebral; Treatment Outcome; United States; Zalcitabine; Zidovudine | 1995 |
[Prescription of antiretroviral and prophylactic drugs in HIV diseases: reality of medical practices].
Antiretroviral and prophylactic therapy given to HIV-infected patients attending hospital (DMI 2 data base) was analyzed according to TCD4+ cell count; 19,020 patients were included in the study. Under 200 TCD4+/mm3, more than 80% of the patients received antiviral therapy, most often AZT (45.3%) or ddI (27.2%). Combined treatment was quite low, less than 8%. Although above 500 TCD4+/mm3, 11.6% of patients received AZT, this study showed that antiretroviral therapy followed French recommendations. This was not the case for prophylaxis: a large proportion of patients under 200 TCD4+/mm3 did not received pentamidine aerosol, or cotrimoxazole, or dapsone. Topics: Anti-Infective Agents; Antiviral Agents; CD4 Lymphocyte Count; Dapsone; Didanosine; Drug Utilization; France; HIV Infections; Hospital Information Systems; Hospital Records; Humans; Pentamidine; Trimethoprim, Sulfamethoxazole Drug Combination; Zalcitabine; Zidovudine | 1995 |
Anti-HIV therapy lowers risk of AIDS, death in patients with intermediate-stage HIV disease.
Topics: Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Survival Rate; Zalcitabine; Zidovudine | 1995 |
AZT studies reinforce benefits of combination.
A new anti-HIV drug, 3TC, taken with AZT is yielding exciting results. An analysis of 6,000 subjects followed for 4 years indicated that patients taking AZT in combination with ddC or ddI survived longer than those who switched to ddC or ddI alone. Data also showed that CD4 counts were the most significant marker for predicting survival, favoring early treatment. Three studies of patients taking AZT and 3TC show that the two antiretrovirals may have a synergistic effect that may increase benefits even more than other drug combinations. The data on the AZT-3TC combination demonstrate increased maintenance of CD4 cell counts, reduced levels of HIV, and continued viral suppression. Topics: Antiviral Agents; CD4-Positive T-Lymphocytes; Didanosine; Drug Synergism; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Lymphocyte Count; Zalcitabine; Zidovudine | 1995 |
Nevirapine triple combo results released.
Preliminary results of ACTG 241 have been released. This study compared the triple therapy of nevirapine plus ddI and AZT against the double combination of ddI and AZT. Preliminary results show participants taking the triple combination had CD4 counts and CD4 percentages that were roughly equivalent to the baseline values. In contrast, the double combination experienced a 25 percent decline in both values. There were about the same number of deaths and disease progressions in both groups. The clinical benefit of the triple combination is still unclear despite the CD4 counts and the lowering of the amount of viral load. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; Erythema; HIV Infections; HIV-1; Humans; Nevirapine; Pyridines; Virus Replication; Zidovudine | 1995 |
Treatment briefs.
Merck & Co. has announced it will launch a sizable expanded access program for its protease inhibitor compound MK-639. This is surprising since less than a month earlier it claimed it could not make any substantial quantity of the drug available for at least another year. Citing limits of its present 3TC production, Glaxo has established a quota system of 350 new enrollments per week in its 3TC/AZT combination study. Some believe this is a way Glaxo has found to limit a financial commitment when it is spending $16 billion to buy out Burroughs Wellcome. The Food and Drug Administration (FDA) is expected to approve the 3TC/AZT combination next Fall. Genentech has announced it will supply its human nerve growth factor (NGF) to a government-sponsored trial (ACTG 291) of the compound in AIDS-related peripheral sensory neuropathy. NGF promises to actually reverse the nerve damage caused by extended dosages of such anti-HIV drugs as ddI, d4T, and especially, ddC. Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Industry; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Nerve Growth Factors; Nervous System Diseases; Pyridines; Recombinant Proteins; Stavudine; Zalcitabine; Zidovudine | 1995 |
Results of pediatric study present new questions.
The Data Safety and Monitoring Board recommended that the AZT alone arm be dropped in a trial (ACTG 152) of HIV-infected children comparing AZT alone, AZT plus ddI, and ddI alone. Children receiving AZT alone were experiencing higher rates of disease progression and drug-associated toxicity. Other studies involving children and AZT alone are being modified as a result. It is likely that the ACTG 152 preliminary results will also cause a change in the pediatric standard-of-care involving AZT monotherapy. Physicians are encouraged to call the National Pediatric HIV Resource Center Physician's hotline at 1-800-362-0071 for guidance in treatment decision-making. Study ACTG 076 has shown that HIV-positive women who took AZT alone significantly reduced the rate of HIV transmission to their child. The loss of an AZT-alone arm in antiretroviral combination therapy studies will not answer the question of which regimen (AZT/ddI or ddI alone) being tested is less toxic. Women interested in ACTG 076 are encouraged to call the Project Inform Hotline at 1-800-822-7411 and ask for the Women and AIDS Fact Sheet and PI Perspective, No. 14. A final issue involves problems in accurately dividing adult ddI doses into appropriate doses for children; use of a different dosage form is suggested to solve this problem. Topics: Adolescent; Child; Child, Preschool; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Pregnancy; Pregnancy Complications, Infectious; Quality of Health Care; Zidovudine | 1995 |
CTG studies yield results. AIDS Clinical Trials Group.
NIAID's AIDS Clinical Trials Group (ACTG) has completed several studies and their findings are reported. Findings from two studies, ACTG 081, involving three therapies for pneumonia prevention, and ACTG 981, examining fluconazole for preventing fungal infections, are reported in The New England Journal of Medicine (March 16, 1995). Other studies reviewed include ACTG 152, using AZT alone and in combination in children, and ACTG 204, examining the effectiveness of valacyclovir and two different doses of acyclovir in preventing cytomegalovirus end stage-organ disease and survival extension. Topics: Acyclovir; Child; Clinical Trials as Topic; Cytomegalovirus Infections; Didanosine; Drug Therapy, Combination; Fluconazole; HIV Infections; Humans; Mycoses; Pneumonia, Pneumocystis; Valacyclovir; Valine; Zidovudine | 1995 |
What we know about anti-HIV drugs.
AIDS patients are able to double their life expectancies after diagnosis. Drug treatment, an integral part in creating this improvement in life expectancy, consists of antiretroviral drugs, drugs that treat and prevent opportunistic diseases, and therapies that treat specific symptoms of AIDS, such as wasting or anemia. Five available drugs for treating HIV are AZT (Retrovir), ddI (Videx), ddC (Hivid), d4T (Zerit), and 3TC (lamivudine). Findings from studies for each drug in such areas as the drug's purpose, dosage level, effectiveness, and side effects are examined. Topics: Antiviral Agents; Didanosine; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; RNA, Viral; Stavudine; Zalcitabine; Zidovudine | 1995 |
Combination treatment and single drugs: interview with Margaret Poscher, M.D. Interview by John S. James.
Margaret Poscher, M.D., Assistant Clinical Professor at the University of California Medical Center, and Director of HIV Clinical Services at the University of California Mt. Zion, speaks favorably about combination antiretroviral therapy for HIV disease. She foresees AZT plus 3TC as being used as initial therapy, when 3TC is approved, for patients who have CD4 counts below 500, or have a certain threshold level of HIV RNA. Individuals with high levels of HIV RNA are more likely candidates for triple combination therapy. Viral load can be used as an indicator to determine which patients are the best candidates for which treatments. Dr. Poscher has seen many changes in CD4 count and viral load when different combination therapies are used. For example, with the combination of d4T and 3TC, Dr. Poscher has seen at least one long, ten-fold, viral load reduction--and when the RNA goes down, the CD4 count goes up. Dr. Poscher suggests using low doses of the antiretrovirals to minimize side effects. Topics: Acyclovir; Administration, Oral; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ganciclovir; HIV Infections; Humans; Lamivudine; Stavudine; Zalcitabine; Zidovudine | 1995 |
Antiretroviral drug resistance.
The clinical significance and public health implications for HIV pathogenesis due to resistance to antiretroviral agents, such as AZT, ddI, ddC, d4T, 3TC, are discussed. Several studies are highlighted, showing that AZT resistance is associated with more rapid clinical progression and death. AZT-resistant viruses are quite tough, and once established, become the dominant circulating quasi-species. Other studies show that the clinical significance of resistance to the dideoxynucleosides (ddI, ddC, d4T, and 3TC) remains incompletely understood. The article notes that, despite widespread clinical practice of using combination treatment regimens, no study has proven that combination therapy delays HIV disease progression or death over the long term. Public health considerations include the proven problem of human- to-human transmission of AZT-resistant HIV. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; RNA, Viral; Stavudine; Viremia; Zalcitabine; Zidovudine | 1995 |
Update on clinical trials of combination therapies for HIV infection.
A list is provided of open trials of combination therapies underway at sites of the AIDS Clinical Trials Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Most trials are open to new patients or are expected to open shortly. Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Child; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; Lamivudine; RNA-Directed DNA Polymerase; Stavudine; Zalcitabine; Zidovudine | 1995 |
Researchers are rethinking role of AZT in drug therapy.
The National Institute of Allergy and Infectious Diseases (NIAID) is reconsidering whether AZT should remain the drug of first choice for the treatment of HIV. The September 14 decision to hold a meeting on the matter is based on preliminary evidence from a NIAID-funded study showing that the drug didanosine, or ddI, is considerably more effective than AZT in treating asymptomatic HIV. The study, AIDS Clinical Trial Group 175, also found AZT used alone to be less effective than combinations of AZT with ddI or zalcitabine (ddC). The death rate for patients taking ddI alone was 5 percent over 147 weeks, 10 percent for those only taking AZT, and 9 percent for those taking ddC and AZT. For AZT naive patients, AZT administered alone did not perform as well in promoting survival and slowing progression to AIDS, compared to those who took ddI alone, or a combination of AZT and either ddI or ddC. NIAID Director, Anthony S. Fauci, said he will ask independent experts to assess the results of the study and two similar studies, CPCRA 007 and the DELTA trial, which evaluated patients with CD4 T-cell counts of less than 200 and less than 350, respectively. For now, Glaxo-Wellcome's AZT remains the drug most recommended for HIV treatment, with ddI and ddC as a second line of defense. AZT's effectiveness was also questioned recently when the AIDS Clinical Trials Group 019 found no clinical benefit from the drug for those who had been infected for some time but had CD4 counts in excess of 500. Topics: Antiviral Agents; CD4 Lymphocyte Count; Didanosine; HIV Infections; Humans; United States; Zidovudine | 1995 |
Update on HIV protease inhibitors.
When HIV replicates, it forms large precursor proteins that are cleaved and processed by HIV protease to generate smaller viral proteins. HIV protease inhibitors interfere with this process, causing viral particles that are formed to be structurally disorganized, nonfunctional, and non-infectious. All of the HIV protease inhibitors in clinical trials, or nearing clinical development, are active against HIV-1 and HIV-2 at nanomolar concentrations, require no intracellular processing for activation, and are effective both in acutely and chronically infected cells. However, two pharmacokinetic problems have been identified: suboptimal oral bioavailability of peptidic inhibitors; and reduced cellular uptake of inhibitor that has become bound to alpha-acid glycoprotein. Three of the ten aforementioned protease inhibitors are in advanced development: saquinavir (Ro-31 8959), indinavir (MK-639), and ritonavir (ABT-538). Saquinavir has been extensively tested. It increases CD4 cell counts, reduces viral load, and its effects are magnified when administered in combination with AZT and ddC. Saquinavir recently entered accelerated approval procedures in the United States. Indinavir, an orally bioavailable protease inhibitor, engenders viral resistance after 12-24 weeks when administered at low doses, but higher doses may produce sustained effects lasting 52 weeks. Ritonavir, like indinavir, is an orally bioavailable protease inhibitor that is effective for a short time before viral mutants emerge. The emergence of resistance is the greatest problem with protease inhibitors. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Design; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Phosphorylation; Pyridines; Quinolines; Ritonavir; Saquinavir; Substrate Specificity; Thiazoles; Valine; Zalcitabine; Zidovudine | 1995 |
Protease inhibitors and prevention of cross resistance.
