indinavir-sulfate and HIV-Infections

Few data are available on antiretroviral therapy (ART) response among HIV-2 infected patients. We conducted a systematic review on treatment outcomes among HIV-2 infected patients on ART, focusing on the immunological and virological responses in adults.. Data were extracted from articles that were selected after screening of PubMed/MEDLINE up to November 2012 and abstracts of the 1996-2012 international conferences. Observational cohorts, clinical trials and program reports were eligible as long as they reported data on ART response (clinical, immunological or virological) among HIV-2 infected patients. The determinants investigated included patients' demographic characteristics, CD4 cell count at baseline and ART received.. Seventeen reports (involving 976 HIV-2 only and 454 HIV1&2 dually reactive patients) were included in the final review, and the analysis presented in this report are related to HIV-2 infected patients only. There was no randomized controlled trial and only two cohorts had enrolled more than 100 HIV-2 only infected patients. The median CD4 count at ART initiation was 165 cells/mm3, [IQR; 137-201] and the median age at ART initiation was 44 years (IQR: 42-48 years). Ten studies included 103 patients treated with three nucleoside reverse transcriptase inhibitors (NRTI). Protease inhibitor (PI) based regimens were reported by 16 studies. Before 2009, the most frequent PIs used were Nelfinavir and Indinavir, whereas it was Lopinavir/ritonavir thereafter. The immunological response at month-12 was reported in six studies and the mean CD4 cell count increase was +118 cells/μL (min-max: 45-200 cells/μL).. Overall, clinical and immuno-virologic outcomes in HIV-2 infected individuals treated with ART are suboptimal. There is a need of randomized controlled trials to improve the management and outcomes of people living with HIV-2 infection.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-Retroviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Female; HIV Infections; HIV-2; Humans; Indinavir; Lopinavir; Male; Middle Aged; Nelfinavir; Ritonavir; Treatment Outcome

The introduction of potent combination antiretroviral therapy (ART) in the treatment of HIV infection has permitted reliable control of disease progression and has markedly improved survival among people with HIV. As a result, health care providers and patients have shifted clinical priorities; whereas once delaying opportunistic illness was a primary focus, increasing emphasis is now placed on preventative health, management of comorbid chronic disease and avoiding long-term toxicities of ART. Although renal disease is common in people with HIV, renal disease specifically due to ART remains relatively rare. Still, as the use of ART continues to increase, health care providers are likely to encounter this potentially serious complication with increasing frequency. Distinguishing ART-related nephrotoxicity from the myriad of other potential causes of renal disease in people with HIV is important in order to avoid unnecessary discontinuation of an appropriate ART regimen. This review focuses on the early recognition of renal disease associated with ART and suggests strategies for management and prevention.

Topics: Adenine; Anti-Retroviral Agents; Atazanavir Sulfate; HIV Infections; Humans; Indinavir; Kidney Diseases; Oligopeptides; Organophosphonates; Pyridines; Tenofovir

HIV-positive children are at high risk of drug resistance, which is of particular concern in settings where antiretroviral options are limited. In this Review we explore resistance rates and patterns among children in developing countries in whom antiretroviral treatment has failed. We did a systematic search of online databases and conference abstracts and included studies reporting HIV-1 drug resistance after failure of first-line paediatric regimens in children (<18 years) in resource-poor regions (Latin America, Africa, and Asia). We retrieved 1312 citations, of which 30 studies reporting outcomes in 3241 children were eligible. Viruses with resistance-associated mutations were isolated from 90% (95% CI 88-93%) of children. The prevalence of mutations associated with nucleoside reverse transcriptase inhibitors was 80%, with non-nucleoside reverse transcriptase inhibitors was 88%, and with protease inhibitors was 54%. Methods to prevent treatment failure, including adequate paediatric formulations and affordable salvage treatment options are urgently needed.

Topics: Adolescent; Africa; Alkynes; Anti-HIV Agents; Asia; Benzoxazines; Child; Child, Preschool; Cross-Sectional Studies; Cyclopropanes; Developing Countries; Drug Resistance, Viral; Female; Health Resources; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Latin America; Lopinavir; Male; Mutation; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Treatment Failure; Viral Load; Zidovudine

To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy.. Systematic review of all protease inhibitor-monotherapy studies published in peer-reviewed journals or presented at conferences to date. Data of randomized controlled trials were pooled to yield common odds ratios.. Twenty-two protease inhibitor-monotherapy studies were identified. In the intent-to-treat analysis, 395 out of 582 (67.9%) patients had undetectable HIV-RNA at the end of follow-up. In the six randomized controlled trials (all lopinavir/ritonavir monotherapy), the risk of therapy failure was greater on monotherapy: 121 out of 364 (33.2%) patients on monotherapy against 64 out of 280 (22.9%) patients on HAART [pooled odds ratio 1.48 (95% confidence interval 1.02-2.13, P = 0.037)]. Regarding patients with successfully resuppressed HIV-RNA upon (re-)introducing nucleoside reverse transcriptase inhibitors (NRTIs) as nonfailures, the risk of therapy failure was comparable: 98 out of 364 (26.9%) against 64 out of 280 (22.9%) patients [odds ratio 1.05 (95% confidence interval 0.72-1.53, P = 0.81)].. The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART. The efficacy improves in patients started on monotherapy after suppressed HIV-RNA for at least 6 months. Ten percent of patients have viral rebound with HIV-RNA levels between 50 and 500 copies/ml. Possible explanations are lack of HIV suppression in particular cells or compartments, alternative resistance mechanisms, and nonadherence. Once proven that reintroduction of NRTIs, in patients with loss of viral suppression, is safe and effective, a broader use of simplification of HAART to protease inhibitor monotherapy might be justified. This review supports that the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy. Arguments for this strategy are NRTI/NNRTI side effects, NRTI/NNRTI resistance, and costs.

Topics: Atazanavir Sulfate; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

In the era of antiretroviral therapy, non-AIDS complications such as kidney disease are important contributors to morbidity and mortality.. To estimate the impact of hepatitis C coinfection on the risk of kidney disease in HIV patients.. Two investigators identified English-language citations in MEDLINE and Web of Science from 1989 through 1 July 2007. References of selected articles were reviewed. Observational studies and clinical trials of HIV-related kidney disease and antiretroviral nephrotoxicity were eligible if they included at least 50 subjects and reported hepatitis C status. Data on study characteristics, population, and kidney disease outcomes were abstracted by two independent reviewers.. After screening 2516 articles, 27 studies were eligible and 24 authors confirmed or provided data. Separate meta-analyses were performed for chronic kidney disease outcomes (n = 10), proteinuria (n = 4), acute renal failure (n = 2), and indinavir toxicity (n = 5). The pooled incidence of chronic kidney disease was higher in patients with hepatitis C coinfection [6.2 versus 4.0%; relative risk 1.49, 95% confidence interval (CI) 1.08-2.06]. In meta-regression, prevalence of black race and the proportion of patients with documented hepatitis C status were independently associated with the risk of chronic kidney disease. The relative risk associated with hepatitis C coinfection was significantly increased for proteinuria (1.15; 95% CI 1.02-1.30) and acute renal failure (1.64; 95% CI 1.21-2.23), with no significant statistical heterogeneity. The relative risk of indinavir toxicity was 1.59 (95% CI 0.99-2.54) with hepatitis C coinfection.. Hepatitis C coinfection is associated with a significant increase in the risk of HIV-related kidney disease.

Topics: Acute Kidney Injury; Black People; Hepacivirus; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney Failure, Chronic; Proteinuria; Risk

People with HIV infection have metabolic abnormalities that resemble metabolic syndrome (hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance), which is known to predict increased risk of cardiovascular disease (CVD). However, there is not one underlying cause for these abnormalities and they are not linked to each other. Rather, individual abnormalities can be affected by the host response to HIV itself, specific HIV drugs, classes of HIV drugs, HIV-associated lipoatrophy, or restoration to health. Furthermore, one component of metabolic syndrome, increased waist circumference, occurs less frequently in HIV infection. Thus, HIV infection supports the concept that metabolic syndrome does not represent a syndrome based on a common underlying pathophysiology. As might be predicted from these findings, the prevalence of CVD is higher in people with HIV infection. It remains to be determined whether CVD rates in HIV infection are higher than might be predicted from traditional risk factors, including smoking.

Topics: Adipose Tissue; Atherosclerosis; Cardiovascular Diseases; Cholesterol, HDL; Comorbidity; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Hypertriglyceridemia; Indinavir; Metabolic Syndrome; Prevalence; Risk Factors; Ritonavir; Terminology as Topic

Topics: Acute Disease; Adult; Chronic Disease; Diagnosis, Differential; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney; Male; Nephritis, Interstitial

Indinavir is one of four first-generation HIV-protease inhibitors and was the most popular amongst them in the late 1990s. It was initially licensed for use alone, given three times daily, administered away from meals and together with at least 1.5 litres of fluid per day. In clinical practice, it became common for clinicians to prescribe it with a ritonavir pharmacokinetic 'boost' to remove the food restriction, reduce the pill burden and enable a more convenient twice-daily dosing schedule. However, at a ritonavir-boosted dosing schedule of indinavir/ritonavir 800/100 mg b.i.d., the regimen proved toxic and poorly tolerable, and its use diminished as newer, better tolerated PIs became available. Recent research has suggested that ritonavir-boosted indinavir administered at lower doses, particularly indinavir/ritonavir 400/100 mg b.i.d., retains potency and is considerably less toxic. As a result, there is interest in its application in resource-constrained settings.

Topics: Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Product Surveillance, Postmarketing; Ritonavir

For over a decade, indinavir has been approved for the treatment of HIV/AIDS; however, following the introduction of new protease inhibitors (PIs) with improved safety and pharmacologic profiles, its use in developed countries has become almost obsolete. In contrast, in resource-limited settings where the majority of people living with HIV/AIDS reside, indinavir is part of the most affordable PI-based highly active antiretroviral treatment regimen. A major drawback of indinavir use is renal toxicity, but low-dose indinavir plus ritonavir (400/100 mg) twice daily is both efficacious and tolerable. Similar low dosing levels in children have also proven successful, but data in pregnant women remains limited. Due to its low cost and proven efficacy indinavir remains a key component of HIV/AIDS treatment in resource-limited settings.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Area Under Curve; Developing Countries; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Molecular Structure; Ritonavir

Topics: Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases

The inclusion of protease inhibitors in 3-drug highly active antiretroviral regimens for treating patients who are infected with human immunodeficiency virus-1 has had a significant impact in increasing survival and decreasing morbidity. However, the effectiveness of this class of drugs may be compromised by the occurrence of drug-related hepatotoxicity, which is problematic especially in individuals co-infected with hepatitis viruses. Based on its clinical and pharmacologic profile, especially its unique pattern of resistance, nelfinavir has been used frequently as a first-line protease-inhibitor therapy for human immunodeficiency virus-1-infected patients. The aim of this study was to identify the relative potential for developing hepatotoxicity for nelfinavir vs other protease inhibitors.. An exploratory meta-analysis of liver enzyme level increases was conducted in a combined total of 4268 patients derived from 3 large recently conducted prospective and retrospective clinical trials and a prospective cohort study.. The results indicate that among 4 commercially available protease inhibitors and a 2-protease inhibitor combination, nelfinavir and indinavir are associated with the lowest rates of occurrence of severe hepatotoxicity (ie, combined estimates of liver enzyme level increases of 2.9% and 3.1%, respectively). The low rate of occurrence of severe hepatotoxicity for nelfinavir was shown even among patients co-infected with hepatitis viruses.. In conclusion, these data provide support for the conclusion that differences in the potential for hepatotoxicity do exist among the commercially available protease inhibitors.

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Nelfinavir

There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Dipeptides; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Models, Molecular; Molecular Mimicry; Molecular Structure; Nelfinavir; Oligopeptides; Organophosphates; Peptides; Phenylbutyrates; Pyridines; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides; Urethane

Human immunodeficiency virus infection is an illness with protean manifestations including hematological abnormalities. Thromboembolic complications in HIV-infected patients have been described. Recent literature describes an incidence ranging from 0.26% to 7.6%; higher incidence is seen in patients with active opportunistic infections or malignancy, and in patients with the acquired immunodeficiency syndrome. A variety of potential mechanisms have been proposed to account for the observed hypercoagulability in HIV-infected patients. These include the presence of antiphospholipid-anticardiolipin antibodies, decreased activities of natural anticoagulants (especially protein S), and increased platelet activation. Recent epidemiological studies emphasize the increased incidence of thromboembolic events including myocardial infarction in the HIV-infected population after the introduction of highly active antiretroviral therapy. The use of protease inhibitors in particular is implicated. A hypercoagulable state and especially thromboses are emerging as clinical issues in HIV-infected patients. Further studies are in order to more clearly delineate the pathophysiologic mechanism(s) of thromboses in HIV-infected patients.

Topics: Adult; Antibodies, Antiphospholipid; Anticoagulants; Antiretroviral Therapy, Highly Active; Aspirin; Cohort Studies; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Indinavir; Middle Aged; Myocardial Infarction; Platelet Activation; Protein S Deficiency; Retrospective Studies; Risk Factors; Thromboembolism; Thrombophilia; Thrombosis

Although protease inhibitors (PIs) have dramatically improved outcomes in HIV-infected patients, half still fail treatment with PI-based combination therapy. Genetic pressure from incomplete viral suppression rapidly selects for HIV variants with protease gene mutations that confer reduced susceptibility to PI drugs. A number of specific amino acid substitutions have been associated with PI resistance. However, high-level resistance to individual PIs requires the accumulation of several primary and secondary mutations, developing along drug-specific, step-wise pathways. HIV variants resistant to saquinavir and ritonavir usually contain L90M and V82A substitutions, respectively. Indinavir resistance may be linked to substitutions at positions 46 or 82. Resistance to nelfinavir is primarily associated with D30N but may alternatively be found with L90M. Resistance during exposure to amprenavir can follow development of I50V, which also may confer resistance to lopinavir. Failure during treatment with atazanavir is closely linked to 150L. The overlapping of these pathways can lead to multiple-PI resistance, limiting therapeutic options in antiretroviral-experienced patients. Reduced susceptibility to more than one PI is most likely to be associated with amino acid substitutions at six positions: 10, 46, 54, 82, 84 and 90. Other mutations (D30N, G48V, I50V or I50L) are relatively specific for particular PIs and are less likely to produce cross resistance. Certain resistance mutations selected by exposure to one PI may actually increase susceptibility to others. Patients newly diagnosed with HIV infection are increasingly found to harbour virus that is resistant to the more commonly used drugs. Newer PIs may select for mutations that result in less cross resistance with older agents.

Topics: Amino Acid Substitution; Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Genetic Variation; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Mutation; Pyridines; Pyrones; Ritonavir; Saquinavir; Sulfonamides

The pharmacokinetics of protease inhibitors center around the microsomal enzyme cytochrome P-450 3A4. As a potent inhibitor of this enzyme, ritonavir can increase the bioavailability and half-life of coadministered protease inhibitors. Evidence suggests that increased exposure to protease inhibitors is clinically relevant. Antiretroviral treatment with low-dose ritonavir-boosted lopinavir, indinavir, and saquinavir has durable virological activity and shows impressive immune reconstitution. Although tolerable in most cases, gastrointestinal side effects, hepatotoxicity, and blood lipid abnormalities remain relevant issues. Additional study will elucidate the advantages and disadvantages of twice-daily, low-dose ritonavir-boosted regimens and determine whether once-daily regimens based on this principle will have a lasting role in clinical practice.

Topics: Antiretroviral Therapy, Highly Active; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Saquinavir

A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infected patients treated with HIV-protease inhibitors (PI). We have recently demonstrated that PI block the angiogenesis and the development of KS lesions induced experimentally in vivo by the inoculation of angiogenic factors or human primary KS cells. These effects of PI occur at the same drug concentrations in plasma of treated individuals, and they are due to the inhibition of cell invasion and of the activation of matrix metalloprotease-2, an enzyme that is key to angiogenesis and tumor growth and invasion. Since PI also block the production of cytokines involved in KS initiation and maintenance, this anti-inflammatory activity of PI may also contribute to the anti-KS effects observed in treated individuals. Thus, by direct and indirect activities PI can simultaneously block several pathways involved in tumor growth, invasion or metastasis. These data indicate that PI should also be investigated and exploited for the therapy of KS and tumors of different histology occurring in non infected individuals.

Topics: Antiretroviral Therapy, Highly Active; Enzyme Activation; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Matrix Metalloproteinase 2; Neovascularization, Pathologic; Saquinavir; Sarcoma, Kaposi

Topics: Atazanavir Sulfate; Drug Administration Schedule; HIV Infections; Humans; Indinavir; Lopinavir; Oligopeptides; Protease Inhibitors; Pyridines; Pyrimidinones; Randomized Controlled Trials as Topic; Saquinavir

Since 1998, many cases of antiretroviral therapy-related paronychia of the toes or fingers and ingrown toenails have been reported. Most of them were related to indinavir. Other indinavir-induced mucocutaneous disorders resembling the adverse effects of systemic retinoid therapy have also been reported. Although there is some uncertainty in the literature regarding a cause-effect relationship, results of several epidemiological and in vitro studies, together with cumulated clinical experience leave no doubt that indinavir causes a retinoid-like effect and nail alterations. Indeed, indinavir is the only antiretroviral drug that produces these disorders, although ritonavir may enhance indinavir-induced retinoid-like effects through pharmacokinetic interactions leading to increased plasma indinavir concentrations. Approximately 30% of patients receiving indinavir show two or more retinoid-like manifestations and 4-9% develop paronychia. These adverse effects are not related to other epidemiological variables such as the patient's sex, age or other risk factors or immune status. They seem to be exposure dependent and, therefore, largely dose-dependent. Chronic paronychia is considered generally to be caused by contact irritants and candidal infection. Nevertheless, indinavir is currently the most frequent cause of chronic or recurrent paronychia in HIV-infected patients. In addition, retinoid-like manifestations such as cutaneous xerosis and cheilitis are frequent mucocutaneous adverse effects related to indinavir. The exact mechanism of indinavir-induced retinoid-like effects is unclear. Hypotheses for pathogenesis include interference with retinoid metabolism by enhancing the retinoic acid signalling pathway, or by increasing retinoic acid synthesis, or by reducing cytochrome p450-mediated retinoic acid oxidative metabolism. Replacement of therapy by an antiretroviral regimen not containing indinavir, while retaining other protease inhibitors and lamivudine, resolves retinoid-like manifestations without recurrences.

Topics: Anti-HIV Agents; HIV Infections; Humans; Incidence; Indinavir; Retinoids; Skin Diseases

Several cases are reported of rheumatological pathology (temporomandibular dysfunction, frozen shoulder, Dupuytren's disease, and tendinitis) most probably related to the intake of indinavir in HIV positive patients. A survey using an anonymous questionnaire of 878 people with HIV infection treated with antiretroviral drugs suggests that other protease inhibitors may also cause arthralgia.

Topics: Adult; Dupuytren Contracture; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Rheumatic Diseases; Shoulder Impingement Syndrome; Temporomandibular Joint Dysfunction Syndrome; Tendinopathy

Although the reduction in HIV-1-related deaths with highly active antiretroviral therapy (HAART) is similar in adults and children, the extent of the changes in two important surrogate markers HIV-1 RNA levels and CD4+ T cell counts, differs widely. In most paediatric studies virological response rates to HAART are inferior to those in adults. This review provides an overview of the paediatric clinical studies using HAART and seeks to improve the understanding of factors that may contribute to success or failure of HAART in children. An overview of all current articles on paediatric clinical trials using HAART is provided. 23 papers were available. HIV-1 RNA loads and CD4+ T cell counts were used as primary outcome measures. Virological response rates were highly variable, both among the different antiretroviral drugs but also among different studies using the same medication. Four studies in which dosages of the administrated protease inhibitor (PI) were adjusted after pharmacokinetic evaluation had superior virological response rates compared with those in which fixed dosages were used. Immunological response rates were more uniform than virological responses. In almost all studies increases of CD4+ T cell counts are reported independent of the extent of the virological response. Side-effects of HAART were generally mild, transient, and of gastrointestinal origin. Significant percentages of patients with serum lipid abnormalities were reported in three paediatric studies. However, signs of clinical lipodystrophy were not observed. The inferior virological response rates, which have been reported in HIV-1 infected children treated with HAART form a reflection of the challenges that are encountered in the treatment of these children. Difficulties with adherence and with the pharmacokinetics of PIs in children require an intensive, child-adjusted approach. A practical approach to therapy in institutions without tertiary care facilities may be induction therapy with a lopinavir containing regimen (lacking a need for therapeutic drug monitoring), to reduce high viral load levels followed by an easily tolerated maintenance regimen, for example containing abacavir or nevirapine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir

To examine the use of low-dose ritonavir as a pharmacokinetic enhancer for HIV protease inhibitors.. Primary articles, review articles, and conference abstracts identified by MEDLINE search (1995-May 2001) and secondary sources.. Low-dose ritonavir (100-200 mg) is increasingly being combined with HIV protease inhibitors to improve their effectiveness and allow less frequent dosing. An evaluation of the clinical evidence supporting this practice was conducted.. Limited outcome data exist for low-dose ritonavir-based regimens in general. Although preliminary data appear promising, more clinical evidence is needed to determine the optimal dosing, long-term safety, and relative effectiveness of this approach. The role of these regimens in early therapy remains to be defined.

Topics: Clinical Trials as Topic; Drug Synergism; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; MEDLINE; Ritonavir; Treatment Outcome

Topics: Carbamates; Drug Resistance, Microbial; Furans; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Mutation; Nelfinavir; Ritonavir; Saquinavir; Sulfonamides

Topics: AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Helicobacter Infections; Helicobacter pylori; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Indinavir; Quality of Life; RNA, Viral; Viral Load

To assess the correlation between antiretroviral treatment and dyslipidaemia in HIV-infected patients, and the role of bezafibrate as a lipid-lowering agent.. We retrospectively compared serum lipid levels of five groups of 40 patients, each of them treated with either saquinavir hard gel, indinavir, or ritonavir (associated with two nucleoside analogues), or dual nucleoside reverse transcriptase inhibitors (NRTI) with or without a non-nucleoside reverse transcriptase inhibitor (NNRTI), or not treated with antiretrovirals, randomly selected from nearly 1000 HIV-infected patients followed-up for >or= 12 months, while on the relevant therapy. Hypertriglyceridaemia was defined by triglyceride levels >or= 172 mg/dl, and hypercholesterolaemia by cholesterol levels >or= 200 mg/dl. All patients with triglyceridaemia > 300 mg/dl and cholesterolaemia > 220 mg/dl for at least 6 months, and unresponsive to a >or= 3-month diet, started bezafibrate (400 mg/day), and were prospectively followed-up at a

Topics: Bezafibrate; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Hypolipidemic Agents; Indinavir; Lipids; Retrospective Studies; Ritonavir; Saquinavir

Clinical and virologic consequences of temporary interruption of HIV therapy are incompletely understood.. To describe a febrile illness that was consistent with the acute HIV syndrome and occurred after interruption of antiretroviral therapy.. Case report.. University clinic.. HIV-infected man.. Plasma viral load, lymphocyte subsets, diagnostic evaluation (including cultures and serologic tests), and analysis of lymph node tissue.. The patient began antiretroviral therapy 3 months after initial HIV exposure and had sustained viral suppression, except during a brief scheduled treatment interruption. One hundred sixty-nine days after resuming therapy, the patient discontinued it again immediately following an influenza vaccination. Eleven days later, he presented with a febrile mononucleosis-like syndrome associated with dramatic shifts in plasma HIV RNA level (<50 to >1 000 000 copies/mL) and CD4 cell count (0.743 x 10(9) cells/L to 0.086 x 10(9) cells/L). Evaluation for alternative causes of fever was unrevealing. Symptoms resolved rapidly with resumption of HIV therapy.. Therapeutic interruption may be associated with profound viral rebound and recurrence of the acute HIV syndrome.

Topics: Acute Disease; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Chronic Disease; Disease Progression; Drug Therapy, Combination; Fever; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Recurrence; Reverse Transcriptase Inhibitors; RNA, Viral; Syndrome; Viral Load; Zidovudine

Healthcare workers are at risk of occupationally acquired HIV infection primarily due to percutaneous exposure to HIV infected blood. The average risk of HIV transmission after such exposure is approximately 0.3%. There is evidence of higher risk for exposures involving an increased volume of blood (deep injury, injury with a device visibly contaminated with source patient's blood and a procedure which involved a needle placed in the source patient's artery or vein) and exposures to source patients with a high viral load. Triple therapy with two nucleoside analogues (zidovudine, lamivudine) and a protease inhibitor (indinavir) is now widely used for post-exposure prophylaxis following occupational exposure to HIV. Most of the evidence for the efficacy of prophylaxis is based on zidovudine monotherapy. Little is known about the long-term toxicity of these drugs in non-infected individuals. Their use in these circumstances requires careful assessment of possible risks and benefits.

Topics: Anti-HIV Agents; Health Personnel; HIV Infections; HIV Seropositivity; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Occupational Exposure; Reverse Transcriptase Inhibitors; United Kingdom; Zidovudine

The development of antiretrovirals has led to a revolution in the care of patients infected with HIV. What was once a uniformly fatal syndrome has become a more treatable, chronic, infectious disease. Central to this revolution have been the protease inhibitors, a class of drugs with potent antiretroviral activity. The first member of this class was approved for use in 1995 and there are now five protease inhibitors approved by the US Food and Drug Administration (FDA): amprenavir, indinavir, nelfinavir, ritonavir and saquinavir. As a result of the magnitude of the HIV pandemic coupled with the clinically proven efficacy of protease inhibitors, there are currently hundreds of ongoing clinical trials with these agents. Trial designs include comparisons between the various licensed protease inhibitors, comparisons of protease inhibitors to other classes of potent antiretroviral drugs, investigations with new protease inhibitors, investigations of protease inhibitor-related toxicities and attempts at simplifying current dosing regimens.

Topics: Carbamates; Clinical Trials as Topic; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Sulfonamides; United States; United States Food and Drug Administration

Fat redistribution (FR) occurring alone or in association with hyperlipidemia has been associated with protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTIs); however, the relationship between FR features, relationship of FR to hyperlipidemia, and pathogenesis of FR is unknown.. To characterize the spectrum of FR, assess relationships among FR features, determine trends in occurrence of FR, and determine relationship of FR to hyperlipidemia.. Review of postmarketing indinavir reports of FR in Merck & Co. Inc.'s database.. 282 reports of FR among HIV-positive patients taking indinavir submitted through the passive postmarketing system to Merck through February 23, 1998.. 282 FR reports were compared across 3 groups: fat accumulation (FA) only, FA with peripheral wasting (FA with PW), and peripheral wasting only (PWO). Of 282 reports, 56% (159 of 282) had FA only, 22% (63 of 282) had FA with PW, and 21% (60 of 282) had PWO. The proportions of reports of PWO was higher in men, whereas the proportion of reports of FA was higher in women. Blood lipids were provided in 93 of 282 reports; were elevated in 69 of 93, and were normal in 24 of 93 reports. Proportions of hyperlipidemia and hypertriglyceridemia reports were significantly higher in the PWO group versus FA only group (p =.024 and.003, respectively) and versus FA with/without PW groups (p =.038 and.005, respectively). Weight gain was more frequently reported in those with FA (100%) or FA with PW (68%), whereas weight loss was usually reported in those with PWO (83%). In all, 98% of patients reporting FR on indinavir for whom a concomitant drug history was available were also taking lamivudine, stavudine, or both. A higher proportion of patients reporting PWO (34 of 60; 56.7%) versus FA (42 of 159; 26.4%) only took both lamivudine and stavudine.. Differences observed from analysis of cases in clinical features, gender, weight change, concomitant medications, and presence of hyperlipidemia among the three groups of FR cases reported to Merck suggests that PWO may be a distinct entity from other features of FR. The data suggest that certain antiretroviral combinations predispose HIV persons to development of FR.

Topics: Adipose Tissue; Adult; Aged; Body Composition; Databases, Factual; Drug Industry; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lipodystrophy; Male; Middle Aged

To report a case of severe and recurrent crystalluria resulting from the use of indinavir and to review the literature describing this adverse effect.. A 26-year-old HIV-positive white woman had recurrent episodes of left-sided flank pain accompanied by dilation of the left renal collecting system while undergoing treatment with a triple-drug regimen including indinavir 1200 mg every 12 hours (full dosage). Typical indinavir crystalluria was observed, with no evidence of stones. Acute episodes were treated with intravenous fluids, diclofenac, and ciprofloxacin. Crystalluria and clinical symptoms eventually resolved with withdrawal of indinavir and substitution with a different protease inhibitor. Renal function remained normal.. A wide spectrum of disorders of the urinary tract can occur in subjects taking indinavir, with potentially severe complications caused by crystalluria and stones. Indinavir is excreted in the urine; the low solubility of those crystals is the critical factor accounting for the risk of stone formation. An elevated pH with a reduced excretion of citric acid contributes to the low urinary solubility of indinavir. Pharmacokinetic interactions with other drugs, leading to elevated plasma concentrations of indinavir, and dehydration could also increase the risk of stone formation. The impact on renal function can be unfavorable over the long-term period. Cornerstones of treatment and prevention are increased fluid intake and possibly urinary acidification. Emergency drainage may be required for patients with severe obstruction. Reducing the dosage of indinavir has been proposed, but this carries the risk of viral mutations with development of resistance.. Treatment with indinavir can result in crystalluria with potentially severe obstruction. All patients taking indinavir, not only those with documented crystalluria or renal effects from the drug, should greatly increase their fluid intake and have renal function checked at baseline and then monitored regularly. Urinalysis also should be performed regularly for appropriate monitoring and prevention.

Topics: Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Urologic Diseases

Topics: CD4 Lymphocyte Count; Clinical Protocols; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Ritonavir; Viral Load

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir

All the currently available protease inhibitors are metabolised by the cytochrome P450 (CYP) enzyme system. All are inhibitors of CYP3A4, ranging from weak inhibition for saquinavir to very potent inhibition for ritonavir. Thus, they are predicted to have numerous drug interactions, although few such interactions have actually been documented either in pharmacokinetic studies or in clinical reports. This article reviews the published literature with an emphasis on the magnitude of interactions and on practical recommendations for management. Many of the drugs commonly taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYPand have been shown to interact with protease inhibitors. Delaviridine is an inhibitor of CYP3A4, but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. Other commonly used drugs are also known to affect protease inhibitor metabolism, including inhibitors such as clarithromycin and the azole antifungals and inducers such as the rifamycins. Drugs that are known to be significantly affected by the protease inhibitors include ethinylestradiol and terfenadine; many other drugs have lesser or potential interactions. Although little specific data is available on the drug interactions of protease inhibitors, this lack of data should not be interpreted as a lack of interaction. Retrospective chart reviews have demonstrated that potentially severe drug interactions are frequently overlooked. Much more clinical data is needed, but pharmacists and physicians must always be vigilant for drug interactions, both those that are already documented and those that are predictable from pharmacokinetic profiles, in patients receiving protease inhibitors.

Topics: Anti-Infective Agents; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Topics: Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Nelfinavir; Ritonavir; Saquinavir

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

Since 1996 indinavir in combination with zidovudine + lamivudine has been the standard regimen in the treatment of HIV infection. Although protease inhibitor (PI) containing therapies are very potent, many problems have now been identified that reduce quality of life such as a high pill burden, multiple daily dosing and dietary constraints. In addition, adverse events, such as lipodystrophy and lipid metabolism changes are being reported more frequently as long-term experience with PI therapy is gained. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be potent partners for antiretroviral combined therapies. Efavirenz is one of the most recent NNRTIs to be developed. Evidence to date suggests that given its potency, convenience and tolerability, efavirenz will have a major role to play in first-line, PI-sparing regimens and long-term suppressive therapy. However, many questions remain unanswered and future research should attempt to address these issues.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Oxazines; Reverse Transcriptase Inhibitors; Zidovudine

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/microL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-li

Topics: Animals; Anti-HIV Agents; HIV Infections; HIV-1; Humans; Indinavir

(1) Recent consensus recommendations agree that first-line treatment of HIV infection should consist of a three-drug regimen combining a protease inhibitor and two nucleoside reverse transcriptase inhibitors. Some recommendations specifically advise against using the current formulation of saquinavir, but none express a preference for one of the other three protease inhibitors currently marketed in France (indinavir, nelfinavir and ritonavir). (2) These HIV protease inhibitors have established efficacy on viral load and the CD4+ lymphocyte count. Saquinavir may have lower virological efficacy. (3) The clinical efficacy of three-drug regimens containing indinavir or saquinavir is well demonstrated in patients at an advanced stage of HIV disease. (4) The risk of viral resistance is not currently a factor in choosing a HIV protease inhibitors. (5) Several epidemiological studies have compared the risk of adverse effects on three-drug regimens including indinavir, ritonavir or saquinavir. In these studies saquinavir was the best-tolerated drug and ritonavir the worst-tolerated. (6) Ritonavir interacts with many drugs. The poor bioavailability of the current saquinavir formulation also leads to risk of interactions. (7) Treatment constraints differ from one protease inhibitor to another, and these must be taken into account case by case. (8) The daily cost of treatment is not currently an important factor in choosing among the various preparations. (9) Taking into account efficacy, adverse effects, interactions and treatment constraints, the combination of indinavir with two nucleoside reverse transcriptase inhibitors currently seems to be the best choice for the largest number of patients. (10) If problems of compliance arise, nelfinavir can be an alternative to indinavir. (11) In patients at an advanced stage of HIV disease who comply well with their treatment, saquinavir can also be an alternative to indinavir.

Topics: Clinical Trials as Topic; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Treatment Outcome

The pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration of protease inhibitors are reviewed. Protease inhibitors are a novel class of drugs used for the treatment of human immunodeficiency virus (HIV) infection. Saquinavir, ritonavir, indinavir, and nelfinavir have been approved in the United States; several other agents are under development. Protease inhibitors selectively block HIV protease, an enzyme involved in the later stages of HIV replication. Various pharmacokinetic differences exist among these agents, including differences in bioavailability, protein binding, and drug interactions. The drugs undergo extensive hepatic metabolism; dosage adjustments should be considered for patients with hepatic dysfunction. Clinical trials have shown protease inhibitors to be effective in reducing HIV RNA levels and increasing CD4+ lymphocyte counts. When protease inhibitors are used in combination with other antiretroviral agents, an additional beneficial effect on these markers occurs. Adverse effects of saquinavir and nelfinavir include mild gastrointestinal disturbances such as diarrhea. Ritonavir is less well tolerated because of gastrointestinal disturbances and circumoral and peripheral paresthesia. Indinavir has been associated with nephrolithiasis and asymptomatic hyperbilirubinemia. The development of resistance to protease inhibitors may be related to suboptimal dosages, noncompliance, or partial compliance. Protease inhibitors are potent and highly selective agents that block a critical step in HIV replication. They are effective and relatively well tolerated, but they are expensive, have extensive drug interaction profiles, and require careful compliance with the prescribed regimen.

Topics: Adult; Antiviral Agents; Child; Clinical Trials as Topic; Contraindications; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Saquinavir

Topics: Adolescent; Adult; Anti-HIV Agents; Hemophilia A; Hemorrhage; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Reverse Transcriptase Inhibitors; Zidovudine

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

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Retina; Retinal Diseases; Ritonavir; Saquinavir

In the treatment of infections caused by rapidly mutating viruses like human immunodeficiency virus (HIV), combination therapy with multiple drugs acting by different mechanisms offers several advantages over monotherapy. It may provide: synergistic effect, possible reduction of dosages and side-effects, and reduction of the chance of drug resistance. In the past few years, hundreds of HIV protease inhibitors have been synthesized and tested in order to overcome the limitations of reverse transcriptase inhibitors like zidovudine and others. In this review, emphasis is placed on the development of HIV protease inhibitors as antiviral agents against HIV, and structure-activity relationship analysis of saquinavir and related compounds. Limitations of some protease inhibitors and ways to overcome the shortcomings are presented. Among these many protease inhibitors four have been marketed during 1995-1997. They are saquinavir, ritonavir, indinavir and nelfinavir. Their different structural features, important physicochemical, pharmacokinetic and clinical profiles are presented in a table form for easy comparison. It is hoped that in the future new drugs based on additional mechanisms can be developed for the treatment of AIDS.

Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Structure-Activity Relationship

The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented.. A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996.. Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care.. Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs.. The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Nelfinavir; Ritonavir; Saquinavir; Viral Load

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

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

Topics: Adolescent; Adult; Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Ritonavir; Saquinavir

Over the last few years, several new antiviral agents have been added to the chemotherapeutic armamentarium. This review discusses advances in the treatment of HIV disease in children and adults. More pronounced antiviral effects have been achieved through the study of new agents such as the protease inhibitors as well as through a better understanding of previously approved drugs, such as reverse transcriptase inhibitors.

Topics: Adult; Antiviral Agents; Child; HIV Infections; Humans; Indinavir; Lamivudine; Nevirapine; Protease Inhibitors; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine

Seldom in the history of medicine has an entire generation of patients with an incurable, progressive, and ultimately fatal disease suddenly been offered the prospect of extended survival and even, perhaps, a "second life." The relatively simultaneous appearance of 2 major treatment developments has created profound changes in therapeutic options and outlook. The first development is an assay of serum levels of human immunodeficiency virus viral copies, providing a critical tool for clinical decision making. The second is the marketing between December 1995 and April 1997 of 4 human immunodeficiency virus protease inhibitors that, combined with previously available antiviral medications, achieve a new level of efficacy. With the advent of these changes come multiple psychiatric research and policy issues. These include the development of strategies to establish and maintain medication adherence. This is a critical task, given the complexity of combination therapy regimens and the rapid onset of viral resistance to protease inhibitors within days to weeks of missed or suboptimal dosing. The psychological issues to be studied include the process of restructuring lives and expectations in the event of clinical benefit or managing the distress associated with clinical failure. Other research questions include the effects of restored health on the appraisal of human immunodeficiency virus risk behaviors, assessment of effect of neurocognitive functioning, and unanswered questions about psychotropic or protease inhibitor drug interactions due to their shared metabolic pathways. Behavioral scientists can inform provision of care to patients who may be considered difficult to treat, such as those with severe and persistent mental illness or active substance abuse or the homeless. This includes the provision of empirical data regarding individual and situational characteristics that are likely to promote or impede adherence, as well as innovative provision systems. Psychiatry can make notable contributions during this turning point in human immunodeficiency virus therapeutics and research.

Topics: Acquired Immunodeficiency Syndrome; Attitude to Health; Drug Approval; Drug Costs; Drug Interactions; Health Policy; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Life Style; Nelfinavir; Primary Prevention; Ritonavir; Saquinavir; United States; United States Food and Drug Administration; Viral Load

Anti-retroviral treatment of human immunodeficiency virus (HIV) infection is undergoing great changes, brought about by a better understanding of the disease pathology. One of the most recent advances has been the introduction of the protease inhibitors, reversible inhibitors of HIV aspartic protease. Published data on the clinical efficacy of these drugs are limited, but preliminary results suggest that, in combination with one or more nucleoside analogues, they represent an important advance in the treatment of patients with advanced HIV infection. The adverse effects and potential for drug interactions, together with the additional cost associated with prescribing these drugs, mean that careful selection and supervision of these patients is imperative.. To present an up-to-date review of the three most recently introduced protease inhibitors.. Based on a review of the literature, abstracts from relevant meetings and information from the pharmaceutical companies.. A review including background data on HIV infection and the treatment options. Detailed information on ritonavir, saquinavir and indinavir.. These new drugs are useful additions to the therapeutic current aims for the treatment of HIV infection. They need to be used under close supervision by specialists.

Topics: Anti-Bacterial Agents; Drug Interactions; Drug Therapy, Combination; Forecasting; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir

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

We report on 4 cases of urinary stone observed in patients treated with the drug Crixivan (Indinavir Sulfate) and review the literature. Comments include stone composition, clinical aspects, treatment and prevention.

Topics: Adult; Anti-HIV Agents; Calcium Oxalate; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Ureteral Calculi; Ureteroscopy; Urinary Calculi

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

Topics: Aspartic Acid Endopeptidases; Drug Resistance, Microbial; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Saquinavir

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nucleosides; Ritonavir; Saquinavir

Topics: Anti-HIV Agents; Clinical Trials as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Saquinavir

The effect of HIV type-1 (HIV-1) subtype on in vitro susceptibility and virological response to darunavir (DRV) and lopinavir (LPV) was studied using a broad panel of primary isolates, and in recombinant clinical isolates from treatment-naive, HIV-1-infected patients in the Phase III trial, AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS).. Patients received DRV/ritonavir (DRV/r) 800/100 mg once daily (n=343) or LPV/ritonavir (LPV/r) 800/200 mg total daily dose (n=346), plus a fixed daily dose of emtricitabine and tenofovir disoproxil fumarate.. DRV demonstrated high antiviral activity against a broad panel of HIV-1 major group (M) and outlier group (O) primary isolates in peripheral blood mononuclear cells, with a median 50% effective concentration (EC(50)) of 0.52 nM. Most (61%) patients in ARTEMIS harboured HIV-1 subtype B; other prevalent subtypes were C (13%) and CRF01_AE (17%); 9% harboured other subtypes. Median EC(50) values (interquartile range) for DRV were 1.79 nM (1.3-2.6) for subtype B, 1.12 nM (0.8-1.4) for C and 1.27 nM (1.0-1.7) for CRF01_AE. Virological response to DRV/r (HIV-1 RNA<50 copies/ml [intent-to-treat, time-to-loss of virological response algorithm]) was 81%, 87% and 85% for patients with subtype B, C and CRF01_AE infections, respectively. Similar results were observed in the LPV/r treatment group.. In vitro susceptibility to DRV was comparable across HIV-1 subtypes in a broad panel of primary isolates and in recombinant clinical isolates. Once daily DRV/r 800/100 mg and LPV/r 800/200 mg were highly effective in ARTEMIS irrespective of the HIV-1 subtype studied, confirming their broad anti-HIV-1 activity.

Topics: Adamantane; Adult; Analysis of Variance; Atazanavir Sulfate; Carbamates; Darunavir; Drug Resistance, Viral; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Microbial Sensitivity Tests; Molecular Typing; Nelfinavir; Neuraminidase; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Saquinavir; Sulfonamides; Viral Load

The aim of this work is to: (1) assess therapeutic drug monitoring of indinavir (IDV) during clinical routine practice in HIV-infected children, whose antiretroviral treatment includes IDV boosted with ritonavir (RTV), and (2) describe a possible relationship between IDV pharmacokinetics and MDR1 genotypes. In 21 ambulatory pediatric patients receiving IDV plus RTV, IDV plasma levels and MDR1 genotypes on exon 26 (C3435T) were determined. Nine of the 21 patients initially receiving 250 mg/m(2) IDV yielded trough levels below 0.10 microg/ml (median: 0.21, range: 0.04-1.31 microg/ml). When the dosage was increased to 400 mg/m(2) IDV plus 100 mg/m(2) RTV b.i.d., all, except 1 patient, achieved levels above 0.10 microg/ml. Pharmacokinetic analysis showed higher volume of distribution median values related to the C/C genotype in comparison with C/T or T/T genotypes for exon 26 (4.57 vs. 1.20 and 1.50 l/kg, respectively; p = 0.002). Although a higher median value of clearance was observed with the C/C genotype, the difference was not statistically significant (1.43 vs. 0.27 and 0.42 l/h, respectively; p = 0.052). These results may be explained by a reduced absorption of the drug, related with lower plasma IDV levels in patients carrying the C/C genotype in exon 26.

Topics: Adolescent; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Exons; Female; Genotype; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Polymorphism, Genetic; Ritonavir; Tissue Distribution

We evaluate by simulation three model-based methods to test the influence of a single nucleotide polymorphism on a pharmacokinetic parameter of a drug: analysis of variance (ANOVA) on the empirical Bayes estimates of the individual parameters, likelihood ratio test between models with and without genetic covariate, and Wald tests on the parameters of the model with covariate. Analyses are performed using the FO and FOCE method implemented in the NONMEM software. We compare several approaches for model selection based on tests and global criteria. We illustrate the results with pharmacokinetic data on indinavir from HIV-positive patients included in COPHAR 2-ANRS 111 to study the gene effect prospectively. Only the tests based on the EBE obtain an empirical type I error close to the expected 5%. The approximation made with the FO algorithm results in a significant inflation of the type I error of the LRT and Wald tests.

Topics: Adult; Algorithms; Analysis of Variance; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bayes Theorem; Computer Simulation; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Likelihood Functions; Male; Models, Biological; Models, Statistical; Nonlinear Dynamics; Pilot Projects; Polymorphism, Single Nucleotide; Software

To evaluate the pharmacokinetic compatibility of a ritonavir-boosted indinavir-fosamprenavir combination among patients with human immunodeficiency virus (HIV).. Single-center, nonrandomized, prospective, multiple-dose, two-phase pharmacokinetic study.. University research center.. Eight adult patients with HIV infection who had been receiving and tolerating indinavir 800 mg-ritonavir 100 mg twice/day for at least 2 weeks. Intervention. After 12-hour pharmacokinetic sampling was performed on all patients (period A), fosamprenavir (a prodrug of amprenavir) 700 mg twice/day was coadministered for 5 days, with a repeat 12-hour pharmacokinetic sampling performed on the fifth day (period B).. Pharmacokinetic parameters were determined for indinavir, ritonavir, and amprenavir: area under the concentration-time curve from time 0 to 12 hours after dosing (AUC(0-12)), maximum plasma concentration (C(max)), and 12-hour plasma concentration (C(12)). For each parameter, the geometric mean, as well as the geometric mean ratio (GMR) comparing period B with period A, were calculated. Indinavir C(max) was lowered by 20% (GMR 0.80, 95% confidence interval [CI] 0.67-0.96), AUC(0-12) was lowered by 6% (GMR 0.94, 95% CI 0.74-1.21), and C(12) was increased by 28% (GMR 1.28, 95% CI 0.78-2.10). Ritonavir AUC(0-12) was 20% lower (GMR 0.80, 95% CI 0.54-1.19), C(max) was 15% lower (GMR 0.85, 95% CI 0.55-1.32), and C(12) was 7% lower (GMR 0.93, 95% CI 0.49-1.76). With the exception of indinavir C(max), the changes in indinavir and ritonavir pharmacokinetic parameters observed after fosamprenavir coadministration were not statistically significant. The geometric means of amprenavir AUC(0-12), C(max), and C(12) were 41,517 ng*hour/ml (95% CI 30,317-56,854 ng*hr/ml), 5572 ng/ml (95% CI 4330-7170 ng/ml), and 2421 ng/ml (95% CI 1578-3712 ng/ml), respectively.. The combination of indinavir 800 mg-ritonavir 100 mg-fosamprenavir 700 mg twice/day appears to be devoid of a clinically significant drug-drug interaction and should be evaluated as an alternative regimen in salvage HIV treatment. This combination may be suitable as part of a background regimen to optimize the therapeutic benefit of newer classes of antiretroviral agents such as the integrase and coreceptor inhibitors in the treatment of multidrug-resistant viruses.

Topics: Adult; Area Under Curve; Carbamates; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Furans; Half-Life; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Organophosphates; Prodrugs; Ritonavir; Sulfonamides

We evaluated the safety and efficacy of a twice daily regimen containing 400 mg of indinavir and 100 mg of ritonavir in 32 human immunodeficiency virus (HIV)-infected women during pregnancy. The median indinavir trough concentration was 208 ng/ml during the third trimester. At delivery, 26 of 28 women on indinavir-ritonavir had HIV RNA levels of <200 copies/ml. No infant was HIV infected. These data are encouraging for the use of this combination for prevention of mother-to-child transmission of HIV.

Topics: Adult; Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

Data from clinical trials present numerous problems for the data analyst. These include non-compliance with the prescribed dosing regimen and inaccurate recollection of dosing history by patients as well as mistakes in recording data. Several methods have been proposed to address these issues. One such technique by Lu et al. (Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J. Pharmacokinet. Pharmacodyn. 28:343-362 (2001)) identifies occasions in pharmacokinetic (PK) data where the preceding dosing history is likely to be unreliable. We used this method, implemented in the software program NONMEM (beta) VI, to clean a dataset containing indinavir (IDV) plasma concentrations from HIV-1 infected patients. The data was also cleaned by inspection in Microsoft Excel using clinical PK criteria. A one-compartment model with first order absorption and elimination was fit to both sets of cleaned data. IDV population PK parameters obtained from these analyses were similar to those reported previously. It is established that IDV nephrotoxicity is related to high IDV exposure. However, no relationships were found between any PK parameters and nephrotoxicity in the "compliance cleaned" dataset. In the "PK cleaned" dataset, the oral clearance and apparent volume were lower by 9.1% and 6.6%, respectively in patients with any type of nephrotoxicity and the maximum IDV concentration (C(max)) was 12.1% higher. In patients suffering from nephrolithiasis in particular, C(max) was 15.5% higher. Accordingly, the use of the non-compliance detection method did not improve the reliability of our dataset over the usual method of applying clinical criteria. In fact, analyses on the compliance-cleaned dataset missed some exposure-toxicity relationships. Thus, automated methods must be tested rigorously with 'real life' datasets, used with caution, and always in conjunction with clinical reasoning to avoid overlooking a signal in noisy data.

Topics: Adult; Data Interpretation, Statistical; Databases as Topic; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney Diseases; Male; Models, Biological; Patient Compliance; Reproducibility of Results; Research Design; Software

We evaluated 19 children using 220-300 mg/m of indinavir (IDV) boosted with 100 mg ritonavir (RTV) (n = 12) or full-dose RTV (n = 7). Geometric mean (GM) (90% confidence interval, CI) of IDV Ctrough in children who took IDV with 100 mg RTV (n = 12) was 0.17 (0.06-0.50) mg/L. For children who took IDV with full-dosage RTV, GM (90% CI) was 0.40 (0.10-1.61) mg/L. C2hours were less than 10 mg/L in all subjects. Eighteen children had good virologic response. This report demonstrates that smaller IDV dosages given with RTV provide efficacious plasma concentrations and can be safely used.

Topics: Antiretroviral Therapy, Highly Active; Child; Drug Synergism; Female; HIV Infections; Humans; Indinavir; Male; Ritonavir; Thailand

To report the tolerance of indinavir combined with ritonavir (IDV/r 800/100 mg) twice daily (bid) in sub-Saharan African HIV-infected adults. HAART-naives patients started zidovudine plus lamivudine plus IDV/r 800/100 mg bid. Follow-up included standardized documentation of morbidity, CD4(+) cell count, creatininemia, plasma HIV-1 RNA, and IDV minimal plasma concentration (C(min)) measurements at month 1 (M1), M3, and M6. Seventy HIV-1-infected adults (68 women, median CD4 235/mm(3)) started HAART. At M6, 63% had undetectable viral load, and the median gain in CD4 since baseline was +128/mm(3). During the first 6 months, 21 patients experimented with 23 treatment modifications (reduction in IDV/r 400/100 mg bid, n = 11; switch to efavirenz, n = 11; zidovudine replaced by stavudine, n = 1), including 22 for digestive intolerance and 1 for severe anemia. At M1, M3, and M6, 67, 59, and 48 patients were still receiving IDV/r 800/100 mg bid, of whom 70%, 72%, and 60% had IDV Cmin above 5 ng/ml, respectively. In these patients, at M1, M3, and M6, the mean (+/- SD) IDV C(min) were 3431 +/- 3835 ng/ml, 2288 +/- 2116 ng/ml, and 1543 +/- 2398 ng/ml, respectively. There was no renal insufficiency of any grade, and no symptoms of urinary stones. The IDV/r 800/100 mg bid-containing regimen led to high IDV Cmin and a high rate of digestive intolerance. There was a surprising lack of nephrological side effects during the 6 months of follow-up, supporting the hypothesis that nephrological tolerance of IDV might be higher in sub-Saharan African individuals than in Americans or Europeans.

Topics: Adult; Cohort Studies; Cote d'Ivoire; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Indinavir; Male; Retrospective Studies; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

We here present the study results of 21 HIV-1 infected children who were treated with indinavir plus low-dose ritonavir and two nucleoside reverse transcriptase inhibitors (NRTIs) for 48 weeks. Although this q12h HAART regimen had potent antiretroviral activity, it was frequently associated with side effects and discontinuation of therapy.

Topics: Adolescent; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Male; Ritonavir

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Mali; Middle Aged; Pilot Projects; Ritonavir; Treatment Outcome

Treatment with indinavir/ritonavir (IDV/RTV) is very effective but hampered by frequent development of IDV-associated adverse events (mainly nephrotoxicity and skin changes). We tested whether dose reduction of IDV guided by therapeutic drug monitoring resulted in improved tolerability without compromising antiviral efficacy.. HIV-infected patients with any IDV/RTV regimen who suffer from IDV-related adverse events were included. Viral load had to be adequately controlled for at least 2 months prior to inclusion. Dose reduction from 800 mg to 600 or 400 mg IDV b.i.d. followed a specified protocol. IDV-related toxicity and IDV plasma concentrations were monitored for 24 weeks. IDV concentrations were quantified with a validated high performance liquid chromatography method.. Twenty patients were included. Reasons for inclusion were: skin abnormalities 11, nephrotoxicity five, metabolic disturbances three, and hypertension one. IDV dose could be lowered to 400 mg b.i.d. in 13, to 600 mg b.i.d. in two patients. Five patients discontinued the treatment. Overall tolerability improved with respect to incidence and severity of adverse events. Median trough concentrations decreased from 1.02 mg/l (range 0.08-7.1) at baseline to 0.48 mg/l (0.11-1.4) after 24 weeks (p = 0.03) and remained above the critical threshold of 0.1 mg/l at any time after dose reduction. There was no change of CD4 cell counts or viral suppression. There were no significant changes in other laboratory parameters (creatinine, bilirubin, triglycerides, cholesterol, blood count, and urinalysis).. Dose reduction of IDV improved tolerability of IDV-containing highly active antiretroviral treatment (HAART). Sufficient IDV trough concentrations were maintained in all patients as was virologic control.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Monitoring; Female; Germany; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypertension; Indinavir; Kidney Diseases; Male; Metabolic Diseases; Middle Aged; Prospective Studies; Ritonavir; Severity of Illness Index; Skin Diseases; Time Factors; Treatment Outcome; Viral Load

This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates.. Population PK of LMV, STV and ZDV was separately evaluated from plasma concentrations obtained in 54, 39 and 27 HIV1-infected patients, respectively, enrolled in the COPHAR1-ANRS102 trial. The primary objective of this trial was to study the pharmacokinetics of indinavir (IDV) and nelfinavir (NFV) in treated patients with a sustained virological response. Concentrations of nucleoside analogs (NA) were measured in plasma as a secondary objective. A one-compartment model with first-order elimination was used, with zero-order absorption for LMV and first-order absorption for STV and ZDV.. Mean parameters [interpatient variability in coefficient of variation (CV%)] of LMV, STV and ZDV were: oral volume of distribution (V/F) 145 l (52%), 24 l (81%) and 248 l (80%), oral clearance (Cl/F) 32 l/h, 16 l/h (74%) and 124 l/h (51%), respectively. For LMV, absorption duration (Ta) was 1.46 h (64%). For STV and ZDV, ka was 0.46 h(-1) and 2.9 h(-1), respectively. We found a systematic effect of combination with NFV vs. IDV. We found that intrapatient variability was greater than interpatient variability (except for STV) and greater than 55% for the three drugs.. This trial enabled the estimation of the population PK parameters of three NA in patients with a sustained virological response, and the median curves could be used as references for concentration-controlled strategies. We observed, as for the protease inhibitors, a great variability of PK parameters.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Interactions; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Models, Biological; Nelfinavir; Reverse Transcriptase Inhibitors; Stavudine; Tissue Distribution; Zidovudine

Our objective was to identify possible differences in protease inhibitor plasma concentrations between and within three protease inhibitor regimens (indinavir, saquinavir and lopinavir all in combination with low-dose ritonavir) and to relate these differences to safety and efficacy. Data originated from pre-defined pharmacokinetic substudies within two randomized 48-week trials evaluating the safety and efficacy of three protease inhibitor regimens. At weeks 4 and 48, plasma was collected and minimum drug plasma concentrations, C(min), were obtained. Out of 656 randomized patients, 283 patients had available C(min) at week 4. Indinavir, saquinavir and lopinavir C(min) were high when combined with low-dose ritonavir. No significant difference in the proportion of patients experiencing treatment failure could be found according to the C(min) within any treatment arm. A saquinavir C(min) > 2000 ng/ml was associated with an increased risk of gastrointestinal grade 3 or 4 adverse events and higher total cholesterol. Overall, there were no changes in C(min) from week 4 to week 48 in patients who remained on therapy. No association between treatment failure and the C(min) could be demonstrated. Associations between high C(min) and toxicity were identified in the saquinavir arm; therefore, dose reductions may be appropriate in certain patients with C(min) several times above the minimum effective concentration.

Topics: Adult; Double-Blind Method; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Saquinavir; Treatment Failure

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

The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce.. This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat.. One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10 HIV RNA was 4.0 (3.3-4.5) and CD4+ T-cell count 166 (40-323) cells/microl. After 112-weeks of study there was no significant difference observed between arms in the mean (SD) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P = 0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (SD) changes in time-weighted CD4+ T-cell count from baseline were similar [88 (84) cells/week/microl three times daily arm; 70 [109] cells/week/microl twice daily arm; P = 0.3).. RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800 mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further research.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Ritonavir; RNA, Viral; Time Factors; Viral Load; Zidovudine

The purpose of this study was to determine the pharmacokinetics and tolerability of three different indinavir and lopinavir/ritonavir dosing regimens.. HIV-infected adults receiving lopinavir/ritonavir 400/100 mg twice daily with food had nine plasma samples taken over a 12 h dosing interval at baseline (BL), after adding indinavir 600 mg twice daily for 10 days (R1), indinavir 800 mg twice daily for 5 days (R2) and lopinavir/ritonavir 533/133 mg plus indinavir 600 mg twice daily for 10 days (R3). Plasma samples were assayed using HPLC.. A total of 12 patients completed the BL visit [10 male; mean (SD) age=43.9 (5.8) years] and 9, 7 and 7 completed R1, R2 and R3 visits, respectively. Two subjects discontinued treatment due to hypertriglyceridaemia. Compared with BL, the R3 lopinavir AUC (P<0.05) and Cmin (P=0.0025) were significantly higher and the R2 AUC trended higher (P=0.09). The indinavir AUC (P=0.030) and Cmax (P=0.035) were significantly higher for R2 compared with R1. There was a trend for increased total bilirubin (TB) after the addition of indinavir (P=0.09). Lopinavir and indinavir AUC, Cmax and Cmin were associated with TB during univariate analyses (P<0.01) while only lopinavir AUC (P=0.0004) and indinavir AUC (P=0.0028) were associated with TB during multivariate analysis. Only indinavir AUC was significant when both drugs were included in the model (P=0.0028).. Elevated lopinavir and indinavir concentrations are associated with elevated TB.

Topics: Adolescent; Adult; Anti-HIV Agents; Bilirubin; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; HIV Infections; Humans; Indinavir; Lopinavir; Male; Middle Aged; Multivariate Analysis; Pyrimidinones

The aim of the study was to investigate relationships among indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes.. Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV-RNA.. Genetically determined CYP3A5 expressors had 44% faster indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log10 changes in HIV-RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA]7/[TA]7 genotypes. No relationships were identified with BCRP.. Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Base Sequence; Black People; Cytochrome P-450 CYP3A; DNA Primers; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Mitochondrial Proteins; Multidrug Resistance-Associated Proteins; Pharmacogenetics; Pilot Projects; Retrospective Studies; Ribosomal Proteins; Saccharomyces cerevisiae Proteins; Zidovudine

to assess the incidence and risk factors for insulin resistance (IR) in a cohort of naive HIV-infected patients 48 weeks after starting highly active antiretroviral therapy (HAART).. prospective, two centre, observational, cohort study.. One-hundred and thirty-seven patients who started HAART and maintained the same regimen for 48 weeks were included. IR was determined by the homeostasis model assessment (HOMA-IR) method. Individuals with a HOMA-IR value >3.8 were defined as insulin resistant. Independent associations with the development of IR at 48 weeks were evaluated.. Seventeen (12.4%) individuals showed a HOMA-IR value >3.8 at baseline and were excluded for incidence analyses. Fifteen patients developed IR at 48 weeks of HAART, giving an incidence of 13%. Independent predictors of the development or IR were indinavir exposure (beta-coefficient 5.45, 95% confidence interval [CI] 1.30-22.8; P=0.02), and hepatitis C virus (HCV) antibody positivity (beta-coefficient 5.22, 95% CI 1.34-20.33; P=0.01). The appearance of IR was associated with a higher BMI (beta-coefficient 1.72 for each 2 kg/m2 increase, 95% CI 1.54-1.94; P=0.02) and with the presence of lipodystrophy at 48 weeks (beta-coefficient 5.59, 95% CI 1.45-21.5; P=0.01).. HAART induces the development of IR in previously naive non-insulin-resistant HIV-infected individuals, with an incidence of 13% in the first year of therapy. Indinavir exposure, and HCV coinfection are associated with an increased risk of developing IR.

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Incidence; Indinavir; Insulin Resistance; Male; Risk Factors

In patients with extensive HIV resistance, one option is to delay salvage therapy until new drugs become available. We hypothesized that this delay period could be based on a simplified treatment, which would reduce drug toxicity, stabilize resistance, and prevent resurgence of wild-type virus.. A prospective 24-week treatment simplification study in HIV-1-infected patients having failed several lines of antiretroviral therapy, with CD4+ T-cell counts > or = 100 cells/ml, plasma HIV RNA (viral load [VL]) > or = 4 log10 copies/ml and a resistance genotype predicting less than two active drugs. Treatment associated ritonavir-boosted low-dose indinavir (200 mg twice daily) and lamivudine (150 mg twice daily). The primary endpoint was a decrease in CD4+ T-cell counts > or = 25% or increase in VL > or = 0.7 log copies/ml relative to baseline.. Twenty-six patients were included. Baseline median VL was 4.5 log10 copies/ml and median CD4+ T-cell count was 290 cells/ml. During the study, 10/26 patients (38%, 95% confidence interval = 20.2-59.4) reached the primary endpoint. No patient had an AIDS-defining event. At week 24, the median change in plasma VL was +0.2 log10 copies/ml (interquartile range (IQR): 0-0.5; P = 0.003). The median change in CD4+ T-cell counts was -49 cells/ml (IQR: -14 to -93, P < 0.001), with a median decline slope of 10 cells/ml/month, which was not different from that measured under full highly active antiretroviral therapy during the 6 months preceding inclusion. There were no significant changes in HIV-1 protease and reverse transcriptase genotypes during the study.. In patients with advanced resistance, treatment simplification prevented resurgence of wild-type HIV, reduced drug burden, but failed to stabilize progression of the immune deficiency.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Viral; Endpoint Determination; Female; France; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Pilot Projects; Ritonavir; Species Specificity; Viral Load

HIV-1 protease inhibitors (PIs) may improve hematopoietic functions owing to their direct effects on bone marrow (BM) progenitor cells. In this study we investigated this hypothesis evaluating the effect of adding ritonavir (RTV) and indinavir (IND) on hematopoietic colony formation assays by colony-forming cell (CFC) and long-term culture-initiating cell (LTC-IC) assays, on apoptosis, on cytokine production and stromal cells, in subjects with HIV-1 infection, and in seronegative controls. After PI addition, CFC and LTC-IC assays in HIV-1-infected patients showed levels of colony growth significantly higher than those observed at baseline; the same PI activity on colony formation was observed in healthy subjects. No significant modifications on Fas, the membrane form of Fas (mFas) and Fas-ligand (FasL) expression, and on cytokine production were observed at BM level after the addition of PIs. At baseline, in HIV-1-infected patients, the majority of the stromal cells appeared as large and rounded, whereas after the addition of RTV or IND the stromal cells exhibited a "fibroblast-like" morphology and produced higher stem cell factor (SCF) and lower MIP-1alpha levels when compared with the stromal production without the addition of IND. RTV and IND increased colony growth of BM obtained either from HIV-1-infected patients or from normal individuals, in parallel with the normalization of functional and morphological characteristics of stromal cells.

Topics: Adult; Apoptosis; Bone Marrow Cells; Cells, Cultured; Cytokines; Female; Hematopoietic Stem Cells; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir; Stromal Cells

To study the respective roles of indinavir concentrations and treatment adherence as predictors of early virologic response, we analyzed the patients of the APROCO cohort treated by indinavir 800 mg TID during the first 4 months. Minimum (Cmin), maximum (Cmax), and the ratio of the measured to expected concentrations (CR) were estimated for each patient at M4, from a population pharmacokinetic analysis of all data. The relationship among virologic success at M4 [plasma HIV RNA (VL) <500 copies/mL], baseline characteristics, estimated indinavir concentrations, and adherence score measured by a self-administered questionnaire, was analyzed by multivariate logistic regression. In the 216 studied patients, baseline median HIV RNA was 4.4 log10 copies/mL, and CD4 cell count was 309/mm. Virologic success was achieved in 195 (90%) patients; it was independently related to baseline viral load (OR = 0.524, CI 0.29-0.93; P = 0.03), antiretroviral treatment naive status (OR = 3.89, CI 1.29-11.76; P = 0.01), and indinavir Cmin (OR = 1.06, CI 1.02-1.10; P = 0.004) when adherence score was not included in the model, whereas full adherence was the only independent related factor when included in the model (OR = 8.8, 95% CI 2.85-27.3; P < 10). In the 168 fully adherent patients, virologic success was more frequent in patients with shorter duration of antiretrovirals at baseline (P = 0.03), lower baseline HIV RNA (P = 0.03), and higher indinavir CR (P < 10); the most discriminating Cmin cut-off was 194 ng/mL. Data on the relationship between indinavir plasma concentration and virologic success are therefore misleading without a concomitant assessment of adherence. These data suggest that any strategy of therapeutic drug monitoring must imply first a combined evaluation of plasma concentrations and adherence level and second an intervention target based on the results of both assessments.

Topics: Adult; Antiretroviral Therapy, Highly Active; Area Under Curve; CD4 Lymphocyte Count; Cohort Studies; Drug Administration Schedule; Female; France; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Multivariate Analysis; Observation; Patient Compliance; Prospective Studies; RNA, Viral; Time Factors; Treatment Outcome

Objectives To compare the efficacy and tolerability of indinavir (IDV)/ritonavir (RTV) at 800/100 and 400/100 mg twice daily (bid) in antiretroviral therapy (ART)-naive patients. Methods An open comparison of two groups of ART-naive patients treated with IDV/RTV 800/100 or 400/100 mg bid plus two nucleoside analogues was carried out. Viral load, CD4 cell count and tolerability were measured at baseline and at weeks 4, 12, 24 and 48. IDV plasma concentrations were measured retrospectively. Results A total of 107 patients were included in the study. Of these, 57 were treated with 800/100 and 50 with 400/100 mg IDV/RTV bid. At week 48, a viral load of <50 HIV-1 RNA copies/mL was achieved by 77 and 64% of the patients, respectively, and the median CD4 cell count increases were +171 and +164 cells/muL (intent-to-treat; P not significant), respectively. Side effects leading to protease inhibitor discontinuation occurred in 61% of subjects in the 800/100 mg group vs. 20% in the 400/100 mg group (P<0.0001). Switching from 800/100 to 400/100 mg dosage improved adverse events in 16 of 20 patients. IDV concentrations were above 0.15 mg/L in 89% of the 28 patients tested in the 400/100 mg group. Conclusions Indinavir/ritonavir 400/100 mg bid provided the same efficacy as 800/100 mg bid at 48 weeks in an ART-naive population, but safety and tolerance were significantly better for 400/100 mg, while convenience was also improved and cost was reduced.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cholesterol; Dose-Response Relationship, Drug; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir; Treatment Outcome; Triglycerides; Viral Load

Cellular HIV-1 DNA level was sequentially measured by quantitative polymerase chain reaction in 141 patients not previously treated with highly active antiretroviral therapy (HAART), who were enrolled in a 72-week randomized trial (ANRS 081 "Trianon") comparing 2 regimens, including 3 drugs from 2 classes (indinavir + stavudine + lamivudine, group 1) or 3 classes (indinavir + stavudine + nevirapine, group 2). The median decrease from baseline to week 72 in cellular HIV-1 DNA level was not significantly different between the 2 groups (0.54 and 0.45 log10 copies/10 peripheral blood mononuclear cells [PBMCs] in groups 1 and 2, respectively), whereas a higher proportion of patients maintained a plasma HIV-1 RNA level less than 20 copies/mL at week 72 in group 1 than in group 2 (79% and 52%; P = 0.0009). Furthermore, the difference in cellular HIV-1 DNA decrease from baseline to week 72 between patients who achieved a plasma HIV-1 RNA level less than 20 copies/mL at week 72 and those who did not was not statistically significant (0.54 and 0.45 log10 copies/10 PBMCs, respectively; P = 0.14). The decay in cellular HIV-1 DNA from baseline to week 72 was higher in antiretroviral-naive patients than in pretreated patients (0.55 and 0.23 log10 copies/10 PBMCs, respectively; P = 0.0008). The cellular HIV-1 DNA level change under therapy was best fitted to a 2-phase decay model with a junction point at week 16, from which its half-life was estimated at 18 weeks during the initial phase and at 104 weeks thereafter. In conclusion, the changes under therapy in cellular HIV-1 DNA level, which were mostly coincident to those of plasma HIV-1 RNA, did not add significant information to the comparison of the viral efficacy of the 2 studied regimens.

Topics: Adult; Anti-HIV Agents; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Leukocytes, Mononuclear; Male; Middle Aged; Nevirapine; Proviruses; RNA, Viral; Stavudine; Treatment Outcome

Protease inhibitors are an effective component of combination antiretroviral treatment for children infected with human immunodeficiency virus 1 (HIV-1), but tolerance or toxicity issues sometimes require an alternative therapeutic strategy.. HIV-1-infected children aged 2-17 years received combination therapy with either stavudine plus ritonavir or with zidovudine, lamivudine, and ritonavir as part of a randomized clinical trial. Twenty-one months after the start of the trial, ritonavir in capsule formulation became unavailable. The treatment regimen for 25 children was switched from ritonavir capsules to indinavir capsules (500 mg/m(2) every 8 h). The other study drugs remained unchanged. A matched-pairs analysis was performed to compare the results for these 25 children with the results for 25 matched children whose treatment regimen continued to include ritonavir (in liquid formulation).. There were no significant differences in the percentage of children with an HIV-1 RNA load of

Topics: Adolescent; Area Under Curve; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Infant; Male; Ritonavir; Viral Load

To study the pharmacokinetics of indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand.. This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24.. Median baseline values for CD4 and viral load were 13cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for indinavir AUC, Cmax and Cmin were 18.1 (15.3-23.8) mg/l x h, 4.1 (3.6-4.8) mg/l and 0.17 (0.12-0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an indinavir Cmin. below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) (P=0.30).. Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.

Topics: Administration, Oral; Adult; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Hospitals; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Thailand

The objectives of this study were to build a population pharmacokinetic model that describe plasma concentrations of indinavir in human immunodeficiency virus (HIV)-infected patients with sustained virological response under a stable antiretroviral combination, and to characterize the effect of covariates and co-medications on indinavir pharmacokinetics. Data were obtained from 45 patients who received different dosages of indinavir: either indinavir alone t.i.d. (mostly 800 mg), either indinavir b.i.d. (mostly 800 mg) with a booster dose of 100 mg of ritonavir. Patients were required to have a baseline plasma HIV RNA <200 copies/mL and to have unchanged antiretroviral treatment for 6 months. Indinavir concentrations were measured at a first visit (one sample before drug administration and five after) and at a second visit 3 months later (before and 1 or 3 h after drug administration). A one-compartment model with first-order absorption and first-order elimination best described indinavir pharmacokinetics. For patients treated with indinavir alone, absorption rate constant was estimated to be 0.43/h, and oral clearance Cl/F was 33 L/h. For patients treated with indinavir plus ritonavir these estimates were 0.25/h and 19 L/h, respectively. Cl/F was found to increase by 1.45-fold in men and by 1.18-fold in patients also receiving zidovudine. Oral volume of distribution (V/F) was 24 L. The inter-individual and intra-individual variability were 117 and 205% for V/F, 42 and 58% for Cl/F, respectively. This population analysis in patients with sustained virological response, quantified the effect of ritonavir on the absorption rate constant and on the clearance of indinavir, showed an increase of Cl/F in men and can be used to draw reference curve for therapeutic drug monitoring.

Topics: Adult; Aged; Algorithms; Antiretroviral Therapy, Highly Active; Area Under Curve; Bayes Theorem; Computer Simulation; Data Interpretation, Statistical; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Models, Statistical; Population; Sex Factors

Different studies have shown that most patients failing a first-line treatment containing a protease-inhibitor (PI) had low PI plasma levels and no PI-related resistance mutations. NOVAVIR was a randomized trial comparing stavudine/lamivudine/indinavir (d4T/3TC/IDV) and zidovudine/lamivudine/indinavir (AZT/3TC/IDV) in patients pretreated with AZT, didanosine (ddI) and/or zalcitabine (ddC) but naive for PIs.. To study the mechanisms of virological failure in NOVAVIR trial through analyses of genotypic resistance profiles of reverse transcriptase (RT) and protease (PR), and plasma IDV concentrations at time to failure.. Plasma HIV-RNA PR and RT sequences were determined in 27 failing patients (d4T/3TC/IDV n=11; AZT/3TC/IDV n=16) at baseline and at time to failure. IDV plasma measurements were performed in both samples.. At baseline, 20 out of the 27 patients had at least two thymidine analogs associated mutations. At time to failure, mutation M184V in the RT gene was present in 22 out of the 27 failing patients. Thirteen out of the 27 (48%) patients had acquisition of PI mutations compared to baseline sequence. Of the 26 patients with adherence data, 13 (50%) subjects were classified as having difficulty in adherence. The proportion of patients with low adherence was higher in the subgroup of patients failing without acquisition of new PI mutations.. In patients experienced with NRTIs, failure to PI-containing regimen may occur in spite of appropriate adherence to therapy and is associated with emergence of PI mutations in half of the cases. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favor the selection of PI resistance mutations.

Topics: Amino Acid Substitution; Drug Resistance, Viral; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Indinavir; Mutation; Treatment Outcome

To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations.. The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults.. Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection.. Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008).. The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.

Topics: Adult; Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Protein Binding; Ritonavir

We compared the response of two standard 3-drug regimens containing two-nucleoside reverse transcriptase inhibitor (Zidovudine +Lamivudine) plus either a protease inhibitor (PIs) (Indinavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs) (Efavirenz) among treatment-naïve or treatment-experienced HIV-infected persons. The obtained results will be compared to clinical trial findings. Through a retrospective study, we compared the virological and immunological response of 119 Tunisian HIV-1 infected patients (North Africa) who started for the first time/ in salvage use a triple antiretroviral treatment containing one NNRTI (group A1/group A2) or one PI (group B1/group B2). Viral load (VL) was analysed with Amplicor HIV-1 Monitor test and drug resistance mutations were examined by using two distinct line probe assays (LiPA). The analysis according to the received treatment showed an average of 0.45 log(10) drop in the mean VL among groups A2 and B2. For naïve patients, 62.5% of group A1 reached an undetectable VL versus 53.5% for group B1 (p < 0.001). With regard to the CD4 cell count change, we observed a mean increase of more than 65% versus baseline within group A1 in comparison with 42% for group B1 (p < 0.001). Genotypic resistance assays showed that patients of group A2 had significantly more resistance mutations than those of group B2 (2.66 vs. 0.75 (p = 0.0039)). Finally, 15 patients who were failing were switched to indinavir or efavirenz. When indinavir was replaced by efavirenz, we observed an increase in the plasma VL. With regard to the effects on immunological and virological outcome of patients using PIs or NNRTIs in a triple antiretroviral therapy, our observations in normal clinical practice supported the reported clinical trial findings but are not in favour of replacing indinavir by efavirenz in failing regimen.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Oxazines; Retrospective Studies; Treatment Outcome; Tunisia; Viremia; Zidovudine

Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir.. Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days 1 to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19.. Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng.h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng.h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed.. Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects.

Topics: Adolescent; Adult; Amlodipine; Calcium Channel Blockers; Diltiazem; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypertension; Indinavir; Male; Middle Aged; Ritonavir

The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir.. HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM).. The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males.. The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Netherlands; Ritonavir

Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity.. Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat.. Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved.. IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.

Topics: Adult; Aged; Alkynes; Anthropometry; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blood Glucose; CD4 Lymphocyte Count; Creatinine; Cyclopropanes; Disease Progression; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lipids; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load

The relationship between MDR1 single nucleotide polymorphisms (SNP) and the pharmacokinetic or pharmacodynamic responses to protease inhibitors has been recently challenged.. The objective of the present study was to determine whether MDR1 genetic polymorphisms in exons 21 and 26 (G2677T/A and C3435T) are in association with indinavir (IDV) plasma concentrations and/or therapeutic response to highly active antiretroviral therapy (HAART) in HIV-infected patients treated with unboosted IDV containing regimens.. MDR1 genotyping was performed in a population of 139 HIV-1-positive patients followed during 72 weeks, as part of the previous study called ANRS 081 'Trianon'. The primary study was a randomized trial comparing over 72 weeks the efficacy of two antiretroviral drug combinations in a population of adult HIV-1-infected patients: group 1, [lamivudine (3TC) - stavudine (d4T) - IDV (800 mg three times daily)] and group 2, [Nevirapine (NVP) - d4T - IDV (1000 mg three times daily)].. MDR1 SNPs analyzed separately or combined into haplotypes did not show any significant association with IDV pharmacokinetics nor response to HAART. Mean modelled IDV peak and trough concentrations, as well as clearance modelled from pharmacokinetic model, after 8 weeks of therapy were not significantly different between patients carrying the wild-type haplotype GG-CC (at position 2677 and 3435 respectively) and others.. Our results do not support an association between MDR1 genetic polymorphisms and modelled IDV clearance or clinical response to HAART.

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; Gene Frequency; Genes, MDR; Genotype; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Polymorphism, Genetic

Six HIV-positive antiretroviral experienced patients initiating therapy with a regimen including lopinavir/ritonavir (400/100 mg twice per day) and indinavir (800 mg twice per day) underwent steady-state pharmacokinetic analysis. The AUC0-12 h of indinavir when combined with lopinavir/ritonavir was comparable with previously published data on indinavir/ritonavir 800/100 mg twice per day in HIV-infected individuals. However, lopinavir AUC0-12 h, Cmax, and C12 h were lower than previously reported in the absence of indinavir. The regimen was well tolerated, although 2 patients developed grade 3 hypertriglyceridemia. No patient discontinued the regimen because of indinavir-related urologic or retinoid-type adverse effects. Further study of the regimen with larger cohorts of patients is necessary.

Topics: Adult; Area Under Curve; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypertriglyceridemia; Indinavir; Lopinavir; Male; Metabolic Clearance Rate; Pyrimidinones

To describe plasma concentrations of indinavir alone or combined with ritonavir, and of nelfinavir and its active metabolite M8, and to measure their variabilities in HIV-infected patients treated with a stable antiretroviral regimen and experiencing a sustained virological response for at least 12 months.. In this prospective trial, blood samples were drawn during a 6-hour time interval between two doses at enrolment to assess protease inhibitor (PI) pharmacokinetic parameters, and 4 months later to assess plasma trough and peak concentrations. Safety and adherence assessments and laboratory data were collected during an 8-month period. PI pharmacokinetic characteristics were analysed using a non-compartmental approach. Inter- and intrapatient variabilities were estimated using a linear mixed-effect model. The impact of different covariates on plasma trough concentrations was investigated. Eighty-eight patients were analysed: 42 treated with indinavir and 46 with nelfinavir.. The interquartile range (IQR) of the plasma trough concentration corrected for the sampling time (Ccalc) was 116-374 microg/L for indinavir alone and 163-508 microg/L for indinavir/ritonavir. Ritonavir significantly increased indinavir elimination half-life and plasma exposure. For nelfinavir, the IQR of Ccalc was 896-2059 microg/L for three-times-daily administration and 998-2124 microg/L for twice-daily administration. Variabilities were high for both PIs. Intrapatient variability for indinavir alone (and indinavir + ritonavir) was 76% (107%) and interpatient variability was 58% (10%) in adherent patients. Intrapatient variability for nelfinavir three times daily (and twice daily) was 41% (74%) and interpatient variability was 62% (50%). Intrapatient variability was lowered in patients with a high adherence level.. Although performed in a homogeneous population, this study documented a high interpatient but also intrapatient variability of indinavir and nelfinavir pharmacokinetics, which should be taken into account when interpreting therapeutic drug monitoring. Once patients have reached a sustained virological response, plasma PI monitoring may have a limited impact.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Multicenter Studies as Topic; Nelfinavir; Patient Compliance; Prospective Studies; Ritonavir; Viral Load

To evaluate the efficacy and safety of indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily in antiretroviral-therapy-naive Thai HIV-1-infected patients.. This was an open-label, non-randomized single arm study. Antiretroviral-naive patients (n=80) with CD4+ cell count < 200 x 10(6)/l were started on stavudine and lamivudine plus indinavir/ritonavir 400/100 mg twice daily. CD4+ cell count and HIV RNA were determined at week 0, 12, 24, 48 and 96. HIV RNA was measured to a level of 50 copies/ml by RT-PCR assay. Primary analysis was statistically performed as intent to treat. The primary endpoint was the percentage of patients with plasma HIV RNA below 50 copies/ml at week 96.. Eighty antiretroviral-therapy-naive patients with median CD4+ cell count 19 x 10(6)/l (range: 2 - 197 x 10(6)/l) and median baseline plasma HIV RNA of 174,000 copies/ml (range 16,800-750,000 copies/ml) were enrolled. In the intent-to-treat analysis at week 96, the proportion of patients with HIV RNA of <50 copies/ml was 68.8% (95% confidence interval [CI]: 68.3-69.3), whereas it was 88.7% (95% CI: 88.1-89.3) in the on-treatment analysis at week 96. The regimen was well tolerated. Hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia were found in 8.3, 33.3 and 37.0% of the patients, respectively. Treatment was stopped in 18 patients; two from intolerance, two switched therapy, four as a result of serious adverse event-related death, and ten were lost to follow-up.. Our study demonstrates that indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily, the least expensive boosted protease inhibitor, appears to be effective and safe up to 96 weeks despite high baseline viraemia and low CD4+ cell count in antiretroviral-naive patients.

Topics: Administration, Oral; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypercholesterolemia; Hyperglycemia; Hypertriglyceridemia; Indinavir; Lamivudine; Male; Ritonavir; RNA, Viral; Stavudine; Thailand; Treatment Outcome; Viral Load; Withholding Treatment

Rifampin is an important drug in the treatment of tuberculosis, but administration of rifampin in combination with protease inhibitors is complicated because of drug-drug interactions. A prospective, controlled, multiple-dose study involving 6 HIV-infected patients receiving a combination of indinavir (800 mg) and ritonavir (100 mg) twice a day was performed to evaluate whether the inducing effect of rifampin on the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 could be overcome by the inhibitory effect of ritonavir. Pharmacokinetic evaluations of steady-state concentrations of indinavir and ritonavir were performed before and after administration of rifampin (300 mg every day for 4 days). An 87% reduction (from 837 to 112 ng/mL) in median indinavir and a 94% reduction (from 431 to 27 ng/mL) in median ritonavir concentrations were seen 12 h after the last dose of rifampin was administered (P=.031). These results strongly indicate that the administration of rifampin with a combination of indinavir (800 mg) and ritonavir (100 mg) could lead to subtherapeutic concentrations of indinavir.

Topics: Adult; Antitubercular Agents; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Middle Aged; Prospective Studies; Rifampin; Ritonavir

Most of the studies evaluating rash in HIV-positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI.. We evaluated all cases of rash observed during a 48-week randomized multicentre trial in 1251 nucleoside-experienced patients who started treatment with protease inhibitors (ritonavir or indinavir) at CD4 counts below 50 cells/microL. Incidence rates for rash were calculated according to gender, clinical status, age, use of highly active antiretroviral therapy (HAART), Pneumocystis carinii pneumonia (PCP) prophylaxis and use of individual antiretroviral drugs at enrollment. Differences between groups defined according to the above characteristics were tested for statistical significance using the log-rank test in a Kaplan-Meier survival analysis. All factors that gave results in the univariate analyses below the significance level of 0.05 were included in a multivariate analysis using a Cox regression model.. During a follow-up period of 9690 person-months, 66 patients (5.3%) developed rash (0.68 events/100 person-months). In the univariate analyses, risk of rash did not differ with trial treatment (indinavir or ritonavir), clinical status, PCP prophylaxis, or age. During follow-up, rash was observed in 7.5% of enrolled women and in 4.5% of enrolled men (P=0.03). Serious rash occurred in 4.5% of enrolled women and in 1.6% of enrolled men (P=0.003). Use of HAART (P<0.001) and inclusion of zidovudine and of zalcitabine in the prescribed regimen (P=0.02) appeared to be associated with a lower risk of rash. In the multivariate analysis, the variables that remained significantly predictive of rash were gender (risk for women compared to men: 1.65, 95% confidence interval (CI): 1.00-2.72, P=0.048) and use of a non-HAART regimen (risk for non-HAART patients compared to HAART: 2.73, 95% CI: 1.49-5.02, P=0.001).. In our study, about 5% of HIV-positive patients who started treatment with protease inhibitors at very low CD4 counts developed rash, generally in the first few weeks after treatment. Risk was significantly higher in women and in patients who did not receive a HAART regimen. Our data indicate that women have a higher risk of rash than men, also with regimens that do not include NNRTI.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Drug Eruptions; Exanthema; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Risk Factors; Ritonavir; Sex Factors; Viral Load

Plasma and cervicovaginal secretion (CVS) samples were collected from 19 human immunodeficiency virus type 1-infected women on lopinavir- or indinavir-containing regimens. Lopinavir and indinavir were detectable in 29 and 93% of CVS samples, respectively, a finding that may be ascribed to these drugs' differences in protein binding and pK(a). The relationship between lopinavir and indinavir pharmacodynamics and viral evolution in the female genital tract should be assessed over time.

Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Female; Genitalia, Female; HIV Infections; HIV-1; Humans; Indinavir; Lopinavir; Protein Binding; Pyrimidinones; Vagina

AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (n = 8), the median predose indinavir concentration (C(0)) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1000 mg of indinavir every 12 h with nelfinavir (n = 10), the median indinavir C(0) was <10 ng/ml (range, <10 to 3740 ng/ml; six subjects had a value of <10 ng/ml), and the C(12 h) was 44 ng/ml (range, <10 to 4236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1200 mg of indinavir every 12 h with nelfinavir (n = 7) had a C(0) of 146 ng/ml (range, 58 to 5215 ng/ml) and a C(12 h) of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h]; P < 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median C(0) value for nelfinavir (n = 9) was 1,779 ng/ml (range, <187.5 to 4579 ng/ml), and the C(12 h) was 1554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Blotting, Western; Female; Half-Life; HIV Infections; Humans; Indinavir; Male; Nelfinavir

To compare CC chemokine mRNA levels from native peripheral blood mononucleated cells (PBMCs) before and 6 months after the initiation of two different regimens of highly active antiretroviral therapy (HAART), we treated group 1 (n = 11) with two nucleoside analogues and the protease inhibitor (PI) indinavir boosted by ritonavir (800/100 mg b.i.d.); group 2 (n = 8) was treated with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz instead of PI. CC chemokine mRNA levels (regulated upon T cell activation expressed secreted [RANTES], macrophage inhibitory protein [MIP]-1alpha, MIP-1beta, monocyte chemotactic protein [MCP]-1, MCP-2) were quantified from PBMCs before and 6 months after the initiation of HAART using a reverse transcription/real-time polymerase chain reaction (PCR) assay. The mRNA levels of MCP-1 and MCP-2 were significantly decreased in both groups (P < 0.05), while MIP-1alpha and MIP-1beta were decreased significantly only in the PI-treated group, but not in the NNRTI group. A moderate decrease of RANTES was observed in both treatment groups. The data suggest that HAART regimens containing either NNRTI or PI are not equivalent with regard to modification of CC chemokine mRNA profiles.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokine CCL8; Chemokines; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Leukocytes, Mononuclear; Macrophage Inflammatory Proteins; Male; Middle Aged; Monocyte Chemoattractant Proteins; Oxazines; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Messenger

To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir.. Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir.. At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir.. Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.

