indinavir-sulfate and Acquired-Immunodeficiency-Syndrome

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

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: Abdominal Abscess; Acquired Immunodeficiency Syndrome; Adult; Aged; AIDS-Associated Nephropathy; Erectile Dysfunction; Humans; Indinavir; Kidney; Kidney Calculi; Lymphoma; Male; Male Urogenital Diseases; Middle Aged; Prostatic Diseases; Prostatitis; Sarcoma, Kaposi; Testicular Diseases; Urination Disorders

Lymphomas are a well-known malignancy in individuals with human immunodeficiency virus type 1 (HIV-1) infection. Most lymphomas are of B-cell lineage and cutaneous involvement is rare. Cutaneous T-cell lymphomas have been previously described in adults with HIV-1 infection but are exceptional in HIV-1 infected-children. The authors report here the extremely rare case of a large-cell cutaneous lymphoproliferation of T-cell lineage expressing Epstein-Barr virus (EBV) antigens in a 15-year-old boy with AIDS and his uncommon clinical presentation. The atypical clinical evolution with a nonaggressive treatment emphasizes that for immunosuppressed patients, the diagnosis of immunosuppression-related lymphoproliferative disorder should be considered before giving the diagnosis of malignant lymphoma when tumoral lymphoid cells express EBV antigens.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Combined Modality Therapy; Diagnosis, Differential; Epstein-Barr Virus Infections; Gene Rearrangement, T-Lymphocyte; Herpesvirus 4, Human; HIV Protease Inhibitors; Humans; Immunophenotyping; Indinavir; Lamivudine; Lymphoma, AIDS-Related; Lymphoma, T-Cell, Cutaneous; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Sarcoma, Kaposi; Skin Neoplasms; Stavudine; Transfusion Reaction; Viral Matrix Proteins

This review deals with clinical applications of compounds that inhibit the action of the protease encoded within the genome of human immunodeficiency virus (HIV). The HIV-protease is essential for viral maturation and represents an important therapeutic target in the fight against AIDS. Following a brief overview of the enzyme structure and function, the article focuses on a number of peptide and non-peptide based HIV-protease inhibitors that are in current clinical use. These drugs are discussed both with respect to their efficacy in treatment of AIDS, and to problems related to insurgence of viral resistance and side effects seen to date in patient populations.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Binding Sites; Carbamates; Clinical Trials as Topic; Computer-Aided Design; Crystallography, X-Ray; Drug Design; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Oligopeptides; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir

Indinavir has been described to cause crystalluria and nephrolithiasis in a variable number of treated patients. Acute renal failure, often reversible with discontinuation of the medication, induction of a diuresis and correction of urinary obstruction if present, occurs in a smaller percent of patients. One recent report described renal biopsy findings, indinavir crystals within cellular casts in the collecting tubules, in a patient receiving this antiretroviral agent. We report a second case of a patient with mild renal insufficiency and pyuria following indinavir therapy and describe similar renal biopsy findings.

Topics: Acquired Immunodeficiency Syndrome; Biopsy; Drug Therapy, Combination; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Pyuria; Time Factors

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

Until recently, treatment for human immunodeficiency virus type 1 (HIV-1) infection was limited to the use of nucleoside inhibitors of the viral enzyme reverse transcriptase. While these agents initially offered promise, they have only modest antiviral activity and the benefits of treatment are limited by the emergence of drug resistance and dose-limiting toxic effects. Development of more potent drugs that target different stages of the virus life cycle has thus been aggressively pursued. Efforts to develop inhibitors of HIV-1 protease have yielded a potent new class of compounds that suppress HIV-1 replication to an extent far greater than was previously attainable. Four protease inhibitors, saquinavir mesylate, ritonavir, nelfinavir, and indinavir sulfate, have been approved by the Food and Drug Administration. Other agents are undergoing active investigation. The purpose of this article is to review the currently available data on those agents that have been approved for clinical use.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Interactions; Drug Resistance; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Nelfinavir; Ritonavir; RNA, Viral; Saquinavir; Sulfonic Acids

In this review the clinical pharmacology of HIV protease inhibitors, a new class of antiretroviral drugs, is discussed. After considering HIV protease function and structure, the development of inhibitors of HIV protease is presented. Three protease inhibitors are reviewed in more detail: saquinavir, indinavir, and ritonavir. Clinical trial results with these agents are evaluated. Furthermore, adverse effects, resistance, dosage and administration, clinical pharmacokinetics, pharmacokinetic-pharmacodynamic relationships, and drug interactions are discussed.