A controversy has developed, initiated by a paper in the April 1995 issue of Nature, over the use of protease inhibitors among AIDS patients. The article, written by Jon Condra and Emilio Emini, reported that HIV developed resistance to indinavir (Merck & Co.'s protease inhibitor), and all other protease inhibitors as well. In response to the study on Merck's product, Roche released information suggesting that their protease inhibitor, saquinavir, does not cause resistance nearly as quickly or as much. Merck is currently studying the combination of indinavir and AZT, and Abbott Laboratories is examining the effects of AZT, ddC, and ritonavir. These studies imply that optimal multi-drug combination therapy should delay drug resistance as well as cross-resistance. The implications are promising for patients with HIV and AIDS. Pharmaceutical companies are conducting additional studies to develop new reverse transcriptase inhibitors and to determine the effectiveness of the combination of two or more protease inhibitors. Each drug trial demonstrates the relationship between dosing and resistance; patients are advised to adhere completely to dosing instructions. Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Carbamates; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Lamivudine; Nelfinavir; Pyridines; Quinolines; Saquinavir; Sulfonamides; Zalcitabine; Zidovudine | 1995 |
New data intensifies interest in hydroxyurea.
Newly publicized trial data are showing that hydroxyurea has strong anti-HIV activity, especially when combined with ddI, which has led to the opening of new trials testing the hydroxyurea/ddI combination. Hydroxyurea's purported mechanism of action against HIV is to inhibit a cellular enzyme, ribonucleotide reductase, that is essential for creating the special nucleotide units needed to form DNA. With fewer natural DNA nucleotides present, HIV's reverse transcriptase enzyme may be more likely to incorporate nucleoside analog compounds, such as AZT or ddI, into the DNA it is creating from HIV's RNA gene template. These nucleoside analogs are defective versions of the natural building blocks and force the viral DNA chain under construction to terminate prematurely. Additional information from various studies and new trials opening in the U.S. and abroad are provided. Topics: Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Hydroxyurea; Mutation; Ribonucleotide Reductases | 1995 |
Closing the circle on HIV--or not.
Developments on antiretroviral therapies for HIV infection from the 1995 Conference on Antimicrobial Agents and Chemotherapy are presented. Drug companies' investigative results concerning their protease inhibitors are discussed, followed by reviews of the ACTG 175 and Delta study results. Particular attention is given to AZT mono and combination therapy issues. Early viral marker data from ACTG 175, the value of combined marker data, vaccines and herpes episodes boosting HIV RNA, and the issue of when and how to do routine viral load testing are demonstrated. Information showing greater benefits of therapy in well-controlled clinical trials is provided, and a brief history of viral suppression is outlined. Topics: Antiviral Agents; Biomarkers; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Interleukin-2; Nelfinavir; Prognosis; RNA, Viral; Zalcitabine; Zidovudine | 1995 |
Review of viral load and combination therapy data from 35th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy.
Research on HIV viral loads and combination therapy was presented at the 35th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Research has shown that ten billion HIV particles are produced daily in an infected individual's body. The HIV particles live freely for about eight hours before infecting CD4 cells, which live for 2.2 days before dying. The virus replicates in about 1.2 days. This is a faster rate of replication than previously thought. The specific proteins needed for cytotoxic lymphocytes to recognize an infected CD4 cell may not be available with so many viral mutations constantly occurring. Combination therapies are believed to decrease drug-resistant strains of HIV by reducing replication and by increasing the number of mutation sites needed for new HIV virions to be produced. A research study, ACTG 175, compared four treatments: zidovudine (ZDV) alone, ddI alone, ZDV plus ddI, and ZDV plus ddC. The results showed that ZDV alone was the least effective treatment, even when it was the initial treatment. ZDV plus ddI was the most effective for people who had previously taken ZDV, and ZDV plus ddC was the most effective for ZDV-naive participants. Delta, a European and Australian trial, reported similar results. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Mutation; RNA, Viral; Zidovudine | 1995 |
Combination therapy increases survival.
A review is provided of Delta and ACTG 175 studies which addressed the use of combination therapies involving AZT. Many researchers and doctors believe the Delta study yielded the most reliable proof of the efficacy of combination therapy versus monotherapy with AZT. Results of the ACTG 175 trial are less reliable because over half of the participants dropped out. Overall, the Delta study shows that those who had T cells between 50 and 350 all benefitted from combination therapy even if they already had symptoms or an AIDS diagnosis; ACTG 175 also showed benefits of combination therapy. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Stavudine; Zalcitabine; Zidovudine | 1995 |
Benefits of combination therapy confirmed.
Two large studies, Delta and ACTG 175, comparing single drug antiviral treatment to combination therapy, are discussed. Three tables supply data showing mortality rates between patients receiving AZT monotherapy and AZT plus either ddI or ddC, and ddI monotherapy. All the combination therapies show lower mortality rates than AZT monotherapy. Based on these results, AZT monotherapy as a standard of practice should not continue. Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Treatment Failure; Zalcitabine; Zidovudine | 1995 |
Hydroxyurea, a potential new anti-HIV agent.
Published evidence from the U.S. and Europe supports the effect of the anticancer drug hydroxyurea against HIV-1, and its potential synergistic effect with ddl. Approved as an oral chemotherapeutic agent for leukemia and other cancers, hydroxyurea acts as a radical free quencher, inhibiting the cellular enzyme ribonucleotide reductase as well as cellular DNA synthesis during the S phase of the cell division, and it may be through this mechanism that hydroxyurea inhibits tumor cell growth. French scientists at the Centre Leon Bernard in Lyon tested hydroxyurea and a related compound, D-aspartic acid beta-hydroxamate alone and in combination with AZT, ddl, or ddC. Total suppression of viral production and total production against the toxic effects induced by viral replication were demonstrated using the combination of either of the two hydroxamates and ddl after 14 days. In test tube experiments conducted at the National Cancer Institute, both hydroxyurea and ddl inhibited or delayed HIV replication in a dose-dependent manner; in combination, they blocked HIV replication by more than 99.9 percent. Topics: Didanosine; DNA Replication; Drug Therapy, Combination; HIV; HIV Infections; Humans; Hydroxyurea; Leukocytes, Mononuclear; Virus Replication; Zalcitabine; Zidovudine | 1995 |
Antiretroviral therapy for adults and children.
Four antiretroviral drugs, ZDV, ddI, ddC, and d4T, have been approved for monotherapy, and ddC is approved in combination with ZDV to treat people with advanced HIV disease. Research shows that there is no period of virologic latency in HIV infection, and rapid viral replication occurs during both asymptomatic and symptomatic stages of the disease, leading to rapid destruction of CD4 cells. Early intervention with antiretrovirals is suggested, balanced to achieve maximum virucidal effect while minimizing resistance. Use of each of the four drugs is discussed. Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Didanosine; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Primary Health Care; Stavudine; Viral Load; Zalcitabine; Zidovudine | 1995 |
A cost analysis of approved antiretroviral strategies in persons with advanced human immunodeficiency virus disease and zidovudine intolerance.
Treatment with zidovudine has been standard therapy for patients with advanced HIV infection, but intolerance is common. Previously, management of intolerance has consisted of symptomatic therapy, dose interruption/discontinuation, and, when appropriate, transfusion. The availability of new antiretroviral agents such as didanosine as well as adjunctive recombinant hematopoietic growth factors makes additional strategies possible for the zidovudine-intolerant patient. Because all of these agents are costly, we evaluated the cost implications of these various strategies for the management of zidovudine-intolerant individuals within a population of persons with advanced HIV disease. We performed a decision analysis using iterative algorithmic models of 1 year of antiretroviral care under various strategies. The real costs providing antiretroviral therapy were estimated by deflating medical center charges by specific Medi-Cal (Medicaid) charge-to-payment ratios. Clinical data were extracted from the medical literature, product package inserts, investigator updates, and personal communications. Sensitivity analysis was used to test the effect of error in the estimation of parameters. The models predict that a strategy of dose interruption and transfusion for zidovudine intolerance will provide an average of 46 weeks of therapy per year to the average patient at a cost of $5,555/year of therapy provided (1991 U.S. dollars). The models predict that a strategy of adding hematopoietic growth factors to the regimen of appropriate patients would increase the average amount of therapy provided to the average patient by 3 weeks (6%) and the costs attributable to therapy by 77% to $9,805/year of therapy provided.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Acquired Immunodeficiency Syndrome; Agranulocytosis; Algorithms; Anemia; Costs and Cost Analysis; Decision Support Techniques; Didanosine; Erythrocyte Transfusion; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; HIV Infections; Humans; Pancreatitis; Quality of Life; Zidovudine | 1994 |
Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy.
To determine the frequency and pattern of development of specific drug resistance mutations for human immunodeficiency virus (HIV) reverse transcriptase in patients switched from zidovudine to didanosine therapy and to examine the relation of the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene to CD4+ T-cell changes and virus burden.. Retrospective analysis of all patients enrolled at Stanford University in protocols where patients were switched from zidovudine to didanosine monotherapy.. A university hospital.. 64 patients infected with HIV who were switched from zidovudine to didanosine monotherapy. Patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex, or were asymptomatic (mean [+/- SD] starting CD4+ T-cell count of 129 +/- 88 cells/mm3).. Serial serum specimens were tested for the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene and for a zidovudine resistance mutation at codon 215 using selective polymerase chain reactions (PCR). Serum HIV RNA levels were determined by quantitative PCR. CD4+ T-cell counts were determined at serial time points.. By 24 weeks of didanosine therapy, the proportion of patients with the didanosine resistance mutation at codon 74 increased from 0% to 56% (36 of 64). In contrast, the proportion of patients with the zidovudine resistance mutation at codon 215 decreased from 84% at the start to 59% after 24 weeks of didanosine therapy (a 25% decrease, 95% lower CI, 15%; P < 0.0001). Patients who developed the codon 74 mutation had a greater decrease in CD4+ T cells after the development of the mutation than did patients without the mutation (P < 0.001). In addition, after 24 weeks of didanosine, patients who developed the codon 74 mutation had a greater serum HIV RNA burden than patients who remained wild type (did not have the mutation) at codon 74 (225,000 compared with 82,400 HIV RNA copies/mL serum; P = 0.01).. Among patients infected with HIV who had advanced disease and were switched from zidovudine to didanosine therapy, more than one half developed the didanosine resistance mutation at codon 74 by 24 weeks of didanosine therapy. Patients who developed the codon 74 mutation had a greater decline in CD4+ T cells after the development of the mutation and had a greater serum virus burden than did patients without the codon 74 mutation. Topics: CD4-Positive T-Lymphocytes; Codon; Didanosine; Drug Resistance, Microbial; Genes, Viral; HIV; HIV Infections; Humans; Leukocyte Count; Mutation; Retrospective Studies; RNA-Directed DNA Polymerase; RNA, Viral; Zidovudine | 1994 |
Safety profile of didanosine among patients with advanced HIV disease who are intolerant to or deteriorate despite zidovudine therapy: results of the Canadian Open ddI Treatment Program.