Topics: Adult; Area Under Curve; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Drug Combinations; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Mass Spectrometry; Middle Aged; Pyrimidinones; RNA, Viral; Semen; Viral Load

An equivalence (non-inferiority) trial comparing antiviral response, tolerability, and adherence with a triple nucleoside regimen containing abacavir 300 mg (ABC) plus a lamivudine 150-mg/zidovudine 300-mg combination tablet (COM) twice daily vs. a regimen containing the protease inhibitor indinavir (IDV) 800 mg three times daily plus COM twice daily (IDV/COM) in antiretroviral-naïve, HIV-infected patients.. Adult patients with plasma HIV-1 RNA levels > or = 5000 copies/mL and CD4+ cell counts > or = 100 cells/mm(3) were randomized to receive open-label ABC/COM (n = 169) or IDV/COM (n = 173) for 48 weeks. The intent-to-treat (ITT) population was the primary population evaluated. ITT: switch/missing equals failure (ITT: S/M = F) and as-treated (AT) analyses were used for assessing the proportion of patients achieving plasma HIV-1 RNA level < 400 and < 50 copies/mL at each clinic visit. In the ITT: S/M = F analysis, patients who switched treatment or had missing values were considered treatment failures; the AT analysis examined virologic data only while patients received study treatment. ABC/COM was considered equivalent (non-inferior) to IDV/COM if the lower limit of the 95% confidence intervals (CIs) about the difference in proportions of ABC/COM- vs. IDV/COM-treated patients attaining plasma HIV-1 RNA < 400 copies/mL exceeded -15% at week 48.. The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log(10) copies/mL and CD4+ cell count was 315 cells/mm(3). ABC/COM met the criterion of equivalence to IDV/COM. In the ITT: S/M = F analysis at Week 48, a greater proportion of ABC/COM-treated patients achieved HIV-1 RNA < 400 copies/mL (66% [109/164] vs. 50% [82/165]; treatment difference 16.6%, 95% CI (6.0, 27.2), p = 0.002) and HIV-1 RNA < 50 copies/mL (60% [99/164] vs. 50% [83/165]; treatment difference 9.6%, 95% CI [-1.1, 20.2]), whereas the AT analysis showed similar proportions achieving these endpoints (< 400 copies/mL: 85 vs. 83%; < 50 copies/mL: 79 vs 81%). Comparable proportions of patients with screening HIV-1 RNA values > 100 000 copies/mL achieved HIV-1 RNA < 400 copies/mL (ABC/COM: 60% [35/58]; IDV/COM: 51% [33/65]; treatment difference 9.6%, 95% CI [-7.9, 27.1]; ITT: S/M = F analysis). A significantly greater proportion taking ABC/COM were > or = 95% adherent (72% [109/151] vs. 45% [70/154] with IDV/COM, p < 0.001). Median increases from baseline in CD4+ cell counts were similar in the two treatment groups (+148 vs. +152 cells/mm(3)). Significantly more patients on IDV/COM reported drug-related adverse events (87% [142/165] vs. 65% [108/164] with ABC/COM, p < 0.001), similar proportions discontinued treatment due to adverse events (13 vs. 10%), and a slightly greater proportion in the ABC/COM group reported serious adverse events (13 vs. 8%). About half of the latter comprised suspected ABC-related hypersensitivity reactions (overall rate, 6%). Most adverse events were gastrointestinal in nature in both treatment groups.. ABC/COM was at least equivalent to IDV/COM over 48 weeks in the treatment of antiretroviral-naïve patients. ABC/COM was associated with a significantly higher adherence rate and lower incidence of drug-related adverse events than IDV/COM. The study was limited in that it was not powered to determine equivalence of treatments within high vs. low viral load strata, adherence was not monitored electronically, and bias could not be ruled out due to the open-label study design.

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Patient Compliance; Reverse Transcriptase Inhibitors; RNA; Surveys and Questionnaires; Therapeutic Equivalency; Treatment Outcome; Zidovudine

To compare dosing convenience and adherence with abacavir (ABC) 300 mg plus a fixed-dose lamivudine 150 mg/zidovudine 300 mg combination tablet (COM) twice daily versus indinavir (IDV) plus COM twice daily in treatment-naïve, HIV-1-infected adults; and to evaluate the association among difficulty taking antiretroviral regimens, adherence, and virologic efficacy.. An open-label, randomized, multicenter, international study compared the COM/ABC and IDV/COM regimens with respect to self-reported adherence and regimen convenience over 48 weeks. Logistic regression analysis (LRA) was done on a patient sub-sample from both groups to evaluate predictors of adherence and virologic response at last time-point on randomized therapy (LTORT).. The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log(10) copies/mL and CD4+ cell count was 315 cells/mm(3). Of 329 patients who were randomized and received treatment, 315 (96%) provided adherence data. Significantly more patients in the ABC/COM group than in the IDV/COM group reported > or = 95% adherence to therapy (76 vs 58%, p < 0.001) and no difficulty in taking their regimen (91 vs 61%, p < 0.001). In both groups, the highest probability of HIV-1 RNA < 400 copies/mL occurred when median adherence was > or = 95%. The probability of HIV-1 RNA < 400 copies/mL declined more rapidly in the IDV/COM group as adherence rates decreased. LRA showed that no difficulty taking any of the drugs in the regimen, ABC/COM treatment group, and male gender were independent significant predictors of > or = 95% adherence (p < 0.05). Median adherence and baseline HIV-1 RNA were significant predictors of HIV-1 RNA < 400 copies/mL (p < 0.05).. Patients reported greater ease of use and superior adherence to ABC/COM than IDV/COM. Patient-reported difficulty taking drugs in a regimen was predictive of reduced adherence, and both of the latter factors were predictive of poorer virologic outcome. Adherence levels of > or = 95% in both treatment groups maximized the probability of patients achieving an HIV-1 RNA < 400 copies/mL.

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Patient Compliance; Reverse Transcriptase Inhibitors; Risk Factors; Treatment Outcome; Zidovudine

Lipoprotein disorders in HIV-positive patients receiving highly active antiretroviral therapy (HAART) are becoming a major concern in HIV treatment, since there is growing evidence for an association between HAART-induced hyperlipidemia and increased cardiovascular risk. Yet relatively few data are available on the possible interactions of HAART and treatment with statins.. In this prospective study, 25 HIV-positive, treatment-experienced patients (five female, 20 male, all Caucasian) were treated with either fluvastatin or pravastatin. Total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels, and serum triglycerides were determined at regular intervals, as well as therapeutic drug monitoring to assess possible drug interactions.. In 13 pravastatin-treated patients, a decrease in total cholesterol levels (from 7.12 mmol/l to 6.29 mmol/l) after 12 weeks of therapy was seen. In 12 patients treated with fluvastatin, a permanent reduction of total cholesterol (from 6.46 mmol/l to 5.31 mmol/l) after 12 weeks was observed. The reduction of LDL levels was 30.2% in the fluvastatin group and 14.4% in the pravastatin group. In eight patients receiving an indinavir-containing HAART, indinavir plasma levels were not significantly influenced. No effect on triglycerides or HDL was observed.. Fluvastatin and pravastatin are efficient in lowering total and LDL cholesterol levels in HIV-positive patients receiving HAART. Furthermore, no influence on indinavir plasma levels could be observed. Therefore, both compounds seem to be a viable treatment option in HAART-induced hypercholesterolemia.

Topics: Adult; Anticholesteremic Agents; Antiretroviral Therapy, Highly Active; Fatty Acids, Monounsaturated; Female; Fluvastatin; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Indinavir; Indoles; Male; Middle Aged; Pravastatin; Prospective Studies; Treatment Outcome

In AIDS Clinical Trial Group (ACTG) study 320, triple-combination antiretroviral therapy including indinavir significantly slowed progression to acquired immunodeficiency syndrome or death, compared with treatment with dual nucleoside reverse-transcriptase inhibitors (NRTIs) alone, in zidovudine-experienced patients with advanced human immunodeficiency virus (HIV) infection. We examined the impact of indinavir on quality of life in participants from this study.. A total of 1156 protease inhibitor- and lamivudine-naive patients stratified by CD4 cell count (

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Quality of Life; Reverse Transcriptase Inhibitors; Sickness Impact Profile; Survival Analysis; Zidovudine

Indinavir is currently used at a fixed dose of 800 mg either three times a day or twice a day in combination with 100 mg of ritonavir. Dosage individualization based on plasma concentration monitoring might, however, be indicated. This study aimed to assess the pharmacokinetic profile of indinavir in patients infected with human immunodeficiency virus to characterize interpatient and intrapatient variability and to build up a Bayesian approach for dosage adaptation. A population analysis was performed with the NONMEM computer program with 569 plasma samples from a cohort of 239 unselected patients receiving indinavir. A one-compartment model with first-order absorption was adapted, and the influences of clinical characteristics on oral clearance (CL) and distribution volume (V) were examined. Predicted average drug exposure and trough and peak concentrations were derived for each patient and correlated with efficacy and toxicity markers. The population estimates of CL were 32.4 liters/h for female and 42.0 liters/h for male patients; oral V was 65.7 liters; and the rate constant of absorption (K(a)) was 1.0 h(-1). CL decreased by 63% with ritonavir intake and was moderately correlated to body weight. Both interpatient variability, best assigned to oral CL (coefficient of variation [CV], 39%) and K(a) (CV, 67%), and intrapatient variability were large (CV, 41%; standard deviation, 670 microg/liter). In conclusion, initial indinavir dosage should be decided according to ritonavir intake and sex, prior to plasma concentration measurements. The high interpatient pharmacokinetic variability represents an argument for therapeutic drug monitoring.

Topics: Adolescent; Adult; Aged; Algorithms; Bayes Theorem; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Models, Biological; Population

We evaluated phenotypic and genotypic markers of drug resistance in human immunodeficiency virus type 1 (HIV-1) at the time of virologic failure (VF) in subjects in the AIDS Clinical Trials Group Protocol 388 (ACTG 388) who received lamivudine-zidovudine (or lamivudine-stavudine) and either indinavir, efavirenz-indinavir, or nelfinavir-indinavir. At VF, phenotypically susceptible HIV-1 was found in 55% of subjects in the nelfinavir-indinavir arm, compared with 22% in the indinavir arm (P=.006). Phenotypic resistance to lamivudine was less common in the efavirenz-indinavir arm (33% of subjects; P=.002) and the nelfinavir-indinavir arm (43%; P=.003), compared with the indinavir arm (78%). Isolated phenotypic resistance to efavirenz at VF occurred in HIV-1 recovered from 33% of subjects in the efavirenz-indinavir arm; 24% of the subjects had HIV-1 with both efavirenz and lamivudine resistance. Results of genotypic tests were similar. The lower frequency of resistance in the nelfinavir-indinavir arm likely reflects decreased drug exposure that is due to intolerance, which is consistent with the lower potency and tolerability of this combination in ACTG 388. The lower frequency of lamivudine resistance in the efavirenz-indinavir arm is consistent with reports in other studies of potent regimens. Thus, although dual resistance to efavirenz and lamivudine occurred at VF in the efavirenz-indinavir arm, this risk was relatively low when evaluated in the context of the potency and tolerability of this regimen.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Male; Nelfinavir; Phenotype; Stavudine; Treatment Failure; Zidovudine

HIV-infected subjects who have lipodystrophy and insulin resistance on prolonged antiretroviral therapy have elevated levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) antigens, markers of impaired thrombolysis that are associated with hyperinsulinemia and increased cardiovascular risk. We studied HIV-infected, protease inhibitor (PI)-naive adults treated with indinavir (n = 11) or amprenavir (n = 14) plus two nucleoside reverse transcriptase inhibitors enrolled in two independent prospective trials. Antiretroviral and immune responses were similar in both studies. Over 8 wk, indinavir was associated with decreased insulin sensitivity, whereas amprenavir was not. Levels of tPA antigen declined by approx 25% with both treatments (p < 0.05 for each); levels of PAI-1 antigen did not change. Levels of the inflammatory marker soluble tumor necrosis factor-alpha receptor II (sTNFr2) correlated positively with tPA antigen (r = 0.33, p = 0.02), and mean (SD) plasma concentrations of sTNFr also declined with treatment (4.44 +/- 1.11 ng/mL pretherapy, 3.75 +/- 1.21 posttherapy, p = 0.007). Short-term improvement in a marker of impaired thrombolysis and increased vascular risk can occur during PI-based antiretroviral therapy, perhaps as a consequence of improvement in HIV-related inflammation. This improvement occurred independent of development of insulin resistance, which occurred only with indinavir.

Topics: Adult; Biomarkers; Blood Glucose; Carbamates; Drug Therapy, Combination; Female; Fibrinolysis; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Inflammation; Insulin Resistance; Male; Plasminogen Activator Inhibitor 1; Prospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Sulfonamides; Tissue Plasminogen Activator

Pharmacokinetic enhancement of protease inhibitors (PIs) with low-dose ritonavir (RTV) for salvage therapy is increasingly common. The purpose of this study was to compare the pharmacokinetics, safety, and tolerability of indinavir (IDV)/RTV at 800/200 mg (arm A) and 400/400 mg (arm B) administered twice daily in HIV-infected subjects failing their first PI-based regimen.. A phase I/II, randomized, open-label, 24-week study was conducted. Formal 12-hour pharmacokinetic evaluations were performed, and study visits occurred at baseline; at weeks 1, 2, and 4; and every 4 week thereafter for 24 weeks. Clinical symptoms and laboratory assessments were collected. Subjects were allowed to switch arms because of toxicity.. Forty-four subjects were enrolled (22 per arm). IDV predose concentration, maximum plasma concentration and area under the curve were significantly higher in arm A. Fifty-five percent and 45% of subjects in arms A and B responded (<200 copies/mL at week 24; P = 0.76), respectively. CD4 cell responses were similar. All subjects had IDV-sensitive virus at baseline and at virologic failure. Tolerability was comparable, but all grade 3 or higher triglyceride increases occurred in arm B and more subjects in arm B switched because of toxicity (5 vs. 1 triglyceride increases).. This is the largest formal pharmacokinetic evaluation of 2 dosage combinations of IDV/RTV in HIV-infected individuals. Pharmacokinetic parameters were consistent with previous results in patients but lower than in seronegative controls. Both regimens exhibited similar tolerability and response rates. High toxicity with a low response suggests that the optimum IDV/RTV combination would include an RTV dose <400 mg and an IDV dose <800 mg in this population.

Topics: Adolescent; Adult; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Drug Administration Schedule; Drug Therapy, Combination; Ethnicity; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir; RNA, Viral; Substance Abuse, Intravenous; Viral Load

Human immunodeficiency virus (HIV) patients on nucleoside or nucleotide reverse transcriptase inhibitors with HIV RNA at <1,000 copies/ml were randomized in an open-label study to administration of combined indinavir/ritonavir (IDV/RTV) at 667/100 mg every 12 h (q12h) or IDV alone at 800 mg q8h to determine the regimens' pharmacokinetics. On day 14, plasma IDV and RTV levels were determined over 24 h. Noncompartmental pharmacokinetics (minimum concentration of drug in serum [C(min)], area under the concentration-time curve from 0 to 24 h [AUC(0-24)], and maximum concentration of drug in serum [C(max)]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C(min) ratio of the combination compared to IDV alone regimen would be >/=2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C(min), AUC(0-24), and C(max) for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM . h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C(min) (90% CI, 4.0, 9.3), an increase in AUC(0-24) (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C(max). Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C(min) for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C(max) was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.

Topics: Area Under Curve; Dose-Response Relationship, Drug; Endpoint Determination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir

We assessed the pharmacokinetics of three different doses of indinavir in five patients. All doses achieved trough concentrations above efficacy thresholds. Toxic trough concentrations were observed in all patients receiving 800 mg, in two patients receiving 600 mg, and in none receiving 400 mg. Indinavir at 400 mg may be efficacious and less toxic in patients taking ritonavir and efavirenz.

Topics: Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; China; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Interactions; HIV Infections; Humans; Indinavir; Male; Middle Aged; Oxazines; Ritonavir

Topics: Adult; CD4 Lymphocyte Count; Cholesterol; Cohort Studies; Drug Therapy, Combination; Dyslipidemias; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Pyrimidinones; Retrospective Studies; Ritonavir; Treatment Outcome; Triglycerides; Viral Load

HIV-1 RNA levels in semen and blood compartments decrease below detection limits during highly active antiretroviral therapy. Despite these therapeutic effects, it is clear that persistent, latent HIV-1 reservoirs are capable of rebounding in the absence of drug treatment or by evolution of escape mutants remain. The current study was designed to examine the presence of latent virus in semen and blood compartments and its evolution following potent combination therapy with indinavir (protease inhibitor) and efavirenz [nonnucleoside reverse transcriptase (RT) inhibitor]. Using an ultrasensitive in situ hybridization assay HIV-1 mRNA was detected in cultured seminal and blood mononuclear cells in all patients up to 1789 days posttherapy. Higher levels of HIV-1 mRNA were consistently detected in seminal mononuclear cells as compared to peripheral blood mononuclear cells (PBMC) in all time points analyzed posttherapy. Analysis of viral RNA from cultured PBMC before and after therapy displayed no evidence of therapy-induced drug resistance in the viral polymerase gene in the majority of patients. However, distinct envelope populations were detected in these viral RNA populations following therapy, indicating possible selection of quasispecies. The observed ongoing replication and evolution in the PBMC viral envelope sequences likely occurred in the seminal compartment HIV populations, given that the seminal cells showed the ability to express HIV-1 mRNA following cultivation. This together with our previous studies (Gupta P, et al.: J Infect Dis 2000;182:79-87) suggest that the genital and blood compartments likely serve as distinct reservoirs harboring latent HIV-1 during prolonged drug therapy.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cells, Cultured; Cyclopropanes; Evolution, Molecular; HIV Infections; HIV-1; Humans; Indinavir; Leukocytes, Mononuclear; Molecular Sequence Data; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Semen; Sequence Analysis, DNA; Viral Load; Virus Latency

Topics: Adult; Antiretroviral Therapy, Highly Active; C-Reactive Protein; Cohort Studies; Coronary Artery Disease; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Risk Factors

To evaluate health-related quality of life (HRQoL) changes in patients treated with indinavir three-times daily after switching to a twice-daily indinavir/ritonavir regimen or continuing with the same regimen.. Patients on HAART including indinavir three-times-daily with undetectable viral load were randomly assigned to continue with this therapy or to change to a twice-daily indinavir/ritonavir (800/100 mg) regimen. The Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire was used as the HRQoL measure.. A total of 118 patients participated in the study, of which 59 (50%) were randomly assigned to continue with the three-times-daily regimen. Patients had a mean age of 39 years and 80% of them were male. At baseline, subjects included in the three-times-daily group presented a significantly greater number of symptoms than subjects in the twice-daily group, but no statistically significant differences were observed in MOS-HIV scores between the groups. In the intention-to-treat (ITT) analysis, a reduction in HRQoL scores was observed in both groups, which was greater in the twice-daily group. In the per protocol analysis, reduction of HRQoL was minimal.. A HRQoL deterioration, greater in the twice-daily group, was observed in this study in the ITT analysis, while HRQoL remained stable in both groups in patients who continued with and tolerated the allocated regimen.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Quality of Life; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load

The combination of indinavir, a protease inhibitor, and reverse-transcriptase inhibitors is widely used in the treatment of HIV-1 infection. However, precipitation of indinavir crystals in the renal tubular lumen due to the drug's aqueous insolubility may result in characteristic symptoms of flank pain or classic renal colic. An in vitro study has shown that addition of escin to synthetic urine containing indinavir delayed the crystallization time of indinavir.. This study examined the efficacy and tolerability of the addition of escin to highly active antiretroviral therapy containing indinavir to delay the crystallization time of indinavir in urine.. This was a multicenter, randomized, open-label, controlled, 4-period crossover trial in which each period lasted 4 weeks. HIV-1-infected adults receiving treatment with indinavir plus 2 nucleoside analogue reverse-transcriptase inhibitors in whom plasma viral loads had been undetectable (HIV-1 RNA <200 copies/mL) for at least 6 months were randomly assigned to 1 of 2 groups based on the timing of the initiation of escin. Group I received escin during the second and third treatment periods, and group II received escin during the first and fourth treatment periods. The primary end point was the in vitro crystallization time of indinavir in 24-hour urine specimens, determined at the end of each 4-week period. Tolerability was assessed based on the number of patients with a rebound in plasma viral load and on the numbers of clinically and biologically relevant adverse events (including those requiring discontinuation of treatment). Clinical and laboratory evaluations were performed throughout each 4-week period.. Fifty HIV-1-infected patients were enrolled, 47 were randomized to treatment (40 [85.1%] men, 7 [14.9%] women; median [interquartile range] age, 36 [34-45] years), and 30 completed the study. Urine pH and plasma and urine indinavir concentrations were unaffected by the addition of escin to antiretroviral treatment. The mean time to the onset of crystallization was 14.7 minutes with escin (95% Cl, 11.8-17.5) and 9.9 minutes without it (95% Cl, 6.7-13.1). Therefore, the addition of escin increased the mean crystallization time by 5.5 minutes (95% Cl, 1.5-9.5; P = 0.008), representing the overall capacity of study treatment to inhibit indinavir crystallization in the urine. Three of 47 patients had mild gastrointestinal symptoms associated with escin treatment. No episodes of nephrolithiasis were recorded during the study or after the completion of study treatment.. The results of this prospective clinical trial of the effect of escin on indinavir crystallization time support the possibility that indinavir-associated nephrolithiasis may be prevented by means other than overhydration. Further research is needed in greater numbers of patients over longer follow-up times.

Topics: Adult; Cross-Over Studies; Crystallization; Escin; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydrogen-Ion Concentration; Indinavir; Kidney Tubules; Male; Middle Aged

To evaluate the pharmacokinetics, efficacy and tolerability of a low-dose boosted indinavir (IDV)/ritonavir (RTV) regimen [100 mg RTV/400 mg IDV twice daily (bid)] in patients previously receiving a standard IDV regimen [800 mg three times a day (tid)].. In a prospective, open-label, cross-over trial, patients with plasma HIV RNA < 200 copies/ml receiving an IDV-containing regimen (800 mg tid) were switched to an RTV/IDV (100/400 mg bid)-containing regimen. Minimal and maximal IDV plasma concentrations ( Cmin and Cmax ) were determined before the switch (day 0), at week 2 and week 4 after the switch. The CD4 cell count and plasma HIV RNA were determined at day 0, week 2 and week 4, then every 8 weeks. The primary end-point was the percentage of patients with plasma HIV RNA below 200 copies ml at week 48.. Twenty patients were enrolled. At baseline, on IDV 800 mg tid, median IDV Cmin was 194 ng/ml and median IDV Cmax was 8449 ng/ml. On RTV/IDV (100/400 mg), median IDV Cmin increased to 536 ng/ml at week 2 and 475 ng/ml at week 4, while Cmax decreased to 2983 ng/ml at week 2 and 2997 ng/ml at week 4 ( P < 0.001). The median area under the IDV plasma concentration-time curve measured in seven patients was 25 126 ng.h/ml, and the IDV half-life (t1/2 ) was 4.4 h. All patients had plasma HIV RNA remaining < 200 copies/ml at week 48. Tolerability of RTV/IDV was excellent.. RTV/IDV (100/400 mg bid) yields significantly higher IDV plasma Cmin and lower IDV Cmax values relative to the standard IDV regimen, thereby improving both tolerability and efficacy.

Topics: Adult; CD4 Lymphocyte Count; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Pilot Projects; Prospective Studies; Ritonavir; RNA, Viral; Viral Load

Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens.. Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period.. Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours.. Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Area Under Curve; Cross-Over Studies; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Rifabutin

The objective of this study was to investigate if sildenafil influences the pharmacokinetics of nelfinavir. Five HIV-infected patients on steady-state nelfinavir-containing therapy were subject to pharmacokinetic sampling for nelfinavir concentration twice: without sildenafil and with sildenafil 25 mg as a single dose. There were no differences in the AUC, T(max), or C(max) of nelfinavir. In a similar design, two patients on indinavir and two patients on ritonavir combined with saquinavir were studied. In accordance with the literature, neither of these two treatments was affected. It is concluded that nelfinavir pharmacokinetics were unaffected by concomitant intake of a single dose of sildenafil.

Topics: Adult; Area Under Curve; Chromatography, High Pressure Liquid; Drug Interactions; Drug Therapy, Combination; Erectile Dysfunction; Half-Life; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Piperazines; Purines; Ritonavir; Saquinavir; Sildenafil Citrate; Sulfones; Vasodilator Agents

To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI).. Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts > or = 100 x 106/l and plasma HIV RNA < 500 copies/ml for > or = 3 months.. Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks.. A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P = 1), 86% (P = 0.87) and 74% (P = 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 x 106/cells/l (IDV/RTV arm) and 60 x 106 cells/l (IDV arm) (P = 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P < 0.001).. Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

A prospective, open-label study was conducted to assess the response to indinavir, efavirenz, and adefovir in human immunodeficiency virus (HIV)-infected patients experiencing viral rebound while receiving therapy with nelfinavir-containing regimens, to determine whether the protease genotype influenced the outcome of the salvage regimen. Genotyping from 29 nelfinavir failures revealed D30N in 17 (59%) and L90M in 11 (38%) cases. Suppression to <400 viral RNA copies/mL was achieved at week 48 in 56% of patients with the D30N virus versus 18% of patients with the L90M virus.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Organophosphonates; Oxazines; Treatment Failure

In order to evaluate the relationship between protease inhibitor (PI) plasma concentrations and viral suppression in individuals receiving highly active antiretroviral therapy (HAART), plasma concentrations and area under the time concentration curve (AUC(0.5-4)) for 35 HIV-infected adults receiving their initial (or first salvage) nelfinavir- (NFV) or indinavir (IDV)-based HAART were studied. Two groups were evaluated: those who had achieved HIV-RNA suppression (HIV-RNA <500 copies/mL, group 1, n=21) and those who had achieved incomplete HIV-RNA suppression (HIV-RNA>500 copies/mL, group 2, n=14) at the time of study entry. NFV one-hour pre-dose concentrations were significantly higher in group 1 compared to group 2 (P=0.023). The NFV AUC(0.5-4) for group 1 approached significance (P=0.068). No significant differences in IDV concentrations or AUC(0.5-4) were found between group 1 and group 2. It is feasible to use PI drug level monitoring in the outpatient setting.

Topics: Adult; Antiretroviral Therapy, Highly Active; Area Under Curve; Cross-Sectional Studies; Drug Monitoring; Drug Resistance, Viral; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir; RNA, Viral

To describe the pharmacokinetics and pharmacodynamics of indinavir with or without low-dose ritonavir in human immunodeficiency virus (HIV)-infected Thai patients.. Thirty-six HIV-1-infected patients who participated in HIV-NAT 005 study gave informed consent to record a pharmacokinetic curve 4 weeks after starting a regimen containing either indinavir 800 mg every 8 h (n = 19) or indinavir 800 mg + ritonavir 100 mg every 12 h (n = 17). Indinavir plasma concentrations were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods.. The median (interquartile range; IQR) body weight of the 36 patients (11 females and 25 males) was 60 (54-72) kg. Median and IQR values for indinavir AUC, Cmax and Cmin were 20.9 (13.1-27.0) mg x h/L, 8.1 (6.6-9.4) mg/L and 0.13 (0.09-0.27) mg/L, respectively, for indinavir 800 mg every 8 h, and 49.2 (42.5-60.4) mg x h/L, 10.6 (8.5-13.2) mg/L and 0.68 (0.43-0.77) mg/L, respectively, for indinavir 800 mg + ritonavir 100 mg every 12 h. These values are not largely different from values found in Caucasian patients, with the exception of relatively high peak levels of indinavir in Thai subjects. Cut-off values for optimal virological efficacy were an indinavir Cmin of 0.10 and 0.25 mg/L for the every 8 h and the every 12 h regimen, respectively; patients with an indinavir AUC greater than 30 (every 8 h regimen) or 60 (every 12 h regimen) mg x h/L were at increased risk of developing nephrotoxicity.. Indinavir pharmacokinetics and pharmacodynamics in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in this population

Topics: Adult; Area Under Curve; Body Weight; Chromatography, High Pressure Liquid; Drug Interactions; Female; Half-Life; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Male; Ritonavir; Thailand

To compare one protease inhibitor (PI)-based and two PI-sparing antiretroviral therapy regimens.. International, open label, randomized study of antiretroviral drug-naive patients, with CD4 lymphocyte counts >/= 200 x 106 cells/l and plasma HIV-1 RNA levels > 500 copies/ml. Treatment assignment to stavudine and didanosine plus indinavir or nevirapine or lamivudine. Primary study endpoint was the percentage of patients with plasma HIV-1 RNA levels < 500 copies/ml after 48 weeks in the intention-to-treat analysis (ITT).. In total, 298 patients were enrolled. After 48 weeks, the percentage of patients in the indinavir, nevirapine and lamivudine arms with HIV-1 RNA < 500 copies/ml was 57.0%, 58.4% and 58.7%, respectively, in an ITT analysis. After 96 weeks of follow-up, these percentages were 50.0%, 59.6% and 45.0%, respectively. The percentage of patients with HIV-1 RNA < 50 copies/ml was significantly less for those allocated to lamivudine in an on-treatment analysis after 48 and 96 weeks of follow-up. Patients in the nevirapine arm experienced a smaller increase in the absolute number of CD4 T lymphocytes. There were no significant differences in the incidence of serious adverse events.. A comparable virological response can be achieved with first-line PI-base and PI-sparing regimens. The triple nucleoside regimen utilized may be less likely to result in viral suppression to < 50 copies/ml, while the nevirapine-based regimen is associated with a lower increase in CD4 T lymphocytes.

Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Lipids; Male; Middle Aged; Nevirapine; Treatment Outcome

Topics: AIDS-Related Opportunistic Infections; Drug Therapy, Combination; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Reverse Transcriptase Inhibitors; Ritonavir

Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (C(min)) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median C(min) for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P = 0.19). Compared to the minimum C(min) range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the C(min) for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P = 0.28), apparent volume of distribution at steady state (V(ss)/F) (P = 0.25), and half-life (t(1/2)) (P = 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (C(max)s) were 8,968 nM (IR, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P = 0.66), and the C(min)s were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P = 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P = 0.62), V(ss)/F (P = 0.33), and t(1/2) (P = 0.37) were similar regardless of the dosing regimen. The median C(max), C(min), CL/F, V(ss)/F, and t(1/2) for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Oxazines; RNA, Viral

Both virological failure and the toxicity of HIV protease inhibitors have been related to interindividual variability of plasma drug concentrations. Therapeutic drug monitoring (TDM) offers the possibility to detect patients with drug concentrations outside therapeutic ranges, who can subsequently benefit from dose modifications.. ATHENA was a randomized controlled clinical trial. Subjects were randomly assigned to either a TDM group, in which the results of drug concentration measurements plus advice were reported to their treating physician, or to a control group for whom TDM results were not reported. This analysis refers to treatment-naive patients who started a regimen containing indinavir or nelfinavir before November 1999.. A total of 147 patients were randomly assigned: 92 to nelfinavir, 55 to indinavir. After one year of follow-up significantly fewer patients in the TDM group had discontinued nelfinavir or indinavir than in the control group: 17.4 versus 39.7%. This was mainly driven by a significantly lower rate of discontinuation because of virological failure in nelfinavir patients: 2.4% in the TDM group versus 17.6% in the control group, and by a non-significant difference in the rate of discontinuation because of toxicity in indinavir patients: 14.3% in the TDM group versus 29.6% in the control group. In a non-completer equals failure analysis of all randomized patients, the TDM group showed a significantly higher proportion of patients with a viral load below 500 copies after 12 months of treatment (78.2 versus 55.1%).. TDM of nelfinavir and indinavir in treatment-naive patients improves treatment response.

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Monitoring; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Prospective Studies; Viral Load

To determine the longitudinal response of HIV in the cerebrospinal fluid (CSF) to highly active antiretroviral therapy (HAART) and to investigate the levels of indinavir penetrating into the CSF.. Open study of HIV-infected subjects naive to therapy with protease inhibitors.. Tertiary care referral center.. Twenty-five participants were begun on indinavir, nevirapine, zidovudine, and lamivudine.. Lumbar punctures were performed prior to therapy and 2 and 6 months after beginning therapy. Plasma and CSF were assayed for routine cell counts, chemistries, HIV load and indinavir levels.. Twenty-two subjects had CSF HIV RNA level data available at all three time points, three others at baseline and 2 months. At month 2 of therapy, nine of 25 (36%) subjects had CSF HIV RNA levels > 50 HIV RNA copies/ml. By 6 months, all 22 subjects had CSF HIV RNA levels < 50 HIV RNA copies/ml. CSF white blood cell counts fell from a baseline mean of 5.3 x 10(6)/l to 1.9 x 10(6)/l (P = 0.013) at 6 months. Plasma indinavir levels declined rapidly while CSF levels remained stable throughout the 8-h dosing interval. The median CSF indinavir level was 71 ng/ml, approximating the upper limit of the 95% inhibitory concentration for indinavir against HIV-1.. CSF HIV RNA levels cannot be expected to fall below 50 HIV RNA copies/ml even after 2 months of therapy on HAART. Prolonged therapy may be required to suppress HIV levels within the central nervous system.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Leukocyte Count; RNA, Viral; Viral Load

Therapeutic control of human immunodeficiency virus type 1 (HIV-1) in peripheral compartments does not assure control in the central nervous system. Inadequate drug penetration may provide a sanctuary from which resistant virus can emerge or allow development of psychomotor abnormalities. To characterize the effect of ritonavir on indinavir disposition into cerebrospinal fluid, seven HIV-infected adults underwent intensive sampling at steady-state while receiving twice-daily indinavir (800 mg) and ritonavir (100 mg). Serial cerebrospinal fluid and plasma samples were obtained at 10 time points from each subject. Free indinavir accounted for 98.6% of drug in cerebrospinal fluid and 55.9% in plasma. Mean cerebrospinal fluid C(max), C(min), and area under the concentration-time curve from 0 to 12 h (AUC(0-12)) values for free indinavir were 735 nM, 280 nM, and 6502 nM h(-1), respectively, and the free levels exceeded 100 nM in every sample. The cerebrospinal fluid/plasma AUC(0-12) ratio for free indinavir was 17.5% +/- 6.4%. This ratio was remarkably similar to results obtained in a previous study in which subjects received indinavir without ritonavir, indicating that ritonavir did not have a substantial direct effect on the barrier to indinavir penetration into cerebrospinal fluid. Low-dose ritonavir increases cerebrospinal fluid indinavir concentrations substantially more than 800 mg of indinavir given thrice daily without concomitant ritonavir, despite a lower total daily indinavir dose.

Topics: Adult; Anti-HIV Agents; Blood-Brain Barrier; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunoglobulin G; Indinavir; Lamivudine; Male; Middle Aged; Ritonavir; Stavudine

To determine intracellular concentrations of indinavir (IDV) and investigate the relationship between plasma and intracellular IDV pharmacokinetics in HIV-infected patients.. A pharmacokinetic study of 10 patients receiving IDV plus dual nucleoside analogue therapy. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and cell counts estimated. IDV was extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular IDV samples were assayed by high performance liquid chromatography linked to mass spectrometry. Data were subjected to non-compartmental pharmacokinetic analysis.. The mean intracellular IDV area under the curve over 8 h (AUC0-8) was lower than the plasma AUC0-8 (7574 +/- 1003 vs 25060 +/- 4171 ng/ml/h; P<0.004). However, both the elimination half-life (t1/2) and the mean residence time (MRT) of IDV intracellularly were prolonged compared with plasma (t1/2: 2.0 +/- 0.3 vs 1.2 +/- 0.09 h; MRT: 3.6 +/- 0.6 vs 2.1 +/- 0.1 h; P<0.05). All patients were responsive to therapy at the time of the study, as assessed by HIV plasma RNA levels. Individual plasma versus intracellular time course results suggest that, due to the prolonged intracellular half-life, some patients may achieve acceptable intracellular IDV concentrations despite sub-therapeutic plasma levels. Similarly, potentially inadequate intracellular concentrations may occur despite therapeutic plasma concentrations.. There is no significant intracellular accumulation of IDV within the lymphocytes of HIV-1-infected patients relative to plasma. However, intracellular concentrations are compatible with reported IDV-free drug concentrations in plasma. The intracellular elimination half-life and mean residence time of IDV are significantly prolonged compared with plasma. This may in part explain why certain patients maintain adequate viral suppression despite sub-therapeutic plasma IDV levels.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Female; Half-Life; HIV Infections; HIV-1; Humans; Indinavir; Intracellular Space; Male; Middle Aged; RNA, Viral

To compare long-term virologic benefits of antiretroviral regimens in persons with advanced human immunodeficiency virus (HIV) disease, a randomized, open-label study was conducted of 517 subjects with no or limited previous experience with antiretroviral therapy. Subjects received lamivudine plus zidovudine and indinavir (indinavir group), efavirenz plus indinavir (efavirenz + indinavir group), or nelfinavir plus indinavir (nelfinavir + indinavir group) and were monitored for 2.1 years. Virologic failure was lower in the efavirenz + indinavir group (P=.04) and higher in the nelfinavir + indinavir group (P=.006), compared with that in the indinavir group. No difference in grade 3 or 4 adverse event rates in the efavirenz + indinavir group (P=.97) and a trend toward an increased rate in the nelfinavir + indinavir group (P=.07), compared with the indinavir group, were noted. A 4-drug regimen containing efavirenz plus indinavir resulted in a superior virologic response, whereas one containing nelfinavir plus indinavir resulted in an inferior response and a greater likelihood of toxicity.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Nelfinavir; Oxazines; Patient Compliance; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir; Saquinavir; Treatment Outcome

Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoid-protease inhibitor interactions (because both share cytochrome P-450 metabolic pathways).. To determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients.. Randomized, placebo-controlled, 21-day intervention trial.. The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California.. 67 patients with HIV-1 infection.. Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals.. HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors.. 62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 x 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was -0.07 (95% CI, -0.30 to 0.13) for marijuana and -0.04 (CI, -0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids.. Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.

Topics: Administration, Oral; Cannabinoids; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dronabinol; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nelfinavir; RNA, Viral; Viral Load

The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity.. This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h.. Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio - fasting/fed and 95% confidence interval (CI): 1.28 (1.08-1.52), P=0.01] and a trend to a shorter indinavir tmax (P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmax and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir.. Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.

Topics: Adult; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination; Fasting; Food; Food-Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Middle Aged; Ritonavir

A double-blind, randomized study of zidovudine-experienced, PI- and lamivudine-naive adults with baseline CD4 cell counts of < or =50 cells/mm3 had demonstrated that the HIV suppression achieved with zidovudine, lamivudine, and indinavir therapy was superior to that achieved with dual-nucleoside or indinavir-only regimens after 24 weeks of therapy. In a 192-week extension of the study, 371 participants received open-label indinavir with or without other antiretroviral drugs. One hundred and eight subjects were originally randomized to receive triple therapy. After 216 weeks, the proportion of subjects with HIV RNA levels of <500 copies/mL were 34%, according to a general estimating equation analysis, 92%, according to an observed data analysis, and 24%, according to an intention-to-treat analysis counting noncompleters as failures; the proportions of subjects with HIV RNA levels of <50 copies/mL were 31%, 85%, and 22%, respectively. Hyperbilirubinemia (experienced by 31% of subjects), nausea (17%), abdominal pain (14%), and nephrolithiasis (13%) were the most common drug-related adverse events during the extension.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Fatigue; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; RNA, Viral; Zidovudine

To assess virological and immunological responses and toxicity in subjects receiving combination antiretroviral therapy.. Six-year follow-up of a single arm of a randomized study of combination antiretroviral therapy.. HIV-infected, zidovudine-experienced patients originally randomized to receive indinavir, zidovudine, and lamivudine had HIV RNA levels and CD4 cell counts assessed over 6 years. Information was collected by questionnaire from subjects who discontinued the study regimen before 6 years. Both on-study and post-study responses were assessed.. Of 33 subjects, 16 (48%) discontinued before 6 years of follow-up. After 6 years, 16 (53%) and 14 (47%) of 30 contributing subjects had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline for 28 contributing subjects was 268 x 10(6) cells/l. Treatment-limiting nephrolithiasis occurred in four subjects. Of the 16 subjects who discontinued the study, 12 had post-study questionnaire data available and seven had HIV RNA < 500 copies/ml on a post-study regimen. In an exploratory analysis combining both on-study and post-study data at approximately 6 years, 26 (79%) and 19 (58%) of 33 had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline was 344 x 106 cells/l.. Antiretroviral therapy with indinavir, zidovudine, and lamivudine suppressed HIV viremia and produced continued CD4 cell increases in a majority of subjects for 6 years. Most subjects who discontinued study medications had HIV RNA levels suppressed on post-study therapy. Though based on a small group, this study demonstrates the durable effects of antiretroviral therapy.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

HIV protease inhibitors (PI) were licensed without a direct evidence of their relative efficacy.. 137 patients attending our clinics between November 1997 and March 1998, to whom treatment with a PI was recommended, were randomized to receive indinavir (IDV), saquinavir (SQV) or ritonavir (RTV). Main outcome variables were one-year mean changes in HIV-RNA plasma concentrations and CD4 cells counts and proportion of patients with HIV viral load below level of detection.. Mean HIV viral load reductions were 0.95 for SQV, 0.72 for IDV and 0.65 for RTV (p = 0.44), equaling losses and changes to failures. In a standard intent-to-treat analysis, mean changes in viral load were 1.16, 1.01 and 1.50 (p = 0.21), respectively. The proportion of patients with undetectable viral load was 50%, with no differences between treatment arms.. No differences were observed in the effectiveness of SQV, IDV and RTV.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Ritonavir; Saquinavir; Viral Load

The aim of this study was to evaluate the heat-dissociated p24 antigen (HD p24 Ag) assay as an alternative low-cost tool for diagnosis of HIV-1 infection and quantitation of HIV-1 RNA levels in African adults mainly infected with HIV-1 CRF02_AG strains. One hundred seventeen plasma specimens were obtained from HIV-1-seropositive subjects enrolled in the ANRS 1220 PRIMO-CI cohort (Abidjan, Côte d'Ivoire, West Africa). Results of the HD p24 Ag assay were comparable with those of HIV-1 RNA levels quantified in the same antibody-positive plasma samples by the Amplicor HIV-1 Monitor assay (1.5 version; Roche Diagnostics, Indianapolis, IN): sensitivity, 95.7% versus 96.6%, respectively; specificity (evaluated with samples from 75 seronegative subjects), 94.7% versus 100%, respectively. HD p24 Ag and HIV-1 RNA assays were weakly correlated (Spearman coefficient correlation, r = 0.33; P < 0.001) except for HIV-1 RNA levels of >/=5 log10 copies/mL (r = 0.62; P < 0.001). Quantitation of HD p24 antigenemia in 76 plasma specimens from 14 patients treated with highly active antiretroviral therapy demonstrated weaker changes during treatment than those observed with the HIV-1 RNA assay. Follow-up of infected patients using both markers showed different results. The reliability of the HD p24 Ag assay is questionable for clinical and biologic management as a surrogate tool for measurement of HIV-1 RNA levels in Africa.

Topics: Adolescent; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Cote d'Ivoire; Drug Combinations; Enzyme-Linked Immunosorbent Assay; HIV Antibodies; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Middle Aged; Prospective Studies; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Sensitivity and Specificity; Zidovudine

We evaluated the safety and efficacy of indinavir 400 mg and ritonavir 400 mg twice daily (RIT/IND 400/400) in HIV-1-infected individuals, using an open label, proof of concept study. All patients received indinavir 400 mg and ritonavir 400 mg twice daily. Patients were followed up to 48 weeks. Nineteen subjects were enrolled, 11 (58%) men and eight (42%) women. The majority were American Black (nine; 47%) or Haitian (eight; 42%). The median baseline plasma HIV-1 viral load (VL) was 5.13 log10 copies/mL and the median CD4 cell count was 112 cells/mm(3). The proportion of compliant patients with VL <400 copies/mL at week 24 was 60% compared with 0% for non-compliant patients (P=0.011 [intent-to-treat] or P=0.085 [on-treatment]). VL at week 4 predicted week 24 VL response. Compliant patients had a median average CD4 cell count increase of 83.2 cells/mm(3) compared with 42.0 cells/mm(3) for non-compliant patients (P=0.010). The median average changes in triglycerides and cholesterol were significantly higher in compliant patients. This is a potent, safe combination for the treatment of HIV-1. VL at week 4 is predictive of viral outcome at week 24. Fasting serum cholesterol and triglycerides were significantly elevated during the study.

Topics: Black People; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Haiti; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Logistic Models; Male; Patient Compliance; Pilot Projects; Predictive Value of Tests; Ritonavir; United States; Urban Population; Viral Load

There is an increased interest in developing once-daily regimens for the treatment of HIV-infected patients. A Phase II study was conducted to investigate the pharmacokinetics, and short-term safety and efficacy of an indinavir/ritonavir combination as part of a once-daily regimen.. HIV-infected patients with either proven poor compliance to HAART regimens in the past or an anticipated poor compliance to such a regimen in the future were eligible for this study. They received a once-daily regimen consisting of indinavir 1200 mg, ritonavir 400 mg, and one or two nucleoside reverse transcriptase inhibitors (NRTIs), also administered once daily with food. A 24 h pharmacokinetic profile was constructed in a subset of patients. Short-term safety and efficacy were evaluated at 4, 12 and 24 weeks after initiation of treatment.. A total of 64 patients were included in this study, of whom 27 (42.2%) were treatment-naive. The geometric mean (+95% CI) of indinavir AUC0-24h, Cmax and Cmin as determined in an unselected group of 16 patients were 84.9 (69.7-103.5) mg/l x h, 12.0 (10.2-14.1) mg/l and 0.15 (0.09-0.26) mg/l, respectively. A large interpatient variability was observed, with five out of the 16 subjects having a Cmin value below the minimum effective concentration of 0.10 mg/l. During the 24 weeks of follow-up nine patients (14.1%) discontinued study medication, two due to medication-related toxicity. Gastrointestinal adverse events were reported most frequently (50.0%), followed by skin effects (45.3%), joint pain (9.4%) and urological complaints (7.8%). No patient developed nephrolithiasis. The median (+interquartile range) serum creatinine level in the 64 patients increased slightly from 74 (63-88) micromol/l to 79 (66-92) micromol/l during the 24 weeks of follow-up. One new patient reached a grade 1 elevation in serum creatinine, which normalized during the follow-up; five other patients with elevated serum creatinine at baseline remained stable. During the 24 weeks of follow-up, the proportion of patients with a viral load <500 copies/ml increased from 35.1% at baseline to 71.4% (ITT NC=F analysis) or 83.3% (OT analysis), and from 0% at baseline to 76.2% (ITT NC=F analysis) or 100.0% (OT analysis) in treatment-experienced and -naive patients, respectively. This was accompanied by a mean increase in CD4 cell count of 52 and 220 cells/mm3 in these two sub-groups, respectively.. The 24-week follow-up data of this study indicate favourable pharmacokinetics of an indinavir/ritonavir 1200/400 mg combination as part of a once-daily regimen consisting also of one or two NRTIs. Short-term safety and efficacy were also satisfactory. Long-term follow up is planned to evaluate the durability of these results.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

TMC125, a next generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), demonstrated a remarkable decline of plasma HIV-1 RNA during a phase IIa study. We compared the initial rate of decline of plasma HIV-1 RNA achieved by TMC125 monotherapy with that of a triple class, five-drug regimen, containing drugs from all three currently licensed classes (zidovudine, lamivudine, abacavir, indinavir and nevirapine).. The decline in plasma HIV-1 RNA of 12 HIV-1 infected, antiretroviral (ART) naive patients treated for 1 week with TMC125 monotherapy was compared with that observed in the ERA study (n = 11). The plasma HIV-1 RNA elimination rate constant was calculated based on at least four plasma HIV-1 RNA measurements during the first week of treatment (first-order elimination) and compared using the Student's t test.. Median ages were 23 and 38 years for TMC125 and ERA patients, respectively (P = 0.001), median baseline plasma HIV-1 RNA levels were 4.2 and 4.8 log10 copies/ml (P = 0.001) and median baseline CD4 T-cell counts were 458 x 10(6) and 360 x 10(6) cells/l (P = 0.08). The median plasma HIV-1 RNA elimination rate constant was 0.68/day in TMC125 treated patients, and 0.56/day in ERA participants (P = 0.24). The median decline in plasma HIV-1 RNA after 7 days was 1.92 and 1.76 log10 copies (P = 0.77) and the median increase of CD4 T cells was 119 x 10(6) and 60 x 10(6) cells/l, respectively (P = 0.29).. Monotherapy with TMC125 in ART-naive, HIV-1-infected individuals resulted in a similar rate of decline of plasma HIV-1 RNA during 1 week of therapy as therapy with a five-drug regimen.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zidovudine

Adherence to highly active antiretroviral therapy is required to obtain an optimal long term virologic response rate of HIV-1-infected children. Plasma concentrations of protease inhibitors (PIs) outside the limits of the reference values indicate nonadherence to antiretroviral therapy in adults. We studied during a 2-year follow-up period routinely taken plasma protease inhibitor concentrations to assess adherence to antiretroviral therapy in HIV-1-infected children.. In 40 children (ages 3 months to 18 years) blood samples were taken at regular outpatient visits every 12 weeks after the start of highly active antiretroviral therapy and analyzed for plasma concentrations of indinavir or nelfinavir by high performance liquid chromatography and for plasma HIV-1 RNA load. The percentage of samples fulfilling the criteria for adherence was assessed for each child by three methods. For each sample a concentration ratio was calculated by dividing the concentration in that sample by the time-adjusted population value. According to Method 1 concentration ratios below or above concentration ratio limits (CORALs) of population data obtained in adults were highly indicative of nonadherence. Because many children have high PI levels, Method 2 evaluated plasma samples of PIs with only the lower CORAL. According to Method 3 only children with plasma samples below the limit of quantification (0.04 mg/l) were considered noncompliant. Differences in adherence rate between virologic responders and virologic nonresponders and between adherence rates and the two protease inhibitors were analyzed. The cumulative incidence of HIV-1 RNA levels >500 copies/ml in children was calculated.. Thirty-one children started treatment with indinavir, and nine children started treatment with nelfinavir. The median adherence rates for indinavir as determined by methods 1, 2 and 3 were 54% [interquartile range (IQR), 25 to 69%], 67% (IQR 50 to 92%) and 80% (IQR 63 to 100%), respectively. For nelfinavir median adherence rates of 60% (IQR 39 to 75%), 100% (IQR 67 to 100%) and 100% (IQR 100 to 100%) were observed. Adherence rates calculated with Method 2 were significantly higher in virologic responders ( = 0.04). Adherence rates calculated with Methods 2 and 3 were significantly lower in children using indinavir compared with those using nelfinavir ( = 0.02 and = 0.02, respectively).. Calculation of adherence rates using the lower limit of CORALs of indinavir or nelfinavir in children may be a useful measurement for the assessment of nonadherence to antiretroviral therapy in children.

Topics: Adolescent; Child; Child, Preschool; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Nelfinavir; Patient Compliance; RNA, Viral; Viral Load

To examine the effect of adherence to therapy on early virological response, later virological failure, and occurrence of adverse events in HIV-infected patients.. A randomized trial of 3-month induction period of zidovudine/lamivudine/indinavir followed by a maintenance phase of zidovudine/lamivudine/indinavir, zidovudine/lamivudine or zidovudine/indinavir.. Adherence was assessed by pill count. In the induction phase, early virological response was defined as plasma HIV-RNA<500 copies/ml at month 2 and in the maintenance phase, virological failure was defined as plasma HIV-RNA >500 copies/ml in two consecutive specimens.. The median adherence rate was 97% in both induction (n=366) and maintenance phase (n=237). In the maintenance phase, pairwise comparisons showed a lower adherence rate in zidovudine/lamivudine/indinavir versus zidovudine/lamivudine (P=0.03), or versus zidovudine/indinavir (P=0.05). Only 13% of patients had an adherence over the maintenance phase of 80% or lower, while 40% of patients occasionally had an adherence rate of 80% or lower during this phase. Among the 362 patients with documented HIV-RNA at month 2, 86% had an early virological response. Adherence of 80% or greater was the only variable statistically predictive to early virological response (P<0.001), while baseline CD4, baseline HIV-RNA, and adherence of 95% or greater were not associated to virological response. In the maintenance phase, adherence, baseline HIV-RNA, HIV-RNA at month 3 and treatment groups were independently predictive to time to virological failure. Analysis by randomized groups indicated that difficulty in adherence (<80%) was predictive to time to failure (P<0.001) only in both indinavir-containing regimens. Occurrence of two or more severe adverse events (grade 3 and 4) was higher in patients with poor adherence although not statistically associated (P=0.12), while no association was found with minor adverse events.. Adherence rate was globally lower in patients maintaining the original triple-drug therapy compared with those receiving less intensive regimens. Adherence rate was a time-dependent variable. Adherence to antiviral regimen of 80% or greater was predictive to early virological response, and adherence rate lower than 80% or 95% was predictive to virological failure, especially in indinavir-containing regimens. Occurrence of adverse events was not clearly associated to adherence.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Patient Compliance; RNA, Viral; Treatment Outcome; Zidovudine

We compared use of a 3-class regimen (nevirapine [Nvp], stavudine [d4T], and indinavir [Idv; 1000 mg 3 times daily]) with use of a 2-class regimen (lamivudine [3TC], d4T, and Idv [800 mg 3 times daily]) for 145 patients infected with human immunodeficiency virus type 1 (HIV-1). At week 72, the plasma HIV-1 RNA level was undetectable in 52% of Nvp recipients versus 79% of 3TC recipients (P<.001). Idv trough levels were 81 ng/mL in the Nvp group and 99 ng/mL in the 3TC group (P=.012). In the Nvp group, 42.5% of patients discontinued the study regimen; in the 3TC group, 22.5% of patients discontinued therapy (P=.013). The rate of resistance to nonnucleoside analogue reverse-transcriptase inhibitors among patients in the Nvp group with virological failure was not different from the rate of resistance to 3TC among patients in the 3TC group with virological failure. These results do not support the use of a 3-class regimen that includes Nvp for patients with no or limited exposure to nucleoside analogues.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Nevirapine; Outcome Assessment, Health Care; Stavudine

Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4(+) cell count of 266 cells/mm(3). Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).

Topics: Adult; Area Under Curve; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir

To compare information on body fat changes from questionnaire and clinical examination and to study lipoatrophy in HIV-1 patients on highly active antiretroviral therapy (HAART).. The study was cross-sectional within a randomized trial. One hundred and sixty-eight male HIV-1 patients were examined by questionnaire and clinical examination. Clinical lipoatrophy was studied and defined as fat wasting in the face, legs and/or arms. Fasting blood samples reflecting lipid and glucose metabolism were taken and the role of indinavir, ritonavir (RTV) and RTV/saquinavir (SQV) on lipoatrophy was investigated.. After a median of 17 months on HAART, concordance rates between information on changes in body fat from questionnaire and clinical examination were significant and varied from 70 to 96%. With a positive criteria of lipoatrophy in both assessments, 14% of patients had lipoatrophy. These patients had lower weight (P = 0.0007), weight loss from baseline (P = 0.003), lower circumferences at all measurements (P < 0.01), lower plasma triglycerides and low-density lipoprotein (LDL) (P < 0.05) and longer treatment with stavudine (P = 0.0009). Homeostasis model assessment (HOMA) estimates for insulin resistance and beta-cell function were comparable. Plasma cholesterol, triglycerides and very low-density lipoprotein (VLDL) were higher in patients receiving RTV or RTV/SQV (P < 0.03).. Questionnaire and clinical assessment provide concordant information on changes in body fat. Lipoatrophic patients on HAART with neither increase in abdominal circumference, nor hyperlipidaemia nor glucose intolerance may have side-effects to protease inhibitor treatment, to nucleoside reverse transcriptase inhibitor treatment (stavudine) or suffer from a drug-independent condition.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Cross-Sectional Studies; Drug Therapy, Combination; Glucose Intolerance; HIV Infections; HIV Protease Inhibitors; HIV Wasting Syndrome; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Male; Middle Aged; Ritonavir; Saquinavir; Stavudine; Surveys and Questionnaires

To evaluate safety and efficacy of the protease inhibitor combination ritonavir/indinavir 100/800 mg twice daily plus 2-3 nucleoside reverse transcriptase inhibitors (NRTI) in antiretroviral-naive patients.. Within this open-label, uncontrolled multicentre trial, antiretroviral-naive patients (n = 57) with median baseline HIV-RNA of 308,000 copies/mL (range 170-3.01 million copies/mL) and median CD4 cell count of 50 cells/microL (range 0-853 cells/microL) were started on 2-3 NRTIs plus ritonavir/indinavir 100/800 mg twice daily. CD4 cell counts and HIV-RNA were determined at weeks 0, 4, 8, 12, 16, 20, 24 and 48. Statistical analysis was performed on treatment as well as intent-to-treat.. Viral load decreased by a median of 3.79 log10 copies/mL (range 2.0-4.60 log10 copies/mL) until week 48. At week 48, 23/57 (40%, intent-to-treat) patients showed a viral load

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; Follow-Up Studies; Germany; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

To compare the incidence of clinical lipodystrophy in HIV-1-infected patients receiving zidovudine or stavudine, in combination with indinavir and lamivudine, in a randomized trial.. NOVAVIR was a randomized multicentre trial comparing stavudine/lamivudine/indinavir and zidovudine/lamivudine/indinavir in 170 patients pretreated with zidovudine, didanosine or zalcitabine (> 6 months), but naive for lamivudine, stavudine and protease inhibitors. The incidence of clinical lipodystrophy and metabolic abnormalities was assessed in a subgroup of 101 patients after 30 months of follow-up.. The incidence of lipoatrophy was increased in the stavudine arm versus the zidovudine arm, as followed: facial atrophy: 48 versus 22% of patients, P = 0.011, lower limb atrophy: 49 versus 22% of patients, P = 0.006, buttock atrophy: 47 versus 20% of patients, P = 0.009, venomegaly: 57 versus 24% of patients, P = 0.001. There was no significant difference in the incidence of clinical signs of central fat accumulation nor in fasting metabolic parameters at month 30 between the two arms. In multivariate analyses, the stavudine arm, previous therapy with didanosine, and a lower CD4 cell count at study entry were associated with an increased risk of lipoatrophy, whereas older patients and women had an increased risk of lipohypertrophy.. Patients receiving stavudine/lamivudine/indinavir had a greater rate of clinical lipodystrophy, mainly lipoatrophy, than those treated with zidovudine/lamivudine/indinavir.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Constitution; Body Mass Index; Female; Follow-Up Studies; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Lamivudine; Male; Middle Aged; Risk Factors; Stavudine; Zidovudine

The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (<50 copies/mL at week 24), late response (<500 copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p <.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.

Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Mutation; Patient Compliance; RNA, Viral; Stavudine; Viral Load; Zidovudine

There is no standard treatment of HIV-infected patients who fail protease inhibitor (PI)-containing antiretroviral therapy. This open-label, noncomparative 24-week study with a 24-week extension evaluated the efficacy, safety, and tolerability of twice-daily indinavir/ritonavir 800/200 mg plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) in this population. Presented here are the results of the 24-week study. Patients were HIV-infected adults who had prior viral RNA (vRNA) suppression (<400 copies/mL), subsequent failure (> or =400 and < or =100,000 copies/mL) on antiretroviral therapy, and at least one new NRTI available for treatment. The proportions of patients achieving plasma vRNA <400 and <50 copies/mL were analyzed with data as observed (DAO) and intention-to-treat (ITT) models using generalized estimating equations (GEE) or counting noncompleters as failures (NC = F). Mean changes from baseline in vRNA and CD4 cell count were evaluated using DAO and an ITT mixed-model approach. Sixty-three patients (87% male) with a mean age of 42 years and mean baseline vRNA and CD4 cell counts of 3.8 log(10) copies/mL and 360 cells/mm(3), respectively, were enrolled. The proportion (95% confidence interval) of patients achieving vRNA <400 and <50 copies/mL at week 24 were 76% (61%, 87%) and 50% (35%, 65%) for DAO, 64% (50%, 75%) and 43% (30%, 56%) for GEE, and 56% (43%, 68%) and 37% (25%, 50%) for NC = F, respectively. At Week 24, baseline vRNA decreased by >1.0 log(10) copies/mL and CD4 cell counts increased by approximately 90 cells/mm(3). Three patients (5%) experienced serious drug-related adverse events. Seven patients (11%) discontinued treatment due to clinical or laboratory adverse events. In this study, the enhanced, twice-daily regimen of indinavir/ritonavir 800/200 mg plus 2 NRTIs provided suppression of HIV in many patients who had failed a PI-containing regimen and was generally well tolerated.

Topics: Acidosis; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Hypercholesterolemia; Hyperglycemia; Hypertriglyceridemia; Indinavir; Kidney Calculi; Male; Middle Aged; Ritonavir; RNA, Viral; Treatment Failure

Low-dose ritonavir can boost plasma levels of indinavir, thereby enhancing its antiretroviral activity despite less frequent dosing. In this open-label, noncomparative, 24-week trial with a 24-week extension phase, HIV-infected protease inhibitor (PI)- and lamivudine-naive adults received indinavir/ritonavir 800 mg/100 mg plus stavudine and lamivudine every 12 hours. The proportions of patients achieving plasma HIV RNA (vRNA) <400 and <50 copies/mL were analyzed with data as observed (DAO) and intention-to-treat models using generalized estimating equations (GEE) or counting noncompleters as failures (NC = F). Eighty-nine patients (80% men) with a median age of 36 years and mean baseline vRNA levels and CD4 counts of 5.01 log(10) copies/mL and 269 cells/mm(3) were enrolled. The proportions (95% confidence interval [CI]) of patients achieving vRNA <400 copies/mL were 93% (84%, 98%), 78% (67%, 86%), and 68% (57%, 78%) at week 24 for DAO, GEE, and NC = F analyses, respectively; the corresponding results at week 48 were 95% (84%, 99%), 65% (53%, 76%), and 45% (35%, 57%). Most patients with vRNA <400 had <50 copies/mL. At week 48, baseline vRNA decreased by >2 log(10) copies/mL and CD4 counts increased by approximately 200 cells/mm(3). Five patients (6%) experienced serious drug-related adverse experiences. Twenty patients (23%) discontinued therapy due to adverse experiences. In this study, twice-daily indinavir 800 mg/ritonavir 100 mg with two nucleoside reverse transcriptase inhibitors provided potent viral suppression and immunologic reconstitution in many PI-naive patients.

Topics: Adult; Aged; Anemia; Anti-HIV Agents; CD4 Lymphocyte Count; Dehydration; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Lipoproteins; Logistic Models; Male; Middle Aged; Pneumonia; Ritonavir; RNA, Viral; Virus Replication

Guidelines recommend both protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens for initial therapy in HIV-positive individuals whilst clinical trial data comparing treatment options remain limited.. To assess whether drug selection (PI versus NNRTI) in antiretroviral-naive patients is related to virological response at 6 months within a clinical cohort.. Databases from two large clinics were used to identify all treatment-naive patients initiating highly active antiretroviral therapy (PI/ two PI or NNRTI). Statistical models determined the likelihood of suppressing HIV viral load < 500 copies/ml, the risk of treatment failure by 6 months, and factors associated with treatment success.. Of 1109 potentially eligible patients 888 met study criteria and were included; 484 were prescribed a PI (40% indinavir, 41% nelfinavir) and 404 were prescribed NNRTI (40% efavirenz, 60% nevirapine). Three treatment arms were compared: efavirenz versus nevirapine versus PI. After stratification by year and centre and adjustment for baseline variables, only treatment group and baseline viral load remained significantly associated with virological suppression at 6 months. Patients on efavirenz were significantly more likely to achieve an undetectable viral load than those on PI or nevirapine. The relative hazard for nevirapine was 0.77 (95% confidence interval, 0.61-0.96, P = 0.02) and that for PI was 0.74 (95% confidence interval, 0.58-0.94, P = 0.01). Efavirenz also performed better in the analysis of treatment failure at 6 months.. Although observational cohort data may be susceptible to significant bias, this study suggests a better initial virological response for efavirenz compared to either nevirapine or the PI. Clinical trial data is required to confirm these findings.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load

Highly active antiretroviral therapy (HAART) initiated during acute human immunodeficiency virus (HIV) infection may preserve HIV-specific CD4+ T cell responses that are thought to enhance HIV-specific CD8+ T cell function. The present pilot study was designed to determine whether preserved HIV-specific immune responses are augmented by the administration of the immunomodulatory agent interleukin (IL)-2. Nine persons recently (<6 months) infected with HIV were randomized to receive HAART alone or HAART plus 3 cycles of intermittent IL-2 during a 12-month period. Although HAART plus IL-2 significantly increased counts of total and naive CD4+ T cells, compared with HAART alone, there was no increase in CD4+ or CD8+ HIV-specific immune responses. In addition, adjuvant IL-2 therapy did not reduce the pool of HIV-infected resting CD4+ T cells. Thus, although intermittent IL-2 plus HAART quantitatively increased CD4+ T cells, this increase was not selective for HIV-specific CD4+ or CD8+ T cell responses in recently infected persons.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Coculture Techniques; Cyclopropanes; Drug Synergism; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interferon-gamma; Interleukin-2; Lamivudine; Lymphocyte Activation; Lymphocyte Subsets; Oxazines; Pilot Projects; Reverse Transcriptase Inhibitors; Stavudine

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

The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV).. Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline.. At day 14, the 8-h area under the curve (AUC(8)) changed by -10.2% (P = 0.15), maximum concentration (C(max)) by -17.4% (P = 0.46), and minimum concentration (C(min)) by -12.2% (P = 0.28) for patients in the NFV marijuana arm (n = 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n = 9): AUC8 had changed by -14.5% (P = 0.074), C(max) by -14.1% (P = 0.039), and C(min) by -33.7% (P = 0.65).. Despite a statistically significant decrease in C(max) of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.

Topics: Adult; Appetite Stimulants; Dronabinol; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Marijuana Smoking; Middle Aged; Nelfinavir

To demonstrate the feasibility of a concentration-controlled approach to combination antiretroviral therapy, and to compare the virological responses and safety of this strategy versus conventional fixed-dose therapy.. A prospective, randomized, 52 week, open-label trial of concentration-controlled compared with conventional dose zidovudine, lamivudine, and indinavir therapy conduced in a university-based general clinical research center in the United States.. Forty antiretroviral-naive individuals with plasma HIV-RNA levels > 5000 copies/ml.. Zidovudine, lamivudine, and indinavir plasma concentrations were measured in all participants. Doses were adjusted in those assigned to concentration-controlled therapy to achieve levels equal to or greater than target values.. The proportion of patients who achieved the desired drug concentrations, the proportion of patients with HIV-RNA levels < 50 copies/ml at week 52, and safety and tolerance in the concentration-controlled versus conventional therapy arms.. Significantly more concentration-controlled recipients achieved the desired concentration targets for all three drugs: 15 of 16 concentration-controlled recipients compared with nine of 17 conventional recipients (P = 0.017) had HIV-RNA levels < 50 copies/ml at week 52. No difference was observed in the occurrence of drug-related clinical events or laboratory abnormalities between the two treatment arms.. Concentration-controlled therapy implemented simultaneously for three antiretroviral agents was feasible, as well tolerated as conventional therapy, and resulted in a greater proportion of recipients with HIV-RNA levels < 50 copies/ml after 52 weeks. These findings provide a scientific basis to challenge the accepted practice of administering the same dose of antiretroviral agents to all adults, ignoring the concentrations actually achieved.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Feasibility Studies; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

First results of Trilège demonstrated that the strategy of less intensive antiviral therapy is less effective than continuation of triple-drug therapy.. To compare the final number of failures at month 18 and to study viral dynamics in patients experiencing a virological failure.. Longitudinal follow-up from a randomized controlled trial.. Forty-three AIDS clinical-trial units.. A total of 279 HIV-1 infected adults randomized in Trilège.. Analysis of recurrent values of HIV RNA > 500 copies/ml beyond time to virologic failure.. A total of 83 patients experienced virological failure by month 18; 10 in the zidovudine (ZDV) + lamivudine (3TC) + indinavir (IDV) arm, 46 in the ZDV + 3TC arm, and 27 in the ZDV + IDV arm, confirming previous results. Whatever the treatment ultimately received, 87% of patients had an HIV RNA < 500 copies/ml at month 18 with no statistical difference between randomized arms. Patients experiencing a failure in the triple-drug regimen had a greater tendency to maintain HIV RNA > 500 copies/ml beyond the time of virological failure than patients in both less intensive treatment groups who experienced failure. Lower levels of HIV RNA at failure and reinitiating of either the original triple-drug regimen or a new combination of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors were associated with lower hazard ratios for developing recurrent HIV RNA > 500 copies/ml.. Results confirmed the failure of a less intensive regimen to maintain patients with a viral suppression (HIV RNA < 500 copies/ml). Although there is a lower incidence of failure in the triple-drug regimen, randomization to a less intensive regimen of ZDV + 3TC or ZDV + IDV was not detrimental, as treatment modification, either to the original triple regimen, or a different regimen was successful.

Topics: Adult; Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Multivariate Analysis; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome; Viral Load; Zidovudine

Clinical, virologic, and immunologic responses to treatment that contained either indinavir or nelfinavir (both regimens included zidovudine and lamivudine) were determined in 32 children infected with human immunodeficiency virus type 1 (HIV-1) who participated for >/= 96 weeks in a prospective, open, uncontrolled multicenter trial. The pharmacokinetics of indinavir and of nelfinavir were determined and showed large interindividual differences. After 96 weeks of therapy, 69% and 50% of the patients had an HIV-1 RNA load that was below the HIV assays' detection limits of 500 and 40 copies/mL, respectively. Virologic failure was associated with poor compliance and younger age (independent of baseline virus load and receipt of pretreatment). Relative CD4 cell counts increased significantly in relation to the median of the age-specific reference value, from a median of 44% at baseline to 94% after 96 weeks. In a high percentage of the children, clinical, virologic, and immunologic response rates to combination therapy were optimal during the initial 2 years of therapy.

Topics: Adolescent; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Lamivudine; Male; Nelfinavir; Netherlands; Prospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Zidovudine

Evaluation of high active antiretroviral therapy (HAART) in human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) patients receiving combined antiretroviral therapy in China.. We initiated the first efficacy trial of zidovudine (AZT) 600 mg/d and lamivudine (3TC) 300 mg/d (brand name: Combivir) plus indinavir (2 400 mg/d) in 15 Chinese chronically infected with HIV in May 1999 at Beijing.. There was a rapid reduction of 2.7 log in the plasma viremia levels in 15 cases 3 months, after treatment, from a mean baseline of 90 743 copies/ml. The mean CD(4) cell counts increased by 67 cells/microliter from a baseline mean value of 471 cells/microliter and the mean CD(8) cell counts reduced by 192/microliter after 12 months of therapy. The ratio of CD(4)/CD(8) increased from 0.35 to 0.56. The average naive CD(4) cell (CD(45)RA + CD(62)L +) count and naive CD(8) cell (CD(45)RA + CD(62)L +) count increased 42 and 19/microliter respectively after one-year treatment. This drug regimen was well tolerated, with mild nausea in all, transient elevated serum bilirubin in three and kidney stone in two patients.. It is effective for the virus with different genotype. The results will form a scientific foundation for the development of therapeutic strategies for HIV infection in China.

Topics: Adult; Aged; Anti-HIV Agents; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; China; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Count; Male; Middle Aged; RNA, Viral; Time Factors; Treatment Outcome; Viremia; Zidovudine

We compared the efficacy and the toxicity of zidovudine (AZT) versus stavudine (d4T), in combination with lamivudine (3TC) and indinavir, in AZT-, dideoxyinosine (ddI)-, and/or dideoxycytosine (ddC)-experienced patients in a randomized comparative multicenter trial. One hundred seventy human immunodeficiency virus type 1 (HIV-1)-infected patients, who had received AZT, ddI, and/or ddC for at least 6 months but were naive for d4T, 3TC, and protease inhibitors, were randomized to AZT at 250 to 300 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h or to d4T at 40 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h. The primary endpoint was time to virological failure, defined as plasma HIV-1 RNA levels of >5,000 copies/ml after at least 8 weeks of antiretroviral therapy. Additional endpoints were change from baseline in CD4 cell counts, AIDS-defining events and adverse events, and proportion of patients with HIV-1 RNA levels of <500 copies/ml and HIV-1 RNA levels of <50 copies/ml. At week 80, 15 patients in the AZT arm and 14 patients in the d4T arm had reached the primary endpoint, and time to virological failure did not differ between the two arms (P = 0.98). In the d4T and in the AZT arms, 67 and 73% of patients, respectively, had HIV-1 RNA levels of <500 copies/ml (P = 0.50). The median change from baseline in CD4 cell count was 195 x 10(6) and 175 x 10(6)/liter for the d4T- and AZT-containing arms, respectively. The proportions of patients with HIV-1 RNA levels of <50 copies/ml at weeks 8, 16, and 24 were similar in the two arms. The occurrence of serious adverse events was not significantly different between arms. In conclusion, in these patients heavily pretreated with AZT, switching from AZT to d4T when initiating indinavir and 3TC did not bring any additional benefit compared to maintaining AZT.

Topics: Adult; Anti-HIV Agents; Double-Blind Method; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine

To determine the long-term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs).. In an open-label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients (n = 93) with a high median baseline HIV-1 RNA level of 210 000 copies/mL (range 17 000-2 943 000) and a median CD4 cell count of 195 copies/microL (range 4-656 copies/microL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4-week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures.. HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks.. Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load.

Topics: Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; Flow Cytometry; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load

Nephrolithiasis is a well-known complication of indinavir treatment and may result in urological symptoms ranging from renal colic to renal insufficiency.. To obtain further knowledge regarding the incidence and risk factors of urological symptoms associated with indinavir sulfate use.. This study was performed in the ATHENA (AIDS Therapy Evaluation National AIDS Therapy Evaluation Centre) cohort of patients infected with human immunodeficiency virus (HIV) receiving antiretroviral therapy in the Netherlands. The incidence rate of urological symptoms was assessed in a subcohort of 1219 patients starting HIV protease inhibitor treatment after 1996. Urological symptoms were defined as an initial report of nephrolithiasis, renal colic, flank pain, hematuria, renal insufficiency, or nephropathy. Using multivariate Cox regression analysis, risk factors for urological symptoms during indinavir treatment were subsequently studied among the subset of 644 patients who started indinavir treatment after 1996.. The incidence of urological symptoms was 8.3 per 100 treatment-years for indinavir vs 0.8 per 100 treatment-years for other HIV protease inhibitors. Risk factors for urological symptoms during indinavir treatment were low weight (relative risk [RR], 2.1; 95% confidence interval [CI], 1.1-3.9), low lean body mass (RR, 1.7; 95% CI, 1.0-2.9), undetectable HIV-1 RNA when starting indinavir treatment (RR, 3.2; 95% CI, 1.5-6.0), prior treatment change because of intolerance (RR, 2.4; 95% CI, 1.2-5.1), indinavir regimens of 1000 mg or more twice daily (RR, 3.1; 95% CI, 1.3-8.2), and warm environmental temperatures (RR, 3.9; 95% CI, 1.7-8.8). Risk estimates were highest among patients with a low lean body mass.. Increased alertness for urological symptoms is warranted for patients starting indinavir treatment, particularly among those with a low lean body mass, during indinavir regimens of 1000 mg or more twice daily, and in warm weather environments.

Topics: Adult; Aged; Cohort Studies; Confidence Intervals; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Indinavir; Male; Middle Aged; Netherlands; Risk Factors; Time Factors; Urologic Diseases

Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge.. To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen.. Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks.. Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States.. A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL.. Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil.. Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility.. Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03).. In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Disease Progression; Double-Blind Method; Drug Resistance, Viral; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir; Organophosphonates; Oxazines; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Saquinavir; Sulfonamides; Treatment Failure; Viral Load

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.

Topics: Adult; Algorithms; Anti-HIV Agents; Area Under Curve; Drug Therapy, Combination; Female; Half-Life; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Patient Compliance; Zidovudine

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

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received 50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

The high rate of protease inhibitor treatment failure in clinical cohorts makes it necessary to define novel salvage therapies. In a prospective study of 31 HIV-infected patients included in a salvage regimen with stavudine, nevirapine, nelfinavir, and saquinavir, viral load decreased a median of 1.65 log(10) and 1.95 log(10) after 6 and 12 months of treatment, respectively, and 35 and 56% of patients had an HIV RNA level below 50 copies/ml at the same time points. At baseline, the mean number of mutations in the protease gene was 10 (2-19), and the V82A and L90M mutations were present in 54 and 21% of patients. The presence of the V82A mutation did not affect significantly the rate of response (36 vs. 38%), whereas the L90M mutation was associated with treatment failure (0 vs. 43%). Plasma trough levels of nelfinavir (NFV) and saquinavir (SQV), in a twice daily dosing regimen, were above the protein-corrected IC(95) in most patients despite the addition of an enzymatic inducer such as nevirapine, and peak levels were 2- and 5-fold increased with respect to standard doses. However, pharmacokinetics of saquinavir-hard gel capsule (SQV-hgc) did not improve significantly in the three times daily dosing regimen. In conclusion, the combination of stavudine, nevirapine, nelfinavir, and saquinavir increased plasma drug levels and produced an adequate virological response in patients who had failed indinavir or ritonavir therapy. This degree of response is not significantly decreased in the presence of genotypic mutations associated with indinavir/ritonavir (IDV/RTV) resistance.

Topics: Adult; Aged; Anti-HIV Agents; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Mutation; Nelfinavir; Nevirapine; Prospective Studies; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Treatment Failure; Viral Load

Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Dose-Response Relationship, Immunologic; Drug Therapy, Combination; Epitopes, T-Lymphocyte; Flow Cytometry; HIV Infections; HIV-1; HLA-DR Antigens; Humans; Immunodominant Epitopes; Immunohistochemistry; Immunophenotyping; Indinavir; Lamivudine; Leukocyte Common Antigens; Prospective Studies; Protein Tyrosine Phosphatase, Non-Receptor Type 1; T-Lymphocytes, Cytotoxic; Viral Load; Zidovudine

This prospective, multicenter, open-label study was designed to determine the antiretroviral activity and safety of a 4-drug regimen: 1000 mg indinavir every 8 h with 200 mg nevirapine, 40 mg stavudine, and 150 mg lamivudine, each given twice daily in amprenavir-experienced subjects. The primary end points of the study were the human immunodeficiency virus (HIV) RNA level and CD4 cell count responses. Fifty-six subjects were enrolled and were changed from amprenavir-containing regimens to the 4-drug regimen. Overall, at week 48, 33 (59%) of 56 subjects had HIV RNA levels <500 copies/mL (intent-to-treat analysis, where missing values equal > or =500 copies/mL) and CD4 cell counts increased by 94 cells/mm(3) from baseline. Subjects who had previously taken amprenavir combination therapy were more likely to experience virologic failure than those who had taken amprenavir monotherapy (odds ratio, 7.7; P=.0012). In this study, most subjects who had taken amprenavir-based regimens and who changed to a 4-drug regimen achieved subsequent durable virologic suppression.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Male; Nevirapine; Odds Ratio; Prospective Studies; RNA, Viral; Safety; Stavudine; Sulfonamides; Time Factors; Treatment Outcome; Viral Load

The objective of this study was to evaluate the pharmacokinetics of indinavir in human immunodeficiency virus-infected children as part of a prospective, open, uncontrolled, multicenter study in The Netherlands. Human immunodeficiency virus type 1-infected children were monitored over 6 months of treatment with zidovudine (120 mg/m(2) every 8 h [q8h]), lamivudine (4 mg/kg of body weight q12h), and indinavir (33mg/kg of metabolic weight [MW] q8h). Four weeks after the start of treatment, the steady-state pharmacokinetics of indinavir were determined by high-pressure liquid chromatography. If patients had an indinavir area under the concentration-time curve (AUC) of below 10 or above 30 mg/liter. h, a dose increase or a dose reduction was made and pharmacokinetic measurements were repeated 4 weeks later. Nineteen patients started with the dose of 33 mg/kg of MW q8h. The median AUC (range) was 10.5 (2.8 to 51.0) mg/liter. h. The median AUC (range) in 17 children treated with 50 mg/kg of MW q8h was 20.6 (4.1 to 38.7) mg/liter. h. Finally, five patients had a dose increase to 67 mg/kg of MW q8h, resulting in a median AUC (range) of 36.6 (27.2 to 80.0) mg/liter. h. After 6 months of treatment, there were 11 children with an AUC of below 20 mg/liter. h, of whom 5 (45%) had a detectable viral load, while this was the case in none of the 11 children with an AUC of higher than 20 mg/liter. h. We conclude that the optimal dose of indinavir in children to obtain drug exposure similar to that observed in adult patients is 50 mg/kg of MW q8h, which approximates 600 mg/m(2) q8h. It would even be better to adjust the indinavir dose based on an AUC of greater than 20 mg/liter. h.

Topics: Adolescent; Area Under Curve; Child; Child, Preschool; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Male; Prospective Studies

To describe the use of second line protease-inhibitor (PI) regimens across Europe and to determine factors associated with virological and immunological response.. Analysis of data from 984 patients with a median follow-up of 21 months enrolled in EuroSIDA. Patients started their second PI-containing regimen at least 16 weeks after starting the first PI-containing regimen and with viral load > 1000 copies/ml.. Virological response was defined as a viral load < 500 copies/ml and immunological response as an increase of 50 x 10(6)/l or more in CD4 lymphocyte count.. The median CD4 cell count at starting the second PI was 171 x 10(6) cells/l; viral load was 4.45 log copies/ml. As a second PI regimen, 45% were using a dual PI, while of those on one PI, indinavir (42%) and nelfinavir (34%) were most common. In multivariate Cox models, a higher viral load at starting the second PI [relative hazard (RH), 0.67 per 1 log higher; 95% confidence interval (CI), 0.58-0.77; P < 0.0001) and a lower CD4 cell count (RH, 1.15 per 50% higher; 95% CI, 1.06-1.26; P = 0.0014) were associated with a reduced probability of virological response. Those who had achieved viral suppression on the first PI-regimen were more likely to respond to the second (RH, 1.65; 95% CI, 1.30-2.10; P < 0.0001) as were those who added one or two new nucleosides to their second PI.. Patients who initiate a second PI regimen at lower viral load, higher CD4 cell count or who added new nucleosides tended to be more likely to achieve a viral load < 500 copies/ml. The roles of cross-resistance and adherence in response to second-line regimens needs further investigation.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir; Prospective Studies; Ritonavir; Saquinavir; Treatment Outcome; Viral Load

Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment.. To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen.. A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe.. Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L.. Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy.. Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48.. The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment.. In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Microbial; Female; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Indinavir; Lamivudine; Male; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; Survival Analysis; Therapeutic Equivalency; Viral Load; Zidovudine

Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for > or = 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4+ T cells/microL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of > or = 0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4+, CD4+ CD45RA+, and CD4+ CD45RO+ T cell counts. CD4+ CD45RA+ (naive) T cells were the major contributor to CD4+ T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression.

Topics: Adolescent; Anti-HIV Agents; CD4 Antigens; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Leukocyte Common Antigens; Male; Protein Tyrosine Phosphatase, Non-Receptor Type 1; RNA, Viral; Viral Load; Zidovudine

To describe the pharmacokinetics, safety, and efficacy of twice-daily indinavir + ritonavir regimens. A cohort-based survey of HIV-infected patients who either used indinavir 800 mg + ritonavir 100 mg twice daily or indinavir 400 mg + ritonavir 400 mg twice daily.. Data were extracted from a database of samples sent to our laboratory for measurement of indinavir + ritonavir plasma concentrations. Patient characteristics, safety, and efficacy measurements were collected by retrospective chart review.. 100 Patients using 800-mg indinavir + 100-mg ritonavir twice daily and 32 patients using 400-mg indinavir + 400-mg ritonavir twice daily were eligible. Median peak and trough concentrations of indinavir were 6.8 and 0.77 mg/L in the 800/100 group and 2.6 and 0.45 mg/L in the 400/400 group. The most frequently found side effects were nausea and vomiting, which occurred in 22.1% and 34.9% of the patients in the 800/100 and the 400/400 groups, respectively. Viral load data were analyzed for patients who switched from 800-mg indinavir three times daily to one of the indinavir + ritonavir twice daily regimens. At the time of switch 63% (800/100 group) and 60% (400/400 group) had an undetectable viral load and this increased to 77% and 70%, respectively, during follow-up. Patients who switched to the 400/400 group discontinued treatment more frequently than patients who switched to the 800/100 group (70% vs. 26%, p =.008).. Indinavir + ritonavir regimens show improved pharmacokinetic properties, allowing twice-daily dosing with food. Clinical data suggest that safety and efficacy is at least as good as with indinavir three-times-daily regimens without ritonavir. Prospective, comparative trials are needed to properly assess the role in HIV therapy of these twice-daily indinavir + ritonavir regimens.

Topics: Cohort Studies; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Retrospective Studies; Ritonavir; Treatment Outcome; Viral Load

Indinavir, an antiretroviral agent, has an influence on the pharmacokinetics of other drugs by acting as an inhibitor of cytochrome P450-mediated drug metabolism. The incidence of tuberculosis has increased dramatically in the past decade because of an epidemic of HIV infection. Rifampicin is still one of the most valuable drugs for the standard treatment of tuberculosis. The objective of this study was to investigate the effects of indinavir on the pharmacokinetics of rifampicin in man. Our study was conducted in eleven HIV-infected patients. All patients received a 600-mg single dose of oral rifampicin on day 1 and 15- and 800-mg oral indinavir three times a day from day 2 to day 15. Rifampicin pharmacokinetic studies were carried out on day 1 and day 15. The results showed that rifampicin concentrations were higher when it was administered with indinavir than when it was administered alone. With concomitant indinavir medication, the mean AUC0-24 of rifampicin was increased by 73%. Therefore, we conclude that indinavir has an inhibitory effect on the metabolism of rifampicin.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Area Under Curve; Drug Interactions; Female; HIV Infections; Humans; Indinavir; Male; Middle Aged; Rifampin

This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART.. Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir.. The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL.. Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

Topics: Adult; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Female; Granulocyte Colony-Stimulating Factor; HIV Infections; Humans; Indinavir; Lamivudine; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neutropenia; Prednisone; Stavudine; Treatment Outcome; Vincristine; Viral Load

The objective of this study was to determine the effects of double-strength grapefruit juice on gastric pH and systemic bioavailability of indinavir in HIV-infected subjects receiving indinavir. Fourteen HIV-infected subjects took 800 mg of indinavir with 6 ounces (180 ml) of water or double-strength grapefruit juice. Gastric pH was measured and blood samples were collected for 5 hours after indinavir dosing. Grapefruit juice increased the mean gastric pH (from 1.39 +/- 0.4 to 3.20 +/- 0.3; p < 0.05) and slightly delayed the absorption of indinavir (tmax increased from 1.12 +/- 0.8 h to 1.56 +/- 0.6 h; p < 0.05). However, there were no significant differences in indinavir exposure. Cmax was 16.7 +/- 7.3 microM with water versus 13.9 +/- 4.2 microM with grapefruit juice (p = NS), and AUC0-8 was 37.5 +/- 19 with water versus 36.9 +/- 15 with grapefruit juice (p = NS). The authors concluded that concomitant administration of grapefruit juice increases gastric pH and delays indinavir absorption but does not uniformly affect the systemic bioavailability of indinavir in HIV-infected subjects.