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Ritonavir; Saquinavir

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

To compare two reduced dose indinavir (IDV) + ritonavir (RTV) combinations guided by therapeutic drug monitoring (TDM) in treatment-naive HIV1-infected patients.. HIV1-infected treatment naive patients were prospectively randomized to treatment with IDV 600 mg or 400 mg BID each in combination with RTV 100 mg BID. Boosted IDV was combined with 2 NRTI, and patients were followed for 48 weeks. IDV-trough levels and initially also peak levels (C2h) were performed to allow dose modification of IDV following a specified protocol.. 14 patients were randomized (age 38 +/- 10.4 years; mean +/- SD; 3 female, 11 male). 8 were treated with 600 mg (group 1), 6 with 400 mg IDV BID (group 2). Efficacy of treatment was good: CD4-cell count increased from 198/microl (14-523; median, range) to 371/microl (214-927) after 48 weeks (p<0.01). All but one patient with adherence problems achieved a viral load below the limit of detection. At the beginning two patients had plasma levels below 0.1 mg/l, most likely due to adherence problems. However, in the course of the observation period all patients had adequate plasma levels. 3 patients in group 1 could further reduce their IDV dose to 400 mg BID due to high plasma (peak and trough) levels. Rate of discontinuation was high (1: 4 pat., 2: 2 pat.), but only one discontinuation was possibly associated with IDV (alopecia; group 2). There were no significant changes in laboratory parameters (bilirubin, triglycerides, cholesterol) or suspicious urine results. Incidence and severity of adverse events was lower than in previous studies.. Despite the low number of patients it seems reasonable to state, that boosted IDV may be used in significantly reduced dose. Efficacy seemed not to be altered, whereas tolerability was improved.

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Ritonavir; RNA, Viral; Treatment Outcome

To report on the incidence of clinical- and laboratory-defined pancreatitis in HIV-1-infected individuals treated with antiretrovirals (ARVs).. Pancreatitis incidence rates were calculated based on a Poisson distribution for subjects enrolled in 1 or more of 20 Adult AIDS Clinical Trials Group studies from October 1989 through July 1999.. A total of 8451 subjects were enrolled. The overall pancreatitis rates were 0.61 per 100 person-years (PYs) clinical and 2.23 per 100 PYs clinical/laboratory. Pancreatitis rates for single, dual, and triple nucleoside reverse transcriptase inhibitors (NRTIs) were similar. Rates of pancreatitis in didanosine (ddI) arms seemed to be dose dependent. Pancreatitis rates in ddI/hydroxyurea (HU) arms were not significantly different from the rates for ddI alone. Overall pancreatitis rates for ddI/stavudine (d4T) trials were high at 4.16 per 100 PYs clinical and 6.25 per 100 PYs clinical/laboratory. The highest rates were seen with the combination of indinavir (IDV)/ddI/d4T with or without HU.. The combination of NRTIs and definition has an impact on the incidence of pancreatitis. Standardization of definition and more comprehensive evaluations are needed to determine how much of this pancreatitis is directly caused by ARVs and how much is attributable to preexisting comorbidities and other known risk factors.