The aim of this study was to ascertain the safety profile of didanosine (Videx; ddI) within the Canadian Open Treatment Program. Symptomatic HIV+ subjects with AIDS or ARC or CD4 < 200/mm3 were eligible to receive didanosine if they were either (a) intolerant to zidovudine (Retrovir, ZDV) or (b) deteriorating despite ZDV therapy. The dose of didanosine (powder formulation) was based on body weight as follows: > or = 75 kg, 375 mg b.i.d.; 50-74 kg, 250 mg b.i.d.; 35-49 kg, 167 mg b.i.d. Participants were monitored with physical examinations and prespecified laboratory studies by their treating physicians on a monthly basis. Follow-up data were collected in a central database through five regional coordinators. A total of 168 physicians across Canada participated in the program, and 825 subjects who started didanosine after July 1, 1990, were included in the analysis. Of these, 97% were male, 88% homosexual, and 59% had a prior diagnosis of AIDS. Reasons for enrolling was ZDV intolerance in 39%, failure in 25%, both in 32%, and other in 4%. Data were prospectively collected until July 31, 1991. Total follow-up was 3,440 patient-months and median follow-up was 4.3 months. A total of 78 deaths were reported, 44 of which occurred within a month after the last dose of didanosine. Causes of death included AIDS-related unspecified causes (13 patients), MAC (11), wasting (7), AIDS-related CNS involvement other than OI's (7), Kaposi's sarcoma (7), Pneumocystis carinii pneumonia (6), sudden death, including suicides and accidents (6), lymphoma (5), toxoplasmosis (4), cryptococcosis (4), cytomegalovirus (3), unspecified causes (2), tuberculosis (1), PML (1), and disseminated histoplasmosis (1). Didanosine was discontinued in 140 (17%) subjects during the study period due to adverse events.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Adult; Amylases; Cause of Death; Cohort Studies; Didanosine; Drug Evaluation; Female; Follow-Up Studies; HIV Infections; Humans; Male; Pancreatitis; Peripheral Nervous System Diseases; Prospective Studies; Risk Factors; Safety; Survival Analysis; Treatment Failure; Zidovudine | 1994 |
[Anti-HIV-therapy. Monotherapy with drugs delaying the course of the disease has limited effect].
Topics: Acquired Immunodeficiency Syndrome; Didanosine; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; Humans; Palliative Care; Zalcitabine; Zidovudine | 1994 |
Chemotherapeutic options in HIV infection.
Topics: Analysis of Variance; Antiviral Agents; Biotransformation; Cell Line; Cells, Cultured; Chromatography, High Pressure Liquid; Didanosine; Drug Interactions; HIV Infections; HIV Seropositivity; HIV-1; Humans; Lymphocytes; Microbial Sensitivity Tests; Tumor Cells, Cultured; Zidovudine | 1994 |
Identification of drug-related genotypic changes in HIV-1 from serum using the selective polymerase chain reaction.
We attempted to detect drug-related HIV-1 pol gene mutations by selective polymerase chain reaction (PCR) using both proviral DNA and viral RNA isolated from patients (pts) with AIDS or ARC receiving antiretroviral therapy. Peripheral blood mononuclear cell (PBM)-associated proviral DNA and serum-derived viral RNA were obtained from eight patients before and after receiving an alternating regimen of AZT and ddC for 15-41 months or ddI monotherapy for 12-26 months. These specimens were examined for the presence of mutations at positions 70, 74, 215 and 219. We noted that selective PCR results can be ambiguous depending on the quantity of DNA template employed. We, therefore, used the minimal quantity of DNA templates that yielded evaluable PCR products in this study. For all the eight pairs of pre- and post-therapy proviral DNA samples, selective PCR results agreed with independently determined nucleotide sequences. Results of reverse transcription of serum-derived viral RNA followed by selective PCR differed in some cases from those using the proviral DNA. In particular, the use of serum viral RNA appeared to allow earlier detection of changes in drug-related mutations than the use of PBM-associated proviral DNA. We conclude that (i) selective PCR using the minimum and sufficient number of PBM-associated proviral DNA and serum viral RNA copies successfully detects the presence of known pol gene mutations; (ii) drug-related mutations may be distinguished earlier in virions in serum (or plasma) than in proviral DNA in PBM; and (iii) quantification of HIV-1 prior to selective PCR may be an important component in monitoring the therapy of HIV-1 infection. Topics: Antiviral Agents; Base Sequence; Didanosine; DNA Primers; DNA, Viral; Efficiency; Evaluation Studies as Topic; Genes, pol; Genotype; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Proviruses; Reproducibility of Results; RNA, Viral; Sensitivity and Specificity; Templates, Genetic; Virion; Zalcitabine; Zidovudine | 1994 |
Synergistic effect of recombinant CD4-immunoglobulin in combination with azidothymidine, dideoxyinosine and 0.5 beta-monoclonal antibody on human immunodeficiency virus infection in vitro.
Data are presented which indicate that combinations of rCD4 immunoglobulin with azidothymidine, dideoxyinosine or 0.5 beta mouse monoclonal antibodies directed against the V3 region of HIV-1, were more effective in treatment of acute HIV infection in vitro than each compound alone. It is suggested that combination therapy with these compounds is more beneficial in treatment of HIV-infected patients than monotherapy, especially with respect to a reduction of the known side effects and the formation of resistant HIV strains after treatment with nucleoside analogues. Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; CD4 Immunoadhesins; Cells, Cultured; Didanosine; Drug Synergism; Drug Therapy, Combination; HIV Infections; Humans; Lymphocytes; Zidovudine | 1994 |
Transient insulin-dependent diabetes mellitus in an HIV-infected patient receiving didanosine.
Topics: Diabetes Mellitus, Type 1; Didanosine; HIV Infections; HIV-1; Humans; Male; Middle Aged; Time Factors | 1994 |
Stabilities of quantitative plasma culture for human immunodeficiency virus, RNA, and p24 antigen from samples collected in VACUTAINER CPT and standard VACUTAINER tubes.
We evaluated the stability of human immunodeficiency virus (HIV) load markers from blood samples collected in VACUTAINER CPT or standard VACUTAINER brand tubes using sodium heparin or sodium citrate as anticoagulants. Quantitative plasma culture and p24 antigen concentrations were determined, and HIV RNA levels in plasma were measured by both reverse transcription-PCR-enzyme-linked immunosorbent assay (RT-PCR-ELISA) and branched DNA methods. All tubes were stored at room temperature for analysis at 2, 24, 48, and 72 h after the blood samples were drawn. No difference was seen between tube types with respect to the HIV titer in plasma or the positivity rate for all samples that demonstrated a fall in titer over time. Unbound p24 antigen levels in plasma decreased during the initial 48-h period in both tube types. Immune complex-dissociated p24 antigen levels decreased in CPT tubes but not in standard VACUTAINER tubes. The HIV RNA copy number in plasma measured by RT-PCR-ELISA was stable in most subjects and was significantly higher in CPT tubes than in standard VACUTAINER tubes at 24 and 72 h after the blood samples were drawn. The branched DNA probe assay detected a significant decline in HIV RNA equivalent in plasma over 72 h in both collection tubes, the decline being more dramatic in the standard VACUTAINER tube than the CPT tube. Overall, interday variability suggests that samples collected for a particular assay should be processed at the same time after blood is drawn and that a particular tube type be used throughout a given study. Topics: Anticoagulants; Blood Specimen Collection; CD4 Lymphocyte Count; Culture Media; Didanosine; DNA, Viral; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; False Negative Reactions; Gels; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Polyesters; Polymerase Chain Reaction; Predictive Value of Tests; RNA, Viral; Severity of Illness Index; Specimen Handling; Viremia; Virus Cultivation; Zidovudine | 1994 |
Antiretroviral therapy in HIV-infected adults. Which regimens are recommended?
The current status of antiretroviral therapy is in a state of flux. Clinical and immunologic benefit of antiretroviral treatment has been demonstrated, but the duration of benefit is finite and the effect on survival uncertain. Failure of antiretroviral treatment is closely associated with development of drug resistance. Strategies that may improve treatment outcome include combining or cycling antiretroviral agents. Given the current uncertainties in antiretroviral therapy, patients should be actively involved in treatment decisions. Topics: Adult; CD4-Positive T-Lymphocytes; Didanosine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; HIV Infections; Humans; Leukocyte Count; Zalcitabine; Zidovudine | 1994 |
Quantitation of human immunodeficiency virus by culture and polymerase chain reaction in response to didanosine after long-term therapy with zidovudine.
Measurements of human immunodeficiency virus by quantitative RNA and DNA polymerase chain reaction (PCR), cell and plasma infectivity dilution cultures, and immune complex-disassociated p24 antigen-capture ELISA were made repeatedly in 10 subjects receiving long-term zidovudine treatment before and after therapy was changed to didanosine. Comparison of baseline assays showed that quantitative cell cultures, plasma RNA, and proviral DNA were measurable in all subjects and that cell culture results were significantly correlated with measures of nucleic acids. Plasma viremia (as indicated by culture) and p24 antigen were detected in three measurements in 3 of 8 and 6 of 10 subjects, respectively. Significant decreases in plasma RNA and cell dilution cultures from baseline were maintained for up to 6 months after initiation of didanosine therapy. These findings demonstrate a decrease in virus burden with the use of didanosine; however, continued detection of plasma RNA suggests that additional antiviral therapy will be required to suppress viral replication. Topics: Adult; CD4-Positive T-Lymphocytes; Didanosine; DNA, Viral; HIV Core Protein p24; HIV Infections; HIV Seropositivity; Humans; Leukocyte Count; Middle Aged; Polymerase Chain Reaction; Proviruses; RNA, Viral; Time Factors; Zidovudine | 1994 |
Dynamics of molecular parameters of human immunodeficiency virus type 1 activity in vivo.
The dynamics of viral activity during different phases of human immunodeficiency virus type 1 (HIV-1) infection were investigated by competitive PCR methods. In particular, we studied the time course of three quantitative molecular parameters of viral activity (genomic RNA copy number in plasma and provirus and late HIV-1 transcript molecule copy numbers in peripheral blood CD4+ T lymphocytes) in untreated patients and patients treated with specific anti-HIV-1 compounds. The results shown here indicate that direct RNA parameters are quantitative molecular indices sensitive enough to be used for a more accurate evaluation of the natural history of this infection and that an indirect parameter, the mean transcriptional activity for each provirus in CD4+ T lymphocytes, may be important in studying this infection in vivo at the molecular level. A dramatic decrease of the indices was evident at seroconversion, but the quantitative values were virtually stable throughout the time the untreated patients were studied during the clinical latency phase. Furthermore, the results indicate that an early response to antiretroviral compounds is detected in most subjects as a decrease in the viral activity level. Topics: Acquired Immunodeficiency Syndrome; Adult; CD4-Positive T-Lymphocytes; Didanosine; Female; HIV Infections; HIV Seropositivity; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Polymerase Chain Reaction; Proviruses; RNA, Viral; Time Factors; Transcription, Genetic; Zidovudine | 1994 |
Quasispecies dynamics and the emergence of drug resistance during zidovudine therapy of HIV infection.