Topics: Adult; Anti-HIV Agents; Beverages; Biological Availability; Chromatography, High Pressure Liquid; Citrus; Cross-Over Studies; Female; Food-Drug Interactions; Gastric Juice; Half-Life; HIV Infections; Humans; Hydrogen-Ion Concentration; Indinavir; Male; Middle Aged; Models, Biological; Time Factors

This study compared the alterations in p-triglyceride (PT) in 111 protease inhibitor (PI)-naive patients on randomized treatment with either indinavir (800 mg 3 times daily), ritonavir (600 mg twice daily) or ritonavir/saquinavir (400 mg each twice daily) and 2 nucleoside reverse transcriptase inhibitors (NRTIs). PT (non-fasting) was measured at regular intervals until week 48. PT levels were evaluated in relation to PI regime, CD4 cell count and prior NRTI experience. The effect on PT levels of changing PI regime was analysed. For 24 patients fasting and non-fasting PT values were correlated. In the ritonavir-containing arms PT levels increased significantly (median PT at baseline: 1.80 mmol/l; week 36: 2.3 mmol/l; p < 0.001). In the indinavir arm no significant rise in PT levels was observed. Comparing the PI arms at week 48 showed significantly higher levels of PT in the ritonavir-containing arms than in the indinavir arm (p < 0.001). There was a high correlation between fasting and non-fasting PT values (p < 0.001, p = 0.88). A significant decline in PT values when changing PI treatment was observed (n = 13, p = 0.016). Ritonavir-containing regimens caused a rapid and sustained elevation of PT values, while indinavir did not significantly affect PT levels.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Triglycerides

Ritonavir (RTV) is a powerful inhibitor of P450 3A4 cytochorme. When given in combination with indinavir (IDV) it increases the IDV trough concentrations (Cmin) allowing a lower IDV dosage in a twice a day regimen, independently of meals. We report tolerance data and IDV Cmin levels observed in plasma and cerebrospinal fluid (CSF) in a cohort of HIV-infected patients treated with the IDV-RTV combination at different dosages of IDV and RTV.. IDV Cmin was assayed 56 times in 40 patients (few patients had received different dosages of the IDV-RTV combination). Tolerance was recorded.. For patients given the IDV-RTV combination at the doses of 800/100 mg b.i.d., 800/200 mg b.i.d. or 400/400 mg b.i.d., the IDV Cmin was 12 times the median IDV IC95. If the Cmin/IC95 ratio was greater than 10 with the 800/100 mg b.i.d. regimen and virological success was achieved, the IDV dosage was reduced to 400 mg b.i.d. For these patients, the 400/100 mg b.i.d. IDV-RTV regimen always gave a Cmin above the IDV IC95. Median Cmin for IDV in CSF was 146 ng/ml (range 71-881 ng/ml), above the IDV IC95. It was possible to control most of the adverse effects by reducing dosage after obtaining the IDV pharmacological levels. Definitive interruption of treatment was required in only 2 cases at mean follow-up of 7.9 months.. The IDV-RTV combination should be used to improve observance of antiretroviral treatments and reduce the risk of virological failure related to low plasma levels. The IDV-RTV combination at 800/100 mg b.i.d. is a useful protocol when IDV efficacy alone is the goal. The 400/400 mg b.i.d. IDV-RTV regimen is an interesting alternative when efficacy of both inhibitors is the goal. Drug assays should be systematic to adapt individual dosages and limit the risk of adverse effects.

Topics: Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Prospective Studies; Ritonavir

Topics: Adult; Aged; CD4 Lymphocyte Count; Cohort Studies; HIV Infections; HIV Protease Inhibitors; Humans; Hypertension; Indinavir; Middle Aged; Retrospective Studies; Statistics, Nonparametric; Viral Load

To compare the clinical response among patients who initiate protease inhibitor therapies with different virological potency.. We analysed patients who started indinavir, ritonavir or saquinavir hard gel capsule (hgc) as part of at least triple therapy during prospective follow-up within the EuroSIDA study.. Changes in plasma viral load (pVL) and CD4 cell count from baseline were compared between treatment groups. Time to new AIDS-defining events and death were compared in Kaplan--Meier models, and Cox models were established to further assess differences in clinical progression (new AIDS/death). Adjustment was made for differences in baseline parameters, in particular pVL, CD4 cell count, and region of Europe.. A total of 2708 patients (median follow-up: 30 months) were included, of which 556 started ritonavir (21%), 1342 indinavir (50%), and 810 saquinavir hgc (30%). The three groups were fairly evenly balanced at baseline regarding CD4 count, previous diagnosis of AIDS and pVL, After 12 months, the median changes in CD4 cell count were 90, 96 and 74 x 10(6) cells/l, respectively;P < 0.001, the proportions of patients with pVL < 500 copies/ml were 47, 54 and 41%; P < 0.001, and the proportions with clinical progression were 11.9, 9.2 and 11.9%, respectively; P = 0.20 (log-rank test). In multivariate models the relative risk of clinical progression for indinavir compared with saquinavir hgc was: 0.77 (0.60--0.99); P = 0.043, and for ritonavir 0.83 (0.62--1.11); P = 0.20.. Saquinavir hgc was associated with an inferior long-term clinical response relative to indinavir, which was consistent with the observed differences in virological and immunological responses.

Topics: Administration, Oral; Adult; Capsules; CD4 Lymphocyte Count; Disease Progression; Drug Therapy, Combination; Follow-Up Studies; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Proportional Hazards Models; Prospective Studies; Ritonavir; Saquinavir; Statistics, Nonparametric; Survival Analysis; Viral Load

A high proportion of individuals receiving highly active antiretroviral treatment (HAART) complain of sexual dysfunction (SD), encompassing a lack of desire or erectile dysfunction.. To determine whether SD was associated with particular components of the HAART regimens and to identify risk factors for the development of SD in patients on HAART.. A survey among patients with HIV infection using an anonymous questionnaire was conducted in 10 European countries between December 1998 and December 1999. A total of 904 individuals currently receiving antiretroviral agents were included in the analyses.. A decrease in sexual interest was significantly more frequently reported by subjects (men and women) using HAART containing protease inhibitors (PI) (308/766, 40%), compared with PI-naive patients (22/138, 16%; OR 3.55; 95% CI 2.15--5.89). In addition, a significantly larger number of PI-experienced men reported a decrease in sexual potency (216/628, 34%) compared with PI-naive men (12/99, 12%; OR 2.56; 95% CI 1.33--5.03). In multivariate analyses the following factors were associated with a decrease in sexual interest: a current PI-containing regimen, a history of a PI regimen, symptomatic HIV infection, age and homosexual contact as HIV transmission mode. Factors associated with a decrease in sexual potency were: current use of a PI-containing regimen, symptomatic HIV disease, age and the use of tranquillisers.. SD appears to be a common side-effect of HAART regimens containing a PI. The potential association between SD and other side-effects of HAART, such as lipodystrophy syndrome and neuropathy, should be investigated further.

Topics: Adult; Antiretroviral Therapy, Highly Active; Erectile Dysfunction; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Multivariate Analysis; Nelfinavir; Prevalence; Risk Factors; Ritonavir; Sexual Dysfunctions, Psychological; Surveys and Questionnaires

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Cohort Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Patient Compliance; Substance Abuse, Intravenous

Topics: Adolescent; Child; Child, Preschool; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Infant; Lamivudine; Male; Nelfinavir; Phenotype; Point Mutation; Reverse Transcriptase Inhibitors; Ritonavir; Time; Viral Load; Zidovudine

To determine whether initiation of antiretroviral therapy that includes the protease inhibitor indinavir causes insulin resistance or abnormal B-cell function in study subjects with HIV infection.. Nonwasted, HIV-infected study subjects who did not have concurrent diabetes were prospectively evaluated by oral and intravenous glucose tolerance testing at baseline, at 2 weeks after starting indinavir monotherapy, and at another 6 weeks after initiating indinavir-based triple-therapy.. Mean CD4 count at entry was 282 cells/microl and median HIV RNA was 33,000 copies/ml; all experienced a virologic response. Fasting glucose increased from 83.2 +/- 3.7 mg/dl at baseline to 86.8 +/- 3.2 at week 2 and 91.7 +/- 3.5 at week 8 (p =.003). Insulin sensitivity by minimal model analysis decreased by 30.5% over 8 weeks, from 3.83 +/- 0.63 min-1 per microU/ml x 10-4 to 3.09 +/- 0.53 at week 2 and 2.66 +/- 0.35 at week 8 (p =.01). Insulin secretion by the acute insulin response to intravenous glucose did not change (baseline 822 +/- 283 microU/ml x min, week 8 880 +/- 289; p = 0.4), and the insulin response to oral glucose (30 minute insulin:glucose ratio) fell from 1.69 +/- 0.54 microU/ml per mg/dl at baseline to 1.18 +/- 0.34 at week 8 (p =.05).. During 8 weeks of indinavir-based therapy, fasting glucose increased and insulin sensitivity decreased, without a compensatory increase in insulin release. This combination of insulin resistance without augmented B-cell response may explain the hyperglycemia and other metabolic abnormalities seen in some protease inhibitor-treated patients.

Topics: Adult; Anti-HIV Agents; B-Lymphocytes; Blood Glucose; Drug Therapy, Combination; Female; Glucose Tolerance Test; HIV Infections; HIV-1; Humans; Indinavir; Insulin; Insulin Resistance; Male; Prospective Studies; Reverse Transcriptase Inhibitors

Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy.. Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression.. Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation.. Treatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm.. Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Topics: Adolescent; Adult; Anti-HIV Agents; Case-Control Studies; CD4 Lymphocyte Count; Drug Therapy, Combination; Enzyme Inhibitors; Female; HIV Infections; Humans; Hydroxyurea; Indinavir; Lamivudine; Male; Nucleic Acid Synthesis Inhibitors; Pancreatitis; Prospective Studies; Survival Analysis; Treatment Failure; Viral Load; Zidovudine

Variable drug penetration of antiretroviral drugs into the genital tract may contribute to the differential evolution of HIV and the emergence of drug resistance. This, in turn, may have an impact on the sexual transmission of resistant HIV in patients treated with antiretroviral drugs. We have measured concentrations of the HIV-1 protease inhibitors indinavir, ritonavir and saquinavir in the blood plasma (BP) and seminal plasma (SP) of 23 HIV-1-positive men. Forty-five time-matched blood and semen samples were obtained. SP concentrations of indinavir exceeded the EC95 of indinavir, corrected for protein binding, of 42 ng/mL at all time intervals. In contrast, the median ritonavir and saquinavir SP concentrations were below the relevant EC95 at all times post drug ingestion. The median SP:BP concentration ratios for indinavir were 0.6, 0.8 and 1.4, respectively, at 0-2, 2-6 and 6-8 h post-drug ingestion. In contrast, the median SP:BP concentration ratios at 0-3, 3-9 and 9-12 h post-drug ingestion were <0.02, <0.04 and <0.04, respectively, for both ritonavir and saquinavir. These differences justify further study of HIV-1 evolution and development of resistance in the genital tract of men taking these anti-HIV drugs.

Topics: Adult; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Ritonavir; Saquinavir; Semen

Limited data are available on antiretroviral drug concentrations in seminal plasma during a dosing interval. Further, since human ejaculate is composed of fluids originating from the testes, the seminal vesicles, and the prostate, all having different physiological characteristics, drug concentrations in total seminal plasma do not necessarily reflect concentrations in the separate compartments. Five human immunodeficiency virus type 1-infected patients on nevirapine (NVP; 200 mg twice a day [b.i.d.]) and/or indinavir (IDV; 800 mg b.i.d. with ritonavir, 100 mg b.i.d.) regimens used a split ejaculate technique to separate seminal plasma in two fractions, representing fluids from the testes and prostate (first fraction) and fluids from the seminal vesicles (second fraction). Split-ejaculate samples were provided at 0, 2, 5, and 8 h after drug ingestion, on separate days after 3 days of sexual abstinence. NVP and IDV showed time-dependent concentrations in seminal plasma, with peak concentrations in both fractions at 2 and 2 to 5 h, respectively, after drug ingestion. The NVP concentrations were not significantly different between the first and second fractions of the ejaculate at all time points measured and were in the therapeutic range, except for the predose concentration in two patients. The median (range) predose IDV concentrations in the first and second fractions of the ejaculate were 448 (353 to 1,015) ng/ml and 527 (240 to 849) ng/ml, respectively (P = 0.7). In conclusion, NVP and IDV concentrations in seminal plasma are dependent on the time after drug ingestion. Furthermore, our data suggest that NVP and IDV achieve therapeutic concentrations in both the testes and prostate and the seminal vesicles throughout the dosing interval.

Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Indinavir; Male; Nevirapine; Semen

Subcutaneous adipocyte apoptosis occurs in lipotrophic areas of patients with highly active antiretroviral therapy (HAART)-associated lipodystrophy. Fourteen patients with HAART-associated lipodystrophy had 2 subcutaneous biopsies for evidence of adipocyte apoptosis, the second after a randomized change to nevirapine (n=8) or after remaining on a regimen of indinavir-based HAART (n=6). Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP-digoxigenin nick end-labeling method. Patients who were switched to nevirapine had a significant decrease in insulinemia and a significant increase in the glucose:insulin ratio. Overall, subcutaneous adipocyte apoptosis increased in 3 patients who were switched to nevirapine and in 3 who continued to receive indinavir but decreased in 2 patients switched to nevirapine and another 2 who continued to receive indinavir. Subcutaneous adipocyte apoptosis continues to occur in lipotrophic areas of patients with HAART-associated lipodystrophy despite switching from indinavir to nevirapine, suggesting that such a strategy will be useless for reversal of lipoatrophy.

Topics: Adipocytes; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Apoptosis; Blood Glucose; Female; HIV Infections; Humans; In Situ Nick-End Labeling; Indinavir; Insulin; Lipodystrophy; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors

A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure.. To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy.. Observational analysis of one treatment group in a phase III trial.. 40 AIDS Clinical Trials units.. 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8.. HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death.. Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]).. The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Protocols; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Logistic Models; Male; Middle Aged; RNA, Viral; Viral Load; Zidovudine

To assess predictors for discontinuation and treatment-limiting adverse drug reactions (TLADR) among patients starting their first protease inhibitor (PI).. Data on patients starting a PI regimen (indinavir, ritonavir, ritonavir/saquinavir and saquinavir hard gel) in a randomized trial (RAS, n = 318) and an observational cohort (OBC, n = 505) were used to document reasons for discontinuation and TLADR. Risk factors for discontinuation of the initial PI/developing TLADR were assessed in Cox models.. A total of 43 (RAS) and 48% (OBC) discontinued the initial PI therapy within less than 2 years. In both populations TLADR were the most common reason for discontinuation. The incidence of TLADR in RAS was: 8.5 (indinavir), 66.0 (ritonavir), 15.6 (saquinavir hard gel) per 100 person-years of follow-up (P < 0.001). Body weight and type of PI initiated were independent risk factors for treatment discontinuation and TLADR in both groups. In OBC, the risk of developing TLADR increased by 12% per 5 kg lower body weight when starting the PI regimen [the relative hazard (RH) was 1.12 (95% confidence interval: 1.05-1.19) per 5 kg lighter], and starting ritonavir was associated with a three- to sixfold higher risk of TLADR relative to other PI regimens. Very similar results were documented in RAS [RH for body weight was 1.18 (1.07-1.29)].. Nearly half of the patients stopped treatment with the initial PI, most commonly as a result of adverse drug reactions. Low body weight and initiation of ritonavir relative to other PIs were associated with an increased risk of TLADRs. Very consistent results were found in a randomized trial and an observational cohort.

Topics: Adult; Cohort Studies; Female; HIV Infections; Humans; Indinavir; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Protease Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Ritonavir; Saquinavir; Treatment Failure; Treatment Refusal; Weight Loss

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Oxazines; Reverse Transcriptase Inhibitors; Viral Load

Topics: Adipose Tissue; Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Viral Load; Zidovudine

In human immunodeficiency virus (HIV)-1 infection, highly increased T-cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4(+) and CD8(+) lymphocyte subpopulations before and during highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67(+) CD4(+) and CD8(+) lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4(+) T cells in the blood was found when the number of these cells were below 100 per microL. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4(+) T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4(+) CD27(+) memory pool. In the CD8(+) T-cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27(+) CD 45RO(+) and CD27(-) CD45RO(+) memory CD8(+) T-cell pool, corresponding with the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8(+) T-cell subsets. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)

Topics: Anti-HIV Agents; Antigens, CD; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; HIV Infections; HIV Seronegativity; HIV-1; Humans; Indinavir; Ki-67 Antigen; Lamivudine; Longitudinal Studies; Lymphocyte Activation; RNA, Viral; Saquinavir; T-Lymphocyte Subsets; T-Lymphocytes; Viral Load; Zidovudine

In the Trilège trial, following induction with a zidovudine, lamivudine, and indinavir regimen, human immunodeficiency virus (HIV) replication was less suppressed by 2-drug maintenance therapy than by triple-drug therapy.. To identify mechanisms of virologic failure in the 3 arms of the Trilège trial.. Case-control study conducted from February to October 1998.. Three urban hospitals in Paris, France.. Fifty-eight case patients with virologic failure (HIV RNA rebound to >500 copies/mL in 2 consecutive samples) randomized to 3 therapy groups: triple drug (zidovudine, lamivudine, and indinavir), 8; zidovudine-lamivudine, 29; and zidovudine-indinavir, 21; the case patients were randomly matched with 58 control patients with sustained viral suppression.. At virologic failure (S1 sample) and 6 weeks later (S2 sample), assessment of protease and reverse transcriptase gene mutations, plasma indinavir level, and degree of viral load rebound; pill count during induction and maintenance periods.. Only 1 primary resistance mutation, M184V, was detected in S1 plasma samples from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in S2 plasma samples from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 S1 plasma samples and in 10 of 11 S2 plasma samples. Indinavir levels were undetectable in all S1 samples but 2 in 7 triple-drug cases tested and in the expected range in 11 of 18 S1 and 5 of 12 S2 zidovudine-indinavir case plasma samples tested. Maintenance adherence rates were lower for cases vs controls for zidovudine (P = .05) and indinavir (P = .05). Low indinavir levels, lower adherence rates for zidovudine (P = .04) and lamivudine (P = .03), and rebound to near-baseline values suggested adherence as cause of early failure for 4 of 8 triple-drug cases. In the zidovudine-lamivudine arm, for which case and control adherence rates did not differ significantly (P = .96), most failures occurred late with low rebound, suggesting suboptimal drug potency. In the zidovudine-indinavir arm, virologic failures may be related to both mechanisms.. During the maintenance phase early and late virologic failures appeared to be related more to problems of adherence and antiretroviral treatment potency, respectively, than to selection of resistant mutant viruses.

Topics: Anti-HIV Agents; Case-Control Studies; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Patient Compliance; Treatment Failure; Viral Load; Zidovudine

To determine the frequency of crystalluria in patients treated with the human immunodeficiency virus protease inhibitor indinavir and to compare methods of detecting crystalluria.. A total of 308 freshly voided urine specimens from 168 patients treated with indinavir were evaluated by manual microscopy of sediment and microscopy with an automated workstation and by dipstick analysis.. Crystals were detected in 22%, 31%, or 32% of specimens using, respectively, an automated workstation, manual microscopy, or both methods. Proteinuria or hemoglobinuria occurred significantly more often in specimens with (28%) than without (18%) crystals. Frequency of crystalluria was unrelated to specific gravity, but it increased at higher pH. Crystals were detected in 21% of specimens with pH less than 6 and 42% of specimens with pH of 6 or higher.. Crystalluria occurs in more than 30% of urine specimens from patients treated with indinavir, but detection rates vary substantially with method of analysis. Manual microscopy detected crystalluria 41% more often than did an automated workstation.

Topics: Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Image Processing, Computer-Assisted; Indinavir; Microscopy, Polarization; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; Urinalysis

The indinavir dosage regimen currently used for human immunodeficiency virus (HIV)-infected children is not based on pharmacokinetic data obtained in the target patient population. The purpose of our study was to characterize indinavir pharmacokinetics and pharmacodynamics in HIV-infected children. Eleven children (age range, 9.0 to 13.6 years; weight range, 21.7 to 56.0 kg) receiving indinavir (500 mg/m(2) every 8 h) in combination with lamivudine and stavudine were studied. The correlation of indinavir pharmacokinetic parameters and demographic parameters was evaluated. Also, the pharmacodynamic relationship between parameters of indinavir exposure and parameters of renal toxicity and immunologic recovery was studied. The area under the indinavir concentration-time curve (AUC) and patient body surface area (BSA) showed a significant negative correlation (r = 0.73; P = 0.012). Patients with smaller BSA had excessive indinavir AUC compared to adults. On the other hand, the median minimum drug concentration in plasma (C(min)) was lower than that reported for adults. The maximum indinavir concentration in serum was higher in patients with renal toxicity (5 out of 11 children), but the difference was not statistically significant (15.3 +/- 8.2 versus 9.8 +/- 4.4 mg/liter; P = 0.19). There was a trend toward higher immunologic efficacy in patients with greater indinavir exposure: the time-averaged AUC of the percentage of CD4(+) lymphocytes over the baseline value for patients with indinavir C(min) > 95% inhibitory concentration (IC(95)) was higher than in patients with C(min) < IC(95) (P = 0. 068). Our study suggests that a dose reduction may be appropriate for children with small BSA and that a 6-h dosage regimen may be indicated for a substantial percentage of patients. Due to the low number of patients enrolled in this study, our results should be confirmed by a larger study.

Topics: Adolescent; Anti-HIV Agents; Area Under Curve; Body Surface Area; CD4 Lymphocyte Count; Child; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Stavudine; Viral Load

To determine the predictors of virological and clinical failure in patients receiving a protease inhibitor as part of triple therapy.. From the French Hospital Database on HIV, 1402 protease inhibitor-naive patients starting a highly active antiretroviral therapy regimen with ritonavir, saquinavir-hard gel capsule (hgc) or indinavir between July 1996 and March 1997, and with measured HIV RNA at baseline and at 12 months, were studied for progression to a new AIDS-defining event (ADE) or death. Virological failure was defined as plasma HIV RNA > 1000 copies/ml at 12 months. Multivariate analyses were performed using Cox models for clinical outcomes and logistic regression for virological outcomes.. During a median follow-up of 14.1 months, 94 (6.7%) patients experienced an ADE or died. At 12 months, 700 patients (49.9%) had virological failure. In the multivariate analysis, baseline CD4 cell count and viral load were found to be independent predictors of both virological and clinical failure. Neither the type of the first protease inhibitor taken nor previous antiretroviral therapy experience was associated with risk of clinical progression. For virological failure, the use of saquinavir-hgc was associated with a significant 1.96-fold increase in risk compared with indinavir; pre-treated patients were at higher risk than antiretroviral therapy-naive patients.. In this study with large samples of patients, the use of saquinavir-hgc was associated with higher risk of virological failure at 12 months than were ritonavir and indinavir; no differences between protease inhibitors were found for clinical progression. As biases cannot be excluded, a longer duration of follow-up will be necessary to answer the question of whether the results are really discrepant or simply reflect the delay between virological failure and clinical manifestations.

Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Ritonavir; RNA, Viral; Saquinavir; Treatment Failure; Viral Load

To compare adherence and clinical outcome with two modalities of highly active antiretroviral therapy (HAART), in HIV-infected patients.. Randomized, open-label, prospective study.. Tertiary care centre in Spain.. A total of 112 non-naive HIV-infected patients, recruited from March 1998 through August 1998, were studied.. Triple drug therapy with stavudine and lamivudine, plus indinavir or nelfinavir.. Adherence, side-effects, and immunological, virological, and clinical efficacy of treatment were assessed at 3-month intervals.. After a median follow-up of 9 months, 32% of patients in the indinavir group versus 50% of those in the nelfinavir group showed adequate adherence in all clinical appointments (P= 0.0559). Adherence was superior in the nelfinavir group in every visit. After 6 months of treatment 48% of subjects in the indinavir group and 70% of those in the nelfinavir group exhibited adequate adherence (P= 0.0311). After 9 months 35% of patients in the indinavir group and 59% of those in the nelfinavir group showed adequate adherence (P= 0.0291). Side-effects provoked discontinuation of treatment in 34% of patients in the indinavir group and 12% of patients in the nelfinavir group (P= 0.0073). Immunological and virological efficacy were similar in both groups.. Adherence to a HAART regimen with stavudine plus lamivudine plus nelfinavir was superior to a regimen with stavudine plus lamivudine plus indinavir. Side-effects provoked more discontinuation of treatment in the indinavir group than in the nelfinavir group.

Topics: Adult; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Lamivudine; Male; Nelfinavir; Patient Compliance; Prospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome

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

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

To investigate the effect of combination antiretroviral therapy on plasma HIV-1 RNA as measured by HIV RNA PCR and to assess their safety and tolerability.. A randomized, multicentre, double-blind, placebo-controlled trial.. Multicentre study in eight European countries, Australia and Canada.. Antiretroviral naive patients (n = 103) with CD4 cell counts between 150 and 500 x 10(6)/l.. Patients were randomly assigned to zidovudine (ZDV; 200 mg three times per day) plus lamivudine (3TC; 150 mg twice per day) or to ZDV + 3TC + indinavir (IND; 800 mg q8h) for 52 weeks.. Degree and duration of reduction of plasma HIV-1 RNA as measured by RNA PCR; Development of drug-related toxicities sufficiently severe to warrant dose modification, interruption or permanent discontinuation.. ZDV + 3TC + IND reduced plasma HIV-1 RNA (P < 0.001) and increased CD4 cell count significantly (P = 0.01) more than ZDV + 3TC. The addition of IND to ZDV + 3TC as initial therapy markedly increased the proportion of patients with plasma HIV-1 RNA values < 500 copies/ml (31/52, 60%) or 20 copies/ml (24/52, 46%) as compared with ZDV + 3TC (9/50, 18% or 2/50, 4% respectively) at week 52 in an intention-to-treat, missing = failure analysis. Assessment of time to virological rebound (> 0.5 log10 copies/ml above nadir) showed that patients who attained a minimum plasma HIV-1 RNA of < or = 20 copies/ml were less likely to rebound than those who did not reach this threshold. The addition of IND to ZDV + 3TC did not result in any significant increase in adverse experiences.. ZDV + 3TC + IND resulted in a considerable improvement compared with the double combination, in reduction in plasma HIV-1 RNA, increase in CD4 cell count and proportion of patients with HIV RNA below the limit of detection. Despite an average 3 log10 decrease in plasma HIV-1 RNA on triple therapy, however, maximal suppression (< or = 20 copies/ml) was only attained in about one-half of the patients in an intent-to-treat analysis.

Topics: Adult; Anti-HIV Agents; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Patient Compliance; Placebos; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine

To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment.. The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points.. Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9-28.9] due to toxicity and 7.6% (95% CI, 4.9-1 0.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32-0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10-3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09-7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80-0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74-5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04-1.26 versus hard-gell saquinavir).. If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.

Topics: Adult; Aged; Anti-HIV Agents; Cohort Studies; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; Humans; Indinavir; Italy; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Time Factors; Treatment Failure; Treatment Refusal

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

It is predicted that HIV-infected individuals in early HIV disease are the most likely group to achieve immune reconstitution following highly active antiretroviral treatment. We assessed whether suppression of HIV replication in this group would improve immune function.. Seventeen antiretroviral-naïve patients in early HIV disease were evaluated for immune function and lymphocyte phenotyping using standard immunological assays.. Absolute CD4+ T-cell number increased from a median of 550 to 800 x 10(6) cells/l while CD8+ T-cell numbers were reduced. The decrease in CD8+ cells correlated with a decrease in the CD8+ memory phenotype. Kinetics of CD4+ naïve and memory T-cell rise indicated that 80% of the maximum CD4+ naïve increase was achieved within 18 weeks whereas maximum CD4+ memory T-cell rise was achieved within 36 weeks. Activation markers (HLA-DR, CD38) and an apoptosis-related marker (CD95) were reduced on CD4+ and CD8+ T cells. Lymphocyte proliferation responses to tetanus toxoid, alloantigen, and anti-CD3/CD28 were restored in patients that were initially unresponsive. At baseline, 31% of the patients responded to HIV p24, which increased to 69% post-therapy. The inducible RANTES response was normalized following therapy whereas inducible interferon-gamma, interleukin (IL)-12, and MIP1beta were elevated. The depressed inducible IL-10 response, however, was not altered after therapy.. This is one of the first studies to demonstrate the restoration of HIV-1 specific responses in non-acute HIV infection, suggesting early intervention with potent antiretroviral therapy may reverse immune-mediated damage not seen with treated patients who have more advanced disease.

Topics: Adolescent; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cytokines; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load; Virus Replication; Zidovudine

Both the natural history of HIV infection and the response to antiretroviral therapy are heterogeneous. Polymorphisms in chemokine receptor genes modulate the natural history of HIV-1 infection. In comparison with subjects with other genotypes, the prognosis for HIV-1-infected CCR5-delta32 heterozygotes is more favorable and that for CCR5 promoter allele 59029A homozygotes is less favorable.. HIV-1-infected adults with a CD4+ lymphocyte count > or = 200 cells x 10(6)/l and a plasma HIV RNA level > or = 1000 copies/ml were treated with indinavir, zidovudine and lamivudine for 6 months. HIV RNA levels were measured at 4-week intervals. Genotyping for chemokine receptor gene polymorphisms (CCR5-delta32, CCR5 59029A/G, CCR2-641) was performed. We examined whether the time to first HIV RNA < 200 copies/ml, frequency of viral suppression failure (HIV RNA > or = 200 copies/ml between weeks 16 and 28 of therapy), or reduction from the pre-treatment HIV RNA level differed by genotype.. Time to first HIV RNA < 200 copies/ml was not predicted by genotype. Among 272 Caucasian patients, viral suppression failure was more common among patients with the CCR5 +/+ ¿ CCR2+/+ ¿ CCR5-59029 A/A genotype (28%) than among all other subjects combined (relative risk, 2.0; P = 0.06). After 24 weeks of therapy, genotype groups differed in the reduction of the HIV RNA level from baseline (P = 0.02); patients with the CCR5 +/+ ¿ CCR2+/+ ¿ CCR5-59029 A/A genotype had a mean reduction of 2.12 log10 copies/ml compared to 2.64 log10 copies/ml among all other groups combined.. Polymorphisms in chemokine receptor genes may explain some of the heterogeneity in sustaining viral suppression observed among patients receiving potent antiretroviral therapy.

Topics: Adult; Alleles; Anti-HIV Agents; Chemokine CXCL12; Chemokines, CXC; Drug Therapy, Combination; Female; Gene Frequency; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Linkage Disequilibrium; Male; Polymorphism, Genetic; Receptors, CCR2; Receptors, CCR5; Receptors, Chemokine; Receptors, Cytokine; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zidovudine

To evaluate the clinical, immunologic, and virologic response to indinavir, zidovudine, and lamivudine in children with human immunodeficiency virus-1 (HIV-1) infection.. Twenty-eight HIV-1-infected children (3 months to 16 years of age) with or without prior treatment with reverse-transcriptase inhibitors and a HIV-1 RNA >5000 copies/mL and/or a CD4 cell count less than the lower limit of the age-specific reference value were treated with indinavir, zidovudine, and lamivudine. Pharmacokinetics of indinavir were determined in each child.. The combination treatment was well tolerated in the majority of patients. Clinical improvement was seen in all patients. After 6 months of therapy, 70% of the patients had an HIV-1 RNA load below 500 copies/mL, whereas 48% of the children had a viral load below 40 copies/mL. Relative CD4 cell counts in relation to the lower limit of the age-specific reference value increased significantly from a median value of 79% at baseline to 106% after 6 months of therapy. The doses of indinavir necessary to achieve area under the curve values comparable to adult values varied from 1250 mg/m(2)/d to 2450 mg/m(2)/d.. Highly active antiretroviral therapy consisting of indinavir, zidovudine, and lamivudine in children reduced HIV-1 RNA to less than 500 copies/mL in 70% of the children within 6 months. Improved CD4 cell counts were observed in most patients, as was a better clinical condition (no invasive or opportunistic infections, increased weight gain). Side effects of the triple therapy were mild. Highly active antiretroviral therapy can be used as successfully in children as in adults.

Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Lamivudine; Male; Netherlands; Prospective Studies; Zidovudine

Topics: Anti-HIV Agents; DNA, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Interleukin-2; Reverse Transcriptase Inhibitors; Time Factors; Treatment Outcome; Viral Load

Cytokines and beta-chemokines play an important role in the complex interaction between HIV-1 and the immune system. We studied platelet-free plasma (PFP) levels and ex vivo production of cytokines and beta-chemokines at different HIV disease stages and the influence of potent protease inhibitor therapy on their production in late-stage patients. Mitogen-induced production of MIP-1alpha, MIP-1beta, and RANTES by PBMCs was higher in HIV-infected patients than in HIV-seronegative controls. Patients with late-stage HIV infection (CD4+ cells <50/microl) showed a higher production of MIP-1alpha and RANTES and lower plasma levels of IL-2 compared with HIV-positive patients at the intermediate stage (CD4+ cells >150/microl). Pretreatment RANTES production correlated negatively with CD4+ and CD8+ cell counts; also, MIP-1alpha production was inversely correlated with CD4+ cell counts. Among patients with a CD4+ cell count <50/microl, RANTES production before protease inhibitor treatment was inversely correlated with viral load. Late-stage patients with IL-2 production higher than 50 pg/ml before treatment showed a more impressive increase in CD4+ cell counts after protease inhibitor therapy. The production of MIP-1alpha, MIP-1beta, RANTES, and IFN-gamma was markedly reduced at 8 weeks and partially restored at 24 weeks after beginning protease inhibitor therapy. PFP levels of RANTES showed a concurrent decrease. Patients with more advanced HIV infection show a higher production of inflammatory cytokines, which is reduced by protease inhibitor therapy. Residual late-stage IL-2 producers may represent a subset of patients with a higher potential for immunologic reconstitution.

Topics: Case-Control Studies; CD4 Lymphocyte Count; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines, CC; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; In Vitro Techniques; Indinavir; Interferon-gamma; Interleukin-2; Leukocytes, Mononuclear; Macrophage Inflammatory Proteins; Ritonavir; RNA, Viral

Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known.. To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial.. Open-label extension of a randomized, double-blind study.. Four clinical research units.. 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20,000 copies/mL and CD4 counts ranging from 50 to 400 cells/mm3.. Indinavir, zidovudine, and lamivudine.. Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses.. After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3). Nephrolithiasis occurred in 12 of 33 patients (36%).. A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Genotype; HIV; HIV Infections; Humans; Indinavir; Kidney Calculi; Lamivudine; Male; Middle Aged; RNA, Viral; Viral Load; Viremia; Zidovudine

Use of human immunodeficiency virus (HIV) drug-resistance testing in therapeutic decision making may be aided by understanding the relationship between results of genotypic and drug-susceptibility phenotypic assays. We investigated this relationship by applying 3 different statistical methods-cluster analysis, recursive partitioning, and linear discriminant analysis-to results for 72 patients followed in the Adult AIDS Clinical Trials Group (ACTG) protocol 333. ACTG 333 was a multicenter, randomized trial comparing 2 formulations of saquinavir (SQV) to indinavir (IDV) in patients with extensive hard-gel SQV experience. Data include protease amino acid sequences and 50% inhibitory concentrations for SQV and IDV at baseline. The 3 methods give similar results showing the association of mutations at codons 10, 63, 71, and 90 with in vitro resistance to IDV and SQV. Recursive partitioning is especially useful because it can identify interactions among mutations at different codons and accommodates many types of data as well as missing observations.

Topics: Adult; Aged; Cluster Analysis; Data Interpretation, Statistical; Drug Resistance, Microbial; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Phenotype; Saquinavir

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

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

Plasma and cerebrospinal fluid (CSF) indinavir concentrations were measured by high-performance liquid chromatography. The median concentration in plasma exceeded that in CSF 10-fold. The modeled CSF curve was flat at 155 nM, and the estimated ratio of the areas under the CSF and plasma concentration-time curves was 6%. We conclude that CSF indinavir concentrations are lower than levels in plasma but exceed the clinical 95% inhibitory concentration range.

Topics: Chromatography, High Pressure Liquid; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

To evaluate hepatic cytochrome P450 (CYP) 3A4 activity in patients infected with the human immunodeficiency virus (HIV) using the erythromycin breath test (ERMBT), and to examine the relationship of the ERMBT to plasma concentrations of indinavir and nelfinavir.. Prospective observational study.. University infectious diseases clinic.. Thirty-nine HIV-positive patients and 47 healthy controls.. After the ERMBT in patients and controls, 25 patients received indinavir or nelfinavir.. Compared with controls, ERMBT variability was significantly greater in HIV-positive patients, including a subset of 19 patients receiving no concurrent drugs reported to alter CYP3A4 activity. Correlation between the ERMBT and first-dose plasma indinavir concentrations nearly reached statistical significance (p=0.07).. Variability in hepatic activity of CYP3A4 in HIV-positive patients may be greater than in controls and may explain some between-subject variability in plasma concentrations of indinavir. However, clearance mechanisms for protease inhibitors are complex, and if it is important to assess systemic exposure, the ERMBT is not a substitute for direct measurement of plasma concentrations.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Anti-HIV Agents; Breath Tests; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Erythromycin; HIV Infections; Humans; Indinavir; Liver; Male; Middle Aged; Mixed Function Oxygenases; Nelfinavir

AIDS Clinical Trials Group protocol 333 was an open-label trial of a switch from saquinavir (SQV) hard capsules (SQVhc) to indinavir (IDV) or saquinavir soft-gel capsules (SQVsgc) after >48 weeks of prior treatment with SQVhc. Eighty-nine subjects received IDV or SQVsgc or continued to receive SQVhc and continued unchanged treatment with non-protease-inhibitor antivirals for 8 weeks. Subjects receiving SQVhc then switched treatment to IDV. Baseline drug susceptibility and protease gene sequencing were done; 12 codons related to IDV and SQV resistance were analyzed. After 112 weeks (median) of SQVhc, the fall in human immunodeficiency virus (HIV) type 1 RNA level from baseline was significantly greater with IDV and was inversely correlated with the number of protease substitutions. The number of substitutions also correlated with baseline CD4 cell count, HIV-1 RNA level, SQV experience, and drug susceptibility. Substitution at codon 10, which occurred only in isolates with >/=2 substitutions, was associated with blunted RNA response. IDV IC(50) correlated with HIV-1 RNA response after the switch to IDV but added little predictive power once the genotype was considered.

Topics: Adolescent; Adult; Capsules; Drug Administration Schedule; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Phenotype; RNA, Viral; Saquinavir; Viral Load

The Danish Protease Inhibitor (PI) Study has enrolled 318 human immunodeficiency virus (HIV)-infected, PI-naive patients for the purpose of comparing 3 PI-containing regimens for the treatment of HIV infection. The regimens include 2 nucleoside analogues in combination with indinavir (Idr), ritonavir (Rtv), or Rtv and saquinavir (Rtv/Sqv). Similar percentages of patients in the 3 study arms achieved reduced levels (

Topics: Adolescent; Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Ritonavir; Saquinavir; Viral Load

The extent to which human immunodeficiency virus (HIV) type 1 drug resistance compromises therapeutic efficacy is intimately tied to drug potency and exposure. Most HIV-1 protease inhibitors maintain in vivo trough levels above their human serum protein binding-corrected IC(95) values for wild-type HIV-1. However, these troughs are well below corrected IC(95) values for protease inhibitor-resistant viruses from patients experiencing virologic failure of indinavir and/or nelfinavir. This suggests that none of the single protease inhibitors would be effective after many cases of protease inhibitor failure. However, saquinavir, amprenavir, and indinavir blood levels are increased substantially when each is coadministered with ritonavir, with 12-h troughs exceeding corrected wild-type IC(95) by 2-, 7-, and 28-79-fold, respectively. These indinavir and amprenavir troughs exceed IC(95) for most protease inhibitor-resistant viruses tested. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.

Topics: Carbamates; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Phenotype; Protein Binding; Ritonavir; Saquinavir; Sulfonamides

Forty-seven patients presenting with primary human immunodeficiency virus (HIV) infection were treated with zidovudine 200 mg 3 times a day, lamivudine 150 mg 2 times a day, and indinavir 800 mg 3 times a day for 1 year. From a mean pretreatment viral RNA level of 4.93 log(10) copies/mL, the proportions of patients having <500 copies/mL at 24 and 52 weeks were 92.0% and 89.2%, respectively. For the 35 patients with data available at 24 and 52 weeks, the corresponding proportions for the <50 copies/mL analysis were 86.6% and 79.3%, respectively. The change in virus load was -2.19 and -2.41 log(10) copies/mL at weeks 8 and 52, respectively. CD4 cell counts increased, from a mean of 546 cells/mm(3), by 142 cells/mm(3) at week 24 and by 210 cells/mm(3) at week 52. Three patients discontinued the study because of drug-related toxicity. Six (12.8%) patients had adverse experiences associated with nephrolithiasis. Combination therapy with zidovudine, lamivudine, and indinavir during primary HIV infection results in a profound and sustained reduction in virus load with concurrent recovery of the CD4 cell population.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Core Protein p24; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Patient Compliance; Zidovudine

Indinavir concentrations were determined in plasma and saliva over a random period of 4 h. On average, levels in saliva were 70% +/- 38% of the corresponding levels in plasma. These findings suggest that saliva might serve as an appropriate specimen for monitoring of plasma indinavir levels in patients treated with indinavir.

Topics: Adult; Drug Monitoring; Feasibility Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Saliva

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.

Topics: Adult; DNA Mutational Analysis; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Mutation; Ritonavir; RNA, Viral; Saquinavir

No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available.. To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV).. Randomized, open-label, multi-center.. Fifteen HIV clinical research centers.. Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml.. d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV.. Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events.. For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm.. These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Thymidine; Zidovudine

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

Topics: Adult; Anticholesteremic Agents; Drug Tolerance; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Indinavir; Male; Nelfinavir; Pilot Projects; Pravastatin; Ritonavir; Saquinavir; Treatment Outcome

To compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine.. Two multicenter, open-label, randomized 24-week studies.. Adults HIV-1 infection, HIV-1 RNA greater than 10000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used.. In Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01).. Three-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug-drug interactions.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Administration Schedule; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

Topics: Child; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Ritonavir

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

The aim of our study is to compare the tolerability of zidovudine/lamivudine/indinavir when used in post-exposure prophylaxis (PEP) subjects and in HIV-infected patients. HIV-negative patients were enrolled as part of the surveillance protocol for professional exposure at the Luigi Sacco Hospital in Milan. HIV-positive patients were selected among all subjects undergoing treatment with zidovudine/lamivudine/indinavir from the CISAI cohort, an Italian cohort for the evaluation of adverse reactions to HAART. In both studies patients were followed prospectively and the severity of the reactions was evaluated using the AIDS Clinical Trial Group adverse experience grading scales. Up to September 1999, 37 HIV-seronegative subjects had undergone treatment with zidovudine/ lamivudine/indinavir. From a total of 1207 patients belonging to the CISAI cohort, 199 were identified as being treated with the same regimen. The frequency of adverse events in the PEP subjects was 70.3% compared to 11.1% for HIV-infected patients. In the first group, adverse events caused treatment interruption in 21 subjects (56.7%) versus 14 patients (7%) among the HIV-infected group. Only one case of a severe event (grade 3-4) was observed in the prophylaxis group against 12 in the treatment group. Our study shows that treatment interruption is eight times higher in HIV-negative subjects compared to HIV-seropositive patients, and that the incidence of adverse events is approximately six times higher, though such events, are for the most part, not severe.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemoprevention; Female; Health Personnel; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Zidovudine

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Pilot Projects; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels.. Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 microg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half.. In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 x 106/L (range, 4-623 x 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 microg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in microg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was >/=0.1 microg/ml. Conversely, IND Cmin was <0.1 microg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily.. Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.

Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Pilot Projects; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load; Zidovudine

In antiretroviral therapy, to improve compliance the need is increasing to develop regimens that combine potency and safety with convenient dosing. The objective of our study was to find a once-daily dosing regimen of a HIV-protease inhibitor, indinavir (IDV), by combining it with ritonavir (RTV). In the study, 12 healthy volunteers took a single IDV dose of 800 mg on day 1. Plasma and urine sampling was done for 12 hours. From day 2 to day 21, participants took RTV liquid 200 mg (group A) or 400 mg (group B) once daily. Repeated pharmacokinetic sampling was performed over the course of 24 hours, after single doses of indinavir 400 mg (day 15), 800 mg (day 18), and 1200 mg (day 21). The best dosage regimen in this pharmacokinetic study was selected based on efficacy and tolerability criteria. The study comprised 10 male and 2 female healthy volunteers, mean age, 25 years (range, 18-50 years), mean weight, 70 kg (range, 52-83 kg). One male participant discontinued on day 8 due to influenza. All other participants completed the study without the occurrence of serious adverse events. RTV inhibited indinavir plasma clearance by 51% to 70%, leading to increased and prolonged IDV exposure. Renal clearance was influenced by the addition of RTV and dosage increments of IDV. The efficacy criterion was best fulfilled by 1200 mg IDV/400 mg RTV, whereas this combination performed most poorly on tolerability criteria. Based on the single dose data, a once-daily regimen of IDV with a low dose of RTV is possible. The best dosage regimen to start with among those studied here appears to be 1200 mg IDV/400 mg RTV, which could be decreased at steady state to 800 IDV/400 RTV or 1200 IDV/200 RTV if toxicity occurs. Steady-state pharmacokinetic data of once-daily IDV/RTV regimens in HIV-infected patients are warranted.

Topics: Adolescent; Adult; Creatinine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Intestinal Absorption; Male; Middle Aged; Ritonavir

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Outcome

To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine.. Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach.. Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017.. Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.

Topics: Adult; Anti-HIV Agents; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Zidovudine

Determine the frequency and nature of interruptions in HIV-1 protease inhibitor treatment in HIV-infected patients.. A longitudinal study included patients treated with antiretroviral protocols including at least one antiprotease and followed from 1 March 1996 through 1 March 1998.. Among the 309 patients followed for the duration of the study, 137 (44.3%) interrupted their antiprotease treatment at least once. Withdrawal was warranted by therapeutic failure in 49.6% of the cases and by drug intolerance in 45.4%. Drug intolerance concerned 37%, 36.7%, 5.7% and 2.9% of the patients taking ritonavir, indinavir, nelfinavir and saquinavir respectively (p < 106). Multivariate analysis demonstrated that saquinavir was significantly associated with better tolerance and with efficacy at least as good as ritonavir or indinavir. The most frequent cause for interrupting treatment were digestive disorders for ritonavir (20% of the treated patients) and lithiasic manifestations for indinavir (9.4%). The ritonavir-hepatitis C association appeared to predispose to drug-induced perturbed liver tests.. Drug intolerance is a frequent cause of treatment interruption. Therapeutic success in HIV infection requires improved efficacy but also better tolerated antiretorviral drugs, particularly antiretroviral drugs.

Topics: Adult; Anti-HIV Agents; Drug Resistance; Female; HIV Infections; HIV-1; Humans; Indinavir; Longitudinal Studies; Male; Middle Aged; Protease Inhibitors

Nevirapine and indinavir have the potential of affecting the pharmacokinetics of each other. In a prospective trial, 24 human immunodeficiency virus (HIV)-infected subjects on stable nucleoside or no therapy were treated with 800 mg of indinavir every 8 h. After 7 days, 200 mg of nevirapine a day was added for 14 days and then increased to 200 mg twice a day. At day 7 (before nevirapine), there was a sevenfold difference among the subjects in indinavir area under the curve (AUC), and there was a significant correlation between indinavir AUC (r2=0.378, P=.019), minimum plasma concentration (Cmin; r2=0.359, P=.023), maximum plasma concentration (Cmax; r2=0.340, P=.028), and plasma HIV RNA decline. Nevirapine significantly reduced median indinavir Cmin (47.5%) and AUC (27.4%) and, to a lesser extent, Cmax (11%). Plasma HIV RNA values were

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Area Under Curve; CD4 Lymphocyte Count; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; RNA, Viral

To determine the clinical efficacy of the HIV-1 protease inhibitor indinavir (IDV) in saquinavir (SQV)-experienced patients and delineate the developing drug-resistance patterns.. Open-label prospective clinical trial.. University hospital research center.. Ten patients who had completed a SQV monotherapy study in which they had received SQV at a dose of 3600 or 7200 mg daily (two and fourfold the standard dose).. At enrollment patients received IDV for 4 weeks as monotherapy, after which zidovudine (ZDV) and lamivudine (3TC) were added to their drug regimen. Patients then received combination therapy (IDV-ZDV-3TC) for an additional 20 weeks to complete a total of 24 weeks of therapy.. Plasma HIV RNA viral load and CD4+ T-cell counts were monitored. Sequencing of the HIV protease gene was performed to determine the development of resistance mutations. Plasma samples for sequencing were taken before initial SQV therapy, after SQV therapy before starting IDV, and after 24 weeks of IDV therapy.. The average duration of high-dose SQV before starting IDV was 58+/-29.2 weeks. A 0.58 log10 RNA copies/ml increase was noted during the 3-week washout phase followed by a mean reduction in plasma HIV RNA viral load of 1.2 log10 RNA copies/ml after 4 weeks of IDV. After the addition of ZDV and 3TC at week 4, HIV RNA continued to fall reaching a mean reduction of 1.96 log10 RNA copies/ml at week 24. Plasma HIV RNA was below 400 RNA copies/ml in six out of nine patients at week 24. CD4+ T-cell counts showed a gradual rise from 328 x 10(6)/l to 453 x 10(6)/l by week 24. SQV therapy had resulted in multiple mutations in the protease gene. Six of the patients had developed five or more mutations: L90M in two, G48V in four (of which three also contained L101), and V82A in three. Patients in whom plasma HIV RNA was not durably suppressed by subsequent IDV combination therapy developed multiple (up to four) additional mutations within 24 weeks, including codons 54, 82 and 93 amongst others. No clear correlation was found between the mutations that had developed in individual patients after SQV and the subsequent efficacy of IDV.. Prolonged use of SQV at potent doses in the presence of elevated viral load levels resulted in the development of multiple resistance mutations. Individual resistance patterns varied greatly between patients, as did their virological response to therapy. Resistance assays may be useful in identifying which patients will benefit from salvage therapy with a second protease inhibitor.

Topics: CD4 Lymphocyte Count; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Mutation; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Viral Load; Zidovudine

To compare the efficacy and safety of indinavir 800 mg three times a day, ritonavir 600 mg twice a day, and a combination of ritonavir 400 mg twice a day and saquinavir 400 mg twice a day, when administered with two nucleoside analogues.. A randomized, open-labelled, controlled trial. Two hundred and eighty-four patients started randomized treatment. The primary end-point was the proportion of patients with HIV RNA of 200 copies/ml or less (Roche Amplicor) and HIV RNA of 20 copies/ml or less (Roche ultradirect assay) at 6 months. Analysis was performed as intent-to-treat, and missing values were accounted for as failures.. As of 1 May 1998, 269 patients should have completed 24 weeks of treatment. The proportion of patients with HIV RNA of 200 copies/ml or less was 71% (indinavir), 67% (ritonavir), and 82% (ritonavir + saquinavir), P = 0.07. In antiretroviral drug-naive patients (n = 119), the corresponding figures were 63, 57, and 89% (P < 0.01), whereas among drug-experienced patients (n = 165) 77, 74, and 77% had HIV RNA of 200 copies/ml or less (P = 0.90). The same pattern was observed in the ultradirect analysis. All three regimens were generally safe, but significantly more patients in the ritonavir group (37%) stopped treatment because of adverse drug reactions compared with the indinavir group (8%) and the ritonavir plus saquinavir group (16%) (P < 0.001).. Treatment with saquinavir plus ritonavir in combination with two nucleoside analogues is generally safe, and has superior short-term antiviral efficacy compared with indinavir and ritonavir also combined with two nucleoside analogues in antiretroviral drug-naive patients. Further follow-up is needed to determine the durability of the viral response.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir; Saquinavir; Time Factors

The purpose of the study was to evaluate the efficacy of treating of HIV infected patients with two nucleoside analogues and one protease inhibitor in clinical practice. Sixty-one patients were included and followed with respect to plasma HIV-RNA, CD4 cell count and side effects up to one year. Median plasma HIV-RNA was reduced from 20,000 to < 200 copies/ml, and the percentage of patients with plasma HIV-RNA < 200 copies per ml increased from 7.5% to 65.2%. The CD4 cell count increased from 180 to 300 x 10(6)/l. Among 49 patients who remained on therapy, the percentage of patients with plasma HIV-RNA < 200 copies/ml increased from 9.8% to 73.7%. It is concluded that triple drug antiretroviral treatment shows significant effects on plasma HIV-RNA and CD4 cell count, and that the results obtained in clinical practice are comparable to results reported from controlled clinical trials.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; N-Glycosyl Hydrolases; Retrospective Studies; Ritonavir; RNA, Viral; Zidovudine

Until December 31st 1997, 163 HIV/AIDS patients were treated with HAART at the Department of Infectious Diseases, Aarhus University Hospital. The patients mainly received a combination of zidovudine, lamivudine and saquinavir. They were observed for an average period of 375 days. HAART was found to increase the amount of CD4 lymphocytes in peripheral blood and decrease the number of HIV-RNA copies. Both effects were seen to be more pronounced in patients naive to antiretroviral treatment. However, 64 patients had their protease inhibitor changed during the observation period, 53% due to failure of suppression of the viral load, 25% due to adverse events and 22% due to other reasons.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Ritonavir; Saquinavir

Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

Topics: Adult; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nelfinavir; Nevirapine; Phenotype; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Salvage Therapy; Saquinavir

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

To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects.. Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC.. All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0-infinity decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean Cmax was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was significantly delayed from I hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects.. Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.

Topics: Adult; Aged; Cross-Over Studies; Eating; Gastric Acidity Determination; HIV Infections; HIV Protease Inhibitors; Humans; Hydrogen-Ion Concentration; Indinavir; Intestinal Absorption; Male; Middle Aged; Viscosity

To compare efficacy and tolerability of saquinavir soft gelatin capsule (SQV-SGC) formulation and indinavir, both given as part of a triple drug regimen containing zidovudine and lamivudine, in HIV-1-infected individuals.. Randomized, open label, multicentre study.. A total of 70 patients who were antiretroviral-naive and who had a CD4 cell count < 500 x 10(6)/I and/or > 10000 HIV RNA copies/ml plasma and/or HIV-related symptoms. Subjects were assigned randomly to zidovudine 200 mg three times per day plus lamivudine 150 mg twice per day plus either SQV-SGC 1200 mg three times per day (SQV-SGC group) or indinavir 800 mg three times per day (indinavir group). Data are presented for all patients up to week 24.. Mean baseline CD4 cell counts (+/- SE) were 301+/-29 x 10(6) cells/l and 310 +/-43 x 10(6) cells/l in the SQV-SGC and indinavir groups, respectively. The log10 median baseline HIV RNA load was 5.00 copies/ml in the SQV-SGC group and 4.98 copies/ml in the indinavir group. No difference in antiretroviral effect between the treatment arms could be demonstrated. Intention-to-treat analysis (last observation carried forward [LOCF]) at week 24 revealed that RNA levels decreased to < 50 copies/ml in 74.3% of patients in the SQV-SGC group and in 71.4% of the patients in the indinavir group (P = 0.78). In the on-treatment analysis the proportion of patients < 50 copies/ml at week 24 was 88.0% in the SQV-SGC group and 84.6% in the indinavir group (P = 0.725). Intriguingly, the mean increase of CD4 cells in the first 24 weeks was 162+/-20 x 10(6) cells/l in the SQV-SGC group and 89+/-21 x 10(6) cells/l in the indinavir group (P = 0.01), but preliminary data indicate that this difference in CD4 cell count gain may disappear after 24 weeks of treatment. Both regimens were generally well tolerated.. During the first 24 weeks of the study, we found no difference in antiviral potency between the indinavir group and the SQV-SGC group. A significantly higher CD4 response in the SQV-SGC group was observed.

Topics: Adult; Anti-HIV Agents; Capsules; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; Gelatin; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Treatment Outcome; Zidovudine

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Topics: Adult; Anti-HIV Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; DNA, Viral; Drug Therapy, Combination; HIV Antibodies; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Prospective Studies; RNA, Viral; T-Lymphocyte Subsets; Viremia; Zidovudine

Potent antiretroviral therapy (ART) with a protease inhibitor-based regimen is commonly used to treat HIV-1-infected patients. Transient treatment interruptions because of drug intolerance or other reasons are not uncommon. HIV-1 dynamics during therapy interruption and its consequences for the subsequent reinitiation of therapy have not been properly studied.. Ten antiretroviral-naive, HIV-1-infected subjects (mean baseline CD4 cell count of 414 cells/mm3 and plasma viral load of 4.8 log10 copies/ml) were treated with the triple drug ART regimen indinavir/zidovudine/lamivudine for 28 days. Therapy was then interrupted for 28 days, after which the same ART regimen was re-started.. HIV-1 in plasma declined during the first 7 days of therapy with T1/2 of 1.5 days, and during days 7-28 with T1/2 of 8.9 days. Once therapy was interrupted, a delay of 4-7 days was observed in all subjects, preceding a rapid viral rebound with a mean doubling time of 1.6 days. Mean viral load after 28 days of interruption was 96% of baseline. Upon reinitiation of the same ART regimen, viral load declined at rates similar to those observed during the initial therapy (T1/2 of 1.6 and 8.0 days, respectively). No resistance-conferring mutations were observed in the HIV-1 reverse transcriptase (RT) and protease regions after the interruption of therapy. Plasma viral loads were maintained below 200 copies/ml in subjects continuing therapy for 4 (n = 9) to 12 (n = 5) months, with a mean CD4 cell count increase of 145 cells/mm3.. The reintroduction of efficient ART therapy after a 1 month interruption shows viral kinetics similar to that of naive patients, and is not associated with the development of resistance. No deleterious effect on the reinitiated therapy was observed in patients who temporarily discontinued ART therapy. Nevertheless, because viral load rebounds back to baseline during treatment interruption, viral suppression is in effect put off by that period of time.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

Evaluation of immunological reconstitution after 2 years of highly active antiretroviral therapy (HAART) in AIDS patients.. Previous data showed the effectiveness of HAART but conflicting evidence of immune reconstitution has been found in severely immunocompromised patients. Therefore, T-cell subsets and functions were analysed during 24 months of HAART in 21 AIDS patients (mean baseline CD4 cell count, 20 x 10(6)/l).. Subjects were tested at baseline and after 4, 12 and 24 months of therapy for clinical symptoms and the following investigations were carried out: plasma HIV RNA, T-cell subsets and lymphoproliferative responses to mitogens (phytohaemagglutinin, anti-CD3), and recall antigens (Candida mannoprotein, tetanus toxoid and recombinant glycoprotein 160).. Increase in body weight, improvement of Karnofsky's score and reduction of opportunistic infections were observed. All patients showed an initial increase in the CD4 memory subset, whereas naive CD4 cells consistently increased only after 1 year. The magnitude of immune recovery was stronger in patients showing a significant reduction in viral load. However seven out of 21 patients who did not reach a sustained suppression of viral load showed also an increase in T-cell subsets. The majority of patients recovered lymphoproliferative responses to mitogens, whereas only four subjects showed a functional response to Candida mannoprotein. No patients showed a response to HIV recombinant glycoprotein 160 or tetanus toxoid.. The immune recovery observed is slower and not complete in severely immunocompromised patients. Our data suggest that HAART may be continued also in the absence of a significant HIV RNA decrease if alternative drugs are not available.

Topics: Adult; Anti-HIV Agents; Antigen Presentation; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypersensitivity, Delayed; Immunologic Memory; Indinavir; Lymphocyte Activation; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; T-Lymphocyte Subsets; T-Lymphocytes

To study the pharmacokinetic properties and clinical efficacy of the HIV-1 protease inhibitor (PI) indinavir in the central nervous system (CNS).. Twenty-five consecutive HIV-1 infected patients on combination therapy that included indinavir, had cerebrospinal fluid (CSF) and plasma samples taken on 32 different occasions, at different times after indinavir administration. CSF and viral load data obtained from these treated patients were compared with those from 36 untreated HIV-1 infected patients of similar immunological and demographic pre-treatment status.. Concentrations of indinavir were measured in CSF and plasma by high-pressure liquid chromatography with ultraviolet light detection and the data were used in pharmacokinetic modelling.. The concentration of indinavir in plasma varied with time over a dose interval by about two orders of magnitude, whereas the concentration in CSF was relatively stable. The median concentration of indinavir in CSF was 210 nmol/l, which is above the 95% inhibitory concentration in vitro. Findings from the pharmacokinetic modelling indicate that indinavir is actively transported out of the CSF (P <0.001 compared with a passive transport-only model). In the PI-treated group there was a reduction in viral load to below 50 copies/ml in most subjects and a normalization of the CSF cell content and IgG-index.. This study has shown that one PI, indinavir, is present in the CSF at therapeutic concentrations, and is likely to contribute to the antiretroviral activities observed within the CNS.

Topics: Adult; Anti-HIV Agents; Blood-Brain Barrier; Cerebrospinal Fluid; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral

A randomized, double-blind, multicenter study of indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection,

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Survival Rate; Zidovudine

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

Sargramostim is a yeast-derived, recombinant human granulocyte-macrophage colony-stimulating factor with therapeutic potential in human immunodeficiency virus (HIV) infection. Its safety and activity when used in combination with protease inhibitors were evaluated in a randomized, double-blind trial in which 20 HIV-infected subjects on stable antiretroviral regimens, including indinavir or ritonavir, received sargramostim or placebo 3 times a week for 8 weeks. Analysis of HIV virus load excluded any 0. 5 log10 increase due to sargramostim (95% confidence interval, -0.68 to 0.44). Sargramostim was well tolerated, and inflammatory cytokines and surrogate markers of disease progression, such as serum levels of interleukin-10 and soluble tumor necrosis factor receptors types Iota and IotaIota, remained stable in subjects receiving sargramostim. Sargramostim treatment was associated with a trend toward decreased HIV RNA (>0.5 log10) and increased CD4+ cell count (>30%). These results became statistically significant only when subjects with baseline virus loads within the limits of detection or baseline CD4 cell count >50 were analyzed. No difference in indinavir pharmacokinetics was observed before or after sargramostim therapy.

Topics: Adult; Anti-HIV Agents; Antigens, CD; Biomarkers; Confidence Intervals; Double-Blind Method; Drug Therapy, Combination; Female; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interleukin-10; Male; Middle Aged; Placebos; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Recombinant Proteins; Ritonavir; RNA, Viral; Viral Load

We examined the effect of an HIV-1-specific immune-based therapy on cell-associated HIV-1 DNA and RNA.. Five HIV-1-infected subjects receiving HIV-1 immunogen plus HAART were compared with three HIV-1-infected subjects who received incomplete Freund's adjuvant (IFA) plus HAART.. Cell-associated HIV-1 RNA or DNA in lymphocytes and monocytes was determined using a dual immunophenotyping/in situ hybridization assay with or without in situ PCR amplification.. Cell-associated HIV-1 RNA in CD4 cells correlated with plasma RNA overall. CD4, HIV-1 gag-pol messenger (m)RNA+ cells decreased in the immunogen plus HAART group compared with the IFA plus HAART group. Decreases in HIV-1 DNA+ CD4 cells were observed in the immunogen plus HAART compared with the IFA plus HAART group. Decreases in HIV-1 gag-pol mRNA+ monocytes were observed in the immunogen plus HAART group compared with the IFA plus HAART group. Consistent with the findings in CD4 cells, decreases in HIV-1 DNA+ monocytes were observed in the immunogen plus HAART group compared with the IFA plus HAART group.. These preliminary observations support the rationale for examining the combination of immune-based therapies and antiretroviral drugs for effective HIV-1 control.

Topics: AIDS Vaccines; Anti-HIV Agents; CD4 Lymphocyte Count; Combined Modality Therapy; DNA, Viral; Drug Therapy, Combination; Freund's Adjuvant; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Monocytes; Pilot Projects; RNA, Viral; T-Lymphocytes, Helper-Inducer; Viral Load; Zidovudine

To explore the steady-state plasma pharmacokinetics of indinavir in twice daily dosing regimens with and without the co-administration of 100 mg ritonavir.. Observational pharmacokinetic study.. HIV-1-infected individuals who use indinavir alone (1200 mg twice daily, n = 6), or the combination of 100 mg ritonavir twice daily plus either 800 mg (n = 6), or 1200 mg indinavir twice daily (n = 2).. Steady-state pharmacokinetics of indinavir and ritonavir were assessed by drawing 12 blood samples during an 8-h period after ingestion of the medication.. Significant differences were observed for indinavir pharmacokinetics between the dosing regimens indinavir 1200 mg twice daily alone and indinavir/ ritonavir 800/100 mg twice daily with respect to the mean trough concentration (0.21 and 0.99 microg/ml, respectively, P = 0.002), the mean maximum concentration (13.79 and 8.74 microg/ml, respectively, P = 0.028), and for the mean plasma elimination half-life (1.6 and 3.2 h, respectively, P = 0.001). The combination indinavir/ritonavir 1200/100 mg twice daily led to very high exposure to indinavir and was not well tolerated. However, the combination indinavir/ritonavir 800/100 mg twice daily was well tolerated and resulted in therapeutic concentrations of indinavir with improved trough concentrations and similar maximum concentrations as observed with the licensed dosage of 800 mg three times daily.. Combination of indinavir and 100 mg ritonavir in twice daily dosing regimens significantly affects the pharmacokinetic profile of indinavir. The results of this observational study provide a pharmacologic basis for the combination of indinavir (800 mg) and ritonavir (100 mg) in twice daily dosing regimens.

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Middle Aged; Ritonavir

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

To analyze virological and clinical efficacy of protease inhibitor based antiretroviral regimens in a cohort of unselected HIV-infected patients.. Prospective analysis of all HIV-infected patients started on protease inhibitor therapy until August 31, 1997 in two outpatient clinics. Partial viral suppression was defined as reduction of HIV-RNA at least 1log(10) below baseline and complete viral suppression as reduction below the limit of detection. Risk factors for clinical and virological failure were analyzed by a Cox proportional hazard model.. 387 patients (median observation time 381 days) were analyzed. In 312 patients (81%) partial and in 265 (68%) complete viral suppression was observed. Secondary failure occurred in 75 patients and could be reversed in 11/75. The probability of virological failure at one year was 51% for complete and 47% for partial suppression. CD4-cells increased by a median of 101/microl overall and 39/microl for patients without partial virologic suppression. 57 clinical events or deaths occurred in 44 pts. Risk factors for virological failure were AIDS at baseline (RR 1.6) and use of Saquinavir vs. Indinavir or Ritonavir (RR 1.7), for clinical failure AIDS at baseline (RR 4. 9), CD4-cell count (0.74 for increase of 50/microl), degree of viral suppression (RR 0.1 for complete suppression) and PI used (Saquinavir vs. Indinavir or Ritonavir, RR 2.7).. Virological failure of PI based combination therapy is common and associated with advanced HIV-infection. Clinical failure is associated with advanced HIV-infection and failure to suppress viral replication.

Topics: Adult; Aged; CD4 Lymphocyte Count; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Ritonavir; Saquinavir; Viral Load

Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen.. The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours).. Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005).. As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.

Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

The impact of human immunodeficiency virus (HIV) protease inhibitors on hepatitis C (HCV) viremia was assessed in 19 patients infected with both HIV and HCV. HIV and HCV RNA levels were measured before and during treatment with protease inhibitors. Before treatment, mean levels of HCV RNA were 5.3 log for HCV RNA and 5.0 log for HIV RNA. CD4 lymphocyte counts were 63/mm3. After 6 weeks of treatment, a mean reduction of 2.1 log10 in HIV RNA (P < .001) and a mean (+/-SE) increase of 73 (+/-21) CD4 and 296 (+/-70) CD8 cells were observed (P < .05). In contrast, both HCV viremia (+0.4 log +/- 0.1) and alanine aminotransferase increased (P < .04). HCV RNA levels returned to baseline after 17 and 32 weeks of treatment. Thus, potent anti-HIV regimens with protease inhibitors may temporarily worsen HCV status despite improvement of HIV parameters.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Viremia

Potent antiretroviral therapy can reduce human immunodeficiency virus (HIV) in plasma to levels below the limit of detection for up to 2 years, but the extent to which viral replication is suppressed is unknown. To search for ongoing viral replication in 10 patients on combination antiretroviral therapy for up to 1 year, the emergence of genotypic drug resistance across different compartments was studied and correlated with plasma viral RNA levels. In addition, lymph node (LN) mononuclear cells were assayed for the presence of multiply spliced RNA. Population sequencing of HIV-1 pol was done on plasma RNA, peripheral blood mononuclear cell (PBMC) RNA, PBMC DNA, LN RNA, LN DNA, and RNA from virus isolated from PBMCs or LNs. A special effort was made to obtain sequences from patients with undetectable plasma RNA, emphasizing the rapidly emerging lamivudine-associated M184V mutation. Furthermore, concordance of drug resistance mutations across compartments was investigated. No evidence for viral replication was found in patients with plasma HIV RNA levels of <20 copies/ml. In contrast, evolving genotypic drug resistance or the presence of multiply spliced RNA provided evidence for low-level replication in subjects with plasma HIV RNA levels between 20 and 400 copies/ml. All patients failing therapy showed multiple drug resistance mutations in different compartments, and multiply spliced RNA was present upon examination. Concordance of nucleotide sequences from different tissue compartments obtained concurrently from individual patients was high: 98% in the protease and 94% in the reverse transcriptase regions. These findings argue that HIV replication differs significantly between patients on potent antiretroviral therapy with low but detectable viral loads and those with undetectable viral loads.

Topics: Amino Acid Sequence; Base Sequence; DNA, Viral; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Genotype; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Lymph Nodes; Molecular Sequence Data; Mutation; RNA, Viral; Viral Load; Virus Replication; Zidovudine

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

The effects of nevirapine, indinavir, and lamivudine in combination were studied among 22 human immunodeficiency virus (HIV)-infected patients with CD4 cell counts < or =50/mm3, whose options for antiretroviral therapy were limited by clinical or laboratory failure or toxicity with previous regimens. Median plasma HIV RNA was 5.16 log10 copies/mL at baseline, decreasing by a median of 3.12 log10 copies/mL at 24 weeks. Median baseline CD4 cell count was 30/mm3, increasing by a median of 95/mm3 at week 24. Adverse reactions led to drug discontinuation in 4 cases. Steady-state pharmacokinetic analysis in 17 patients was consistent with an interaction between nevirapine and indinavir. Nevirapine plasma levels were within the expected range, while indinavir levels were lower than expected. Despite this interaction, the combination of nevirapine, indinavir, and lamivudine was safe and well-tolerated and had substantial antiviral and immunologic effects lasting for the 24-week study.

Topics: Anti-HIV Agents; Consumer Product Safety; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Nucleosides; Pilot Projects; Prospective Studies; Reverse Transcriptase Inhibitors; Treatment Failure; Viral Load

Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose.. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks.. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy.. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

Topics: Adolescent; Adult; Biological Availability; Capsules; CD4 Lymphocyte Count; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infant; Lamivudine; Male; Suspensions; Viral Load; Virus Replication; Zidovudine

Combination antiretroviral therapy can markedly suppress human immunodeficiency virus (HIV) replication but the duration of HIV suppression varies among patients.. To compare the antiretroviral effect of a 3-drug regimen started simultaneously or sequentially in patients with HIV infection.. A multicenter, randomized, double-blind study, modified after at least 24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up through 100 weeks.. Four clinical research units. Ninety-seven patients with HIV infection who had taken zidovudine for at least 6 months with serum HIV RNA level of at least 20000 copies/mL and CD4 cell count of 0.05 to 0.40 x 10(9)/L.. Patients were initially randomized to receive 1 of 3 antiretroviral regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks of blinded therapy, all patients received open-label 3-drug therapy.. Antiretroviral activity was assessed by changes in HIV RNA level and CD4 cell count from baseline. Data through 100 weeks were summarized.. Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL and increased CD4 cell count to a median of 0.209 x 10(9)/L above baseline at 100 weeks. When these 3 drugs were initiated sequentially, only 30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine group and 13 of 29 in the indinavir group, respectively) had a sustained reduction in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased to 0.101 to 0.163 x 10(9)/L above baseline at 100 weeks.. A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years. Sequential initiation of the same 3 drugs is much less effective.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Viral Load; Zidovudine

Topics: Anti-HIV Agents; Body Mass Index; Cohort Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nutritional Status; Patient Compliance; Prospective Studies; Ritonavir; Serum Albumin; Viral Load; Weight Gain

To compare the antiretroviral effect and safety of zidovudine (ZDV)-lamivudine (3TC) with that of stavudine (d4T)-3TC.. In an open randomized controlled trial antiretroviral therapy-naive patients who had CD4+ counts > or = 200 x 10(6)/l and plasma HIV RNA load > or = 10000 copies/ml were randomized to receive ZDV-3TC (200 mg three times daily and 150 mg twice daily, respectively) or d4T-3TC (40 mg and 150 mg, both twice daily). If the plasma HIV RNA level at week 8 or thereafter was > 500 copes/ml, indinavir was added at the next scheduled visit. Genotypic resistance analysis of the reverse transcriptase gene was performed at week 0 and 12. Results over 24 weeks were reported.. Forty-seven patients were treated (24 took ZDV-3TC; 23 took d4T-3TC). Plasma HIV RNA levels decreased from median 4.80 to 3.15 log10 copies/ml (ZDV-3TC, P < 0.0001) and from 4.98 to 3.03 log10 copies/ml (d4T-3TC, P < 0.0001) after 12 weeks of treatment. Indinavir was added at week 12 in 11 out of 21 patients with ZDV-3TC and in 10 out of 22 patients with d4T-3TC. Median virus load at week 24 was 2.41 log10 and 2.29 log10 copies/ml (P=0.14), respectively. Seventy-five per cent (15 out of 20; ZDV-3TC) and 95% (18 out of 19; d4T-3TC) of patients had a virus load of < 500 copies/ml. Genomic evidence for 3TC resistance was found in all patients tested (11/11 ZDV-3TC and 12/12 d4T-3TC). At week 12, CD4 cell counts had increased with a median of 110 x 10(6)/l in the ZDV-3TC group (baseline, 315 x 10(6)/l) and a median of 115 x 10(6)/l in the d4T-3TC group (baseline 290 x 10(6)/l). At week 24, the median increases were 90 and 120 x 10(6)/l, respectively. Overall the increase of CD4+ cells was higher in the d4T-3TC group (P=0.02).. d4T-3TC is at least as effective as ZDV-3TC, but 3TC resistance emerged in all patients investigated. The virological response of the dual nucleoside combination is of short duration. However, after addition of indinavir the virus load could be reduced to < 500 copies/ml in the majority of patients. The increase in CD4+ cell count was significantly greater in the d4T-3TC group. To prevent 3TC resistance, the drug should not be used in regimens containing only two nucleosides, irrespective the virus load at baseline.

Topics: Adult; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Homosexuality, Male; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine

We assessed the efficacy of adding indinavir in patients with advanced HIV-1 infection, who were previously exposed to different reverse transcriptase (RT) nucleoside analogues. Twenty-five patients with an initial median CD4 cell count of 20 cells/mm3 (range, 0-80 cells/mm3) were treated with indinavir (800 mg three times per day) for 24 weeks. The median initial viral load was 5.4 log (range, 3.6-6.7 log). Of these patients, 56% (14 of 25) had an initial decrease in viral load of >1 log and sustained response of >0.5 log of HIV-1 RNA from baseline. Twelve of these 14 responder patients (85%) showed a sustained RNA response undetectable by NASBA assay, and no genotypic changes in protease were detected at week 24. In those with a temporary or absent response to indinavir, either resistant viruses or lack of compliance was observed. In compliant patients (15 of 16), relatively small increases in 50% inhibitory concentration (IC50) to indinavir and only two to three amino acid changes were sufficient to produce treatment failure. Phenotypic drug-resistant assays at 24 weeks revealed cross-resistance to ritonavir in all the patient isolates and to saquinavir in one third of the isolates. We observed an initial and persistent response to the addition of indinavir in patients with advanced disease and prolonged antiretroviral treatment. Therapy failure, as defined by increases in viral RNA, was associated with either lack of compliance or the development of low level indinavir-resistant virus. Clinical studies need to be designed to determine to what extent these viruses may respond to other protease inhibitors.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Cell Line; Drug Resistance, Microbial; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Phenotype; Ritonavir; RNA, Viral; Saquinavir; Viral Load

To verify the effectiveness of highly active antiretroviral therapy (HAART) and to identify any factors predictive of clinical outcome in a clinical setting.. Observational study.. Treatment failure (i.e., the occurrence of new or recurrent AIDS-defining events, death or any definitive discontinuation) and the course of CD4+ cell counts and HIV RNA copies were evaluated in 250 heavily pretreated HIV-infected patients starting HAART [153 with indinavir (IDV), 55 with ritonavir (RTV), 43 with saquinavir (SQV)]. Univariate and multivariate analyses were performed to identify predictors of worse outcome.. During a median follow-up of 8 months, 75 patients (30%) had treatment failure because of the occurrence of an AIDS-defining event or death (n = 24), inefficacy (n = 24), or severe intolerance (n = 27). Twenty new and six recurrent AIDS-defining events, and nine deaths occurred (six out of 20 AIDS-defining events and two out of nine deaths within 1 month of treatment). CD4+ counts were above 200 x 10(6)/l at AIDS diagnosis in only two patients. None of the SQV patients, 12 (7.8%) of the IDV patients, and 15 (27.3%) of the RTV-treated patients were considered non-compliant. The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20-5.03; versus IDV). Low compliance partially determined outcome in RTV-treated patients; both severe immunodepression and AIDS at baseline were predictive of treatment failure. There was a 10-fold increase in CD4+ cell counts in the patients treated with IDV and RTV; the best virological outcome occurred in IDV-treated patients, with 68.4% of patients showing undetectable HIV RNA copies after 6 months.. HAART was effective in 70% of patients; low compliance and previous AIDS diagnosis represented predictive factors of therapy failure.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Observation; Ritonavir; RNA, Viral; Saquinavir; Treatment Failure

To determine the nutritional changes that occur in HIV-infected patients receiving protease inhibitor (PI) therapy and to determine the effects of PI treatment on physical functioning and health perceptions in patients with HIV infection.. Longitudinal data analysis of 38 patients from a large Nutrition and HIV cohort.. Patients were included if they had started PI therapy after enrollment in the cohort, if they had taken the drug for at least 4 months without interruption and if data on weight, body composition and viral loads were available.. Mean person-months of follow-up was 8.1 months before and 12.2 months after PI treatment. Weight (1.54 kg, P < 0.0001), body mass index (0.50 kg/m2, P < 0.0001), physical functioning (8.52 points, P = 0.0006) and current health perception (6.7 points, P = 0.01) increased significantly, and the daily caloric intake increase was close to significance (915.5 kJ/day, P = 0.06), after treatment with PI. Lean body mass did not change. Patients who responded to PI therapy with decreased viral load (n = 28) had significantly greater weight gain per month than non-responders.. PI therapy of HIV infection is associated with weight gain and improvement in quality of life indices. The weight gain is mainly in fat mass, with no change in lean body mass (skeletal muscle). Optimal therapy of HIV-infected patients with weight loss may require highly active antiretroviral therapy combined with an anabolic stimulus such as exercise, anabolic steroids or human growth hormone.

Topics: Adult; Body Composition; Body Weight; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Longitudinal Studies; Male; Middle Aged; Nutritional Status; Ritonavir; Saquinavir; Viral Load

HIV infection accelerates natural course of HCV infection, but impact of antiretroviral treatment on HCV infection is not well known. The aim of this study is to compare the change of HCV viral load in patients on combination of 2 nucleoside analogues and in patients on combination of 2 nucleoside analogues and protease inhibitor. HCV and HIV viral load, lymphocyte CD4 counts, alanine aminotransferase (ALT) and aspartate amino transferase (AST) were measured before and 3 months after starting treatment in 2 groups: Group 1 (n = 15) treated with 2 nucleoside analogues and Group 2 (n = 15) treated with 2 nucleoside analogues and a protease inhibitor. Results show a significant increase in lymphocyte and a significant decrease in HIV viral load in the both group but no significant change in HCV viral load and in ALT and AST. In conclusion efficiency of anti-HIV therapy (combination of 2 nucleoside analogues with or without a protease inhibitor) doesn't seem to have any impact on the course of HCV viremia in HIV-coinfected patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Alanine Transaminase; Anti-HIV Agents; Aspartate Aminotransferases; CD4 Lymphocyte Count; Disease Progression; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Substance Abuse, Intravenous; Treatment Outcome; Viral Load; Viremia

Combination antiretroviral therapy with indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy.. HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy.. During maintenance treatment, 23 percent of the subjects receiving indinavir and 23 percent of those receiving zidovudine and lamivudine, but only 4 percent of those receiving all three drugs, had loss of viral suppression (P<0.001 for the comparison between triple-drug therapy and the other two maintenance regimens). Subjects with greater increases in CD4 cell counts during induction therapy, higher viral loads at base line (i.e., at the beginning of induction therapy), and slower rates of viral clearance were at greater risk for loss of viral suppression. The presence of zidovudine-resistance mutations in HIV RNA at base line was strongly predictive of the loss of viral suppression in subjects treated with zidovudine and lamivudine.. The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavir alone or zidovudine and lamivudine.

Topics: Adult; Anti-HIV Agents; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Multivariate Analysis; Remission Induction; RNA, Viral; Treatment Failure; Viral Load; Zidovudine

The long-term effectiveness of potent three-drug antiretroviral regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection is limited by problems related to compliance and tolerability. We investigated whether two-drug maintenance therapy would suppress viral replication after a three-month period of aggressive triple-drug induction therapy.. A total of 378 HIV-1-infected adults who had not received previous antiretroviral treatment received three months of induction therapy consisting of 300 mg of zidovudine every 12 hours, 150 mg of lamivudine every 12 hours, and 800 mg of indinavir every 8 hours. The 279 patients in whom the plasma HIV-1 RNA titer fell below 500 copies per milliliter after two months of triple-drug therapy, and who completed the induction phase, were randomly assigned at month 3 to one of the following three open-label maintenance regimens: zidovudine, lamivudine, and indinavir; zidovudine and lamivudine; or zidovudine and indinavir. The primary end point was an increase in HIV-1 RNA levels to 500 copies or more per milliliter during the maintenance phase.. The proportion of patients who reached the primary end point was significantly higher among patients receiving zidovudine plus lamivudine (29 of 93 patients, P<0.001) or zidovudine plus indinavir (21 of 94, P=0.01) than among patients receiving continued triple-drug therapy (8 of 92). This higher failure rate in the groups treated with the two-drug maintenance regimens was also observed in the subgroup of patients with maximally suppressed HIV-1 RNA (below 50 copies per milliliter) at the time of randomization to maintenance therapy.. In HIV-1-infected adults not previously treated with antiretroviral drugs whose plasma HIV-1 RNA levels fell below 500 copies per milliliter after three months of induction therapy with zidovudine, lamivudine, and indinavir, two-drug maintenance therapy was less effective in sustaining a reduced viral load than continued three-drug therapy.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Remission Induction; RNA, Viral; Treatment Failure; Viral Load; Zidovudine

Highly active antiretroviral therapy (HAART) can produce marked increases in peripheral blood CD4+ T cells and decreases in HIV plasma RNA copy numbers. However, it is not clear whether these absolute changes will be accompanied by a recovery in the known naive CD4+ T cell depletion or a decrease in the marked CD8+ T cell activation.. Twenty-nine patients were enrolled in studies of either nucleoside therapy alone or nucleoside therapy combined with a protease inhibitor (zidovudine + lamivudine + indinavir). One hundred and ninety-one examinations were carried out at three baseline time points and during 40 weeks of follow-up to evaluate the effect of HAART on CD4+ memory/naive phenotype and CD8+ T cell activation.. CD4+ and CD8+ T cell number, CD62L/CD45RA expression on CD4+ T cells and CD38 expression on CD8+ T cells were measured by three-color flow cytometry.. Most protease inhibitor treated patients had a significant rise in CD4+ numbers. The marked rise in the CD4+ T cells seen in individuals in this study was not accompanied over a 40-week period by a change in the abnormally low CD4+ naive compartment, and thus was almost completely of memory phenotype. The CD38 expression on CD8+ cells fell during treatment, and decreased to a greater degree than the comparable rise in CD4+ T cell counts. This decrease continued in many patients after the CD4+ T cell rise or viral load decline had plateaued.. HAART results in changes in activation to a greater extent than absolute changes in CD4+ T cell numbers, but is not accompanied by an increase in naive CD4+ T cells. Measurements of CD4+ T cell numbers alone may not allow appropriate interpretation of immune activation or immune competence in patients receiving those drugs.