Topics: Acquired Immunodeficiency Syndrome; Didanosine; Drug Therapy, Combination; HIV-1; Humans; Hydroxyurea; Incidence; Indinavir; National Institutes of Health (U.S.); Pancreatitis; Reverse Transcriptase Inhibitors; Stavudine; United States

The approximate incidence of indinavir urolithiasis in HIV positive patients receiving the drug is 10%. The exact mechanism of lithogenesis is still unknown. Pure indinavir stones are radiolucent on plane abdominal X-ray or CT scan. Indinavir urolithiasis can be associated with acute unilateral renal colic or severe azotaemia.. 20 HIV patients were treated conservatively by increasing oral fluid intake (urine production of 2 l/day and more), discontinuation of indinavir therapy for 1 week and acidification of urine with l-methionin (urine pH 5,3-5,8). Some patients were additionally treated with endoscopic procedures.. In all patients renal function normalized. Increase of oral fluid intake, especially during the first 2 hours after intake of indinavir and during night prevented recurrence of indinavir urolithiasis.. HIV positive patients with renal colic or renal insufficiency and roentgenological absence of radio-opaque stone formations should make the urologist consider indinavir urolithiasis as a possible diagnosis.

Topics: Acquired Immunodeficiency Syndrome; Adult; Female; Fluid Therapy; HIV Protease Inhibitors; Humans; Indinavir; Male; Methionine; Middle Aged; Treatment Outcome; Urinary Calculi

We evaluated zidovudine-experienced patients for whom treatment with indinavir, lamivudine, and zidovudine failed, for indinavir-resistant minority variants. Of 10 patients with plasma human immunodeficiency virus type 1 RNA suppression and subsequent rebound, 6 without primary indinavir-resistance mutations underwent clonal analysis. One had evidence of V82A in 9 of 30 clones at week 24, with no increase at week 40. The dominant week-40 82V-M184V clones had changes at protease codons 62-64, compared with all clones at week 24 and minority clones at week 40. Resistance to indinavir can emerge during treatment failure in nucleoside-experienced patients but may be missed by routine sequence analysis. Selection for indinavir-resistant variants on treatment with indinavir, lamivudine, and zidovudine may occur slowly, depending on the genetic context in which they arise.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Drug Resistance, Viral; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Mutation; RNA, Viral; Zidovudine

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

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Bayes Theorem; Benzoxazines; Cyclopropanes; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Indinavir; Male; Models, Biological; Nelfinavir; Oxazines; Population Surveillance; Treatment Failure

To provide insight into the dynamics and source of residual viremia in human immunodeficiency virus (HIV) patients successfully treated with antiretroviral therapy, 14 intensely monitored patients treated with indinavir and efavirenz sustaining HIV RNA at <50 copies/ml for >5 years were studied. Abacavir was added to the regimen of eight patients at year 5. After the first 9 months of therapy, HIV RNA levels had reached a plateau ("residual viremia") that persisted for over 5 years. Levels of residual viremia differed among patients and ranged from 3.2 to 23 HIV RNA copies/ml. Baseline HIV DNA was the only significant pretreatment predictor of residual viremia in regression models including baseline HIV RNA, CD4 count, and patient age. In the four of five patients with detectable viremia who added abacavir to their regimen after 5 years, HIV RNA levels declined rapidly. The estimated half-life of infected cells was 6.7 days. Decrease in activated memory cells and a reduction in gamma interferon production to HIV Gag and p24 antigen in ELISpot assays were observed, consistent with a decrease in HIV replication. Thus, in patients treated with efavirenz plus indinavir, levels of residual viremia were established by 9 months, were predicted by baseline proviral DNA, and remained constant for 5 years. Even after years of highly suppressive therapy, HIV RNA levels declined rapidly after the addition of abacavir, suggesting that productive infection contributes to residual ongoing viremia and can be inhibited with therapy intensification.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; DNA, Viral; HIV-1; Humans; Indinavir; Longitudinal Studies; Oxazines; RNA, Viral; Time Factors; Viremia

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; HIV-1; Humans; Indinavir; Male; Nelfinavir; Organophosphonates; Oxazines; Phenotype; Reverse Transcriptase Inhibitors; Treatment Failure