To investigate the roles of mutation, competition and population dynamics in the emergence of drug resistant mutants during zidovudine therapy.. A mathematical model of the population dynamics of the viral quasispecies during zidovudine therapy was investigated.. The model was used to simulate changes in the numbers of uninfected and infected cells and the composition of the viral quasispecies in the years following initiation of therapy. Resulting scenarios in asymptomatic and AIDS patients were compared. The model was also used to investigate the efficacy of a treatment regimen involving alternating zidovudine and dideoxyinosine therapy.. The behaviour of the model can be divided into three stages. Before therapy, mutation maintains a small pool of resistant mutants, outcompeted to very low levels by sensitive strains. When therapy begins there is a dramatic fall in the total viral load and resistant strains suddenly have the competitive advantage. Thus, it is resistant strains that infect the rising number of uninfected CD4+ cells. During this second stage the rapid effects of population dynamics swamp any effects of mutation between strains. When the populations of infected and uninfected cells approach their treatment equilibrium levels, mutation again becomes important in the slow generation of highly resistant strains.. The short-term reduction in viral replication at the initiation of therapy generates a pool of uninfected cells which cause the eventual increase in viral burden. This increase is associated with (but not caused by) a rise in frequency of resistant strains which are at a competitive advantage in the presence of the drug. When therapy is ceased, reversion of resistance is slow as resistant strains are nearly as fit as sensitive strains in the absence of drug. Topics: CD4-Positive T-Lymphocytes; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Genes, pol; HIV; HIV Infections; Humans; Leukocyte Count; Models, Biological; Mutation; Population Dynamics; Species Specificity; Virus Replication; Zidovudine | 1994 |
Lower socioeconomic status and shorter survival following HIV infection.
We studied the association between socioeconomic status and survival in a prospective study of 364 HIV-infected homosexual men who were recruited during 1982-84. The participants were divided by annual income; those earning above Canadian $10,000 (high-income; n = 274) and those below $10,000 (low-income; n = 90) at recruitment. The latter threshold closely approximated to the poverty level for this population. Low income men were significantly younger than high income men but the groups were similar with respect to baseline CD4 counts, subsequent use of anti-retrovirals and prophylaxis against Pneumocystis carinii pneumonia (PCP), and number of visits attended during follow-up. Subjects were followed for a median of 9.5 years (range 1.8-13.1). By Dec 31, 1993, there were 135 deaths yielding a cumulative mortality rate of mean 45% (SD 4.0) at 11.5 years. Men aged 30 or more at infection had poorer survival than those under 30 (mortality risk ratio 1.56; 95% CI 1.09-2.24; p = 0.015), and longer survival was significantly associated with a higher CD4 count at the earliest seropositive visit. The age-adjusted mortality risk ratio for low income men compared with high income men was significantly increased at 1.63 (95% CI 1.11-2.40; p = 0.013). The significant risk of death for low income men persisted despite adjustment for age at infection, CD4 count, use of zidovudine, dideoxyinosine, and dideoxycytidine, use of PCP prophylaxis, and year of infection. We cannot attribute our findings to income loss as a result of more rapid HIV progression because the same effect was present in people who provided income data before seroconversion. Similarly, our findings are not due to differential access to care because the study was done within the context of a universal health care system, and the two income groups received treatments equally. This finding is consistent with the association of lower socioeconomic status with increased morbidity and mortality observed within large populations and in other diseases. Topics: Acquired Immunodeficiency Syndrome; Adult; British Columbia; CD4 Lymphocyte Count; Cohort Studies; Didanosine; Health Services; HIV Infections; HIV Seropositivity; Homosexuality, Male; Humans; Income; Male; Pneumonia, Pneumocystis; Regression Analysis; Socioeconomic Factors; Survival Rate; Zalcitabine; Zidovudine | 1994 |
[HIV infection--current possibilities in antiviral therapy].
Three drugs are currently available to treat HIV infection: zidovudine, didanosine, and zalcitabine. They resemble the natural nucleosides and inhibit retrotranscriptase, an enzyme which transforms HIV's genomic RNA into DNA. Indications for treatment are symptomatic HIV infection and, in asymptomatic patients, moderate immunodeficiency with a CD4-lymphocyte count below 350/mm3. In patients who have not yet received antiviral treatment, zidovudine remains the drug of choice, in spite of its toxicity for the bone marrow, which is particularly problematic in those with advanced immunodeficiency. Unfortunately, HIV develops resistance to zidovudine, and its efficacy wanes after a few months. When that happens, zidovudine may be replaced by didanosine, which is mainly toxic for the pancreas, or by zalcitabine, which causes peripheral neuropathy. A number of drugs are being developed. Among these, nonnucleoside retrotranscriptase inhibitors are well tolerated, but rapid development of resistance is problematic. Resistance seems less of a problem for inhibitors of the viral protease, but biodispensibility of these drugs is poor. Topics: Antiviral Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Pancreatitis; Zalcitabine; Zidovudine | 1994 |
Synergistic anti-human immunodeficiency virus type 1 effect of hydroxamate compounds with 2',3'-dideoxyinosine in infected resting human lymphocytes.
The cellular models generally used in the in vitro evaluation of anti-human immunodeficiency virus compounds are dividing cells. A model constituted by resting lymphocytes may more accurately reflect a drug's future efficacy in humans, since viral DNA synthesis is known to take place in quiescent cells, creating a reservoir of infected cells awaiting activation to complete their viral replication cycle and to produce infectious virions. We report here the activity of 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, and two hydroxamates, D-aspartic acid beta-hydroxamate and hydroxycarbamate (hydroxyurea), alone and in various combinations, in an in vitro model based on resting lymphocytes. In our model, resting peripheral blood lymphocytes were infected with human immunodeficiency virus type 1 and treated with drugs for 7 days, at which time drugs were removed and the cells were activated by phytohemagglutinin. We show that under these conditions 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, and 2',3'-dideoxycytidine, alone or in combination, neither fully inhibit viral production nor protect lymphocytes from the cytopathic effect of viral replication, at concentrations corresponding to the peak plasma levels observed in a typical treatment schedule in humans. In contrast, we report the synergistic effect of treatment by each hydroxamate with 2',3'-dideoxyinosine of infected resting lymphocytes, resulting in the total suppression of viral production, total protection against the cytopathic effect induced by viral replication, and no effect on the ability of the cells to replicate in this cell culture system. Topics: Antiviral Agents; Asparagine; Aspartic Acid; Cell Survival; Cells, Cultured; Didanosine; Drug Synergism; HIV Infections; Humans; Hydroxyurea; In Vitro Techniques; Lymphocyte Activation; Lymphocytes; Virus Replication; Zalcitabine; Zidovudine | 1994 |
A clinicopathologic report of the retinal lesions associated with didanosine.
Didanosine, a purine analogue with antiretroviral activity, is used in the treatment of human immunodeficiency virus disease. Associated toxic effects of didanosine include pancreatitis, peripheral neuropathy, and retinopathy. The retinal lesions associated with didanosine therapy were studied in a 6-year-old girl with acquired immunodeficiency syndrome. Gross examination disclosed multiple well-circumscribed depigmented lesions in the midperipheral retina. Microscopic examination of these lesions showed multiple areas of retinal pigment epithelial (RPE) loss, some surrounded by areas of hypertrophy or hypopigmentation of the RPE. Partial loss of the choriocapillaris and neurosensory retina were also noted in areas of diseased RPE. Transmission electron microscopy showed numerous membranous lamellar inclusions and cytoplasmic bodies in the RPE cells. These data show that didanosine primarily affects the RPE and that the choriocapillaris and overlying neurosensory retina are also dystrophic in areas of RPE loss. Topics: Child, Preschool; Choroid Diseases; Didanosine; Female; HIV Infections; Humans; Hypertrophy; Pigment Epithelium of Eye; Retinal Diseases | 1994 |
MT-2 cell tropism of human immunodeficiency virus type 1 isolates as a marker for response to treatment and development of drug resistance.
The correlation of the tropism of human immunodeficiency virus type 1 (HIV-1) isolates for MT-2 cells with response to zidovudine and didanosine treatment and with development of drug resistance was studied. Patients with MT-2-negative but not MT-2-positive HIV-1 had a significant increase in CD4+ lymphocyte counts during the first 6 months of treatment. In both groups and for both drugs, the rate of CD4+ lymphocyte decline decreased after the start of treatment. MT-2-positive isolates were more likely than MT-2-negative isolates to show reduced sensitivity to zidovudine and didanosine. Because the differences in zidovudine sensitivity were first evident after 12 months of treatment, drug resistance was probably not the cause of poor response early in zidovudine treatment in patients with MT-2-positive HIV-1. Thus, patients with MT-2-positive virus have limited benefit from treatment with single nucleoside analogues. Knowledge of MT-2 cell tropism may be important in clinical trials and for choosing treatments for patients. Topics: Adult; Biomarkers; CD4 Lymphocyte Count; Cell Line; Didanosine; Disease Progression; Drug Resistance, Microbial; Female; HIV Infections; HIV-1; Humans; Male; Prognosis; Virus Replication; Zidovudine | 1994 |
[Current developments in antiviral chemotherapy. Part 4: Foscarnet, zidovudine, didanosine].
Topics: AIDS-Related Opportunistic Infections; Didanosine; Dose-Response Relationship, Drug; Drug Administration Schedule; Foscarnet; Herpesviridae Infections; HIV Infections; Humans; Zidovudine | 1994 |
Hyperosmolar nonketotic diabetic syndrome following treatment of human immunodeficiency virus infection with didanosine.
To determine whether didanosine (DDI), one of the drugs commonly used to treat infection with human immunodeficiency virus (HIV), contributes to the development of diabetes and hyperosmolar nonketotic diabetic syndrome (HNKDS).. One female patient was treated with DDI for infection with HIV during pregnancy. Soon after starting DDI treatment, she developed diabetes, which progressed to HNKDS.. Although not reported in the literature, hyperglycemia following treatment with DDI has been noted in 82 patients and is usually associated with pancreatitis. DDI should be recognized as one of the drugs known to potentially cause diabetes and HNKDS. With the increasing use of DDI and other drugs that cause hyperglycemia, such as pentamidine and dapsone, blood glucose should be monitored frequently in the HIV-infected patients. Topics: Adult; Blood Glucose; Didanosine; Female; HIV Infections; HIV Seropositivity; Humans; Hyperglycemia; Hyperglycemic Hyperosmolar Nonketotic Coma; Monitoring, Physiologic; Pregnancy; Pregnancy Complications, Infectious; Pregnancy in Diabetics; Zidovudine | 1994 |
Effect of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine on establishment of human immunodeficiency virus type 1 infection in cultured CD8+ lymphocytes.
Several groups have shown that peripheral CD8+ lymphocytes can be infected with human immunodeficiency virus type 1 (HIV-1), resulting in noncytopathic infection and persistent production of viral particles. We studied the ability of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) to inhibit the establishment of HIV-1 infection in CD8+ cells that were derived from cultures of peripheral blood lymphocytes exposed to both virus and drug. In situ infection of CD8+ cells was demonstrated by double flow cytometry analysis by using both anti-glycoprotein 120 (anti-gp120) and anti-CD8 monoclonal antibodies. At higher concentrations of drug (e.g., 0.4 microM AZT), the production of viral particles was inhibited for over 2 months, as assessed by p24 antigen levels in the culture medium. We also performed a time course experiment to determine whether HIV-1 infection of CD8+ cells would be affected by treatment of peripheral blood lymphocytes with AZT or ddI for different intervals following exposure to virus. Quantitative PCR revealed that 0.4 microM AZT, added as late as 24 h after infection, interfered with the formation of proviral DNA in CD8+ cells. Both HIV-1 load and the production of progeny virions by CD8+ cells, as monitored by reverse transcriptase activity in culture fluids, were inhibited by both AZT and ddI in a dose-dependent manner. Topics: Antibodies, Monoclonal; Base Sequence; CD8 Antigens; Cells, Cultured; Didanosine; DNA Probes; DNA, Viral; Flow Cytometry; HIV Infections; HIV-1; Humans; Lymphocytes; Molecular Sequence Data; Zidovudine | 1994 |
Clarification of didanosine dosages.