Topics: Anti-HIV Agents; Antigens, CD; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Flow Cytometry; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Immunophenotyping; Indinavir; Lamivudine; Lymphocyte Activation; Statistics, Nonparametric; T-Lymphocyte Subsets; Viral Load; Zidovudine

To study the relationship between the CD4+ cell response after initiation of protease inhibitors and the occurrence of opportunistic infections and survival.. Prospective observational cohort study.. HIV-1-seropositive subjects followed-up in HIV centres of Bordeaux University Hospital, Southwest France who were prescribed at least one available protease inhibitor between January and December 1996 were included in this analysis. A Cox model estimated the independent effect of baseline covariates and CD4+ cell response, considered as a time-dependent covariate, on the occurrence of new AIDS-defining opportunistic infection, new AIDS-defining events, new AIDS-defining opportunistic infection or death.. A total of 556 HIV-positive patients were prescribed at least one protease inhibitor: 34% saquinavir, 52% indinavir, and 14% ritonavir. Median CD4+ cell count at baseline was 95 x 10(6)/l and mean plasma HIV RNA was 5.0 log10 copies/ml. After a median follow-up of 230 days, 65 patients experienced a new episode of opportunistic infection, 79 patients experienced at least one AIDS-defining event, and 24 had died. On average, the increase in CD4+ cell count was 42 x 10(6)/l (SD, 74) after a median of 49 days. In the multivariate analysis of opportunistic infection or death, each 50% higher CD4+ cell count at baseline was associated with a 23% reduction [95% confidence interval (CI), 14-30] of risk. Each 50% increase in CD4+ cell count during follow-up was associated with a 9% reduction (95% CI, 2-15) of risk, adjusted for the presence of AIDS prior to protease inhibitor therapy (hazard ratio, 3.76 versus absence of AIDS; P < 0.01) and haemoglobin level (hazard ratio, 0.48 if > 11 g/dl versus <11 g/dl; P < 0.01).. Our results show, at least indirectly, how protease inhibitors might produce clinical stabilization. This result may be due to improved functionality of CD4+ cells in patients started on protease inhibitors.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Disease Progression; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Predictive Value of Tests; Prospective Studies; Risk Factors; Ritonavir; Saquinavir

Topics: Antiviral Agents; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Lamivudine; Lymphocyte Count; Male; Saquinavir; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Oxazines; Reverse Transcriptase Inhibitors; Zidovudine

Topics: Adult; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Reference Values; Ritonavir

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zidovudine

Topics: Adult; Anti-HIV Agents; Drug Approval; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nevirapine; Ritonavir; Saquinavir; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Disease Progression; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Sex Factors; Zidovudine

An AIDS Clinical Trials Group study examined whether less intensive maintenance antiretroviral regimens could be effective after the initial use of highly active induction therapy. Results from 309 patients, who were evaluated in the maintenance phase, demonstrated that 6 months of therapy with AZT/3TC/IDV, followed by less intensive treatment, is not an effective strategy. Results suggest that once viral suppression has been achieved, intensity of therapy should not be lessened.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

We investigated the relationships between changes in CD4 lymphocytes counts over 24 weeks after the initiation of therapy with indinavir at dosages of > or = 2.4 g/day (n = 15) in human immunodeficiency virus-positive patients and compared them to the baseline values. Starting CD4 count were linked to the time-weighted average CD4 cell count (return) through a nonlinear effect model. The diminution of destruction of CD4 cells after the initiation of indinavir therapy was estimated by fitting simultaneous differential equations to the data by using a linked lymph node (LN)-blood (BL) (two-compartment) system in which there is a constant rate of generation (R), first-order transfer rate constants (KLN-BL and KBL-LN) of compartment exchange, and first-order rate constants of CD4 destruction in the absence and presence of indinavir (KLN-OUT1 and KLN-OUT2). The half-life of CD4 lymphocytes was calculated from the rate constants by standard two-compartment methods. The CD4 lymphocyte counts at the start and return were linked in a sigmoid-Emax model were the maximal effect (Emax) was at 574.6 cells/microliters and 50% of the effect occurred at 157.1 cells/microliters (r2 = 0.94; P < 0.001). The mean +/- standard deviation (median) KLN-OUT2 was 0.574 +/- 0.202 (0.589), indicating that indinavir decrease the destruction of CD4 cells by circa 41 to 42%. The mean (median) CD4 half-life was 11.5 +/- 5.72 day (10.3 days). In multivariate analysis, KLN-OUT2 was significantly correlated with starting the CD4 cells count and the change in the CD4 cell count on therapy. The relationship between CD4 lymphocyte half-life and the starting CD4 lymphocyte count was hyperbolic, with a rapid increase in half-life as the CD4 count decreased. On the basis of the calculated half-life, the average production (destruction) of CD4 lymphocytes was approximately 3 x 10(9) cells/day, with an individual variation of 44-fold. These findings suggest that (i) the CD4 lymphocyte cell count at the start is significantly correlated to both the decrease in the destruction rate of CD4 cells and the degree of change in the CD4 lymphocytes on therapy, (ii) the lower the initial CD4 lymphocyte count, the higher the amount of CD4 lymphocyte turnover and the lower the ability of the immune system to increase absolute CD4 lymphocyte levels after viral suppression, consistent with a decreased regenerative capacity with progression of disease; and (iii) the increase in CD4 lymphocytes is likely secondar

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kinetics

Virus load determination has become indispensable for the management of HIV patients, but depends on expensive assays of a low throughput. We evaluated whether a highly improved HIV-1 p24 antigen detection procedure which involves heat-mediated immune complex dissociation and signal-amplification-boosted enzyme-linked immunosorbent assay (ELISA) was suitable for antiretroviral treatment monitoring.. Virus load in plasma was determined for 127 plasma samples taken at 0, 2, 6, 12, 18, 24, 30 and 36 weeks from 23 patients with CD4+ T cells < 50 x 10(6)/l who received indinavir 800 mg three times daily in addition to prior antiretroviral treatment. Tests included polymerase chain reaction (PCR) for viral RNA, measured prospectively with the Roche Amplicor kit, and retrospective batch testing of heat-denatured samples for p24 antigen by the DuPont HIV-1 p24 Core Profile ELISA linked with a tyramide signal amplification step. Particle-associated reverse transcriptase (RT) by the product-enhanced RT (PERT) assay was determined as an independent third-opinion viral load marker.. p24 antigen was detected as sensitively as viral RNA. Overall detection during a median observation time of 25 weeks (range, 0-39) amounted to 75.6% for antigen and 73.6% for RNA. The antigen detection limit was 0.2 pg/ml. Antigen was detectable in all 23 baseline samples, whereas RNA was undetectable in one. Antigen and RNA levels in 79 samples positive for both markers correlated with r = 0.714 (P < 0.0001). Average changes in levels of p24 antigen and RNA at eight timepoints correlated with r = 0.982 (P < 0.0001). In individual patients, the two parameters behaved similarly, and in certain cases virtually identically. RT activity was measurable in all samples.. The performance of this antigen detection procedure is comparable to RNA PCR, thus providing a simple, high throughput alternative in monitoring the efficacy of antiretroviral treatment.

Topics: Adult; Aged; Anti-HIV Agents; Enzyme-Linked Immunosorbent Assay; Female; Heating; HIV Antigens; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Indinavir; Male; Middle Aged; Outcome and Process Assessment, Health Care; Prospective Studies; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load

The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine.. A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death.. The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results.. Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Zidovudine

The new protease inhibitors are potent inhibitors of the human immunodeficiency virus (HIV), and in combination with other antiretroviral drugs they may be able to cause profound and sustained suppression of HIV replication.. In this double-blind study, 97 HIV-infected patients who had received zidovudine treatment for at least 6 months and had 50 to 400 CD4 cells per cubic millimeter and at least 20,000 copies of HIV RNA per milliliter were randomly assigned to one of three treatments for up to 52 weeks: 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours combined with 150 mg of lamivudine twice daily; or all three drugs. The patients were followed to monitor the occurrence of adverse events and changes in viral load and CD4 cell counts.. The decrease in HIV RNA over the first 24 weeks was greater in the three-drug group than in the other groups (P<0.001 for each comparison). RNA levels decreased to less than 500 copies per milliliter at week 24 in 28 of 31 patients in the three-drug group (90 percent), 12 of 28 patients in the indinavir group (43 percent), and none of 30 patients in the zidovudine-lamivudine group. The increase in CD4 cell counts over the first 24 weeks was greater in the two groups receiving indinavir than in the zidovudine-lamivudine group (P< or =0.01 for each comparison). The changes in the viral load and the CD4 cell count persisted for up to 52 weeks. All the regimens were generally well tolerated.. In most HIV-infected patients with prior antiretroviral therapy, the combination of indinavir, zidovudine, and lamivudine reduces levels of HIV RNA to less than 500 copies per milliliter for as long as one year.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; RNA, Viral; Viral Load; Zidovudine

Variability in CD4+ T-lymphocyte measurements has been described for both normal and human immunodeficiency virus (HIV)-infected persons. Clinical protocols use CD4+ cell counts as surrogate markers for disease progression or response. In this study, we determined the variability of CD4+ T-lymphocytes below 100 cells/microl when measured less than 7 days apart. Two consecutive lymphocyte subset measurements were performed in 55 patients using CD3/CD4 antibodies in a flow cytometer (Epics Profile II). Specimens were collected between 8:00 and 10:00 am within the same week. Data from the first and second measurements were compared. The average total lymphocyte count on the first measurement was 1,064 (360-2,853), and on the second 1,162 (320-2,223; P = 0.07); the percentage CD4 was 1.76 (0-8) on the first, and on the second 1.98 (0-9; P = 0.3); the absolute CD4 cell count on the first measurement was 16.6 (0-57) and on the second 22.8 (0-93; P = 0.01). Statistically significant differences were found between the first and second absolute CD4 T-lymphocytes but not in the CD4 percentage. These differences probably are due to variations in total lymphocyte count. For research protocols, repeating CD4+ cell determinations within a short period is advisable, to ensure a homogeneous population. On the other hand, for day-to-day patient follow-up, a combination of clinical criteria and both percentage and absolute CD4+ cell counts should be used to make treatment decisions, because repeating CD4 cell measurements can be very costly.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; HIV Infections; Humans; Indinavir; Leukocyte Count; Lymphocyte Count; Reproducibility of Results; Sensitivity and Specificity; Time Factors

To describe protease inhibitor-induced urinary stone disease in patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) who are taking indinavir sulfate (Crixivan), a protease inhibitor, for the treatment of AIDS.. Patients with HIV/AIDS and symptomatic renal colic temporally related to the initiation of indinavir sulfate therapy were prospectively identified. Seven patients (mean age 42 years; all men) with HIV and renal colic who were taking indinavir were identified. Retrospective chart reviews and patient interviews were performed.. Indinavir therapy averaged 5.7 months prior to presentation with renal colic. All patients had microscopic hematuria. One patient presented with acute azotemia from bilateral urinary obstruction. Six patients had no history of urinary stones prior to initiating indinavir. The median number of symptomatic urinary stone episodes after initiating indinavir was two stones per patient. All patients had moderate- to high-grade urinary obstruction from radiolucent calculi. Abdominal computed tomography (CT) demonstrated hydronephrosis without urinary calcifications. Three patients spontaneously passed stones and 4 required intervention. Yellow debris and/or brown matrix-like material was seen endoscopically. Stone analysis revealed pure protease inhibitor. Six patients (86%) eventually discontinued protease inhibitor therapy.. Protease inhibitor-induced urinary stones are radiolucent and can cause high-grade ureteral obstruction. Protease inhibitor-induced urinary stones were not identified on unenhanced abdominal CT scans. The radiolucent gelatinous nature of such stones makes lithotripsy a poor choice of treatment. Ureteral stenting may allow spontaneous stone passage if symptomatic obstruction occurs. Urologists may encounter a greater number of patients with symptomatic protease inhibitor-induced urinary calculi as these medications become more popular.

Topics: Adult; Colic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Kidney Diseases; Male; Prospective Studies

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36-52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.

Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Lymph Nodes; RNA, Viral; Viral Load; Zidovudine

ACTG 320, a clinical trial comparing indinavir/AZT/3TC to AZT/3TC was stopped early when it became clear that the 3-drug combination was superior to the 2-drug combination. Aside from the superiority of one combination over the other, the study was considered controversial by activists based on the following: the study was not long enough to determine long-term toxicity; the study did not determine when to start therapy since only patients with CD4 counts under 200 were selected and results were driven by those with CD4 counts under 50; the concerns about the opportunity cost of using government resources for product-oriented trials; and enrollment of persons in suboptimal trials because they had no other options. Disease progression, death, and other clinical endpoint issues are addressed. Therapies are changing so rapidly that studies lasting long enough to determine clinical endpoint benefits may no longer be the most effective.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Treatment Outcome; Zidovudine

141W94 (VX-478) is a novel HIV-1 protease inhibitor with an IC50 of 0.08 microM against HIV-1 (strain IIIB) and a mean IC50 of 0.012 microM against six HIV clinical isolates. 141W94 was synergistic on the basis of isobologram analysis with each of the following reverse transcriptase inhibitors: AZT, 935U83, 524W91, 1592U89 and ddl, 141W94 was also synergistic with saquinavir and additive with either indinavir or ritonavir. Resistance to 141W94 has been reported in vitro passage experiments. The binding of 141W94 to human alpha 1-acid glycoprotein was relatively weak (Kd = 4 microM) and the off-rate for the drug is very fast (> or = 100 s-1). Only a 2-fold reduction of in vitro antiviral activity was observed in the presence of 45% human plasma. No serious drug associated adverse experiences were reported in a Phase I placebo-controlled, single-dose escalation, pharmacokinetic and safety study. The average concentration of 141W94 at 8 and 12 h after single doses of 900 and 1200 mg, respectively, was in excess of 10 times the IC50. As 141W94 is synergistic with a variety of anti-HIV-1 agents and exhibits a unique cross resistance profile compared to other protease inhibitors, 141W94 is considered a good candidate for combination therapy.

Topics: Carbamates; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Pyridines; Quinolines; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides; Thiazoles; Valine

To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639.. An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system.. The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively).. MK-639 appears to have significant dose-related antiviral activity and is well tolerated.

Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Pyridines; Receptors, Tumor Necrosis Factor; RNA, Viral

Merck has announced a compassionate use lottery of Crixivan (formerly known as MD-639 and L-735, 524), a protease inhibitor for the treatment of HIV disease. Crixivan will be made available without cost to 1,400 eligible people in the United States, of which 1,100 will be randomly selected using specific criteria. The patient must be clinically stable, be able to follow directions, and have stable laboratory status. Outside the United States, Crixivan will be made available to approximately 750 patients from 29 countries in Europe, South America, Canada, and Australia. Merck will pay for the drug (including shipping), the post-selection central laboratory tests, and the urine pregnancy test, if needed. No other costs will be borne by the company.

Topics: CD4 Lymphocyte Count; Clinical Trials, Phase III as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Patient Selection; Pyridines; Randomized Controlled Trials as Topic; United States

Because of a better understanding of viral replication and viral variance during primary infection, an early aggressive intervention strategy in the course of HIV-1 infections is being favored by virologist David Ho, M.D. Two studies suggest that the rate of progression to AIDS can be predicted by the level at which an infected person's viral load eventually plateaus, the HIV setpoint. If viral therapy can help lower the viral load setpoint so that the immune system has a more stable equilibrium, it might slow disease progression. A six-month study by the European Australian Cooperative evaluated AZT therapy versus a placebo in 77 people with primary HIV infection. Although the results were difficult to interpret because the two groups were not matched at entry, the AZT-treated group had a viral load reduction that was seventy percent greater than the control group. There was no rebound in viral load after treatment discontinuation. This data supports the theory that treatment during primary infection may delay the development of resistance to AZT treatment. Dr. Ho believes even greater benefits can be expected from the more potent treatment combinations in trials (e.g., AZT/3TC/ritonavir, AZT/3TC/indinavir, or indinavir monotherapy). The possibility still remains that HIV resistance to early aggressive therapy will limit a person's options for treatment later in the disease course.

Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Cohort Studies; Controlled Clinical Trials as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Placebos; Pyridines; Ritonavir; Thiazoles; Valine; Zalcitabine; Zidovudine

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

Kidney injury is a serious comorbidity among HIV-infected patients. Intravenous drug use is listed as one of the risk factors for impaired renal function; however, this group is rarely assessed for specific renal-related risks.. Patients attending methadone program from 1994 to 2015 were included in the study. Data collected included demographic data, laboratory tests, antiretroviral treatment history, methadone dosing and drug abstinence. Patients' drug abstinence was checked monthly on personnel demand. We have evaluated two study outcomes: (1) having at least one or (2) three eGFR < 60 ml/min (MDRD formula).. In total, 267 persons, with 2593 person-years of follow-up were included into analyses. At the time of analyses, 251 (94%) were on antiretroviral therapy (ARV). Fifty-two (19.5%) patients had 1eGFR and 20 (7.5%) 3eGFR < 60. In univariate analysis, factors significantly increasing the odds of impaired renal function were: female gender, detectable HIV RNA on ART, age at registration per 5 years older, atazanavir use and time on antiretroviral treatment per 1 year longer. In the multivariate model, only female gender (OR 4.7; p = 0.002), time on cART (OR 1.11; p = 0.01) and baseline eGFR (OR 0.71; p = 0.001) were statistically significant.. We have demonstrated a high rate of kidney function impairment among HIV-1 positive patients in the methadone program. All risk factors for decreased eGFR in this subpopulation of patients were similar to those described for general HIV population with very high prevalence in women. These findings imply the need for more frequent kidney function monitoring in this subgroup of patients.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Drug Therapy, Combination; Female; Glomerular Filtration Rate; HIV Infections; Humans; Indinavir; Kidney Diseases; Male; Methadone; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Poland; Risk Factors; Sex Factors; Tenofovir; Time Factors

Indinavir (IDV), an antiretroviral protease inhibitor used in treatment of HIV infection, has limited entry into brain due to efflux by the P-glycoprotein presented in blood-brain barrier. The aim of present study was to develop lactoferrin-treated nanoemulsion containing indinavir (Lf-IDV-NEs) for delivery to brain.. Indinavir-loaded nanoemulsions (IDV-NEs) were prepared by high-speed homogenization method, and then lactoferrin was coupled to IDV-NEs by water soluble EDC method.. The hydrodynamic diameters, polydispersity index, and zeta potential of IDV-NEs were 112 ± 3.5 nm, 0.20 ± 0.02, and -33.2 ± 2.6 mV, respectively. From in vivo studies in animal model of rats, the AUC. It can be concluded that applying both lactoferrin-treated and non-treated nanoemulsions clearly leads to significant brain penetration enhancement of indinavir, an effect which is more pronounced in the case of Lf-IDV-NEs with the higher drug residence time in brain.

Topics: Animals; Area Under Curve; Blood-Brain Barrier; Drug Carriers; Drug Liberation; Emulsions; HIV Infections; HIV Protease Inhibitors; Indinavir; Injections, Intravenous; Lactoferrin; Male; Nanoparticles; Permeability; Polysorbates; Rats; Rats, Sprague-Dawley

The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of α7-nicotinic acetylcholine receptors to acetylcholine.. Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling.. Indinavir's effects on α7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model.. At low concentrations (0.0003-10 μmol/l) indinavir acts as a positive allosteric modulator (EC50 = 0.021 μmol/l), whereas at concentrations greater than 10 μmol/l (30-100 μmol/l) indinavir acts as an inhibitor of the α7-nicotinic acetylcholine receptor.. At concentrations greater than 10 μmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; CHO Cells; Cognitive Dysfunction; Cricetulus; HIV Infections; HIV Protease Inhibitors; Indinavir; Nicotinic Antagonists; Patch-Clamp Techniques

HIV-associated sensory neuropathy (HIV-SN) is the most frequent manifestation of HIV disease. It often presents with significant neuropathic pain and is associated with previous exposure to neurotoxic nucleoside reverse transcriptase inhibitors. However, HIV-SN prevalence remains high even in resource-rich settings where these drugs are no longer used. Previous evidence suggests that exposure to indinavir, a protease inhibitor commonly used in antiretroviral therapy, may link to elevated HIV-SN risk. Here, we investigated whether indinavir treatment was associated with the development of a "dying back" axonal neuropathy and changes in pain-relevant limb withdrawal and thigmotactic behaviours. After 2 intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hind paw mechanical hypersensitivity, which peaked around 2 weeks post first injection (44% reduction from baseline). At this time, animals also had (1) significantly changed thigmotactic behaviour (62% reduction in central zone entries) comparing with the controls and (2) a significant reduction (45%) in hind paw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hind paw mechanical hypersensitivity observed with indinavir treatment. Furthermore, we found a small but significant increase in microglia with the effector morphology in the lumbar spinal dorsal horn in indinavir-treated animals, coupled with significantly increased expression of phospho-p38 in microglia. In summary, we have reported neuropathic pain-related sensory and behavioural changes accompanied by a significant loss of hind paw skin sensory innervation in a rat model of indinavir-induced peripheral neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.

Topics: Amines; Analgesics; Animals; Calcitonin Gene-Related Peptide; Calcium-Binding Proteins; Cyclohexanecarboxylic Acids; Disease Models, Animal; Exploratory Behavior; Gabapentin; gamma-Aminobutyric Acid; Ganglia, Spinal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; HIV Infections; HIV Protease Inhibitors; Hyperalgesia; Indinavir; Male; Metacarpus; Microfilament Proteins; Microglia; Neuralgia; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Wistar; Spinal Cord; Statistics, Nonparametric

HIV patients on combination oral drug therapy experience insufficient drug levels in lymph nodes, which is linked to viral persistence. Following success in enhancing lymph node drug levels and extending plasma residence time of indinavir formulated in lipid nanoparticles, we developed multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA). These anti-HIV LNPs were prepared, characterized, scaled up, and evaluated in primates with a focus on plasma time course and intracellular drug exposure in blood and lymph nodes. Four macaques were subcutaneously administered anti-HIV LNPs and free drug suspension in a crossover study. The time course of the plasma drug concentration as well as intracellular drug concentrations in blood and inguinal lymph nodes were analyzed to compare the effects of LNP formulation. Anti-HIV LNPs incorporated LPV and RTV with high efficiency and entrapped a reproducible fraction of hydrophilic PMPA. In primates, anti-HIV LNPs produced over 50-fold higher intracellular concentrations of LPV and RTV in lymph nodes compared to free drug. Plasma and intracellular drug levels in blood were enhanced and sustained up to 7 days, beyond that achievable by their free drug counterpart. Thus, multiple antiretroviral agents can be simultaneously incorporated into anti-HIV lipid nanoparticles to enhance intracellular drug concentrations in blood and lymph nodes, where viral replication persists. As these anti-HIV lipid nanoparticles also prolonged plasma drug exposure, they hold promise as a long-acting dosage form for HIV patients in addressing residual virus in cells and tissue.

Topics: Adenine; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Carriers; Drug Combinations; HIV Infections; HIV Protease Inhibitors; HIV-1; Indinavir; Lipids; Lopinavir; Lymph Nodes; Macaca; Nanoparticles; Organophosphonates; Ritonavir; Tenofovir; Viral Load; Virus Latency

Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance.

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Drug Resistance, Viral; Fluorometry; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Microbial Sensitivity Tests; Ritonavir; Saquinavir

Human immunodeficiency virus (HIV)-1 protease is one of the most promising drug target commonly utilized to combat Acquired Immune Deficiency Syndrome (AIDS). However, with the emergence of drug resistance arising from mutations, the efficiency of protease inhibitors (PIs) as a viable treatment for AIDS has been greatly reduced. I50V mutation as one of the most significant mutations occurring in HIV-1 protease will be investigated in this study. Molecular dynamics (MD) simulation was utilized to examine the effect of I50V mutation on the binding of two PIs namely indinavir and amprenavir to HIV-1 protease. Prior to the simulations conducted, the electron density distributions of the PI and each residue in HIV-1 protease are derived by combining quantum fragmentation approach molecular fractionation with conjugate caps and Poisson-Boltzmann solvation model based on polarized protein-specific charge scheme. The atomic charges of the binding complex are subsequently fitted using delta restrained electrostatic potential (delta-RESP) method to overcome the poor charge determination of buried atom. This way, both intraprotease polarization and the polarization between protease and the PI are incorporated into partial atomic charges. Through this study, the mutation-induced affinity variations were calculated and significant agreement between experiments and MD simulations conducted was observed for both HIV-1 protease-drug complexes. In addition, the mechanism governing the decrease in the binding affinity of PI in the presence of I50V mutation was also explored to provide insights pertaining to the design of the next generation of anti-HIV drugs.

Topics: Carbamates; Furans; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Dynamics Simulation; Point Mutation; Protein Binding; Sulfonamides

To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.

Topics: Calibration; Chromatography, Micellar Electrokinetic Capillary; Desvenlafaxine Succinate; Drug Interactions; Electrophoresis, Capillary; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Limit of Detection; Polymers; Spectrometry, Mass, Electrospray Ionization; Stereoisomerism; Tandem Mass Spectrometry; Venlafaxine Hydrochloride

Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure.

Topics: Anti-HIV Agents; Cross-Sectional Studies; Drug Resistance, Viral; Genetic Fitness; Genotype; HIV Infections; HIV-1; Humans; Indinavir; Models, Biological; Mutation; Treatment Outcome; Zidovudine

We previously modeled the in vivo evolution of human immunodeficiency virus-1 (HIV-1) under drug selective pressure from cross-sectional viral sequences. These fitness landscapes (FLs) were made by using first a Bayesian network (BN) to map epistatic substitutions, followed by scaling the fitness landscape based on an HIV evolution simulator trying to evolve the sequences from treatment naïve patients into sequences from patients failing treatment. In this study, we compared four FLs trained with different sequence populations. Epistatic interactions were learned from three different cross-sectional BNs, trained with sequence from patients experienced with indinavir (BNT), all protease inhibitors (PIs) (BNP) or all PI except indinavir (BND). Scaling the fitness landscape was done using cross-sectional data from drug naïve and indinavir experienced patients (Fcross using BNT) and using longitudinal sequences from patients failing indinavir (FlongT using BNT, FlongP using BNP, FlongD using BND). Evaluation to predict the failing sequence and therapy outcome was performed on independent sequences of patients on indinavir. Parameters included estimated fitness (LogF), the number of generations (GF) or mutations (MF) to reach the fitness threshold (average fitness when a major resistance mutation appeared), the number of generations (GR) or mutations (MR) to reach a major resistance mutation and compared to genotypic susceptibility score (GSS) from Rega and HIVdb algorithms. In pairwise FL comparisons we found significant correlation between fitness values for individual sequences, and this correlation improved after correcting for the subtype. Furthermore, FLs could predict the failing sequence under indinavir-containing combinations. At 12 and 48 weeks, all parameters from all FLs and indinavir GSS (both for Rega and HIVdb) were predictive of therapy outcome, except MR for FlongT and FlongP. The fitness landscapes have similar predictive power for treatment response under indinavir-containing regimen as standard rules-based algorithms, and additionally allow predicting genetic evolution under indinavir selective pressure.

Topics: Bayes Theorem; Computational Biology; Drug Resistance, Viral; Evolution, Molecular; Genetic Fitness; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kaplan-Meier Estimate; Models, Statistical; Treatment Failure; Viral Load

To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period.. IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 μg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg ml(-1), the suggested minimum target.. Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative.. Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Dose-Response Relationship, Drug; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies; Ritonavir; Young Adult

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

Medical studies often involve semi-competing risks data, which consist of two types of events, namely terminal event and non-terminal event. Because the non-terminal event may be dependently censored by the terminal event, it is not possible to make inference on the non-terminal event without extra assumptions. Therefore, this study assumes that the dependence structure on the non-terminal event and the terminal event follows a copula model, and lets the marginal regression models of the non-terminal event and the terminal event both follow time-varying effect models. This study uses a conditional likelihood approach to estimate the time-varying coefficient of the non-terminal event, and proves the large sample properties of the proposed estimator. Simulation studies show that the proposed estimator performs well. This study also uses the proposed method to analyze AIDS Clinical Trial Group (ACTG 320).

Topics: Acquired Immunodeficiency Syndrome; Computer Simulation; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Likelihood Functions; Regression Analysis; Risk

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

The era of highly active antiretroviral therapy (HAART) has controlled AIDS and its related disorders considerably; however, the prevalence of HIV-1-associated neurocognitive disorders has been on the rise in the post-HAART era. In view of these developments, we investigated whether a HAART drug combination of 3'-azido-2',3'-deoxythymidine (AZT) and indinavir (IDV) can alter the functionality of the blood-brain barrier (BBB) endothelial cells, thereby exacerbating this condition. The viability of hCMEC/D3 cells (in vitro model of BBB) that were exposed to these drugs was significantly reduced after 72h treatment, in a dose-dependent manner. Reactive oxygen species were highly elevated after the exposure, indicating that mechanisms that induce oxidative stress were involved. Measures of oxidative stress parameters, such as glutathione and malondialdehyde, were altered in the treated groups. Loss of mitochondrial membrane potential, as assessed by fluorescence microscopy and decreased levels of ATP, indicated that cytotoxicity was mediated through mitochondrial dysfunction. Furthermore, AZT+IDV treatment caused apoptosis in endothelial cells, as assessed by the expression of cytochrome c and procaspase-3 proteins. Pretreatment with the thiol antioxidant N-acetylcysteine amide reversed some of the pro-oxidant effects of AZT+IDV. Results from our in vitro studies indicate that the AZT+IDV combination may affect the BBB in HIV-infected individuals treated with HAART drugs.

Topics: Acetylcysteine; Adenosine Triphosphate; Antiretroviral Therapy, Highly Active; Apoptosis; Blood-Brain Barrier; Caspase 3; Cell Line, Transformed; Cytochromes c; Endothelial Cells; Glutathione; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Zidovudine

Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.

Topics: Adult; Body Weight; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Monte Carlo Method; Ritonavir; Thailand; Young Adult

Topics: Amino Acid Substitution; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Evolution, Molecular; Follow-Up Studies; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Male; Polymorphism, Genetic; Sequence Analysis, DNA

Many malaria-endemic areas are also associated with high rates of human immunodeficiency virus (HIV) infection. An understanding of the chemotherapeutic interactions that occur during malaria and HIV co-infections is important. Our previous studies have demonstrated that some antiretroviral protease inhibitors are effective in inhibiting Plasmodium falciparum growth in vitro. Currently, studies examining the interactions between antiretroviral protease inhibitors and antimalarial drugs are being conducted, but the data are limited. In this study, we examined the synergistic interactions between the antiretroviral protease inhibitor indinavir and chloroquine (CQ) in chloroquine-resistant and chloroquine-sensitive malaria parasites in vitro and in vivo. In vitro, by using modified fixed-ratio isobologram method, fractional inhibitory concentrations index (FICI) was calculated to indicate the interaction between the two drugs. The results demonstrated that indinavir interacted synergistically with chloroquine against both chloroquine-sensitive P. falciparum clone 3D7 (mean FICI 0.784) and multidrug-resistant P. falciparum clone Dd2 (mean FICI 0.599). In vivo drug interactions were measured using a 4-day suppressive test in a rodent malaria model infected with Plasmodium chabaudi. We observed that indinavir enhanced the antimalarial activity of chloroquine against both the chloroquine-sensitive line P. chabaudi ASS and the chloroquine-resistant line P. chabaudi ASCQ. More importantly, chloroquine had a 100% clearance of asexual parasites when used in combination with indinavir at an appropriate dose ratio (10 mg/kg CQ + 1.8 g/kg indinavir) where there was no obvious toxicity. We conclude from this study that the combination of indinavir and chloroquine may become a novel antimalarial drug regimen.

Topics: Animals; Antimalarials; Chloroquine; Coinfection; Drug Synergism; Female; HIV Infections; HIV Protease Inhibitors; Indinavir; Malaria; Mice; Plasmodium chabaudi; Plasmodium falciparum

Indinavir, an antiretroviral protease inhibitor used in treatment of HIV infection has limited penetration into brain due to efflux of P-glycoprotein. The aim of this work was to develop transferrin coupled submicron lipid emulsions (SLEs) containing indinavir for delivery to brain. Stearylamine containing SLEs were prepared, characterized, tested for stability and optimized formulation (SLE-4) was developed. Transferrin was coupled to get SLE-6 by water soluble EDC method and purified by gel filtration. The coupled transferrin was quantified by modified Bradford dye assay method. The fluorescent dye (DiD oil) incorporated SLEs were used to check the brain specific delivery of SLEs. The in vivo pharmacokinetic and tissue distribution were conducted in mice. During pharmacokinetic studies, there was no significant difference in the serum levels of indinavir from SLE-1, SLE-4 and SLE-6 formulations at all time points. In tissue distribution studies the therapeutic availability (TA) of indinavir in brain from SLE-6 was 4.69, 3.1 and 1.7 times higher than drug solution, SLE-1 and SLE-4 respectively whereas, the TA of indinavir from SLE-4 was 2.76 and 1.82 times the drug solution and SLE-1. The brain to serum ratios with SLE-6 were above one indicates the brain specific delivery. The brain delivery of indinavir was improved with transferrin ligand attachment to SLEs by receptor mediated transcytosis.

Topics: Amines; Animals; Brain; Chromatography, Gel; Drug Carriers; Drug Stability; Emulsions; Fluorescent Dyes; HIV; HIV Infections; HIV Protease Inhibitors; Indinavir; Lipids; Male; Mice; Microscopy, Fluorescence; Microtomy; Particle Size; Receptors, Transferrin; Tissue Distribution; Transferrin

Animal pharmacokinetic and tissue distribution assays of antiretroviral therapeutic drugs require accurate drug quantification in biological fluids and tissues. Here we report a simple, rapid, and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of commonly used antiretroviral drugs ritonavir (RTV), indinavir (IDV), atazanavir (ATV), and efavirenz (EFV) in mouse serum and tissues (liver, kidney, lung, and spleen). These antiretroviral drugs are currently the cornerstones of common therapeutic regimens for human immunodeficiency virus (HIV) infection. Chromatographic separation was achieved using a gradient mobile phase (5% acetonitrile in methanol and 7.5mM ammonium acetate (pH 4.0)) on an ACQUITY UPLC(®)BEH Shield RP 18 column. All compounds eluted within a 7 min run time. Lopinavir was used as an internal standard. Detection was achieved by dual positive and negative ionization modes on a quadrupole linear ion trap hybrid mass spectrometer with an electrospray ionization (ESI) source. The dynamic range was 0.2-1000 ng/mL for RTV, IDV, and ATV, and 0.5-1000 for EFV. The method was validated and showed high and consistent intra-day and inter-day accuracy and precision for all analytes. This method is used to support the preclinical development studies of targeted- and sustained-release combination ART (nanoART). The current data demonstrate a 1.5-4 fold increase in serum and tissue AUC of nanoformulated ATV, RTV, and EFV administered to mice when compared to native drug. In addition, the tested formulation enhanced exposure of the same anti-HIV drugs in mouse tissues.

Topics: Alkynes; Animal Structures; Animals; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; HIV Infections; Humans; Indinavir; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Pyridines; Ritonavir; Tandem Mass Spectrometry

Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored.. The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence.. Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel.. These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.

Topics: Antibiotics, Antineoplastic; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

Europe is currently observing a significant rise in non-B subtypes. Consequently, the effect of genetic variability on therapy response or genotypic resistance interpretation algorithms is an emerging concern. The purpose of this study is to investigate the amino acid substitutions selected under drug pressure in the protease of human immunodeficiency virus type 1 (HIV-1) subtypes B and G, and determine if there are any significant differences. We investigated therapy-related and subtype-related substitutions in the protease, considering subtype, overall protease inhibitor treatment and individual drug exposure. Many mutations were significantly related to protease inhibitor (PI) therapy, with mutations exclusive to subtype B or subtype G. Some mutations are at positions related to resistance in both subtypes, but the amino acid substitution is different. Other mutations were significantly associated with subtype and PI selective pressure (p<0.05), pointing towards a differential selective pressure in both subtypes. We confirmed previous reports on the subtype-dependent selection of D30N and 89I, and identified a new mutation with such differential selective pressure: 37D was preferentially selected by lopinavir in subtype B. Other novel mutations found under therapy pressure were 13A, 35N, K55R, I66F, I72L/T, T74S, 82M and 89I/V. Our study indicates that even though in general, drug selective pressure and resistance pathways are relatively similar between subtypes B and G, some differences do occur, leading to subtype-dependent substitutions.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genetic Variation; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Phylogeny; Pyrimidinones; Selection, Genetic; Sequence Analysis, Protein

HIV infected patients often take at least three anti-HIV drugs together in Highly Active Antiretroviral Therapy (HAART) and/or Ritonavir-Boosted Protease Inhibitor Therapy (PI/r) to suppress the viral replications. The potential drug-drug interactions affect efficacy of anti-HIV treatment and major source of such interaction is competition for the drug metabolizing enzyme, cytochrome P450 (CYP). CYP3A4 isoform is the enzyme responsible for metabolism of currently available HIV-1 protease drugs. Hence administration of these drugs in HARRT or PI/r leads to increased toxicity and reduced efficacy in HIV treatment. We used computational molecular docking method to predict such interactions by which to compare experimentally measured metabolism of each HIV-1 protease drug. AutoDock 4.0 was used to carry out molecular docking of 10 HIV-protease drugs into CYP3A4 to explore sites of reaction and interaction energies (i.e., binding affinity) of the complexes. Arg105, Arg106, Ser119, Arg212, Ala370, Arg372, and Glu374 are identified as major drug binding residues, and consistent with previous data of site-directed mutagenesis, crystallography structure, modeling, and docking studies. In addition, our docking results suggested that phenylalanine clusters and heme are also participated in the binding to mediate drug oxidative metabolism. We have shown that HIV-1 protease drugs such as tipranavir, nelfinavir, lopinavir, and atazanavir differ in their binding modes on each other for metabolic clearance in CYP3A4, whereas ritonavir, amprenavir, indinavir, saquinavir, fosamprenavir, and darunavir share the same binding mode.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Computational Biology; Cytochrome P-450 CYP3A; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

The aims of the present study were to estimate the prevalence of renal impairment (RI) among HIV-infected adult patients and to investigate the associated factors.. A cross-sectional survey was conducted in a French hospital-based cohort. Clearance of creatinine (CC) was calculated using the Cockcroft-Gault formula. Four stages of RI were defined: mild (60-90 mL/min), moderate (30-60), severe (15-30) and end stage (<15). Logistic regression models were used to investigate factors associated with RI.. The male/female ratio of the 2588 patients enrolled was 3:1 and the median age was 42 years. At the time of assessment of CC, the median CD4 count was 430 cells/microL and HIV plasma viral load (VL) was<50 copies/mL in 60%. The overall prevalence of RI was 39.0%: 34.2% mild, 4.4% moderate, 0.3% severe and 0.2% end-stage. Mild RI was associated with female gender [odds ratio (OR)=3.3: 95% CI 2.6-4.3)], age >50 years (OR=9.8: 7.4-13.0) and 40-50 years (OR=1.9: 1.5-2.4), body mass index (BMI) <22 kg/m(2) (OR=3.3: 2.7-4.3) and tenofovir exposure (OR=1.4: 1.0-1.9 for <1 year and OR=1.5: 1.2-2.0 for >1 year). Advanced RI (CC <60 mL/min) was associated with age >50 years (OR=5.6: 2.9-10.9) and 40-50 years (OR=2.2: 1.1-1.4), BMI <22 kg/m(2) (OR=1.5: 1.0-2.4), hypertension (OR=2.5: 1.4-2.5) and indinavir (IDV) exposure >1 year (OR=2.3: 1.5-3.6).. This survey confirms the high prevalence of RI in HIV-infected patients and indicates the importance of the investigation of renal function especially in women, older patients, those with a low BMI or treated with tenofovir or IDV.

Topics: Adenine; Adult; Anti-HIV Agents; Body Mass Index; CD4 Lymphocyte Count; Creatinine; Epidemiologic Methods; Female; France; HIV Infections; Humans; Hypertension; Indinavir; Kidney; Kidney Function Tests; Male; Middle Aged; Organophosphonates; Renal Insufficiency; Tenofovir

Most malaria endemic regions are co-infested with HIV infection. Treatment of one may affect outcome of the other in co-infected individuals. HIV protease inhibitors, indinavir or nelfinavir, are important antiretroviral drugs and artemisinin is central to malaria treatment. We show these protease inhibitors augment the antimalarial activity of artemisinin against P. falciparum in vitro.

Topics: Antimalarials; Artemisinins; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Malaria; Nelfinavir

We propose a systematic approach for a better understanding of how HIV viruses employ various combinations of mutations to resist drug treatments, which is critical to developing new drugs and optimizing the use of existing drugs. By probabilistically modeling mutations in the HIV-1 protease or reverse transcriptase (RT) isolated from drug-treated patients, we present a statistical procedure that first detects mutation combinations associated with drug resistance and then infers detailed interaction structures of these mutations. The molecular basis of our statistical predictions is further studied by using molecular dynamics simulations and free energy calculations. We have demonstrated the usefulness of this systematic procedure on three HIV drugs, (Indinavir, Zidovudine, and Nevirapine), discovered unique interaction features between viral mutations induced by these drugs, and revealed the structural basis of such interactions.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Models, Molecular; Mutation; Nevirapine; Protein Binding; Protein Structure, Tertiary; Zidovudine

We introduce a dose-finding algorithm to be used to identify a level of dose that corresponds to some given targeted response. Our motivation arises from problems where the response is a continuously measured quantity, typically some pharmacokinetic parameter. We consider the case where an agreed level of response has been determined from earlier studies on some population and the purpose of the current trial is to obtain the same, or a comparable, level of response in a new population. This relates to bridging studies. The example driving our interest comes from studies on drugs for HIV that have already been evaluated in adults and where the new studies are to be carried out in children. These drugs have the ability to produce some given mean pharmacokinetic response in the adult population, and the goal is to calibrate the dose in order to obtain a comparable response in the childhood population. In practice, it may turn out that the dose producing some desired mean response is also associated with an unacceptable rate of toxicity. In this case, we may need to reevaluate the target response and this is readily achieved. In simulations, the algorithm can be seen to work very well. In the most challenging situations for the method, those where the targeted response corresponds to a region of the dose-response curve that is relatively flat, the algorithm can still perform satisfactorily.

Topics: Adult; Algorithms; Child; Clinical Trials, Phase I as Topic; Computer Simulation; HIV Infections; Humans; Indinavir; Pharmacokinetics

To identify risk factors for acute renal failure (ARF) in HIV-infected patients.. Observational cohort study of HIV-infected patients attending a South London HIV centre between January 1999 and December 2008.. ARF was defined as a transient, more than 40% reduction in renal function as assessed by estimated glomerular filtration rate. Multivariate Poisson regression analysis was used to identify baseline and time-updated factors associated with ARF.. The incidence of ARF was 2.8 (95% confidence interval 2.41-3.24) episodes per 100 person-years. We observed a stepwise increase in ARF incidence with time accrued at lower CD4 cell count and at lower estimated glomerular filtration rate, with adjusted incidence rate ratios of 1 (reference), 1.56 (0.97-2.48), 2.08 (1.11-3.91), 6.38 (3.18-12.78) and 10.29 (5.11-20.98) for CD4 cell counts of more than 350, 201-350, 101-200, 51-100 and of 50/microl or less, and 1 (reference), 1.46 (0.86-2.51), 4.19 (2.37-7.42) and 27.00 (16.13-44.95) for estimated glomerular filtration rate more than 90, 75-89, 60-74 and less than 60 ml/min, respectively. Ethnicity, hepatitis B or C coinfection, exposure to combination antiretroviral therapy with or without indinavir, tenofovir or atazanavir and HIV viraemia were not associated with ARF.. Current levels of immunodeficiency and renal function were independent predictors of HIV-associated ARF.

Topics: Acute Kidney Injury; Adenine; Adult; Atazanavir Sulfate; CD4 Lymphocyte Count; Cohort Studies; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; London; Male; Oligopeptides; Organophosphonates; Pyridines; Risk Factors; Tenofovir

Human Immunodeficiency Virus Type 1 exists in vivo as quasispecies, and one of the genome's characteristics is its diversity. During the antiretroviral therapy, drug resistance is the main obstacle to effective viral prevention. Understanding the molecular evolution process is fundamental to analyze the mechanism of drug resistance and develop a strategy to minimize resistance.. The molecular evolution of drug resistance of one patient who had received reverse transcriptase inhibitors for a long time and had treatment which replaced Nevirapine with Indinavir was analyzed, with the aim of observing the drug resistance evolution pathway.. The patient, XLF, was followed-up for six successive times. The viral populations were amplified and sequenced by single-genome amplification. All the sequences were submitted to the Stanford HIV Drug Resistance Database for the analysis of genotypic drug resistance.. 149 entire protease and 171 entire reverse transcriptase sequences were obtained from these samples, and all sequences were identified as subtype B. Before the patient received Indinavir, the viral population only had some polymorphisms in the protease sequences. After the patient began Indinavir treatment, the variants carrying polymorphisms declined while variants carrying the secondary mutation G73S gained the advantage. As therapy was prolonged, G73S was combined with M46I/L90M to form a resistance pattern M46I/G73S/L90M, which then became the dominant population. 97.9% of variants had the M46I/G73S/L90M pattern at XLF6. During the emergence of protease inhibitors resistance, reverse transcriptase inhibitors resistance maintained high levels.. Indinavir-resistance evolution was observed by single-genome amplification. During the course of changing the regimen to incorporate Indinavir, the G73S mutation occurred and was combined with M46I/L90M.

Topics: Amino Acid Substitution; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Evolution, Molecular; Follow-Up Studies; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Male; Polymorphism, Genetic; Sequence Analysis, DNA

An amperometric drug metabolism biosensor consisting of cytochrome P450-3A4 (CYP3A4) encapsulated in a didodecyldimethylammonium bromide (DDAB) vesicular system on a Pt disk electrode was developed for the determination of indinavir, a protease inhibitor antiretroviral drug. Cyclic, square wave and pulse voltammetric responses of the bioelectrode showed quasi-reversible electrochemistry of the Fe(3+)/Fe(2+) redox species of the heme thiolate CYP3A4 enzyme under aerobic and anaerobic conditions. The biosensor exhibited excellent response to indinavir with a detection limit and response time of 6.158 x 10(-2)mgL(-1), and 40s, respectively. The detection limit is well below the plasma concentration of indinavir (8h after intake) which range from 0.13 to 8.6mgL(-1).

Topics: Aerobiosis; Anaerobiosis; Biosensing Techniques; Clinical Trials, Phase I as Topic; Cytochrome P-450 CYP3A; Electricity; Electrochemistry; Electrodes; Enzymes, Immobilized; HIV Infections; HIV Protease Inhibitors; Indinavir; Molecular Structure; Oxidation-Reduction; Platinum; Quaternary Ammonium Compounds; Silver; Silver Compounds; Water

HIV-1 group M is classified into nine different subtypes. Most antiretroviral (ARV) drugs have been developed for subtype B, and the response of non-B subtypes in terms of susceptibility and the acquisition of drug resistance when facing those drugs is largely unknown. In this study, we aimed to address differences in the impact of protease inhibitor (PI)-selected mutations on subtypes B and G.. ARV-treated, HIV-positive patients regularly monitored at the Hospital de Egas Moniz, in Lisbon, Portugal, were examined for the presence of PI-associated primary mutations (301 subtype B and 184 subtype G), and for the selection of those mutations over the time of PI exposure. Forty-three subtype G patients were phenotyped for susceptibility to all available PIs through VIRCO's Antivirogram, and compared with a similar dataset of subtype B patients.. Mutation I54V/L was selected by nelfinavir in subtype G isolates, a mutation not previously described for this drug in subtype B. L90M was associated with a lower reduction in the susceptibility of subtype G to nelfinavir when compared with subtype B, and with no reduced susceptibility to saquinavir. This was compensated for by the acquisition of M89I in subtype G. L90M did not reduce the susceptibility of subtype G to saquinavir, in contrast to subtype B. Likewise, the pattern I54V/L-L90M did not reduce the susceptibility of subtype G to indinavir and saquinavir. Indinavir-associated mutations M46I/L, I84V and V82A/F/T developed earlier in subtype B across the time of exposure to that drug when compared with subtype G counterparts.. Our results provide proof of principle and support the growing evidence that subtype-specific responses to ARVs exist. Data presented here highlight inconsistencies in current genotyping interpretation algorithms inadequately applied to all HIV-1 subtypes.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation, Missense; Nelfinavir; Portugal; Saquinavir; Selection, Genetic

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety.. Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2-ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration-time curve (AUC) and maximum (C(max)) and trough concentrations (C(trough)) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety. A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and C(trough) were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir C(max) (median 3.6, range 2.1-5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2-8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range -0.7 to 1.4 vs. median 0.6, range -0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs.. The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Area Under Curve; Clinical Trials as Topic; Cohort Studies; Cytochrome P-450 CYP3A; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Metabolic Clearance Rate; Middle Aged; Models, Statistical; Multicenter Studies as Topic; Pharmacogenetics; Pilot Projects; Polymorphism, Genetic; Prospective Studies; Treatment Outcome

Current understanding of adipogenesis derives mainly from studies with in vitro cell culture systems with divergent experimental requirements. We aimed to investigate the discrepancy between the anti-adipogenic effects of the HIV protease-inhibitor indinavir (IDV) in vitro and the lack of evidence that IDV inhibits adipogenesis in humans.. We studied cell viability and adipogenesis in murine 3T3-F442A, 3T3-L1 and primary human subcutaneous preadipocytes (phsPA). Differentiation was studied after activation of the established four signalling pathways in different combinations. We analyzed CCAAT/enhancer-binding protein (C/EBP) alpha and peroxisome proliferator-activated receptor (PPAR) gamma expression and triacylglyceride accumulation. Cells were exposed to IDV at concentrations around therapeutic C(max) levels and higher (10 muM and 20 muM) for up to 30 days.. Under insulin and fetal calf serum (FCS) input, IDV inhibited 3T3-F442A differentiation, an effect that was partially rescued by the addition of 3-isobutyl-1-methylxanthine (IBMX) stimulation. Combined stimulation with FCS, insulin, dexamethasone (DEX) and IBMX led to normal 3T3-L1 differentiation even in the presence of IDV. However, omission of IBMX rendered this cell line sensitive to IDV's anti-adipogenic effects. Differentiation of phsPA requiring complete adipogenic stimulation was not affected by IDV presence.. Our data suggest that the potency of IDV to impair differentiation under partial stimulation disappears when all of the differentiation pathways are activated. Such compensatory mechanisms might be responsible for the inability of the drug to affect adipogenesis in vivo.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Dose-Response Relationship, Drug; Gene Expression Regulation; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Mice; PPAR gamma

Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery.. NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography.. Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited.. These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cell Survival; Cells, Cultured; Cyclopropanes; HIV Core Protein p24; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Macrophages; Microscopy, Atomic Force; Monocytes; Nanoparticles; Ritonavir

A new class of potent sulfoximine inhibitors for HIV-1 protease has been designed and synthesized. Substitution of the sulfoximine moiety into different parent compounds yields different inhibition effects. While our previously studied sulfoximine-based inhibitors display potency of 2.5 nM (IC(50)) against HIV-1 protease, introduction of the sulfoximine moiety into the asymmetric Indinavir yielded only micromolar inhibition. Docking studies showed structural variations in their modes of binding which explains this unexpected observation. The implication of these observations in the development of other sulfoximine inhibitors is discussed.

Topics: Chemistry, Pharmaceutical; Crystallography, X-Ray; Drug Design; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Hydrogen Bonding; Imines; Indinavir; Inhibitory Concentration 50; Models, Chemical; Molecular Structure; Protein Binding; Stereoisomerism; Structure-Activity Relationship; Sulfoxides

Genotypic resistance is currently assessed through direct sequencing, which cannot detect resistant strains below 20%. We compared the genotypic resistance profile of virions and proviruses using population-based analysis and single genome sequencing of the protease region of the pol gene in samples collected from five individuals in whom indinavir monotherapy resulted in treatment failure. Single genome sequencing showed that not all strains present the same resistance mutations, which can be dispersed across different HIV genomes. The resistance profile found in plasma was very similar to that found in peripheral blood mononuclear cells (PBMCs), confirming the utility of assessing proviral DNA as for a means of determining antiretroviral resistance.

Topics: Amino Acid Sequence; Drug Resistance, Viral; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Leukocytes, Mononuclear; Molecular Sequence Data; Mutation; Plasma; Proviruses; Sequence Alignment; Treatment Failure; Virion

Documentation regarding the renal complications of paediatric HIV infection from developing countries is scarce. In the era prior to highly active antiretroviral therapy (HAART), HIV-infected children in Jamaica who developed HIV-associated nephropathy (HIVAN) progressed to end stage renal disease (ESRD) and death within a few months of diagnosis. With increased public access to antiretroviral therapy since 2002 and subsequent survival, renal complications are increasingly recognized among the surviving cohort of infected children.. A cohort of 196 HIV-infected children was followed in four multicentre ambulatory clinics from September 1, 2002 to August 31, 2005 as part of the Kingston Paediatric and Perinatal HIV/AIDS Programme, Jamaica. We describe the clinical presentations and natural history of those patients who developed renal complications.. Urinary tract infections were the most common diagnosis, occurring in 16.8% of patients, with a high recurrence rate and the most common organism was Escherichia coli. Four of seven patients who started indinavir developed complications of nephrolithiasis and tubulointerstitial nephropathy. Six patients (3%) fulfilled the criteria for HIVAN, five of whom were male. Median age at diagnosis was five years; all presented with advanced HIV disease, nephrotic syndrome or nephrotic range proteinuria and three with chronic renal failure. Patients received standard medical management and were initiated on angiotensin-converting enzyme (ACE) inhibitors and HAART While the mortality ratio was 50%, only one death was associated with HIVAN and the median survival time was 3.1 years.. HIV-infected children present with a variety of renal complications. With improved survival since the introduction of HAART, the incidence of HIVAN is expected to increase among this maturing paediatric cohort. Early detection and treatment will optimize the outcomes for these children.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Cohort Studies; Female; HIV Infections; Humans; Indinavir; Infant; Infant, Newborn; Jamaica; Male; Nephritis, Interstitial; Nephrolithiasis; Prospective Studies

We have shown previously using the dually perfused isolated human placenta model that the maternal to foetal transfer of the antiviral protease inhibitor drug indinavir is substantially lower than the transfer in the opposite direction. This finding is not consistent with passive diffusion and indicates that a carrier-mediated mechanism is involved in retarding the movement in the maternal to foetal direction. The efflux transporter P-gp located in the apical membrane domain of the placental trophoblast cells has been implicated as the likely cause of the differential bi-directional transport.. The present study also utilizes the human perfused human isolated placenta to investigate the possible inhibitory effects of the P-gp inhibitor PSC833 and the P-gp substrate/inhibitor ritonavir on the maternal to foetal transfer clearance of indinavir. The studies, which were conducted such that each placenta served as its own control, demonstrated a statistically significant increase in the maternal to foetal transfer of indinavir in the presence of PSC833 but not in the presence of ritonavir, a protease inhibitor that is often used in combination with other protease inhibitors in dual therapy. The lack of effect of ritonavir is most likely related to the relatively low inhibitory activity at the clinically relevant concentration used in this study.. To investigate the effect of P-gp inhibition on the maternal to foetal transfer of indinavir.. Term human placentae (n = 12) were from non-HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P-gp inhibitors PSC833 (n = 7) or ritonavir (n = 5), in the perfused human placenta. Antipyrine and [(3)H]-vinblastine were included as markers of passive diffusion and P-gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0 min; PSC833 or ritonavir was added at 25 min. Steady-state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index).. Indinavir clearance index increased between the control (0.25 +/- 0.03) and PSC833 phases (0.37 +/- 0.14) (95% CI of the difference -0.23, -0.002). Vinblastine clearance index increased from (0.25 +/- 0.08) to (0.34 +/- 0.06) in the control and PSC833 phases, respectively (95% CI of difference -0.14, -0.05). Indinavir clearance index was unchanged between control (0.34 +/- 0.14) and ritonavir phases (0.39 +/- 0.13) (95% CI of the difference -0.19, 0.08). Vinblastine clearance index increased from (0.24 +/- 0.12) to (0.32 +/- 0.12) in the control and ritonavir phases, respectively (95% CI of the difference -0.15, -0.009).. Maternal to foetal transfer clearance of indinavir and vinblastine increased following P-gp inhibition. The potential role for co-administration of P-gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Maternal-Fetal Exchange; Placenta; Pregnancy; Ritonavir

HIV infection is associated with an increased risk of coronary artery disease, but the contribution of inflammation versus antiretroviral drugs is not well understood. Fibrinogen is an inflammatory factor associated with atherosclerosis.. A total of 1131 HIV-infected patients and 281 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had plasma fibrinogen levels measured. Multivariable linear regression identified factors associated with fibrinogen.. HIV-infected patients had higher levels of fibrinogen compared with controls (males: 25 mg/dl higher, P = 0.006; females: 21 mg/dl higher, P = 0.39). Among HIV-infected persons, median levels of fibrinogen were 11% higher in patients currently using any protease inhibitor (PI) compared with those not using a PI (P < 0.0001). The strongest univariate associations were with the individual PIs, ritonavir and indinavir. Patients taking indinavir boosted with ritonavir had median fibrinogen levels 8% higher than those on indinavir alone (P = 0.049). Lower levels of fibrinogen were seen in those HIV-infected patients currently using any nonnucleoside reverse transcriptase inhibitor (NNRTI) compared to those not using an NNRTI (nevirapine -14.4%, P < 0.0001; efavirenz -7%, P = 0.0002). The associations of ritonavir, indinavir, efavirenz and nevirapine with fibrinogen levels persisted after multivariable analysis and were independent of other antiretroviral use.. Protease inhibitor use is associated with elevated fibrinogen levels which may contribute to increased risk of atherosclerosis in HIV-infected patients. Conversely, NNRTI use is associated with lower fibrinogen levels which may decrease risk of atherosclerosis.

Topics: Adult; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Case-Control Studies; Cyclopropanes; Female; Fibrinogen; HIV Infections; Humans; Indinavir; Linear Models; Male; Nevirapine; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir

The authors had for aim to compare the therapeutic efficiency and tolerance of 2 NRTI+efavirenz (EFV) versus 2 NRTI+indinavir (IDV) in HIV infected adults in Abidjan.. A retrospective and multicentric study was made on 327 HIV-1 naive patients, 142 in the EFV group and 185 in the IDV group followed in Abidjan from November 1998 to December 2003. The analysis concerned clinical advents (opportunistic infections) and immunovirological parameters (CD4, viral load). Patients received 2 NRTI such as AZT+3TC or D4T+3TC combined either with EFV or IDV. The principal judgement criterion was therapeutic failure. We assessed the percentage of patients with undetectable viral load and the frequency of grade 3-4 adverse effects after 24 months of follow-up.. Clinical improvement of patients' state and regression of opportunistic infections were identical in the two groups. The average gain of CD4 was superior to 177 in EFV versus +219 in IDV (p=0.004). The percentage of patients with undetectable viral load was 66% for EFV versus 59% for IDV (p=0.04). The frequency of adverse effects was more elevated with EFV than IDV, 39% versus 23% (p=0.002) initially, but seemed to decrease later.. HAART with EFV is at least as efficient as with IDV in terms of reduction of viral load and increased CD4 count and is an excellent low-cost first line treatment.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Cote d'Ivoire; Drug Tolerance; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Two novel human immunodeficiency virus protease mutations, I84C and I84A, were identified in patient isolates. The mutants with I84C displayed high-level resistance (median, at least 56-fold) to nelfinavir and saquinavir, but the majority remained susceptible to lopinavir. In contrast, isolates with the I84A mutation exhibited>or=33-fold median increased levels of resistance to nelfinavir, indinavir, amprenavir, ritonavir, lopinavir, saquinavir, and atazanavir. Isolates with the I84A or I84C mutation tended to be more resistant than the isolates with the I84V mutation. Modeling of the structure of the mutant proteases indicated that the I84V, I84C, and I84A mutations all create unoccupied volume in the active site, with I84A introducing the greatest change in the accessible surface area from that of the wild-type structure.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Resistance, Viral; Genes, gag; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Nelfinavir; Oligopeptides; Pyridines; Ritonavir; Saquinavir; Virus Replication

Human immunodeficiency virus-infected women (n=16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.

Topics: Adult; Cytochrome P-450 CYP3A; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant, Newborn; Liver; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Infectious

We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.

Topics: Amino Acid Sequence; Drug Design; Drug Resistance, Multiple, Viral; Furans; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Sulfonamides; Urethane; Virus Replication

A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.

Topics: Cell Line; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indicators and Reagents; Indinavir; Structure-Activity Relationship

The effectiveness of anti-retroviral therapies (ART) depends on its ultimate ability to clear reservoirs of continuous human immunodeficiency virus (HIV) infection. We reasoned that a principal vehicle for viral dissemination, the mononuclear phagocytes could also serve as an ART transporter and as such improve therapeutic indices. A nanoparticle-indinavir (NP-IDV) formulation was made and taken up into and released from vacuoles of human monocyte-derived macrophages (MDM). Following a single NP-IDV dose, drug levels within and outside MDM remained constant for 6 days without cytotoxicity. Administration of NP-IDV when compared to equal drug levels of free soluble IDV significantly blocked induction of multinucleated giant cells, production of reverse transcriptase activity in culture fluids and cell-associated HIV-1p24 antigens after HIV-1 infection. These data provide "proof of concept" for the use of macrophage-based NP delivery systems for human HIV-1 infections.

Topics: Anti-HIV Agents; Cell Fusion; Cell Survival; Cells, Cultured; Cytoplasm; HIV Core Protein p24; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Macrophages; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Nanoparticles

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Topics: Bayes Theorem; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Mutation; Nelfinavir; Saquinavir

Large intra-individual variability in plasma levels may limit the interest of therapeutic drug monitoring based on a single determination. Indinavir concentrations were determined both in plasma and hair samples, and correlated with concomitant plasma HIV-RNA in 43 HIV-infected patients. In multivariate analysis, significant association was found between HIV-RNA below 50 copies/ml and indinavir concentrations in hair but not in plasma, suggesting that hair concentrations gave more extensive information on drug exposure than a single plasma sample.

Topics: Antiretroviral Therapy, Highly Active; Confidence Intervals; Drug Combinations; Hair; HIV Infections; HIV-1; Humans; Indinavir; Odds Ratio; Ritonavir

Viral suppression after antiretroviral therapy is monitored by determining plasma HIV-1 through viral load assays. However, such assays only provide HIV-1 replication rates at the moment samples are drawn and do not reflect any trend in viremia fluctuation preceding sample collection. The objective of this study was to correlate the optical density (OD) of the less sensitive HIV-1 enzyme immunoassay (EIA), used in the serologic testing algorithm for recent HIV seroconversion, with viral loads in a group of HIV-infected patients on antiretroviral therapy. We studied samples from 20 previously antiretroviral-naive subjects treated with the zidovudine-lamivudine combination plus indinavir for a 20-week period. Viral loads were assessed using the less sensitive HIV-1 EIA at baseline and at 4-week intervals. There was a strong correlation between lower OD and viral load after introduction of antiretroviral drugs (p < 0.01). The ODs tended to decrease in parallel with drops in viral loads and remain steady when viral loads did not change significantly. These results suggest that the less sensitive HIV-1 EIA may be used as a complementary method for monitoring the efficacy of antiretroviral therapy, with special appeal in resource-poor areas where health professionals have limited laboratory expertise.

Topics: Anti-HIV Agents; Drug Monitoring; HIV Infections; HIV-1; Immunoenzyme Techniques; Indinavir; Lamivudine; Sensitivity and Specificity; Time Factors; Virus Replication; Zidovudine

HIV-infected patients are at increased risk of decreased bone mineral density. Some studies have implicated antiretroviral therapy as a contributor to the decreased bone mineral density seen in treated HIV-1 patients. In this study we explore the interactions between protease inhibitors (PI) and primary human osteoblast gene expression, highlighting a group of dysregulated genes that potentially are key factors in reducing bone formation. Runx-2 mRNA expression, calcium deposition, and alkaline phosphatase (ALP) activity decreased significantly in human osteoblast cultures after exposure to the PIs nelfinavir (NFV) and indinavir (IDV). Saquinavir (SQV), ritonavir (RTV), indinavir (IDV), or nelfinavir (NFV) exposure induced significant changes in genotypic expression as assessed by gene-chip microarray analysis. The altered genes from each group were compared to each other and a list of 8 upregulated and 13 downregulated genes only after NFV and IDV exposure was identified. This set includes TIMP-3, which has previously been demonstrated to be involved in osteoblast differentiation and extracellular matrix development processes. Silencing TIMP-3 mRNA expression using siRNA duplexes enhanced calcium deposition and ALP activity significantly, even after exposure to NFV and IDV. Our data suggest a link between reduced osteoblastic phenotype and a group of 21 altered genes following NFV and IDV treatment, and also suggest TIMP-3 may be involved in the PI-induced inhibition of osteoblast function.

Topics: Alkaline Phosphatase; Calcium; Cell Line; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Oligonucleotide Array Sequence Analysis; Osteoblasts; Ritonavir; Saquinavir; Tissue Inhibitor of Metalloproteinase-3; Up-Regulation

Indinavir plasma levels are associated with antiretroviral efficacy; however, little data are available regarding toxicity. We assessed the relationship between indinavir pharmacokinetic (PK) characteristics and severe nephrolithiasis as well as other severe or serious adverse reactions. Patients included in the ANRS CO8 APROCO-COPILOTE cohort and receiving 800 mg indinavir three times daily as a first-line protease inhibitor were eligible for this study. To be included in the analysis, their plasma sample at month 1 (M1) had to be available (n = 282) to estimate using population PK modeling, indinavir PK characteristics, ie, maximum (Cmax) and trough plasma (Cres) concentrations, area under the curve (AUC), and observed/predicted concentration ratio (CR). A Cox model was used to estimate the independent effect of Cmax, Cres, AUC, and CR on the hazard of severe nephrolithiasis and serious adverse reactions. At M1, median Cmax was 6205 ng/mL, Cres 631 ng/mL, AUC 24,242 ng . h/mL, and CR 0.6. After a median follow up of 12 months, 11% of patients (30 of 282) had experienced at least one serious adverse reaction among which 12 were nephrolithiasis. In the multivariate analyses, early high indinavir Cres (ie, >/=1000 ng/mL at M1) was associated with a higher rate of severe nephrolithiasis (hazard ratio = 6.7; 95% confidence interval = 1.8-25.2; P < 0.01) and was also associated with a higher rate of all serious adverse reactions but only when nephrolithiasis were included among those cases. Prospective and early indinavir Cres determination should be recommended in the patient's care management and dosage adjustments.

Topics: Adult; Age Factors; Area Under Curve; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nephrolithiasis; Proportional Hazards Models; Prospective Studies

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

The role of exposure to antiretrovirals in chronic renal failure (CRF) is not well understood. Glomerular filtration rates (GFR) are estimated using the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) equations.. Baseline was arbitrarily defined as the first recorded GFR; patients with two consecutive GFR < or = 60 ml/min per 1.73 m(2) were defined as having CRF. Logistic regression was used to determine odds ratio (OR) of CRF at baseline. ART exposure (yes/no or cumulative exposure) prior to baseline was included in multivariate models (adjusted for region of Europe, age, prior AIDS, CD4 cell count nadir, viral load, hypertension and use of nephrotoxic anti-infective therapy).. Using CG, the median GFR at baseline (n = 4474) was 94.4 (interquartile range, 80.5-109.3); 158 patients (3.5%) had CRF. Patients with CRF were older (median, 61.9 versus 43.1 years), had lower CD4 cell count nadirs (median, 80 versus 137 cells/microl), and were more likely to be diagnosed with AIDS (44.3 versus 30.4%), diabetes (16.5 versus 4.3%) or hypertension (53.8 versus 26.4%), all P < 0.001. In a multivariate model any use of indinavir [odds ratio (OR) 2.49; 95% confidence interval (CI), 1.62-3.83] or tenofovir (OR, 2.18; 95% CI, 1.25-3.81) was associated with increased odds of CRF, as was cumulative exposure to indinavir (OR, 1.15 per year of exposure; 95% CI, 1.06-1.25) or tenofovir (OR, 1.60; 95% CI, 1.20-2.15). Highly consistent results were seen using the MDRD formula.. Among antiretrovirals, only exposure to indinavir or tenofovir was associated with increased odds of CRF. We used a confirmed low GFR to define CRF to increase the robustness of our analysis, although there are several potential biases associated with this cross-sectional analysis.

Topics: Adenine; Adult; Aged; Anti-Retroviral Agents; CD4 Lymphocyte Count; Creatinine; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypertension; Indinavir; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Organophosphonates; Prospective Studies; Reverse Transcriptase Inhibitors; Tenofovir

The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms on the pharmacokinetic parameters of indinavir in HIV-infected patients.. Twenty-eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real-time PCR assays and direct sequencing for MDR1 and by PCR-SSCP analysis for CYP3A5.. The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T genotype and ritonavir were identified as statistically significant covariates (P

Topics: Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Polymorphism, Genetic; Prospective Studies; Ritonavir

Non-linear mixed-effects models (NLMEMs) are used to improve information gathering from longitudinal studies and are applied to treatment evaluation in disease-evolution studies, such as human immunodeficiency virus (HIV) infection. The estimation of parameters and the statistical tests are critical issues in NLMEMs since the likelihood and the Fisher information matrix have no closed form. An alternative method to numerical integrations, in which convergence is slow, and to methods based on linearization, in which asymptotic convergence has not been proved, is the Stochastic Approximation Expectation-Maximization (SAEM) algorithm. For the Wald test and the likelihood ratio test, we propose estimating the Fisher information matrix by stochastic approximation and the likelihood by importance sampling. We evaluate these SAEM-based tests in a simulation study in the context of HIV viral load decrease after initiation of an antiretroviral treatment. The results from this simulation illustrate the theoretical convergence properties of SAEM. We also propose a method based on the SAEM algorithm to compute the minimum sample size required to perform a Wald test of a given power for a covariate effect in NLMEMs. Lastly, we illustrate these tests on the evaluation of the effect of ritonavir on the indinavir pharmacokinetics in HIV patients and compare the results with those obtained using the adaptative Gaussian quadrature method implemented in the SAS procedure NLMIXED.

Topics: Algorithms; Computer Simulation; Data Interpretation, Statistical; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Longitudinal Studies; Models, Statistical

Several studies have revealed the frequency of antiretroviral (ARV) drug prescription errors. We analyzed highly active antiretroviral therapy (HAART) prescribing practices for human immunodeficiency virus (HIV)-infected patients undergoing hemodialysis in France.. Prescribed ARV drug doses in our cohort (consisting of all HIV-infected patients who underwent hemodialysis from 1 January 2002 and were prospectively followed up until 1 January 2004) were compared with the recommended doses for patients undergoing hemodialysis. The log-rank test was used to compare the outcomes among different groups of treated patients.. One hundred seven of the 129 patients in our cohort received a total of 317 ARV drugs, 59% of which were improperly prescribed. The dosing was too low for 18% of the patients and too high for 39% of the patients. Twenty-eight patients (26%) did not receive any of their ARV drugs at the recommended dose. The lowest prescribed dose (8% of the daily recommended dose) was observed with indinavir and zidovudine, and the highest prescribed dose (1000% of the recommended dose) was observed with stavudine. Among patients who received HAART, those who were prescribed an insufficient dose of a protease inhibitor had more-severe HIV disease and worse 2-year survival than did the other patients (mean rate of survival+/-standard deviation, 79.5%+/-7.5% vs. 95.4%+/-2.6%, respectively; P<.02). For dialyzable ARV drugs, the delay between ARV drug receipt by the patients and dialysis sessions was not respected in 9% of cases, and in 73% of cases, it was not known whether the patients took the ARV drugs before or after dialysis sessions.. This is, to our knowledge, the first study to show a significant association between ARV drug prescription errors and survival in patients undergoing dialysis.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; France; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kaplan-Meier Estimate; Medication Errors; Prospective Studies; Renal Dialysis; Stavudine; Zidovudine

Three HIV-seropositive patients were diagnosed with urolithiasis related to the use of indinavir. The first patient was a 45-year-old white male with severe haemophilia who presented with fever and flank pain referred to the glans penis. Ultrasound and intravenous pyelography (IVP) revealed a concrement in the left renal pelvis. Discontinuation of indinavir and acidification of the urine did not reduce the stone load. Percutaneous nephrolithotripsy was then performed. The second patient, a 41-year-old white male, presented at the emergency ward with flank pain and fever. Ultrasound examination showed dilatation of the left kidney. A percutaneous nephrostomy catheter was inserted. Antegrade contrast imaging showed a concrement in the proximal ureter. The patient underwent extracorporeal shock wave lithotripsy. A second antegrade image made a few days later showed no evidence of stone material. The third patient was a 56-year-old white male with a previous history of indinavir-associated urolithiasis. He presented at the emergency ward with flank pain and haematuria. A CT urography showed dilatation of the right kidney and distal portion of the right ureter with no evidence of concrement. The symptoms resolved after a percutaneous nephrostomy catheter was inserted and the antiviral medication was modified. The catheter was removed 2 weeks later. At last follow-up, none ofthe 3 patients had symptoms of urolithiasis. These cases illustrate that, although conservative therapy for indinavir-related urolithiasis can be sufficient, minimally invasive endourological surgery is sometimes necessary.

Topics: Adult; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Pelvis; Lithotripsy; Male; Middle Aged; Nephrostomy, Percutaneous; Treatment Outcome; Urolithiasis

Complaints of dry skin in HIV-infected individuals were reported after the advent of HAART. The objective of the study was to evaluate the prevalence of dry skin and associated factors in HIV-infected and control subjects.. Cross-sectional.. A total of 1026 HIV-infected subjects and 274 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had skin assessed by self-report and examination. Multivariable logistic regression identified factors associated with dry skin.. Self-reported dry skin was more prevalent in HIV-infected subjects than controls. In multivariable analysis, HIV infection was associated with self-reported dry skin. In HIV-infected men, current indinavir use, CD4 cell count less than 200 cells/microl and recent opportunistic infections were associated with dry skin. Indinavir use had an elevated risk in men with CD4 cell counts of 200 cells/microl or greater but not with CD4 cell counts less than 200 cells/microl. In HIV-infected women, a CD4 cell count less than 200 cells/microl was associated with dry skin; indinavir use did not reach statistical significance but, as in men, indinavir use had an elevated risk in those with higher CD4 cell counts than in those with CD4 cell counts less than cells/microl.. Dry skin is more common in HIV-infected individuals than controls. In HIV-infected individuals, low CD4 cell counts and indinavir use in those with higher CD4 cell counts are associated with dry skin.

Topics: Adult; Antiretroviral Therapy, Highly Active; Case-Control Studies; CD4 Lymphocyte Count; Cross-Sectional Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Prevalence; Risk Factors; Skin Diseases; United States

Anemia, which may develop due to direct effect of the virus or indirect effect of zidovudine a widely used antiviral agent for the treatment, is not an uncommon complication in human immundeficiency virus (HIV) infections. In this report, a 26 years old male HIV positive patient who developed rapid anemia in the HAART (Highly active anti-retroviral therapy) protocol including zidovudine, was presented. The patient has been followed since May 2003 without anti-retroviral therapy. He was diagnosed as alpha-thalassemia trait, because of the low mean red blood cell volume (MCV), high red blood cell count and living in an Mediterranian country. However, no treatment for thalassemia had been given in this period, since the other laboratory findings [hemoglobin, hematocrit, red cell distribution width index (RDWI), iron and iron binding capacity, transferrin saturation and ferritin levels] were normal. During the follow-up of patient, HAART protocol with zidovudine, lamivudine and indinavir, was started depending on the findings of low CD4+ T-cell count (443/mm3) and high HIV serum load (1,330,000 copies/ml). In the second month of the therapy the hemoglobin level decreased to 12.9 gr/dL, and then to 9.9 gr/dL in the fourth month, while it was 14.5 gr/dL before anti-retroviral therapy. Although the patient had no hemolysis findings, and his serum folic acid level was normal, folbiol treatment was initiated with the possibility of the presence of folic acid deficiency at cellular level. Anemia resolved with folic acid replacement without discontinuation of zidovudine or a reduction in dosage. It was thought that the presence of alpha-thalassemia co-morbidity has facilitated the development of anti-retroviral-induced anemia in this patient. As a result, it is concluded that thalassemia should be considered in the differential diagnosis of anemia in HIV positive patients, especially for the ones from Mediterranian countries.

Topics: Adult; alpha-Thalassemia; Anemia; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Diagnosis, Differential; Folic Acid; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Zidovudine

Indinavir, used for the treatment of HIV disease, forms distinctive crystals in the urine. The crystalluria has been associated principally with several urinary tract abnormalities which may require discontinuation of the drug. We present a case of progressive leucocyturia and renal impairment occurring during indinavir treatment which illustrates vividly the impact of the crystalluria on the tubulointerstitial renal compartment.

Topics: Adult; Crystallization; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Leukocytes; Nephritis, Interstitial; Urine

The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.. Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.. Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).. Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each--to varying degrees--associated with various metabolic disturbances.

Topics: Adipose Tissue; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Body Composition; Body Fat Distribution; Body Mass Index; Cholesterol; Cholesterol, HDL; Cyclopropanes; Extremities; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Intra-Abdominal Fat; Male; Reverse Transcriptase Inhibitors; Ritonavir; Thailand; Triglycerides

Lopinavir/ritonavir plus indinavir was administered once daily as directly observed protease inhibitor-only therapy in 12 heavily pretreated HIV-1-infected patients with multiple virological failures and advanced immunosuppression (CD4 cell count 95 x 10 cells/microl). The treatment was well tolerated. At weeks 12, 24 and 48, most patients on treatment achieved viral suppression of less than 400 copies/ml and a corresponding median CD4 T-cell count increase. Pharmacokinetic data indicated therapeutic concentrations for both protease inhibitors in most patients.

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Middle Aged; Patient Compliance; Pilot Projects; Pyrimidinones; Ritonavir; Treatment Outcome

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.

Topics: Adult; Aged; Anti-HIV Agents; Crystallization; Female; HIV Infections; Humans; Hydrogen-Ion Concentration; Indinavir; Male; Middle Aged; Specific Gravity; Urinalysis; Urine

Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PR(F53L) showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PR(F53L) was determined in the unliganded form at 1.35 Angstrom resolution in space group P4(1)2(1)2. The tips of the flaps in PR(F53L) had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50'. The changes in interactions between the flaps agreed with the reduced stability of PR(F53L) relative to wild-type PR. The altered flap interactions in the unliganded form of PR(F53L) suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants.

Topics: Catalytic Domain; Crystallography, X-Ray; Drug Resistance, Viral; Enzyme Stability; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; In Vitro Techniques; Indinavir; Kinetics; Ligands; Models, Molecular; Point Mutation; Protein Conformation; Static Electricity

We developed a novel HIV-1 dynamic model with consideration of pharmacokinetics, drug adherence and drug susceptibility to link plasma drug concentration to the long-term changes in HIV-1 RNA observation after initiation of therapy. A Bayesian approach is proposed to fit this model to clinical data from ACTG A5055, a study of two dosage regimens of indinavir (IDV) with ritonavir (RTV) in subjects failing their first protease inhibitor treatment. The HIV RNA testing was completed at days 0, 7, 14, 28, 56, 84, 112, 140, and 168. An intensive pharmacokinetic (PK) evaluation was performed on day 14 and multiple trough concentrations were subsequently collected. Pill counts were used to monitor adherence. IC(50) for IDV and RTV were determined at baseline and at virologic failure. Viral dynamic model fitting residuals were used to assess the significance of covariate effects on long-term virologic response. As univariate predictors, none of the four PK parameters C(trough), C(12 hour), C(max), and AUC was significantly related to virologic response (p > 0.05). By including drug susceptibility (IC(50)), or IC(50) and adherence measured by pill counts together, C(trough), C(12 hour), C(max) and AUC were each significantly correlated to long-term virologic response (p = 0.0055,0.0002,0.0136,0.0002 with IC(50) and adherence measured by pill counts considered). The IC(50) and adherence measured by pill counts alone were not related to the virologic response. In predicting virologic response adherence measured by pill counts did not provide any additional information to PK parameters (p = 0.064), to drug susceptibility IC(50) (p = 0.086), and to their combination (p = 0.22). Simple regression approaches did not detect any significant pharmacodynamic (PD) relationships. Any single factor of PK, adherence measured by pill counts and drug susceptibility did not contribute to long-term virologic response. But their combinations in viral dynamic modeling significantly predicted virologic response. The HIV dynamic modeling can appropriately capture complicated nonlinear relationships and interactions among multiple covariates.

Topics: Algorithms; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Bayes Theorem; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Indinavir; Models, Biological; Regression Analysis; Reverse Transcriptase Inhibitors; Ritonavir; T-Lymphocytes; Viral Load

Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therapeutic drug monitoring in patients with virological success but established nephrotoxicity on an indinavir-containing regimen.. We measured indinavir C(trough)/C(2h), serum creatinine, pyuria, blood pressure (BP), weight and HIV RNA. The major endpoint of interest was the number of patients achieving a normal creatinine level 20 weeks following final indinavir dose adjustment. Primary analysis was by intention to treat (ITT).. A total of 35 patients were enrolled; mean (SD) age 40.3 (5.8) years; mean (SD) BMI 21.5 (2.8) kg/m(2). At baseline 6/35 (17%) had a serum creatinine concentration within normal limits, but were offered enrolment because of previous nephrotoxicity (nephrolithiasis and/or abnormal serum creatinine), and a screening pharmacokinetic profile associated with increased nephrotoxicity risk. By ITT analysis 11/35 (31%) had normal creatinine at study end (P = 0.18). Of the 29 patients with abnormal creatinine at baseline, 7/29 (24.1%) had normal creatinine at study end (P = 0.016). Patients had a median (IQR) indinavir per dose adjustment over the study of 400 (400-800) mg. We observed improvements in estimated creatinine clearance, pyuria, resting BP and indinavir pharmacokinetic profile. HIV RNA control was maintained with continued immune recovery despite lower indinavir doses.. Patients experiencing nephrotoxicity on an indinavir-containing regimen were safely maintained on indinavir by means of therapeutic drug monitoring. Parameters of renal function improved but did not return to baseline values, at least in the short-term.

Topics: Adult; Blood Chemical Analysis; Blood Pressure; Body Weight; Creatinine; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney; Kidney Function Tests; Male; Middle Aged; Pyuria; RNA, Viral; Thailand

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

Mutation proI47A has recently been associated with lopinavir/ritonavir (LPV/r) resistance. Only four out of 1859 specimens (0.2%) sent for drug resistance testing (219 drug-naive and 1650 antiretroviral-experienced) showed I47A. All belonged to patients failing LPV/r. The prevalence among protease inhibitor-experienced patients was 0.6%. Phenotypic testing showed that proI47A caused high-level lopinavir resistance (> 100-fold) and cross-resistance to amprenavir, whereas it caused hypersusceptibility to saquinavir. ProI47A should thus be considered the primary lopinavir resistance mutation.

Topics: Carbamates; Codon; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Mutation; Nelfinavir; Phenotype; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides

Topics: Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Oxazines; Ritonavir; Treatment Outcome; Tuberculosis, Pulmonary

To investigate the association between the UGT1A1*6 (G71R) and UGT1A1*28 (promoter (TA)7-repeat) genotypes and hyperbilirubinaemia in Thai patients treated with indinavir, and characterize the inhibition of human UGTs by indinavir in vitro.. Ninety-six Thai HIV patients receiving indinavir, 800 mg t.i.d. or 800 mg b.i.d. "boosted" with ritonavir (100 mg b.i.d.), had serum bilirubin levels measured to 24 weeks post-treatment and were genotyped for UGT1A1*6 and UGT1A1*28. The inhibition selectivity and kinetics of indinavir were determined using a panel of recombinant human UGTs.. UGT1A1*6 and UGT1A1*28 frequencies in the Thai patients were 10.4% and 15.6%, respectively. Total, conjugated (direct) and unconjugated (indirect) serum bilirubin concentrations increased significantly at 24 weeks of indinavir treatment for all four genotypes, with a trend towards higher levels depending on the number of UGT1A1 mutant alleles; *6/*28 > *6 > *28 > reference. The hazards ratio (HR) for serious hyperbilirubinaemia (total bilirubin > 2.5 mg/dl) at week 24 was statistically significant only in those patients carrying the UGT1A1*6 (HR 2.87) and UGT1A1*6/*28 (HR 11.42) genotypes. The Ki values for indinavir inhibition of UGT1A1 and UGT1A1*6 were 4.1 and 10.7 mumol/l respectively. However, indinavir was also shown to inhibit other human UGTs, notably UGT1A3 and UGT1A7.. In contrast to Caucasian HIV-infected patients treated with indinavir, the promoter polymorphism (UGT1A1*28) is of less significance than the coding region (UGT1A1*6) mutation as a risk factor for hyperbilirubinaemia. The Ki values determined for indinavir inhibition of UGT1A1 are consistent with an interaction in vivo, with an additive effect in patients with already impaired bilirubin glucuronidation activity.

Topics: Adult; Bilirubin; Gene Frequency; Glucuronosyltransferase; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; In Vitro Techniques; Indinavir; Inhibitory Concentration 50; Polymorphism, Genetic; Promoter Regions, Genetic; Thailand

In HIV-infected persons on highly active antiretroviral therapy, residual virus is found in lymphoid tissues. Indinavir concentrations in lymph node mononuclear cells of patients on highly active antiretroviral therapy were approximately 25% to 35% of those in blood mononuclear cells, suggesting that drug insufficiency contributes to residual virus in lymphoid tissues. Therefore, we developed novel lipid-indinavir nanoparticles targeted to lymphoid tissues. Given subcutaneously, these nanoparticles provided indinavir concentrations 250% to 2270% higher than plasma indinavir concentrations in both peripheral and visceral lymph nodes. Improved indinavir delivery was reflected in reduced viral RNA and CD4(+) T-cell rebound. This study optimized lipid nanoparticle formulation with respect to indinavir in lymphoid tissues of HIV-infected macaques. Regardless of lipid characteristic tested (charge, fluidity, and steric modification), indinavir binds completely to lipid at pH 7.4 but is reversed at pH 5.5 or lower. Compared with previous formulations, nanoparticles composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine (DSPC:mPEG-DSPE) provided 6-fold higher indinavir levels in lymph nodes and enhanced drug exposure in blood. Enhanced anti-HIV activity paralleled improved intracellular drug accumulation. Collectively, these data suggest that indinavir nanoparticles composed of DSPC:mPEG-DSPE provided the most effective lymphoid delivery and could maximally suppress the virus in lymphoid tissues.

Topics: Animals; Anti-HIV Agents; CD4 Lymphocyte Count; Cell Line; Disease Models, Animal; Drug Carriers; HIV Infections; HIV-2; Hydrogen-Ion Concentration; Indinavir; Injections, Subcutaneous; Lipids; Lymph Nodes; Lymphoid Tissue; Macaca nemestrina; Nanostructures; Phosphatidylcholines; RNA, Viral; Tissue Distribution

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 microM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4(+) T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.

Topics: Animals; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Delivery Systems; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Microscopy, Electron, Scanning; Nanostructures; Nanotechnology; Tissue Distribution

The authors evaluated the pharmacokinetics and tolerability of indinavir/lopinavir/ritonavir in a protease inhibitor only combination.. Plasma drug levels of patients taking indinavir/lopinavir/ritonavir 800/400/100mg twice daily (n = 24, group 1) were compared to patients taking either lopinavir/ritonavir 400/100mg (n = 35, group2) or indinavir/ritonavir 800/100mg (n = 33, group3) twice daily plus nucleos(t)ide reverse transcriptase inhibitors (NRTI). Steady-state drug concentrations were measured by LC/MS/MS. Minimum and maximum concentrations (C subsetmin, C subsetmax), area under the concentration-time curve (AUC subset0-12h), total clearance (CL subsettot) and half-life (t1/2) were calculated. HIV viral load, CD4 cell count and adverse events causing early termination of therapy were correlated over a period of 48 weeks.. Plasma levels of lopinavir/ritonavir were significantly enhanced when combined with indinavir compared to a regimen of lopinavir/ritonavir+NRTI: Mean lopinavir AUC subset(0-12h) 80,912 ng*h/mL vs. 60,548 ng*h/mL; C subsetmin 4,633 ng/mL vs. 3,258 ng/mL; C subsetmax 8,023 ng/mL vs. 6,710 ng/mL. Mean ritonavir AUC(0-12h) 6,907 ng*h/mL vs. 3,467 ng*h/mL; Cmin 220 ng/mL vs. 125 ng/mL; C subsetmax 1,059 ng/mL vs. 522 ng/mL. Indinavir levels were comparable for both indinavir containing regimen. A significantly smaller number of patients stopped indinavir/lopinavir/ritonavir therapy (group1: 16.7%) than indinavir/ritonavir + NRTI treatment (group3: 45.5%) due to adverse events. Virological failure was the main reason for early termination of treatment with indinavir/lopinavir/ ritonavir before week 48 (group1: 50%).. indinavir/lopinavir/ritonavir 800/400/ 100mg twice daily represents a therapy option with an adequate safety but only short term efficacy for extensively pretreated patients.