To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48.. In a prospectively, randomized, open, single-centre study, antiretroviral-naive patients (CD4 cell count > or =200 cells/microl and a plasma HIV-1 RNA level 10,000 copies/ml) were assigned to a combination of zidovudine/lamivudine or stavudine/lamivudine. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (>500 copies/ml).. Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indinavir was added in 89% (42/47) of the patients. Only one discontinuation occurred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log10 copies/ml to <500 copies/ml in 100% of patients and <50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA decreased from 4.98 log10 copies/ml at baseline to <500 copies/ml in 100% of patients and <50 copies/ml in 66.7% of the patients. On an intent-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudine and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/microl, with 150 cells/microl in the zidovudine/lamivudine arm, and from 290 cells/microl, with 310 cells/microl in the stavudine/lamivudine arm (P=0.0001). However, the percentage of CD4 cells did not differ in each group. In the zidovudine/lamivudine group 9/10 and 5/5, and in the stavudine/lamivudine group 11/11 and 6/6 had a CSF HIV-1 RNA level <50 copies/ml at week 12 and 48, respectively. The CSF indinavir concentration ranged from 50 to 170 ng/ml.. The long-term HIV-1 suppression observed in this study is remarkable, as adding a single antiretroviral agent to a failing regimen goes against current notions of adequate therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Follow-Up Studies; HIV-1; Humans; Indinavir; Lamivudine; Middle Aged; Prospective Studies; RNA, Viral; Zidovudine

This study investigated whether immune restoration occurred in 26 human immunodeficiency virus (HIV) type 1-infected children treated first with indinavir for 16 weeks and then with combination antiretroviral therapy for >2 years. Compared with baseline, a significant, although modest, decrease in virus loads (maximum median, -0.86 log(10)) and increase in the number of CD4(+) lymphocytes, especially naive cells, were observed at several time points after 2 years. A maximum of 7% of treated children achieved undetectable viremia. There was a marked increase in the proliferative response and skin reactivity to recall antigens. However, responses to an HIV antigen remained depressed, and the production of interleukin-12 remained unchanged and abnormally low. The magnitude of virus suppression did not correlate with these measures of functional immune reconstitution. These findings suggest that long-term nonsuppressive antiretroviral therapy can induce limited improvement in immune function in pediatric AIDS patients and that the effect of suppressive treatments should be investigated.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Antigens; HIV Protease Inhibitors; Humans; Indinavir; Interleukin-12; Lamivudine; Male; Phytohemagglutinins; T-Lymphocytes; Time Factors; Treatment Outcome; Viral Load; Zidovudine

To compare the efficacy, tolerability and safety of a ritonavir 400 mg/saquinavir hard gel fomulation 400 mg twice daily versus an indinavir 800 mg once every 8 h containing first-line protease inhibitor (PI) treatment regimen.. Open, randomized, multicentre clinical trial. PI-naive patients received either ritonavir/saquinavir and one nucleoside reverse transcriptase inhibitor (NRTI) or indinavir and two NRTIs. Intention-to-treat (ITT) and on-treatment (OT) analyses were performed.. The baseline characteristics of the study participants were similar in both arms, 67 patients (37%) were naive to antiretroviral treatment. The proportion of patients who achieved a plasma viral load below the level of detection of 400 copies/ml at week 48 was 43% (39/90) in the ritonavir/saquinavir arm and 63% (57/90) in the indinavir arm (P=0.005, I

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Viral Load

To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients.. Randomized, open-label, multi-center study.. Adult AIDS clinical trials units.. Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks.. Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV.. Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint.. At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm.. Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Delavirdine; Female; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Viral Load; Zidovudine

CD4 T cell responses were studied for >2 years in 27 zidovudine-experienced patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who received triple combination drug therapy with indinavir, zidovudine and lamivudine or zidovudine plus lamivudine or zidovudine alone for 24-42 weeks before switching to the three-drug therapy. Subjects initially given the three drugs had viremia suppressed to undetectable levels and increases in T cell proliferative and cytokine responses to microbial antigens through 2 years of follow-up. Patients receiving the triple-drug therapy after either indinavir or zidovudine-lamivudine treatment had similar increases in T cell responses only if they also had suppression of virus load. CD4 T cell reactivity to HIV-1 antigens was not restored. Prolonged indinavir-zidovudine-lamivudine treatment has significant but incomplete enhancing effects on CD4 T cell reactivity, which could be important in host control of microbial and persistent HIV-1 infections.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antigens, Bacterial; CD4-Positive T-Lymphocytes; Cell Division; Chemokines; Cytokines; Double-Blind Method; Female; HIV Antigens; HIV-1; Humans; Indinavir; Lamivudine; Male; Mitogens; RNA, Viral; Viremia; 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