Topics: Adult; Child; Didanosine; HIV Infections; Humans | 1994 |
What to do when zidovudine fails.
Topics: Didanosine; HIV Infections; Humans; Zalcitabine; Zidovudine | 1994 |
Prophylactic zalcitabine and interferon-alpha for a large-bore needlestick exposure to human immunodeficiency virus.
Topics: Adult; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infectious Disease Transmission, Patient-to-Professional; Interferon alpha-2; Interferon-alpha; Needlestick Injuries; Recombinant Proteins; Zalcitabine; Zidovudine | 1994 |
Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy.
We report two cases of fulminant hepatic failure in HIV-1-infected patients treated with didanosine (ddI). Clinical manifestations including vomiting, diarrhoea and dyspnoea were identical in both cases. Biological data mainly revealed hepatic failure and lactic acidosis. Histological examination of liver biopsies showed diffuse microvesicular steatosis. The outcome was fatal in both patients. The only comparable case previously reported (Lai et al., 1991) showed close similarities in the clinical, biological and histological manifestations with microvesicular steatosis. This prompted us to suspect that ddI might be responsible for fulminant hepatitis in all three AIDS patients. This toxic effect may be added to the list of potential adverse events occurring during ddI therapy. Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Aged; AIDS-Related Opportunistic Infections; Didanosine; Hepatic Encephalopathy; HIV Infections; Humans; Male; Middle Aged | 1994 |
Intermittent therapy.
Topics: Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1994 |
Successful treatment of HIV-related thrombocytopenia with didanosine (ddI)
Topics: Adult; Didanosine; HIV Infections; HIV-1; Humans; Immunoglobulins, Intravenous; Male; Platelet Count; Thrombocytopenia | 1994 |
Pharmacotherapy of HIV. APhA Editorial Board on Pharmaceutical Care for Patients with HIV Infection.
Topics: Adult; CD4 Antigens; Didanosine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Male; Pharmaceutical Services; Zalcitabine; Zidovudine | 1994 |
[Therapeutic strategies against HIV: status in 1994 and future prospectives].
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Forecasting; HIV Infections; Humans; Male; Zalcitabine; Zidovudine | 1994 |
Pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine.
To define predictive or contributory risk factors for pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine (ddI), the authors evaluated 95 children, 3 months to 18 years of age, who had received ddI at 60 to 540 mg/m2 per day for a mean of 56 weeks. Pancreatitis developed in 7 patients (7%) but resolved in all upon withdrawal of ddI. Neither age, sex, nor CD4 count at study entry was predictive of pancreatitis, but pancreatitis appeared more likely to develop in hemophiliacs than in other patients (4 of 23 vs 3 of 72). Pancreatitis developed only in patients who received ddI at the highest dose levels (7 of 60 patients who received ddI at a dose > or = 360 mg/m2 per day vs 0 of 35 patients who received < or = 270 mg/m2 per day). Patients in whom pancreatitis developed had received a higher mean daily dose of ddI than patients with normal amylase and lipase levels throughout the study (348 mg/m2 vs 282 mg/m2), but no relationship with the cumulative dose or the duration of ddI therapy was observed. Although a statistically significant relationship between ddI plasma concentration (area under the curve) and pancreatitis was not conclusively demonstrated, as the number of patients in whom pancreatitis actually developed was small, such a relationship may have been obscured.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Adolescent; Alanine Transaminase; Amylases; Aspartate Aminotransferases; Child; Child, Preschool; Didanosine; Dose-Response Relationship, Drug; Female; HIV Infections; Humans; Incidence; Infant; Lipase; Male; Pancreatitis | 1993 |
Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine.
The bisheteroarylpiperazine nonnucleoside reverse transcriptase (RT) inhibitor atevirdine effectively inhibits human immunodeficiency virus type 1 (HIV-1) in vitro. Clinical isolates with a wide range of 50% inhibitory concentrations (IC50s) of zidovudine (IC50, 0.003 to > 2.0 microM) and didanosine (IC50, 0.02 to > 10.0 microM) were inhibited by atevirdine (median IC50, 0.74 microM; range, 0.06-1.60). Cross-resistance to atevirdine in zidovudine- or didanosine-resistant isolates was not observed. Combinations of atevirdine and zidovudine were highly synergistic against zidovudine-resistant clinical isolates of HIV-1. By contrast, these combinations were mostly additive when tested against zidovudine-susceptible isolates. Combinations of atevirdine and didanosine were additive in their effects against both didanosine-susceptible and -resistant isolates. These data suggest that the interaction of atevirdine with HIV-1 RT is different than that of other nonnucleoside RT inhibitors and that combinations of atevirdine and zidovudine may be useful in patients with AIDS who have initially received monotherapy with zidovudine. Topics: Antiviral Agents; Cells, Cultured; Didanosine; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Piperazines; Reverse Transcriptase Inhibitors; Virus Replication; Zidovudine | 1993 |
Effect of resistance on combination chemotherapy for human immunodeficiency virus infection.
The effect of 3 drug combinations (AZT/FLT, AZT/ddI and FLT/ddI) upon the replication of AZT-sensitive and -resistant human immunodeficiency virus (HIV) was studied. The 3 combinations synergistically inhibited drug sensitive virus. However, AZT resistant virus showed an altered response to the combinations containing AZT: synergy was replaced by addition or antagonism. Thus, the susceptibility to a drug may affect the synergistic effect of combinations containing that drug. Other drug combinations may not be affected, since the AZT resistant virus retained a synergistic response to the combination of FLT/ddI. The synergistic effect could be regained upon reversion of resistance; a viral isolate taken after cessation of therapy, which had reverted to sensitivity to AZT, regained the synergistic response to drug combinations containing AZT. These results have implications for the use of combination chemotherapy to treat infection with HIV. Drug combinations will be most useful if the virus is sensitive to all components in the combination. It might be preferable to avoid the inclusion in combinations of drugs to which there is resistance, since we saw an antagonistic effect for combinations containing AZT in AZT resistant virus. Other combinations not containing the drug to which resistance has arisen may maintain their synergistic effect and remain good choices. Thus, a strategy of monitoring drug sensitivity and altering the combination therapy accordingly would appear to offer promise for the treatment of HIV infection. Topics: Antiviral Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; RNA-Directed DNA Polymerase; Virus Replication; Zidovudine | 1993 |
[Use of an apoptosis test in the biological follow up of patients infected with HIV].
Among biological parameters, spontaneous apoptosis has been studied in lymphocyte culture of HIV seropositive patients. Apoptosis seems to be related with CD4+ deletion. Topics: Apoptosis; CD4 Lymphocyte Count; Cells, Cultured; Didanosine; HIV Infections; Humans; Lymphocytes; Zidovudine | 1993 |
Does drug interaction cause failure of PCP prophylaxis with dapsone?
Topics: Dapsone; Didanosine; Drug Interactions; HIV Infections; Humans; Pneumonia, Pneumocystis; Retrospective Studies; Rifampin | 1993 |
Use of didanosine in zidovudine-intolerant patients infected with human immunodeficiency virus.
One hundred fifty-one patients who were positive for antibody to human immunodeficiency virus (HIV) and intolerant of zidovudine received oral didanosine at a dose adjusted by weight to a maximum of 12.5 mg/(kg.d). After 1 year of follow-up, 49 patients were still receiving didanosine; 19 had died during therapy and 23 thereafter. Therapy had been discontinued in 10 cases because of continued deterioration in health and in the remainder because of adverse reactions. Only 11 of 38 patients with positive results in an ELISA for p24 antigen before therapy had a significant reduction in titer. CD4 lymphocyte subset counts were more likely to rise for patients who had only constitutional disease due to HIV than for those with AIDS. Eleven percent of treated patients gained > 2.5 kg. Diarrhea was the commonest side effect, occurring in 60% of cases. Pancreatitis developed in six cases (with two deaths) and asymptomatic hyperamylasemia in 13. Seven patients developed glucose tolerance in the diabetic range. Peripheral neuropathy was documented in 12 instances but was reversible on cessation of therapy in six. Topics: CD4-Positive T-Lymphocytes; Didanosine; HIV Core Protein p24; HIV Infections; Humans; Leukocyte Count; Male; Zidovudine | 1993 |
Didanosine and ACTG 116A.
Topics: Didanosine; HIV Infections; Humans; Zidovudine | 1993 |
Measurement of HIV virus load and genotypic resistance by gene amplification in asymptomatic subjects treated with combination therapy.
Quantification of viral load in HIV disease has become increasingly important as a marker of antiviral efficacy. We applied gene amplification techniques in vivo to asses antiretroviral activity of combination therapy. Five HIV-infected subjects, four of whom were drug naive, were administered combination therapy with zidovudine (ZDV) and didanosine (ddI). Plasma and peripheral blood mononuclear cells (PBMC) were obtained twice at baseline and then at 1, 3, 6, 9, and 12 months after the initiation of therapy. Results show that plasma HIV RNA copy number fell from 2,170 +/- 660/ml to undetectable at 1 month, with continued suppression at 12 months. HIV proviral DNA copy number decreased from 3.9 to 3.0 log10/10(6) CD4+ T cells at 12 months. Cell dilution cultures were positive in 4 of 5 subjects at baseline and in only 1 of 5 after 12 months. CD4+ T-cell count increased from 390 +/- 30/mm3 pretherapy, to 505 +/- 66/mm3 after 6 months of therapy, but returned to baseline levels after 12 months of therapy. No mutations were detected from PBMC DNA for codon 215 and 74 in the HIV pol gene from the drug-naive subjects. These findings suggest that gene amplification techniques can be used to study changes in viral load or genotype and can be applied in real time to samples from patients involved in clinical trials. Topics: CD4-Positive T-Lymphocytes; Codon; Didanosine; Drug Therapy, Combination; Gene Amplification; Genes, Viral; HIV; HIV Infections; Humans; Leukocyte Count; RNA, Viral; Zidovudine | 1993 |
Quantitation of unintegrated HIV-1 DNA in asymptomatic patients in the presence or absence of antiretroviral therapy.
The objective of this work was to determine the amount of unintegrated human immunodeficiency virus (HIV) DNA (HIV uDNA) in asymptomatic individuals in the presence or absence of antiretroviral therapy. Twenty-one healthy seropositive individuals with no history of any opportunistic infection or previous use of nucleoside antiretrovirals, and 9 similarly asymptomatic individuals who had initiated nucleoside antiretroviral therapy within the last 24 months were studied. All patients had CD4 lymphocyte counts above 400/microliters. All subjects administered antiretrovirals received 400-600 mg of zidovudine daily for 2-24 months. Two individuals additionally received 400 mg of dideoxyinosine (ddI) daily for 4 and 5 months. Patient peripheral blood mononuclear cells (PBMCs) were examined for integrated and unintegrated HIV DNA by a quantitative PCR assay. In addition, CD4 counts were measured, and free and immune complex dissociated p24 antigen was detected in plasma by ELISA. The mean percentage of HIV uDNA in asymptomatic individuals not on therapy was 59%, with 95% confidence limits from 50 to 69%. In contrast, patients on therapy had a mean of only 13% HIV uDNA, with confidence limits from 2 to 25% (p < 0.001). These findings indicate that a significant amount of HIV DNA in infected, healthy patients not on therapy is in the unintegrated form, and that the amount of HIV uDNA in asymptomatic patients on nucleoside therapy is much less. The amount of HIV uDNA in PBMCs deserves further study as a new marker of the efficacy of antiretroviral therapy. Topics: Adult; Antiviral Agents; Biomarkers; CD4-Positive T-Lymphocytes; Didanosine; DNA, Viral; Female; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Leukocyte Count; Male; Middle Aged; Zidovudine | 1993 |
The Concorde trial.