Topics: Adult; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Mass Spectrometry; Maximum Tolerated Dose; Metabolic Clearance Rate; Pyrimidinones; Ritonavir; Viral Load

To evaluate the effects of combined antiretroviral drugs (HAART) on liver CYP3A4 activity using the [(14)C-N-methyl]-erythromycin breath test (ERMBT).. HIV-infected patients (31 women, 30 men) with mean (+/- SD) age of 38 +/- 9 years were enrolled and underwent complete clinical and laboratory evaluation. Patients were divided into five groups and were treated with two nucleoside analogues (NAs) and one of the following: nelfinavir alone (n = 13), any ritonavir-boosted protease inhibitor with (n = 8) or without (n = 13) nevirapine, nevirapine alone (n = 15), or a third NA (n = 12). Three or four ERMBTs were performed 7 days prior to (D-7) and at the beginning of treatment (D0), D14 (only for patients taking nevirapine) and on D28.. Mean baseline liver CYP3A4 activity displayed high interindividual variability (47%) but low intraindividual variability (15%). Women had 30% higher ERMBT values than men [2.7 +/- 1.3 vs. 1.9 +/- 0.7; 95% confidence interval (CI) 20.5, 49.5; P = 0.003]. The ERMBT data correlated with body weight, alpha- and beta-globulins and alanin aminotransferases (0.10 < r(s) < 0.20; P < 0.01). Whereas nevirapine had no effect on liver CYP3A4 activity, nelfinavir-based and ritonavir-boosted drug regimens inhibited it by 69% (95% CI 64.7, 72.9; P = 0.005) and by 95% (95% CI 93.3, 96.7; P = 0.001), respectively.. Evaluation of the effect of HAART on liver CYP3A4 activity may aid in preventing inappropriate treatment regimens in HIV-infected patients.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Breath Tests; Cohort Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Erythromycin; Female; HIV Infections; Humans; Indinavir; Liver; Male; Nelfinavir; Nevirapine; Ritonavir; Sex Factors

HIV-associated vasculitis is an infrequent entity, and only few data about its long-term evolution is available.. We report the long-term outcome of a patient with central nervous system HIV-associated periarteritis nodosa and then discuss the therapeutic options for this class of vasculitis.. This observation highlights the role of HAART in the treatment of HIV-associated vasculitis. Persistent remission can be obtained when viral replication is under control.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Central Nervous System Infections; Female; Follow-Up Studies; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Polyarteritis Nodosa; Stavudine; Time Factors; Treatment Outcome; Virus Replication; Zalcitabine

Topics: Adult; Aged; CD4 Lymphocyte Count; Cohort Studies; Female; Follow-Up Studies; HIV Infections; Humans; India; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir

Treatment with indinavir (IDV), a protease inhibitor, is frequently associated with renal abnormalities. We determined the incidence of renal failure (creatinine clearance <80 mL min-1 1.73 (m(2))-1) in HIV patients treated with highly active antiretroviral therapy, including IDV, and investigated the possible mechanisms and risk factors of IDV nephrotoxicity. Thirty-six patients receiving IDV were followed for 3 years. All were assessed for age, body weight, duration of infection, duration of IDV treatment, sulfur-derivative use, total cholesterol, triglycerides, magnesium, sodium, potassium, creatinine, and urinalysis. We also determined renal function in terms of creatinine clearance, urine osmolality and fractional excretion of sodium, potassium, and water. Urinary nitrate (NO3) excretion was measured in 18 IDV-treated patients and compared with that of 8 patients treated with efavirenz, a drug without renal side effects. Sterile leukocyturia occurred in 80.5% of the IDV-treated patients. Creatinine clearance <80 mL min-1 1.73 (m(2))-1 was observed in 22 patients (61%) and was associated with low body weight and the use of sulfur-derivatives. These patients also had lower osmolality, lower urine volume and a higher fractional excretion of water compared to the normal renal function group. Urinary NO3 excretion was significantly lower in IDV-treated patients (809 +/- 181 microM NO3-/mg creatinine) than in efavirenz-treated patients (2247 +/- 648 microM NO3-/mg creatinine, P < 0.01). The lower NO3 excretion suggests that IDV decreases nitric oxide production.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; Creatinine; Cyclopropanes; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Function Tests; Male; Middle Aged; Nitrates; Nitrites; Oxazines; Prospective Studies; Renal Insufficiency; Reverse Transcriptase Inhibitors; Risk Factors

To compare baseline susceptibility to protease inhibitors among HIV-1 isolates of subtypes C, F, G and CRF02_AG, and to identify polymorphisms that determine the differences in susceptibility.. A total of 42 samples of drug-naive patients infected with subtypes G (n=19), CRF02_AG (n = 10), F (n = 6) and C (n = 7) were phenotyped and genotyped with the Antivirogram and the ViroSeq 2.0 genotyping system, respectively. A Bayesian network approach was used for a preliminary analysis of the collected data and the dependencies indicated by the network were statistically confirmed.. CRF02_AG samples were found to be more susceptible to nelfinavir and ritonavir than other subtypes. Hypersusceptibility to these drugs was associated with the 70R polymorphism. 37D/S/T was associated with reduced susceptibility to indinavir and 89M with reduced susceptibility to lopinavir. Susceptibility to tipranavir was the lowest among the subtype F samples and the highest for subtype G samples, with samples carrying 57R being more susceptible than samples carrying 57K.. Our study suggests that there are baseline susceptibility differences between subtypes and these differences are due to naturally occurring polymorphisms in these subtypes. The predictive value for phenotype of these polymorphisms was even valid in subtypes where these polymorphisms are less prevalent. Taking into account such polymorphisms should improve current algorithms for interpretation of genotyping results in a subtype-independent way.

Topics: Algorithms; Bayes Theorem; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Models, Genetic; Nelfinavir; Phenotype; Polymorphism, Genetic; Pyridines; Pyrones; Ritonavir; Sulfonamides

Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.. Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.. Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.. ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Topics: Adult; Alkynes; Benzoxazines; Cohort Studies; Cyclopropanes; Female; Genetic Variation; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Male; Middle Aged; Nelfinavir; Orosomucoid; Oxazines; Phenotype; Pyrimidinones; Ritonavir; Switzerland

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Hepatitis; HIV Infections; Humans; Indinavir; Liver Function Tests; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

We have investigated whether chemotherapy for HIV-related systemic non-Hodgkin's lymphoma (NHL) affects the pharmacokinetics of protease inhibitors.. This was a prospective, open-label, non-randomized, two-way crossover trial in HIV-1-infected patients treated with highly active antiretroviral therapy and chemotherapy for NHL. Seven patients received indinavir at a dosage of 800 mg three times daily and three patients received nelfinavir at a dosage of 750 mg three times daily. Chemotherapy consisted of adriamycin, cyclophosphamide, vincristine and prednisolone (CHOP). Each patient had blood samples for protease inhibitor pharmacokinetics drawn concomitantly with or independently of the CHOP cycle.. When indinavir was given concomitantly with CHOP, the AUC(0-8) increased by 38% (20.5 +/- 9.0 versus 14.9 +/- 9.5 mg.h/L; P=0.03), and was comparable to historical controls. By contrast, the AUC(0-8) of indinavir administered without CHOP was lower than expected. A similar trend was observed with nelfinavir. Likewise, we observed a significant number of patients with C(0) and C(8) below the IC(50) for the wild-type virus (0.1 mg/L) when the drug was administered without CHOP.. Therapeutic drug monitoring of protease inhibitors should be part of the work-up in HIV-infected patients receiving chemotherapy for NHL.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cross-Over Studies; Cyclophosphamide; Doxorubicin; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nelfinavir; Prednisone; Prospective Studies; Vincristine

The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae. Term placentae (n = 5) were obtained from non-HIV-infected pregnant women. To investigate transport mechanisms, the steady-state transfer of indinavir was compared to those of antipyrine (a marker of passive diffusion) and [(3)H]vinblastine (a marker of P-glycoprotein [P-gp] transport) in the maternal-to-fetal and fetal-to-maternal directions in each placenta. Indinavir and antipyrine perfusate concentrations were determined by using reverse-phase, high-performance liquid chromatography; [(3)H]vinblastine concentrations were measured by liquid scintillation. The antipyrine transfer clearance in each direction did not differ (P = 0.76), a finding consistent with passive diffusion. However, the maternal-to-fetal transfer clearance of vinblastine, normalized to that of antipyrine (clearance index) (0.31 +/- 0.05), was significantly lower than the fetal-to-maternal clearance index of vinblastine (0.67 +/- 0.17; P = 0.017), suggesting the involvement of placental P-gp. Similarly, the maternal-to-fetal clearance index of indinavir (0.39 +/- 0.09) was significantly lower than its fetal-to-maternal clearance index (0.97 +/- 0.12; P < 0.001). These results represent the first evidence for differential transfer of a xenobiotic in the intact human placenta. The use of transport modulators to increase the maternal-to-fetal transfer of PIs as a possible strategy to reduce mother-to-child transmission of HIV warrants investigation.

Topics: Biological Transport; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Maternal-Fetal Exchange; Perfusion; Placenta; Pregnancy; Pregnancy Complications, Infectious

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Drugs, Generic; Female; HIV Infections; Humans; Indinavir; Male; Middle Aged; Ritonavir

Topics: Contraindications; Drug Labeling; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pregnancy; Pregnancy Complications, Infectious

The clearance of cytomegalovirus viraemia in HIV-1-infected patients may partly result from the inhibition of cytomegalovirus protease by HIV-1 protease inhibitors contained in highly active antiretroviral therapy. We used a computational method to calculate the binding affinity of six HIV-1 protease inhibitors to cytomegalovirus protease based on its X-ray crystallography structure. The calculations showed that amprenavir and indinavir occupy the substrate-binding site of the cytomegalovirus protease with high affinity, and may be implicated in alleviating cytomegalovirus infection.

Topics: AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Binding Sites; Carbamates; Crystallography, X-Ray; Cytomegalovirus; Cytomegalovirus Infections; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Structure; Peptide Hydrolases; Sulfonamides

The objective of this study was to evaluate HIV postexposure prophylaxis (PEP) protocol in rape victims.. The victims were assigned to 1 of 3 categories, according to the severity of exposure (I-low, II-moderate, III-high). HIV PEP was provided to victims in groups II (Zdv + 3TC) and III (Zdv + 3TC + PI) until 72 hours after exposure. The follow-up was 6 months.. From May 1997 to October 2001, 347 victims were attended. PEP was offered to 278 victims (141 in group II and 137 in group III). Side effects were more common in group III (P <0.01). No seroconversion was diagnosed in the 180 victims that completed the follow-up. Univariate analysis showed that the schooling level, knowledge of the aggressor's HIV status, and the use of PEP were associated with compliance.. Triple therapy was associated with side effects, which suggested that drug regimes should be reviewed. The variables related to a high risk of HIV transmission were also significant for compliance.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Brazil; Child; Child, Preschool; Cohort Studies; Drug Administration Schedule; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Nelfinavir; Patient Compliance; Prospective Studies; Rape; Sexually Transmitted Diseases; Zidovudine

Several studies suggest that therapeutic drug monitoring of protease inhibitors and nonnucleoside reverse transcriptase inhibitors may contribute to the clinical outcome of HIV-infected patients. Because of the growing number of antiretroviral drugs and of drug combinations than can be administered to these patients, an accurate high-performance liquid chromatographic (HPLC) method allowing the simultaneous determination of these drugs may be useful. To date, the authors present the first simultaneous HPLC determination of the new protease inhibitor atazanavir with all the others currently in use (M8 nelfinavir metabolite included) and the 2 widely used nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. This simple HPLC method allows the analysis all these drugs at a single ultraviolet wavelength following a 1-step liquid-liquid extraction procedure. A 500-muL plasma sample was spiked with internal standard and subjected to liquid-liquid extraction using by diethyl ether at pH 10. HPLC was performed using a Symmetry Shield RP18 and gradient elution. All the drugs of interest and internal standard were detected with ultraviolet detection at 210 nm. Calibration curves were linear in the range 50-10,000 ng/mL. The observed concentrations of the quality controls at plasma concentrations ranging from 50 to 5000 ng/mL for these drugs showed that the overall accuracy varied from 92% to 104% and 92% to 106% for intraday and day-to-day analysis, respectively. No metabolites of the assayed compounds or other drugs commonly coadministered to HIV-positive patients were found to coelute with the drugs of interest or with the internal standard. This assay was developed for the purpose of therapeutic monitoring (TDM) in HIV-infected patients.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Calibration; Carbamates; Chromatography, Liquid; Cyclopropanes; Drug Stability; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Specimen Handling; Spectrophotometry, Ultraviolet; Sulfonamides

Intensification therapy adding a boosted protease inhibitor (PI) to a failing regimen has the potential to worsen the resistance profile. Sixty-six patients included in four different boosted PI intensification studies were assessed and resistance mutations in the reverse transcriptase and protease genes were evaluated at baseline and 4 weeks after the initiation of the intensification strategy. Only one of the 66 patients developed changes in their pattern of mutations able to generate or increase resistance to new drugs.

Topics: Antiretroviral Therapy, Highly Active; Carbamates; Drug Resistance, Multiple, Viral; Follow-Up Studies; Furans; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lopinavir; Mutation; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides; Treatment Failure; Viral Load

Protease inhibitor based antiretroviral therapy (PI-ART) was introduced in 1996 and has greatly reduced the incidence of HIV-related morbidity and mortality in the industrialised world. PI-ART would thus be expected to have a positive effect on health-related quality of life (HRQL). On the other hand, HRQL might be negatively affected by strict adherence requirements as well as by short and long-term adverse effects. The aim of this study was to assess the influence of two years of first generation PI-ART on HRQL in patients with a relatively advanced state of HIV-infection. Furthermore, we wanted to investigate the relation between developments in HRQL and viral response, self-reported adherence and subjective experience of adverse effects in patients with PI-ART.. HRQL was measured by the Swedish Health-Related Quality of Life Questionnaire (SWED-QUAL). Sixty-three items from the SWED-QUAL forms two single-item and 11 multi-item dimension scales. For this study, two summary SWED-QUAL scores (physical HRQL composite score and emotional HRQL composite score) were created through a data reduction procedure. At the 2-year follow-up measurement (see below), items were added to measure adherence and subjective experience of adverse effects. Demographic and medical data were obtained from specific items in the questionnaires and from the medical files. Seventy-two patients who were among the first to receive PI-ART (indinavir or ritonavir based) responded to the questionnaire before the start of PI-ART. Of these, 54 responded to the same instrument after two years of treatment (13 had died, four had changed clinic and one did not receive the questionnaire).. The main findings were that the emotional HRQL deteriorated during two years of PI-ART, while the physical HRQL remained stable. Multiple linear regression analyses showed that experience of adverse effects contributed most to the deterioration of emotional HRQL.. In this sample of patients with relatively advanced state of HIV-infection, our data suggested that a negative development of physical HRQL had been interrupted by the treatment and that the emotional dimension of HRQL deteriorated during two years after start of PI-ART. Subjective experience of adverse effects made a major contribution to the decrease in emotional HRQL. The results underline the importance of including HRQL measures in the evaluation of new life prolonging therapies.

Topics: Adult; Aged; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Patient Compliance; Quality of Life; Reverse Transcriptase Inhibitors; Ritonavir; Sampling Studies; Sickness Impact Profile; Surveys and Questionnaires; Sweden; Time Factors; Treatment Outcome

To assess the steady-state pharmacokinetics of two reduced doses of indinavir boosted with ritonavir (indinavir/ritonavir) in HIV-infected Thai patients.. Thirteen immunocompromised antiretroviral-naive patients (6 males, 7 females) initiated 600/100 mg indinavir/ritonavir, zidovudine and lamivudine, every 12 h. After 1 month, blood samples were taken at pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h after drug intake. Indinavir dosing was then reduced to 400 mg (twice daily) and 1 week later an identical series of samples were drawn. Patients then resumed 600 mg of indinavir. HIV-1 RNA viral load was determined at 8, 24 and 48 weeks. Indinavir plasma levels were determined by HPLC and pharmacokinetic parameters by non-compartmental analysis.. Median (range) weight was 58 kg (51-73) for men and 53 kg (46-59) for women. On 600 mg of indinavir, median indinavir AUC, C(max), and C(min) were 39.3 mg.h/L (20.6-50.5), 6.2 mg/L (3.7-9.0) and 0.41 mg/L (0.12-0.77), respectively, and on indinavir 400 mg, 18.3 mg.h/L (11.1-33.0), 3.8 mg/L (2.2-7.8) and 0.17 mg/L (0.10-0.39), respectively. No renal complications were observed. At 48 weeks, 6/13 (46%) patients had stopped 600 mg of indinavir due to intolerability (gastrointestinal and cutaneous), and 5/7 (71%) patients had a HIV-1 viral load <50 copies/mL.. Reduced doses of indinavir/ritonavir maintained adequate indinavir plasma levels compared to current guidelines suggesting that these doses are efficacious in this setting. Considering the poor tolerability of 600 mg of indinavir, the 400 mg of indinavir may be preferred due to its lower exposure indices but long-term efficacy data are needed.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Male; Ritonavir; RNA, Viral

Simplification of combined antiretroviral therapy in HIV-infected patients is possible, but virological success can be compromised by the development or emergence of resistant viruses.. Worsening renal functioning in a patient under successful combination antiretroviral therapy resulted led to the replacement of indinavir by abacavir. Eight weeks later, his viral load rose and he developed a mutant virus resistant to all the nucleoside analogs.. Our case report illustrates the danger of streamlining combined antiretroviral therapy composed only of nucleoside analogs in patients already successfully treated with nucleoside analogs, by exposing them to the risk of the emergence of a mutant virus.

Topics: Aged; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Male; Mutation; Viral Load

During 2 periods between 1997 and 1999, the Aproco-Copilote (ANRS CO 008) cohort enrolled all HIV-infected patients who began antiretroviral therapy containing a PI in 47 French centers and who volunteered to participate (1281 patients) in order to describe and analyze their long-term clinical course and the benefits of treatment. Complete adherence (more than 95% of drugs actually taken) during the first 4 months of therapy appears crucial in maintaining virological response to therapy over time. Adherence depends on how patients experience the treatment but also on external factors such as their relationship with physicians and social workers. Virological failures were classified in two groups: those sensitive to the PI prescribed and related to poor adherence (no detectable PI) or patients with resistance related to pharmacokinetic issues (detectable but insufficient PI levels). Between April 1997 and May 2004, 118 patients died, and 188 episodes of AIDS and 1178 other severe events were recorded. Follow-up at 5 years was estimated at 90% and the probability of progression towards a new episode of AIDS 16%. Risk of AIDS onset was greatest during the first year and declined thereafter. Severe morbidity unrelated to AIDS or the side effects of treatment was frequent and gradually predominated. The only patients for whom AIDS was the most frequent severe morbidity were those who started treatment with CD4 cell counts < 50/mm3. The cumulative probability of a serious antiretroviral-induced adverse event (mainly hypertransaminasemia) was 30% at 5 years; 2/3 of these events occurred during the first 6 months of follow-up. Factors associated with the 169 events attributed to the first PI prescribed included: plasma HIV RNA >100,000 copies/ml, increased transaminase levels, creatinine clearance <70 ml/min, HCV or HBV co-infection, and prescription of indinavir. Other studies are underway on the associated factors specific to each of the events to delineate the respective roles of the virus, the treatments and other factors.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Cohort Studies; Creatine; Female; Follow-Up Studies; France; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Outcome Assessment, Health Care; Patient Compliance; Risk Factors; RNA, Viral; Transaminases

The third round of the International Interlaboratory Quality Control Program for Therapeutic Drug Monitoring in HIV infection (QC-program) consisted of the analysis not only of plasma samples but also of patient cases. The case was composed of different topics related to the therapeutic drug monitoring of antiretroviral drugs. The participants were asked to give recommendations concerning dose adjustments, changes to the regimen, and drug-drug interactions to observe whether the expert recommendations were comparable. Of the 30 participants of the QC-program, 16 returned their comments and recommendations with regard to the patient case. The drug level was easy to judge: approximately 90% were able to correctly do so. Almost half of the recommendations (44%) given were satisfactory. Levels of knowledge regarding HIV treatment appeared to be variable among the respondents and for this reason were partly incomparable.

Topics: Anti-Retroviral Agents; Carbamazepine; Drug Interactions; Drug Monitoring; Drug Resistance, Viral; HIV Infections; Humans; Indinavir; Nelfinavir; Nevirapine; Patient Compliance; Quality Control; Surveys and Questionnaires

HIV infection can be associated with different types of arthropathies which are often underdiagnosed. We present the case of a 52 year old HIV positive man on highly active antiretroviral therapy including indinavir who developed an acute painful oligoarthritis. We present this case on HIV associated arthritis and include a review on other HIV specific types of arthritis (acute symmetric arthritis and painful articular syndrome) which are assumed as entities exclusively apparent in HIV patients. The pathophysiology of arthritis in HIV infected patients is not yet completely understood but a direct role of the HIV on the initiation of synovitis is suspected in some of them. Additionally, there is evidence that antiretroviral drugs, in particular the protease inhibitor indinavir, can lead to arthritic complications as well.

Topics: Antiretroviral Therapy, Highly Active; Arthritis, Infectious; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Synovitis

Topics: Adult; Antihypertensive Agents; Area Under Curve; Bosentan; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Hypertension, Pulmonary; Indinavir; Male; Metabolic Clearance Rate; Sulfonamides

Angiogenesis is thought to play a major role in the development of Kaposi's sarcoma (KS), considered by many to be a hyperplastic disorder caused in part by local production of inflammatory cytokines. The antiangiogenic effects of protease inhibitors, in particular ritonavir, have been suggested in laboratory work to lead to regression of KS, and recent data have shown the importance of ritonavir as a model of pharmaceutical development. As our clinical cohort data has shown that non-nucleoside reverse transcriptase inhibitor-based regimens are not inferior to protease inhibitor-based therapy in the prevention of KS, we investigated the specific contribution of ritonavir to chemoprevention of this AIDS-defining illness. In a logistic regression analysis, we found that ritonavir-based therapy confers no advantages compared to other regimens in the prevention of KS. This is consistent with data suggesting that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Reverse Transcriptase Inhibitors; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

Since their introduction, hepatotoxicity has been associated with the use of human immunodeficiency virus (HIV)-1 protease inhibitors (PIs). However, the complexity of the HIV-infected patient and the combinations of medications used to treat HIV complicate the understanding of the independent effects of PIs in the development of drug-induced liver injury (DILI). I discuss the current understanding of PI-associated hepatotoxicity. Of the PI regimens studied, the greatest risk of DILI has been observed among patients receiving full-dose ritonavir. Similarly, hepatitis B and/or C virus coinfection has been associated with a greater risk of DILI, compared with those with no hepatitis. Although the specific mechanism by which viral hepatitis increases this risk is not known, patients with cirrhosis may have decreased cytochrome P450 activity, leading to increased PI exposure. Clearly, further research is needed to define the interaction of PIs and chronic viral hepatitis in the development of DILI.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Chemical and Drug Induced Liver Injury; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Indinavir; Oligopeptides; Pyridines

Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), as well as the TC:HDL-c ratio, were compared in patients receiving different antiretroviral therapy regimens. Patients receiving first-line regimens including protease inhibitors (PIs) had higher TC and TG levels and TC : HDL-c ratios than did antiretroviral-naive patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir-containing regimens were associated with higher TC and TG levels and TC : HDL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HDL-c levels, and receipt of saquinavir was associated with lower TC : HDL-c ratios. Patients receiving nonnucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naive patients, although the risk of having lower HDL-c levels was lower than that in patients receiving a single PI. Efavirenz was associated with higher levels of TC and TG than was nevirapine.

Topics: Adult; Anti-HIV Agents; Cholesterol; Coronary Disease; Cross-Sectional Studies; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Lipids; Logistic Models; Male; Prospective Studies; Ritonavir; Saquinavir; Triglycerides

A simple, fast and reliable capillary electrophoresis (CE) method for determination of indinavir sulfate, a potent protease inhibitor used in human immunodeficiency virus (HIV) therapy, in commercial and simulated capsule formulations is described. The analysis was performed in a 75microm i.d. uncoated fused-silica capillary with 27cm length (effective length of 19.4cm) using a 20mmoll-1 phosphate buffer at pH 2.52. Samples were injected hydrodynamically by applying 0.5psi pressure during 2s. The applied voltage was 28kV. Direct UV detection at 214nm led to an adequate sensitivity without interference from sample excipients and known impurities. For quantitative purposes, diazepam was used as internal standard. Under optimized conditions, the migration times for indinavir sulfate and diazepam were 1.06 and 1.66min, respectively. Analytical curve of peak area ratios versus concentration in the range of 20.0-100.0microg/ml gave a coefficient of correlation of 0.9992, establishing the method linearity. The limits of detection and quantitation were 4.61 and 14.0microg/ml, respectively. The within-day precision expressed as relative standard deviation was <1.5% for 10 consecutive sample injections. An average recovery of 100.81+/-0.56% at three concentration levels was obtained. Based on the performance characteristics, the proposed methodology was found suitable for the determination of indinavir sulfate in capsule formulations, presenting additional advantages inherent to the CE technology, such as low consumption of reagents and column endurance.

Topics: Chemistry, Pharmaceutical; Electrophoresis, Capillary; HIV Infections; HIV Protease Inhibitors; Indinavir

We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Viremia

The incidence of HIV-1-related infection diseases and the mortality of AIDS have dramatically decreased since highly active antiretroviral therapy began to be used clinically in China in 1999. And we initiated a second clinical trial using a combination of Efavirenz and Indinavir to observe the effects of the immunoreaction.. Twenty patients with laboratory-confirmed chronic HIV-1 infection were recruited. Blood samples were collected initially and during the weeks after initiation of treatment. Within 48 hours of blood sampling, peripheral blood plasma and mononuclear cells were separated using routine methods. HIV-1 viral load was measured in thawed plasma samples. Within 48 hours of peripheral blood sampling, CD4(+) and CD8(+) T cell subsets were enumerated.. The drug regimen was efficient in reducing HIV-1 plasma viral load and increasing total CD4(+) T cell counts. The percentage of CD4(+) and CD8(+) T cell subsets expressing CD38 and HLA-DR activation markers was positively correlated with plasma viral load and tended to normalize.. The combination of Efavirenz and Indinavir was generally well tolerated and efficient at reducing HIV-1 RNA. Furthermore, the treatment improved the immunological function.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adult; Aged; Alkynes; Anti-HIV Agents; Antigens, CD; Benzoxazines; CD4-CD8 Ratio; Chronic Disease; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HLA-DR Antigens; Humans; Indinavir; Male; Membrane Glycoproteins; Middle Aged; Oxazines; Viral Load

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Pilot Projects; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral

Topics: Adult; Antiretroviral Therapy, Highly Active; Blepharitis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Recurrence

So far, no pediatric doses for indinavir combined with ritonavir have been defined. This study evaluated the pharmacokinetics of 400 mg of indinavir/m(2) combined with 125 mg of ritonavir/m(2) every 12 h (q12h) in 14 human immunodeficiency virus type 1-infected children. The area under the concentration-time curve from 0 to 24 h and the minimum concentration of drug in serum for indinavir were similar to those for 800 mg of indinavir-100 mg of ritonavir q12h in adults, while the maximum concentration of drug in serum was slightly decreased, with geometric mean ratios (90% confidence intervals in parentheses) of 1.1 (0.87 to 1.3), 0.96 (0.60 to 1.5), and 0.80 (0.68 to 0.94), respectively.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Child; Child, Preschool; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Prospective Studies; Ritonavir

Topics: Antibiotics, Antitubercular; CD4 Lymphocyte Count; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Rifampin; Tuberculosis; Viral Load

Topics: Adult; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lipodystrophy; Male; Reverse Transcriptase Inhibitors; Zidovudine

Lamivudine is now available as 300 mg tablets for once-a-day treatment of HIV-infected adults. In HIV-infected adults, 300 mg lamivudine in a single daily dose has similar efficacy to 150 mg lamivudine in two daily doses. The 300-mg tablets may make treatment more convenient.

Topics: Adult; Child; Drug Therapy, Combination; France; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Protease Inhibitors; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

The introduction of the so-called highly active antiretroviral therapies has had an impact on the natural history of the HIV infection. The aim of this contribution is to assess the differences in terms of plasma viral load (VL), as a reflection of therapy success or failure. A retrospective study was made of the changes in VL in two cohorts of patients depending on the drugs included in the triple therapy prescribed to them. The comparison of the triple therapies containing any reverse transcriptase inhibitor and different protease inhibitors, indinavir (IDV) (239 patients) versus saquinavir (SQV) or ritonavir (RTV) (138 subjects), showed a significantly higher percentage of patients reaching a 'non-detectable' VL among those receiving indinavir (67.8% versus 54.3%; P = 0.011). The interval before VL levels rose above 30,000 RNA copies/ml was different in the two groups: 385 days (276-495 days) for therapies including indinavir, and 239 days (86-391 days) for saquinavir or ritonavir. This seems to support the excellent behaviour of indinavir when its efficiency is compared with other protease inhibitors acting as potential competitors.

Topics: Antiretroviral Therapy, Highly Active; Cohort Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Retrospective Studies; Ritonavir; Saquinavir

There is evidence to suggest a pharmacokinetic-pharmacodynamic relationship in HIV-infected patients receiving protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART); however, the effective trough PI plasma concentrations achieved have not been precisely determined.. The relationship between HIV viral load and concomitant PI trough plasma concentration (C(trough)) was evaluated in 101 patients receiving at least 4 months of thrice daily indinavir (IDV)-containing (n=68) or nelfinavir (NFV)-containing (n=33) HAART. The more discriminating C(trough) efficacy thresholds were determined statistically for each PI by using the raw C(trough) and the time-corrected C(trough), using the precise delay since the last PI intake and the half-life of each PI.. For IDV (P=0.002) and NFV (P=0.019) median C(trough) levels were higher in patients with undetectable viral load [0.23 mg/L (n=30) and 2.3 mg/L (n=16) respectively] than in patients with detectable viral load [0.11 mg/L (n=38) and 0.6 mg/L (n=17) respectively]. C(trough) levels of IDV (r=-0.45; P<0.0001) and NFV (r=-0.43; P=0.011) were correlated with the concomitant viral load. The more discriminating C(trough) efficacy thresholds were estimated statistically as 0.12 mg/L for IDV and 0.5 mg/L for NFV. When C(trough) values were time-corrected, the C(trough) efficacy thresholds, 8 h after the last intake, were 0.15 mg/L for IDV and 0.65 mg/L for NFV.. These results support the importance of achieving minimal effective C(trough) to improve the virological efficacy of PI-containing HAART, and specify the target concentrations for IDV and NFV.

Topics: Antiretroviral Therapy, Highly Active; Chi-Square Distribution; Drug Monitoring; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Retrospective Studies; Treatment Outcome; Viral Load

Topics: Hair Diseases; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; Hyperpigmentation; Indinavir; Male; Nail Diseases

Risk factors associated with the occurrence of protease inhibitor (PI)-related severe and serious adverse drug reactions (SADRs) were analyzed in a prospective cohort of 1155 patients who initiated PI-containing therapy. During a total follow-up of 2037 patient-years, 169 SADRs were reported, yielding a rate of 8 incidents per 100 patient-years (95% confidence interval [CI], 6.8-8.6). The most frequent SADRs were elevated transaminase levels (in 49 events); renal colic (27); abnormal hematological findings (23); and metabolic (18), neuromuscular (7), pancreatic (6), cutaneous (6), cardiovascular (5), and psychiatric disorders (5). Among baseline characteristics, plasma human immunodeficiency virus RNA levels of >or=5 log(10) copies/mL (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2), elevated aspartate aminotransferase levels (HR, 1.1 for each 20 IU of elevation; 95% CI, 1.1-1.2), creatinine clearance levels of <70 mL/min (HR, 2.1; 95% CI, 1.2-3.7), test results positive for hepatitis C virus antibodies or hepatitis B surface antigenemia (HR, 2.6; 95% CI, 1.8-3.7), and receipt of indinavir (HR, 1.7; 95% CI, 1.2-2.4) were independently predictive of a SADR. SADRs were frequent in the first 4 months after initiation of highly active antiretroviral therapy but continued to occur after that time period.

Topics: Adult; Colic; Female; Hepatitis, Viral, Human; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Indinavir; Kidney Diseases; Male; Probability; Prospective Studies; Renal Insufficiency; Risk Factors; Time Factors; Transaminases

Topics: Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Middle Aged; Pyrimidinones; Ritonavir; Thrombocytopenia

The purpose of this study was to investigate placental transfer and amniotic fluid concentrations of protease inhibitors when they are given to pregnant women who are infected with human immunodeficiency virus.. Fifty-eight mothers who received antiretroviral therapy that included > or =1 protease inhibitors for clinical indications at the time of delivery were enrolled in the study. Maternal blood samples and amniotic fluid were obtained during delivery or cesarean delivery, and paired cord blood samples were obtained by venipuncture immediately after the delivery. Drug concentrations were measured with high performance liquid chromatography.. Most maternal protease inhibitor plasma concentrations (38/66 concentrations) were below the trough concentrations that are recommended for therapeutic drug monitoring. Cord blood concentrations were below the assay limit of detection in 10 of 40 samples for nelfinavir and 25 of 40 samples for its metabolite M8, 9 of 11 samples for ritonavir, 4 of 6 samples for indinavir, 5 of 6 samples for saquinavir but were detectable in 3 of 3 samples for amprenavir. Among the 24 amniotic fluid samples that were available, the concentrations below the detection limit were 10 of 16 samples for nelfinavir, 11 of 16 samples for M8, 1 of 3 samples for indinavir, 4 of 4 samples for ritonavir, and 0 of 1 samples for amprenavir. There were significant correlations between cord blood and maternal concentrations of nelfinavir and its metabolite M8.. Placental transfer of the human immunodeficiency virus protease inhibitors is generally low; however, it may differ greatly according to the molecule.

Topics: Adult; Amniotic Fluid; Carbamates; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Maternal-Fetal Exchange; Nelfinavir; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Saquinavir; Sulfonamides

Topics: Aneurysm, False; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Femoral Artery; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Middle Aged; Oligopeptides; Postoperative Hemorrhage; Pyridines; Streptococcal Infections; Ultrasonography, Doppler, Color; Vascular Surgical Procedures

To report a case of indinavir-induced urolithiasis, and the greater risk of this occurrence in individuals with spinal cord injury (SCI) who require fluid restriction for an intermittent catheterization program (ICP).. Case report.. A 38-year-old man with a T4 ASIA A SCI (according to the American Spinal Injury Association classification scale) and human immunodeficiency virus (HIV) infection was using an ICP and taking indinavir (a protease inhibitor) as part of his antiviral regimen. Cystoscopy was performed to rule out recurrent urethral condylomata. He was found to have a bladder stone measuring 0.5 cm x 0.5 cm x 0.3 cm, which, on analysis, was composed of indinavir (100% exterior, 90% interior). The bladder stone was removed under direct visualization. The plain abdominal radiograph did not reveal any stones.. Indinavir is a frequently used drug for the treatment of HIV that has the potential to induce urinary lithiasis. This is particularly problematic for individuals with SCI who are on fluid restriction and an ICP. Therefore, cystoscopy and monitoring for indinavir-induced urolithiasis should be undertaken in individuals with SCI who are taking indinavir. Considerations include switching to a different protease inhibitor or choosing an entirely new HIV drug cocktail with less potential for urolithiasis.

Topics: Adult; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Spinal Cord Injuries; Urinary Bladder Calculi; Urinary Catheterization

Residual analysis is a useful class of techniques for the evaluation of the goodness of a fitted model. Checking the underlying assumptions is important since most linear regression estimators require a correctly specified regression function and independent and identically distributed errors to be consistent. For uncensored data, the examination of the residuals of the fitted model is a standard tool for checking whether or not the underlying model assumptions hold. Such analysis has not been widely developed for censored data. Hillis (Statistics in Medicine 1995; 14:2023-2036) developed a residual plot for model checking when the response variable of a linear model is right-censored, and Gomez et al. (Statistics in Medicine 2003; 22:409-425) proposed residuals in models with interval-censored covariates. In this paper, we propose a new definition of residuals for linear models that incorporate interval-censored covariates. This definition can be also applied when the response variable is interval-censored. These new residuals are shown to perform better in model checking than other types of residuals in this context. We illustrate them with a data set from an AIDS clinical trial study.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV; HIV Infections; Humans; Indinavir; Likelihood Functions; Linear Models; Models, Biological; Multivariate Analysis; Time Factors; Treatment Failure

HIV-1 infection is associated with serious cardiovascular complications, but the roles of HIV-1, viral proteins, and highly active antiretroviral therapy (HAART) drugs are not understood. HAART decreases the overall risk of heart disease but leads to metabolic disturbances and possibly coronary artery disease. We investigated toxicities of HIV-1, HIV-1 glycoprotein 120 (gp120), and HAART drugs for human coronary artery endothelial cells (CAECs), brain microvascular endothelial cells, and neonatal rat ventricular myocytes (NRVMs). HIV-1 and gp120, but not azidothymidine (AZT), induced apoptosis of NRVMs and CAECs. Ethylisothiourea, an inhibitor of nitric oxide synthase, inhibited apoptosis induction by gp120. AZT, HIV-1, and gp120 all damaged mitochondria of cardiomyocytes. HAART drugs, AZT, and indinavir, but not HIV-1, produced intercellular gaps between confluent endothelial cells and decreased transendothelial electrical resistance. In conclusion, HIV-1 and gp120 induce toxicity through induction of cardiomyocyte and endothelial cell apoptosis. HAART drugs disrupt endothelial cell junctions and mitochondria and could cause vascular damage.

Topics: Animals; Animals, Newborn; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Apoptosis; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Drug Combinations; Electric Impedance; Endothelial Cells; Endothelium, Vascular; Gap Junctions; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Indinavir; Mitochondria, Heart; Myocytes, Cardiac; Thiourea; Zidovudine

To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.. Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy.. The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.. The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.. Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.

Topics: Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Chronic Disease; Drug Therapy, Combination; Female; Hepatitis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Lopinavir; Male; Nelfinavir; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Saquinavir; Treatment Outcome

Interval-censored observations of a response variable are a common occurrence in medical studies, and usually result when the response is the elapsed time until some event whose occurrence is periodically monitored. In this paper we consider a multivariate regression setting in which the explanatory variable is interval censored. Use of an ad hoc method of analysis for such data, such as taking the midpoint of the interval-censored covariate and applying ordinary least-squares, is not in general valid. We develop a likelihood approach, together with a two-step conditional algorithm, to jointly estimate the regression coefficients as well as the marginal distribution of the covariate. The resulting estimators are asymptotically normal. The performance of the method is assessed via simulations, and illustrated using data from a recent HIV/AIDS clinical trial to assess the association between waiting time between indinavir failure and subsequent viral load at enrolment. Extensions of the procedure to other parametric distributions are discussed.

Topics: Adult; Computer Simulation; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Likelihood Functions; Linear Models; Middle Aged; Multivariate Analysis; Recurrence; Statistics as Topic; Viral Load

Symptomatic nephrotoxicity is a well-known complication of indinavir treatment. However, little is known about the relevance of other abnormalities, such as leukocyturia during use of indinavir. We determined the prevalence, risk factors, and consequences of persistent leukocyturia in a prospectively monitored cohort of indinavir users in three adult outpatient clinics. Patients were monitored for nephrotoxicity at regular visits (every 3 months) between August 1998 and September 2000. Monitoring involved urine dipstick analysis and microscopy for pH, erythrocytes, leukocytes, and indinavir crystals. The urine albumin concentration/creatinine concentration ratio and serum creatinine and indinavir plasma concentrations were measured, and urinary tract infection was excluded. Urologic symptoms were retrieved from medical records. Of 184 patients with at least one assessment, 35% had leukocyturia (i.e., >75 cells/microL) at least once during the study period, which coincided with mild increase in the serum albumin level, erythrocyturia, and crystalluria. Thirty-two (24%) of 134 patients with two or more assessments had persistent leukocyturia (i.e., on two or more occasions). Risk factors were indinavir plasma concentration of >9 mg/L, urine pH of >5.7, and crystalluria. Persistent leukocyturia was associated with a gradual loss of renal function but not with urologic symptoms. The data show that leukocyturia is a frequent finding and emphasize the need for monitoring renal function during indinavir treatment, even in the absence of urologic symptoms.

Topics: Adult; Albuminuria; Cohort Studies; Creatinine; Crystallization; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydrogen-Ion Concentration; Indinavir; Kidney Diseases; Leukocytosis; Male; Middle Aged; Prospective Studies; Risk Factors

The authors assessed CSF and plasma HIV-1 RNA and neuropsychological test performance (composite neuropsychological test Z score [NPZ-4]) in 25 HIV-1-infected subjects 4 and 8 weeks after beginning potent antiretroviral therapy that included a protease inhibitor. In the 14 subjects who entered the study on no antiretroviral treatment, NPZ-4 improvement was associated with decline in CSF HIV-1 RNA at both visits (p = 0.001 and p = 0.02), and those treated with zidovudine or indinavir had greater improvement in NPZ-4 at both visits compared to those treated with other drugs (p = 0.003 and p = 0.01).

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cognition Disorders; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Neuropsychological Tests; RNA, Viral; Time Factors; Viral Load; Viremia; Zidovudine

Topics: CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; Homosexuality, Male; Humans; Indinavir; Male; Middle Aged; Thrombocytopenia

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Oxazines; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Viral Load; Viremia; Zidovudine

A reversed-phase high-performance liquid chromatography method for the simultaneous quantitative determination of the currently available HIV protease inhibitors amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, the active nelfinavir metabolite M8, and the nonnucleoside reverse transcriptase inhibitor nevirapine in human plasma is described. The method involved liquid-liquid extraction from plasma, followed by high-performance liquid chromatography with an OmniSpher 5 C18 column and ultraviolet detection set at a wavelength of 215 nm for the protease inhibitors and 280 nm for nevirapine. The runtime was 25 minutes. The assay has been validated over the concentration range of 0.05 to 30 mg/L for indinavir, nelfinavir, ritonavir, and saquinavir, 0.07 to 30 mg/L for amprenavir and lopinavir, and 0.05 to 15 mg/L for M8 and nevirapine. This method proved to be simple, accurate, and precise and is useful for the therapeutic drug monitoring of protease inhibitors and the nonnucleoside reverse transcriptase inhibitor nevirapine on a routine basis.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Chromatography, High Pressure Liquid; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir

To assess the contribution of the determination of concentrations of indinavir (IND) in plasma to the assessment of self-reported adherence and keeping of appointments to withdraw drugs from the hospital pharmacy.. Adherence was assessed using three criteria: questionnaires, punctuality at appointments to withdraw drugs, and plasma concentrations of IND. Blood samples were obtained from 106 HIV-infected patients who had been receiving IND in combination with two nucleoside reverse transcriptase inhibitors for longer than 6 months. Logistic regression analysis was carried out, and receiver operating characteristic curves were drawn.. The kappa index showed a low concordance for the three measures. When pharmacy appointments and self-report are used together, the nondetection of drug levels is more reliably predicted (AUC = 0.75). With the viral load as the gold standard, plasma levels contribute nothing to the information given by the other two measures combined (AUC = 0.63, AUC = 0.64).. Measurement of adherence to highly active antiretroviral therapy is complex. Because there is no gold standard for it, we demonstrated that each of three common adherence measures has shortcomings that can be minimized in a combined measurement system. Indinavir plasma levels appear to provide no additional information, so further studies are undoubtedly necessary.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Patient Compliance; Pharmacy; ROC Curve; Surveys and Questionnaires

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Diabetes Insipidus, Nephrogenic; HIV Infections; Humans; Indinavir; Lamivudine; Male; Ritonavir; Stavudine

Recent evidence suggests that as a group protease inhibitors (PIs) may accelerate certain factors associated with atherosclerosis. The objective of this study was to evaluate the effect of individual PIs (indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) on certain factors associated with atherosclerosis. Persons who took saquinavir and/or ritonavir were compared with those on other PIs. Between May 2000 and July 2001, the lipid profiles, C-reactive protein (CRP) levels, coronary artery calcium (CAC) scores, and blood cell morphologic parameters were measured in 98 black adult participants aged 25 to 45 years with HIV-1 infection in Baltimore, Maryland. Among these 98, there were 55 (56.1%) taking PIs. Students' t-test and chi2 test were used to detect the between-group differences. Study participants in both the PI and non-PI groups were similar in age, sex, body mass index, blood pressure, red and white blood cell counts, time since HIV diagnosis, and duration on anti-retroviral therapy. Compared with those who took non-PI regimens, those who took indinavir, nelfinavir, or saquinavir had significantly higher levels of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Those taking any PI had significantly higher total cholesterol and low-density lipoprotein. Those taking nelfinavir, ritonavir, or saquinavir were more likely to have a higher CAC score (>5) than those on non-PI regimens. There were no differences in the lipid profiles, MCV, MCH, CRP, and CAC between those taking saquinavir and/or ritonavir and those taking other PIs. Overall, the changes noted might lead to anticipation of clinical changes linked to accelerated atherosclerosis in patients on PIs.

Topics: Adult; Arteriosclerosis; Biomarkers; Black People; C-Reactive Protein; Calcium; Cholesterol; Coronary Artery Disease; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Nelfinavir; Pyrimidinones; Ritonavir; Saquinavir

Protease inhibitor (PI)-based combination antiretroviral therapy is often indicated for treatment of maternal HIV disease, but little is known about PI pharmacokinetics during pregnancy. Increased cytochrome P450 activity may affect the disposition of PI and decrease drug exposure.. Steady-state PI pharmacokinetics, measured by the area under the plasma concentration versus time curve (AUC(tau)), were evaluated in women on stable antiretroviral regimens containing nelfinavir (n = 9) or indinavir (n = 4) with or without ritonavir (n = 2) during the second and third trimesters of pregnancy and postpartum. Cytochrome P450 activity was assessed by measuring the urine 6 beta-hydroxycortisol to cortisol ratio (6 beta-OHF/F).. AUC(tau) in women on indinavir alone decreased and 6 beta-OHF/F ratios increased during pregnancy compared with postpartum control values (n = 2). Nelfinavir results demonstrated no clear change and were highly variable.. The results for indinavir suggest that metabolic induction occurs during pregnancy, which apparently resolves spontaneously postpartum. This may warrant dosage adjustment during pregnancy. This induction is offset by concomitant use of ritonavir. Nelfinavir results were variable and, therefore, the impact of pregnancy on nelfinavir disposition was not fully determined.

Topics: Adult; Female; Gestational Age; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydrocortisone; Indinavir; Nelfinavir; Pregnancy; Pregnancy Complications, Infectious; Viral Load

In survival studies, information lost through censoring can be partially recaptured through repeated measures data which are predictive of survival. In addition, such data may be useful in removing bias in survival estimates, due to censoring which depends upon the repeated measures. Here we investigate joint models for survival T and repeated measurements Y, given a vector of covariates Z. Mixture models indexed as f (T/Z) f (Y/T,Z) are well suited for assessing covariate effects on survival time. Our objective is efficiency gains, using non-parametric models for Y in order to avoid introducing bias by misspecification of the distribution for Y. We model (T/Z) as a piecewise exponential distribution with proportional hazards covariate effect. The component (Y/T,Z) has a multinomial model. The joint likelihood for survival and longitudinal data is maximized, using the EM algorithm. The estimate of covariate effect is compared to the estimate based on the standard proportional hazards model and an alternative joint model based estimate. We demonstrate modest gains in efficiency when using the joint piecewise exponential joint model. In a simulation, the estimated efficiency gain over the standard proportional hazards model is 6.4 per cent. In clinical trial data, the estimated efficiency gain over the standard proportional hazards model is 10.2 per cent.

Topics: Algorithms; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Computer Simulation; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Longitudinal Studies; Models, Biological; Proportional Hazards Models; Randomized Controlled Trials as Topic; Survival Analysis

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

Topics: Adult; Drug Hypersensitivity; Female; Guideline Adherence; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Needlestick Injuries; Occupational Diseases; Occupational Exposure; Zidovudine

To evaluate the long-term efficacy and pharmacokinetics of indinavir (IDV)/ritonavir (RTV) 400/100 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors.. The study was retrospective with a prospective pharmacokinetic study at a single centre. All HIV-1-infected patients who started the regimen in the period from January 1999 to February 2001 were included in the study. Plasma HIV RNA and CD4 cell counts were recorded from baseline to week 120. Results were evaluated as intention-to-treat and on-treatment analyses with separate analyses for protease inhibitor naive and experienced patients. Patients who were still on the regimen by August 2001 were asked to participate in a pharmacokinetic evaluation.. Twenty-one patients started treatment with the regimen (median follow-up: 116 weeks). The percentage of patients with below 20 HIV-1 RNA copies/mL was 70.0% at week 120 and the median CD4 cell count increased from 320 to 607 cells/microL (P=0.062). The median IDV morning and evening Cmin were 434 ng/mL and 220 ng/mL, respectively.. Treatment with the IDV/RTV 400/100 mg regimen appears to be efficacious for up to 2 years. However, rather low IDV Cmin suggests that the regimen should be evaluated further before its widespread use and that the regimen probably should be guided by pharmacokinetic evaluation.

Topics: Adolescent; Adult; Aged; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Retrospective Studies; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Virological failure under protease inhibitor (PI)-based antiretroviral regimens is often not explained by the selection of resistance mutations. The role of low indinavir (IDV) plasma levels in treatment failure was assessed in 46 subjects experiencing early virological failure to a first-line IDV-containing triple combination. Overall, 69% of patients showed subtherapeutic IDV plasma levels (it was not detected at all in 75% of them). Subjects with detectable but suboptimal IDV levels developed more IDV resistance mutations. Thus, drug monitoring may be useful to assess treatment adherence and risk of drug resistance in early virological failures. This information may be crucial for choosing the most appropriate rescue intervention.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Mutation; Reverse Transcriptase Inhibitors; Treatment Failure

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Oxazines; Ritonavir; Thailand; Viral Load

OBJECTIVE To determine the rate of virological rebound and factors associated with rebound among patients on highly active antiretroviral therapy (HAART) with previously undetectable levels of viraemia. DESIGN An observational cohort study of 2444 patients from the EuroSIDA study. METHODS Patients were followed from their first viral load under 400 copies/ml to the first of two consecutive viral loads above 400 copies/ml. Incidence rates were calculated using person-years of follow-up (PYFU), Cox proportional hazards models were used to determine factors related to rebound. RESULTS Of 2444 patients, 1031 experienced virological rebound (42.2%). The incidence of rebound decreased over time; from 33.5 in the first 6 months after initial suppression to 8.6 per 100 PYFU at 2 years after initial suppression (P < 0.0001). The rate of rebound was lower for treatment-naive compared with treatment-experienced patients. In multivariate models, patients who changed treatment were more likely to rebound, as were patients with higher viral loads on starting HAART. Treatment-naive patients were less likely to rebound. Among pretreated patients, those who were started on new nucleosides were less likely to rebound. CONCLUSION The rate of virological rebound decreased over time, suggesting that the greatest risk of treatment failure is in the months after initial suppression. Treatment-naive patients were at a lower risk of rebound, but among drug-experienced patients, those who added new nucleosides had a lower risk of rebound, as were patients with a good immunological response.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Europe; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Failure; Viral Load; Viremia

This paper develops methods for using HIV-1 genotypic information to group patients who are expected to have similar patterns of sensitivity or resistance to two or more drugs. The methods presented are an extension of prediction based classification to handle multiple drug responses. Here, the goal is to determine the probability that one antiretroviral therapy will be more favourable than another for an individual given the specific genotypic or other characteristics of the infecting viral population. This approach requires a model relating genotype to a vector of drug specific phenotypic responses. A comparison of Nelfinavir and Indinavir is provided using 2746 protease sequences and corresponding in vitro sensitivity assays provided to us by the Virco Group.

Topics: Amino Acid Sequence; Anti-HIV Agents; Cluster Analysis; Genotype; HIV Infections; HIV-1; Humans; Indinavir; Models, Genetic; Models, Statistical; Molecular Sequence Data; Nelfinavir

To study changes in indinavir exposure over time in HIV-1-infected children.. Protease inhibitor (PI)-naive HIV-1-infected children were treated with indinavir, zidovudine and lamivudine. Steady-state plasma pharmacokinetic (PK) sampling was carried out as standard of care. The AUC(0-8) was targeted between 15 and 30 mg h/L. PK sampling was repeated after dosage adjustment until the AUC(0-8) reached target values. Patients were included when the time interval between PK samplings was > or =2 years and differences in dosage/m2 <10% between PK samplings 1 and 2. Corrections of dose for changes in body size were carried out.. Six children were enrolled with a median age of 5.2 years (range 1.7-13.6 years). All had a viral load below 500 copies/mL. The geometric mean (GM) of the AUC(0-8) decreased from 25.3 mg h/L at the first PK-day to 19.1 mg h/L at the second PK-day [geometric mean ratio (GMR): 0.76 (95% C.I.: 0.48-1.20)]. The GM of Cmax decreased from 11.8 to 10.4 mg/L [GMR: 0.88 (95% C.I.: 0.59-1.32)]. The GM of Cmin decreased from 0.08 to 0.07 mg/L [GMR: 0.86 (95% C.I.: 0.62-1.18)]. All children had an AUC(0-8) above 15 mg h/L on the first PK-day; three had an AUC(0-8) below 15 mg h/L on the second PK-day. In two of these three children, the plasma viral load was >500 copies/mL.. Changes in indinavir exposure were observed over time. In two patients, decreased indinavir exposure was associated with virological failure. Therapeutic drug monitoring should be carried out over time since this may prevent subtherapeutic dosing in children.

Topics: Adolescent; Area Under Curve; Case-Control Studies; Child; Child, Preschool; Female; HIV Infections; HIV-1; Humans; Indinavir; Infant; Male; Time Factors

Indinavir (IDV) is a protease inhibitor that successfully suppresses HIV-1 replication as part of anti-retroviral therapy. There is evidence to suggest that IDV may also act non-specifically upon host proteases. In this study we investigated whether IDV could modulate protease-dependent molecules involved in dendritic cell (DC) migration - a pivotal process in immunoregulation. Human monocyte-derived DC were exposed to IDV (IDV-DC) and transendothelial migration (TEM) to inflammatory chemokines was determined. TEM of IDV-DC was significantly impaired compared to non-treated DC (p<0.01). Phenotypic analysis revealed that IDV-DC had reduced DC-SIGN expression, correlating with reduced adhesion to immobilized ICAM-2. Nevertheless, the reduction in migration following exposure to IDV could not be fully attributable to DC-SIGN interactions alone. Investigation of IDV-DC interactions with the underlying matrix protein, fibronectin, demonstrated that IDV significantly impaired DC binding to immobilized fibronectin (p<0.01). IDV appeared to act upon VLA-4 and VLA-5 since addition of antagonist monoclonal antibodies (mAb) similarly reduced adhesion of non-treated DC to fibronectin. Combined blockade of DC using anti-VLA-4, VLA-5 and anti-DC-SIGN mAb inhibited TEM to a similar extent as IDV. Our results strongly suggest that IDV inhibits host proteases necessary for DC migration and may, therefore, affect DC immunoregulation in HIV-1-infected patients.

Topics: Antigens, CD; CD83 Antigen; Cell Adhesion Molecules; Cell Movement; Dendritic Cells; Endothelium; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunoglobulins; Indinavir; Integrin alpha4beta1; Integrin alpha5beta1; Lectins, C-Type; Membrane Glycoproteins; Receptors, Cell Surface

To analyze factors associated with long-term (>or=2 years) suppression of virus load (VL), we performed a nested case-control analysis of 1235 Human Immunodeficiency Virus Outpatient Study cohort participants who were well characterized by multiple VL and CD4(+) cell count determinations. Of these patients, 286 (23.1%) had maintained undetectable VLs (i.e., <400 copies/mm(3) or <50 copies/mm(3)) for >or=2 years. Being treatment naive at the start of antiretroviral therapy was associated with a greater likelihood of achieving long-term suppression of VL (odds ratio [OR], 1.5; 95% confidence interval, 1.0-2.0; P=.028). In multivariate models, abacavir, indinavir, efavirenz, and drug combinations that included both lamivudine and indinavir were the most effective treatments for achieving long-term suppression of VL (adjusted OR for each, >3.6; P value for each, <.01). Long-term suppression of VL is more likely in treatment-naive than in treatment-experienced patients, but there were several drugs--abacavir, efavirenz, indinavir, and drug combinations including lamivudine and indinavir--that appeared to be effective, whether they were part of a first or subsequent drug regimen.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Case-Control Studies; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Outpatients; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load

Protease inhibitors (PI) are an important HIV-1 treatment tool. The HIV-1 genetic diversity as a result of antiretroviral exposure is a potential barrier to successful antiretroviral therapy.. To describe the impact of the selective pressure of the PI Indinavir in the protease region of the pol gene of HIV-1.. We have examined the extent of protease sequence heterogeneity in previously antiretroviral drug naive HIV-1 infected individuals receiving Indinavir as monotherapy for at least 48 weeks.. Analysis based on the consensus of this group of sequences showed regions with higher and lower polymorphism. The degree of genetic variation was greater in regions less critical for the structure and function of the enzyme. To investigate the selective pressure imposed by drug therapy, we have analyzed the rate of synonymous (ds) and nonsynonymous (dn) substitutions. The three critical regions for enzyme activity showed ds/dn ratio >1. whereas other regions had ds/dn ratio <1. The detected amino acid mutations had a trend to be conservative, thus maintaining the physical chemical amino acid characteristics. Phylogenetic analysis established the presence of subtype B (n=38), subtype F (n=9), and B/F recombinants within the protease region of pol gene (n=3). More prevalent detected mutations, thought to contribute to antiretroviral resistance, were L63P (42%), L10I (35%), M36I (30%), V82A/T/F (26%).. A great deal of predicted cross-resistance between PIs was observed. Out of the 50 individuals, 34% were considered to have major mutations to Indinavir, and 66% had minor or no mutations to Indinavir. Viral loads were significantly higher among patients with major mutations, compared with patients minor/no mutations, although no differences in the CD4 counts were found. The viral load at baseline and nadir (week 4) was able to predict the group of individuals with greater chances of selecting drug resistance related mutations.

Topics: DNA, Viral; Genetic Variation; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Phylogeny; Sequence Homology, Amino Acid

To assess responses to indinavir (IDV)-ritonavir (RTV)-based regimens among HIV-1 infected patients with prior failure of protease inhibitors, and to assess the effects of adherence to therapy and pre-existing genotypic and phenotypic resistance on this response.. Twenty-eight patients initiating salvage regimens with IDV-RTV (800 mg and 200 mg twice daily, respectively) plus one or more reverse transcriptase inhibitor (RTI) were identified retrospectively. Genotypic and phenotypic susceptibilities to multiple antiretroviral agents were determined on viral samples collected at initiation of the salvage regimens, and adherence to therapy was determined through patient self-reporting. Response to therapy (viral RNA

Topics: Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Patient Compliance; Phenotype; Retrospective Studies; Ritonavir; Salvage Therapy; Treatment Failure; Viral Load

Diabetes mellitus was diagnosed in 16 out of 1011 HIV-positive patients over a median follow-up of 289 days (person-year incidence 2.06, 95% confidence interval 1.18-3.33). Significant risk factors for the onset of diabetes were older age and antiretroviral therapy with stavudine or indinavir. Older men with HIV infection should be considered at higher risk of diabetes, and caution maybe warranted in the use of both indinavir and stavudine in these patients.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-HIV Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine

Topics: Administration, Oral; Cannabinoids; Dronabinol; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nelfinavir; RNA, Viral; Viral Load

To describe the adverse event profile for indinavir sulfate overdose.. Analysis of indinavir overdose reports in Merck & Co., Inc.'s safety database through the first 5 years following US licensure of indinavir. Reports were classified as acute (single high dose in excess of 2400 mg), chronic (multiple extra doses, not exceeding 2400 mg per dose), single extra dose (not exceeding 2400 mg) and dose not reported.. Seventy-nine reports of indinavir overdose were reviewed (15 acute, 43 chronic, 13 single extra dose and 8 dose not reported). A total of 52/79 (66%) reports were associated with adverse events. For acute overdose reports with adverse events, indinavir doses ranged from 2.8 g to 48 g (median 6 g; mean 13 g); for acute overdose reports without adverse events, indinavir doses ranged from 4 g to 80 g (median 56 g; mean 45 g). Adverse events following acute and chronic exposures were similar; the most commonly reported adverse events included nausea, vomiting, abdominal pain and nephrolithiasis. Of the 52 patients with adverse events, 39 recovered, 6 had not recovered at the time of reporting and no information regarding outcome was provided in 7 reports.. Overdose with indinavir was associated with adverse events in the majority of reports. These were most commonly gastrointestinal and renal events, and were generally consistent with the known safety profile of indinavir. The majority of patients recovered.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Child; Child, Preschool; Drug Overdose; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Middle Aged; Suicide

The multidrug transporter P-glycoprotein (P-gp) is expressed in HIV-1 target cells, in a range of pharmacological barriers and in AIDS-associated tumours. P-gp substrates include HIV-1 protease inhibitors (PIs) and anticancer drugs, which are efficiently effluxed from multidrug-resistant (MDR) cells.. The aim of this study was to investigate the effect on human CD4 T-lymphoblastoid CEMrev cells of saquinavir and other PIs in terms of P-gp expression and to characterize the functional and biochemical patterns of PI-induced P-gp molecules.. CEMrev cells no longer expressing detectable amounts of P-gp were cultured for a prolonged period in the presence of 10 microg/mL saquinavir (CEMsaq10) and tested for P-gp expression and function. Subsequently, CEMsaq10 cells were transferred into medium containing 15 microg/mL saquinavir (CEMsaq15) and cultured for several months. These cell lines were continuously monitored for P-gp expression, function and immunochemical patterns. A similar strategy was adopted to determine whether other PIs, such as ritonavir and indinavir, were able to induce P-gp expression in CEMrev cells.. Compared with the drug-diluent control, the exposure of CEMrev cells to 10 microg/mL saquinavir induced, in a consistent fraction of cells (45-50%), de novo expression of functioning P-gp molecules. The transfer of CEMsaq10 cells to 15 microg/mL saquinavir was associated with a dramatic increase in P-gp expression and function (85-90% of CEMsaq15 cells expressed P-gp and effluxed P-gp dye substrates). These saquinavir-induced P-gp molecules included 75-kDa molecules as well as the classical 170-kDa form of P-gp, suggesting induction of a particular isoform of P-gp termed mini-P-glycoprotein. Conversely, ritonavir and indinavir induced transient P-gp expression in a small percentage of the CEMrev cells.. Treatment of human CD4 T-lymphoblastoid CEMrev cells with saquinavir caused over-expression of functioning P-gp molecules. This de novo acquired MDR phenotype, which differed from that induced by other PIs, was stable, as expression and activity of P-gp were observed in CEMsaq10 and CEMsaq15 cells during prolonged in vitro culturing, even in drug-free conditions.

Topics: Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; CD4-Positive T-Lymphocytes; Cells, Cultured; Drug Resistance, Multiple; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Immunohistochemistry; Indinavir; Phenotype; Ritonavir; Saquinavir

To describe changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of HIV-2-infected patients receiving antiretroviral (ARV) therapy in Abidjan, Côte d'Ivoire.. Consecutive blood samples were collected from 18 HIV-2-infected ARV-naive patients who had received ARV therapy in the UNAIDS drug access initiative (UNAIDS-DAI) in Abidjan between August 1998 and July 2000. Changes in HIV-2 plasma viral load, CD4+ cell counts, and genotypic and phenotypic drug resistance testing were determined.. At baseline, 11 (61%) of the 18 patients initiated highly active antiretroviral therapy (HAART) and seven (39%) received dual therapy. No significant change in median viral load was observed at 2 months (P = 0.09), at 6 months (P = 0.06), and at 12 months of therapy (P = 0.26). No significant increase in CD4+ cell counts was observed at 12 months (P = 0.10). All four patients on indinavir-containing HAART had undetectable viral loads at 2-4 months of therapy. However, none of seven patients on nelfinavir-containing HAART had a substantial decrease in viral load. Viruses from 14 patients were analyzed, 12 of which (86%) had at least one primary resistance mutation that is known to confer resistance to HIV-1 virus. Three patients had the multi-drug-resistant mutation, Q151M, two of whom showed reduced susceptibility to zidovudine, didanosine, stavudine and zalcitabine.. Our limited findings show that nelfinavir-containing regimens may have limited virologic benefit to HIV-2-infected patients.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV-2; Humans; Indinavir; Male; Middle Aged; Mutation; Nelfinavir; Patient Compliance; Viral Load

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

Analysis of indinavir levels in HIV-positive patients indicated that drug concentrations in lymph node mononuclear cells (LNMCs) were about 25-35% of mononuclear cells in blood. To enhance lymphatic delivery of anti-HIV drugs, a novel drug delivery strategy was designed consisting of lipid-associated indinavir (50-80 nm in diameter) complexes in suspension for subcutaneous (SC) injection. Due to the pH-dependent lipophilicity of indinavir, practically all the drug molecules are incorporated into lipid phase when formulated at pH 7.4 and 5:1 lipid-to-drug (m/m) ratio. At pH 5.5, about 20% of drugs were found in lipid-drug complexes. Effects of lipid association on the time course of plasma indinavir concentrations were determined in macaques (Macaca nemestrina) administered with either soluble or lipid-associated formulation of indinavir (10 mg/kg, SC). Results yielded about a 10-fold reduction in peak plasma concentration and a 6-fold enhancement in terminal half-life (t1/2beta = 12 vs. 2 hours). In addition, indinavir concentrations in both peripheral and visceral lymph nodes were 250-2270% higher than plasma (compared with <35% with soluble lipid-free drug administration in humans). Administration of lipid-associated indinavir (20 mg/kg daily) to HIV-2287-infected macaques (at 30-33 weeks after infection) resulted in significantly reduced viral RNA load and increased CD4 T cell number concentrations. Collectively, these data indicate that lipid association greatly enhances delivery of the anti-HIV drug indinavir to lymph nodes at levels that cannot be achieved with soluble drug, provides significant virus load reduction, and could potentially reverse CD4 T cell depletion due to HIV infection.

Topics: Animals; CD4 Lymphocyte Count; Cholesterol; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; In Situ Hybridization; Indinavir; Liposomes; Lymphoid Tissue; Macaca; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Viral Load; Viremia; Virus Replication

Highly active antiretroviral therapy (HAART) has been shown to have a beneficial effect on several opportunistic and other coinfections of HIV infected individuals. The effect of HAART on HCV coinfections is controversial. We describe the case of a patient, in whom a close temporal relationship between changes in HIV viremia, HCV viremia and ALT levels was observed. Longterm suppression of HIV replication by HAART was associated with a normalization of ALT levels and finally clearance of the HCV infection. Our data suggest that improved immune functions due to reductions of the HIV load led to a better control and finally resolution of the HCV infection in this patient.

Topics: Acute Disease; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nevirapine; Viral Load; Viremia

Indinavir and nelfinavir plasma levels were studied in 407 patients having plasma HIV RNA <500 copies/mL after 4 months of treatment with these drugs. For each drug, an observed/predicted (O/P) ratio was calculated between individual and mean time-adjusted population plasma drug levels. The relationship between the O/P ratio and the risk of rebound of plasma HIV RNA >500 copies/mL beyond month 4 was studied using Cox proportional hazard models. Median follow-up was 20 months. There was no association between indinavir plasma levels and risk of virologic rebound, whereas low nelfinavir + M8 (active nelfinavir metabolite) plasma levels were associated with a higher risk of virologic rebound. In multivariate analysis, the adjusted relative hazard of virologic rebound for patients with an O/P ratio of nelfinavir + M8 metabolite <0.8 compared with others was 2.2 (P = 0.01). In some patients, plasma levels of nelfinavir sufficient to achieve early viral response may not be sufficient to maintain it in the long term. This may be related to insufficient compliance with dietary recommendations. Monitoring of nelfinavir plasma levels thus seems useful, even in patients having early virologic response.

Topics: Biotransformation; Cohort Studies; Follow-Up Studies; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; RNA, Viral; Time Factors; Treatment Failure; Viral Load

Insertions in the protease gene of HIV-1 were rarely found and are not associated with reduced effectiveness of protease inhibitors although they are thought to be selected by protease inhibitor therapy. This is the first report of a 6-basepair insertion in the protease gene prior to protease inhibitor therapy.

Topics: Base Pairing; Base Sequence; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Treatment Failure; Viral Load

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

Topics: Ascorbic Acid; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

The contributions of viral drug resistance, drug pharmacokinetics, and treatment adherence to failure of protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) have been explored in isolation. We examined the interactions between these factors. Patients on their first PI-based HAART combination for >6 months with plasma HIV viral load (VL) >1000 copies/mL ("viremic" group) were compared with patients with a stable VL <50 copies/mL ("nonviremic" group). Data were collected on adherence (measured electronically), PI plasma levels (sampled randomly, at trough and twice after an observed dose), viral genotype, and phenotype. Mean adherence was significantly lower in the viremic group (84.3% versus 100.1%; p =.005). In the viremic group, substitutions in HIV protease were detected most frequently in the following positions in subjects on indinavir (IDV): L10I/V (35.7%), M46I/L (35.7%), A71T/V (35.7%), V82A (42.9%); and for subjects on nelfinavir (NFV): D30N (50.0%), V77I (56.3%), N88D (37.5%). Phenotypic resistance was detected in 20% of isolates from patients on IDV and 42% on NFV. Lower adherence was associated with detection of fewer resistance substitutions (r = 0.52; p =.005) and less phenotypic resistance (rho = 0.56, p =.005). There were no differences between the groups in pharmacokinetics. However, in viremic subjects, lower postdose NFV levels were associated with higher resistance (rho = -0.61, p =.02).

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir; Patient Compliance; Viral Load

We report a 27 years old male, treated with Indinavir as a prophylactic anti-HIV agent, who consulted for left ureteral pain. Intravenous and retrograde pyelograms disclosed a radioluscent stone, that was removed surgically. The physical-chemical study of the stone, demonstrated indinavir sulphate crystals.

Topics: Adult; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Radiography; Ureteral Calculi

Because increased bone marrow lymphopoiesis might contribute to immunologic reconstitution during highly-active antiretroviral therapy (HAART), we examined the effect of HAART on CD34(+) cell subsets in bone marrow from HIV-infected patients.. In 12 HIV-infected patients, bone marrow and peripheral blood were collected before then 4 and 26 weeks after initiating HAART. Bone marrow in 28 HIV-seronegative controls was also examined. Immunophenotypic analyses of CD34(+) cell subsets in bone marrow were performed by flow cytometry.. Our main findings in bone marrow were: (i) HIV-infected patients had increased proportions of CD34(+)cells expressing T- and B-cell markers before initiating HAART; (ii) in contrast, these patients had decreased proportions of CD34(+) cells expressing myeloid-associated markers; (iii) although HAART induced an increase in peripheral T-cell counts, the percentage of CD34(+)cells expressing T-cell markers tended to decrease during such therapy; (iv) HAART induced a decrease in serum IgG accompanied by a slight decrease in the proportion of CD34(+)cells expressing B-cell markers; (v) in contrast, HAART induced a significant increase in peripheral granulocyte counts, accompanied by a slightly increased proportion of CD34(+) cells expressing myeloid-associated molecules.. Our findings are compatible with an HIV-related block in T-cell differentiation, leading to accumulation of T-cell progenitors in bone marrow, and such a block may be removed by HAART.

Topics: Adult; Antigens, CD34; Antiretroviral Therapy, Highly Active; beta 2-Microglobulin; Bone Marrow Cells; Case-Control Studies; Female; Flow Cytometry; HIV Infections; HIV Protease Inhibitors; Humans; Immunoglobulin G; Immunophenotyping; Indinavir; Lamivudine; Leukocyte Count; Male; Middle Aged; Stavudine; T-Lymphocyte Subsets; Zidovudine

Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children.. A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with indinavir.. Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir.. The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic hematuria. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months.. Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavir-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L x h, and a C(max) >12 mg/L.

Topics: Child; Child, Preschool; Creatinine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney Diseases; Leukocytosis; Male; Prospective Studies; Urinalysis

We report the first case of acute cholecystitis due to indinavir-induced cholelithiasis in a patient infected with human immunodeficiency virus who had been receiving indinavir for 56 months. Infrared spectroscopy demonstrated that the gallstone was composed of indinavir monohydrate (50%), calcium bilirubinate (28%), calcium palmitate (10%), cholesterol (7%), and proteins (5%). The role of high-level chronic unconjugated hyperbilirubinemia coupled with high blood concentrations of indinavir is discussed.

Topics: Acute Disease; Adult; Bilirubin; Cholelithiasis; Cholesterol; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Palmitic Acid

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; CD4 Lymphocyte Count; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunocompromised Host; Immunosuppression Therapy; Indinavir; Lamivudine; Lymphoma, AIDS-Related; Male; Methotrexate; Middle Aged; Prednisone; Reverse Transcriptase Inhibitors; Stavudine; T-Lymphocyte Subsets; Vincristine

Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P = 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.

Topics: Adolescent; Adult; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Leukocytes, Mononuclear; Male; Middle Aged; Ritonavir; Saquinavir; Subcellular Fractions; U937 Cells

To measure the unbound plasma concentrations of saquinavir (SQV) and indinavir (IDV) and to relate them to the total plasma concentrations in order to establish the unbound percentage of protease inhibitors in vivo during a full dosage interval profile.. HIV-infected subjects (n = 35; median CD4 cell count = 340 x 10(6) cells l-1, range: 120-825; viral load < 50 copies ml-1 in 22/35) treated with SQV or IDV containing regimens were studied. Plasma drug samples were collected at 0, 2, 4, 8 and 12 h postdose for the twice daily regimens and 0, 1, 2, 4 and 8 h for the three times daily regimens. Ultra-filtration was used to separate unbound IDV and SQV in plasma and their respective concentrations were measured by a fully validated method using high performance liquid chromatography-mass spectometry (h.p.l.c.-MS/MS).. Based on the ratio AUCunbound/AUCtotal, the median unbound percentage (95% CI for differences) of SQV and IDV from all the samples studied was 1.19% (0.99, 1.58%) and 36.3% (35.1, 44.2%), respectively. No significant difference was seen in the percentage binding of SQV between patients receiving SQV alone (median = 1.49%) or with ritonavir (median = 1.09%; P = 0.141; 95% CI for difference between medians = -0.145, 0.937) over the pharmacokinetic profile. Similarly, no significant difference was seen in the percentage binding of IDV in patients receiving IDV alone (median 35.2%) or with ritonavir (median = 41.3%; P = 0.069; 95% CI for difference between medians = -0.09, 15.4). The unbound concentrations of SQV (P < 0.0001; 95% CI for r(2) = 0.634, 0.815) and IDV (P < 0.0001; 95% CI for r(2) = 0.830, 0.925) remained constant as a proportion of total concentration over the full dosing profile.. These in vivo data confirm previously published in vitro measurements of SQV and IDV protein binding. The unbound percentage of both protease inhibitors remained constant over the dosing interval.

Topics: Adult; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Saquinavir; Time Factors

A non-isotopic neutravidin-based reverse transcriptase (RT) assay adapted for high throughput screening of HIV activity is described. Using a 96-well microtitre plate, HIV particles are lysed and the RT enzyme released into a reaction mixture containing poly(A) RNA, biotinylated oligo d(T) and fluorescein-labelled dUTP (FI-dUTP). With poly(A) as a template and oligo d(T) as primer, the viron RT incorporates FI-dUTP into an elongating DNA strand. The resulting product is captured on a neutravidin-coated 96-well plate and the unincorporated nucleotides removed by a series of washing steps. A simple ELISA is subsequently performed using a monoclonal antifluorescein antibody conjugated to alkaline phosphatase. Quantification of RT activity is facilitated by a colorimetric readout. The assay was validated in the context of a diagnostic HIV-1 phenotyping assay. Using supernatants from HIV-1 infected lymphocyte cultures the assay was shown to be as sensitive as a radioactive assay and the RT activity correlated well with levels of cell-associated HIVp24. Importantly, even minor reductions of RT activity by virus variants with reduced fitness could be distinguished.

Topics: Avidin; Colorimetry; Drug Resistance, Multiple, Viral; Gene Products, gag; HeLa Cells; HIV Core Protein p24; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Mass Screening; Protein Precursors; Ritonavir; Saquinavir; Sensitivity and Specificity; T-Lymphocytes

Topics: CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Microbial; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Multicenter Studies as Topic; Mutation; Plasma; Prospective Studies; RNA, Viral; Saquinavir

In a prospective study evaluating risk factors for indinavir-related renal colic in 555 HIV-infected patients receiving highly active antiretroviral therapy, followed-up fir 24 months, 23.6% developed one or more renal colic episodes, and 50 patients stopped indinavir. No correlation was observed between renal colic onset and sex, age, CD4 cell count, history, and hepatitis B or C virus co-infection, but baseline anthropometric values were significantly related to the onset of renal colic.

Topics: Adult; Body Mass Index; Colic; Dose-Response Relationship, Drug; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Kidney Diseases; Male; Predictive Value of Tests; Prospective Studies; Risk Factors

Topics: Adult; Anti-HIV Agents; Chemoprevention; Exanthema; Female; General Surgery; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Neutropenia; Occupational Exposure

Topics: Adult; Diabetes Mellitus; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir

Suboptimal levels of antiretroviral drugs result in virologic failure in HIV-infected patients treated with highly active antiretroviral therapy (HAART).. To assess the relationship between levels of indinavir in hair and virologic outcome.. Cross-sectional study.. 7 AIDS clinics in France.. 89 HIV-infected patients who received HAART that included indinavir.. Patients were classified as responders or nonresponders on the basis of viremia at the time of hair collection. In nonresponders, levels of indinavir in hair and resistance mutations in the protease gene were assessed at baseline and at the time of indinavir measurement.. Mean indinavir levels (+/-SD) were significantly higher in the 65 responders than in the 24 nonresponders (24.4 +/- 16 microg/g vs. 12.9 +/- 8.6 microg/g) (P < 0.001). Nonresponders with intermediate levels of indinavir in hair had more mutations in the protease gene than did nonresponders with low levels of indinavir in hair.. Indinavir levels in hair are associated with virologic outcome in patients receiving HAART.

Topics: Absorption; Antiretroviral Therapy, Highly Active; Cross-Sectional Studies; Drug Resistance, Viral; Female; Genotype; Hair; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Monitoring, Physiologic; Patient Compliance; RNA, Viral; ROC Curve; Viral Load

Topics: Antiretroviral Therapy, Highly Active; Hair; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Monitoring, Physiologic; Patient Compliance; RNA, Viral; Viral Load

Topics: Absorption; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; Hair; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Monitoring, Physiologic; Patient Compliance; Viral Load

This report describes a 47-year-old woman with human immunodeficiency virus (HIV) and end-stage renal disease on hemodialysis, treated with combination antiretroviral drug therapy, who developed an acute, severe type B lactic acidosis 24 hours after homograft root replacement for endocarditis. She fully recovered after HIV medication was discontinued, along with administration of riboflavin and supportive measures including hemodialysis. The timing of this complication and previous reports suggest that open heart surgery may be a risk factor for nonischemic (type B) lactic acidosis in patients taking nucleoside analogue reverse transcriptase inhibitors.

Topics: Acidosis, Lactic; Anti-HIV Agents; Aortic Valve; Female; Heart Valve Prosthesis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Failure, Chronic; Lamivudine; Middle Aged; Postoperative Complications; Renal Dialysis; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nevirapine; Reverse Transcriptase Inhibitors; Viral Load

Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of > or =0.5 log(10) copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.

Topics: Adult; Area Under Curve; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Logistic Models; Male; Phenotype; Prospective Studies; Ritonavir

Low doses of ritonavir, a strong inhibitor of cytochrome P450 3A4, enhances the pharmacokinetic profile of indinavir with increased serum levels. We assessed the indinavir-ritonavir 400/200 twice daily combination in 17 HIV-infected patients focusing on the pharmacokinetic data and the tolerance of this regimen. IDV trough and peak concentrations were measured by high-performance liquid chromatography. Median indinavir trough and peak concentrations were 553 ng/ml and 3626 ng/ml, respectively. A good tolerance was observed except for three patients who experienced a major toxicity. Only one dose adjustment was related to indinavir toxicity. Considering the fact that Cmax is mainly responsible of the adverse effects, particularly renal stones, the indinavir-ritonavir 400/200 mg twice daily regimen offers a well-tolerated combination with an increased Cmin but a lower Cmax compared with both the standard tid regimen and higher dose of IDV-RTV regimens.

Topics: Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Indinavir; Male; Ritonavir; Viral Load

The mean risk of acquiring HIV after an occupational exposure, injecting drug use or sexual exposure varies from < 0.1 to 3%. A high plasma HIV-RNA of the source increases the risk of each of the exposures. Other factors, such as the volume of the inoculum involved to which the individual was exposed, other sexually transmitted diseases and ruptures of mucous membranes are associated with a higher risk of HIV transmission. Based on the calculated risk, post-exposure prophylaxis (PEP) should be recommended. In the Netherlands, prescription of PEP in the occupational setting is a standard procedure and has proved to be feasible. This was associated with a high percentage (62%) of mild and reversible toxicity and a small percentage (2%) of serious adverse events related to antiretroviral drugs, i.e. nephrolithiasis (due to indinavir) and toxic hepatitis (due to nevirapine). In The Netherlands so far no HIV-seroconversions have been recorded after an occupational accident.

Topics: Adult; Anti-HIV Agents; Blood-Borne Pathogens; Chemoprevention; Female; HIV Infections; Humans; Indinavir; Infection Control; Male; Medical Staff, Hospital; Needlestick Injuries; Occupational Exposure; Personnel, Hospital; Prognosis; Risk Assessment; Risk Management; Safety

Indinavir is a protease inhibitor used in the treatment of HIV infected individuals and as post-exposure prophylaxis. Indinavir is associated with various adverse effects including gastrointestinal, a lipodystrophy syndrome and nephrolithiasis. We describe indirect hyperbilirubinemia as an adverse effect of indinavir in a person on post-exposure prophylaxis (PEP).

Topics: Adult; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; India; Indinavir; Lamivudine; Liver Function Tests; Needlestick Injuries; Prognosis; Risk Assessment; Severity of Illness Index; Zidovudine

In a survey of 247 HIV-infected patients which received at least six months of combined antiretroviral therapy including the protease inhibitor nelfinavir during the last two years (2000-2001), the specific primary genotypic mutation D30N (with or without the minor mutation N88D), was detected in only four of the 149 (2.7%) subjects who received genotypization after virological failure. Three of these cases of primary nelfinavir resistance occurred among the 84 patients who were protease inhibitor- and/or non-nucleoside reverse transcriptase inhibitor-na ve, while the last episode was registered in a female patient treated since five years, who received an indinavir-based therapy of nearly 12-month duration (interrupted because of untoward kidney effects). During the subsequent follow-up, the substitution of nelfinavir had a favourable laboratory and clinical outcome in all reported patients who continued a different highly active anti-HIV treatment, while a significantly less positive virological and immunological response was seen in all the remaining subjects, and especially in those who experienced virological failure after undergoing at least two prior changes of combined antiretroviral therapy, and were borne by a broad spectrum of protease gene mutations (save those regarding codons 30 and 88). Due to its exclusive resistance pattern, nelfinavir may represent a favorable first-line choice among protease inhibitor-based regimens, since it may spare further treatment options even in the same pharmacological class. In fact, cross-resistance with other protease inhibitors may be limited also in patients experiencing prior long-term antiretroviral therapy, from second-line to rescue regimens, provided that they were pre-treated with drugs other than nelfinavir.

Topics: Anti-HIV Agents; Codon; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Italy; Male; Mutation; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy

Topics: Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Sex Factors

Antiretroviral therapy (ART) currently represents the best way to avert the lethal consequences of chronic persistent HIV-1 infection. It leads to significant reductions of plasma viremia, often to undetectable levels, but it can also be linked with the reduction and disappearance of detectable HIV-specific CD8 T-cell responses.. Here we describe a group of patients in whom ongoing replication of HIV, particularly transcription of Nef mRNA species, was detected despite prolonged and clinically successful antiretroviral treatment. Modest, but significant, numbers of HIV-specific CD8 T cells and CD4 T-cell responses were found in these subjects, with the strongest responses directed towards Nef epitopes. Detailed phenotypic analysis of the HIV-specific CD8 cells demonstrated low perforin levels and persistent expression of CD27, a phenotype associated with incomplete differentiation of cytotoxic T lymphocytes (CTL).. This immature CTL phenotype has been described previously in association with chronic HIV disease, but its continued persistence is surprising in the setting of prolonged viral suppression on therapy and the presence of HIV-specific CD4 cell activity.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD28 Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; HIV Antigens; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunophenotyping; Indinavir; Interferon-gamma; Lamivudine; Membrane Glycoproteins; Palatine Tonsil; Perforin; Pore Forming Cytotoxic Proteins; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome

Sustained elevations in CD4 cell counts commonly occur despite incomplete viral suppression with protease inhibitor-based antiretroviral therapy.. To determine the incidence and risk factors associated with return of CD4 cell count to pre-therapy levels in patients experiencing virologic failure of protease inhibitor therapy.. This is a clinic-based cohort study of HIV-infected adults who failed to maintain durable viral suppression on a protease inhibitor-based regimen.. Virologic failure was defined as persistent plasma HIV RNA level > 500 copies/ml. Immunologic failure was defined as return of CD4 cell count to pre-therapy levels.. A total of 291 patients experienced virologic failure on a protease inhibitor-based regimen and had a treatment-mediated CD4 cell increase above pre-therapy levels at the time of virologic failure. If patient data were censored at the time a successful salvage regimen was initiated, then the median time to immunologic failure after the onset of virologic failure was 3 years. If patient data were also censored at the time therapy was discontinued, then 36.8% of the cohort experienced immunologic failure after 3 years of continuous virologic failure. The change in viral load from a pre-treatment baseline, and not the absolute level of viremia achieved, was a strong and independent predictor of immunologic failure. Discontinuing therapy was associated with immunologic failure independent of viral load changes.. Reduction in T CD4+ cell numbers may eventually occur during prolonged virologic failure of a protease inhibitor-based regimen and is predicted by the degree of virologic suppression below a pre-therapy 'set-point'.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Ritonavir; RNA, Viral; Saquinavir; Time Factors; Treatment Failure; Viremia

Highly active antiretroviral therapy (HAART) is a combination of an HIV protease inhibitor (PI), one or two reverse transcriptase inhibitors (RTIs) and/or non-nuclease reverse transcriptase inhibitors (NNRTIs). This combination therapy is able to reduce peripheral HIV viral load, elevate CD4+ cell counts and improve the clinical outcome.. To evaluate the impact of HAART therapy, including one PI, on the prevalence of skin diseases in patients with HIV/AIDS.. The study was performed by collecting data about HIV populations followed at the 'M. Bufalini' Infectious Diseases Unit and San Patrignano Medical Centre, Italy. The medical records regarding the dermatological diseases of such people were retrospectively examined in 12-month periods before (1996) and after (1999) the introduction of HAART.. The two groups of patients were matched for age, gender and stage of HIV disease. During the first part of the study, 328 of the 456 patients (72%) sought medical advice 689 times for dermatoses. In the second period, 196 of the 502 patients (39%) made a total of 255 visits. There was a considerable decrease in the number of dermatological visits (-63%) and patients with dermatological problems (-40%). In the group that did not receive HAART, 66% of the patients had cutaneous infections, 25% had inflammatory cutaneous disorders, 8% adverse cutaneous drug reactions and 1% cutaneous neoplasms. In the group of patients treated with HAART, cutaneous infections were observed in 53% of patients, while 21% of patients had inflammatory dermatoses, 20% of patients showed adverse cutaneous drug reactions, and 1% had skin cancers. The remaining 5% asked to see a dermatologist for cosmetic reasons.. The group of patients who received combination regimens including PIs had significantly lower cutaneous morbidity than those treated with nucleoside analogs alone. This tendency included both opportunistic infections and inflammatory cutaneous diseases. Adverse cutaneous drug reactions related to multidrug combination therapy were significantly higher in the group receiving HAART.