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

Study 006 is a pivotal Phase III, multicentre, randomized, open-label study designed to compare the antiretroviral activity and tolerability of efavirenz (EFV) + zidovudine (AZT) + lamivudine (3TC) with indinavir (IDV) + AZT + 3TC and EFV + IDV. Using both the 'observed data' analysis and intent-to-treat non-completer = failure analysis, the results at 48 weeks showed that efavirenz, in combination with AZT + 3TC was superior to IDV + AZT + 3TC. EFV + AZT + IDV was shown to be equally effective in patients with high and low baseline viral loads. Toxicities resulting in premature discontinuations were 3-fold higher in the IDV + AZT + 3TC arm than in both efavirenz-containing arms. Preliminary results suggested that efavirenz increased high density lipid (HDL) levels but the clinical significance of this observation is unknown. The results from Study 006 indicate that the combination EFV + AZT + 3TC is a highly active protease inhibitor-sparing regimen for first-line treatment of HIV-infected patients.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Humans; Indinavir; Lamivudine; Lipid Metabolism; Oxazines; Viral Load; Zidovudine

The purpose of the present study was to evaluate the impact of modern antiretroviral therapy in patients with acquired immunodeficiency syndrome (AIDS)-related lymphoma who were treated with standard chemotherapy. Twenty-nine patients with AIDS were treated with triple antiretroviral therapy, including protease inhibitors, were treated with a chemotherapy regimen involving cyclophosphamide 750 mg/m2, i.v. day 1; vincristine 1.4 mg/m2, i.v. day 1; mitoxantrone 10 mg/m2, i.v. day 1; and bleomycin 10 mg/m2, i.v. day 14. Granulocyte colony stimulating factor 5 ug/kg/day, started on day 5 of every cycle was administered to ameliorate the presence of severe myelosuppression. Complete response (CR) was observed in 21 cases (72%, 95% confidence interval; 63% to 83%). At three years the time to treatment failure (TTF) was 85%; disease free survival (DFS) 62%; and overall survival 55%. Eleven patients died secondary to tumor progression and only three patients died secondary to opportunistic infections. Chemotherapy was well tolerated, only 12% of the cycles developed granulocytopenia grade 3 and eleven episodes of infection-related granulocytopenia were observed. Delay on treatment was observed on 39 cycles (22%) N. death secondary to chemotherapy were recorded.. The use of modern antiretroviral therapy improved the prognosis of patients with AIDS-related lymphoma, because patients could receive adequate dose intensity of chemotherapy and the presence of opportunistic infections secondary to AIDS declines with the use of protease inhibitors. Future studies will consider the use of more intensive chemotherapy in an aim to improve the CR rate and overall survival.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Disease-Free Survival; Drug Therapy, Combination; Female; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lymphoma, AIDS-Related; Male; Middle Aged; Mitoxantrone; Prognosis; Survival Rate; Vincristine; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Adult; Carbamates; Furans; HIV Protease Inhibitors; Humans; Indinavir; Reverse Transcriptase Inhibitors; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Humans; Indinavir; Organic Chemicals; Oxazines; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Indinavir; Lamivudine; Oxazines; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Humans; Indinavir; Nucleosides; Pilot Projects