Topics: Didanosine; HIV Infections; Humans; Time Factors; Zidovudine | 1993 |
Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy.
To investigate the occurrence of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy and factors associated with the development of these lymphomas.. The charts of 55 patients with advanced HIV infection receiving zidovudine (formerly known as azidothymidine [AZT])-based therapy and 61 patients receiving dideoxyinosine (ddI) were examined for the occurrence of NHL. Stored samples from the AZT-based treatment cohort were examined retrospectively for parameters predictive of the subsequent development of lymphoma.. Eight of 55 patients receiving AZT-based therapy developed NHL, yielding an estimated probability of 12% (95% confidence interval [CI], 4.7% to 27.1%) after 24 months, and 29.2% (95% CI, 15.2% to 48.7%) after 36 months. Four of 61 patients receiving ddI developed NHL, yielding a 6.2% (95% CI, 2.1% to 17%) estimated probability after 24 months, and 9.5% (95% CI, 3.6% to 22.8%) after 36 months. The difference between these cohorts was not significant (two-tailed P [P2] = .13). Patients with less than 50 CD4 cells/microL developed NHL at a significantly higher rate (P2 = .0085). This was particularly true for patients who presented with primary CNS lymphoma (PCNSL). For patients receiving AZT-based therapy, pretreatment serum interleukin-6 (IL-6) levels were somewhat higher in those who subsequently developed NHL than in those who did not (P2 = .048).. HIV-infected patients with profound immunodeficiency, especially those with less than 50 CD4 cells/microL, are at substantial risk of developing NHL and particularly PCNSL. Additional studies are needed to define the role of other factors such as IL-6 in the pathogenesis of these opportunistic tumors. Topics: CD4-Positive T-Lymphocytes; Didanosine; HIV Infections; Humans; Interleukin-6; Leukocyte Count; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Risk Factors; Zidovudine | 1993 |
The use and toxicity of didanosine.
Topics: CD4-Positive T-Lymphocytes; Didanosine; HIV Infections; Humans; Leukocyte Count | 1993 |
Relationship between anti-p24 antibody levels and p24 antigenemia in HIV-infected patients.
We studied the influence of HIV p24 antigen immune complexing with anti-p24 antibodies on the assessment of their respective levels in HIV-positive sera. ELISAs were used to evaluate anti-p24 antibody levels and p24 antigenemia, with or without acid dissociation. Observations include the following: (1) p24 antigenemia usually coexisted with low anti-p24 levels; (2) the p24 antigen concentration inversely correlated with anti-p24 antibody levels; and (3) acid dissociation increased the percentage of p24 antigen-positive sera, mostly when anti-p24 was low. In contrast, (1) antigenemia and antibodies varied independently in antiretroviral-treated AIDS patients, undetectable p24 antigen coexisting then with low anti-p24; (2) after acid dissociation, antigen was still undetectable in 83% of sera with high antibody levels, and in 20% with low antibody levels; and (3) acid dissociation did not increase low anti-p24 levels. Whereas the first set of observations indicates that p24 antigen and anti-p24 antibodies can be engaged in immune complexes, the second set indicates that p24 antigen and antibodies were not inevitably linked in such complexes: they may actually be indicative of two distinct biological phenomena. Topics: Antigen-Antibody Complex; Didanosine; HIV Antibodies; HIV Core Protein p24; HIV Infections; Humans; Prognosis; Viremia; Zidovudine | 1993 |
Decreased anti-human immunodeficiency virus type-1 activities of 2',3'-dideoxynucleoside analogs in MOLT-4 cell sublines resistant to 2',3'-dideoxynucleoside analogs.
Human T-lymphoid MOLT-4 cells were grown continuously for more than 1 year in medium containing either 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxycytidine (ddC) at concentrations similar to peak plasma levels found in clinical trials in patients with AIDS. To test antiviral activities of the nucleoside analogs against HIV-1 in the cell sublines designated MOLT-4r-AZT, MOLT-4r-ddI and MOLT-4r-ddC, the number of infected cells, p24 HIV-1 antigen in culture medium and syncytium formation of infected cultures were determined. The results showed that anti-HIV-1 activities of AZT, ddI and ddC were significantly decreased in the resistant MOLT-4 cell sublines grown continuously with the respective nucleoside analog, probably due to the development of cell populations resistant to the drugs. Topics: Cell Line; Culture Media; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Microscopy, Electron; Time Factors; Zalcitabine; Zidovudine | 1993 |
[Acral erythema occurring after didanosine (Videx) therapy].
Topics: Adult; Didanosine; Erythema; Foot Dermatoses; Hand Dermatoses; HIV Infections; Humans; Male; Product Surveillance, Postmarketing | 1993 |
[Treatment--medical management of HIV carrier].
Topics: Accidents, Occupational; Adjuvants, Immunologic; AIDS-Related Opportunistic Infections; Animals; Carrier State; Didanosine; Female; HIV Infections; Humans; Immunologic Factors; Male; Needles; Pneumonia, Pneumocystis; Zidovudine | 1993 |
[BRM and drug combination therapy of HIV carriers].
Topics: Carrier State; Cytokines; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Immunologic Factors; Male; Zidovudine | 1993 |
[Early treatment in HIV infection].
Topics: Acquired Immunodeficiency Syndrome; Carrier State; CD4 Antigens; Didanosine; HIV Infections; Humans; Zidovudine | 1993 |
[Treatment by antiviral drugs of HIV-infected patients].
Topics: Acyclovir; Antiviral Agents; Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Interferon-alpha; Zalcitabine; Zidovudine | 1993 |
The use and toxicity of didanosine.
Topics: Didanosine; Drug Administration Schedule; HIV Infections; Humans | 1993 |
Treating HIV infection: what pharmacists need to know.
Topics: Adult; AIDS-Related Opportunistic Infections; Didanosine; Education, Pharmacy, Continuing; Female; HIV Infections; Humans; Male; Middle Aged; Pharmacists; Risk Factors; Zidovudine | 1993 |
HIV-related thrombocytopenia.
Topics: Didanosine; HIV Infections; Humans; Recurrence; Thrombocytopenia; Zidovudine | 1993 |
Metabolism of didanosine (ddI) by erythrocytes: pharmacokinetic implications.
Topics: Didanosine; Erythrocytes; HIV Infections; Humans; Male | 1993 |
Population-based estimates of antiretroviral therapy and anti-Pneumocystis prophylaxis in San Francisco: 1991.
Using data from the San Francisco Men's Health Study and the San Francisco General Hospital Cohort, we derived partially population-based estimates of human immunodeficiency virus (HIV) antiretroviral therapy and Pneumocystis carinii prophylaxis use in HIV-infected men in 1991. Zidovudine, didanosine, and dideoxycytidine were the antiretroviral therapies and aerosolized pentamidine, trimethoprim-sulfamethoxazole, and dapsone were the Pneumocystis prophylaxis evaluated. Among 81 men (29 of whom had AIDS) with < or = 200 CD4 cells, 76 (94%) had ever used and 56 (69%) were currently using an antiretroviral drug; 73 (90%) had ever used and 61 (75%) were currently using Pneumocystis prophylaxis. Among 127 men with 201-499 CD4 cells, 95 (75%) had ever used and 81 (64%) were currently using antiretroviral therapy; 49 (39%) had ever used and 36 (28%) were currently using Pneumocystis prophylaxis. Among 122 men with > or = 500 CD4 cells, 29 (24%) were currently receiving antiretroviral therapy. Forty-three men had discontinued antiretroviral therapy, 29 (67%) because of side effects. Thirty-seven men with < or = 500 CD4 cells had never used antiretroviral drugs: 48% because of feeling well and 28% because of possible side effects. Compared with 1987-1989, there were substantial increases in both antiretroviral therapy and anti-Pneumocystis prophylaxis use. Topics: AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antiviral Agents; Cohort Studies; Dapsone; Didanosine; Drug Combinations; Follow-Up Studies; HIV Infections; Humans; Male; Pentamidine; Pneumonia, Pneumocystis; San Francisco; Sulfamethizole; Trimethoprim; Zalcitabine; Zidovudine | 1993 |
Antiretroviral therapy.
Topics: Didanosine; Dideoxynucleosides; HIV Infections; Humans; Zalcitabine; Zidovudine | 1993 |
Antiretroviral therapy and medical management of the human immunodeficiency virus-infected child. Working Group on Antiretroviral Therapy: National Pediatric HIV Resource Center.
Topics: AIDS-Related Opportunistic Infections; Antiviral Agents; Child; Child, Preschool; Didanosine; HIV Infections; Humans; Immunoglobulins, Intravenous; Infant; Zalcitabine; Zidovudine | 1993 |
Didanosine therapy in patients with HIV infection.
Topics: Didanosine; HIV Infections; Humans | 1993 |
Clinical perspectives in the treatment of HIV disease: the role of didanosine. Introduction.
Topics: Didanosine; HIV Infections; Humans | 1993 |
Clinical perspectives in the treatment of HIV disease: the role of didanosine. Chicago, Illinois, 28 September 1991.
Topics: Didanosine; HIV Infections; Humans | 1993 |
The didanosine Expanded Access Program: safety analysis.
The didanosine Expanded Access Program was designed by the Bristol-Myers Squibb Company (Princeton, NJ) to provide didanosine for treatment of patients who could not be enrolled in clinical trials. This program consisted of two protocols: a treatment IND (investigational new drug) protocol for patients intolerant of zidovudine and an open-label protocol for patients whose clinical condition was deteriorating despite continued therapy with zidovudine. Information from the safety data base derived from study of the first 7,806 patients enrolled has shown that the major adverse events associated with didanosine therapy are pancreatitis (which can be life-threatening), peripheral neuropathy, and diarrhea. Pancreatitis was reported for 5% of the patients. Those with a history of pancreatitis were more likely to develop pancreatitis. In contrast to zidovudine, didanosine has been found to be minimally myelosuppressive. In general, hematologic parameters remained stable, especially for patients who entered the program with normal baseline values. The results of this program suggest that patients pretreated with zidovudine for prolonged periods are able to tolerate didanosine well. Topics: Clinical Protocols; Didanosine; Drugs, Investigational; Female; HIV Infections; Humans; Male | 1993 |
Dideoxyinosine-associated nephrotoxicity.
Topics: Diabetes Insipidus; Didanosine; Fanconi Syndrome; HIV Infections; Humans; Kidney; Male; Middle Aged | 1993 |
[Antiretroviral therapy].
Topics: Clinical Trials as Topic; Didanosine; HIV Infections; Humans; Zidovudine | 1993 |
Using convergent combination therapy, researchers stopped the human immunodeficiency virus (HIV) from reproducing in test tubes.
Topics: Didanosine; Drug Therapy, Combination; HIV Infections; Humans; In Vitro Techniques; Pyridones; Zidovudine | 1993 |
Parvovirus B19 infection in human immunodeficiency virus type 1-infected persons failing or intolerant to zidovudine therapy.