Topics: Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Italy; Male; Morbidity; Prevalence; Reverse Transcriptase Inhibitors; Skin Diseases; Treatment Outcome; Viral Load; Zidovudine

Growth failure is a common feature of children with human immunodeficiency virus type 1 (HIV-1) infection. Children who are treated with mono or dual nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy show a temporary increase in weight gain and linear growth rate. In adults, protease-inhibitor-containing antiretroviral therapy is associated with a sustained weight gain and increased body mass index (BMI). Experience with protease inhibitors and growth in children is still limited. The data mainly deal with short-term effects on growth.. To evaluate the effect of highly active antiretroviral therapy (HAART) on growth in children with HIV-1 infection.. We analyzed selected growth parameters, clinical data, and laboratory results as part of a prospective, open, uncontrolled, multicenter study to evaluate the clinical, immunologic, and virologic response to HAART consisting of indinavir, zidovudine, and lamivudine in children with HIV-1 infection. Height and weight were measured at 0, 12, 24, 36, 48, 60, 72, 84, and 96 weeks after initiation of HAART. Information about the children's growth before enrollment in the study was retrieved from the hospital medical records and/or the school doctor or health center. BMI was calculated. z Scores were used to express the standard deviation (SD) in SD units from the Dutch reference curves for age and gender. Viral loads and CD4+ T-cell counts were examined prospectively and related to these growth parameters. z Scores were also calculated for CD4+ T-cell counts to correct for age-related differences. A z score of 0 represents the P50, which is exactly the age/sex-appropriate median. A height z score of -1 indicates that a child's height is 1 SD below the age- and gender-specific median height for the normal population. Virologic responders were defined as those who either reached an undetectable viral load (<500 copies/mL) or had a >1.5 log reduction in viral load compared with baseline at week 12 after the initiation of HAART, which was maintained during the follow-up period. RESULTS.. Twenty-four patients were included (age: 0.4-16.3 years at baseline), with a median HIV-1 RNA load of 105 925 copies/mL (5.03 log), a median CD4+ T-cell count of 0.586 x 10(9)/L (median z score: -2.28 SD), a median height z score of -1.22, a median weight z score of -0.74, and a median baseline BMI z score of -0.32. Eleven patients were naive to antiretroviral therapy, and 13 patients had received previous treatment with NRTI monotherapy. Twenty children used indinavir and 4 children used nelfinavir as part of HAART. VIROLOGIC AND IMMUNOLOGIC RESPONSES TO HAART: Seventeen children were virologic responders, and 7 children were virologic nonresponders. In patients naive to NRTIs, median baseline viral loads were significantly higher than in pretreated patients. However, at weeks 48 and 96, there was no significant difference between the viral loads of both groups. At baseline, there was no significant difference in CD4+a T-cell z scores between virologic responders and nonresponders or between naive and pretreated patients. During 96 weeks of HAART, the increase of CD4+ T-cell z score was significantly higher in responders than in nonresponders. The increase in CD4+ T-cell z score was not significantly different for naive and pretreated patients. HEIGHT, WEIGHT, AND BMI z SCORE CHANGES: We found that there was a trend toward a significantly increased z score change during 96 weeks of HAART compared with the z score change before HAART initiation for height and weight, but not for BMI. GROWTH AND VIROLOGIC RESPONSE TO HAART: When the data were analyzed separately for virologic responders and nonresponders, virologic responders showed significant increases in height and weight. The height and weight of virologic nonresponders did not change significantly. The BMI did not change significantly in responders or in nonresponders. GROWTH AND IMMUNOLOGIC RESPONSE TO HAART: The increase of weight and BMI z scores from baseline correlated positively with the CD4+ T-cell z score increase from baseline. It did not correlate with absolute CD4+ T-cell count increase. Height z score increase did not correlate with CD4+ T-cell z score or with absolute CD4+ T-cell counts. GROWTH AND PREVIOUS NRTI TREATMENT: The height z score decrease from week -48 to baseline was significantly larger in naive than in pretreated patients. The weight and BMI z score change from week -48 to baseline was not significantly different for pretreated and naive patients. From baseline to week 96,. HAART has a positive influence effect on the growth of HIV-1-infected children. This effect is sustained for at least 96 weeks. Height and weight are favorably influenced in children in whom HAART leads to a reduction of the viral load of at least 1.5 log or to <500 copies/mL and to an increase in the CD4+ T-cell z score. In contrast to the increase of the BMI in adults on HAART, BMI did not increase in all children effectively treated with HAART. BMI increased more in children with an advanced stage of infection and a poor nutritional status at baseline. Data from pretreated and naive patients were difficult to interpret, because the baseline characteristics of these 2 groups differed too much.

Topics: Antiretroviral Therapy, Highly Active; Body Height; Body Mass Index; Body Weight; Child; Child Development; Child, Preschool; Growth; HIV Infections; HIV-1; Humans; Indinavir; Infant; Treatment Outcome; Viral Load

Topics: Adult; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; RNA, Viral; Saliva

Dendritic cells are susceptible to human immunodeficiency virus (HIV) infection and may transmit the virus to T cells in vivo. Scarce information is available about drug efficacy in dendritic cells because preclinical testing of antiretroviral drugs has been limited predominantly to T cells and macrophages. We compared the antiviral activities of hydroxyurea and two protease inhibitors (indinavir and ritonavir) in monocyte-derived dendritic cells and in lymphocytes. At therapeutic concentrations (50 to 100 microM), hydroxyurea inhibited supernatant virus production from monocyte-derived dendritic cells in vitro but the drug was ineffective in activated lymphocytes. Concentrations of hydroxyurea insufficient to be effective in activated lymphocytes cultured alone strongly inhibited supernatant virus production from cocultures of uninfected, activated lymphocytes with previously infected monocyte-derived dendritic cells in vitro. In contrast, protease inhibitors were up to 30-fold less efficient in dendritic cells than in activated lymphocytes. Our data support the rationale for testing of the combination of hydroxyurea and protease inhibitors, since these drugs may have complementary antiviral efficacies in different cell compartments. A new criterion for combining drugs for the treatment of HIV infection could be to include at least one drug that selectively targets HIV in viral reservoirs.

Topics: Cells, Cultured; Dendritic Cells; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Indinavir; Lymphocyte Activation; Ritonavir; T-Lymphocytes

Topics: Anti-HIV Agents; Blood; Carbamates; Cerebrospinal Fluid; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; Genitalia; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Mutation; Phenotype; Randomized Controlled Trials as Topic; Retrospective Studies; Ritonavir; Sulfonamides; Time Factors; Viral Load

Therapeutic drug monitoring (TDM) of protease inhibitors (PI) is gaining increasing importance for the management of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). The PI indinavir (IDV) is widely used in HAART regimens. Combinations of IDV with ritonavir (RTV) have been used to increase the plasma concentration of IDV. However, the desirable IDV concentration range in clinical practice remains to be elucidated.. To study the value of TDM for IDV in clinical practice, a retrospective analysis of 501 plasma samples of patients treated with IDV in various dosages was performed. IDV levels were determined during routine outpatient visits. Analysis was performed by high pressure liquid chromatography (HPlC) with UV detection.. A widespread range of IDV plasma concentrations was seen both within and between patients. The mean IDV level during therapy with IDV 2.4 g/d was 3,260 ng/ml (95% CI: 2,903 ng/ml; 3,618 ng/ml). IDV levels at a dose of IDV 1.6 g/d in combination with RTV resulted in a mean IDV plasma concentration of 4,191 ng/ml (95% CI: 3,356 ng/ml; 5,026 ng/ml). There was no significant difference between plasma levels at the doses of 2.4 g/d and 1.6 g/d. 35 of all 130 patients treated with IDV reached only suboptimal IDV plasma concentrations below the limit of 150 ng/ml. There was no statistically significant difference between the number of patients below an IDV plasma concentration of 150 ng/ml in the various dosage regimens.. During therapy with IDV in a b.i.d. scheme, similar IDV plasma concentrations and a comparable number of patients with subinhibitory plasma concentrations were observed when compared to a therapeutic regimen with t.i.d. dosing. In this study, even at various times of plasma sampling after oral ingestion, TCM facilitated the surveillance of patients compliance.

Topics: Antiretroviral Therapy, Highly Active; Chromatography, High Pressure Liquid; Drug Monitoring; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Patient Compliance; Retrospective Studies; Ritonavir

Drug interactions are an important and emerging problem in the treatment of HIV-infected patients. Protease inhibitors, like nonnucleoside reverse transcriptase inhibitors, are metabolized by the cytochrome P-450 enzyme system and each of these antiretroviral agents may interact with other drugs metabolized by this system. Some protease inhibitors may also interact with glucuronosyl transferase activity affecting plasma concentrations of drugs metabolized through this pathway. We describe a case of an HIV-infected patient, taking levothyroxine for hypothyroidism and clinically stable, who, after the introduction of an antiretroviral regimen containing indinavir, developed a pharmacological hyperthyroidism.

Topics: Adult; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperthyroidism; Hypothyroidism; Indinavir; Thyroxine

This paper establishes a framework for understanding the complex relationships between HIV-1 genotypic markers of resistance to antiretroviral drugs and clinical measures of disease progression. A new classification scheme based on the probabilities of how new patients will respond to antiretroviral therapy given the available data is proposed as a method for distinguishing among groups of viral sequences. This approach draws from existing cluster analysis, discriminant analysis, and recursive partitioning techniques and requires a model relating genotypic characteristics to phenotypic response. A data set of 2,746 sequences and the corresponding Indinavir 50% inhibitory concentrations are described and used for illustrative purposes.

Topics: Amino Acid Sequence; Cluster Analysis; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Inhibitory Concentration 50; Models, Genetic; Molecular Sequence Data; Multigene Family; Multivariate Analysis; Mutation; Phenotype; Predictive Value of Tests; Viremia

Cardiovascular complications occurring in patients infected by the human immunodeficient virus (HIV) have considerably changed since the appearance, in April 1996, of highly active antiretroviral tri-therapy (HAART), associating reverse transcriptase and protease HIV-1 inhibitors. The spectacular efficacy of anti-proteases has led to the almost complete disappearance of these opportunistic complications. However, in May 1998, acute coronary accidents were reported in the literature, thus questioning the possible responsibility of antiprotease treatment in the occurrence of accelerated atheroma.. We report a series of 8 seropositive patients in whom an acute coronary event had occurred between February 1997 and February 1999.. The patients were young and all exhibited cardiovascular risk factors (smoking, dyslipidemia) and were treated with HIV-1 protease inhibitors. Six patients presented myocardial infarction, one patient unstable angina and one patient effort angina.. A rise in triglycerides was observed principally on ingestion of ritonavir and a rise in cholesterol and LDL-cholesterol with all the antiprotease agents. Glucose intolerance was observed with indinavir. The occurrence of acute coronary events appeared to be related to antiprotease treatment (at the origin of metabolic disorders, endothelial dysfunction...), although it was impossible to say whether the antiprotease agents were responsible for the early atheroma or whether they simply contributed to the event. The coronary lesions were characterized by their number (single artery) and their topography (proximal or median). Nelfinavir may carry less cardiovascular risks than the other antiproteases. Mean term prognosis was relatively good, after therapeutic adjustment (change in antiprotease, strategic measures against cardiovascular risk factors, introduction of anti-anginal treatment...).. Larger and longer studies would help to specify the role of antiproteases in the occurrence of early coronary events. Rigorous monitoring (lipid and glucose measurements, tests to search for myocardial infarction,..) together with the development of new antiretroviral molecules would reduce the number of coronary events in this type of patient.

Topics: Adult; Angina Pectoris; Angina, Unstable; Cholesterol; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Myocardial Infarction; Risk Factors; Ritonavir; Saquinavir; Smoking; Time Factors; Triglycerides

We retrospectively evaluated the incidence of side effects and treatment intervention according to indinavir trough concentration in 63 patients taking indinavir-ritonavir 800/100 mg twice daily. Median indinavir trough concentration was 1446 ng/mL at 800/100 mg twice daily associated with 60% of measured toxicity. Among patients with indinavir trough concentration >500 ng/mL, 46 of 49 had a dosage adjustment and 17 have had more than two dosage adjustments. The primary reason for dosage adjustment was toxicity in 69% (43 cases). Renal and cutaneous toxicity were predominant.After dosage adjustment, median indinavir trough concentration was 459 ng/mL, which was associated with 8% of toxicity. Trough concentrations >500 ng/mL were correlated with increased toxicity (p <.05) and more treatment intervention (p =.02). In conclusion, achievement of indinavir trough concentrations <500 ng/mL appears to be safe, and an optimal concentration range for indinavir trough concentration could be 150 to 500 ng/mL for an indinavir-ritonavir twice daily regimen.

Topics: Adult; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Protease Inhibitors; Retrospective Studies; Ritonavir

We retrospectively evaluated correlates of increases in CD4 cell count in antiretroviral agent-naive subjects with fewer than 50 copies per milliliter of plasma human immunodeficiency virus ribonucleic acid who were participating in a study of indinavir, lamivudine, and zidovudine therapy. Pharmacologic data from intensive pharmacokinetic studies and baseline patient characteristics were evaluated as predictors of the increase in CD4 count from baseline to weeks 24, 56, and 80. Relations were investigated with regression analysis. Of all covariates, maximum plasma concentration (C(max)) of indinavir was significantly and uniquely associated with increases in CD4 count from baseline to all end points (P =.002 at week 80; n = 20). At week 80, subjects with a C(max) greater than the overall group median value of 7 microg/ml had an increase in CD4 count of 358 cells/microl versus 197 cells/microl for those with a C(max) less than 7 microg/ml (P =.006). These data suggest distinct pharmacodynamic relations exist for immune reconstitution and suppression of plasma human immunodeficiency virus ribonucleic acid. We hypothesize this new finding may be associated with expression of P-glycoprotein.

Topics: Adult; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Regression Analysis; Retrospective Studies; RNA, Viral; Statistics, Nonparametric

The author, a 33-year-old man employed as a tropical diseases specialist in Zambia, accidentally cut himself during an operation on an HIV positive patient. After washing the wound, he took zidovudine and lamivudine and, on the advice of a counsellor and following logistical discussions with the Dutch Embassy, indinavir as well. Blood test results for HIV antibodies on the day of the accident, after 1 month and after 3 months were negative. After six months, two Zambian tests were positive and two Dutch tests negative. A confirmative test in the Netherlands using blood flown over from Zambia was negative for both anti-HIV and HIV RNA. For health professionals working abroad, there is a protocol for post-exposure prophylaxis. However, improvements to this can be made, for example, how and where diagnostic tests are carried out and where reliable HIV tests are carried out.

Topics: Adult; Anti-HIV Agents; Health Personnel; HIV Infections; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Male; Reverse Transcriptase Inhibitors; Zambia; Zidovudine

The treatment of HIV-1-infected patients with triple-drug combination therapy results in profound suppression of viral replication. In most therapy-naive patients plasma HIV-1-RNA levels (pVL) drop below the lower limit of quantification (LLQ) of currently used assays. In a large percentage of such patients, more sensitive assays provide evidence of residual viral replication. The question is whether more potent therapy can further suppress this residual replication.. Thirty control patients who, using very strict criteria, had not experienced virological failure during 3 years of standard therapy, were compared with 10 patients treated with a five-drug regimen, consisting of three different classes of antiretroviral drugs (alternative multidrug regimen). A modified ultrasensitive assay with an LLQ of 5 copies/ml was used to re-test plasma obtained at week 48 and at three timepoints at and around week 144.. At weeks 48 and 144 pVL could be quantified significantly more frequently in control patients than in patients using the alternative multidrug regimen (week 48: 42 versus 0% with quantifiable pVL, P = 0.017; week 144: 60 versus 14% with at least one quantifiable pVL, P = 0.036, respectively). A low baseline CD4T cell count was predictive of quantifiable pVL in control patients, but not in alternative multidrug patients.. This proof-of-principle study demonstrates that the use of an alternative multidrug regimen results in stronger long-term suppression of pVL compared with clinically successful treatment with standard therapy.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Follow-Up Studies; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load; Virus Replication; Zidovudine

Topics: Hand; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Osteogenesis; Osteosclerosis; Periosteum; Radiography; Vitamin A

A selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of the six human immunodeficiency virus (HIV)-protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethyl ether, the six protease inhibitors and the two non-nucleoside reverse transcriptase inhibitors are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer 50 mmol/L pH 5.65. A sequential ultraviolet detection (5-minute sequence set at 240 nm for nevirapine acquisition, 22-minute sequence set at 215 nm for other antiretroviral drugs acquisition followed by a sequence set at 260 nm for internal standard acquisition) allowed for simultaneous quantitation of the six protease inhibitors, nevirapine, and efavirenz. Calibration curves were linear in the range 100 ng/mL to 10,000 ng/mL. The limit of quantitation was 50 ng/mL for all drugs except nevirapine (100 ng/mL). Average accuracy at four concentrations ranged from 88.2% to 110.9%. Both interday and intraday coefficients of variation were less than 11% for all drugs. The extraction recoveries were greater than 62%. This method is simple and shows a good specificity with respect to commonly co-prescribed drugs. This method allows accurate therapeutic monitoring of amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz, and nevirapine.

Topics: Alkynes; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Monitoring; Furans; HIV Infections; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

Reversible posterior leukoencephalopathy syndrome (RPLS) is an uncommon entity related to multiple and different pathologies, the most common being hypertensive crisis. It is believed to be secondary to the breakdown on the blood-brain barrier. At the beginning, it is undistinguishable from other leukoencephalopathies. However, the disappearance of brain lesions after removal of the potential cause, establish the differential diagnosis with other leukoencephalopathies. We present the case of an HIV-infected patient with a RPLS related to a hypertensive crisis short after the initiation of indinavir-containing highly active antiretroviral therapy. Once blood pressure was controlled and indinavir replaced by nelfinavir, white matter lesions at magnetic resonance imaging disappeared. The clinical and radiologic evolution excludes other diagnosis as progressive multifocal leukoencephalopathy and points indinavir as a potential hypertension-inducing agent in HIV-infected predisposed subjects.

Topics: Adult; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Protease Inhibitors; Humans; Hypertensive Encephalopathy; Indinavir; Magnetic Resonance Imaging; Male

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Saquinavir; Viral Load

We retrospectively analyzed 155 urine cytology samples (78 from patients treated with indinavir; 77, no indinavir) from 90 HIV+ patients to evaluate possible association between human polyomavirus and hematuria and to describe indinavir-associated urinary cytologic findings. The CD4 count also was recorded. Variables studied included the presence of cellular viral changes consistent with polyomavirus infection (PVCs), microscopic hematuria, multinucleated cells, indinavir crystals, neutrophils, and eosinophils. Twenty-two samples (15.8%) from patients with CD4 counts of more than 200/microL (>200 x 10(6)/L) showed PVCs. Multinucleated cells, of presumed histiocytic origin based on morphologic features and selective immunocytochemical findings, were present in a higher percentage of samples from indinavir-treated patients. Neutrophils were present in a higher percentage of indinavir-treated patients. Indinavir crystals were identified in 9 samples (12%) from patients receiving indinavir The lower percentage of PVCs in HIV+ patients with high CD4 counts likely represents an indirect antipolyomavirus indinavir effect by boosting immunity. Multinucleated cells (presumably histiocytic) and acute inflammation are associated with indinavir therapy. Indinavir crystals have a characteristic fan or circular lamellate appearance. Because indinavir crystals may be associated with genitourinary disease, recognizing and reporting them is clinically relevant in HIV+ patients.

Topics: BK Virus; CD4 Lymphocyte Count; Crystallization; Female; Giant Cells; Hematuria; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Neutrophils; Polyomavirus Infections; Retrospective Studies; Tumor Virus Infections

To determine whether treatment with protease inhibitors (PIs) is associated with male sexual dysfunction, we conducted a retrospective, cohort study of 254 adult male PI recipients who received care from the staff-model division of a large managed care organization in New England between 1993 and 1998. After a median of 5.0 years of observation, 80 incident cases of sexual dysfunction were observed. Relative to unexposed individuals, the rate of sexual dysfunction adjusted for confounding was most elevated with use of ritonavir (hazard ratio [HR], 2.83; 95% confidence interval [CI], 1.34-5.97; p =.006) followed by indinavir (HR, 1.69; 95% CI, 0.84-3.37; p =.14), nelfinavir (HR, 1.53; 95% CI, 0.66-3.54; p =.32) and saquinavir (HR, 1.25; 95% CI, 0.53-2.96; p =.60). We conclude that PIs, especially ritonavir, appear to increase the risk of sexual dysfunction.

Topics: Adolescent; Adult; Aged; Cohort Studies; Erectile Dysfunction; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Managed Care Programs; Middle Aged; Nelfinavir; New England; Retrospective Studies; Ritonavir; Saquinavir

Topics: Absorptiometry, Photon; Adult; Aged; Bone Density; Cohort Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors

To assess a possible association between antiretroviral treatment and paronychia, we conducted a retrospective cohort study of 288 human immunodeficiency virus-positive protease inhibitor recipients. Indinavir treatment-adjusted for age, sex, CD4 count, diabetes status and other antiretroviral drug exposures-was significantly associated with paronychia of the great toe (hazard ratio 4.7; 95% confidence interval 1.6-13.9).

Topics: Adult; Aged; CD4 Lymphocyte Count; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Paronychia; Retrospective Studies; Viral Load

We examined the prevalence of cleavage site mutations, both within and outside the gag region, in 28 protease inhibitor (PI) cross-resistant patients treated with indinavir, ritonavir, and/or saquinavir compared to control patients treated with reverse transcriptase inhibitors. Three human immunodeficiency virus protease cleavage sites within gag (p2/NC, NC/p1, and NC/TFP) showed considerable in vivo evolution before and after therapy with indinavir, ritonavir, and/or saquinavir. Another gag cleavage site (p1/p6(gag)) showed a trend compared to matched controls. The other eight recognized cleavage sites showed relatively little difference between PI-resistant cases and controls. An A-->V substitution at the P2 position of the NC/p1 and NC/TFP cleavage sites was the most common (29%) change selected by the PIs used in this study.

Topics: Amino Acid Sequence; Amino Acid Substitution; Case-Control Studies; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Mutation; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir

Recent advances in the ability to detect people at the early stages of HIV infection now permit the initiation of antiretroviral treatment before the full complement of antiviral immune responses has evolved. However, the influence of early treatment interventions on the developing anti-HIV immune response is unknown. This study investigates the impact of standard highly active antiretroviral therapy (HAART) during the primary stages of HIV infection on the plasma HIV-1 RNA level, CD4(+) and CD8(+) lymphocyte counts, and the CD8(+) cell anti-HIV response. Individuals treated with HAART within 6 months of infection showed dramatic and rapid reductions in HIV-1 RNA levels along with modest increases in CD4(+) cell number and decreases in CD8(+) cell numbers. A significant reduction in the level of CD8(+) cell noncytotoxic suppression of HIV replication was observed over time in most participants receiving HAART. Importantly, those individuals choosing not to receive therapy maintained low but detectable HIV-1 RNA levels and showed no reduction in their CD8(+) cell antiviral response. These results suggest that either continued antigenic challenge is required to sustain CD8(+) cell-mediated anti-HIV activity, or that HAART has some inhibitory effect on this important immunologic function during the early stages of infection.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Depression, Chemical; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Immunity, Cellular; Indinavir; Lamivudine; Lymphocyte Count; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Refusal; Viral Load; Viremia; Zidovudine

The resistance of human immunodeficiency virus type 1 (HIV-1) to drugs is a major cause of antiretroviral treatment failure. We have compared direct sequencing to a line probe assay (LiPA) for the detection of drug resistance-related mutations in 197 clinical samples, and we have investigated the sequential appearance of mutations under drug pressure. For 26 patients with virological failure despite the use of two nucleoside analogues and one protease inhibitor (indinavir [n = 6], ritonavir [n = 10], and saquinavir [n = 10]), genotypic resistance assays were carried out retrospectively every 3 months for up to 2 years by using direct sequencing (TruGene; Visible Genetics) and a LiPA for detection of mutations in the reverse transcriptase (INNO-LiPA HIV-1 RT; Innogenetics) and the protease (INNO-LiPA HIV Protease, prototype version; Innogenetics) genes. Comparison of the results from both assays found rare major discrepancies (<1% of codons analyzed). INNO-LiPA detected more wild-type-mutant mixtures than sequencing but suffered from a high rate of codon hybridization failures for the reverse transcriptase. LiPA detected earlier and more frequently than sequencing the transient mixed virus population that contained I84V, which appears before V82A in the protease sequence. Mutations M461, G48V, and L90M were often transient and drug pressure related. In conclusion, direct sequencing and LiPAs give concordant results for most clinical isolates. LiPAs are more sensitive for the detection of mixed virus populations. Mutation I84V appears in minor populations in the early steps of the pathways of resistance to indinavir and ritonavir. The fact that some mutations can be found only transiently and in minor virus populations highlights the importance of a low detection limit for resistance assays.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Drug Resistance, Microbial; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Male; Mutation; Polymerase Chain Reaction; Retrospective Studies; Ritonavir; RNA, Viral; Saquinavir; Treatment Failure

Ten severely immunocompromised HIV-HCV co-infected patients were enrolled in a quantifiable HCV-RNA assay. Serum alanine aminotransferase, HCV-RNA levels and HIV viral loads were determined at baseline, at month three and at month six after initiation of a highly active antiretroviral therapy including an HIV protease inhibitor. HCV genotypes were determined using a line probe assay kit. Our results suggested that this therapy did not result in lower HCV viraemia, whatever the HCV genotypes, and probably had no effect on the outcome of chronic viral hepatitis C. As our patients were severely immunocompromised and their mean increase of CD4 cell counts was less than 50/mm(3), we cannot reach any conclusions about the impact of the improvement of immune status on the HCV-RNA load.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Hepacivirus; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load; Viremia; Virus Replication

Topics: Anti-HIV Agents; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Lamivudine; Risk Factors; Zidovudine

In order to determine prognostic factors associated with treatment failure (TF) in advanced HIV-infected patients treated with a regimen including indinavir, a prospective cohort study of 80 patients was set up between 1 March and 31 December 1996. TF time was calculated using the Kaplan-Meier method, from treatment induction to the first of the following events: treatment modification for adverse event or lack of significant virological and/or immunological response, AIDS-defining diagnosis or death. Date of point was 31 December 1998. Multivariate analysis was performed using a Cox model. At baseline, 60% of the patients were AIDS-free, median viral load and CD4+ count were respectively 4.8 log/ml and 79/microl. After a median follow-up of 26 months, 70% of the patients experienced a TF in a median time of 8 months. Seventy-two per cent presented an hyperbilirubinaemia (>2 mg/dl). In multivariate analysis, initial AIDS stage (hazard ratios [HR]=1.94, P=0.04) and digestive intolerance (HR=2.32, P=0.003) were predictive of TF. Conversely, hyperbilirubinaemia was associated with a better outcome (HR=0.35, P<0.0001). These 2 latter parameters very likely reflected patients' treatment compliance.

Topics: Adult; Antiretroviral Therapy, Highly Active; Biomarkers; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Indinavir; Male; Prognosis; Treatment Failure

Although prolactin (PRL) is now recognized as a cytokine and persistent immune activation is a common immunopathogenic feature of the human immunodeficiency virus infection (HIV), the circumstances associated with the onset of hyperprolactinemia during the course of this infection remain controversial. Given that PRL is able to exert not only endocrinologic effects but also immunologic influences, a study was conducted to investigate whether raised serum levels of PRL were more likely to prevail when HIV-infected patients developed concomitant infections. Serum PRL concentrations, as well as immunoglobulin isotypes, plasmatic viral burden, CD3+, CD4+, CD8+, CD19+, and natural killer (NK) cell counts were measured in 46 nonselected HIV-infected patients stratified on the basis of the presence or absence of clinically active concomitant infections. Serum PRL levels were significantly higher in patients presenting secondary infections as compared with the asymptomatic ones, with hyperprolactinemia being detected in 10/18 (55%) and 2/28 (7%) of these patient groups, respectively. Hyperprolactinemia was not related with viral burden, antiretroviral treatment, gender differences, or CD4+ cell counts. CD3+, CD4+, CD8+, and CD19+ cells were significantly lower in the group presenting active infections, whereas comparisons in NK cell counts, immunoglobulin levels and HIV viral burden revealed no differences between groups. These results provide evidence that hyperprolactinemia is more prevalent during the onset of secondary infections, which might have diagnostic and therapeutic consequences.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anti-Infective Agents; CD4-CD8 Ratio; Female; HIV Infections; Humans; Immunoglobulins; Indinavir; Lamivudine; Male; Prolactin; Sex Factors; T-Lymphocyte Subsets; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load; Zidovudine

To analyse cell membrane proteins (CMP) acquired by HIV-1 present in the plasma of asymptomatic patients, and their modifications after a cycle of highly active antiretroviral therapy (HAART) and interleukin (IL)-2.. Plasma samples from eight drug-naive asymptomatic subjects underwent immobilized antibody capture (IAC) to detect CMP on the surface of circulating HIV-1. The CMP considered were lymphocyte subset markers (CD45RA, CD45RO), activation markers (HLA-DR), adhesion molecules (LFA-3), costimulatory proteins (B7-2), lymph-node homing receptors (CD62L) and pro-apoptosis molecules (FasL). This analysis was repeated after one cycle of HAART + IL-2, after virus rebound.. LFA-3, followed by CD45RO and HLA-DR, are the most represented CMP on the surface of circulating virions in naive asymptomatic patients; CD45RA, CD62L, B7-2 and FasL are detected only occasionally. After rebound, a significant reduction of CD45RO and HLA-DR, but not of LFA-3, is observed on virions, whereas CD45RA and CD62L, as well as other molecules, are not affected, remaining almost undetectable.. Assuming that CMP on HIV-1 reflect the cellular origin of virions, activated T cells expressing CD45RO, HLA-DR, and LFA-3 may be the main source of HIV-1 in asymptomatic patients. After a cycle of HAART + IL-2, followed by therapy interruption, CD45RA and CD62L are detected on virions rarely, indicating that even during virus rebound, expanded naive T cells do not become a major target of virus replication. Furthermore, the presence of HLA-DR on rebound HIV-1 is decreased, consistent with decreased activation of the HIV-producing cells. More extensive investigation may clarify the significance of these findings with respect to pathogenesis.

Topics: Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; B7-2 Antigen; CD4 Lymphocyte Count; CD58 Antigens; Fas Ligand Protein; HIV Infections; HIV Protease Inhibitors; HIV-1; HLA-DR Antigens; Humans; Indinavir; Interleukin-2; L-Selectin; Lamivudine; Leukocyte Common Antigens; Membrane Glycoproteins; Membrane Proteins; Reverse Transcriptase Inhibitors; Stavudine; Viremia; Virion

We studied the human immunodeficiency virus type 1 phenotypic and genotypic profiles of a dual drug-resistant isolate (isolate 14aPost-DR) selected for zidovudine (ZDV) and lamivudine (3TC) resistance and then cultured in the presence of 3TC and a protease inhibitor: indinavir (IDV), ritonavir, or KNI-272. The IDV-treated virus was highly resistant to 3TC, ZDV, and IDV and accumulated protease mutations at positions M46I and V82F. A change from alanine to valine was observed in 4 of 10 clones in the P2 position of the p7-p1 Gag-protease cleavage site, linked to position M46I in the dominant viral quasispecies. Previous 3TC resistance did not impair the development of additional mutations in the protease and Gag-protease cleavage regions.

Topics: Drug Resistance, Microbial; Drug Resistance, Multiple; Evolution, Molecular; Gene Products, gag; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Microbial Sensitivity Tests; Molecular Sequence Data; Reverse Transcriptase Inhibitors; Zidovudine

To compare the clinical and economic outcomes associated with triple therapy containing efavirenz or indinavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs; zidovudine and lamivudine) in HIV-positive patients.. An economic model based on viral load and CD4+ cell counts to predict long term outcomes such as progression to AIDS and AIDS-related death was developed and then analysed using data from a randomised clinical trial. Cost estimates from the healthcare system perspective were based on data from 6 state, all-payor databases, the AIDS Cost and Services Utilisation Study, and other literature. Analyses were carried out for time horizons between 5 and 15 years.. HIV-positive patients with limited exposure to NRTIs. Initial regimens consisted of efavirenz or indinavir, each combined with 2 NRTIs. A maximum of 2 switches to other regimens was permitted.. The efavirenz-containing triple therapy regimen was predicted to prolong survival at a savings of up to 10,923 US dollars (1998 values) relative to initial therapy with the indinavir-containing regimen. Patients who receive efavirenz are expected to have 11% greater survival at 5 years and fewer treatment failures (28 vs 52%, at 2 years). Overall, the economic and health benefits predicted for the efavirenz-containing regimen were robust to reasonable variation in key parameters.. The superior clinical trial outcomes for efavirenz-containing regimens should translate into substantial economic and health benefits.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Disease Progression; Drug Costs; Drug Therapy, Combination; Health Care Costs; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Models, Economic; Oxazines; Reverse Transcriptase Inhibitors

To determine the safety and antiviral effect of protease inhibitors (PIs) over 36 months in pediatric patients infected with the human immunodeficiency virus (HIV).. Observational study. Pediatric immunodeficiency clinic.. Twenty-one children.. Demographics, dosage regimens, genotype data, viral RNA and CD4+ lymphocyte counts, adverse drug events (ADEs), laboratory tests, and compliance were evaluated over 3 years. Data were analyzed by chi2, repeated measures analysis of variance, and paired t tests.. Twenty-one pediatric patients (aged 3 mo-15 yrs) received PIs over the study period. Average daily doses were ritonavir 26 mg/kg in 12 patients, nelfinavir 94 mg/kg in 16, indinavir 49 mg/kg in 5, and saquinavir 43 mg/kg in 4. Five patients developed resistance to an existing PI. Overall compliance was 70%. Baseline HIV-1 RNA plasma concentrations were significantly higher than average follow-up concentrations during 3-36 months in patients taking ritonavir (p<0.001) and nelfinavir (p<0.001). Sample size was insufficient for indinavir or saquinavir. Sixty ADEs occurred, diarrhea being most common. Of patients with ADEs, 55% required increased monitoring and 43% treatment. Ritonavir was associated with the most ADEs (28), followed by nelfinavir (16), indinavir (11), and saquinavir (5). Significant increases between baseline and follow-up cholesterol levels were found with ritonavir (p=0.02) and nelfinavir (p=0.001), and for serum creatinine (p=0.02) and triglycerides (p=0.02) with ritonavir. Follow-up triglycerides were significantly higher than baseline for indinavir (p=0.003).. Nelfinavir and ritonavir were effective in decreasing HIV-1 viral loads and improving CD4+ lymphocyte counts. Ritonavir was associated with more ADEs than other PIs. Changes in cholesterol, serum creatinine, and triglycerides were noted with some PIs.

Topics: Adolescent; Blood Chemical Analysis; CD4 Lymphocyte Count; Child; Child, Preschool; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Male; Nelfinavir; Ritonavir; RNA, Viral; Saquinavir; Viral Load

Topics: Aged; Antiretroviral Therapy, Highly Active; Dexamethasone; Didanosine; Femur Head Necrosis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Prednisone; Zidovudine

Topics: Acute Disease; Adult; Alcoholism; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Porphyria Cutanea Tarda

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.

Topics: Cohort Studies; DNA, Viral; Female; Genitalia; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Longitudinal Studies; Lymph Nodes; Male; Molecular Sequence Data; Randomized Controlled Trials as Topic; RNA, Viral; Time Factors; Viral Load; Viremia; Virus Replication; Zidovudine

A longitudinal study was conducted to evaluate the viral shedding present in cervicovaginal secretions of HIV-1-seropositive women receiving antiretroviral therapy. A total of 128 paired cervicovaginal and blood samples was obtained from 37 women during a median follow-up period of 21 months. A sensitive, competitive, polymerase chain reaction and a reverse transcription polymerase chain reaction were used for the simultaneous quantitation of HIV-1 proviral DNA and RNA in cervicovaginal cells and cell-free RNA in cervicovaginal secretions, as well as HIV-1 RNA in peripheral blood. The cumulative probability of detecting proviral DNA in genital secretions was significantly higher over time in women with detectable viremia than in women in whom HIV-1 RNA was persistently undetectable in plasma (< 50 copies/ml) (P = 0.028 by log-rank test). The presence and amount of proviral DNA, cell-associated RNA and cell-free RNA in the cervicovaginal secretions were positively correlated with the presence of detectable viremia or the number of HIV-1 RNA copies in plasma (Spearman rank correlation, 0.290, 0.279, and 0.305, respectively; all P < 0.01), but no correlation was found with the CD4+ cell count. In addition, vaginal infections were positively correlated with the detection of proviral DNA in cervicovaginal secretions (odds ratio, 2.60; 95% confidence interval, 1.07-5.70). However, the positive correlation between the presence and amount of HIV in cervicovaginal secretions and the viral load in plasma provides no assurance that HIV shedding does not occur in the genital tract of women with undetectable HIV-RNA in plasma.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Female; Genitalia, Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Longitudinal Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Statistics, Nonparametric; Viral Load; Viremia; Virus Shedding; Zidovudine

Topics: Adult; Crystallization; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Urinalysis; Urologic Diseases

To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen.. A cross-sectional analysis of antiretroviral susceptibility.. HIV clinics in six metropolitan areas.. Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after > or = 6 months of antiretroviral therapy, including the use of one protease inhibitor for > or = 3 months.. The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC50) compared with drug sensitive control virus.. At study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors.. The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.

Topics: Adult; CD4 Lymphocyte Count; Cross-Sectional Studies; Drug Resistance, Microbial; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Phenotype; RNA, Viral; Treatment Failure; Viral Load

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

We report a case of hypercholesterolemia that occurred 2 weeks after the start of highly active antiretroviral therapy following a needlestick exposure to human immunodeficiency virus (HIV) in an HIV-negative health care worker who was receiving thyroid replacement therapy. The elevated thyrotropic hormone level and hypercholesterolemia resolved after the antiretroviral therapy was stopped.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Interactions; Female; Health Personnel; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Indinavir; Lamivudine; Nelfinavir; Occupational Exposure; Reverse Transcriptase Inhibitors; Thyroxine; Zidovudine

The vast majority of HIV-1 infections in Africa are caused by the A and C viral subtypes rather than the B subtype prevalent in the United States and Western Europe. Genomic differences between subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. Because some amino acid polymorphisms occur at sites that have been associated with drug resistance in the B subtype, it is important to assess the effectiveness of protease inhibitors that have been developed against different subtypes. Here we report the enzymatic characterization of HIV-1 proteases with sequences found in drug-naive Ugandan adults. The A protease used in these studies differs in seven positions (I13V/E35D/M36I/R41K/R57K/H69K/L89M) in relation to the consensus B subtype protease. Another protease containing a subset of these amino acid polymorphisms (M36I/R41K/H69K/L89M), which are found in subtype C and other HIV subtypes, also was studied. Both proteases were found to have similar catalytic constants, k(cat), as the B subtype. The C subtype protease displayed lower K(m) values against two different substrates resulting in a higher (2.4-fold) catalytic efficiency than the B subtype protease. Indinavir, ritonavir, saquinavir, and nelfinavir inhibit the A and C subtype proteases with 2.5-7-fold and 2-4.5-fold weaker K(i)s than the B subtype. When all factors are taken into consideration it is found that the C subtype protease has the highest vitality (4-11 higher than the B subtype) whereas the A subtype protease exhibits values ranging between 1.5 and 5. These results point to a higher biochemical fitness of the A and C proteases in the presence of existing inhibitors.

Topics: Adult; Amino Acid Sequence; Catalysis; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Nelfinavir; Protein Structure, Secondary; Ritonavir; Saquinavir; Uganda

HIV-1 can persist in infected patients despite undetectable plasma viremia. To characterize the residual viral load, repetitive blood and tonsillar samples were collected from 11 HIV-1-positive individuals before and during 96 weeks of therapy with zidovudine, lamivudine, and indinavir. HIV-1 RNA in tonsils was quantified by RT-PCR and infectious HIV-1 provirus by the limiting dilution assay. Genotypic resistance analyses and biological characterization were performed on plasma virus, blood, and tonsillar isolates. Tonsillar infectious HIV-1 provirus and HIV-1 RNA declined by 2 and 3 log(10), respectively, but 10(3)-10(4) cells, less than 0.5% of the total body CD4(+) T cell population carrying infectious HIV-1 provirus, remained involved in active viral replication of drug-sensitive R5 viruses. Thus, the dominant HIV-1 residual infection consists of < or = 10(6) latently infected CD4(+) cells. Plasma HIV-1 RNA decline of > 1.5 log(10) during the first 2 weeks of therapy may indicate low levels of this latent reservoir. Whereas the reservoir of latently infected cells remains stable, actively replicating HIV-1 continuously declines during prolonged antiretroviral therapy. Thus, although viral eradication seems unlikely, antiretroviral therapy may induce an extended period of virologic latency in HIV-1-positive individuals.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Longitudinal Studies; Lymphoid Tissue; Phenotype; Proviruses; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Viral Load; Viremia; Virus Replication; Zidovudine

Topics: Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Ritonavir; Treatment Outcome

Highly active antiretroviral therapy in HIV-1 infected patients is associated with a lipodystrophy syndrome, characterized by wasting of peripheral fat, central adiposity, hyperlipidaemia and insulin resistance. The CT findings are presented and the differential diagnosis is discussed.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Mass Index; HIV Infections; Humans; Indinavir; Lamivudine; Lipodystrophy; Male; Tomography, X-Ray Computed; Treatment Outcome; Zidovudine

Topics: Antiretroviral Therapy, Highly Active; DNA, Viral; Drug Resistance, Microbial; Hair; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Longitudinal Studies; RNA, Viral; Viral Load

A rapid, simple and sensitive high-performance liquid chromatographic (HPLC) assay has been developed for the simultaneous quantification of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma. The method involved the solid-phase extraction of the five drugs and the internal standard (I.S., verapamil) from 400 microl of human plasma. The HPLC analysis used a reversed-phase C18 analytical column and a mobile phase consisting of a gradient with 15 mM phosphate buffer (pH 5.75)-acetonitrile and UV monitoring. The method was linear over the therapeutic concentration range for the five HIV-protease inhibitors. The accuracy of the method ranged from 98.2 to 106.7% and the precision values ranged from 1.4 to 8.1% for intra-day precision and from 3.1 to 6.4% for the inter-day values.

Topics: Carbamates; Chromatography, High Pressure Liquid; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Reference Standards; Reproducibility of Results; Ritonavir; Saquinavir; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Sulfonamides

To assess the impact of highly active antiretroviral therapy (HAART) on the prevalence and progression of CMV retinitis (CMVR) among AIDS patients with baseline CD4 cell counts <100 cells x 10(6)/l.. A longitudinal cohort study of 1292 patients. CD4 cell counts and HIV viral load measurements were obtained before commencing therapy, at 3 months, 1 year, 2 years, and at last follow up. The CMVR prevalence rate was measured for the subgroup with baseline CD4 cell counts <100 cells x 10(6)/l. CMVR adverse event (AE) rates per 100 person days at risk were calculated for the subgroup with CMVR and baseline CD4 cell counts <100 cells x 10(6)/l.. 1292 patients were started on HAART. 8% of patients had CD4 counts <50 cells x 10(6)/l and 40% had detectable HIV viral load at last follow up. The prevalence of CMVR for the subgroup with baseline CD4 <100 cells x 10(6)/l was 10%. For those with baseline CD4 <100 cells x 10(6)/l, the mean CMVR AE rate was greatest during the first 6 months of follow up after HAART commencement (p <0.003). The mean AE rate per 100 person days at risk was 0.36 (95% CI 0.167 to 0.551) before starting HAART, and 0.14 (95% CI 0.085 to 0.199) after starting HAART (p = 0.03).. HAART significantly prolongs the disease-free intervals in patients with pre-existing disease but recurrences persist within the first 6 months of starting therapy. AE were absent beyond 18 months of follow up in all patients including those with persistently low CD4 counts and detectable HIV viral load indicating clinical immunorestoration. New methods for monitoring the response to therapy are needed to identify those at risk.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cytomegalovirus Retinitis; Follow-Up Studies; HIV Infections; Humans; Indinavir; Longitudinal Studies; Middle Aged; Nelfinavir; Prevalence; Protease Inhibitors; Ritonavir; Saquinavir; Viral Load

Topics: Adipose Tissue; Adult; Aged; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Middle Aged; Nelfinavir; Retrospective Studies; Ritonavir; Saquinavir; Triglycerides

To determine the factors contributing to changes in bone mineral density (BMD) over time in HIV-infected patients receiving highly active antiretroviral therapy (HAART).. Analyses of lumbar spine BMD in 183 male Caucasian participants in the Western Australian HIV Cohort study, comprising a longitudinal analysis of data from 54 patients on stable HAART regimens, and a cross-sectional analysis comparing data from 131 protease inhibitor (PI)-treated patients and 52 PI-naive (including 28 antiretroviral treatment-naive) patients.. Average lumbar spine BMD remained stable or increased over the time frame considered. Although there was no evidence of a change of average BMD over time in patients receiving nelfinavir (P = 0.92), there was evidence of increasing bone density in the indinavir group (average increase, 0.31 z-score per year; P < 0.001). Lower initial z-scores in the longitudinal analysis were significantly associated with lower pre-HAART BMI (P = 0.003), consistent with results of the cross-sectional analysis in which lowest BMI prior to initial dual X-ray absorptiometry scan was associated with decreased BMD (P = 0.02, overall group). Although PI therapy was also associated with decreased BMD in a univariate analysis of the cross-sectional data (P = 0.04), this effect was abrogated in a multiple linear regression analysis (P = 0.11) with lowest BMI remaining significant (P = 0.04).. We found no evidence, overall, of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens, and propose that indinavir therapy may be associated with an increase in bone mineral density over time. Pre-HAART BMI was an independent and powerful determinant of an individual's initial z-score in the longitudinal analysis, and adjustment for this effect in a cross-sectional analysis abrogated the association between PI therapy and decreased lumbar spine z-score.

Topics: Body Mass Index; Bone Density; Cohort Studies; Cross-Sectional Studies; Heart; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Longitudinal Studies; Male; Nelfinavir; Osteocalcin

Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy for suppression of HIV, but its effects on the immune system are relatively unknown. Recently, it has been reported that PIs inhibit lymphocyte apoptosis. In the present study we have investigated the effects of ex vivo addition of IDV on lymphocyte activation and apoptosis in cells from HIV-infected children (n = 18) and from healthy uninfected individuals (controls, n = 5) as well as in Jurkat and PM1 T-cell lines. Pretreatment of control peripheral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-dependent inhibition of lymphoproliferative responses to different activation stimuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phase in anti-CD3 monoclonal antibody-stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apoptosis of PBMCs from HIV-infected or uninfected individuals or of Fas-induced apoptosis in Jurkat and PM1 T cell lines were not inhibited by IDV. Moreover, IDV did not inhibit activation of caspases-1, -3, -4, -5, -9, and -8 in lysates of Jurkat T cells undergoing Fas-induced apoptosis. The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV.

Topics: Adolescent; Antibodies, Monoclonal; Apoptosis; Caspase Inhibitors; Caspases; CD3 Complex; Cell Cycle; Cell Line; Cells, Cultured; Child; Child, Preschool; Enzyme Inhibitors; fas Receptor; G1 Phase; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infant; Jurkat Cells; Lymphocyte Activation; Lymphocytes; Resting Phase, Cell Cycle

In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown.. To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL).. Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995).. Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine.. Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up.. Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance.. Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Microbial; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Predictive Value of Tests; Prevalence; Proportional Hazards Models; Retrospective Studies; RNA, Viral; Viral Load; Viremia; Virus Replication; Zidovudine

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

P-glycoprotein (P-gp) has been found expressed in normal human cells, such as bone marrow and peripheral blood cells. The aim of this study was to investigate whether HIV-protease inhibitors (HIV-PIs) interact with P-gp efflux function in normal human peripheral blood lymphocytes (PBLs) and CD34+ progenitor cells. Moreover, we analyzed the in vivo effect of HIV-PIs on P-gp function in PBLs from HIV-infected patients receiving highly active antiretroviral therapy (HAART). We found that HIV-PIs (i.e., ritonavir, saquinavir, nelfinavir and indinavir) interfere with P-gp function in normal PBLs as demonstrated by the reduced efflux of rhodamine 123 (Rh123). This effect was dose-dependent and suggested the following hierarchy: ritonavir > saquinavir > nelfinavir > indinavir. We further analyzed the effect of HIV-PIs on the P-gp function in specific PBLs subsets. Our results show an HIV-PI-induced inhibition of P-gp function in CD4+ and CD8+ T cell subsets, mostly caused by the effect on the naive compartment of both CD4+ and CD8+ T cells. The same inhibitory effect was found in CD34+ hematopoietic progenitor cells. With respect to the in vivo evaluation of P-gp function in PBLs from HIV-infected patients, we found reduced levels of Rh123 efflux that reached the lowest value in AIDS patients receiving HAART. We concluded that HIV-PIs interfere with P-gp function in major cellular targets for HIV infection, such as CD4+ T cells and CD34+ progenitor cells. This ability may contribute to P-gp efflux function defect found in HIV-infected patients and suggests that drug interaction studies are crucial to an overall understanding of the effects of this important group of drugs.

Topics: Adult; Antigens, CD34; Antiretroviral Therapy, Highly Active; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Fluorescent Dyes; Hematopoietic Stem Cells; HIV Infections; HIV Protease Inhibitors; Humans; In Vitro Techniques; Indinavir; Lymphocytes; Male; Nelfinavir; Rhodamine 123; Ritonavir; RNA, Viral; Saquinavir

A retrospective person-time analysis of the randomized and non-randomized extension phases of four phase III trials was performed to assess the incidence of adverse cardiovascular events in 2680 HIV-infected patients receiving indinavir or nucleoside reverse transcriptase inhibitor therapy, or both. The observed rate of cardiovascular events was not increased in patients receiving indinavir-based regimens compared with therapy without a protease inhibitor. Extrapolation of these findings is limited by the brief length of therapy and the small number of cases.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Randomized Controlled Trials as Topic; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors

The HIV protease inhibitor indinavir may cause nephrolithiasis and interstitial nephritis. The renal consequences of indinavir-associated nephrotoxicity are uncertain. We report a case of papillary necrosis in a patient treated with indinavir. An asymptomatic HIV-infected woman experienced right-sided renal colicky pain during treatment with indinavir. She passed a non-solid stone and continued indinavir treatment. Intravenous pyelogram performed 20 months later following an episode of left-sided colicky pain showed right-sided papillary necrosis. Indinavir-associated nephrolithiasis and chronic interstitial nephritis were the only possible causes identified in this patient. Physicians should be aware that indinavir nephrolithiasis may cause papillary necrosis.

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney Papillary Necrosis

To assess the pattern of drug resistance mutations selected in HIV-1-infected patients failing a first line triple combination therapy including indinavir.. Plasma samples from 87 patients collected at the time of the first virological rebound (> 50 HIV-RNA copies/ml) were examined for the presence of drug-resistant genotypes.. The mean level of plasma viraemia at rebound was 7824 HIV-1 RNA copies/ml in 73 subjects with good compliance, whereas it was 359,460 HIV-1 RNA copies/ml in 14 patients who admitted to poor adherence. Genetic sequence analysis yielded results for 51 (70%) of the patients having good adherence. More than half of them (26/51, 51%) carried primary mutations associated with resistance to nucleoside analogues. In contrast, primary protease inhibitor resistance mutations were recognized less frequently (14/51, 27%; P < 0.05). Moreover, in 23 (45%) patients there was no evidence of drug-resistant viruses at all. The most frequent drug-resistant genotypes in the reverse transcriptase gene were at codons 184 (n = 19), 215 (n = 14) and 41 (n = 8), whereas for the protease they were at codons 46 (n = 10), 82 (n = 9) and 90 (n = 7). No resistance genotypes were found among non-compliant patients.. The overall rate of drug-resistant HIV genotypes was 38% (28/73) in patients with good adherence and who were experiencing a first virological failure under a triple combination regimen including indinavir; resistance to nucleoside analogues was more frequent than resistance to indinavir. Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Male; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load

Topics: Atrophy; Child, Preschool; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Kidney Cortex

Topics: Abdominal Pain; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Nelfinavir; Oxazines; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Muscle, Skeletal; Osteoporosis

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Ritonavir

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Ritonavir; Viral Load

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Industry; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Viral Load

Topics: Adult; Blood Glucose; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Insulin; Lipodystrophy; Male

Topics: Anti-HIV Agents; Blood Glucose; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Insulin; Nelfinavir

Indinavir is a well-known cause of crystal-induced acute renal failure, dysuria and flank pain, and nephrolithiasis. Recently a more insidious tubulointerstitial lesion has been recognized as secondary to the drug. We report a case of a hepatitis C-positive patient on long-term indinavir therapy for human immunodeficiency virus (HIV) who developed a slowly progressive rise in serum creatinine. Renal biopsy revealed a diffuse interstitial infiltrate with numerous eosinophils and scarring. The tubules showed focal necrosis and dilation with elongated crystals present within their lumina. The elevated serum creatinine decreased to a new baseline over several months with the discontinuation of indinavir. We review the literature of renal syndromes associated with indinavir focusing on chronic progressive tubulointerstitial injury and speculate on risk factors and potential mechanisms of indinavir-induced renal injury.

Topics: Adult; Biomarkers; Blood Urea Nitrogen; Creatinine; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Male

A retrospective study of cases of paronychia associated with anti-retroviral therapy diagnosed in two general hospitals is here reported. Lesions appeared from 3 and 48 months after institution of therapy. At diagnosis, 84.6% of patients were on indinavir therapy. CD4 values ranged from 120 and 1,332 cells/mm3 and viral load was lower than 200 copies/ml in 92.3 of cases. Conservative therapy was applied in 7 patients and surgery in 6. In all patients indinavir therapy was discontinued, and cure was achieved 16 weeks later. The "retinoid" effect of indinavir is discussed as likely pathogenic explanation for this complications. We advocate for topic therapy and change of anti-retroviral therapy, reserving surgery for patients not responding to therapy. Pain and functional limitation caused by this non uncommon complication (1.6% of our patients treated with anti-retroviral agents) makes its knowledge necessary and an active search by clinicians in patients receiving indinavir therapy.

Topics: Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Paronychia; Retrospective Studies

Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in approximately 10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (K(I) = 183 microM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher K(I) (360 microM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.

Topics: Animals; Bilirubin; Carcinoma, Hepatocellular; Glucuronosyltransferase; HIV Infections; HIV Protease Inhibitors; Hyperbilirubinemia; Indinavir; Male; Rats; Rats, Gunn; Rats, Wistar

Topics: Adolescent; Adult; Erectile Dysfunction; HIV Infections; HIV Protease Inhibitors; Hormones; Humans; Indinavir; Male; Middle Aged; Penile Erection; Peripheral Nervous System; Predictive Value of Tests; Reverse Transcriptase Inhibitors; Surveys and Questionnaires

To report a case of symptomatic hyperbilirubinemia resulting from the addition of ritonavir to an indinavir-containing antiretroviral regimen.. A 27-year-old white woman developed symptomatic hyperbilirubinemia and anemia while receiving an indinavir/ritonavir-containing antiretroviral (ARV) regimen that required disruption of therapy. Extensive laboratory examinations were performed including determination of indinavir and ritonavir concentrations. The findings were attributed to two independent processes, an unconjugated hyperbilirubinemia due to indinavir and anemia due to zidovudine.. Indinavir-induced hyperbilirubinemia is generally regarded as an adverse event with no clinical relevance that does not cause significant liver toxicity and does not necessitate discontinuing indinavir. It manifests primarily as an increase in unconjugated bilirubin and is reported to be dose related. We believe that the severe hyperbilirubinemia in this patient was a result of high indinavir concentrations that occurred due to metabolic inhibition caused by ritonavir. The anemia in this case was consistent with erythrocyte maturation arrest due to zidovudine rather than hemolysis.. Combination ARV therapy is the current standard of care for treating patients infected with HIV. It is important for providers to consider that, despite much improved pharmacokinetic profiles associated with pharmacokinetically enhanced protease inhibitor regimens, there may be undesirable effects that may differ in frequency or severity than when drugs are used individually.

Topics: Aged; Anti-HIV Agents; Blood Cell Count; Blood Chemical Analysis; Drug Combinations; Female; HIV Infections; Humans; Hyperbilirubinemia; Indinavir; Ritonavir

Early assessment of antiretroviral drug efficacy is important for prevention of the emergence of drug-resistant virus and unnecessary exposure to ineffective drug regimens. Current US guidelines for changing therapy are based on measurements of plasma HIV-1 RNA concentrations 4 or 8 weeks after the start of treatment with cut-off points of 0.75 or 1.00 log, respectively. We investigated the possibility of assessing drug efficacy from measurements of plasma HIV-1 concentrations made during the first week on therapy.. The kinetics of virus decay in plasma during the first 12 weeks of treatment was analysed for 124 HIV-1-infected patients being treated for the first time with a protease inhibitor. Patients with a continuous decline of HIV-1 concentrations and in whom HIV-1 was either undetectable or declined by more than 1.5 log at 12 weeks were defined as good responders; the rest were poor responders.. The individual virus decay rate constants (k) at day 6 correlated significantly (r>0.66, p<0.0001) with changes in HIV-1 concentrations at 4, 8, and 12 weeks, and correctly predicted 84% of the responses with a cut-off value of k=0.21 per day (in log scale). Reduction in plasma HIV-1 of less than 0.72 log by day 6 after initiation of therapy predicted poor long-term responses in more than 99% of patients.. These results suggest that changes in HIV-1 concentration at day 6 after treatment initiation are major correlates of longer-term virological responses. They offer a very early measure of individual long-term responses, suggesting that treatment could be optimised after only a few days of therapy.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Clinical Trials as Topic; Cohort Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Logistic Models; Predictive Value of Tests; Ritonavir; RNA, Viral

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Protocols; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; RNA, Viral; Viral Load; Zidovudine

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Food-Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Ritonavir; United States

The authors describe a case of severe CMV retinitis in a young adult AIDS patient who recovered following first a course of ganciclovir and then HAART. Six months after the initial episode while still under successful HAART, the patient developed an acute episode of retinitis despite a persistent significant improvement in the immunological picture and a very low level of CMV reactivation. The acute episode can be related to an enhanced individual reactivity to minor CMV replication.

Topics: Acute Disease; Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Cidofovir; Cytomegalovirus Retinitis; Cytosine; Drug Therapy, Combination; Ganciclovir; HIV Infections; Humans; Indinavir; Lamivudine; Male; Organophosphonates; Organophosphorus Compounds; Zidovudine

Topics: Anxiety; Depression; Drug Interactions; Female; Herb-Drug Interactions; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; Humans; Hypericum; Indinavir; Male

T-cell responses were evaluated prospectively in 41 patients with acute human immunodeficiency virus type 1 (HIV-1) infection (30 untreated and 11 receiving zidovudine, lamivudine, and indinavir) and in 38 uninfected adults. By 6-12 months, treated patients had significantly greater median Candida and tetanus lymphoproliferative responses (stimulation index [SI], 76 and 55, respectively) than did untreated patients (SI, 7 and 6, P=.02 and.001, respectively), and the responses of treated patients surpassed those of uninfected adults (SI, 19 and 32, P= .002 and .101, respectively). Unlike the patients in the untreated group, the patients in the treated group mounted a 6-fold increased HIV-1 p24 response (SI increase, 1.0 to 5.7, P= .01) within 3 months. HIV-1-specific cytotoxicity remained detectable in most treated patients. Thus, combination therapy administered within 3-4 months of infection was associated with improved T-cell memory responses that were distinct from those of untreated patients. The amplified HIV-1-specific T-cell responses may help maintain cytotoxic activities.

Topics: Acute Disease; Adult; Anti-HIV Agents; Candida; CD4 Lymphocyte Count; Chronic Disease; Cytokines; Cytotoxicity, Immunologic; Drug Therapy, Combination; Female; HIV Antigens; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; T-Lymphocytes; Tetanus Toxoid; Viral Load; Zidovudine

We have evaluated the use of an ultrasensitive reverse transcriptase (RT) activity assay to monitor plasma viremia in two human immunodeficiency virus type 1 (HIV-1) group O-infected patients treated with stavudine, lamivudine, and indinavir. After a initial decline in RT levels observed at 4 weeks of therapy, RT-based plasma viremia returned to baseline values at 28 or 44 weeks of treatment. The rebound in levels of RT activity was associated with the detection of phenotypic resistance to lamivudine and with the Met184Val mutation. Analysis of RT activity in plasma provides a sequence-independent means of monitoring virus loads in HIV-1 group O-infected patients.

Topics: Adult; Anti-HIV Agents; Female; Guinea; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Molecular Sequence Data; Spain; Stavudine; Viral Load; Viremia

Loss of viral suppression in patients infected with human immunodeficiency virus (HIV), who are receiving potent antiretroviral therapy, has been attributed to outgrowth of drug-resistant virus; however, resistance patterns are not well characterized in patients whose protease inhibitor combination therapy fails afterachieving viral suppression.. To characterize drug susceptibility of virus from HIV-infected patients who are failing to sustain suppression while taking an indinavir-containing antiretroviral regimen.. Substudy of the AIDS Clinical Trials Group 343, a multicenter clinical research trial conducted between February 1997 and October 1998.. Twenty-six subjects who experienced rebound (HIV RNA level > or =200 copies/mL) during indinavir monotherapy (n = 9) or triple-drug therapy (indinavir, lamivudine, and zidovudine; n = 17) after initially achieving suppression while receiving all 3 drugs, and 10 control subjects who had viral suppression while receiving triple-drug therapy.. Drug susceptibility, determined by a phenotypic assay and genotypic evidence of resistance assessed by nucleotide sequencing of protease and reverse transcriptase, compared among the 3 patient groups.. Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 10(2) to 10(5) copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03).. Loss of viral suppression may be due to suboptimal antiviral potency, and selection of a predominantly indinavir-resistant virus population may be delayed for months even in the presence of ongoing indinavir therapy. The results suggest possible value in assessing strategies using drug components of failing regimens evaluated with resistance testing.

Topics: Anti-HIV Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Phenotype; RNA, Viral; Treatment Failure; Viral Load; Zidovudine

The impact of emergence of genetic resistance, soon after the beginning of antiretroviral therapy, on the genotype of other viral loci not implicated in the development of resistance was studied in four human immunodeficiency type 1 (HIV-1)-infected patients subjected to indinavir monotherapy. Two patients were chosen because they showed no decrease in virus load during the study period and two were selected because they showed a rapid decline in plasma viraemia after the initiation of therapy and a virus rebound after 12 weeks of treatment. The evolution of virus sequences was analysed within the four infected patients by examining virus sequences spanning the protease and C2-V3 env genes by RT-PCR of plasma samples obtained at the beginning and after 12 weeks of therapy. PCR products from the two genomic regions from the two sample points per patient were cloned and 10-15 clones from each sample were sequenced. Genotypic indinavir resistance was present in the four patients after 12 weeks of therapy. The overall protease and C2-V3 env regions quasispecies diversity at time zero was higher than that after 12 weeks of therapy, but this difference was more significant in the two patients who showed a reduction in virus load soon after the initiation of treatment. C2-V3 env sequences indicated that changes during emergence of resistance to indinavir were only detected in the two patients who showed a drastic reduction in virus load. Thus, a temporal relationship was observed between the start of therapy, a drastic reduction in virus load and a drift in the HIV-1 env quasispecies.

Topics: Amino Acid Sequence; Cloning, Molecular; Drug Resistance, Microbial; Evolution, Molecular; Gene Frequency; Genes, env; HIV Envelope Protein gp120; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Peptide Fragments; Reverse Transcriptase Polymerase Chain Reaction; Sequence Alignment; Sequence Analysis, DNA; Viral Load

Topics: HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; RNA, Viral; Treatment Outcome

The introduction of HIV-1 protease inhibitors into the treatment of patients infected with HIV-1 has had a major influence on clinical practice. However, the use of protease inhibitors is frequently associated with the development of resistance and several side effects and interactions with other drugs have been reported.. We present the first pediatric patient with paronychia with pyogenic granuloma associated with the administration of the protease inhibitor indinavir. Clinical findings are discussed in view of a possible interference of indinavir with endogenous retinoid metabolism.. Considerable evidence advocates the mediation of indinavir side effects by impaired oxidative metabolism of retinoic acid through the inhibition of cytochromes P450 3A by indinavir rather than by impaired formation of 9-cis-retinoic acid.

Topics: Adolescent; Child; Granuloma, Pyogenic; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Paronychia; Retinoids; Skin Diseases; Toes

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

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

A study of HIV post-exposure prophylaxis in 28 recipients showed that indinavir-containing regimens were poorly tolerated. This finding has implications for compliance and efficacy of the currently recommended combinations.

Topics: Anti-HIV Agents; Drug Combinations; Drug Tolerance; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; London; Needlestick Injuries; Patient Compliance; Personnel, Hospital; Retrospective Studies; Zidovudine

Antiretroviral therapy increases the number of both CD4+ and CD8+ T cells in the blood of HIV-1-positive patients with advanced disease. In the present study, we have examined the kinetics of CD4+ and CD8+ T cell restoration in blood and lymphoid tissue in asymptomatic HIV-1-positive individuals with high CD4+ cell counts during highly active antiretroviral treatment. Tonsillar biopsies and blood samples were collected at baseline and at regular intervals during the following 48 weeks and from HIV-1-negative controls. Mononuclear cells from blood and tonsils were phenotyped and quantified by three-color flow cytometry. After 48 weeks of therapy, blood CD4+ cell counts in the HIV-1-infected group were comparable to those found in uninfected controls. Naive CD4+ T cells in blood increased during the initial 2 weeks in parallel with reduced plasma viremia. Both naive and memory CD4+ T cells in blood reached normal numbers by week 48, whereas the CD4+ naive/memory cell ratio in tonsils was within normal range throughout the study. The level of memory CD8+ T cells in blood declined during the first 8 weeks in parallel with a reduction in the tonsillar memory CD8+ T cells. Naive CD8+ T cells in the blood increased after 4 weeks, while the level of naive CD8+ T cells in tonsils remained unaltered. Our data indicate that in the early stages of HIV-1 infection antiretroviral therapy normalizes CD4+ cell counts and causes a decrease in the level of memory CD8+ cells in blood and lymphoid tissue, suggesting reduced CD8+ cell turnover in response to reduced viral replication.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Male; Palatine Tonsil; Reverse Transcriptase Inhibitors; T-Lymphocyte Subsets; Time Factors; Viremia; Zidovudine

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

Topics: Adult; Atrophy; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypertension; Indinavir; Kidney

Indinavir sulfate has been reported to cause asymptomatic crystalluria and nephrolithiasis in patients with human immunodeficiency virus (HIV) infection. Patients taking indinavir may present with asymptomatic crystalluria, nephrolithiasis with frank renal colic and obstruction, flank pain in the absence of nephrolithiasis, and dysuria or urgency. Asymptomatic crystalluria has been described as benign. Discontinuation of the drug has not been recommended in the absence of nephrolithiasis. We report two HIV-positive patients receiving indinavir who developed acute interstitial nephritis with foreign body giant cell reaction on renal biopsies. Both patients had asymptomatic crystalluria, although crystals were associated with clumps of white blood cells (WBCs) on urinalysis in one patient. Both cases show that the inflammatory response was significant enough to lead to tubular injury and acute renal impairment. Our findings suggest that asymptomatic crystalluria attributable to indinavir may illicit an inflammatory response with acute renal insufficiency, warranting monitoring of renal function, especially in patients with crystalluria.

Topics: Adult; Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney; Male; Middle Aged; Nephritis, Interstitial; Urine

Efficacy of a 3-drug combination (Zidovudine (AZT) + Lamivudine (3TC) + Indinavir (IDV)) has been evaluated in 17 anti-viral naive patients with HIV infection for 24 months. Our genotypic resistance assay was able to analyze more than 80% of the patients whose viral load (VL) was over 3,000 copies/ml. This therapy was continued in 11 patients (65%) for 24 months. Among them, VL was undetectable (VL < 400 copies/ml) in patients at 24 month (47% by intent-to-treat, 72% by on treatment). Of the 11 patients, a 3TC resistance-related mutantion was detected in only one case. The therapy was discontinued in 6 cases. Main reasons of the discontinuation were side effects. However, if the therapy was switched to other combinations when VL was undetectable, VL remained undetectable in 5 cases at 24 month.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Zidovudine

The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-cell responses. We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-gamma) production by CD8(+) T cells. In some patients, particularly those initiating three-drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of anti-HIV-1 CD8(+) T cells that correlated with decreases in HIV-1 RNA and increases in T-cell counts. In the other patients, HIV-1-specific T-cell functions either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HIV-1 RNA. These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8(+) T cells specific for the cytomegalovirus pp65 matrix protein. The level and breadth of CD8(+) cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN-gamma production and HLA tetramer staining after combination therapy, were related to the corresponding responses prior to treatment. There was, however, a stable, residual population of potentially immunocompetent HIV-1-specific T cells remaining after therapy, as shown by tetramer staining of CD8(+) CD45RO(+) cells. These results indicate that new strategies will be needed to target residual, immunocompetent HIV-1-specific CD8(+) T cells to enhance the effectiveness of antiretroviral therapy in patients with advanced immunodeficiency.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cell Lineage; Drug Therapy, Combination; Gene Products, gag; Gene Products, pol; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Interferon-gamma; Lamivudine; Longitudinal Studies; Lymphocyte Activation; Peptides; Phenotype; Phosphoproteins; Reverse Transcriptase Inhibitors; T-Lymphocytes, Cytotoxic; Viral Load; Viral Matrix Proteins; Zidovudine

Topics: Antidepressive Agents; Drug Antagonism; HIV Infections; HIV Protease Inhibitors; Humans; Hypericum; Indinavir; Plants, Medicinal

Topics: Adult; Anti-HIV Agents; Hemolysis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

Antiretroviral therapy (ART) and Caesarean section (CS) delivery significantly reduce the risk of vertically transmitted HIV infection. Attention must focus on determining the optimal management strategy for HIV-positive pregnancies. Guidelines must reflect not only the activity and tolerability of combination ART in pregnancy for mother and infant and the potential short and long-term infant toxicity, but also whether surgical delivery can confer an added benefit if combination ART had reduced plasma viraemia to undetectable levels. To aid the development of management strategies for the Republic of Ireland, a retrospective detailed review of all HIV-positive pregnancies since the introduction of combination ART was undertaken. Since 1997 there have been 25 deliveries to 24 women. Combination ART reduced plasma viraemia to undetectable levels in 76% mothers at delivery. The CS rate was 28% and no unanticipated infant toxicity was encountered. To date no infant has proven infected. Three infants have seroreverted and 24 of 26 infants have had at least 2 negative HIV ribonucleic acid (RNA) and polymerase chain reaction (PCR) tests. Two infants are less than one month old. In this study, the CS rate of 28% is below that reported from many centres yet no vertical transmission was found. Given the efficacy of ART in reducing plasma viraemia, the additional benefit of CS for these women is questionable.

Topics: Adolescent; Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Infant; Lamivudine; Male; Nelfinavir; Nevirapine; Pregnancy; Pregnancy Outcome; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Outcome; Zidovudine

To report a case of antiretroviral therapy failure caused by an interaction between carbamazepine and indinavir.. A 48-year-old HIV-positive white man was treated with antiretroviral triple therapy, consisting of indinavir, zidovudine, and lamivudine. His HIV-RNA (viral load) became undetectable (<400 copies/mL) less than two months after this therapy was started; this was confirmed one month later. Shortly after the start of antiretroviral therapy, the patient developed herpes zoster, which was treated with famciclovir. Tramadol was initially prescribed for postherpetic neuralgia; however, this was substituted with carbamazepine due to insufficient analgesic effect. Indinavir plasma concentrations decreased substantially during carbamazepine therapy. Carbamazepine was stopped after 2.5 months and, two weeks later, the HIV-RNA was detectable (6 x 103 copies/mL). Resistance for lamivudine was observed in that blood sample; resistance for zidovudine might have been present, and resistance to indinavir was not detected. A few months later, a further increase of the HIV-RNA occurred (300 x 103 copies/mL), after which the therapy was switched to a new antiretroviral regimen containing nevirapine, didanosine, and stavudine.. Physicians may prescribe carbamazepine for HIV-infected patients to treat seizures or postherpetic neuralgia, which are complications of opportunistic infections such as herpes zoster or toxoplasmosis. Carbamazepine is a potent enzyme inducer, predominantly of the CYP3A enzyme system, while HIV-protease inhibitors such as indinavir are substrates for and inhibitors of CYP3A. Therefore, an interaction between these drugs could be expected. A low dose of carbamazepine (200 mg/d) and the usual dose of indinavir (800 mg q8h) in our patient resulted in carbamazepine concentrations within the therapeutic range for epilepsy treatment; indinavir concentrations dropped substantially. The virologic, resistance, and plasma drug concentration data, as well as the chronology of events, are highly indicative of antiretroviral treatment failure due to the interaction between carbamazepine and indinavir.. Concomitant use of carbamazepine and indinavir may cause failure of antiretroviral therapy due to insufficient indinavir plasma concentrations. Drugs other than carbamazepine should be considered to prevent this interaction. Amitriptyline or gabapentin are alternatives for postherpetic neuralgia; valproic acid or lamotrigine are alternatives for seizures. When alternate drug therapy is not possible, dosage adjustments, therapeutic drug monitoring, and careful clinical observation may help reduce adverse clinical consequences.

Topics: Anti-HIV Agents; Anticonvulsants; Carbamazepine; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Drug Therapy, Combination; HIV; HIV Infections; Humans; Indinavir; Male; Middle Aged; Seizures; Treatment Failure

Topics: Alkynes; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Oxazines; Research Design; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine

Since the availability of protease inhibitors in 1997, there has been a great change in antiretroviral therapy but also new long term side effects have emerged, mainly metabolic changes such as hypertriglyceridemia, hypercholesteremia and hyperglycemia. Besides, fat redistribution has been observed. Fat wastes in the face and limbs but accumulates in the adipose tissue of the dorsocervical and abdominal region and the breasts. The mechanism of these changes remains unclear. For therapy a protease inhibitor free therapy or lipid lowering drugs may be tried. 29 of our 224 patients developed lipodystrophy. 27 of these patients had been treated with a protease inhibitor (17 patients with indinavir); 2 of the patients had never received protease inhibitors.

Topics: Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperglycemia; Hypertriglyceridemia; Indinavir; Lipodystrophy; Male; Syndrome

As part of an on-going study on the suitability of a formal therapeutic drug monitoring (TDM) of antiviral drugs for improving the management of HIV infection, a high-performance liquid chromatography method has been developed to quantify simultaneously in plasma five HIV protease inhibitors (PIs) (i.e., indinavir, amprenavir, saquinavir, ritonavir, nelfinavir) and the novel non-nucleoside reverse transcriptase inhibitor efavirenz. After viral inactivation by heat (60 degrees C for 60 min), plasma (600 microl), with clozapine added as internal standard, is diluted 1:1 with phosphate buffer, pH 7 and subjected to a solid-phase extraction on a C18 cartridge. Matrix components are eliminated with 2 x 500 microl of a solution of 0.1% H3PO4 neutralised with NaOH to pH 7. PIs and efavirenz are eluted with 3 x 500 microl MeOH. The resulting eluate is evaporated under nitrogen at room temperature and is reconstituted in 100 microl 50% MeOH. A 40-microl volume is subjected to HPLC analysis onto a Nucleosil 100, 5 microm C18 AB column, using a gradient elution of MeCN and phosphate buffer adjusted to pH 5.15 and containing 0.02% sodium heptanesulfonate: 15:85 at 0 min-->30:70 at 2 min-->32:68 at 8 min-->42:58 at 18 min-->46:54 at 34 min, followed by column cleaning with MeCN-buffer, pH 5.15 (90:10), onto which 0.3% AcOH is added. Clozapine, indinavir, amprenavir, saquinavir, ritonavir, efavirenz and nelfinavir are detected by UV at 201 nm at a retention time of 8.2, 13.0, 16.3, 21.5, 26.5, 28.7 and 31.9 min, respectively. The total run time for a single analysis is 47 min, including the washing-out and reequilibration steps. The calibration curves are linear over the range 100-10,000 ng/ml. The absolute recovery of PIs/efavirenz is always higher than 88%. The method is precise with mean inter-day relative standard deviations within 2.5-9.8% and accurate (range of inter-day deviations -4.6 to +4.3%). The in vitro stability of plasma spiked with PIs/efavirenz at 750, 3000 and 9000 ng/ml has been studied at room temperature, -20 degrees C and +60 degrees C. The method has been validated and is currently applied to the monitoring of PIs and efavirenz in HIV patients. This HPLC assay may help clinicians confronted to questionable compliance, side effects or treatment failure in elucidating whether patients are exposed to adequate circulating drug levels. The availability of such an assay represents an essential step in elucidating the utility of a formal TDM for the opt

Topics: Alkynes; Benzoxazines; Calibration; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Stability; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Oxazines; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

Topics: Adult; Anti-HIV Agents; Child; Cytokines; Drug Therapy, Combination; HIV Infections; HIV Seronegativity; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Zidovudine

Topics: Antidepressive Agents; Depression; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Hypericum; Indinavir; Phytotherapy; Plants, Medicinal

To ascertain whether initiation of protease inhibitors was associated with a change in depressive symptoms among persons infected with HIV.. Study subjects included men and women who were enrolled in the HIV/AIDS Drug Treatment Program and who had completed an annual participant survey before and after initiating triple combination therapy with a protease inhibitor. Depressive symptoms were assessed using the Centre for Epidemiologic Studies-Depression scale (CES-D). Statistical analyses to determine the change in CES-D total and subscale scores before and after protease inhibitor use were conducted using parametric and multivariate methods.. Our analysis was restricted to 453 participants. Of these 234 (52%) were depressed at baseline (CES-D score > or = 16). Compared with nondepressed participants, depressed participants were slightly younger (p = .048), less likely to be employed (p < .001) and more likely to have an annual income less than $10,000 per annum (p < .001). After adjusting for CD4 count, employment status, income, age, and CES-D total or subscale score at baseline, we found a significant improvement in total scale score (p = .001) and depressive mood (p = .002), positive affects (p = .005), and somatic symptoms (p = .011) subscale scores at follow-up. There was no significant change in the interpersonal relations score over the study period.. Our findings indicate that in addition to conferring impressive clinical benefits, protease inhibitor use is associated with a significant improvement in HIV-positive individuals' mental health.

Topics: Adult; Anti-HIV Agents; Depression; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Psychiatric Status Rating Scales; Reverse Transcriptase Inhibitors; Saquinavir; Treatment Outcome

We report a case of post-kala-azar dermal leishmaniasis (PKDL) in a woman with AIDS which occurred 13 months after a diagnosis of visceral leishmaniasis concomitantly with immunological recovery induced by highly active retroviral therapy. Cytokine pattern at the time of visceral leishmaniasis and PKDL diagnosis was studied and pathogenic implications were discussed.

Topics: Adult; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Indinavir; Lamivudine; Leishmania infantum; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Stavudine

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

A HIV-1 patient database was scanned in March 1998, and 750 patients were identified who had received HAART including indinavir. Of these, 28 cases had nephrolithiasis; and 85 asymptomatic indinavir-treated patients were randomly selected as controls. The characteristics of cases and controls were compared by analysis of variance for quantitative parameters and by Fisher's exact test for classes.. We observed a significant increase in the incidence of nephrolithiasis in patients co-infected with HIV-1 and either hepatitis C virus (HCV) (HCV RNA-positive) or hepatitis B virus (HBV) (HBs antigen-positive) (odds ratio and 95% confidence intervals: 2.8 and 1.1-7.7), whereas no significant differences were demonstrated between cases and controls with regard to age (42.4 +/- 8.0 versus 39.8 +/- 9.8 years), sex (male patients 70.4 versus 74.1%), duration of HIV-1 infection (8.6 +/- 3.1 versus 7.7 +/- 4.0 years), duration of indinavir treatment (16.1 +/- 5.8 versus 14.1 +/- 5.4 months), AST increase > or = 1.25 of normal (29.6 versus 25.9%), or ALT increase > or = 1.25 of normal (33.3 versus 22.4%). In co-infected patients, ALT increase (> or = 1.25 of normal), but not AST increase, at the time of indinavir initiation was statistically related to the occurrence of nephrolithiasis.. We found a significant increase of nephrolithiasis incidence in patients co-infected with HIV-1 and HCV or HBV, which suggests that underlying multifactorial hepatic damage may limit liver catabolism of indinavir, and consequently increase its renal excretion and the risk of nephrolithiasis. Caution is therefore advised when initiating indinavir treatment in HIV patients with evidence of HBV or HCV infection.

Topics: Adult; Anti-HIV Agents; Case-Control Studies; Databases, Factual; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Incidence; Indinavir; Kidney Calculi; Male; Middle Aged; Reverse Transcriptase Inhibitors

We retrospectively studied 38 Italian recently HIV-1-infected subjects who seroconverted from 1994 to 1997 to investigate: (i) the prevalence of nucleoside reverse transcriptase inhibitors (NRTI)-related mutations at primary infection; (ii) the proportion of naturally occurring mutations in reverse transcriptase (RT) and protease regions of patients naive for non-nucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs); (iii) the drug-susceptibility to NRTIs and PIs in subjects with NRTI- and/or PI-related mutations; and (iv) the outcome of seroconverters treated with various NRTIs or NRTI/PI regimens. Baseline HIV-1 plasma viraemia and absolute CD4 count at baseline could not be used to distinguish patients with NRTI- and/or PI-related pre-existing mutations from those with wild-type virus (P = 0.693 and P = 0.542, respectively). The frequency of zidovudine-related mutations was 21% in the study period. The response to treatment was not significantly different in subjects with or without genotypic zidovudine-related mutations at primary infection (P = 0.744 for HIV-1 RNA and P = 0.102 for CD4 cells). Some natural variation (2.6%) was present within regions 98-108 and 179-190 of RT involved in NNRTI resistance. The high natural polymorphism in the protease region present in our patients was similar to that reported by others. In our study some PI-associated substitutions, thought to be compensatory in protease enzymatic function, could confer intermediate to high PI-resistance. As discrepancies between genotypic and phenotypic results may exist in recent seroconverters, our data suggest that the role of transmitted NRTI- and PI-resistant variants remain to be fully elucidated in vivo.

Topics: Anti-HIV Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Gene Products, pol; Genotype; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Mutation; Phenotype; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Outcome; Zidovudine

Hyperglycemia and new-onset diabetes mellitus have been reported to occur in HIV-infected patients treated with protease inhibitors.. To determine the effect of protease inhibitor therapy on serum glucose in a predominantly minority patient population.. Retrospective record review.. Clinical HIV program of an urban Veterans Affairs medical center.. All HIV-infected patients receiving a protease inhibitor over a one-year period from September 1996 through August 1997.. One hundred seventeen patients not previously known to be diabetic received protease inhibitors; seven (6%) developed symptomatic diabetes mellitus. Eight other patients had one or more serum glucose values >150 mg/dL. Mean random glucose values for patients who did not develop diabetes were higher during therapy than prior to initiation of protease inhibitors.. Urban minority HIV-infected patients receiving combination antiretroviral therapy including a protease inhibitor may be at increased risk for the development of hyperglycemia and diabetes mellitus. Risk factors for diabetes mellitus should be identified and blood glucose monitored in all patients receiving protease inhibitors.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperglycemia; Indinavir; Male; Middle Aged; Minority Groups; Retrospective Studies; Risk Factors; Ritonavir; Saquinavir; Urban Population

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors

Topics: Adolescent; Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Transfusion Reaction; Zidovudine

Topics: Adolescent; Adult; Cheilitis; Female; HIV Infections; Humans; Indinavir; Male; Middle Aged; Nails, Ingrown; Paronychia; Protease Inhibitors; Skin Diseases; Time Factors

Topics: Adult; Anti-HIV Agents; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Nelfinavir; Ritonavir; Saquinavir; Triglycerides

We present the case of a 55-year-old heterosexual man who had a generalized alopecia and mood changes associated with the antiretroviral protease inhibitor; indinavir within 6 months of use. This was reversed within 3 months of change of therapy to the protease inhibitor, nelfinavir with demonstrable changes in his Hospital Anxiety and Depression (HAD) scale scores.

Topics: Alopecia; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Irritable Mood; Male; Middle Aged

Long-term therapeutic success of powerful antiretroviral treatments dependent on patient adherence. This study was conducted to assess the difficulties HIV-infected patients with advanced-stage disease encounter in adhering to antiretroviral treatments with a protease inhibitor.. A prospective self-administered questionnaire survey was conducted at our outpatient clinic for 2 months. CD4 counts and HIV viral loads were also determined.. Seventy-one percent of the study population which included 262 responded to the questionnaire. The survey was made a median 215 days after initiating the antiprotease treatment with indinavir (71% of the cases), ritonavir (13%), saquinavir (6%), or a combination of protease inhibitors (10%). At onset of antiprotease treatment, mean CD4 count was 171+/-150/mm(3) and mean HIV viral load was 75,000 copies/ml. The treatment was considered to be difficult to take by 43% of the patients; 66% stated they had forgotten to take their drugs at least once a month. It was most difficult to take the drugs prescribed for the afternoon. Shifts of 1 hour were observed in 58% of patients. Non-adherence was frequent (1 failure to take drugs per week), observed in 13% of patients. Most often, the patients stated they had forgotten to take their drugs because of occupational or relational difficulties (52%). Non-adherence increased with duration of treatment. The drug most often associated with non-adherence was indinavir (73%). Age and sex did not influence adherence. Mean RNA HIV serum level was lower than at onset of the antiprotease treatment in the most non-adherent patients. At the time of the questionnaire, there was no difference in serum RNA HIV level or in the percentage of patients with an undetectable level between non-adherent and adherent patients.. This survey confirmed difficulties in adherence are frequent and worsen with time. No relationship was found between non-adherence and reduction in viral load, suggesting that a short-term effect of these very active drugs despite lack of perfect adherence. Other factors (pharmacology, sensitivity to antiretroviral drugs.) also play a major role in therapeutic success.

Topics: Adult; Aged; CD4 Lymphocyte Count; Cross-Sectional Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Patient Compliance; Prospective Studies; Ritonavir; Saquinavir; Severity of Illness Index; Surveys and Questionnaires; Viral Load

To compare self-reported nonadherence with antiretroviral therapy (ART) with predose plasma levels of protease inhibitor (PI).. A cross-sectional study of consecutive patients from a university-based HIV clinic in Rome, Italy, was conducted. One hundred and forty HIV-infected patients were prescribed regimens containing ritonavir or indinavir. A patient questionnaire assessing knowledge of treatment regimen, adherence behavior, reasons for taking and missing therapy, factors influencing adherence, and health behaviors was administered. A predose PI plasma level was measured concurrently.. By patient report, 12% missed at least one dose "yesterday," and 24% missed doses in the last 3 days; 14% had a predose plasma concentration below the assay limit of quantitation (2 ritonavir and 18 indinavir samples). Confusion, poor psychological well-being, long office wait, running out of drugs between visits, having relatives to remind the patient to take medication, children, and alteration of sense of taste were related to unquantifiable predose levels of PI. In multivariable analysis, reported nonadherence (odds ratio [OR], 15.8; 95% confidence interval [CI], 4.0-63.3) and confusion (OR, 9.9; 95% CI, 1.4-69.6) were related to unquantifiable predose levels of PI.. Self-report of missing a dose of antiretroviral medication "yesterday" was related to an unmeasurable plasma PI level.

Topics: Adult; Analysis of Variance; Anti-HIV Agents; Cross-Sectional Studies; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Hospitals, University; Humans; Indinavir; Male; Outpatient Clinics, Hospital; Patient Compliance; Ritonavir; Rome; Treatment Refusal

The presence of the HIV-protease inhibitor indinavir in saliva was analyzed to investigate whether salivary indinavir concentrations are applicable to monitor compliance and/or predict plasma indinavir levels. Fourteen HIV-infected outpatients treated with indinavir and 24 healthy volunteers who ingested a single dose of indinavir were included. Paired plasma and citric-acid-stimulated saliva samples were analyzed by high-performance liquid chromatography (HPLC). Stimulated salivary indinavir concentrations showed a high correlation (r = 0.85, p < 0.01) with corresponding plasma levels. The median saliva/plasma ratio was 65% (P25 50%; P75 94%). The ratios were independent of the plasma concentration; however, a relation with time after ingestion was seen. The unbound fraction of indinavir in plasma was not significantly correlated with the saliva/plasma ratio after stimulated saliva collection, in contrast with a subset of nonstimulated saliva from healthy volunteers, where we did find a significant correlation. Although stimulated salivary indinavir concentrations are highly correlated with plasma concentrations, it is not possible to predict plasma indinavir levels by the salivary concentrations for purposes of therapeutic drug monitoring, due to large interindividual and intraindividual variation. Nevertheless, monitoring compliance by measuring the presence of indinavir in saliva is possible: ingestion of indinavir can be assessed with a sensitivity of 84.8% in the whole dosing interval or with 98.8% between 1 and 6 hours after the last dose, which is comparable with plasma.