In previous natural history studies and clinical trials, AIDS-related cytomegalovirus (CMV) retinitis has occurred primarily in patients with absolute CD4 counts of 50 cells/microL or less (0.05 x 10(9)/L) at the time of diagnosis.. We report five patients identified from our clinical practices who were diagnosed with CMV retinitis while their CD4 counts were above 195 cells/microL. We also analysed, based on CD4 counts, 76 AIDS patients with newly diagnosed CMV retinitis whose CD4 lymphocyte enumerations were done in laboratories that maintained certification in a common external quality control programme.. 5-24 weeks before retinitis was diagnosed, all five patients had had absolute CD4 lymphocyte counts of less than 85 cells/microL, and 4-7 weeks before diagnosis, all five patients had started taking highly active antiretroviral treatment (HAART) regimens. Only one (4%) of 27 patients enrolled in the trial between July, 1995, and February, 1996, had an absolute CD4 count of more than 50 cells/microL, and none of 27 had an absolute CD4 count of more than 100/microL on entry to the trial. However, from March, 1996 (when indinavir and ritonavir were approved by the FDA for marketing in the USA), to August, 1996, 14 (29%) of 49 patients had CD4 counts of more than 50/microL and seven (14%) of 49 had a CD4 count of more than 100 cells/microL on entry.. These findings suggest that the early immunological effects of HAART may not provide sufficient protection to prevent CMV retinitis in patients who have very low CD4 counts when therapy is started. Clinicians should note that CMV retinitis may now occur in patients who have CD4 counts of more than 100 cells/microL.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; CD4 Lymphocyte Count; Cytomegalovirus Retinitis; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Saquinavir; Zidovudine

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

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Indinavir; Infectious Disease Transmission, Vertical; Lamivudine; Male; Pilot Projects; Retrospective Studies; Stavudine; Zidovudine

Merck will conduct two large trials to test MK-639, a protease inhibitor. One trial is for people who have never taken AZT or other antiretrovirals, and the other is for those who have used AZT. These trials will be conducted in numerous cities across the United States, with other trials to be conducted in foreign countries. The first trial is seeking 780 people with CD4 counts between 50 and 500; the second trial needs 90 people with CD4 counts between 50 and 400. Contact the Merck Protease Inhibitor Information Line, (800) 379-1332 for information on both trials.

Topics: Acquired Immunodeficiency Syndrome; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Zidovudine

Protocol 39, Merck's study of the protease inhibitor MK-639 in persons with CD4 count under 50, will recruit 420 patients in 12 U.S. cities. To enter the blinded portion of the study, patients need to have taken AZT for at least six months, and not have taken 3TC. They will be randomly assigned to receive either MK-639 alone, AZT plus 3TC, or a combination of all three drugs. Volunteers who have not taken AZT for six months, who are intolerant to AZT, or who have taken 3TC, may be eligible for the unblinded portion of the study in which they will receive open-label MK-639. Additional entry criteria include being at least 18 years old, not being pregnant, not having acute hepatitis, no prior use of protease inhibitors, no use of investigational agents or immunomodulators within 30 days prior to the study, and no use of immunosuppressive therapy within two weeks prior to the study. Also, the CD4 count must have been below fifty on two separate tests at least a week apart. For more information, call the Merck protease inhibitor information line, 800-379-1332.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; CD4 Lymphocyte Count; Drug Industry; Drug Therapy, Combination; HIV Protease Inhibitors; Hotlines; Humans; Indinavir; Lamivudine; Patient Selection; Pyridines; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine

Three studies involving the Merck protease inhibitor MK-639 are enrolling subjects. These studies involve combining MK-639 with AZT in people with T4 cell counts between 50 and 500, with 3TC and AZT in people with T4 cell counts between 50 to 400, and with 3TC and AZT in people with T4 cell counts under 50. To participate, a person must be 18 years or older and have blood test results in the normal range. Persons with a history of elevated, indirect bilirubin will not be allowed to participate.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Pyridines; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine

Highly active antiretroviral therapy (HAART) has increased the survival of HIV-infected patients. However, adverse effects play a major role in adherence to HAART. Some protease inhibitors (mainly atazanavir and indinavir) act as inhibitors of uridine diphosphate-glucuronosyltransferase (UGT1A1), the enzyme responsible for hepatic conjugation of bilirubin. Variations in the promoter region of the UGT1A1 gene (UGT1A1*28, rs8175347) can influence bilirubin plasma levels, modulating the susceptibility to hyperbilirubinemia. Aiming to analyze the association between UGT1A1*28 allele and hyperbilirubinemia in individuals exposed to HAART, we evaluated 375 HIV-positive individuals on antiretroviral therapy. Individuals carrying the UGT1A1*28 allele had a higher risk of developing severe hyperbilirubinemia [prevalence ratio (PR)=2.43, 95% confidence interval (CI) 1.08-5.45, p=0.032] as well as atazanavir users (PR=7.72, 95% CI=3.14-18.98, p<0.001). This is the first description of such an association in Brazilian HIV patients, which shows that in African-American and Euroamerican HAART users, the UGT1A1*28 allele also predisposes to severe hyperbilirubinemia, especially in those exposed to atazanavir.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alleles; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Bilirubin; Brazil; Cross-Sectional Studies; Female; Genotype; Glucuronosyltransferase; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Indinavir; Male; Oligopeptides; Predictive Value of Tests; Pyridines; Risk Factors; Severity of Illness Index

HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/μl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Coinfection; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Indinavir; Male; Pilot Projects; Prospective Studies; Rifampin; Ritonavir; RNA, Viral; Thailand; Treatment Failure; Tuberculosis; Viral Load

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

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

Misspecification of the covariance structure for repeated measurements in longitudinal analysis may lead to biased estimates of the regression parameters and under or overestimation of the corresponding standard errors in the presence of missing data. The so-called sandwich estimator can 'correct' the variance, but it does not reduce the bias in point estimates. Removing all assumptions from the covariance structure (i.e. using an unstructured (UN) covariance) will remove such biases. However, an excessive amount of missing data may cause convergence problems for iterative algorithms, such as the default Newton-Raphson algorithm in the popular SAS PROC MIXED. This article examines, both through theory and simulations, the existence and the magnitude of these biases. We recommend the use of UN covariance as the default strategy for analyzing longitudinal data from randomized clinical trials with moderate to large number of subjects and small to moderate number of time points. We also present an algorithm to assist in the convergence when the UN covariance is used.

Topics: Acquired Immunodeficiency Syndrome; Bias; CD4 Lymphocyte Count; Computer Simulation; Humans; Indinavir; Lamivudine; Longitudinal Studies; Models, Statistical; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Zidovudine

Studies of HIV dynamics in AIDS research are very important in understanding the pathogenesis of HIV-1 infection and also in assessing the effectiveness of antiviral therapies. Nonlinear mixed-effects (NLME) models have been used for modeling between-subject and within-subject variations in viral load measurements. Mostly, normality of both within-subject random error and random-effects is a routine assumption for NLME models, but it may be unrealistic, obscuring important features of between-subject and within-subject variations, particularly, if the data exhibit skewness. In this paper, we develop a Bayesian approach to NLME models and relax the normality assumption by considering both model random errors and random-effects to have a multivariate skew-normal distribution. The proposed model provides flexibility in capturing a broad range of non-normal behavior and includes normality as a special case. We use a real data set from an AIDS study to illustrate the proposed approach by comparing various candidate models. We find that the model with skew-normality provides better fit to the observed data and the corresponding estimates of parameters are significantly different from those based on the model with normality when skewness is present in the data. These findings suggest that it is very important to assume a model with skew-normal distribution in order to achieve robust and reliable results, in particular, when the data exhibit skewness.

Topics: Acquired Immunodeficiency Syndrome; Bayes Theorem; CD4 Lymphocyte Count; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Models, Statistical; Nonlinear Dynamics; Normal Distribution; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load

This case reported to a patient with AIDS who presented persistent sterile leukocyturia and hematuria, lower back pain, bladder suffering symptoms, and renal papillary necrosis which were thought to be secondary to urinary tuberculosis but were demonstrated to be indinavir-associated side effects. The intention of this report is to remind medical professionals involved in the care of HIV+ patients of this possible association in order to avoid unnecessary investigation and to stress the need of careful periodical assessment of renal function and urinalysis in patients treated with indinavir.