To determine the incidence of B19 infection in patients with AIDS who were being treated with dideoxyinosine, serial sera (n = 28) taken over a 2-year period from 14 individuals were analyzed with respect to anti-B19 serology and the presence of B19 DNA. All 14 individuals were anti-B19 IgM negative. Nine of 14 had B19 viremia by Southern analysis of polymerase chain reaction product. Five of 9 with B19 viremia had > or = 1 anti-B19 IgG-positive sample; none of 5 without viremia had anti-B19 IgG. Four of 9 viremic individuals had serially positive samples. All 4 had severe anemia (hemoglobin < 8.5 g/dL) while taking zidovudine. A fifth individual whose severe anemia resolved after zidovudine was discontinued did not have B19 viremia. Therefore, a significant proportion of this group of patients with AIDS who developed severe anemia while receiving zidovudine had persistent B19 infection. These results suggest that B19 infection should be considered in anemic patients with AIDS. Topics: Adult; AIDS-Related Opportunistic Infections; Antibodies, Viral; Didanosine; Erythema Infectiosum; HIV Infections; Humans; Incidence; Male; Middle Aged; Parvovirus B19, Human; Zidovudine | 1993 |
Combination therapy for HIV infection: getting closer.
Topics: Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1992 |
Trial of three drugs for HIV-infected patients.
Topics: Clinical Trials as Topic; Didanosine; HIV Infections; Humans; Zalcitabine; Zidovudine | 1992 |
Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages.
Monocyte/macrophages (M/M) are important targets for HIV in the body, and represent the majority of cells infected by the virus in some body compartments such as the central nervous system (CNS). M/M can be different from T-lymphocytes in terms of surface antigens, cell replication and drug metabolism. Thus, we evaluated, in M/M and in T-lymphocytes, the pattern of viral inhibition induced by various anti-HIV drugs, and assessed some of the mechanisms of action related to such antiviral activity. Inhibitors of HIV binding on CD4 receptors have similar activity in M/M and T-lymphocytes, while AZT and other dideoxynucleosides (ddN) are in general more active against HIV in M/M than in T-lymphocytes. This phenomenon can be related to the increased ratio in M/M of ddN-triphosphate/deoxynucleoside-triphosphate, and can at least in part explain the ability of zidovudine and didanosine in improving neurological dysfunctions in AIDS patients. Moreover, the antiviral activity of AZT (but not of other ddN- or HIV-binding inhibitors) is potently enhanced by cytokines like granulocyte-macrophage colony stimulating factor (GM-CSF) in M/M, while anti-HIV activity of TIBO compounds in M/M is not down-modulated by GM-CSF and other cytokines. Finally, non-toxic concentrations of adriamycin, an anticancer drug reported to be active against DNA viruses, can inhibit HIV replication in M/M (but not in T-lymphocytes). Taken together, these results suggest that M/M are selective targets for HIV with peculiarities different from those of T-lymphocytes. Thus, promising anti-HIV compounds should be evaluated both in T-cells and in M/M before reaching clinical trials. This may help in selecting drugs with good chances of being effective in patients with HIV-related disease. Topics: Adenine; Antibodies, Viral; Antiviral Agents; Benzodiazepines; CD4 Antigens; Cytokines; Didanosine; Doxorubicin; Drug Interactions; HIV; HIV Infections; Humans; Imidazoles; Leukocytes, Mononuclear; Lymphocytes; Macrophages; Monocytes; Organ Specificity; Organophosphonates; Zalcitabine; Zidovudine | 1992 |
Treatment of HIV infection: the antiretroviral nucleoside analogues. Introduction.
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Evaluation; HIV Infections; HIV-1; Humans; Nucleosides; Zalcitabine; Zidovudine | 1992 |
The transfer of anti-human immunodeficiency virus nucleoside compounds by the term human placenta.
The purpose of this study was to compare the maternal-fetal placental transfer of 2',3'-dideoxyinosine and 2',3'-dideoxycytidine with that of 3'-azido-2', 3-dideoxythymidine (azidothymidine).. The perfusion system used carbon 14-labeled antipyrine as a reference compound to determine the clearance index of each compound. The inhibitor dipyridamole and the endogenous bases were used to determine if these anti-human immunodeficiency virus compounds crossed the placenta other than by simple diffusion.. The clearance index of azidothymidine was 0.29 +/- 0.04 at maternal concentrations of 1.0 to 10 micrograms/ml, and the clearance index of 2',3'-dideoxyinosine was 0.14 +/- 0.05, which was 48% of the clearance index of azidothymidine. The clearance index of 2',3'-dideoxyinosine was essentially identical to azidothymidine in the range from 1 to 10 micrograms/ml. The results of the closed-closed studies suggest that at therapeutic peak concentrations of 1 to 2 micrograms/ml of these compounds in the maternal circulation therapeutic levels will be reached in the fetal circulation.. These anti-human immunodeficiency virus inhibitors appear to cross the placenta rapidly by simple diffusion because (1) the transfer of the drugs to the fetal circulation was not saturable even at 100 micrograms/ml, (2) there was no change in clearance index with the addition of 300 mumol/L of thymidine, inosine, cytosine, or 30 mumol/L dipyridamole, and (3) there was no accumulation against the maternal fetal or fetal maternal concentration gradient. Topics: Antiviral Agents; Chromatography, High Pressure Liquid; Didanosine; Female; HIV Infections; Humans; Maternal-Fetal Exchange; Osmolar Concentration; Placenta; Pregnancy; Zalcitabine; Zidovudine | 1992 |
Criteria for use of didanosine in adult and pediatric patients.
Topics: Adult; Child, Preschool; Didanosine; HIV Infections; Humans; Infant; Leukocyte Count; Zidovudine | 1992 |
Testing an anti-HIV trio.
Topics: Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine | 1992 |
Xerostomia associated with didanosine.
Topics: Didanosine; HIV Infections; Humans; Salivation; Xerostomia | 1992 |
[HIV-1 proviral DNA sequences in the saliva of patients with HIV infection].
In order to understand the significance of presence of HIV-1 in saliva, we searched for by PCR HIV-1 proviral sequences in the saliva cells of 49 HIV-1 infected patients. Seven out 49 specimens resulted positive, 4 of which were from patients with PGL, 1 with ARC and 2 with AIDS. Four patients had a CD4+ lymphocyte counts < 200/cmm and in 3 patients the CD4+ lymphocyte count ranged from 200 to 400/cmm. Two patients were treated with AZT, 1 with DDI and 4 had no antiretroviral treatment. In conclusion, although HIV-1 proviral sequences have been found in saliva of HIV-1 infected patients, a larger group of patients should be investigated to define more precisely the role of HIV-1 in saliva. Topics: Base Sequence; CD4-Positive T-Lymphocytes; Didanosine; DNA, Viral; Genes, env; HIV Infections; HIV-1; Humans; Leukocyte Count; Molecular Sequence Data; Polymerase Chain Reaction; Proviruses; Saliva; Zidovudine | 1992 |
[AIDS. 3rd European conference on the clinical aspects and treatment of HIV infection. Paris, 12-13 March 1992. 4th German AIDS congress. Wiesbaden, 25-28 March 1992. 8th International AIDS Conference. Amsterdam, 19-24 July 1992].
Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Zidovudine | 1992 |
Didanosine and amylase monitoring.
Topics: Adult; Amylases; Clinical Enzyme Tests; Didanosine; Drug Monitoring; Female; HIV Infections; Humans; Male; Middle Aged; Pancreatitis; Xerostomia | 1992 |
Starting therapy for an HIV-infected patient.
This monthly series was developed from the AOA Task Force on AIDS Writers' Workshop, held August 16 to 18, 1991, in New York. The workshop was sponsored by an education grant from Burroughs Wellcome. It will provide brief clinical updates and perspectives on the human immunodeficiency virus (HIV). Readers may request tear sheets from the AOA editorial offices. Topics: Didanosine; HIV Infections; Humans; Zidovudine | 1992 |
Continued zidovudine or didanosine for human immunodeficiency virus infection.
Topics: Didanosine; HIV Infections; Humans; Zidovudine | 1992 |
Cerebral artery aneurysms in children infected with human immunodeficiency virus.
More than 250 children treated at our institution on antiretroviral treatment protocols have been monitored with brain imaging studies. We documented the occurrence and progression of aneurysms of major cerebral arteries in two children with advanced human immunodeficiency virus infection. In both cases these lesions remained clinically silent initially, despite progression to marked dilation. Topics: Brain; Cerebral Angiography; Child; Didanosine; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Intracranial Aneurysm; Magnetic Resonance Imaging; Male; Zidovudine | 1992 |
Approval for broader use of DDI.
Topics: Didanosine; Drug Approval; HIV Infections; HIV-1; Humans; United States; United States Food and Drug Administration; Zidovudine | 1992 |
DDI more effective than AZT.
Topics: Didanosine; HIV Infections; Zidovudine | 1992 |
Treatment of patients with advanced HIV infection and zidovudine intolerance with dideoxyinosine.
Topics: Adult; Didanosine; Drug Tolerance; HIV Infections; Humans; Male; Middle Aged; Zidovudine | 1992 |
An improved method for monitoring efficacy of anti-retroviral therapy in HIV-infected individuals: a highly sensitive HIV p24 antigen assay.
Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured by a highly sensitive HIV p24 antigen-capture enzyme-linked immunosorbent assay (ELISA) in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) otherwise negative for HIV p24 antigen measured by a commercial antigen-capture ELISA. The assays were performed at baseline and at several intervals during treatment with either zidovudine (ZDV) or dideoxyinosine (ddl). To further enhance the rate of antigen detection, serum was pretreated with hydrochloric acid to denature antibody in immune complexes. Utilizing this assay system, we monitored these patients for drug efficacy. HIV p24 antigen levels obtained by using this sensitive assay decreased in 3 of 8 patients receiving ZDV during 8 weeks of ZDV treatment. Similarly, ddl administration was associated with a decrease of HIV p24 antigen levels in 3 of 5 patients. Thus, the use of the highly sensitive HIV p24 antigen assay permitted the monitoring of surrogate HIV p24 antigen as a measure of efficacy of anti-retroviral therapy in all of these patients who were otherwise HIV p24 antigen-negative at the onset of anti-retroviral therapy. Topics: Biomarkers; Didanosine; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; HIV Core Protein p24; HIV Infections; Humans; Sensitivity and Specificity; Zidovudine | 1992 |
[AIDS from the CIA?].
Topics: Didanosine; Government Agencies; HIV Infections; HIV-1; HIV-2; Humans; Mass Media; Zidovudine | 1992 |
Plasma HIV-1 viremia in HIV-1 infected individuals assessed by polymerase chain reaction.