Topics: Adolescent; Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hydrogen-Ion Concentration; Indinavir; Male; Middle Aged; Orosomucoid; Patient Compliance; Saliva

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

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hypercholesterolemia; Hypertriglyceridemia; Indinavir; Middle Aged; Nausea; Oxazines; Ritonavir

To model the dynamics of HIV-1 rebound in patients receiving suboptimal therapy after suppression of plasma viremia to < 200 copies/ml by triple combination therapy.. Mathematical modeling of data from 23 patients switched to indinavir maintenance therapy after viral replication was suppressed with a combination of indinavir, zidovudine and lamivudine. Modeling of HIV-1 rebound among 24 patients on zidovudine/lamivudine maintenance was also performed for comparison.. Evaluation of slopes of rebound and of their heterogeneity; calculation of the basic reproductive number (Ro, the number of newly infected cells arising from each productively infected cell); regression analyses for predictors of the slope of rebound.. Rebound of plasma HIV RNA followed a sigmoid curve with an initial exponential phase. There was significant heterogeneity in the slopes of rebound for individual patients (P < 0.001). In the indinavir maintenance rebounds, the average initial slope was estimated to be 0.587/day (doubling time 1.2 days). The slopes of rebound in patients on zidovudine/lamivudine maintenance tended to be less steep on average (P = 0.025). Among patients taking indinavir maintenance, the average Ro for the initial rebound of viremia was 4.3; in multivariate regressions, the slope of rebound was steeper during early rebound and in patients with higher viral load at the start of triple therapy or a higher CD4 cell count when indinavir monotherapy was initiated. The slope was less steep in patients with a greater increase in the number of CD4 cells during triple therapy.. The rates of viral load increase among patients with viral rebound while receiving less than triple therapy are similar to those reported in patients interrupting therapy. Variability among patients may depend on viral fitness, target cell availability and extent of immune reconstitution.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Models, Biological; Predictive Value of Tests; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Virus Replication; Zidovudine

Topics: Adult; Anti-HIV Agents; Arthritis; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Synovial Fluid

Topics: Acne Vulgaris; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Isotretinoin; Reverse Transcriptase Inhibitors

The administration of antiretroviral compounds to our cohort of HIV-infected patients was assessed since 1994, on the ground of some epidemiological, clinical, and therapeutic variables. During the six-year study period, a significant increase of mean prescription rate of overall anti-HIV agents was observed, with a nearly 10-fold rise of mean prescribed daily doses per 1,000 patients-year. In particular, lamivudine and indinavir represented the most frequently administered drugs, among nucleoside analogues and protease inhibitors, respectively. A significant increase of the percentage of HIV-infected patients undergoing combined antiretroviral therapy (79.3% in 1999), and the mean number of drugs prescribed per patient (3.02 in 1999), was concurrently detected. The progressive changes of antiretroviral therapy guidelines were responsible for a nearly 16-fold increase of expenditures directly related to antiretroviral drug administration in 1999 compared with 1994 (with over 41% of costs related to protease inhibitors). On the other hand, a substantial modification of HIV disease evolution occurred in our patient cohort in terms of absolute morbidity and mortality figures, as expressed by a drop of notified AIDS cases and AIDS-related deaths ranging from 2.5 to 5 times, during the considered period.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Cohort Studies; Drug Costs; Drug Prescriptions; Health Expenditures; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Italy; Lamivudine; Retrospective Studies; Reverse Transcriptase Inhibitors

Topics: Adult; Cheilitis; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

Topics: Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Salvage Therapy

The therapeutic success of an antiretroviral salvage regimen containing protease inhibitors (PI) is limited by PI-resistant viral strains exhibiting various degrees of resistance and cross-resistance. To evaluate the extent of cross-resistance to the new PI amprenavir, 155 samples from 132 human immunodeficiency virus type 1-infected patients were analyzed for viral genotype by direct sequencing of the protease gene. Concomitantly, drug sensitivity to indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir was analyzed by a recombinant virus assay. A total of 111 patients had been pretreated with 1-4 PI, but all were naive to amprenavir. A total of 105 samples (67.7%) were sensitive to amprenavir; 25 samples (16.1%) were intermediately resistant, and another 25 samples were highly resistant (4- to 8-fold- and >8-fold-reduced sensitivity, respectively). The mutations 46I/L, 54L/V, 84V, and 90M showed the strongest association with amprenavir resistance (P < 0. 0001). The scoring system using 84V and/or any two of a number of mutations (10I/R/V/F, 46I/L, 54L/V, and 90M) predicted amprenavir resistance with a sensitivity of 86.0% and a specificity of 81.0% within the analyzed group of samples. Of 62 samples with resistance against 4 PI, 23 (37.1%) were still sensitive to amprenavir. In comparison, only 2 of 23 samples (8.7%) from nelfinavir-naive patients with resistance against indinavir, saquinavir, and ritonavir were still sensitive to nelfinavir. Amprenavir thus appears to be an interesting alternative for PI salvage therapy.

Topics: Carbamates; Drug Resistance, Microbial; Drug Resistance, Multiple; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Ritonavir; Saquinavir; Sulfonamides

Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones. We evaluated a cohort of patients positive for HIV on indinavir to determine the incidence of indinavir nephrolithiasis and identify risk factors for indinavir stone formation.. Our cohort study of the prevalence of indinavir nephrolithiasis included 155 patients with HIV for 5,732 patient-weeks. The same cohort was then used for a retrospective chart review to assess patient age, weight, duration of drug use, time to stone formation, CD4 count, creatinine, alanine transaminase, and urinary pH and specific gravity as risk factors for stone formation.. We estimated the cumulative incidence of indinavir stone formation by the Kaplan-Meier product limit estimator method. At 78 weeks 43.2% of patients had stones (95% confidence interval [CI] 0.292 to 0.543). Increasing age was the only variable that was a statistically significant predictor of indinavair urolithiasis (relative risk 0.955, 95% CI 0.918 to 0.993, p = 0.0159). The mean duration plus or minus standard deviation of indinavir use was statistically the same in each group (42.5 +/- 27. 2 and 40.3 +/- 27.1 weeks in those without and with stones, respectively) despite the observed mean time to stone formation of 23.0 +/- 19.8 weeks.. The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported. Nephrolithiasis during indinavir use does not appear to induce patients to withdraw from the drug.

Topics: Adult; Age Factors; Cohort Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney Calculi; Multivariate Analysis; Proportional Hazards Models; Retrospective Studies; Risk Factors

To quantify unbound indinavir concentrations and characterize indinavir plasma protein binding in HIV-infected adults.. Pharmacokinetic study in antiretroviral-naive, HIV-infected persons with CD4 T lymphocytes > 100 x 10(6) cells/L and HIV-RNA in plasma >5000 copies/ml at baseline who were participating in an open-label study of zidovudine, lamivudine and indinavir therapy.. Eight men underwent 8 h intensive pharmacokinetic studies for indinavir on two occasions 6 months apart. Unbound indinavir was separated by ultra-filtration, and unbound and total concentrations were quantified by a validated high-performance liquid chromatography method.. Overall indinavir protein binding was 61+/-6%, with a range among the profiles of 54 to 70%. Indinavir binding was higher at the 8 h post-dose concentration compared with the 1 h post-dose concentration (66 versus 57%, P = 0.0006).. The mean 61% protein binding for indinavir in these HIV-infected persons is similar to the in vitro report of 60%. However, the fraction bound was concentration-dependent, and considerable variability in binding was present among patients. Quantification of unbound protease inhibitor concentrations opens new avenues of research to advance our understanding of the pharmacologically-relevant moieties of antiretroviral agents and thereby the pharmacotherapy of HIV infection.

Topics: Adult; Blood Proteins; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Protein Binding

To describe our experience with human immunodeficiency virus (HIV) infected patients receiving protease inhibitor therapy who presented with adhesive capsulitis of the shoulder.. Between July 1996 and December 1999, 8 HIV-infected patients (7 male) treated with protease inhibitors who presented with adhesive capsulitis of the shoulder were retrospectively identified. Diagnosis of adhesive capsulitis relied on clinical features including shoulder pain and both active and passive restricted range of motion (ROM). All available clinical and radiographic data were reviewed.. Onset of symptoms was insidious, and at presentation, patients complained of shoulder pain, which was bilateral in 4 of the 8 cases. Physical examination showed global restriction of active and passive ROM of the glenohumeral joint. The mean delay between initiation of HIV protease inhibitors and onset of shoulder pain was 14 months (range 2 to 36). The protease inhibitor therapy always included indinavir. No underlying condition associated with secondary adhesive capsulitis of the shoulder, including shoulder trauma, diabetes mellitus, thyroid disease, pulmonary or cardiac diseases could be identified. In all 8 patients, despite continuation of therapy with indinavir, both shoulder pain and restricted ROM completely resolved, after a mean disease course of 7.4 months.. Adhesive capsulitis of shoulder seems to be a new adverse event of HIV protease inhibitor therapy. In all reported cases, patients were treated with indinavir. Further observations will be necessary to confirm adhesive capsulitis as a side effect.

Topics: Adult; Bursitis; Female; HIV Infections; Humans; Indinavir; Male; Middle Aged; Pain; Protease Inhibitors; Range of Motion, Articular; Recovery of Function

To assess genotypic resistance mutations in patients with virological failure with highly active antiretroviral therapy (HAART) METHODS: Genotyping of reverse transcriptase (RT) and protease (PRO) HIV-1 genes were carried out in 33 adherent patients failing on HAART.. Resistance mutations were found in 32 of the 33; 27 of them (81.8%) being primary mutations: 26 (78.8%) in the RT gene and 60 (60.6%) in the PRO gene. Overall, 66.6% had genotypic resistance to two drugs and 60.6% showed resistance to drugs belonging to the two main classes of antiretroviral drugs. At the time of treatment failure, 72.7% had on their therapeutic regimen one antiretroviral drug to which they had resistance mutations, 48.5% had genotypic resistance to two drugs of the therapeutic regimen and 21.2% to three drugs.. Most adherent patients failing on HAART carry drug resistant genotypes. These patients may constitute a reservoir of multidrug resistant HIV that may limit treatment options in the future.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Microbial; Endopeptidases; Female; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Mutation; Nevirapine; Protease Inhibitors; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Treatment Failure; Zidovudine

Topics: Adult; Anuria; Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Urine

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

A 60-year-old male had tested in 1986, at age 46, positive for human immunodeficiency virus (HIV). In mid-1996 he was started on a protease inhibitor regimen, which included indinavir, lamivudine and stavudine, and remained on this therapy until his death. In April 1999 he was hospitalized after a fainting episode. Although examination focusing on cardiac disease did not disclose any remarkable findings, he died suddenly one week after being discharged from hospital. At autopsy the kidneys were enlarged, with a total weight of 500 g, patchy pale gray and pinkish. Microscopy showed leukocytic cell casts in many of the tubules and collecting ducts. In many of these casts there were clefts left by crystals. In the interstitium, both in the cortex and the medulla, there was focal inflammation and fibrosis. Death was attributed to sudden cardiac dysfunction, probably ventricular fibrillation as a consequence of severe nephropathy with electrolyte disturbances. It is likely that kidney damage developed secondary to the indinavir treatment as indinavir can cause not only nephrolithiasis but also crystal-induced acute renal failure.

Topics: Acute Kidney Injury; AIDS Dementia Complex; Antiretroviral Therapy, Highly Active; Crystallization; Death, Sudden, Cardiac; Diagnosis, Differential; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Solubility; Stavudine; Syncope; Ventricular Fibrillation; Water-Electrolyte Imbalance

This research comprised a pilot open prospective clinical study comparing T-cell subset reconstitution in antiretroviral-naive patients, after 12 months of HAART when treatment was initiated in early stages (ES; n = 18) of infection versus advanced stages (AS; n = 20).. 10 healthy HIV-negative individuals. Immunophenotypic markers were evaluated before and after 6-and 12-months' therapy. Functional assays were performed in one subset.. Viral load (VL) was < 200 copies/ml in all patients. Median percentages of CD4+ pretherapy were 33% and 6%, respectively, in the ES and AS groups, increment after 12 months of therapy was +15% and +13% respectively. Only the ES group achieved normal values. Declines of CD8+ percentage were significantly higher in the ES (-18%) than in the AS group (-2%). CD4+ memory and naive cells in the ES group were similar to those of controls before treatment and did not change after therapy. In contrast, CD4+ memory and naive cells in the AS group did not reach normal levels despite treatment. In the ES group, there was a significant increment in CD8+ naive cells (+8%) and a decrement in CD8+CD38+ cells (-17%), both populations reached values close to normal, whereas these subsets remained far from normal in the AS group. Improvement of lymphoproliferative response after therapy was observed in both groups. One patient in the ES group showed positive LPR against p24 after treatment. After 12 months' highly active antiretroviral therapy, only those who began such therapy in ES disease reached values within the range of healthy controls. To achieve a more complete immunologic reconstitution, early initiation of potent antiretroviral therapy should be recommended.

Topics: Adult; Aged; Antibodies, Monoclonal; Antiretroviral Therapy, Highly Active; Female; Flow Cytometry; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Lymphocyte Count; Male; Middle Aged; Pilot Projects; Prospective Studies; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Viral; Scintillation Counting; Statistics, Nonparametric; Stavudine; T-Lymphocyte Subsets; Tritium; Viral Load

The objective of this work was to assess the prevalence of human immunodeficiency virus-related oral lesions (HIV-ROL) in HIV-positive/acquired immunodeficiency syndrome (AIDS) patients receiving highly active antiretroviral therapy (HAART) including HIV-protease inhibitors. One hundred fifty-five (154) AIDS patients (69 intravenous drug users [IDU], 53 heterosexuals, 29 males who have sex with males, 1 transfused, and 2 of unknown contagious source) receiving HAART, were examined. We found the following prevalences: HIV-ROL 53.2%; oral candidiasis 34.4%; hairy leucoplakia 26.6%; xerostomia 15.5%; herpes simplex labialis 1.9%; HIV/periodontitis-gingivitis 0.6%. No cases of Kaposi's sarcoma were observed. The highest prevalence of HIV-ROL was found in the IDU group, and in patients with viral load more than 10,000 copies and CD4(+) cell count less than 200. Using our historical controls, this suggests that the prevalence of all oral lesions, particularly oral candidiasis, herpes simplex labiali, Kaposi's sarcoma, and periodontal disease has decreased more than 30% after the institution of HAART.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Candidiasis, Oral; Case-Control Studies; CD4 Lymphocyte Count; Female; Gingivitis; Herpes Labialis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Leukoplakia, Hairy; Male; Middle Aged; Mouth Diseases; Periodontitis; Prevalence; Viral Load; Xerostomia; Zidovudine

Topics: Antimalarials; Antiretroviral Therapy, Highly Active; Drug Interactions; Half-Life; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Malaria; Mefloquine; Nelfinavir

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Follow-Up Studies; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Liver Function Tests; Male; Ritonavir

Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Retrospective Studies; Spain; Stavudine; Treatment Outcome

A 40-year-old HIV-infected woman developed nausea, vomiting, and epigastric pain and died following her third dose (per study protocol) of interleukin (IL)-2. Her HIV infection was diagnosed in 1996. Her last CD4 cell count was 390/microL, and her viral load was negligible (as of November 28, 1998). She had no known general risk factors for thrombosis other than HIV infection, injection drug abuse, and antiretroviral therapy with indinavir. Abdominal films showed no sign of mechanical obstruction but a generalized gas distention of the bowel, which was suggestive of paralytic ileus. Autopsy revealed dilation of the small bowel with extensive necrosis and hemorrhage involving all the segments. The superior and inferior mesenteric arteries revealed severe atherosclerosis. The stenotic celiac artery was occluded by a recent thrombus at the aortic ostium. Clinicians need to be aware of the potential for thrombosis and accelerated atherosclerosis in HIV-infected patients. Both injection drug abuse and protease inhibitors, such as indinavir, have been shown to be risk factors for thrombosis. However, it is likely IL-2 contributed to the severe thrombosis in this patient, although definitive proof is lacking. An acute awareness of intestinal infarction in HIV-infected patients is warranted.

Topics: Adult; Anti-HIV Agents; Celiac Artery; Female; HIV Infections; Humans; Indinavir; Infarction; Interleukin-2; Intestines; Mesenteric Arteries; Mesenteric Vascular Occlusion; Radiography; Thrombosis

Topics: Adult; Anti-HIV Agents; Diabetes Mellitus; Diagnosis, Differential; HIV Infections; Humans; Indinavir; Male

To assess the prognostic role of proviral DNA in peripheral blood mononuclear cells (PBMC) of patients with undetectable viremia over long-term highly active antiretroviral therapy (HAART).. Eighty-two human immunodeficiency virus (HIV)-1-infected patients, free of acquired immunodeficiency syndrome (AIDS), received zidovudine plus lamivudine plus indinavir. Levels of plasma HIV-RNA, and PBMC proviral DNA and RNA unspliced (US) transcripts were evaluated by using competitive polymerase chain reaction (cPCR) assays, every 3 months over 1 year.. Among patients with undetectable viremia at baseline, 13 of 18 with CD4 cell count 350/mm3 or less and 12 of 16 with CD4 between 351 and 700/mm3, constantly maintained undetectable RNA levels; in these patients, a mean proviral DNA decrease of 0.67 6 0.7 and 1.03 6 0.53 log (P < 0.001), respectively, a significant decrease of RNA-US transcripts (P < 0.001), and significant correlations between decreases of proviral DNA and RNA-US transcripts (P = 0.008 and P < 0.001, respectively) were observed.. Proviral DNA quantitation permits the continued monitoring of HAART in patients with undetectable viremia.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; DNA, Viral; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Polymerase Chain Reaction; Proviruses; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viremia; Zidovudine

St. John's wort, an herbal treatment for depression, should not be combined with certain drugs, including some antiretrovirals. St. John's wort can speed up the body's elimination of some drugs. When HIV medications are used, blood levels could drop low enough to allow resistance to occur. So far, St. John's wort has been tested only with the protease inhibitor indinavir (Crixivan), but it is likely to affect other drugs in that class and possibly non-nucleoside reverse transcriptase inhibitors. This warning follows a study by the National Institutes of Health (NIH) on dosing and blood levels of indinavir in HIV-negative test subjects. More information on the study is available on The Lancet's Web site. The text of the FDA's advisory letter is included.

Topics: Depression; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Hypericum; Indinavir; Plants, Medicinal

Topics: Drug Resistance, Microbial; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Practice Guidelines as Topic

Topics: Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir

The genetic variation of the human immunodeficiency virus type 1 (HIV-1) protease gene (prt) permits the classification of HIV-1 strains into five distinct protease subtypes, which follow the gag subtyping patterns. The susceptibilities of non-B-subtype strains to protease inhibitors (PIs) and other antiretroviral drugs remain largely unknown. Subtype F is the main non-B strain contributing to the Brazilian epidemic, accounting for 15 to 20% of these infections. In this work, we report the findings on 81 isolates from PI-naive Brazilian patients collected between 1993 and 1997. In addition, the relevant PI resistance mutations and their phenotypes were determined in vitro for 15 of these patients (B = 9 and F = 6). Among these, the subtype F samples evidenced high sensitivities in vitro to ritonavir and indinavir, with MICs at which 50 and 90% of the isolates are inhibited similar to those of both the Brazilian and the U.S. subtype B isolates. Analysis of the 81 Brazilian prt sequences demonstrated that the subtype F consensus sequence differs from the U.S. and Brazilian subtype B consensus in eight positions (I15V, E35D, M36I, R41K, R57K, Q61N, L63P, and L89M). The frequency of critical PI resistance substitutions (amino acid changes D30N, V82A/F/T, I84V, N88D, and L90M) among Brazilian isolates is very low (mean, 2.5%), and the associated secondary substitutions (amino acid positions 10L, 20K, 36M, 46M, 48G, 54I, 63P, 71A, and 77A) are infrequent. These observations document the relative rarity of resistance to PIs in the treatment of patients infected with HIV-1 subtype F in South America.

Topics: Amino Acid Sequence; Anti-HIV Agents; Brazil; DNA, Viral; Genetic Variation; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Microbial Sensitivity Tests; Molecular Sequence Data; Phylogeny; Saquinavir; Sequence Homology, Amino Acid

Interest has recently focused on anti-HIV prophylaxis in case of sexual exposure. A circular from the French Ministry of Health (DGS/DH n(o) 97/560, 12 August 1997) envisages such treatment in certain risk situations such as sexual aggression. The toxic risk of prescribing a tritherapy or a bitherapy, even for a short period of a few weeks must be considered.. A 20-year-old rape victim with an uneventful medical history was given a prophylactic regimen including zidovudine, laminovudine and indinavir. Three months later, she developed free-bilirubin jaundice with biological signs of hemolysis.. We draw attention to the risk of severe adverse effects of short-duration anti-HIV prophylaxis in apparently healthy subjects. The protocol must included careful patient information and rigorous surveillance.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Bilirubin; Female; HIV Infections; Humans; Indinavir; Jaundice; Rape; Retroviridae Infections; Zidovudine

Topics: Adult; Hemophilia A; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney; Male; Time Factors; Ultrasonography

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antifungal Agents; Drug Interactions; Fluconazole; HIV Infections; HIV Seropositivity; Humans; Indinavir

Significant diversity exists in amino acid sequences encoding HIV-1 protease in individuals naive for protease inhibitors, which could influence the rate of evolution of resistance. High-level resistance to indinavir requires multiple substitutions among at least 11 amino acid sites, and no single substitution was observed in all of 29 resistant isolates obtained from patients on long-term indinavir monotherapy. We have analyzed the evolution of PR in these sequences. The divergence from the baseline amino acid sequence by week 24 was 4%, increasing more than 7% by week 60. The mean difference between sequences from different patients at baseline was 6% (3-9%), rising to 10% after 40 weeks (3-16%), although at all time points nonsynonymous substitutions were less frequent than synonymous nucleotide changes. Analysis of associations between variants at different amino acid sites using a mutual information statistic revealed four pairs of sites to be significantly associated. In three cases these associations included residue 82. Clusters of baseline and week 24 amino acid sequences identified by maximum parsimony did not correlate significantly with the IC95 to indinavir, although a weak correlation of baseline clusters with phenotype at the week 24 time point was suggested.

Topics: Amino Acid Sequence; Drug Resistance, Microbial; Genetic Variation; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Phylogeny; Time Factors

To evaluate specific urological abnormalities in patients treated with the protease inhibitor indinavir.. A series of 155 consecutive human immunodeficiency virus-positive patients were treated with indinavir 800 mg p.o. three times a day. Of these, 14 (9%) treated for 1-321 (average 110) days experienced severe flank pain and were subjected to clinical and laboratory examinations.. Abdominal X-ray was consistently negative for stones. Ultrasonography showed upper-tract dilatation in 12 patients. Intravenous urography showed obstruction above a radiolucent obstacle in 7 patients; in 2 cases, there was a marked delay in urine excretion on the obstructed side. The mean urine pH was 6. Urine culture was negative. Serum uric acid, phosphorus, and calcium levels were normal. In 8 patients there was slight renal insufficiency, and 4 patients required ureteral stenting. In all cases, hyperhydration and oral analgesia led to a favorable outcome. In 3 patients, chemical analysis of the stone demonstrated monohydrate indinavir crystals.. In our experience, indinavir therapy is associated with urolithiasis in 9% of the cases. Hydration, analgesia, and acidification of the urine usually lead to a favorable clinical outcome. Prophylactic hydration and acidification of the urine are extremely important.

Topics: Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Prospective Studies; Urinary Calculi

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lipodystrophy; Male; Middle Aged

We report the case of a 38-year-old male who developed renal insufficiency while on the protease inhibitor, indinavir. This patient had an increase in serum creatinine over a period of approximately one year, along with persistently abnormal urinalysis. A renal biopsy was performed and showed marked tubular crystal deposition. The indinavir was discontinued, and after two months the patient's serum creatinine and urinalysis returned to normal. To our knowledge this is the second case of indinavir associated nephropathy.

Topics: Adult; Biopsy; Clinical Trials, Phase I as Topic; Creatinine; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Glomerulus; Male; Renal Insufficiency

To assess the relationship between indinavir-associated urological complaints and indinavir plasma concentrations.. Case series, comparing indinavir plasma concentrations in cases with average concentrations in a control group.. Patients taking 800 mg indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of indinavir plasma concentrations from a control group of 14 patients taking 800 mg indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of indinavir.. Seventeen patients (five women) were enrolled and the indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with indinavir concentrations above the upper 95% limit, indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months.. Urological complications occurring during indinavir treatment were associated with elevated indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Urologic Diseases; Viral Load

Topics: Acute Disease; Adult; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Porphyrias

Topics: Adult; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Psoriasis; Reverse Transcriptase Inhibitors; Viral Load; Zalcitabine; Zidovudine

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Thrombocytopenia

We report a case of simultaneous infection with hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) in a 26-year-old Japanese homosexual man. He was admitted to our hospital for acute hepatitis caused by HBV. At that time, HIV-1antibody (Ab) was not detected in his serum. After 6 months, he was readmitted to our hospital for further examination of his liver because of confined liver enzyme abnormalities. Anti-HIV- Ab was detected in his serum by both enzyme immunosorbent assay (EIA) and particle agglutination (PA). His serum HIV-1 RNA level was 50 x 10(4) copies/ml and serum levels of HBV DNA polymerase (DNA-P) and HBV DNA were 6535cpm and 3 plus (>1000 copies/ml). His clinical course and laboratory data suggested progression from acute to chronic hepatitis related to coinfection with HIV-1. The diagnosis was chronic active hepatitis caused by HBV as an opportunistic infection due to coinfection with HIV-1. We began highly active antiretroviral therapy (HAART) because interferon (IFN) therapy was ineffective. HAART was started at an initial dosage of 600 mg zidovudine (AZT), 300 mg lamivudine (3TC), and 2400 mg indinavir (IDV) daily. After 4 weeks, the serum level of HBV DNA-polymerase (p) had decreased markedly to 37cpm and that of HIV-1 RNA had decreased to below the sensitivity threshold, indicating considerable suppression of the replication of these viruses by the treatment. But HBV DNA remained at low levels. Although the incidence of HBV infection in patients with HIV-1 infection has been reported to be high in the United States and Europe, simultaneous HBV and HIV-1 infection leading to persistent HBV infection is rare.

Topics: Adult; Anti-HIV Agents; Biopsy, Needle; Drug Therapy, Combination; Gene Products, pol; Hepatitis B Antibodies; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Liver; Male; Zidovudine

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Students, Medical; Travel; Zidovudine

A model was developed to gain insight into the potential clinical and economic impact of antiretroviral therapy for HIV-infected patients. Observed HIV RNA levels and CD4 cell counts are used in the model to estimate the probability that an individual progresses from asymptomatic infection to the first AIDS-defining illness and death and to estimate the total net cost of care and long-term cost-effectiveness of antiretroviral therapy. The model was applied to patients in a clinical trial (Merck protocol 035) that compared the surrogate marker response to triple therapy with indinavir (IDV; 800 mg every 8 hr) plus zidovudine (ZDV; 200 mg every 8 hr) plus lamivudine (3TC; 150 mg twice a day) to double therapy with ZDV+3TC. The model projected that for an individual without AIDS who received triple therapy the progression to AIDS and death would be delayed more than for a patient who received double therapy with ZDV+3TC if no other treatment options were offered. Because of this delay in disease progression, the total discounted cost over the initial 5-year period was projected to be $5100 lower for patients who received triple therapy compared with double therapy if suppression with triple therapy lasts up to 3 years. If suppression with triple therapy lasts up to 5 years, costs were projected to be higher with the triple combination, but 81% of the cost is offset by lower disease costs as a result of fewer patients progressing to AIDS. Over 20 years, total discounted cost was projected to be higher for the triple-therapy regimen primarily because of a longer estimated survival time. At 20 years, the incremental cost per life-year gained by adding IDV to a ZDV+3TC regimen was estimated at $13,229, which is well within the range of other widely accepted medical interventions.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Cost-Benefit Analysis; Costs and Cost Analysis; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Models, Biological; Models, Economic; Outcome and Process Assessment, Health Care; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome; Viral Load; Zidovudine

This study investigated the effects of a combination antiretroviral drug regimen (indinavir and two nucleoside analogs or ritonavir and saquinavir) on the levels of CD34+ colony-forming units (CFU-Cs) in the peripheral blood of HIV-1+ patients. Ten patients who were receiving combination antiretroviral drug therapy were studied and their peripheral blood CD34+ CFU-Cs were measured prior to, 1 month after, and 4 to 6 months after the commencement of therapy. The levels of CD4+ T cells increased significantly in these patients (paired t test, p = 0.0027) and plasma viral load became undetectable in all but one patient studied. Measurements of the CFU-Cs showed that their levels tended to increase on the commencement of therapy, and these levels became significantly higher than baseline by 4-6 months (paired t test, p = 0.0293). Analysis of the different colony phenotype demonstrated that the main contributor to this increase consisted of burst-forming unit erythroid (BFU-E) cells. These data also demonstrated that there was an inverse correlation between the rise in CFU-Cs at 4-6 months compared with CD4+ cell, CD8+ cell, and neutrophil counts, and hemoglobin concentration, at baseline. The demonstrated increase in the levels of CD34+ CFU-Cs suggests that HIV-1 may have an inhibitory effect on these cells in vivo, and that this inhibition may be abrogated by suppression of viral replication.

Topics: Adult; Anti-HIV Agents; Antigens, CD34; Cells, Cultured; Drug Therapy, Combination; Hematopoietic Stem Cells; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Middle Aged; Ritonavir; Saquinavir

Topics: Anti-HIV Agents; Creatinine; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Kidney; Kidney Function Tests; Male; Retrospective Studies

Human papilloma virus (HPV)-related cutaneous manifestations occur with increased frequency and severity among HIV-infected persons. In this report, we describe an HIV-infected man with persistent, severe cutaneous hand warts that did not respond to multiple therapies, including liquid nitrogen cryotherapy, topical dinitrochlorobenzene, topical podophyllin, and intralesional interferon-alfa injections. Approximately 1 year after starting a potent protease inhibitor-containing antiretroviral regimen, the patient's recalcitrant cutaneous warts markedly diminished in size, even though the patient did not receive any specific therapy for the warts after starting aggressive antiretroviral therapy. The patient continued on a potent protease inhibitor-containing antiretroviral regimen and, approximately 2 years later, the warts completely resolved. Our patient's dramatic clinical improvement of cutaneous HPV infection that followed protease inhibitor-containing antiretroviral therapy provides a clear-cut example that protease inhibitor-containing combination antiretroviral therapy can produce significant clinical benefit.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; Cryosurgery; Dinitrochlorobenzene; Hand Dermatoses; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interferon-alpha; Keratolytic Agents; Male; Papillomaviridae; Papillomavirus Infections; Podophyllin; Treatment Outcome; Tumor Virus Infections; Warts

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anti-HIV Agents; Antiviral Agents; Bacterial Vaccines; Blood Donors; Clinical Trials as Topic; Drug Therapy, Combination; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interferons; Lamivudine; Middle Aged; Multicenter Studies as Topic; Pneumonia, Pneumococcal; Randomized Controlled Trials as Topic; Ribavirin; Streptococcus pneumoniae; Transfusion Reaction; Zidovudine

We report six HIV patients who developed painful periungual inflammation of several nails during treatment with the antiretroviral drugs indinavir and lamivudine. The lesions appeared 2-12 months after starting treatment. The occurrence of paronychia in HIV patients has recently been reported in two groups of patients receiving either indinavir or lamivudine. Dermatologists should be aware of this recently reported and probably not uncommon side-effect of antiretroviral treatment in order to avoid an invasive approach to the nail lesions.

Topics: Administration, Topical; Adult; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Clobetasol; Drug Therapy, Combination; Female; Glucocorticoids; HIV Infections; Humans; Indinavir; Lamivudine; Male; Middle Aged; Mupirocin; Paronychia

A sensitive high-performance liquid chromatographic method has been developed for the simultaneous determination of the four licensed HIV-protease inhibitors indinavir, nelfinavir, saquinavir and ritonavir. An aliquot of 500 microl plasma, spiked with internal standard, was extracted with 0.5 ml 0.1 M NH4OH and 5 ml methyl tert.-butyl ether. After evaporating, the residue was dissolved in eluent consisting of acetonitrile-50 mM phosphate buffer, pH 5.63 (40:60, v/v). Subsequently, the eluent was washed with hexane. Chromatography was performed using a C18 reversed-phase column and gradient elution with a linear increase of acetonitrile from 36 to 66%. Ultraviolet detection at 215 nm was used. Linearity of the method was obtained in the concentration range of 45-30 000 ng/ml for all four analytes. The method was validated extensively and stability tests under various conditions were performed. The assay is now in use to analyse plasma samples from patients treated with (combinations of) HIV-protease inhibitors.

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Reproducibility of Results; Ritonavir; Saquinavir; Spectrophotometry, Ultraviolet

Human immunodeficiency virus type 1 (HIV-1) amino acid substitutions observed during antiretroviral drug therapy may be caused by drug selection, non-drug-related evolution, or sampling error introduced by the sequencing process. We analyzed HIV-1 sequences from 371 untreated patients and from 178 patients receiving a single protease inhibitor. Amino acid substitution patterns during treatment were compared with inferred substitution patterns arising evolutionarily without treatment. Our results suggest that most treatment-associated amino acid substitutions are caused by selective drug pressure, including substitutions not previously associated with drug resistance.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Genetic Variation; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Nelfinavir; Ritonavir; Saquinavir

HIV-induced CD4 lymphocyte depletion is partially reversed by antiretroviral therapy but it is unclear if the degree to which the CD4 count rises depends on viral suppression (if so, the extent of viral suppression required to achieve a maximal CD4 count rise), whether the rise is sustainable and whether it occurs in patients with CD4 count <10 x 10(6) cells/l. We aimed to address these issues.. We studied CD4 count and plasma HIV RNA values every 4 weeks for 72 weeks in 154 patients starting indinavir-containing regimens.. Mean baseline HIV RNA and CD4 count were 4.8 log10 copies/ml and 180 x 10(6) cells/l, respectively. Overall, there was a mean increase in CD4 count of 143 x 10(6) cells/l by 72 weeks. The adjusted mean increase (adjusted for initial viral load, CD4 count and age) was strongly related to the mean viral suppression over the follow-up period (P < 0.0001). Importantly, there was a highly significant difference (P = 0.0004) in the rise in CD4 count between those with 2-3 log suppression (161 x 10(6) cells/l) and those with > 3 log suppression (314 x 10(6) cells/l; mean 3.6 log suppression in this group), suggesting that with even greater suppression the rise in CD4 lymphocytes may be still larger. We also studied whether CD4 counts were still rising after 72 weeks in patients with sustained suppression of at least 3 log in viral load. There was a significant (P = 0.004; paired t-test) rise in count of 43 x 10(6) cells/l between weeks 64 and 72 in these patients, suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed. Patients with initial CD4 counts < 10 x 10(6) cells/l experienced no smaller rises than those at higher levels, even after adjustment for other factors.. These results strongly support a direct causal relationship between HIV replication and CD4 lymphocyte count depletion. The rise in those with > 3 log suppression provides the best available indicator of the potential for natural CD4 regeneration in HIV-infected patients. However, since still greater CD4 count rises may be seen with more suppressive regimens, it may not be possible to study the intrinsic CD4 regenerative capacity until such regimens are available.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load

Topics: Adult; Anti-HIV Agents; HIV Infections; Humans; Indinavir; Kidney Calculi; Male; Radiography

To determine the variability of indinavir pharmacokinetics in patients attending an outpatient clinic, and to explore relationships between indinavir exposure and antiviral effect.. Open, formal pharmacokinetic evaluation.. University-affiliated clinical research center.. Forty-three adults infected with the human immunodeficiency virus (HIV) receiving therapy with indinavir and concomitant nucleoside reverse transcriptase inhibitors.. Indinavir concentrations were measured after patients were observed taking an 800-mg oral dose, and pharmacokinetic parameters were determined using a one-compartment oral absorption model. Virologic and pharmacologic characteristics were compared in a subset of 23 patients who were protease inhibitor naive before receiving indinavir.. Mean indinavir pharmacokinetics were similar to those reported previously. Significant intersubject variability in systemic exposure was observed in patients receiving the same dosage; the 8-hour area under the curve (AUC8) ranged from 5.4-68.0 microM x hour. In protease inhibitor-naive subjects, the indinavir AUC8 was statistically higher in those with undetectable plasma HIV RNA (30.7 microM x hr) versus detectable plasma HIV RNA (22.4 microM x hr, p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8-hour concentrations were also significantly higher in patients with undetectable plasma HIV RNA (both p=0.007).. Indinavir plasma concentrations were highly variable among patients receiving the same dosage. Patients with an undetectable plasma HIV RNA level who were protease inhibitor naive had statistically higher indinavir concentrations and slower oral clearance than the group with detectable HIV RNA. Relationships between indinavir concentrations and anti-HIV effect provide a basis for quantifying the pharmacologic contribution to the heterogeneity in therapeutic response.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

Topics: Anti-HIV Agents; Dacryocystorhinostomy; Drug Therapy, Combination; HIV Infections; HIV Seropositivity; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Male; Middle Aged; Needlestick Injuries; Occupational Exposure; Ophthalmology; Primary Prevention; Risk Factors; Zidovudine

To assess the impact of long-term virus suppression on the peripheral blood CD4 T cells integrated and total HIV-1 DNA loads in patients receiving highly active antiretroviral therapy (HAART).. A total of 10 HIV-1-infected patients receiving a triple combination therapy (two nucleoside analogues and one protease inhibitor) were longitudinally studied to compare integrated and total HIV-1 DNA loads. HIV-1 DNA quantification was performed using a quantitative nested polymerase chain reaction (PCR) on genomic peripheral blood mononuclear cell (PBMC) DNA obtained at baseline and at 48 weeks of HAART.. All the study patients showed an early and sustained decrease in plasma HIV-1 RNA to below the limit of detection (200 copies/ml). Concordant with the plasma viral decline, a significant increase in the CD4 T cell count was observed (P = 0.007). A statistically significant fivefold decrease in total HIV-1 DNA was detected after 48 weeks of HAART (P = 0.005). However, no statistically significant change was noted after the therapy when the integrated HIV-1 DNA copy number was compared (P = 0.333). Taken together, these results suggest that in the patients analysed the integrated HIV-1 DNA does not decay rapidly after HAART.. Within the study cohort the total amount of PBMC HIV-1 DNA decreased drastically after 48 weeks of HAART. Nevertheless, the integrated HIV-1 DNA did not significantly decay during this period. Although the data presented here are limited by the number of patients analysed, our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Proviruses; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load

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

Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38(+) activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Cytotoxicity, Immunologic; Drug Therapy, Combination; Epitopes, T-Lymphocyte; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Longitudinal Studies; Reverse Transcriptase Inhibitors; Stavudine; T-Lymphocytes, Cytotoxic; Viral Load; Viremia; Zidovudine

We evaluated the radiographic characteristics as well as the clinical management of urolithiasis induced by systemic therapy with indinavir sulfate, a protease inhibitor utilized in the treatment of HIV infection.. Fifteen consecutive HIV-positive male patients (average age 41.3 years) who presented with urolithiasis while being treated with indinavir sulfate (average time 11.1 months) were studied.. All patients presented with flank pain, and eight had gross hematuria. All but one patient had microscopic hematuria. The location of the stones was the kidney in three, the proximal ureter in four, and the distal ureter in nine. One patient had both a renal and a proximal ureteral stone. The stones were radiolucent on CT imaging in five patients and could not be seen in five. In the five cases in which a stone was not definitely identified, a diagnosis of urolithiasis was established on the basis of ureteral obstruction and periureteral/renal streaking noted on CT. Treatment included observation with hydration in eight patients, ureteral stent placement in two patients, ureteroscopy in three patients, and extracorporeal shockwave lithotripsy in two patients. Stones were analyzed in five patients and proved to be 100% indinavir in three and a mixture of indinavir, calcium oxalate monohydrate, and calcium oxalate dihydrate in two.. Urolithiasis is a recognized complication of treatment with indinavir sulfate. Pure indinavir stones cannot be seen on CT unless intravenous contrast medium is utilized. Mixed calcium and indinavir stones can occur and may be radiopaque. The majority of HIV-positive patients with symptomatic urolithiasis can be treated conservatively with hydration. Metabolic evaluation of these patients with identification and correction of factors predisposing to stone formation may minimize future recurrences. Administration of this effective medication thus can continue uninterrupted.

Topics: Adult; Endoscopy; Follow-Up Studies; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lithotripsy; Male; Middle Aged; Stents; Tomography, X-Ray Computed; Ureteroscopy; Urinary Calculi

To assess the efficacy of salvage therapy containing ritonavir and saquinavir after failure of indinavir- or nelfinavir-containing regimens, and to determine correlates of success or failure.. Retrospective chart review. SETTING. The Moore Clinic - the HIV clinic of Johns Hopkins Hospital.. Forty-one HIV-infected patients were identified through physician contacts, referrals from other providers, and review of a comprehensive clinical database.. To determine response to salvage therapy, HIV-1 viral RNA (absolute and log10-transformed) was measured using the Roche Amplicor quantitative HIV-1 RNA assay after initiation of the salvage regimen. Potential correlates of response included: viral RNA at the time of switch; viral RNA at the time of switch as a percentage of baseline viral RNA; magnitude of decline in viral RNA; and the interval between virologic failure of single protease inhibitor therapy and switch to the salvage regimen.. Thirteen (56.5%) of 23 patients failing indinavir responded to salvage therapy (HIV RNA < 400 copies/ml) with persistence throughout the follow-up period (median of 37 weeks; range 18-67 weeks). Mean absolute viral RNA at the time of switch was 20 238 copies/ml (median, 9281) compared with 42 953 copies/ml (median, 24 650) for the 10 non-responders. Mean log10 viral RNA at switch was 3.804 for responders versus 4.405 for non-responders (P = 0.040). Among four responders who had failed nelfinavir, mean viral RNA was 9634 copies/ml and mean log10 viral RNA was 3.749 at the time of switch. Two non-responders had a mean viral RNA of 21 551 and a mean log10 viral RNA of 4.037 at switch.. In contrast with previous reports, salvage regimens containing ritonavir and/or saquinavir can be effective and durable following the failure of combination regimens containing either indinavir or nelfinavir. Salvage therapy may be more likely to succeed when it is initiated early in failure at low viral loads.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Retrospective Studies; Ritonavir; RNA, Viral; Salvage Therapy; Saquinavir; Treatment Failure; Viral Load

Protease inhibitors (PIs) are recently introduced drugs that have improved the survival of HIV-infected patients when given in combination with two reverse transcriptase inhibitors. The HIV-1 protease gene is naturally highly polymorphic. Selection pressure due to IP use can result in major or minor resistance-associated mutations (RAMs). This study investigated whether presence before IP therapy of minor RAMs on the protease gene predicts the virological response. Of the 58 PI-naive patients included in the study, 12 had received two nucleoside reverse transcriptor inhibitors, 14 had received indinavir, 16 ritonavir, and 28 saquinavir-SGC. Viral load was measured on D0 (prior to PI initiation) and at M3 and M6 (Roche Monitor 1.5 with 200 and 20 copies/ml as the thresholds). The protease gene was fully sequenced on D0 using the ABI 377 automatic sequencer after RNA amplification by nested RT-PCR. None of the viral strains exhibited major mutations, but 57 of 58 (98%) had at least one minor mutation (median number of substitutions, 4), 60% had 1 to 4 substitutions, and 40% had 5 to 9 substitutions. Substitutions seen with a prevalence > 20% were located at codons 15, 35, 37, 41, 63, and 77. Numbers of substitutions at M3 and M6 were not correlated with viral load or the nature of the PI used, and neither were they significantly different between patients with more or fewer than 20 copies/ml. These data suggest that the protease genotype at PI initiation does not predict the efficacy of a regimen including a PI and is of no assistance in deciding whether or not to include a PI in a triple combination regimen.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Substitution; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Polymorphism, Genetic; Predictive Value of Tests; Reverse Transcriptase Polymerase Chain Reaction; Saquinavir; Viral Load

Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy.. To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes.. Cross-sectional evaluation.. 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir.. Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro.. In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells.. The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Topics: Adult; Animals; Anti-HIV Agents; C-Peptide; Cells, Cultured; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Glucagon; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Insulin; Insulin Resistance; Islets of Langerhans; Male; Phospholipases A; Proinsulin; Rats; Rats, Sprague-Dawley

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Stavudine; Viremia; Zidovudine

The effects of therapeutically relevant concentrations of the human immunodeficiency virus (HIV) proteinase inhibitors saquinavir and indinavir on the in vitro proteinase activity of Candida albicans were investigated with isolates from HIV-infected and uninfected patients with oral candidiasis. After exposure to the HIV proteinase inhibitors, proteinase activity was significantly reduced in a dose-dependent manner. These inhibitory effects, which were similar to that of pepstatin A, and the reduced virulence phenotype in experimental candidiasis after application of saquinavir indicate the usefulness of these HIV proteinase inhibitors as potential anticandidal agents.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Aspartic Acid Endopeptidases; Candida albicans; Candidiasis, Oral; Dose-Response Relationship, Drug; Fungal Proteins; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pepstatins; Saquinavir

Combination therapy with protease inhibitors and nucleoside analogues dramatically suppresses plasma HIV-1 RNA and delays progression to AIDS, but the impact on HIV-associated malignancy remains to be established. We therefore examined incidence trends of Kaposi's sarcoma and non-Hodgkin's lymphoma in patients with advanced HIV infection in nine AIDS Clinical Trial Group studies of antiviral therapies for HIV and cytomegalovirus infections. Among a total of 6587 patients enrolled between November 1987 and February 1997, there were 280 cases of Kaposi's sarcoma and 68 cases of non-Hodgkin's lymphoma. Incidence rates per 100 person-years of both malignancies declined in concert with decreases in mortality, but the decreases in Kaposi's sarcoma were more profound and consistent than the decreases in non-Hodgkin's lymphoma. These data suggest that current therapies have ameliorated the incidence of Kaposi's sarcoma, but may not have had an equal effect on non-Hodgkin's lymphoma.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus Retinitis; Foscarnet; Ganciclovir; HIV Infections; Humans; Incidence; Indinavir; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Retrospective Studies; Sarcoma, Kaposi

Many patients infected with human immunodeficiency virus type 1 (HIV-1) have suboptimal responses to protease inhibitor-based therapy. We retrospectively evaluated a cohort of 104 HIV-positive adults, most of whom had previously received antiretrovirals, to identify the frequency and clinical predictors of incomplete response to potent HIV-1 protease inhibitors. Sixty-two (60%) of the patients had an incomplete response, defined as a plasma HIV-1 RNA level of >400 copies/mL after 20 weeks of therapy. Logistic regression analysis identified the following independent risk factors for incomplete response: elevated baseline plasma HIV-1 RNA level (P = .03), low baseline weight (P = .01), chemoprophylaxis for Pneumocystis carinii pneumonia (P = .04), and active illicit drug use (P = .04). Regular prescription of narcotics or benzodiazepine anxiolytics (P = .01) and use of any Internet site (P = .01) predicted a more favorable response. Identifying factors that predict suboptimal response to protease inhibitors improves our understanding of interpatient variability in response to therapy and should foster strategies that enhance the effectiveness of current and future regimens.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nelfinavir; Prognosis; Retrospective Studies; Ritonavir

Evaluation of the treatment of complicated ureteric stones in patients treated with indinavir.. From March 1997 to May 1998, 10 patients (7 males, 3 females, aged 30 to 56 years), treated by triple combination therapy for HIV infection, were drained for stones attributed to indinavir (CRIXIVAN), which had become obstructive and complicated. The duration of treatment with indinavir ranged from 14 days to 2 years. No patient had a history of urological disease. One patient presented with bilateral stones. All patients presented complicated clinical features: fever in 3 cases; severe pain in 8 cases, with delayed excretion more than 4 hours on IVU in 6 cases. All stones were radiolucent except for one slightly radioopaque stone. The stone was situated in the lumbar ureter in 3 cases, iliac ureter in 1 case and pelvic ureter in 8 cases.. In 10 out of 11 cases, a double J stent was inserted, preceded by drainage by simple ureteric catheter (infected urine) in 1 case and by percutaneous nephrostomy (PCN) with antegrade insertion of the stent (failure of the retrograde route) in 1 case. No complementary stone fragmentation or extraction treatment was necessary after this procedure. Stents were left in place for 3 to 7 weeks. In one case, a stone of the lumbar ureter required PCN followed by extracorporeal lithotripsy.. In the case of complications requiring a urological procedure, insertion of a double J stent allows curative treatment of very friable indinavir stones, which are fragmented by passage of the stent.

Topics: Adult; Anti-HIV Agents; Colic; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; Humans; Indinavir; Male; Middle Aged; Stents; Ureteral Calculi; Ureteral Diseases

Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir.. Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir.. Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established.

Topics: Adult; Anti-HIV Agents; Arteriosclerosis; Child; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Indinavir; Lipids; Lipoprotein(a); Lipoproteins; Logistic Models; Male; Nelfinavir; Risk Factors; Ritonavir; Saquinavir; Thyrotropin

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Mutation; Ritonavir; Saquinavir; Viral Load

We analyzed the influence of temperature, humidity, and atmospheric pressure on the 1-year incidence of nephrolithiasis among human immunodeficiency virus type 1-infected patients treated with indinavir. One hundred three patients (13.6%) developed 326 episodes of nephrolithiasis. Eighty-two patients (79.6%) had more than one episode (range, two to seven episodes). The overall incidence ranged from 0 to 10.2 episodes per 100 patients exposed per month. There was a significant correlation between temperature and the overall incidence of nephrolithiasis and the incidence of recurrences but not with the incidence of first episodes. Nephrolithiasis was not related to humidity or atmospheric pressure. Our data support the standard recommendation of drinking at least 1.5 L of water daily to prevent nephrolithiasis in most patients treated with indinavir irrespective of meteorologic factors. However, the risk of nephrolithiasis is higher for a certain subgroup of patients when the environment is hot irrespective of adequate water intake.

Topics: Atmospheric Pressure; HIV Infections; HIV Protease Inhibitors; Humans; Humidity; Incidence; Indinavir; Kidney Calculi; Prospective Studies; Temperature

Alterations in lipid metabolism have been associated with the use of protease inhibitors. Sequential lipid analyses were performed on serum samples from human immunodeficiency virus-infected antiretroviral-naive patients who received indinavir in combination with two nucleoside reverse transcriptase inhibitors. Serum levels of cholesterol, triglycerides, high-density lipoproteins (HDLs), and low-density lipoproteins (LDLs) were measured at baseline and at periodic intervals. After 48 weeks of indinavir therapy, mean serum levels +/- SD rose as follows: cholesterol, from 167.2 +/- 36.0 to 206.3 +/- 32.4 mg/dL (P < .0005); triglycerides, from 110.4 +/- 47.5 to 158.4 +/- 72.5 mg/dL (P < .0101); and LDLs, from 106.6 +/- 35.1 to 136.1 +/- 31.6 mg/dL (P = .0029). There was no significant change in the serum HDL fraction. Mean serum lipoprotein (a) levels +/- SD rose from 6.5 +/- 1.4 to 9.6 +/- 2.0 mg/dL after 30 weeks (P = .0695). Potential mechanisms for the noted increases include alterations in serum lipoprotein lipase activity or changes in hepatic lipid metabolism. The clinical significance of these changes remains to be determined.

Topics: Cholesterol; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lipoproteins, HDL; Lipoproteins, LDL; Prospective Studies; Triglycerides

A case is reported of a woman who was exposed to human immunodeficiency virus through self-insemination. She was artificially inseminated with fresh semen obtained from a gay man in whom HIV seroconversion was taking place. Postexposure prophylaxis with antiretrovirals was initiated 10 days later, and despite successful conception, HIV infection was not established. A healthy male infant was subsequently delivered with no obvious toxicity related to medication.

Topics: Adult; Antiviral Agents; Female; HIV Infections; HIV Seropositivity; Humans; Indinavir; Insemination, Artificial, Heterologous; Lamivudine; Male; Pregnancy; Tissue Donors; Zidovudine

The purpose of this study was to investigate the taste properties of protease inhibitors which are essential components of drug regimes used to treat human immunodeficiency virus (HIV) infection. In this study, the taste properties of four protease inhibitors (indinavir, ritonavir, saquinavir, and nelfinavir) were investigated in unmedicated HIV-infected patients and healthy controls. Three of the four protease inhibitors (indinavir, ritonavir, and saquinavir) were found to be predominantly bitter (with additional qualities of medicinal, metallic, astringent, sour, and burning). Nelfinavir was found to be relatively tasteless. HIV-infected and uninfected control subjects detected protease inhibitors at similar concentrations, but HIV-infected subjects perceived suprathreshold concentrations as more bitter than controls. Detection thresholds ranged from 0.0061 mM for saquinavir in HIV-infected patients to 0.0702 mM for ritonavir in uninfected control subjects. Suprathreshold studies indicated that protease inhibitors modified the taste perception of a variety of other taste compounds. These results are consistent with clinical findings that protease inhibitors produce taste complaints that can impact patient compliance.

Topics: Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir; Ritonavir; Saquinavir; Taste; Taste Disorders

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Salvage Therapy; Saquinavir; Treatment Failure; Viral Load

Topics: Diabetic Ketoacidosis; Drug Therapy, Combination; Glucose Intolerance; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine

Topics: Abdomen; Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lipodystrophy; Magnetic Resonance Imaging; Syndrome; Time Factors

Topics: Acquired Immunodeficiency Syndrome; Adult; Anemia, Hemolytic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

Lamivudine and indinavir are two medications used to treat human immunodeficiency virus (HIV) that have recently been reported to cause paronychia. The nails of the great toes are commonly affected. This is the second report of paronychia and ingrown toenails due to indinavir and the first report of recurrent paronychia and ingrown toenails associated with this drug.

Topics: Adult; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nails, Ingrown; Paronychia; Recurrence; Toes

The prevalence of erectile dysfunction in HIV-infected men is estimated to be 33%. Sildenafil citrate (Viagra; Pfizer Ltd, Sandwich, Kent, UK) is the first oral drug for this condition. Since sildenafil and the protease inhibitors are both metabolized by, and act as inhibitors of cytochrome P450 3A4, we evaluated the pharmacokinetics of the combination sildenafil plus indinavir in HIV-infected patients.. Six patients at steady state in treatment with indinavir participated in the study. On the first day blood samples for indinavir assay were drawn at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. On the second study day patients received a single dose of 25 mg of sildenafil in addition to their routine morning medication. Blood samples were taken as described. Separated plasma was stored at -80 degrees C until analysis by high performance liquid chromatography. In a parallel study, the effect of indinavir, ritonavir, saquinavir and nelfinavir on the in vitro hepatic metabolism of sildenafil was assessed.. The geometric mean area under the concentration curve for 0-8 h (AUC0-8h) and maximum plasma concentration (Cmax) for indinavir were 19.69 microg/ml h (range, 9.19-31.99 microg/ml h) and 7.02 microg/ml (range, 2.33-16.17 microg/ml), respectively, on the first study day. In the presence of sildenafil, the mean AUC0-8h and Cmax of indinavir were 22.37 microg/ml h [range, 10.08-37.25 microg/ml h; 95% confidence interval (CI) for difference between means, -15 to 13.25) and 9.11 microg/ml (range, 3.41-22.78 microg/ml; 95% CI, -13 to 6.37), respectively. The geometric mean AUC0-8h and Cmax for sildenafil were 1631 ng/ml h (range, 643-2970 ng/ml h) and 384 ng/ml (range, 209-766 ng/ml) respectively. The AUC for sildenafil was 4.4 times higher than data from historical controls given either 50 mg or 100 mg of sildenafil and dose normalized to 25 mg. Indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro [concentration producing 50% inhibition of control enzyme activity (IC50) = 0.39 +/- 0.17 microM, mean +/- SD].. Co-administration of sildenafil 25 mg did not significantly alter the plasma indinavir levels. However, plasma sildenafil AUC was markedly increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in this clinical setting.

Topics: Adult; Drug Interactions; Erectile Dysfunction; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Adult; Aged; Anti-HIV Agents; Case-Control Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Nails, Ingrown; Reverse Transcriptase Inhibitors

Topics: Adult; Anti-HIV Agents; Bursitis; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Shoulder Joint

Protease inhibitors are important components in anti-retroviral regimens. In this retrospective study 29 HIV-infected patients treated with a regimen of zidovudine, lamivudine and saquinavir hard gel in 1 centre in Denmark were compared with 58 patients treated with zidovudine, lamivudine and ritonavir or indinavir followed at 5 other centres in Scandinavia. All patients were naive to anti-retroviral therapy prior to institution of the actual anti-retroviral regimen and were followed for a median of 1.3 and 1.4 y respectively. The 2 groups did not differ significantly with respect to age, gender, route of infection, ethnic background, viral load, CD4 count, AIDS at baseline or frequency of clinical controls. Six and 12 months after initiating anti-retroviral therapy, 31% and 34% of the patients on the saquinavir regimen obtained HIV-RNA < or = 500 compared with 76% and 73% in the control group (p < 0.001). In contrast to viral load, the increase in CD4 count did not differ significantly between the 2 groups. In conclusion, we found that with respect to suppression of viral load a regimen of saquinavir, zidovudine and lamivudine seemed to be inferior to a regimen of zidovudine, lamivudine and ritonavir or indinavir.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Controlled Clinical Trials as Topic; Denmark; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Multicenter Studies as Topic; Retrospective Studies; Ritonavir; RNA, Viral; Saquinavir; Viral Load; Zidovudine

We evaluated the frequency of and reasons for discontinuation of protease inhibitor therapy in a cohort of HIV-infected patients in a prospective observational study. We included 230 HIV-infected patients who had started protease inhibitor therapy between November 1996 and July 1997. Mean baseline CD4 count was 138 cells/microl and HIV-RNA 4.5 log10. Forty-five percent of patients had prior AIDS and 77% had been treated with nucleoside analogues. Saquinavir-treated patients were at a less advanced stage of HIV disease. Overall, 41.3% of patients discontinued therapy, and their last HIV-RNA measured higher than that of patients who continued therapy: 4.07 vs. 2.70 log10 (p < 0.0001). Reasons for discontinuation of therapy were poor adherence (including abandonment) (18.6%), drug intolerance (12.1%), virological failure (7%) and physician decision (3.5%). In a multivariate model, factors associated with drug discontinuation were not taking indinavir (OR 0.26, 95% CI 0.12-0.59) and being pretreated with nucleoside analogues (OR 3.42, 95% CI 1.58-7.42). We concluded that in routine clinical practice a high proportion of patients discontinued protease inhibitors during the first 6 months of therapy, the main reason being the patient's own decision (abandonment or poor adherence). Psychological support and counselling are warranted in patients when initiating protease inhibitor therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Analysis of Variance; Cohort Studies; Counseling; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Practice Patterns, Physicians'; Prospective Studies; Ritonavir; Saquinavir; Treatment Refusal; Viral Load

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; HIV Infections; Humans; Indinavir; Lamivudine; Stavudine; Virus Replication

Clinical, virologic, and immunologic outcomes were analyzed in children with vertically transmitted human immunodeficiency virus (HIV) infection (n = 25) and clinical symptoms and evidence of immunosuppression to establish the efficacy of 18 months' treatment with stavudine, lamivudine, and indinavir. Children were naive for treatment with protease inhibitors and lamivudine and had minimal exposure to stavudine. At 1, 6, 12, and 18 months, the proportions of patients with HIV-RNA <400 copies/mL were 79%, 100%, 94%, 87% in Centers for Disease Control and Prevention (CDC) immunologic class 2 and 50%, 67%, 67%, 72% in CDC immunologic class 3. At 12 months, the median CD4(+) count and percent increased significantly in both CDC immunologic class groups, but to a greater extent in the class 3 group. In the 12- to 18-month period, there were no significant changes within the groups. In both groups there was a steady increase in the proportion and number of children with positive skin test responses. Children in class 2 were more likely to have a positive delayed-type hypersensitivity response and a greater number of positive responses. Lymphocyte proliferative response to recall antigens improved significantly in all patients. The rate of increase in positive test results was faster in children in class 2 than in those in class 3. Only minor clinical events occurred during 18 months of therapy. Potent antiretroviral therapy achieves a sustained benefit in HIV-infected children, but immune reconstitution is more likely achieved in children with less advanced disease.

Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Cell Division; Child; Drug Therapy, Combination; HIV Infections; Humans; Hypersensitivity, Delayed; Indinavir; Infectious Disease Transmission, Vertical; Lamivudine; Skin Tests; Stavudine; T-Lymphocytes; Treatment Outcome

To study the effects of antiretroviral therapy on T cell activation in blood and tonsils from HIV-1 infected individuals in relation to CD4 cell count, plasma viremia, and infectious HIV-1 provirus.. A 48-week study of viral load and T cell subsets in blood and tonsils from 12 HIV-1-positive individuals with a mean CD4 cell number of 400 x 10(6) cells/l treated with a combination of zidovudine, lamivudine, and indinavir.. Tonsil biopsies and blood samples were collected at regular intervals. Lymphocytes were phenotyped and quantified by three-color flow cytometry; infectious provirus was quantified by a limiting dilution assay. HIV-1-negative individuals were included as controls.. The fraction of tonsillar CD8 T cells expressing CD69, CD38, or HLA-DR in the patients with suppressed virus replication declined to levels comparable with that in controls by 48 weeks and showed a strong positive correlation with tonsillar infectious provirus and plasma viremia. The level of CD4 T cell activation was within normal range in tonsils throughout the study. The fraction of HLA-DR+ cells within CD4 and CD8 T cells in blood declined rapidly in parallel with plasma viremia but remained slightly higher compared with that in uninfected individuals.. Antiretroviral therapy normalizes tonsillar CD8 T cell activation in HIV-1-positive individuals in parallel with suppression of viral replication, indicating reduced CD8 cell turnover. Normal tonsillar CD4 T cell activation suggests limited CD4 cell turnover in early HIV infection. Activated CD8 T cells in lymphoid tissue is superior to that in blood as an immunological marker for the virological response to antiretroviral therapy.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adult; Anti-HIV Agents; Antigens, CD; Antigens, Differentiation; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; HIV Infections; HIV-1; HLA-DR Antigens; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Male; Membrane Glycoproteins; NAD+ Nucleosidase; Palatine Tonsil; Proviruses; T-Lymphocyte Subsets; Time Factors; Viremia; Virus Replication; Zidovudine

Topics: Alkynes; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral

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

To compare adherence and clinical outcome with highly active antiretroviral therapy (HAART) in intravenous drug users (IDUs) and subjects with other HIV risk behaviours (non-IDUs).. A total of 133 non-naive HIV-infected patients, 95 (71%) IDUs and 38 (29%) non-IDUs received triple drug therapy with stavudine, lamivudine, and indinavir. Adherence, side effects, and immunological and virological efficacy of treatment were assessed every 3 months.. During a median follow-up of 12 months, 43 patients (32% of the total) showed adequate adherence in all clinical appointments. Adherence was superior in non-IDUs than in IDUs in every visit, but a significant difference was found only at 6 months, when 22 (58%) non-IDUs versus 37 (39%) IDUs were adherent (P = 0.047). Mildly increased bilirubin was observed in 69 (52%) patients, and renal colic in 34 (26%). No difference in side effects was found between IDUs and non-IDUs. After 6 months of treatment, 35 (43%) participants presented a CD4 cell count increase >100x10(6)/l, and 47 (58%) achieved undetectable HIV RNA (lower limit of detection: 200 copies/ml). CD4 cell count and HIV RNA responses were similar in both groups.. Adherence to the employed HAART regimen was poor. Non-IDUs were more adherent than IDUs, but the difference between both groups was small. Side effects and efficacy were similar in IDUs and non-IDUs.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Patient Compliance; Reverse Transcriptase Inhibitors; Stavudine; Substance Abuse, Intravenous

The long term effectiveness of combination therapy at reducing viral loads in seminal fluid and blood plasma obtained from HIV-1 infected men who had undergone previous antiretroviral therapy was assessed.. Samples of semen and blood were obtained from a cohort of 12 nucleoside reverse transcriptase inhibitor experienced men before and during 25-68 weeks of combination therapy, which included the protease inhibitor indinavir. HIV-1 RNA titres present in the cell free blood and seminal plasma samples were determined using the nucleic acid sequence based amplification (NASBA)/Nuclisens assay system.. Viral RNA was detected in 9/12 and 7/12 baseline blood plasma and seminal plasma samples, with median viral titres of 10(4.81) and 10(4.56) per ml, respectively. By the end of the study period the detection rates of HIV RNA in the blood and seminal plasma samples were 5/12 and 2/12, respectively, with the median viral titres below the assay cut off level for both sample types. Of the nine patients who had detectable viral RNA in the baseline sample, only three cleared virus from both compartments by the end of the study.. These data show that stable reduction of blood and seminal fluid viral titres is not achievable in a significant proportion of nucleoside reverse transcriptase inhibitor experienced men.

Topics: Drug Therapy, Combination; Gene Amplification; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Risk Factors; RNA, Viral; Semen; Statistics, Nonparametric; Viral Load

A new high-performance liquid chromatographic method for the simultaneous determination of indinavir, saquinavir and ritonavir in human plasma is described. Quantitative recovery following liquid-liquid extraction with diethyl ether from 500 microl of human plasma was achieved. Subsequently, the assay was performed with a linear gradient starting at 67 mM potassium dihydrogenphosphate-acetonitrile (65:35 to 40:60, v/v) as a mobile phase, a Phenomenex C18 column and UV detection at 240 and 258 nm, respectively. Linear standard curves were obtained for concentrations ranging from 75 to 20,000 ng/ml for indinavir, from 10 to 6000 ng/ml for saquinavir, and from 45 to 30,000 ng/ml for ritonavir. The calculated intra- and inter-day coefficients of variation were below 6%.

Topics: Chromatography, High Pressure Liquid; Drug Stability; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kinetics; Ritonavir; Saquinavir; Sensitivity and Specificity

Indinavir therapy has demonstrated promise in the treatment of HIV-1 infection in clinical trials; however, its efficacy in a U.S. Veterans Affairs Medical Center, where access to therapy is generally unimpeded, is unknown. A review of the Miami cohort was conducted for the year beginning May 1996 to evaluate response to indinavir plus two nucleoside analogues. Of 483 HIV-1-positive patients (97% male; mean age, 46.7+/-9.7 years), 266 were offered indinavir based on their having CD4 counts <200 cells/microl or viral loads >10,000 copies/ml. Of these patients, 36% were adherent and experienced significant reductions in viral loads (-93,325+/-147,911 copies/ml) and elevations in CD4+ (111+/-103 cells/microl) and CD8+ (225+/-338 cells/microl) T cell counts. Adherent patients with baseline CD4 counts <100 cells/microl were 4.5 times more likely to have follow-up viral loads >10,000 copies/ml than those with CD4 >200 cells/microl. Adherent patients with CD4 counts <100 cells/microl did not show evidence of immune "exhaustion" because they were equal to those with CD4 counts >200 cells/microl in their capacity to replenish CD4 cells. Nonadherence to the regimen resulted in loss of therapeutic benefit and suggested that strategies to enhance adherence may become an essential component of treatment.

Topics: Adult; CD4 Lymphocyte Count; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Hospitals, Urban; Hospitals, Veterans; Humans; Indinavir; Male; Middle Aged; Patient Compliance; Reverse Transcriptase Inhibitors; Treatment Outcome; United States; United States Department of Veterans Affairs; Viral Load

Topics: Adolescent; Adult; Data Interpretation, Statistical; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male

Topics: Administration, Oral; Adult; Fenofibrate; Hemophilia A; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Hypolipidemic Agents; Indinavir; Male; Transfusion Reaction

Topics: Adult; Anti-HIV Agents; HIV Infections; Humans; Indinavir; Lamivudine; Male; Smoking; Smoking Cessation; Zidovudine

Topics: Adult; Anti-HIV Agents; HIV Infections; Humans; Indinavir; Lamivudine; Purpura, Thrombotic Thrombocytopenic; Stavudine

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

The objectives of this study were to document the prevalence of facial lipodystrophy in patients with HIV infection receiving protease inhibitors and to identify associated factors. All patients with HIV infection receiving protease inhibitors seen at an HIV clinic in Hong Kong during a 2-month period, from August to October 1997, were assessed for facial lipodystrophy. Among 29 patients who had been receiving indinavir for 3 months or more, facial lipodystrophy was found in 7 (24%). Facial lipodystrophy in these patients was found to be an isolated event and was not associated with noticeable wasting elsewhere. The development of facial lipodystrophy was not found to be associated with age, sex, ethnicity, route of HIV transmission, CD4 cell count, history of AIDS-defining illness, or concurrent anti-retroviral treatment. Facial lipodystrophy was not observed in patients who had received indinavir for less than 3 months. The condition was also not found in patients taking other protease inhibitors, although this could be due to the small sample size. Prospective study of this condition with a larger sample and with objective anthropomorphic measurements would be desirable. In conclusion, facial lipodystrophy is a common occurrence among patients receiving indinavir, and physicians should be alerted to this condition.

Topics: Adult; Face; Female; HIV Infections; HIV Protease Inhibitors; Hong Kong; Humans; Indinavir; Lipodystrophy; Male; Middle Aged; Prevalence; Retrospective Studies

This case report describes a 32-year-old woman treated with indinavir who developed mild to moderate flank pain, malaise, and low-grade fever. Sterile pyuria preceded increased serum creatinine levels. Workup revealed persistent pyuria, normal-sized kidneys, a normal intravenous pyelography, and negative urinary cultures. Renal biopsy showed interstitial nephritis and chronic inflammation. Collecting ducts contained crystals. Two months after treatment with indinavir was discontinued, serum creatinine levels returned to normal and pyuria disappeared. Sterile pyuria in patients taking indinavir may help to identify patients at risk for renal dysfunction and interstitial nephritis. Markedly increasing the fluid intake above the recommended dosage may ameliorate or even reverse the process of tubulointerstitial disease.

Topics: Adult; Female; Fever; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nephritis, Interstitial; Pain; Pyuria

Recent U.S. and French studies indicate that antiretroviral therapy that includes three or more drugs will need to be continued indefinitely for viral suppression to be maintained. These studies used combinations of Indinavir (Crixivan), Zidovudine (AZT), and Lamivudine (Epivir). Triple-drug therapy requires that patients take five or more pills two or three times a day, which is a challenging regimen to follow. The AIDS Clinical Trials Group Study 343 found that when patients on triple-drug combinations changed to two drugs or monotherapy, the virus rebounded in a significant number of patients. The idea of putting people on aggressive treatment early on in the disease is now being challenged by many researchers and clinicians.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Therapy, Combination; France; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Patient Compliance; United States; Zidovudine

The U.S. Food and Drug Administration approved a new 333 mg capsule of the protease inhibitor Indinavir. The new dosage formulation is important because a higher dose of 1000 mg every 8 hours is easier to manage with the 333 mg capsules than with the standard 400 mg capsules. In addition, the 400 mg capsules, which are used with the standard 800 mg dose, will now be available in single unit blister packs, making storage and dispensing easier.

Topics: Anti-HIV Agents; Capsules; Drug Packaging; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; United States; United States Food and Drug Administration

A new study shows that Sustiva (efavirenz) taken in combination with Stavudine (d4T) and Lamivudine (3TC) was effective in reducing viral load to below 400 copies/mL in all patients observed. Sustiva, manufactured by DuPont, was studied in a 48-week trial, and results were reported at the 9th European Conference of Clinical Microbiology and Infectious Diseases in Berlin. In a second study, Sustiva in combination with AZT/3TC or Indinavir showed a reduction in viral load in both vaginal and cerebrospinal fluids in two groups of patients.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cerebrospinal Fluid; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Oxazines; Reverse Transcriptase Inhibitors; Stavudine; Vagina; Viral Load; Zidovudine

A French study confirms recent reports of hair loss in men as a side effect of the protease inhibitor Crixivan (Indinavir). All ten men in the study experienced various types of hair loss, which grew back several months after switching to another protease inhibitor or NNRTI. Ingrown toenails are another side effect recorded by a different French study, corroborating reports from patients taking Crixivan. Patients on Crixivan, experiencing these symptoms, should discuss them with their doctor.

Topics: Alopecia; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nails, Ingrown; Toes

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

Drug resistance to protease inhibitors (PIs) often requires patients to resort to entirely different drug combinations, called salvage or rescue therapy. A study at the San Francisco General Hospital compared the effectiveness of two salvage regimens for patients who had used Indinavir or Ritonavir. The most effective combination was Nelfinavir, Saquinavir, abacavir, and Nevirapine. Most of the 20 subjects in the study had not been exposed to these drugs previously. Study details include results on viral loads and drug side effects. In addition, phenotypic testing was used to measure the effectiveness of the treatment and to track viral suppression.

Topics: Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Protease Inhibitors; Ritonavir; Salvage Therapy; Treatment Outcome

People on highly active antiretroviral therapy (HAART) struggle with cumbersome and difficult medication schedules, including food restrictions, side effects, and toxicities. Several poster sessions at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) presented studies on regimens that would require fewer pills and less frequent dosing. These simpler regimens would improve adherence and quality of life. Data from single-dose studies of Crixivan with Norvir and Fortovase with or without Norvir in HIV-negative participants were presented. Although results look promising, significant issues remain, including responses in HIV-positive people and resistance.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Patient Compliance; Ritonavir; Saquinavir

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Randomized Controlled Trials as Topic

Topics: Anti-HIV Agents; HIV Infections; Humans; Indinavir; Platelet Count

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Polymerase Chain Reaction; RNA, Viral; Zidovudine

Inhibitors of HIV-1 protease produce a rapid decrease in plasma HIV-1 RNA, with concomitant increases in CD4 T-helper lymphocyte counts. The main side-effects of the protease inhibitors currently in use include gastrointestinal disturbances, paraesthesias, hyperbilirubinaemia, and nephrolithiasis. The increasing use of these agents in patients with advanced HIV-1 infection and CD4 counts of less than 50 cells/microL may be associated with unforeseen adverse effects not observed in earlier studies of patients with higher CD4 counts.. Five HIV-infected patients with baseline CD4 lymphocyte counts of less than 50 cells/mL were admitted to the Beth Israel Deaconess Medical Center (Boston, MA, USA) with high fever (> 39 degrees C), leucocytosis, and evidence of lymph-node enlargement within 1-3 weeks of starting indinavir therapy. Informed consent was obtained for studies that entailed CD4 lymphocyte counts, immunophenotyping, isolator blood cultures, and radiological scans. Biopsy samples of cervical, paratracheal, or mesenteric lymph nodes were taken for culture and pathology in four patients.. Lymph-node biopsy samples showed that focal lymphadenitis after initiation of indinavir resulted from unsuspected local or disseminated Mycobacterium avium complex (MAC) infection. The prominent inflammatory response to previously subclinical MAC infection was associated with leucocytosis in all patients and with an increase in the absolute lymphocyte counts in four patients. Three patients with follow-up CD4 counts showed two-fold to 19-fold increases after 1-3 weeks of indinavir therapy. Immunophenotyping after therapy in two patients showed that more than 90% of the CD4 cells were of the memory phenotype.. The initiation of indinavir therapy in patients with CD4 counts of less than 50 cells/mL and subclinical MAC infection may be associated with a severe illness, consisting of fever (> 39 degrees C), leucocytosis, and lymphadenitis (cervical, thoracic, or abdominal). The intense inflammatory reactions that make admission to hospital necessary may be secondary to significant numbers of functionally competent immune cells becoming available to respond to a heavy mycobacterial burden. Prophylaxis or screening for subclinical MAC infection, or both, should therefore be done before the beginning of protease-inhibitor therapy in patients with advanced HIV infection.

Topics: Adult; AIDS-Related Opportunistic Infections; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Tuberculosis, Lymph Node

Topics: Anti-HIV Agents; Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

Topics: Adult; Allergens; Drug Hypersensitivity; HIV Infections; Humans; Indinavir; Male; Severity of Illness Index

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Patient Education as Topic; Primary Nursing; Ritonavir; Saquinavir

Topics: Alopecia; Anti-HIV Agents; HIV Infections; Humans; Indinavir

Topics: Anti-HIV Agents; Chemical and Drug Induced Liver Injury; HIV Infections; Humans; Indinavir; Male; Middle Aged

Topics: Adult; Anti-HIV Agents; Crystallization; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Renal Insufficiency; Stavudine

Topics: Adult; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Hepatitis A; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver Failure; Male

Topics: Abdomen; Adipose Tissue; Back; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir

After the addition of the protease inhibitor indinavir to combination drug regimens for HIV-1 infection, some patients have experienced an increase in abdominal girth with symptoms of abdominal fullness, distension, or bloating. We aimed to find out whether this collection of symptoms was associated with changes in abdominal fat and whether such changes were associated with indinavir use.. Abdominal computed tomography was used in ten HIV-1-positive patients who had such abdominal symptoms to measure total adipose tissue (TAT) and visceral adipose tissue (VAT) at the umbilicus (L4 vertebral level). The VAT:TAT ratio in the ten cases was compared with that in ten HIV-1-infected patients who had been using indinavir without abdominal symptoms for at least 6 months and ten HIV-1-infected patients who were not using indinavir.. The mean VAT:TAT ratios for the three groups-non-users, symptom-free indinavir users, and symptomatic indinavir users-were 0.40 (SD 0.15), 0.59 (0.18), and 0.70 (0.20), respectively (p=0.004). The VAT:TAT ratio correlated with duration of indinavir use (r=0.47, p=0.01). The mean areas of VAT for the three groups were 106 cm2 (SD 72), 141 cm2 (65) and 202 cm2 (93), respectively (p=0.03). The mean body-mass index of the groups was similar, and patients in the two indinavir groups did not gain a significant amount of weight after starting the drug. Serum triglyceride values increased after starting indinavir and correlated with VAT:TAT ratios.. Our data suggest that some HIV-1-infected patients on indinavir treatment accumulate intra-abdominal fat that may cause abdominal symptoms. Recent evidence suggests that other HIV-1 protease inhibitors may be associated with changes in body-fat distribution. Larger studies of protease-inhibitor treatment are needed to investigate this association further and to investigate metabolic or endocrine mechanisms that may underlie this phenomenon.

Topics: Abdomen; Adipose Tissue; Adult; Anti-HIV Agents; Body Composition; HIV Infections; HIV-1; Humans; Indinavir; Male; Protease Inhibitors; Radiography, Abdominal; Tomography, X-Ray Computed

RANTES has been found to suppress human immunodeficiency virus type 1 (HIV-1) replication. To further elucidate the role of this chemokine in HIV-1 infection, RANTES levels were analyzed in serum and platelet-free plasma (PFP) in 53 HIV-1-infected patients and 20 controls. RANTES levels were significantly elevated in both serum and PFP in all clinical stages of HIV-1 infection, with the highest levels in CDC groups A and B. In longitudinal testing, the progressors were characterized by a pronounced decline in serum levels over time; the nonprogressors, however, had only a slight reduction or an increase in RANTES levels. During 16 weeks of indinavir therapy, there was an increase in circulating RANTES levels and enhanced release of RANTES from stimulated CD8+ lymphocytes. The decline in RANTES levels along with disease progression is compatible with RANTES having a beneficial role in HIV-1-infected patients. The increase in RANTES levels during protease inhibitor-containing regimens may represent a previously unrecognized immunologic effect of such therapy.

Topics: Adult; CD8-Positive T-Lymphocytes; Chemokine CCL5; Disease Progression; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Longitudinal Studies; Male; Middle Aged; Plasma; Polymerase Chain Reaction; RNA, Viral; Severity of Illness Index; Survivors

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; HIV Infections; Humans; Indinavir

Topics: Adult; Biopsy; Crystallization; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney Tubules, Collecting; Male; Microscopy, Electron, Scanning; Nephritis, Interstitial

Topics: Acute Disease; Adult; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Respiratory Insufficiency

Topics: Adult; Anti-HIV Agents; Drug Tolerance; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Ritonavir

Lipodystrophies are rare cutaneous disorders characterized by the symmetrical loss of subcutaneous fat from the body surface. The cause of lipodystrophy is not known, but a possible genetic predisposition is likely and either overt diabetes mellitus or insulin resistance are often associated.. Case study.. Eight patients who developed either partial or generalized lipodystrophy after protease inhibitor therapy.. In all eight patients lipodystrophy occurred after 2-12 months of starting indinavir and was not preceded by weight loss or inflammatory skin disease. Short-term follow-up after withdrawal of therapy showed no change in the patients' appearance. One patient developed glycosuria as lipodystrophy became manifest. In three cases glucose tolerance test was performed revealing a high level of insulin between the first and third hour of loading.. In our view, lipodystrophy is an unwanted side-effect of protease inhibitor therapy causing noticeable disfigurement.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Indinavir; Lipodystrophy; Male; Middle Aged; Protease Inhibitors

Topics: Adult; Anti-HIV Agents; Gynecomastia; HIV Infections; Humans; Indinavir; Male

This study explores whether previous failures on antiretroviral drug regimens preclude the possibility of immune restoration. This was assessed by evaluating T cell subset changes in individuals who received a salvage regimen of highly active antiretroviral therapy (HAART) after initially failing protease inhibitor monotherapy. Ten HIV-1-infected asymptomatic patients received a regimen of indinavir, zidovudine, and 3TC after failing saquinavir monotherapy. Changes in absolute numbers of naive, memory, and activated CD4+ and CD8+ T cells expressing a selection of CD45RA, CD62L, CD45RO, HLA-DR, and CD38 markers were monitored prospectively over 6 months. These measurements were correlated with plasma viral load along with alterations in a selected CD8+ V alpha/Vbeta T cell receptor (TCR) repertoire. Over 6 months there was a progressive increase in numbers of CD4+ memory (CD45RA-CD62L+) and naive (CD45RA+CD62L+) T cells, which displayed a modest inverse correlation with viral load. Two phases of CD8+ memory cell changes were identified, consisting of a transient increase in CD45RA+CD62L- numbers after 2 months and thereafter a progressive rise in CD45RA-CD62L+ cells until 6 months. A strong correlation existed between reduced viral load and loss of activated CD8+CD38+HLA-DR+ cell numbers. There was also a temporary broadening of the CD8+ V alpha/Vbeta TCR repertoire at 8 weeks, which became skewed after 6 months in parallel with reduced viral suppression. Closer analysis of naive and memory cell subset proportions in individual patients revealed that enlarged pools of naive subsets were evident in those patients with rebounds in viral load. Overall, drug-experienced patients responding to HAART displayed increased numbers of naive and memory CD4+ subsets, and reduced CD8+ cell activation with a loss of TCR skewing.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Lymphocyte Activation; Lymphocyte Count; Middle Aged; Prospective Studies; Receptors, Antigen, T-Cell, alpha-beta; RNA, Viral; T-Lymphocyte Subsets; Viral Load; Zidovudine

Topics: Hemophilia A; Hemorrhage; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Thrombocytopenia

To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy.. Cross-sectional study.. Outpatient clinic of a university teaching hospital.. HIV-infected patients either receiving at least one protease inhibitor (n=116) or protease inhibitor-naive (n=32), and healthy men (n=47).. Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed.. HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P=0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P=0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus.. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Topics: Adult; Anti-HIV Agents; Body Composition; Cross-Sectional Studies; Diabetes Mellitus; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Insulin Resistance; Lipodystrophy; Male; Nelfinavir; Risk Factors; Ritonavir; Saquinavir; Syndrome

To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year.. Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues.. The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load.. Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

Topics: Adult; Aged; Anti-HIV Agents; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Zidovudine

Topics: Adult; Anti-HIV Agents; Codon; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genes, pol; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Mutation; Prospective Studies; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Virus Latency; Zidovudine

Topics: Anti-HIV Agents; Anticoagulants; Drug Antagonism; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Ritonavir; Warfarin

Topics: Acute Kidney Injury; Anti-HIV Agents; Child; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Evaluation; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viremia; Zidovudine

The effects of two antiretroviral triple combinations including the protease inhibitor indinavir on the surrogate markers, viral load and CD4 cells were evaluated.. Fifteen patients with high viral load or disease progression under their prior antiretroviral therapy were switched to zidovudine/lamivudine/indinavir (Group A, n = 10) or stavudine/lamivudine/indinavir (Group B, n = 5). Serial determinations of viral load and CD4 cells were performed.. The median reduction of the viral load was 0.6 log after 3 months and 0.8 log after 6 months in Group A and 2.5 and 2.4 log after 3 and 6 months in Group B, respectively. After 3 and 6 months 3 of 10 patients in Group A and 3 of 5 patients in Group B had viral load reductions below the detection limit of the assay. Patients with an additional switch of nucleoside analogues at start of indinavir therapy (regardless of the specific reverse transcriptase inhibitor used) had significantly better reductions of the viral load than patients without such a switch (median 2.3 log vs. 0.2 log after 6 months, P < 0.05). In Group A the median of the relative increase of CD4 cells was 37% after 3 months and 57% after 6 months (P = 0.002); in Group B the medians of the relative increase of CD4 cells were 145 and 163% (not significant), respectively. Two patients from Group A and 1 from Group B developed renal calculi, which resolved after adequate hydration. One patient was withdrawn because of intractable vomiting attributed to indinavir.. In a small cohort of HIV-infected pediatric patients with extensive prior antiretroviral treatment, triple therapy including indinavir had a sustained effect on the decrease of the viral load and the increase of CD4 cells similar to results obtained in antiretrovirally experienced adults. This effect was significantly better in patients with an additional switch of a nucleoside analogue at start of triple therapy with indinavir than in patients without such a change.

Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infant; Lamivudine; Male; Reverse Transcriptase Inhibitors; Statistics, Nonparametric; Viral Load; Zidovudine

Topics: Anti-HIV Agents; Genes, env; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Ritonavir; Saquinavir

Topics: Adult; Anti-HIV Agents; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Ritonavir; Saquinavir; Treatment Failure

Topics: Anti-HIV Agents; Cost-Benefit Analysis; HIV Infections; Humans; Indinavir; Lamivudine; Occupational Exposure; United States; Zidovudine

The performance of the high-density oligonucleotide array methodology (GeneChip) in detecting drug resistance mutations in HIV-1 pol was compared with that of automated dideoxynucleotide sequencing (ABI) of clinical samples, viral stocks, and plasmid-derived NL4-3 clones. Sequences from 29 clinical samples (plasma RNA, n = 17; lymph node RNA, n = 5; lymph node DNA, n = 7) from 12 patients, from 6 viral stock RNA samples, and from 13 NL4-3 clones were generated by both methods. Editing was done independently by a different investigator for each method before comparing the sequences. In addition, NL4-3 wild type (WT) and mutants were mixed in varying concentrations and sequenced by both methods. Overall, a concordance of 99.1% was found for a total of 30,865 bases compared. The comparison of clinical samples (plasma RNA and lymph node RNA and DNA) showed a slightly lower match of base calls, 98.8% for 19,831 nucleotides compared (protease region, 99.5%, n = 8272; RT region, 98.3%, n = 11,316), than for viral stocks and NL4-3 clones (protease region, 99.8%; RT region, 99.5%). Artificial mixing experiments showed a bias toward calling wild-type bases by GeneChip. Discordant base calls are most likely due to differential detection of mixtures. The concordance between GeneChip and ABI was high and appeared dependent on the nature of the templates (directly amplified versus cloned) and the complexity of mixes.

Topics: Anti-HIV Agents; Drug Resistance, Microbial; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Oligonucleotides; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; RNA, Viral; Sensitivity and Specificity; Sequence Analysis, DNA; Zidovudine

The presence of latently infected, resting CD4(+) T cells carrying replication-competent HIV-1 has been demonstrated in chronically infected individuals who are antiretroviral therapy naive as well as in those who are receiving highly active antiretroviral therapy (HAART). It is not clear, however, whether the establishment of a pool of latently infected CD4(+) T cells can be blocked by early initiation of HAART after primary infection. The present study demonstrates that initiation of HAART in infected individuals as early as 10 days after the onset of symptoms of primary HIV-1 infection did not prevent generation of latently infected, resting CD4(+) T cells carrying integrated HIV-1 DNA as well as infectious HIV-1 despite the successful control of plasma viremia shortly after institution of HAART. Furthermore, there was no correlation between either the duration of HAART at the time of study (range: 0.2-17 months) or the time of initiation of HAART after the onset of symptoms of primary HIV-1 infection (range: 0.3-4 months) and the frequencies of resting CD4(+) T cells carrying either integrated HIV-1 DNA or infectious virus. These results underscore the rapidity with which latent reservoirs are established in primary HIV-1 infection and indicate that it is unlikely that early treatment during primary infection can prevent establishment of a pool of latently infected, resting CD4(+) T cells as long as treatment is initiated after plasma viremia becomes evident.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Virus Integration; Virus Latency; Virus Replication; Zidovudine

To evaluate the virologic activity of a ritonavir plus saquinavir-containing regimen in patients who have failed an indinavir or ritonavir-containing regimen.. Patients were identified through a retrospective study evaluating the incidence of indinavir or ritonavir failure in our clinic.. Eighteen patients failing indinavir or ritonavir therapy and who switched to a ritonavir-saquinavir-containing regimen were evaluated. Indinavir or ritonavir failure was defined as a plasma viral load > 1500 copies/ml (branched DNA) after 16 weeks of continuous therapy.. All patients switched to ritonavir (400 mg twice daily) plus saquinavir (400 mg twice daily) and received concurrent therapy with two nucleoside reverse transcriptase inhibitors (NRTI). Twelve of the 18 patients modified their NRTI regimen at the time ritonavir-saquinavir was initiated.. Plasma viral load was monitored using a branched DNA assay. Genotypic analysis was performed using a point mutation differential hybridization technique, and was confirmed with direct sequencing.. Fourteen out of 18 patients completed at least 24 weeks of therapy; the remaining four patients discontinued therapy after week 12 due to a lack of virologic response or intolerance. Plasma viral load decreased a median 1.4 log10 after 4 weeks of treatment with ritonavir-saquinavir. Only four patients had a greater than 0.5 log10 decrease in viral load after 24 weeks of therapy. In eight out of 10 patients evaluated, the V82A mutation was present at the time of the switch to ritonavir-saquinavir. Viral rebound on ritonavir-saquinavir was associated with the emergence of mutations at amino acids 46, 48, 54 and 90.. The combination of ritonavir, saquinavir and two NRTI resulted in a moderate but transient suppression of viral replication in patients who have failed indinavir or ritonavir therapy. Failure of ritonavir-saquinavir may be associated with the emergence of mutations associated with resistance to ritonavir/saquinavir monotherapy, particularly the L90M mutation.

Topics: Anti-HIV Agents; Cohort Studies; DNA, Viral; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nucleic Acid Hybridization; Point Mutation; Polymerase Chain Reaction; Retrospective Studies; Ritonavir; Saquinavir; Treatment Failure; Viral Load

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Mass Spectrometry

Topics: Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Indinavir; Male

Topics: Adipose Tissue; Adult; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male

A major problem with the use of human immunodeficiency virus type 1 (HIV-1) protease inhibitors as monotherapy has been an unacceptably high rate of emergence of resistance. To examine possible influences on the time to emergence of resistance, 24-week data were examined from five studies in which indinavir had been administered as monotherapy or as a component of combination therapy. Monotherapy data indicated a correlation between the level of HIV-1 RNA achieved and the risk of emergence of resistance: the lower the level, the lower the risk. When combination and monotherapy regimens were compared, the group receiving indinavir + lamivudine + zidovudine had a significantly lower risk of resistance, even after adjusting for the minimum HIV-1 RNA level achieved. The findings indicate that if at all possible, HIV-1-infected patients should receive combination chemotherapy to minimize the emergence of resistance to the protease inhibitor portion of the regimen. The goal of therapy should be to decrease the HIV-1 RNA load to a less-than-detectable level.

Topics: Anti-HIV Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male

To compare the viral suppression of two antiretroviral regimens using three drugs or five drugs.. Two open-label studies using a three-drug (zidovudine, lamivudine and ritonavir) and a five-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug-naive patients, except for one in the five-drug study.. Participants with > or = 10 000 HIV-1 RNA copies/ml in plasma at baseline were compared by means of Kaplan-Meier curves for time to < 50 copies/ml, as well as linear regression analysis for the first phase of decline using log-transformed copy numbers.. The elimination rate constants for HIV-1 RNA in 15 participants of the three-drug study were compared with nine participants of the five-drug study. The level of < 50 copies/ml was reached earlier when using the five-drug than when using the three-drug regimen (P log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first 2 weeks after the initiation of therapy. When the viral load declines were calculated from day 2 onwards, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens.. With the five drugs used in this study, the median time to reach < 50 HIV-1 RNA copies/ml was 8 weeks shorter than with the three-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple-drug therapy can be improved upon.

Topics: Adult; Anti-HIV Agents; Data Interpretation, Statistical; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Virus Replication; Zidovudine

To assess the rate of long-term effectiveness and factors associated with response to protease inhibitor therapy in a cohort of HIV-infected patients.. Prospective, non-randomized study in a tertiary care centre.. A total of 400 HIV-infected patients who started on protease inhibitor therapy (saquinavir, 28%; ritonavir, 26%; indinavir, 46%) from March 1996 to March 1997.. Long-term virological and immunological effectiveness were defined as HIV RNA levels below 200 copies/ml and CD4+ cell count increase greater than 100 x 10(6)/l, respectively, after 12 months of therapy.. Fifty-seven per cent of patients had a prior AIDS-defining illness, and 91% had received nucleoside analogues for a median time of 28 months. Median CD4+ count was 86 x 10(6) cells/l and HIV RNA level was 4.46 log10 copies/ml. The global rate of virological and immunological effectiveness at 1 year was 45 and 59%, respectively. In a logistic regression analysis, treatment failure was associated with higher baseline HIV load [relative risk (RR), 2.10; P<0.01], prior antiretroviral therapy (RR, 2.07; P<0.01), and use of saquinavir (RR, 1.55; P = 0.03), whereas a reduction of more than 1 log10 in HIV load within the first 3 months on therapy was strongly associated with response (RR, 0.65; P<0.01). There was no strict correlation between virological and immunological effectiveness (r = -0.35; P = 0.01).. Nearly half of the patients maintain undetectable HIV load after 1 year of therapy, although important immunological benefit can be obtained in a greater proportion of patients. These data suggest the use of the most potent antiretroviral therapy in pretreated patients with high HIV load, and the capacity of initial virological decline to predict the long-term outcome.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Ritonavir; RNA, Viral; Saquinavir; Time Factors

To determine the effectiveness and safety of adding delavirdine mesylate to a treatment regimen that included indinavir and nucleoside analog reverse transcriptase inhibitors in patients in whom combination therapy had failed.. Observational study.. Private practice.. HIV-1-positive patients with peripheral blood CD4+ lymphocyte counts < 300 x 10(6)/l in whom antiretroviral therapy had failed or whose condition was deteriorating. Of the 53 patients who were eligible for the study, 47 took part; for the majority of these patients indinavir combination therapy had been unsuccessful. the majority of the patients were male (98%), white (92%) and homo/bisexuals (96%).. Delavirdine added to current therapy (usually zidovudine, indinavir and lamivudine); in approximately half of the patients zidovudine was replaced with stavudine.. Plasma HIV-1 RNA levels; peripheral blood CD4+ and CD8+ lymphocyte counts. Safety of the therapy was assessed by monitoring side-effects.. Mean baseline CD4+ lymphocyte count was 127 x 10(6)/l and mean baseline HIV-1 plasma RNA was 5 log10 copies/ml. Adding delavirdine to the therapeutic regimen produced a rapid and sustained decrease in the mean plasma HIV-1 RNA of 1.1 log10 copies/ml over 6 months; 18-21% of patients showed decreases of 2-3 log10 copies/ml. Viral burden in 33% of subjects declined below the assay's limit of detection (2.6 log10 copies/ml) after 6 months. CD4+ lymphocyte counts increased by 66-90% in each group between 1 and 9 months (mean increase approximately 60 x 10(6)/l after 6 months). Adding delavirdine to current therapy was well tolerated. Side-effects reported were: skin rash, 28%; nausea, 9%; kidney stones, 9%; diarrhea, 6%; flank pain, 2%; proteinuria, 2%. Three patients reported serious medical events all of which resolved and none of which were attributed to delavirdine.. Adding delavirdine to the combination regimen of patients in whom protease inhibitor therapy had failed often resulted in a rapid and remarkable decrease in viral load, sustained improvement in CD4+ lymphocyte counts and viral load, and clinical improvement with minimal toxicity.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Delavirdine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Failure; Viral Load; Zidovudine

Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Failure, Chronic; Male; Renal Dialysis

Topics: Anti-HIV Agents; Diabetic Ketoacidosis; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Middle Aged

Dental health care professionals continue to suffer exposure incidents from instruments contaminated with blood and/or body fluids from patients. Each of these cases requires that a rigid protocol be followed for their evaluation. New information regarding the risk factors for HIV-seroconversion following an exposure incident have been identified. Recent data has demonstrated that a 79 percent reduction in disease transmission may be possible with a new combination drug therapy. The anti-retroviral drugs included in this new regimen are now standard in the management of occupational exposure to HIV. Several factors set dentistry apart from other health care occupations, and these differences appear to have an effect on the risks associated with occupational exposures. This article explores these risk factors and the new recommendations for postexposure care.

Topics: Anti-HIV Agents; Blood-Borne Pathogens; Dental Staff; Dentistry; HIV Infections; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Mandatory Reporting; Occupational Exposure; Risk Factors; Risk Management; Surveys and Questionnaires; Zidovudine

Topics: Anti-HIV Agents; Drug Therapy, Combination; Forensic Medicine; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Occupational Exposure; Zidovudine

Indinavir sulfate is a protease inhibitor used in the treatment of the human immunodeficiency virus (HIV). This case report describes the radiographic and urologic manifestations of indinavir urolithiasis in two pediatric patients with acquired immunodeficiency syndrome (AIDS). Management involves aggressive hydration and surgical intervention when indicated.

Topics: Adolescent; Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Radiography; Ureteral Calculi; Ureteral Obstruction

Topics: Adolescent; Anti-HIV Agents; Child; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Pilot Projects; Protease Inhibitors; Ritonavir; Treatment Outcome

We describe the unique CT features of ureteric calculi in six HIV-infected patients receiving indinavir, the most commonly used HIV protease inhibitor, which is associated with an increased incidence of urolithiasis.. Ureteric obstruction caused by precipitated indinavir crystals may be difficult to diagnose with unenhanced CT. The calculi are not opaque, and secondary signs of obstruction may be absent or minimal and should be sought carefully. Images may need to be obtained using i.v. contrast material to enable diagnosis of ureteric stones or obstruction in patients with HIV infection who receive indinavir therapy.

Topics: Adult; Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Tomography, X-Ray Computed; Ureteral Calculi; Ureteral Obstruction

Topics: Anti-HIV Agents; HIV Infections; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Kidney Diseases; Occupational Diseases; Occupational Exposure

Highly active antiretroviral therapy (HAART) decreases viral load and increases CD4 T-cell counts in patients with advanced HIV-1 infection. Whether HAART can improve CD4 T-cell function, and the biological characteristics affecting immune reconstitution, remain unclear. We undertook an open prospective pilot study to address these issues. Both treatment-naïve and previously treated patients were included.. 20 patients (seven naïve, 13 previously treated) were treated with one protease inhibitor and two reverse-transcriptase inhibitors and followed up for 12 months. We measured CD4-cell proliferation in response to cytomegalovirus and tuberculin antigens and counted subsets of CD4 cells at baseline and months 1, 3, 6, 9, and 12. Patients who had no antigen-specific reactivity at baseline but developed it while receiving HAART were classified as immunological responders.. Four patients had antigen-specific reactivity at baseline compared with 14 at month 12 (p <0.001). Between month 3 and month 12 viral load fell by a median of 1.5 log copies/mL from baseline (4.6 log copies/mL) and CD4-cell count increased by a median of 63/microL (from 93/microL). Ten patients (six of seven naïve, four of 13 previously treated) were immunological responders. They differed significantly from the ten non-responders in that their viral-load reduction was sustained for 12 months, the increase in CD4 count was greater, and they showed an early increase in memory CD4 T cells with an increase of naïve T cells.. HAART can induce sustained recovery of CD4 T-cell reactivity against opportunistic pathogens in severely immunosuppressed patients. This recovery depends not on baseline values but on the amplitude and duration of viral-load reduction and the increase of memory CD4 T cells.

Topics: Adult; Anti-HIV Agents; Antibodies, Monoclonal; CD4-Positive T-Lymphocytes; Cell Division; Female; HIV Infections; HIV-1; Humans; Immunocompetence; Indinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Time Factors; Viral Load

Topics: Abdomen; Adipose Tissue; Adult; Anti-HIV Agents; Body Composition; Female; HIV Infections; HIV-1; Humans; Indinavir; Pneumonia, Pneumocystis; Protease Inhibitors

To study the relationship between effective antiretroviral therapy, monitored by CD4 counts, and it s influence on the clinical course of AIDS associated Kaposi's sarcoma.. Four representative cases with AIDS and advanced Kaposi's sarcoma (KS) showed improvement of histologically proven KS s in various sites, including pulmonary disease, treated with liposomal doxorubicin. CD4 counts increased significantly during administration of triple antiretroviral therapy. In three cases chemotherapy cycles were extended and subsequently discontinued for 4, 14 and 4 months, respectively, without any relapse. In one other case interferonalpha therapy has been started overlapping with doxorubicin prior to permanent discontinuation of doxorubicin.. Data of those patients suggest that in patients with increasing CD4 counts KS's chemotherapy intervals should be extended or even discontinued. In some patients change of therapy to interferon alpha can be considered. A potent combined antiretroviral therapy may enhance efficiency of KS treatment even in patients with high CD4 counts.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antineoplastic; Doxorubicin; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interferon-alpha; Lamivudine; Liposomes; Male; Remission Induction; Reverse Transcriptase Inhibitors; Sarcoma, Kaposi; Stavudine

To examine the relationship between HIV protease genotype and altered protease inhibitor sensitivity of isolates from patients after therapy with saquinavir (SQV) in its hard gelatin formulation.. Forty-one post-therapy isolates and corresponding baseline samples were obtained from 37 patients in four different clinical trials after therapy with SQV for 16-147 weeks. Post-therapy isolates were selected on the basis of preliminary sequence or drug sensitivity data.. Fifteen out of 17 isolates without detectable Val-48 or Met-90 mutations retained sensitivity to SQV. (The remaining isolates showed only a marginal increase in median inhibitory concentration.) In addition, three out of 15 isolates with Met-90 retained sensitivity to all other protease inhibitors tested (indinavir, ritonavir, amprenavir, nelfinavir). Of the isolates showing reduced sensitivity to SQV, six out of 22 retained sensitivity to all other protease inhibitors, whereas only four out of 22 showed broad cross-resistance to all protease inhibitors tested. The reduction in sensitivity correlated closely with the presence of Val-48 or Met-90. Subsequent accessory substitutions were also linked to reduced sensitivity. However, significant linkage was observed only between mutations at residues 48 and 82 and between those at residues 82 and 74.. Recruitment of Val-48/Met-90 mutations was not found to be synonymous with cross-resistance. Indeed, the majority of isolates with these mutations retained sensitivity to at least one protease inhibitor (Val-48, 86%; Met-90, 77%). The recruitment of accessory mutations may occur only after the selection of key resistance mutations. Furthermore, Met-90 was found to be a poor marker of cross-resistance in SQV-treated patients.

Topics: Amino Acid Substitution; Carbamates; Clinical Trials as Topic; Databases, Factual; DNA, Viral; Furans; Genetic Linkage; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Methionine; Nelfinavir; Phenotype; Polymerase Chain Reaction; Ritonavir; Saquinavir; Sulfonamides; Valine

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

Uveitis is an ocular manifestation rarely observed in HIV-infected patients. We observed three cases of anterior uveitis without progressive retinitis in HIV patients receiving antiprotease treatment.. The first patient developed a first episode of uveitis during ritonavir therapy. Two other episodes occurred with indinavir. The second patient developed uveitis when treated with indinavir. In the third patient, the first episode developed with indinavir and a second with a ritonavir-saquinavir combination. Uveitis was unilateral in 4 episodes. Clinical manifestations were red irritable eyes and, in 2 episodes, reduced visual acuity. The antiprotease was interrupted in 4 of the 6 episodes and clinical course was rapidly favorable.. Pure anterior uveitis should suggest drug induction in HIV infected patients; rifabutin is often the cause. Infectious causes predominate in case of total uveitis associating choroid and retinal involvement. Cytomegalovirus, herpes zoster, syphilis, and toxoplasmosis have been incriminated. Antiproteases would appear to be a new cause of anterior uveitis in HIV-infected patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Rifabutin; Ritonavir; Saquinavir; Uveitis; Uveitis, Anterior; Visual Acuity

Diarrhea due to infection with Microsporidium (M) or Cryptosporidium (C) raises significant therapeutic challenges in HIV-infected patients. The usefulness of protease inhibitor therapy was evaluated in 20 HIV-positive patients with positive tests for M and/or C. There were 17 men and three women with a mean age of 42.5 years (range, 26-64 years). Two patients had category B disease and 18 category C disease according to the 1993 CDC classification scheme (CD4 count before therapy, 72/mm3; mean viral burden, 4.6 log). Seventeen patients had chronic diarrhea (due to M in 12 cases and to C in five), and the remaining three patients were asymptomatic M carriers. Clinical symptoms resolved after addition to the antiretroviral regimen of indinavir (n = 17) or saquinavir (n = 3). Mean weight gain was 10.5 kg. Karnofsky's index improved. Twelve patients, including one of the three who were asymptomatic at baseline, had negative follow-up stool cultures. The mean CD4 count increase was 125/mm3, and the mean viral burden decrease was 1.285 log. These data suggest that protease inhibitors may be capable of eradicating M and/or C infection refractory to other treatments. The reason for this effect may involve partial restoration of immune function due to inhibition of HIV replication.

Topics: Adult; AIDS-Related Opportunistic Infections; Animals; Anti-HIV Agents; Cryptosporidiosis; Diarrhea; Drug Therapy, Combination; Feces; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunocompetence; Indinavir; Male; Microsporida; Microsporidiosis; Middle Aged; Reverse Transcriptase Inhibitors; Saquinavir; Treatment Outcome

Topics: Anti-HIV Agents; Cost-Benefit Analysis; Female; HIV Infections; Humans; Indinavir; Lamivudine; Male; Models, Theoretical; Reproducibility of Results; Sexual Behavior; Zidovudine

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lipodystrophy; Male; Middle Aged

To analyse the characteristics of opportunistic infections in patients receiving highly active antiretroviral treatment (HAART).. A retrospective study performed in seven hospitals, included all patients starting treatment by ritonavir or indinavir between 26 March and 31 December 1996. Patients were evaluated for the development of AIDS-defining events. Clinical evaluation, plasma HIV-1 RNA quantification, CD4 cell count were recorded at baseline and at the onset of the event.. Four hundred and eighty-six patients were included: 44.2% had a CD4 cell count below 50 x 10(6) cells/l. Fifty clinical events were recorded in 46 patients with a mean follow-up of 6.1 months, of which 34 events (68%) were observed during the first 2 months of HAART. Eighteen of these occurred despite a reduction of viral load by at least 1.5 log10) and a 100% increase of the CD4 cell count compared with that at the onset of the event, corresponding to 11 cytomegalovirus infections, five mycobacterial infections, one case of cryptococcosis, and one case of Varicella-Zoster virus-related acute retinal necrosis. Among the 16 events observed after the second month, six occurred despite a marked biological improvement, corresponding to a recurrence in five of six patients who had stopped their maintenance therapy. Events were one cytomegalovirus infection, two mycobacterial infections, one episode of oesophageal candidiasis and one cryptococcal meningitis.. In patients at high risk of developing an opportunistic infection prior to the institution of a HAART regimen, prophylaxis should not be discontinued during the first 2 months of treatment, and maintenance therapy should be carried on despite a significant increase in the CD4 cell count.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Candidiasis; CD4 Lymphocyte Count; Cryptococcosis; Cytomegalovirus Infections; Disease Progression; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Hospitals, University; Humans; Indinavir; Mycobacterium Infections; Pneumonia, Pneumocystis; Retrospective Studies; Ritonavir; RNA, Viral; Toxoplasmosis, Cerebral; Viral Load

Topics: Adult; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Time Factors; Urinary Calculi

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Enzyme Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Omeprazole; Proton Pump Inhibitors

To determine whether the protease inhibitor indinavir sulfate, which is extremely insoluble at physiologic pH levels and which is known to be associated with nephrolithiasis, is associated with crystalluria at a usual therapeutic dose.. Freshly voided urine from 27 male human immunodeficiency virus patients being treated with indinavir at a dose of 800 mg, tid, in an outpatient setting and from 20 healthy subjects undergoing routine physical examination was subjected to dipstick urinalysis and microscopic examination of urinary sediments.. Three (11%) of 27 patients treated with indinavir developed highly characteristic crystalluria during the course of therapy. No such crystals were observed in the urine of the 20 healthy subjects.. Indinavir crystalluria was identified in asymptomatic patients treated with usual therapeutic doses of the drug. Screening urines of patients taking indinavir may be useful in identifying patients at risk for developing nephrotoxicity.

Topics: Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Hydrogen-Ion Concentration; Indinavir; Kidney Calculi; Male; Risk Factors; Urine

Triple antiretroviral therapy combining reverse transcriptase and protease inhibitors modifies the prognosis of human immunodeficiency virus (HIV) infection, with dramatic improvement in immune status. The precise impact, if any, of anti-HIV triple therapy on hepatitis C virus (HCV) infection is unknown. We describe an unusual case of rapidly evolving HCV-related cirrhosis that paralleled restoration of immune status in an HIV-infected patient and discuss the possible link between such a severe course of hepatitis C and anti-HIV triple therapy.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Liver Cirrhosis; Reverse Transcriptase Inhibitors; Stavudine

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Hair; HIV Infections; HIV-1; Humans; Indinavir; Patient Compliance; Treatment Outcome

We have examined the effect of potent antiretroviral regimens on the latent reservoirs of HIV-1. The HIV-1 DNA in the peripheral blood mononuclear cells (PBMC) of 10 patients with undetectable plasma HIV-1 RNA (<20 copies/ml) who had received combination antiretroviral therapy was assayed every 12 weeks. No evidence of residual viral replication was found in the PBMC after 24 weeks of treatment. Although HIV-1 DNA remained detectable in all patients, it decreased significantly from 3.5 log copies/10(6) cells (range, 1.8-4.7 log copies/10(6) cells) to 2.3 log copies/10(6) cells (range, 0.6-3.1 log copies/10(6) cells) after 60 weeks of suppressive therapy. Analysis based on 6 patients who reached 60 weeks showed a slow decline with an estimated half-life of 40 weeks (range, 26-163 weeks). Genotypic analysis by sequencing the HIV-1 pol gene revealed no changes in the reverse transcriptase or protease coding regions after 48 to 60 weeks of therapy. The findings suggest that, in addition to potent antiretroviral regimens, new strategies must be developed to ensure eradication of the latent reservoir of provirus, and hence of the virus itself.

Topics: Adult; Amino Acid Sequence; Anti-HIV Agents; Base Sequence; CD4 Lymphocyte Count; DNA, Viral; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genes, pol; Genotype; Half-Life; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Leukocytes, Mononuclear; Longitudinal Studies; Male; Molecular Sequence Data; Mutation; Retrospective Studies; RNA, Viral; Zidovudine

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Antigens, CD; Antigens, Differentiation; CD8-Positive T-Lymphocytes; Child; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Membrane Glycoproteins; NAD+ Nucleosidase; Stavudine; Viremia

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Nelfinavir; Nevirapine; Peripheral Nervous System Diseases; Saquinavir; Zidovudine

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Leukocytes, Mononuclear; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load

Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; Health Personnel; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Occupational Exposure; Practice Guidelines as Topic; United States; United States Public Health Service; Zidovudine

Topics: Adult; Anti-HIV Agents; HIV Infections; Humans; Indinavir; Kidney Calculi; Kidney Diseases; Male; Protease Inhibitors

Topics: Aged; Anti-HIV Agents; Gynecomastia; HIV Infections; Humans; Indinavir; Male; Middle Aged; Protease Inhibitors

Indinavir use is associated with a spectrum of renal and urinary tract complications including nephrolithiasis, renal colic and pain without recognizable lithiasis, and a picture of crystalluria-dysuria. A frank nephropathy has not been recognized as part of the spectrum.. A retrospective analysis of 106 HIV-infected individuals receiving indinavir was performed with the purpose of identifying the frequency and risk factors for indinavir-associated nephropathy and urinary complications. Individuals receiving ritonavir or nelfinavir served as controls.. A sustained elevation of creatinine (>20%, into abnormal range) was identified in 20 (18.6%) subjects treated with indinavir but not with other protease inhibitors. Creatinine elevation was associated with treatment duration of more than 54 weeks [odds ratio (OR), 7.1; 95% confidence interval (CI), 1.8-27.7], low baseline body mass index < or = 20 kg/m2 (OR, 4.0; 95% CI, 1.0-16.6), and use of trimethoprim-sulphamethoxazole (TMP-SMX; OR, 4.6; 95% CI, 1.5-13.8). Lower urinary specific gravity (P = 0.015), and leukocyturia (P<0.001) were frequently associated features of indinavir nephropathy. No patient developed severe renal impairment and abnormalities were reversible upon discontinuation of the drug. Complications (renal colic, or pain and dysuria) occurred after a mean of 36 weeks (95% CI, 23-48) of indinavir treatment in 13 subjects (12.3%), eight of whom (62%) presented elevated creatinine during follow-up. Only long-term exposure to TMP-SMX (>160 weeks) was identified as a potential risk for the occurrence of a clinical event (OR, 4.7; 95% CI, 1.2-19.2).. A crystal nephropathy, characterized by serum creatinine elevation, loss of concentrating ability of the kidney, leukocyturia, and renal parenchymal image abnormalities, is a frequent complication of indinavir therapy. Identification of individuals at risk, particularly those with low body mass index or receiving TMP-SMX prophylaxis, may help the decision to initiate indinavir or chose an alternative protease inhibitor in order to minimize renal and urinary tract adverse events.

Topics: Adult; Creatinine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Failure, Chronic; Kidney Function Tests; Male; Retrospective Studies; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Urologic Diseases

To assess whether treatment of HIV-positive children by antiretroviral drugs for a 6-month period would improve immune function significantly.. Immunological assessment of 89 HIV-positive children who received protease inhibitor monotherapy for 12-16 weeks as part of phase I/II studies, followed by triple antiretroviral therapy for an additional 12 weeks, was conducted. Immunological parameters were assessed in vitro at four time points (at enrollment, at weeks 2-4, at weeks 12-16, and at weeks 24-28). Assessments included: cytokine production by monocytes, T-cell proliferation to mitogen or recall antigens (including an HIV antigen) and apoptotic cell death. Plasma levels of tumor necrosis factor (TNF)-alpha and soluble TNF receptor (sTNF-R) were also measured, in addition to CD4+ T-lymphocyte counts and viral load. In addition, limited analyses were performed on samples from 17 children after 120 weeks of therapy, including 104 weeks of triple therapy.. At enrollment, the 89 children exhibited severe immune defects. Antiretroviral therapy raised CD4+ T-lymphocyte counts significantly and decreased viral loads. In contrast, the in vitro immune parameters studied were not improved, except for plasma levels of sTNF-RII which decreased in parallel with the decrease in viral load. In addition, there was a trend towards increased skin test reactivity for the ritonavir-treated children. No differences were seen in the immune parameters whether the patients were treated with mono- or triple therapy. Results obtained after 120 weeks of therapy demonstrated that defective interleukin-12 production was not restored by long-term therapy.. After 6 months of therapy, with the exception of decreased sTNF-RII levels, and a trend towards increased skin test reactivity, restoration of several defective cellular immune responses did not occur despite significantly decreased viral loads and increased CD4+ T-lymphocyte counts.

Topics: Adolescent; Anti-HIV Agents; Apoptosis; CD4 Lymphocyte Count; Child; Child, Preschool; Clinical Trials as Topic; Cytokines; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Immunity, Cellular; Indinavir; Infant; Lymphocyte Activation; Reverse Transcriptase Inhibitors; Ritonavir; T-Lymphocytes; Time Factors; Tumor Necrosis Factor-alpha; Viral Load

Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation.. To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection.. Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection.. There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for hemophiliacs and 156 (range 5-611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02).. Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor.

Topics: Adult; Anti-HIV Agents; Female; Hemophilia A; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Indinavir; Kidney Calculi; Male; Risk Factors

Topics: Adult; Angina Pectoris; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Proviruses; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Viremia

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; Indinavir; Lamivudine; Male; Proviruses; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

A 29-year-old hemophiliac with HIV infection for which he was receiving antiretroviral treatment (ART) with indinavir, zidovudine and zalcitabine reported increasing swelling of the neck. Physical examination noted a soft to doughy swelling, not sensitive to pressure, extending from the neck to between the shoulder blades.. Ultrasonography and magnetic resonance imaging revealed the swelling to consist of an accumulation of subcutaneous fat without capsule. Cytology demonstrated benign fatty tissue. Blood triglycerides totalled 667 mg/dl.. The typical location, absence of a capsule and the cytological finding confirmed the clinical diagnosis of drug-induced benign symmetrical lipomatosis (BSL, also called peripheral lipodystrophy) in ART. A connection with the hyperlipoproteinaemia is supported by the observation that the patient used to have a normal fat metabolism; the onset of BSL coincided with a massive increase in triglyceride levels. The hyperglyceridaemia and clinical signs improved on a low-fat diet.. BSL can occur in the course of ART in HIV infection, when reverse-transcriptase inhibitors or protease inhibitors are being taken. Medication should not be changed, when antiretroviral treatment is adequate. To reduce the symptoms low-fat diet should be tried, as well as administration of HMG-CoA-reductase inhibitors or, if necessary, surgical liposuction.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Hemophilia A; HIV Infections; Humans; Indinavir; Lipomatosis, Multiple Symmetrical; Male; Zalcitabine; Zidovudine

Topics: Adipose Tissue; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lipomatosis, Multiple Symmetrical; Male; Middle Aged

Topics: Adult; Bursitis; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Shoulder Joint; Stavudine

A 37-year old patient, HIV-1-infected, consulted for progressive weakness and dyspnea on exertion, increasing over three months. Complete blood count showed pancytopenia, while the bone marrow revealed severe hypoplasia. Other investigations, including serology for CMV, vitamin levels, Coombs test, gastroscopy and colonoscopy were non contributing. A diagnosis of zidovudine-induced medullary aplasia was made; the clinical course was favourable after this drug was replaced by triple therapy. The authors discuss the differential diagnosis of cytopenias in the patient infected by HIV and they suggest a diagnostic approach.

Topics: Adult; Anemia, Aplastic; Anti-HIV Agents; Bone Marrow; HIV Infections; HIV Seropositivity; HIV-1; Humans; Indinavir; Lamivudine; Male; Pancytopenia; Stavudine; Zidovudine

In three patients, a 36-year-old HIV seropositive homosexual man and two women aged 35 and 59 years who had acquired HIV infection through heterosexual contact, signs of lipodystrophy developed after prolonged anti-HIV triple therapy. The observed syndrome is seen after prolonged use of HIV protease inhibitors: it is characterized by peripheral fat wasting, central fat accumulation, hyperlipidaemia and insulin resistance. Typically the subcutaneous fatty tissue disappears resulting in prominent zygomata, veins and muscles and thinning of extremities and buttocks. In addition to abdominal fat accumulation, there have been reports on the occurrence of a dorsocervical fat pad, the so-called buffalo hump. Lipodystrophy caused by protease inhibitors is a risk factor for cardiovascular disease. Recognition of the syndrome is essential for adequate follow-up and possible treatment.

Topics: Adult; Cardiovascular Diseases; CD4 Lymphocyte Count; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Treatment Outcome; Wasting Syndrome

A case is presented of an HIV-infected man who developed Stevens-Johnson syndrome shortly after the initiation of treatment with indinavir. This is the first case ever reported of this adverse drug reaction occurring with an HIV protease inhibitor.

Topics: Adult; Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Stevens-Johnson Syndrome

To study the virological, immunological and clinical effects of the protease inhibitor indinavir in human immunodeficiency virus (HIV)-infected patients with CD4 counts < 50 cells/mm3, indinavir was added to prior treatment with nucleoside analogues in a prospective open-label study in 23 HIV-infected patients with median CD4 count of 10 cells/mm3 and median serum HIV-1 RNA load of 27,508 copies/ml. Addition of indinavir induced a decrease in HIV-1 RNA levels to < 400 copies/ml in 15 patients that was maintained until week 36 of the study in 8 (35%) patients. The median increase in CD4 cell counts was 92 cells/mm3 (range 55-258 cells/mm3) and in CD8 counts was 245 cells/mm3 (range 51-1552 cells/mm3) at week 30. The treatment induced a significant CD8 T cell expansion, consisting in the first 6 weeks of predominantly memory CD45RO+ cells and followed by expansion of naive cells from week 12 on, and a significant decrease in the proportion of activated CD8/CD38 cells. In addition, significant increases in T cell proliferation following stimulation with phytohaemagglutinin and significant decreases in the rates of spontaneous apoptosis of CD4+ and CD8+ T cells were observed. In conclusion, the addition of indinavir induced restoration of both memory and naive CD8 T cells. Corresponding evidence of improving T cell function, as assessed by enhanced lymphoproliferative capacity and diminished propensity to undergo apoptosis, provides evidence for treatment-induced regeneration of immune function even in patients with severe immunodeficiency.

Topics: Adult; Aged; Apoptosis; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; RNA, Viral; T-Lymphocyte Subsets

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Saquinavir; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; California; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; Hotlines; Humans; Indinavir; Patient Selection

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Nevirapine; Viral Load

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Saquinavir; Viral Load; Zidovudine

Topics: Anti-HIV Agents; Carbamates; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Saquinavir; Sulfonamides; Viral Load; Zidovudine

Studies indicate that patients who have responded well to intensive antiretroviral therapy should continue their current treatment regimen rather than switch to less intensive therapy during the maintenance phase. Data from ACTG 343, a study to determine the sustaining of HIV suppression with fewer drugs, reveals that less intensive antiviral maintenance therapies were less effective than continuation of the triple-drug regimen; findings were statistically significant. Viral load rebound was far more prevalent in one- or two-drug maintenance regimens than in the triple-drug therapies. Further, data show viral load rebound more likely when the patient's viral load had not gone below 200 copies of HIV RNA/ml within four weeks of initiating triple-therapy. Findings from other multiple-drug trials and immune stimulating reactions from vaccine trials are summarized.

Topics: AIDS Vaccines; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Saquinavir; Stavudine; Viral Load; Zidovudine

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

Gilead Sciences has seen beneficial results from two trials of adefovir dipivoxil (Preveon) in the treatment of HIV. An additional trial of adefovir dipivoxil was a success, dramatically reducing hepatitis B viral load by 99.99 percent. GS 411 assigned treatment-naive patients to one of five regimens that included indinavir (Crixivan) and adefovir. The results suggest that adefovir, which is metabolized differently and has different side effects, may be an alternative for some nucleoside analogs. GS 408 added adefovir to the regimens of treatment-experienced patients and showed a marked decrease in viral load for those patients who used adefovir versus a placebo. Adefovir dipivoxil may also be used effectively against other viruses such as CMV, HHV6 and Epstein-Barr. Long-term effectiveness in controlling the HIV virus has yet to be determined.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Drugs, Investigational; Hepatitis B; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; United States

The number of people joining research studies has dropped since stronger and more effective anti-HIV drugs have been manufactured and approved. However, trials are still enrolling people who are not doing well on their current treatments. Information about trials for people who are failing nelfinavir (Viracept) or indinavir (Crixivan) and the eligibility criteria for many of these studies are provided. Several studies for people who have failed one or more treatments are in the planning stages.

Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Patient Selection; Salvage Therapy; Treatment Failure; Viral Load

The 1998 Retrovirus Conference in Chicago, while not providing any major breakthroughs, confirmed the impact of combination therapy in dramatically reducing viral load in the blood and lymph nodes and increasing CD4+ and other blood cell counts. Companies are beginning to test their drugs using a user-friendly twice-daily schedule and are providing more information about new drugs. Side effects of protease inhibitors are also becoming better documented. The Conference revealed two trends in protease inhibitor use: the increased simultaneous use of two protease inhibitors (PIs) and the switch to twice-daily dosing for some drugs. Several studies involving double combinations of PIs are highlighted, including nelfinavir/indinavir, nelfinavir/saquinavir, and ritonavir/saquinavir. The dosage combinations that work best are still unclear, but physicians seem to have the most experience with ritonavir/saquinavir. Reports indicated that the best results of anti-HIV therapy are reported in people who are using the drugs for the first time. Researchers are still uncertain as to why some HIV-infected people develop AIDS and others do not, and are still unclear as to how protease inhibitors affect the immune system.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Viral Load

Two studies examining twice-daily dosing of indinavir and nelfinavir are presented. Six-month results for nelfinavir indicated the decrease in viral load levels in both twice- and thrice-daily dosing regimens to be about the same. Limited data on indinavir after 20 weeks show viral load drops to below 500 copies in 75 percent of subjects on twice-daily dosings, but only 46 percent of subjects on the regular regimen. It is hoped that the twice-daily dosing will uncomplicate pill taking schedules.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir

A new study on medical marijuana, funded by the National Institutes of Health (NIH), is recruiting volunteers. Volunteers will be paid $1,000, and the study design requires participants to spend 25 days in San Francisco General Hospital's research ward, without leaving and without receiving visitors. Volunteers will be randomly selected to smoke marijuana, take dronabinol, or take placebo capsules. The goal is to find out what is safe and effective for HIV/AIDS patients. The study will look at the nausea-relieving qualities of the drug and its impact on viral load, testosterone levels, energy intake, and body composition. Eligibility requirements are specified, and contact information is included.

Topics: Cannabis; Clinical Trials as Topic; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Patient Selection; Phytotherapy; San Francisco

In [name removed] v. Smith County, Texas U.S. Magistrate Judith K. Guthrie dismissed an HIV-infected inmate's suit against prison officials, where he had received less than optimal drug therapy for his disease. Inmate [name removed] received appropriate doses of AZT and 3TC, but initially did not receive Crixivan; when he did receive it, it was at half the dose he took prior to incarceration. Dismissal was based on rulings by the 5th U.S. Circuit Court that inmates suing prison officials, claiming deliberate indifference, must show more than negligence. The judge further dismissed the inmate's claims under the Americans with Disabilities Act (ADA) and the Rehabilitation Act, saying that those Federal statutes are not applicable to correctional facilities. This ruling predated the U.S. Supreme Court's finding that prisons are subject to the ADA statutes.

Topics: Anti-HIV Agents; Disabled Persons; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Prisoners; Reverse Transcriptase Inhibitors; Texas; Zidovudine

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

Data collected from several studies can provide guidance on new therapies for treatment-experienced patients. A study comparing two different triple-drug combination therapies, both using Indinavir, showed no significant differences in antiviral activity. A study of a triple-drug regimen that included Delavirdine, produced more favorable results than two different dual combination regimens. A small study indicated that "recycling" previously used antiviral drugs with two new drugs into a 6-drug regimen had positive short-term effects as a salvage therapy. However, adherence to such a regimen may prove difficult. A larger study of another salvage therapy, which used Ritonavir plus Saquinavir plus two NARTIs, had different results depending on whether the patient had been treated previously with Ritonavir or with Saquinavir. Two other studies examined different dosages of Nelfinavir or Indinavir and found that twice-a-day dosing may be as effective as three times a day. More research is needed to supplement the available knowledge for treating patients who most need alternative therapies.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Delavirdine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Menstrual Cycle; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy; Viral Load

Two studies examined the effectiveness of reducing the dosage of anti-HIV medications for patients who have achieved a viral load under 200 copies of HIV RNA. Both studies revealed that the maintenance dosage was not as effective at suppressing viral levels as a triple-drug combination. The results of these studies indicate that participants may not have had ample time to reach the optimal response to their original regimen, before switching to a maintenance regimen. Additional studies are needed to assess the effectiveness of maintenance therapies. A chart of antiviral drugs, the manufacturers, and the trade names is provided.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; RNA, Viral; Viral Load; Zidovudine

As a result of a study that was testing dosing levels of Indinavir (Crixivan) with AZT/3TC, Merck & Co. has advised doctors to administer Indinavir only at the 800 mg three times per day dosage. A subsequent trial is being conducted using Indinavir twice daily in combination with Ritonavir or Nelfinavir to see if taking Indinavir twice daily, at higher dosages, can be as effective as taking Indinavir three times a day.

Topics: Biological Availability; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

A change in dosing of Indinavir (Crixivan) from two times per day to three times per day is recommended for patients who are taking Indinavir with nucleoside analogs. However, twice daily dosing is still being used in trials that combine Indinavir with a protease inhibitor. The change in dosing was based on clinical trials which showed that 91 percent of participants at the three-dose level had a lower viral load than at the two-dose level, when combining Indinavir with AZT plus 3TC. Patients currently on a twice-a-day regimen are advised to consult their physicians about changing their treatment.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

A study by Merck, Inc. of twice-a-day Indinavir (Crixivan), taken with AZT and 3TC, was discontinued because of poor long-term results. The standard dose of Indinavir with AZT and 3TC produced significantly better results in lowering viral load. Other trials of twice-a-day Indinavir with Ritonavir or Nelfinavir will continue.

Topics: Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Viral Load

Merck has discontinued testing the twice-daily dosing of its protease inhibitor Crixivan (Indinavir) in combination with reverse transcriptase inhibitors (RTIs). Merck recommends that patients on the twice-daily dosing regimen be changed back to the original dosing schedule of 800 mg of Crixivan three times a day. The decision to discontinue the twice-daily dosing is based on an analysis of a study at the 24-week mark, which showed that dosing three times daily was more effective in reducing viral load to below detectable levels. The company will continue to study twice-daily dosing in combination with other protease inhibitors. Contact information is provided.

Topics: Clinical Trials as Topic; Drug Industry; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; United States

Long-term combination therapy with protease inhibitors has often led to increased CD4+ cell counts and decreased viral loads, which can contribute to overall clinical improvement in patients. However, individual results can vary widely. A French study of 162 patients is detailed in which patients received Indinavir in combination with 2 nucleoside analogues. Among the participants, some experienced increased CD4+ counts without a significant drop in viral load, while others experienced a significant decrease in viral load without an increase in their CD4+ counts. Study details and results are reported. Results from this study suggest that increasing CD4+ counts may provide a "protective effect" against life-threatening infections.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Viral Load

Efavirenz (Sustiva) is the first once-daily dosing anti-HIV drug approved by the Food and Drug Administration. The non-nucleoside reverse transcriptase inhibitor (NNRTI) is highly potent and more convenient than other therapies, and is used to treat HIV-1 in both adults and pediatric patients. It is effective in combination therapy, and patients on efavirenz had fewer side effects than patients on other triple combinations therapies. It remains to be seen if efavirenz will be used in first-line therapy. Some reports show that patients who are taking other drugs that affect the central nervous system suffer additional central nervous system side effects from efavirenz. There are reports of cross-resistance with other drugs in the same class, and limited data that is available on fetal toxicity suggests that women of childbearing age need to be counseled carefully before taking this drug.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Child; Cyclopropanes; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Oxazines; Patient Compliance; Reverse Transcriptase Inhibitors; Zidovudine

Merck and Company has announced that it is discontinuing trials for the twice-daily dosage of Indinavir (Crixivan). Study results indicate that the experimental regimen was not as effective in reducing viral loads when compared to the standard three times daily regimen. Studies are continuing on the effectiveness of the twice-daily dosage when combined with other protease inhibitors. Merck recommends the three times daily regimen for any patients using Indinavir in combination with nucleoside analogs.

Topics: Clinical Trials as Topic; Drug Industry; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; United States

French researchers have been studying the relationship between CD4 counts and viral load in patients with advanced cases of immune suppression. Dr. Vittecoq, M.D. and colleagues evaluated CD4 counts and viral load, as well as clinical status for 90 patients every 3 months for a 15-month period. The patients were on a triple therapy regimen that included Indinavir (Crixivan). The clinical benefits of Indinavir when combined with a nucleoside were apparent since less than 5 percent of the patients developed an AIDS-related complication.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Disease Progression; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Viral Load

New anti-HIV drugs that are expected to become available in the future are discussed. The potent protease inhibitor amprenavir (Agenerase) is expected to be available in pharmacies by early 1999. Results of a study of treatment-naive, HIV-positive people showed that those taking amprenavir as part of a three-drug combination therapy, with AZT and 3TC, had better viral reduction than those using AZT and 3TC alone. In a French study of the non-nucleoside reverse transcriptase inhibitor Nevirapine, and a similar study of Delavirdine, a majority of participants had HIV RNA levels below the limit of detection. Further comparative studies are needed between Nevirapine, Delavirdine and the more costly, highly publicized competitor, efavirenz. Several studies of regimens that include protease inhibitors compare dosing twice daily to three times a day. A Canadian study describes salvage therapies, for people who have failed previous treatment with protease inhibitors, that can include up to nine drugs. Because there is a shortage in the development of new types of HIV drugs, people are encouraged to carefully consider when to begin treatment and what medical options are available.

Topics: Anti-HIV Agents; Carbamates; Delavirdine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nevirapine; Reverse Transcriptase Inhibitors; Salvage Therapy; Sulfonamides

Although Merck reports that Crixivan is most effectively absorbed when taken without food, many patients need to eat something with the drug to prevent an upset stomach. The manufacturer has developed a six-page list of food combinations that can be safely taken with the medication; the list is available through the PWA Health Group. All combinations meet specific nutrient guidelines for acceptable amounts of carbohydrates, proteins, fat, and calories. Several suggested snacks are listed.

Topics: Food; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

A change in body shape has been associated with protease inhibitor usage. Increased fat in the abdomen, commonly called Crix belly, has been reported in both men and women. Women have also reported breast enlargement, accompanied by redness and tenderness. Symptoms abate when the protease inhibitors are discontinued. The exact cause of this syndrome has not been identified.

Topics: Adult; Breast Diseases; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

The Community Research Initiative on AIDS is currently screening potential volunteers for clinical trials. Current studies include the effects of protease inhibitors on blood sugar, the effectiveness of twice a day Crixivan dosing, the effectiveness of adefovir dipivoxil in combination with protease inhibitors, the effectiveness of DMP 266 in combination with several drugs, and the effects of Oxandrolone on weight loss in women. Participants will be reimbursed after enrollment. Contact information and eligibility requirements are included.

Topics: Adenine; Alkynes; Anabolic Agents; Anti-HIV Agents; Benzoxazines; Blood Glucose; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Organophosphonates; Oxandrolone; Oxazines; Patient Selection; Reverse Transcriptase Inhibitors; Weight Loss

Topics: Anti-HIV Agents; Blood-Borne Pathogens; Chemoprevention; Drug Combinations; Guidelines as Topic; Health Personnel; HIV Infections; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Occupational Diseases; Zidovudine

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Zidovudine

Topics: Anti-HIV Agents; Climate; Drinking; Florida; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi

Topics: AIDS-Related Opportunistic Infections; Cryptosporidiosis; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; Humans; Indinavir; Male; Middle Aged

Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.

Topics: CD4-Positive T-Lymphocytes; Disease Progression; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interleukin-2; Leukocyte Common Antigens; Phenotype; Receptors, Antigen, T-Cell, alpha-beta; RNA, Messenger; Twins, Monozygotic

Topics: Anti-HIV Agents; Blood Platelets; HIV Infections; Humans; Indinavir; Leukocyte Count; Neutrophils; Platelet Count

Topics: Crystallization; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Urine

Topics: Adult; Anti-HIV Agents; Colic; Drug Therapy, Combination; Female; HIV Infections; Humans; Indinavir; Kidney Diseases; Zidovudine

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

Occupational exposure to HIV continues to be a concern for health care workers. Preventing exposure through the use of universal precautions is the primary means of protection. New Public Health Service interagency work group recommendations for postexposure chemoprophylaxis provide information to help manage occupational exposure to HIV.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; Chemoprevention; Child; Dental Auxiliaries; Dentists; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Occupational Diseases; Occupational Exposure; Practice Guidelines as Topic; Risk Factors; United States; United States Public Health Service; Universal Precautions; Zidovudine

Two different responses to the therapy were observed in a group of patients receiving the protease inhibitor indinavir. In one, suppression of virus replication occurred and has persisted for 90 weeks (bDNA, < 500 human immunodeficiency virus type 1 [HIV-1] RNA copies/ml). In the second group, a rebound in virus levels in plasma followed the initial sharp decline observed at the start of therapy. This was associated with the emergence of drug-resistant variants. Sequence analysis of the protease gene during the course of therapy revealed that in this second group there was a sequential acquisition of protease mutations at amino acids 46, 82, 54, 71, 89, and 90. In the six patients in this group, there was also an identical mutation in the gag p7/p1 gag protease cleavage site. In three of the patients, this change was seen as early as 6 to 10 weeks after the start of therapy. In one patient, a second mutation occurred at the gag p1/p6 cleavage site, but it appeared 18 weeks after the time of appearance of the p7/p1 mutation. Recombinant HIV-1 variants containing two or three mutations in the protease gene were constructed either with mutations at the p7/p1 cleavage site or with wild-type (WT) gag sequences. When recombinant HIV-1-containing protease mutations at 46 and 82 was grown in MT2 cells, there was a 68% reduction in its rate of replication compared to the WT virus. Introduction of an additional mutation at the gag p7/p1 protease cleavage site compensated for the partially defective protease gene. Similarly, rates of replication of viruses with mutations M46L/I, I54V, and V82A in protease were enhanced both in the presence and in the absence of Indinavir when combined with mutations in the gag p7/p1 and the gag p1/p6 cleavage sites. Optimal rates of virus replication require protease cleavage of precursor polyproteins. A mutation in the cleavage site that enhanced the availability of a protein that was rate limiting for virus maturation would confer on that virus a significant growth advantage and may explain the uniform emergence of viruses with alterations at the p7/p1 cleavage site. This is the first report of the emergence of mutations in the gag p7/p1 protease cleavage sites in patients receiving protease therapy and identifies this change as an important determinant of HIV-1 resistance to protease inhibitors in patient populations.

Topics: Anti-HIV Agents; Binding Sites; Cell Line, Transformed; Drug Resistance, Microbial; Gene Products, gag; Genetic Variation; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Phenotype; Substrate Specificity

To determine whether, as predicted by predator-prey dynamics, early withdrawal of antiretroviral therapy, i.e. when the number of CD4+ lymphocytes is still elevated, results in an overshoot of HIV-1 viraemia due to infection of increased numbers of available target cells at that time.. Five HIV-1-infected individuals were identified who discontinued antiretroviral therapy for various reasons after 8-19 days, and from whom stored serum samples obtained before, during, and shortly after treatment were available for measurement of HIV-1 RNA load. A mathematical model was designed to assess whether increased target cell availability could quantitatively explain the clinical observations.. After therapy withdrawal, increases in the HIV-1 RNA load to levels exceeding pretreatment values by log10 0.6-1.5 copies/ml were observed after 2-17 days in all four of the individuals who had treatment-induced increases in CD4+ cell counts at the time of therapy withdrawal. Increases in viraemia were maximal within a few days, and subsequently seemed to wane until the pretreatment equilibrium between virus and its target cells was attained. Mathematical modelling confirms that these transient increases in viraemia can be explained by increased availability of target cells at the time of therapy withdrawal.. Transient rises in HIV-1 viraemia do occur following early therapy withdrawal. These rises especially warrant consideration in short-term antiretroviral regimens for prevention of mother-to-child transmission, as are being studied in developing countries, since they could result in an increased transmission risk during the post-partum period through breast-feeding. This possibility needs to be investigated urgently.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Indinavir; Models, Biological; Nevirapine; Pyridines; Risk Factors; RNA, Viral; Substance Withdrawal Syndrome; Viral Load; Viremia; Zidovudine

Topics: Adult; Anti-HIV Agents; Castleman Disease; Herpesvirus 8, Human; HIV Infections; HIV Protease Inhibitors; HIV-1; Homosexuality, Male; Humans; Indinavir; Male; RNA, Viral

Topics: Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; Health Personnel; HIV Infections; HIV-1; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Occupational Exposure; Saquinavir; Zidovudine

Two patients with oliguric acute renal failure (ARF) attributed to crystalluria and nephrolithiasis with obstructive uropathy caused by the human immunodeficiency virus protease inhibitor indinavir are described. In both patients, ARF resolved with administration of intravenous fluids. One patient required urologic intervention to relieve bilateral ureteral obstruction.

Topics: Acute Kidney Injury; Adult; Crystallization; Fluid Therapy; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi; Male

To report a case of renal toxicity associated with administration of indinavir sulfate in a pediatric hemophiliac with HIV infection.. A 16-year-old white hemophiliac boy with HIV infection secondary to tainted coagulation factor VIII was treated with indinavir sulfate. The patient developed gross hematuria, proteinuria, pyuria, abdominal pain, increased bilirubin, an elevated serum creatinine (SCr) of 1.2 mg/dL (baseline 0.9-1.0), and symptoms of renal colic within 1 month of starting indinavir sulfate therapy. Approximately 2 months later the patient developed a low-grade fever with a further increase in SCr. He was prescribed a 10-day course of cefpodoxime proxetil for a possible urinary tract infection. One week later, the patient developed fever, chills, nausea, vomiting, decreased appetite, sterile pyuria, nasal congestion, and an elevated SCr of 1.3-1.7 mg/dL. Indinavir sulfate and cefpodoxime proxetil were discontinued and the patient was suspected of having tubulointerstitial nephritis secondary to indinavir sulfate. The patient's nephritis resolved and the SCr decreased to 1.1 mg/dL within 1 month of discontinuing indinavir sulfate.. This case demonstrates the potential for renal toxicity with the use of indinavir sulfate in HIV-infected hemophiliacs.

Topics: Adolescent; Factor VIII; Hemophilia A; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nephritis, Interstitial

To review the short-term response and safety of protease inhibitor therapy in HIV-infected children.. Retrospective chart review of open-label protease inhibitor-containing combination therapy.. Two urban pediatric HIV centers.. Twenty-eight HIV-infected children were prescribed 30 protease inhibitor-containing antiretroviral therapy combinations. The median age at initiation of protease inhibitor antiretroviral therapy was 79 months. Patients had been on previous antiretroviral therapy for a mean of 45.5 months.. Of the 28 children who completed at least 1 month of therapy, 26 experienced marked virologic and immunologic improvement (mean maximal decrease in viral load 1.90 log10 copies/ml; SD, 0.8; mean maximal rise in CD4+ lymphocytes of 279 x 10(6)/l; SD, 300 x 10(6)/l). Eleven patients achieved a viral nadir of < 400 copies/ml, and seven sustained this level of viral suppression for a mean of 6 months. Indinavir use was associated with a high incidence of renal side-effects, including two patients who developed interstitial nephritis. Two patients on ritonavir experienced a significant elevation of liver enzymes.. Protease inhibitor therapy was associated with substantial short-term virologic and immunologic improvement in this primarily heavily pretreated cohort, with 25% maintaining a viral load of < 400 copies/ml after 6 months of therapy. There was a significant rate of adverse events. Pharmacokinetic and safety data are needed to guide aggressive antiretroviral therapy in HIV-infected children, and further treatment options are required for those failing or intolerant to the available protease inhibitors.

Topics: Anti-HIV Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Male; Protease Inhibitors; Retrospective Studies; Ritonavir; Saquinavir; Stavudine; Zidovudine

Topics: Adult; Anti-HIV Agents; Breast; Female; HIV Infections; Humans; Hypertrophy; Indinavir

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Guideline Adherence; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Patient Compliance; Treatment Refusal

In evaluating current combination drug regimens for treatment of human immunodeficiency virus (HIV) disease, it is important to determine the existence of viral reservoirs. After depletion of CD8 cells from the peripheral blood mononuclear cells (PBMCs) of both patients and normal donors, activation of patient CD4 lymphocytes with immobilized antibodies to CD3 and CD28 enabled the isolation of virus from PBMCs of six patients despite the suppression of their plasma HIV RNA to fewer than 50 copies per milliliter for up to 2 years. Partial sequencing of HIV pol revealed no new drug resistance mutations or discernible evolution, providing evidence for viral latency rather than drug failure.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Coculture Techniques; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Lymphocyte Activation; Mutation; RNA, Viral; T-Lymphocyte Subsets; Viral Load; Viremia; Virus Activation; Virus Latency; Virus Replication; Zidovudine

Topics: AIDS-Related Opportunistic Infections; Follow-Up Studies; Herpesvirus 8, Human; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Middle Aged; Remission Induction; Sarcoma, Kaposi

Topics: Budd-Chiari Syndrome; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Portal Vein

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Treatment Outcome; Zidovudine

Topics: Adult; AIDS-Related Opportunistic Infections; Citalopram; Diagnosis, Differential; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nervous System Diseases; Selective Serotonin Reuptake Inhibitors; Serotonin; Syndrome

To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors.. Retrospective study in two German tertiary care treatment centres.. A total of 198 HIV-infected patients treated with protease inhibitors in 1996.. Levels of HIV RNA 1-6 months after start of treatment; definition of treatment failure of < 1 log10 reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures.. A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P = 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P = 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P = 0.05), and 4.62 for treatment with saquinavir versus indinavir (P = 0.001).. An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Ritonavir; RNA, Viral; Saquinavir; Treatment Failure

Topics: Abdominal Pain; Adult; Anti-HIV Agents; Dermatitis, Exfoliative; Fever; HIV Infections; Humans; Indinavir; Male; Renal Insufficiency

Topics: Adult; Anti-HIV Agents; HIV Infections; Humans; Indinavir; Kidney Diseases; Kidney Function Tests; Male

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

Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome

The development of HIV protease inhibitors has dramatically improved the treatment prognosis of HIV-infected patients. The treatment, however, is associated with the potential for adverse events that are unique to protease inhibitors. One of them, Indinavir, can lead to the development of urinary stones. Three weeks after starting treatment with Indinavir, Zidovudine and Lamivudine, a 66-year-old patient developed symptomatic hydronephrosis on the right side due to multiple Indinavir stones blocking the ureter. Microhematuria and characteristic crystals were found in the urine. After interruption of treatment and increased fluid intake, the crystallurea was not longer detectable and the patient became asymptomatic within 3 days. Nephrostomy and ureteral stent placement were not necessary. Patients on treatment with Indinavir are required to maintain a fluid intake of at least 1.5-2 l/day to reduce the risk of crystallization and urinary stones. Pharmacologic metaphylaxis to prevent crystallization is not recommended.

Topics: Aged; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Ureteral Calculi; Ureteral Obstruction; Zidovudine

A sensitive high-perforrmance liquid chromatographic assay has been developed to determine the concentrations of the HIV-protease inhibitor indinavir in human plasma. The sample pretreatment involved a protein precipitation procedure using 100 microl of human plasma and 400 microl of acetonitrile. Chromatography was carried out on an Octadecyl column using a mobile phase of acetonitrile-water (40:60, v/v). The water phase contained 50 mM phosphate buffer pH 6 and 4 g/l tetramethylammoniumchloride. Ultraviolet detection at 210 nm was used. The method has been validated with regard to specificity, detection limit, lower and upper limit of quantitation, recovery, accuracy, and inter- and intra-assay precision. Stability tests under various conditions were performed. The bioanalytical assay is now in use for the determination of indinavir in several clinical pharmacokinetic studies in HIV-infected patients.

Topics: Acetonitriles; Administration, Oral; Adult; Chromatography, High Pressure Liquid; Circadian Rhythm; Drug Stability; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Osmolar Concentration; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Time Factors

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Zidovudine

Topics: Diabetes Complications; Diabetes Mellitus; HIV Infections; HIV Protease Inhibitors; Humans; Hyperglycemia; Indinavir; Nelfinavir; Ritonavir; Saquinavir

Topics: AIDS Serodiagnosis; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Zidovudine

Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Drug Combinations; HIV Infections; Humans; Indinavir; Stavudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine

The results of ACTG 320 confirm that patients taking a combination of three drugs survived significantly longer than those taking two drugs, underscoring the importance of aggressive treatment. Combination approaches using protease inhibitors can reduce the risk of death.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Stavudine; United States; Zidovudine

A study funded by the National Institute of Allergy and Infectious Diseases (NIAID) has shown that combination protease inhibitor therapy plus two nucleoside analogues is significantly more effective than using two nucleoside analogs alone in reducing the occurrence of AIDS-defining illnesses and death. Since preliminary results of ACTG 320 provided such strong evidence, the board recommended early termination of enrollment and study closure.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; United States; Zidovudine

ACTG 320, to no one's surprise, was halted early when results clearly showed two-drug therapy was inferior to a three-drug regimen. Many thought the study was unnecessary because previous studies already concluded that triple combinations were more effective. So-called body count trials, as ACTG 320 was viewed, will no longer be performed if the Food and Drug Administration (FDA) and medical conservatives accept results from earlier trials.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethics, Medical; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Reverse Transcriptase Inhibitors; Zidovudine

Several clinical trials have been shut down earlier than planned, following the striking results shown in the trials. ACTG 320, studying whether an AZT/3TC combination was more effective if indinavir was added, was opposed early on because it seemed a waste of resources. The risk of disease progression was halved when indinavir was added. Merck Protocol 028, another disease progression trial, targeted a treatment-naive population with advanced HIV. The trial took place in Brazil because the AIDS-infected population had less access to treatment than people in the U.S., and was halted immediately following a major newspaper article on it. ACTG 333 tested the consequences of long-term use of hard capsule saquinavir, and found that it is poorly absorbed and there is only a very modest effect on HIV.

Topics: Anti-HIV Agents; Brazil; CD4 Lymphocyte Count; Clinical Trials as Topic; Disease Progression; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Saquinavir; Stavudine; United States; Viral Load; Zidovudine

The Centers for Disease Control and Prevention (CDC) will convene a panel to consider sanctioning a morning after treatment to prevent HIV transmission from sex with an infected partner. The meeting was prompted by advocates who say people exposed to HIV should be given the same antiretroviral therapy recommended in the case of occupational exposure. The complex therapy involves a regimen of AZT and 3TC taken both with food and on an empty stomach. There are often severe side-effects.

Topics: Anti-HIV Agents; Centers for Disease Control and Prevention, U.S.; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Risk-Taking; Sexual Behavior; United States; Zidovudine

Critical issues are addressed concerning when to use nelfinavir, a newly approved protease inhibitor. Because of a resistance mutation that occurs as a result of taking nelfinavir, the following questions arise: if resistance emerges in a patient naive to protease inhibitor therapy, will that person be able to take another protease inhibitor without cross resistance occurring, and if resistant virus emerges after using another protease inhibitor, will subsequent use of nelfinavir offer any benefit? Much speculation has been made on these issues, based particularly on nelfinavir's causing mutation in an area of HIV protease not seen previously; therefore, some believe cross resistance will not occur to other protease inhibitors. One strategy is to combine nelfinavir with saquinavir -- not because it will necessarily inhibit HIV, but because it increases the blood level of saquinavir to higher levels. Clinical trials adding nelfinavir to other antiretroviral drugs showed dramatic decreases in viral load, but making comparisons to other drug regimens is difficult due to multiple differences between regimens. Some researchers believe that nelfinavir is similar to indinavir and ritonavir as far as antiretroviral efficacy. Nelfinavir is different because it penetrates the central nervous system. Nelfinavir does not have to be taken on as strict a schedule as other protease inhibitors, and should be taken with food. Certain drugs should not be taken with nelfinavir, such as the antihistamines astemizole and terfenadine, the motility agent cisapride, the benzodiazepines triazolam and midazolam, and the antimycobacterial agent, rifampin. When compared with other antiretrovirals, nelfinavir appears to be better tolerated with fewer toxic side effects.

Topics: Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Mutation; Nelfinavir; Ritonavir; Saquinavir; Sulfonic Acids

Merck is adding a warning label to indinavir (Crixivan) as a result of 20 cases of hemolytic anemia reported among the 140,000 people currently using the drug. The disease causes a premature destruction of red blood cells, and the most common symptoms are fatigue, jaundice and discolored urine. The condition progresses rapidly and requires quick treatment. Mild cases are treated by stopping the drug, moderate cases are treated with the corticosteroid prednisone, and severe cases may require blood transfusions.

Topics: Anemia, Hemolytic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

A 3-drug AIDS treatment trial, ACTG 320, was halted early after it became clinically evident that the therapy was superior to 2-drug combinations in reducing death rates and new AIDS-related illnesses. The study demonstrates the superiority of indinavir/AZT (or d4T) plus 3TC over AZT (or d4T) plus 3TC. These results show that protease inhibitor-containing 3-drug regimens offer greater benefits to patients with advanced disease, but leaves open the question of whether to start similar 3-drug therapy in patients with earlier stages of HIV disease. The Centers for Disease Control and Prevention (CDC) announced an overall 12 percent reduction in AIDS deaths in the United States in 1996. Total deaths from AIDS in New York City were reduced approximately 30 percent in 1996, but it is believed greater access to care and wider use of other 2- and 3-drug regimens have also contributed to the reduction. Analyses have also shown dramatic reductions in AIDS-related death rates in Los Angeles and a 28 percent reduction in home health care costs; both contributed to by the new 3-drug combinations. Since France's medical centers began using the 3-drug combination therapy in 1995 and 1996, they have reported a 35 percent decrease in AIDS-defining illnesses and AIDS-related hospital stays, and a reduction in hospital costs.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Recent studies are indicating that the standard version of saquinavir is not an appropriate anti-HIV regimen protease inhibitor for beginning therapy. In addition, the new soft gel capsule formulation of saquinavir shows better activity than the available hard gel formulation (HGC), warranting its classification as a highly active antiviral for patients who have not previously used the HGC. Studies are showing that patients who had previous HGC therapy do not gain significant benefit from the new drug, suggesting that HGC saquinavir should not be used as first-line therapy. Advertising that promoted the improved drug has been withdrawn at the request of Project Inform because of the lack of warning labels necessary due to dosing problems. An indinavir study in Brazil (study had questionable ethics) reveals a dramatic difference in the percentage of people developing AIDS in groups receiving indinavir compared to those receiving AZT alone. Also, small studies of intravenous PMPA are showing that this nucleotide analogue reverse transcriptase inhibitor possesses potent anti-HIV activity. An oral form of PMPA has been developed and is currently undergoing clinical trials. While clinical studies are showing which drugs are most effective, there is still limited practical information on the best uses, causing physicians to experiment with dosages without the benefit of clinical trial information.

Topics: Adenine; Anti-HIV Agents; Brazil; CD4 Lymphocyte Count; Clinical Trials as Topic; Dosage Forms; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infusions, Intravenous; Organophosphonates; Organophosphorus Compounds; Saquinavir; Tenofovir; Viral Load

ACTG 333 tested the effectiveness of other protease inhibitors in patients who had been on saquinavir for two years. Early data showed that neither indinavir (Crixivan) nor the new version of saquinavir known as the soft gel cap (SGC) had an effect on T4 cell counts or HIV levels. The people in the study only switched their protease inhibitor, not the other anti-HIV drugs that they were taking. As a result, new Federal guidelines specify that all anti-HIV drugs should be changed when protease inhibitors are changed. The U.S. Public Health Service also recommends against using saquinavir as a first protease inhibitor because it is poorly absorbed by the body.

Topics: Clinical Trials as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Practice Guidelines as Topic; Saquinavir; Time Factors

Scientists are seeking to unravel the mystery of chemokine receptors in an attempt to develop treatments for HIV infection; however, receptor experts are realizing that the picture is more complicated than they first imagined. Scientists want to know, among other things, what parts of each coreceptor are essential for viral fusion with target cells, what makes macrophage-tropic viruses switch their preference to T-lymphocytes, why HIV goes after chemokine receptors in the first place, and how fusion and entry occur. Other issues discussed include whether blocking coreceptors for HIV will actually curb this disease, virus turnover in monkey studies showing that SIV may go through the cycle as many as 100 times per day, and studies showing that the first days of infection may predict the course of disease. Final comments concern the use of ritonavir plus indinavir in treatment combinations for children with HIV and the latest progress toward vaccine development. Understanding these and other puzzles might help scientists to develop drugs to block receptors active in HIV infection and perhaps curb HIV. More than 14 biotechnology and pharmaceutical firms are working to design coreceptor blockers, despite the opinions of several leading researchers that the drugs are not terribly promising. Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Disease (NIAID), notes that a famous attempt to block HIV's primary receptor failed, and David Ho, the man who demonstrated why CD4 would not work as therapy, is similarly cautious. According to Ho, drug makers will have no trouble developing compounds that keep HIV off chemokine receptors, such as CCR5 or CXCR4, but whether those compounds will slow disease progression is another question.

Topics: AIDS Vaccines; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Chemokines; Child; Drug Therapy, Combination; Genetic Predisposition to Disease; Heterozygote; HIV Infections; HIV Protease Inhibitors; HIV-1; Homozygote; Humans; Indinavir; Lymphocyte Activation; Lymphocyte Depletion; Macaca; Macrophages; Mutation; Receptors, CCR5; Receptors, CXCR4; Ritonavir; Simian Immunodeficiency Virus; T-Lymphocytes; Virus Replication

Indinavir (Crixivan) absorption is strongly influenced by meals, and patients taking indinavir need to coordinate their food intake to make sure that effective levels of the drug are absorbed by their bodies. Indinavir is ideally taken without food. The American Dietetic Association developed a food list of low-fat, low-protein, low-calorie snacks or meals that a patient can take if they cannot tolerate the drug on an empty stomach. Serving sizes must be strictly adhered to, and patients are cautioned that there are other factors besides food that may influence indinavir absorption.

Topics: Diet; Diet, Fat-Restricted; Diet, Protein-Restricted; Guidelines as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir

Double protease inhibitor combinations may be effective in some AIDS patients who do not respond to or who are intolerant of routines with a single protease inhibitor, according to an in vitro study at Harvard. The most commonly used combination was ritonavir (Norvir) and saquinavir. The findings showed anti-HIV effects on strains never exposed to treatment, as well as HIV strains that were resistant to AZT and nucleoside analogs. Little patient data is available, but what is available seems to contradict the laboratory tests. Further research is needed to resolve the conflict.

Topics: Drug Antagonism; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Saquinavir

Anti-HIV therapy research continues to show promising results and a research update is presented on the following antiviral topics: efavirenz (DMP 266, Sustiva), indinavir (Crixivan), indinavir plus ritonavir (Norvir), hard vs. soft gel saquinavir, nelfinavir (Viracept) cross-resistance, and T-20 (pentafuside). Tables present regimen results, including viral load drop and CD4 cell increases. Difficulties in preventing viral resistance are also discussed. Situations to avoid include using dosing schedules that do not sufficiently suppress the virus, waiting for viral load to return to pre-treatment levels before switching drugs, and not switching drugs to at least two new potent compounds when changing combination therapy. The challenge for patients who have failed previous drug therapies is to develop strategies that allow them to extend the effectiveness of their options long enough for at least two new potent drugs to become available.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dosage Forms; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir

Topics: Antiviral Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; Thiazoles; Valine

The US Food and Drug Administration (FDA) has approved the marketing of five new drugs for treatment of HIV infection. Stavudine (D4T; Zerit -- Bristol-Myers Squibb) and lamivudine (3TC; Epivir -- Glaxo Wellcome) are nucleoside analogs similar to zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC). Saquinavir (Invirase -- Roche), ritonavir (Norvir -- Abbott) and indinavir (Crixivan -- Merck) are protease inhibitors, a new class of anti-HIV drugs.

Topics: Antiviral Agents; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Lamivudine; Pyridines; Quinolines; Ritonavir; Saquinavir; Stavudine; Thiazoles; Valine; Zalcitabine

Topics: Drug Approval; Drug Costs; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; United States; United States Food and Drug Administration

Topics: Drug Costs; Drug Resistance; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Pyridines; Quinolines; Ritonavir; Saquinavir; Thiazoles; Valine

Topics: Accidents, Occupational; Antiviral Agents; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Practice Guidelines as Topic; Pyridines; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine

Topics: Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines

Topics: Acute Disease; Administration, Oral; Adult; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Thrombocytopenia

Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.

Topics: Base Sequence; DNA, Viral; Drug Resistance, Microbial; Genetic Variation; Genotype; HeLa Cells; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Phenotype

Topics: Adult; Anti-HIV Agents; Computer Graphics; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Time Factors; Zidovudine

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Zidovudine

Topics: Anti-HIV Agents; Biotechnology; Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; United States; United States Food and Drug Administration

Topics: Antiviral Agents; Health Personnel; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Occupational Exposure; Pyridines; United States; United States Public Health Service; Virus Replication; Zalcitabine; Zidovudine

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir

Topics: Dose-Response Relationship, Drug; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Patient Compliance

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; Foundations; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; National Institutes of Health (U.S.); Research; Ritonavir; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Viral Load; Zalcitabine; Zidovudine

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

The Food and Drug Administration's (FDA) Antiviral Drugs Advisory Committee met February 27 to March 1, 1996. At the meeting, the FDA granted full approval of ritonavir for the treatment of advanced AIDS. Ritonavir manufacturer, Abbott Laboratories, characterized the drug as generally well-tolerated, with the most common side effects being nausea, vomiting, and diarrhea. The committee also recommended accelerated approval of Merck's protease inhibitor, indinavir. Results of several clinical studies and protocols are presented. The committee voted against somatropin (Serostim), the recombinant human growth hormone, for treatment of AIDS-related wasting syndrome. They cited too many gaps in the research data. The manufacturer, Serono, is currently negotiating with the FDA on the best way to pursue approval. The committee also unanimously recommended that ddI (Videx) be indicated as a first-line treatment for HIV. The drug appears to be superior to AZT in delaying disease progression and death.

Topics: Antiviral Agents; Device Approval; Drug Approval; Drug Therapy, Combination; Growth Hormone; HIV Infections; HIV Protease Inhibitors; Human Growth Hormone; Humans; Indinavir; Pyridines; Recombinant Proteins; Ritonavir; Thiazoles; United States; United States Food and Drug Administration; Valine; Virology

The Food and Drug Administration's (FDA) Drug Advisory Committee made significant changes to the way HIV infections are treated at its February 28 to March 1, 1996 meetings. As a result, AZT is no longer considered to be the centerpiece of first-line anti-HIV therapy, and CD4 cell counts are no longer the primary laboratory standards used to judge the effectiveness of a drug. The FDA recommended the approval of two older nucleoside analogs (ddI and ddC) and two new protease inhibitors (ritonavir and indinavir). Serono Laboratories' application for approval of its human growth hormone was rejected, largely because of the poor way the company presented its findings. Ritonavir demonstrated an ability to extend survival and delay the onset of new opportunistic infections in people with advanced HIV disease. Although ritonavir is more effective than AZT, the combination of the two drugs was no better than ritonavir monotherapy. There is no long-term data available on the safety of ritonavir. The committee recommended indinavir after the manufacturer, Merck, provided impressive safety and surrogate marker data for the drug alone and in combination with AZT. Charts are included to summarize the drugs' regimen. There is a growing conviction within the FDA that four-drug combination therapy will be the most effective means of treating HIV. However, treatment success will vary on an individual basis.

Topics: Antiviral Agents; Drug Approval; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; Thiazoles; United States; United States Food and Drug Administration; Valine; Zidovudine

The Food and Drug Administration (FDA) approved the use of indinavir, Merck's protease inhibitor, for treatment of HIV infection in adults. Because FDA approval was quicker than the manufacturer expected, there will be problems producing and distributing the drug. Merck contracted with Stadtlander's Pharmacy, a mail-order buyer's club, to manage indinavir distribution. Activists are complaining that the program will be awkward and unworkable. The factory retail price for indinavir will be $4,380 per year. Merck established a financial assistance program for patients who are uninsured or unable to qualify for other programs. Alternative ways of getting the drug under this program are also explained.

Topics: Adult; Drug Industry; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines

Indinavir (Crixivan) is one of the protease inhibitors approved for HIV treatment by the Food and Drug Administration (FDA). All studies to date have been limited to examining its effect on T4 cell changes and HIV viral load levels. Current studies are looking at indinavir in combination with AZT and 3TC. After sixteen weeks of combination therapy, viral loads in patients dropped to levels below those that can be measured with standard tests. However, these studies were done on small groups, and there are larger tests currently being held. Reducing the amount of virus also reduces the risk of disease progression and death. HIV can become resistant to the effects of indinavir, but this resistance occurs more slowly than with the other protease inhibitors. Using it in combination with a nucleoside analog drug seems to significantly delay resistance.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines

This matrix compares the use and characteristics of three protease inhibitors: indinavir (Crixivan), ritonavir (Norvir), and saquinavir (Invirase). Dose, storage, effect on disease progression, and effects on CD4 counts are compared. Also included are side effects, potential drug interactions, availability, and cost.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Pyridines; Quinolines; Ritonavir; Saquinavir; Thiazoles; Valine

Study data are presented on the use of protease inhibitors. Indinavir shows particularly potent antiviral activity and a modest side effect profile. Three indinavir studies are highlighted. Ritonavir appears to be effective in people with advanced HIV disease by helping to stem the progression of disease. Highlights from two ritonavir studies are presented. Two small studies involving nelfinavir are discussed, showing potent antiviral activity with high doses of the drug, and better performance when used in combination with d4T. It is cautioned that use of these drugs requires careful strategic thinking.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Placebos; Pyridines; Ritonavir; Stavudine; Thiazoles; Valine

The Centers for Disease Control and Prevention (CDC) in Atlanta recommends that health care workers receive preventive therapy for high-risk exposures to HIV-infected blood. The change follows a much-publicized case-control study of 31 health care workers who had been occupationally infected with HIV (23 from the United States, 5 from France, and 3 from the United Kingdom) and 679 health care workers who had reported exposure to HIV between 1988 and 1994. The study showed a statistically significant finding that workers who did not receive AZT after exposure were more likely to seroconvert than those who did receive the drug. The study also showed that certain exposures, such as a deep needlestick involving a hollow-bore needle containing blood from a late-stage AIDS patient, had a significantly greater chance of transmission than the average 1 in 300 odds of infection. A chart detailing the estimated risk of infection from each exposure type and recommendations for treatment is included. The New York Department of Health will send out its revised guidelines in June 1996.

Topics: Antiviral Agents; Blood-Borne Pathogens; Centers for Disease Control and Prevention, U.S.; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Infectious Disease Transmission, Patient-to-Professional; Lamivudine; Occupational Exposure; Pyridines; Risk Factors; United States; Zalcitabine; Zidovudine

Glaxo Wellcome, responding to criticism about its lack of interest in providing financial assistance to those covered by ADAP (AIDS Drug Assistance Program), has broadened the financial assistance program for 3TC; Merck has also come under similar criticism in its policy regarding financial assistance for indinavir. Congress has made an extra $52 million available in 1996 for ADAP expenses, and New York and California have already decided to cover protease inhibitors starting in July. ADAP's ability to cover costs of the new anti-HIV treatments remains questionable.

Topics: Antiviral Agents; California; Drug Costs; Financing, Government; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Insurance, Pharmaceutical Services; New York; Pyridines

DMP 266, a nonnucleoside reverse transcriptase inhibitor, has been effective as a monotherapeutic agent in reducing viral load. How long it remains effective is unknown, and resistance development is a problem. Two trials testing combinations with DMP 266 are beginning. One test using DMP 266 with indinavir is already considered flawed because indinavir is provided as a monotherapy first. Indinavir monotherapy is believed to help HIV resistance to evolve, especially in people with high baseline viral loads. Participants who are on the monotherapy risk not receiving the full benefit from indinavir and other protease inhibitors because they trigger similar resistance mutations.

Topics: Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Reverse Transcriptase Inhibitors

The Food and Drug Administration (FDA) approved two new protease inhibitors for treatment of AIDS. Ritonavir (Norvir) and indinavir (Crixivan) have been approved for both monotherapy and combination therapy, and appear to have relatively few side effects. Reports on clinical trials of both drugs are reported. Saquinavir (Invirase) also has FDA approval, but currently has a low absorption rate; better formulations are expected to increase absorption. Early trials indicate that triple drug combinations may suppress HIV replication to very low levels.

Topics: Drug Approval; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; Thiazoles; United States; United States Food and Drug Administration; Valine

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

Some of the most dramatic reductions in HIV viremia have been observed among patients treated with indinavir sulfate (Crixivan). How the hypothesis that HIV protease maintains the infectious nature of the virus led to Merck's development of indinavir is discussed. Also examined are results of the early clinical studies on indinavir's safety and pharmacokinetics, and research into the dynamics of HIV replication and the mechanisms of resistance. Several studies are highlighted that demonstrate the effectiveness of indinavir in reducing plasma viremia and increasing CD4 cell counts, thus providing the basis for marketing approval. Descriptions of ongoing clinical trials of indinavir, both open and closed trials, are listed, including duration, end points, sites, and contacts.

Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Viremia; Virus Replication

The Food and Drug Administration (FDA) approved two new protease inhibitors--ritonavir and indinavir--for the treatment of HIV infection in adults. Ritonavir (Norvir), developed by Abbott Laboratories, received full approval for use alone or in combination with nucleoside analogue medications in patients with advanced HIV disease. Two encouraging studies on ritonavir are described. An ongoing phase III trial showed mortality to be 43 percent lower than for patients receiving standard therapy alone. In a separate study, untreated HIV-infected individuals who were given a triple combination of ritonavir plus AZT and ddC showed significant increases in CD4+ T cells counts and decreases in viral load for at least six months. Indinavir (Crixivan), developed by Merck, received accelerated approval for monotherapy and combination therapy for the treatment of HIV infection in adults when therapy is warranted. New data on indinavir showed decreases in levels of HIV in 22 out of 25 patients who had taken a triple combination of indinavir, AZT and 3TC. In another study of patients taking a combination of indinavir, ddI, and AZT, 60 percent of the patients' HIV levels were reduced to undetectable levels. In addition to ritonavir and indinavir, saquinavir (Invirase, Hoffmann-La Roche) is another protease inhibitor approved for use in conjunction with nucleoside analogues for the treatment of HIV infection.

Topics: Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; Thiazoles; United States; United States Food and Drug Administration; Valine

There are now nine approved anti-HIV drugs, all of which are meant to keep the level of HIV as low as possible, prevent further damage to the immune system, and stop the progression of the disease. The combination of drugs prescribed depends on which the doctor feels will best stop disease progression based on the side effects, the patient's treatment history, and the patient's current symptoms. Drug resistance is always a threat, and guidelines are given to assess the risks of a patient developing resistance. Each of the approved drugs is highlighted, along with guidelines for their use, their strengths and weaknesses, and special assistance programs offered by the pharmaceutical manufacturer.

Topics: Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Pyridines; Quinolines; Ritonavir; Saquinavir; Thiazoles; Valine

The AIDS Clinical Trials Group (ACTG) will begin in October 1996, a new clinical trial that will compare three long-term maintenance regimens. Recruits in the randomized double-blind study, ACTG 343, will receive induction therapy with AZT, 3TC, and indinavir (Crixivan; IDV), the Merck protease inhibitor. Volunteers with an undetectable HIV RNA after 6 months will be randomized to one of three maintenance regimens: AZT/3TC vs. IDV alone vs. continuing on AZT/3TC/IDV. Treatment will be withdrawn from subjects with undetectable HIV RNA at 6-month intervals, after the initial 6-month maintenance therapy. If any virus is detected, the combination of AZT/3TC/IDV will be resumed. The investigators hope to compare the proportion of patients who sustain suppression of HIV RNA among the three regimens during the maintenance phase and after therapy is withdrawn.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; Humans; Indinavir; Lamivudine; Pyridines; Zalcitabine; Zidovudine

Clinical trials of the immune system protein interleukin-2 (IL-2) show encouraging results. Preliminary findings of a Phase II study show that self-administered injections dramatically raise the levels of CD4+ T cells in patients with early HIV infection. These findings complement an earlier study that demonstrated the effectiveness of intravenous infusion of IL-2. Side effects include mild to moderate flu-like symptoms. Preliminary results also show that IL-2 is effective in combination with indinavir.

Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Immunotherapy; Indinavir; Interleukin-2; Virus Replication

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

Health care workers who deal with HIV patients are trained and knowledgeable in universal precautions. However, they remain at risk of seroconversion from accidental exposure, and new treatment options are highlighted. Theories on viral dynamics and aggressive antiretroviral regimens suggest that health care workers receive post exposure prophylaxis. Risk factors are identified; needlesticks, which are thought to be the most risky, result in seroconversion only 0.2 to 0.3 percent of the time.

Topics: Anti-HIV Agents; Disease Transmission, Infectious; Drug Therapy, Combination; Guidelines as Topic; Health Personnel; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Occupational Exposure; Risk Factors; Viral Load; Zidovudine

Topics: Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Pyridines

Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture. We now report the characterization of resistant variants isolated from patients undergoing therapy with the protease inhibitor MK-639 (formerly designated L-735,524). Five of these variants, isolated from four patients, exhibited cross-resistance to all members of a panel of six structurally diverse protease inhibitors. This suggests that combination therapy with multiple protease inhibitors may not prevent loss of antiviral activity resulting from resistance selection. In addition, previous therapy with one compound may abrogate the benefit of subsequent treatment with a second inhibitor.

Topics: Base Sequence; Cell Line; DNA Primers; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HeLa Cells; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Mutation; Pyridines

The results of small, rapid clinical trials, reported in January in newspapers and journals, have led to the discovery that the "turnover" of new virus in the body is far more rapid than previously believed. The findings suggest that the immune system might have the ability to recover if HIV reproduction could be stopped for a longer time, although the virus would not be eradicated. The new understanding of how HIV behaves in the body was made possible by new antiviral drugs and by the new blood test which measures plasma HIV RNA. The work validates the use of small, rapid trials, and emphasizes the problem of HIV developing resistance to drugs. The researchers emphasized the need to use combination treatments because the more drugs that are added, the less likely the virion will be resistant to all of them. The most important unanswered question about HIV disease may be how it progresses from early, asymptomatic infection to late-stage illness. The fear is that researchers will assume that the new understanding of HIV explains this and research could be prematurely downgraded due to the rush of enthusiasm from these new findings. The pro's and con's of the interpretations of the findings and suggestions of what should be studied are discussed. The impact of these findings will be on the strategy of research and development of new AIDS treatments.

Topics: Antiviral Agents; CD4 Lymphocyte Count; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nevirapine; Pyridines; Reverse Transcriptase Inhibitors; Viremia; Virus Replication

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

The debate of monotherapy vs. combination therapy during the July 25th-27th Consensus Symposium on Combined Antiviral Therapy is discussed. Specific topics addressed at the Lisbon conference included whether the protease inhibitor, indinavir, could antagonize the effects of ZDV plus 3TC; synergy claimed with VX-478 and ZDV, ddI, and other reverse transcriptase inhibitors; a proposal that ablative therapy against HIV during the first weeks of infection could become a reasonable tactic when patients are diagnosed very early; a discussion of recent data suggesting that cross-resistance of HIV to several protease inhibitors is not an insurmountable problem and that convergent therapy with the drugs remains a possibility; and indications that HIV doubly resistant to 3TC and ZDV can emerge, at least when 3TC is started first and ZDV is added later.

Topics: Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; HIV; HIV Infections; Humans; Hydroxyurea; Indinavir; Interleukin-2; Lamivudine; Mutation; Pyridines; RNA, Viral; Zalcitabine; Zidovudine

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