We established a method to estimate the amounts of HIV-1 particles in plasma from patients with HIV-1 infection by using polymerase chain reaction (PCR) following reverse transcription (RT) of viral RNA (RNA-PCR) and assessed the potential usefulness of this approach to monitor the changes of viral load in patients with AIDS or AIDS-related complex (ARC) receiving 2',3'-dideoxyinosine (ddI). Plasma samples were obtained from 77 patients with HIV-1 infection (49 AIDS/ARC and 28 asymptomatic seropositives). Following ultracentrifugation of plasma, RNA was extracted from the pelleted virus and subjected to RT and PCR. The number of HIV-1 virus particles in each sample was determined using known amounts of HIV-1 DNA as reference control for PCR. The current plasma RNA-PCR technique quantitatively detected HIV-1 particles in plasma from 76 of 77 (98.7%) HIV-1-infected individuals examined. The numbers of HIV-1 particles in plasma from patients with AIDS or ARC were markedly higher than those in plasma from asymptomatic seropositive individuals (p less than 0.0001). Higher levels of plasma HIV-1 particle numbers were detected in individuals with lower CD4+ T cell counts. Patients (n = 10) who received oral ddI at doses greater than or equal to 6.4 mg/kg/day for 8 to 14 weeks had a profound decrease in plasma HIV-1 particle numbers (p = 0.0051). Patients (n = 7) receiving ddI for 45 to 71 weeks also had a decrease (p = 0.018). It should be noted, however, that more research is required to evaluate the usefulness of this technique in assessing the disease status and monitoring the activity of antiretroviral therapy. Topics: Base Sequence; Didanosine; DNA, Viral; HIV Core Protein p24; HIV Infections; HIV Seropositivity; HIV-1; Humans; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Viral; Viremia | 1992 |
Retinal lesions in children treated with dideoxyinosine.
Topics: Child; Didanosine; Female; HIV Infections; Humans; Retinal Diseases | 1992 |
Intestinal permeability in HIV infection: proper controls are necessary.
Topics: California; Congresses as Topic; Didanosine; HIV Infections; Humans; Intestinal Absorption; Research Design; Zidovudine | 1992 |
From the National Institutes of Health.
Topics: Acquired Immunodeficiency Syndrome; Child; Didanosine; HIV Infections; Humans; National Institutes of Health (U.S.); United States; Zidovudine | 1992 |
Bacterial infections in human immunodeficiency virus type 1-infected children: the impact of central venous catheters and antiretroviral agents.
We conducted a retrospective study to analyze the impact of central venous catheters (CVCs) and antiretroviral therapy on the frequency and the patterns of bacterial infections in children infected with human immunodeficiency virus during a 3-year period. Among 204 bacterial infections other than otitis media reviewed, soft tissue infection (n = 69), bacteremia (n = 57), pneumonia (n = 27) and sinusitis (n = 27) were encountered most frequently. Catheter-related staphylococcal infection was the most common infection in children with CVCs, particularly in those who were less than 6 years old. In children without CVCs, Streptococcus pneumoniae was the most frequent organism. Younger children had more CVC-related infections whereas children with lower CD4 counts had more CVC-related and CVC-unrelated infections. A lower frequency of CVC-unrelated infections was detected in patients who received antiretroviral therapy, especially those receiving a continuous infusion of zidovudine. These data suggest that increased frequency and altered patterns of bacterial infections are associated with the use of CVCs in these patients, but antiretroviral therapy may reduce the frequency of CVC-unrelated infections. Topics: Adolescent; Antiviral Agents; Bacterial Infections; Catheterization, Central Venous; Child; Child, Preschool; Didanosine; Female; HIV Infections; HIV-1; Humans; Male; Retrospective Studies; Zalcitabine; Zidovudine | 1991 |
Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection.
Adverse effects stemming from the therapeutic use of dideoxynucleoside derivatives continue to occur in patients with AIDS or AIDS-related complex. For example, the continued use of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-didoxycytidine (ddC), both of which confer clinical benefits in AIDS patients, may be complicated by anemia, neutropenia and thrombocytopenia and ddC also causes peripheral neuropathy. Subsequently, the National Toxicology Program (NTP) has undertaken efforts to define and characterize the toxicities associated with currently employed and potential AIDS therapeutics in experimental animals, with particular emphasis on the hematopoietic and immune systems. In addition to AZT and ddC, 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydrodideoxythymidine (d4T) have been examined. The present studies describe: (1) the development of a poorly regenerative macrocytic anemia in mice exposed to AZT or ddC. This anemia demonstrates a rapid and progressive time course of toxicity and reversibility after cessation of treatment; (2) the selective suppression of erythroid progenitor cells in mice exposed to d4T without concomitant effects on myeloid stem cells. Myelotoxicity appears to show metabolism-dependent strain-specificity and is more evident following in vitro exposure than in vivo exposure; and (3) the immunosuppressive effects following subchronic (30-day) exposure. Of the nucleoside derivatives studied, only ddA and ddI altered immune function and these changes were confined to suppression of antibody responses. It can be concluded that the overall similarities in the hematopoietic and immune system effects between rodents and humans indicate that such animal toxicology studies provide important information relevant to the toxicity of these drugs. Topics: Animals; Bone Marrow; Didanosine; Dideoxyadenosine; Female; HIV Infections; Immune System; Immunoglobulin M; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Zalcitabine; Zidovudine | 1991 |
Ribavirin for HIV.
Topics: Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Ribavirin | 1991 |
[Combination therapies with anti-retroviral agents in HIV and AIDS infections].
Topics: Acquired Immunodeficiency Syndrome; Anti-Bacterial Agents; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Interferons; Zalcitabine; Zidovudine | 1991 |
Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine.
Dideoxycytidine (ddC) and dideoxyinosine (ddI) are nucleoside derivatives that exhibit antiretroviral activity against the human immunodeficiency virus (HIV). Both of these agents are under active investigation as potential therapies for patients with HIV infection. In addition, both drugs may be obtained for HIV-infected individuals who cannot tolerate zidovudine. A major focus of the research effort involving these agents has been to define their toxicities. Both agents may cause peripheral neuropathy. We wish to report a patient who developed severe neuropathy following the administration of ddI that was given shortly after the patient was removed from a clinical trial of ddI. The rapid development of toxicity indicates that this side effect is additive or synergistic for these agents. Topics: Adult; AIDS-Associated Nephropathy; Antiviral Agents; Didanosine; Drug Synergism; Drug Therapy, Combination; HIV Infections; Humans; Male; Peripheral Nervous System Diseases; Zalcitabine | 1991 |
Human immunodeficiency virus infection of human lymph nodes in the SCID-hu mouse.
The SCID-hu mouse is a small animal in which human hematolymphoid organs can be engrafted and maintained in vivo. In this study, parameters are described for reproducible infection of SCID-hu mice after i.v. inoculation. Infection was found to be dependent upon the time after inoculation, the virus isolate, the titer of virus, and the human target organ implanted into the mouse. Ten to 14 days after the i.v. administration of HIV isolates derived freshly from patients (e.g., JR-CSF, JR-FL, SM), 100% of engrafted human lymph nodes in SCID-hu mice were infected; greater than 95% of these animals were also viremic. Implants of human thymus or connective tissue, as well as the endogenous murine hematolymphoid organs, were not infected. As demonstrated by a combination of in situ hybridization and immunohistochemistry, both T-lymphoid and myelomonocytic lineage cells were infected in this system. HIV isolates that have been adapted to growth in vitro (e.g., HTLV-IIIb) were not infectious. When either 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxyinosine (ddIno) was administered to SCID-hu mice before HIV infection, the animals were protected in dose ranges similar to those used in man. This animal model may now be used as an efficient intermediate step between the lab and the clinic to study the infectious process in vivo and to best select efficacious antiviral compounds against HIV. Topics: Animals; Antiviral Agents; Didanosine; DNA, Viral; HIV; HIV Infections; Humans; Immunohistochemistry; Immunologic Deficiency Syndromes; Lymph Nodes; Macrophages; Mice; Nucleic Acid Hybridization; Polymerase Chain Reaction; T-Lymphocytes; Transplantation, Heterologous; Zidovudine | 1991 |
[Anti-retroviral therapy of HIV-infection. With preliminary results of the Swiss postmarketing surveillance of zidovudine].
In the last few years, the treatment of HIV infection has advanced considerably due to the development of active antiretroviral compounds. Many substances with different mechanisms of action show strong activity against HIV in vitro and many of them are now under clinical investigation. But immense effort is needed to develop a clinically effective and tolerable drug for daily use from a substance active in vitro. Presently, zidovudine is the only drug that can be used for the treatment of HIV infection outside of clinical studies. The efficacy of zidovudine was demonstrated in patients with symptomatic HIV infection as well as in patients with advanced asymptomatic disease. The clinical signs of efficacy are significantly delayed progression of HIV infection and lower frequency of opportunistic infections, with decreased severity. It is evident that zidovudine does not cure the HIV infection. In Switzerland treatment with zidovudine is evaluated by post-marketing surveillance (PMS). All patients on zidovudine are seen periodically in the hospitals with a specialized division for HIV infection. Clinical and laboratory follow-ups are recorded. Until the beginning of October 1990, 1171 patients with symptomatic HIV infection have been treated with zidovudine in the setting of this PMS. 62% of all registered patients are currently receiving zidovudine. 20% died of AIDS. 15% of all patients received at least one blood transfusion. Hematotoxicity is the most frequent and serious side effect of zidovudine and can require definitive termination of therapy. The side effects are dose related and occur more severely in patients with advanced disease. The ideal dosage of zidovudine has not yet been defined. Recently published studies showed efficacy with doses as low as 500 mg/d. Consequently, patients in Switzerland receive 10 mg zidovudine/kg body weight as the maximum dose, divided into two or more single daily doses. Patients with asymptomatic HIV infection are regularly treated with 500 mg/d. Zidovudine-intolerant patients with symptomatic HIV infection can currently enter a controlled clinical trial of antiretroviral therapy with dideoxyinosine (ddI), which has a different spectrum of side effects but is only minimally toxic to bone marrow. Topics: Didanosine; Hematologic Diseases; HIV Infections; Humans; Opportunistic Infections; Product Surveillance, Postmarketing; Switzerland; Zidovudine | 1991 |
Availability of dideoxyinosine.
Topics: Clinical Protocols; Didanosine; Drugs, Investigational; HIV Infections; Humans; Zidovudine | 1991 |
From the Food and Drug Administration.
Topics: Adult; Child; Didanosine; HIV Infections; Humans; United States; United States Food and Drug Administration | 1991 |
Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors.
We have previously described a recombinant protein, designated CD4(178)-PE40, consisting of the human immunodeficiency virus (HIV) envelope glycoprotein-binding region of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas aeruginosa exotoxin A. By virtue of its affinity for gp120 (the external subunit of the HIV envelope glycoprotein), the hybrid toxin selectively binds to and kills HIV-1-infected human T cells expressing surface envelope glycoprotein and also inhibits HIV-1 spread in mixed cultures of infected and uninfected cells. We now report that CD4(178)-PE40 and reverse transcriptase inhibitors exert highly synergistic effects against HIV-1 spread in cultured human primary T cells. Furthermore, combination treatment can completely eliminate infectious HIV-1 from cultures of human T-cell lines. This conclusion is based on protection of a susceptible cell population from HIV-induced killing, complete inhibition of virus protein accumulation, and elimination of HIV DNA (as judged by quantitative polymerase chain reaction analysis). The results highlight the therapeutic potential of treatment regimens involving combination of a virostatic drug that inhibits virus replication plus an agent that selectively kills HIV-infected cells. Topics: ADP Ribose Transferases; Bacterial Toxins; CD4 Antigens; Cells, Cultured; Didanosine; Drug Synergism; Exotoxins; HIV; HIV Infections; Humans; Immunotoxins; In Vitro Techniques; Pseudomonas aeruginosa Exotoxin A; Reverse Transcriptase Inhibitors; T-Lymphocytes; Virulence Factors; Virus Replication; Zidovudine | 1990 |
Drugs for HIV infection.
Topics: Didanosine; HIV Infections; Humans; Zalcitabine; Zidovudine | 1990 |
Dideoxyinosine for HIV infection.
Topics: Didanosine; HIV Infections; Humans | 1989 |