Topics: Acquired Immunodeficiency Syndrome; Diagnosis, Differential; Glomerular Filtration Rate; HIV Protease Inhibitors; Humans; Indinavir; Kidney Papillary Necrosis; Male; Middle Aged; Tuberculosis, Urogenital

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

Indinavir, a protease inhibitor that is commonly used to treat HIV infection, may cause crystal formation within the renal tubules when urine pH is above 3.5. Crystallization in the urine may lead to intrarenal crystal deposition and acute renal failure (ARF).. To establish the beneficial urological management of acute renal failure caused by indinavir treatment of HIV/AIDS patients.. Five HIV positive patients (four men, one woman) with a mean age of 32 years (range 28-36 years) were referred to our Department of Urology from an AIDS outpatient Clinic, because of the development of postrenal acute renal failure with continuously elevated creatinine and urea plasma levels after indinavir therapy. Among the initial therapeutic maneuvers, indinavir administration was interrupted for 1 week while bilateral double-J ureteral stents were inserted in all the HIV/AIDS patients, during the first 24-72 h to secure upper-tract drainage. Concurrently urine has been acidified by oral administration of the amino acid L: -methionine and oral fluid intake was increased.. All the patients responded well to the treatment and their renal function was effortlessly restored to normal within a few days.. HIV-positive patients receiving indinavir therapy might be complicated by acute renal failure, mainly due to intrarenal crystal deposition (tubules) or urolithiasis (postrenal obstruction). This adverse effect may simply manage by the discontinuation of indinavir administration, urine acidification, as well as the possible early insertion of bilateral double-J ureteral stents.

Topics: Acquired Immunodeficiency Syndrome; Acute Kidney Injury; Adult; Comorbidity; Female; HIV Protease Inhibitors; HIV Seropositivity; Humans; Indinavir; Male; Stents

The reduction of neutrophils apoptosis is one of the main non-virological effects of protease inhibitor (PI) therapy. We explore here whether this may be due to the cross-inhibition of calpain, an important non-virological target of PI in vitro. We found that the high basal level of neutrophils apoptosis in AIDS patients is strictly related to an increased intracellular calpain activity. Both alterations disappear after PI treatment, with apoptosis and calpain going back to normal levels after 3 months of PI therapy, independently of a proficient antiviral effect. PI drugs exerted a similar antiapoptotic and anticalpain effects on neutrophils in ex vivo experiments: strikingly, the effects were mimicked by commercially available calpain inhibitors. This study shows, for the first time, that apoptosis of neutrophils in AIDS patients is mediated by calpain, and that neutrophil survival in PI treated AIDS patients is a non virological effect due to calpain inhibition.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Apoptosis; Benzoxazines; Calpain; Case-Control Studies; Caspase 3; Caspases; Cells, Cultured; Cyclopropanes; Female; HIV Protease Inhibitors; Humans; Indinavir; Kinetics; Leukocytes, Mononuclear; Male; Neutrophils; Oxazines; Proteasome Endopeptidase Complex; Zidovudine

Body composition changes complicate antiretroviral therapy. Improvements in lipoatrophy after a switch in nucleoside reverse-transcriptase inhibitors (NRTIs) have been demonstrated. We investigated 60 patients switching from failed NRTIs to ritonavir-boosted indinavir and efavirenz.. Body composition (assessed by dual-energy x-ray absorptiometry scan and by single-slice computed tomography of the abdomen through the level of the fourth lumbar vertebra [L4] and the mid-right thigh) and fasted metabolics were measured at the baseline time-point at switch and at weeks 48 and 96 thereafter. Mitochondrial DNA and RNA were extracted from right-thigh subcutaneous fat and peripheral-blood mononuclear cells (PBMCs) at weeks 0 and 48. The primary end point was the change in mean limb fat over 48 weeks.. At week 96, we observed increases in mean (standard deviation [SD]) limb fat (+620 [974] g; P=.003), L4 subcutaneous adipose tissue (+20 [35] cm(2); P<.001), mid-thigh subcutaneous adipose tissue (+5 [10] cm(2); P<.001), and L4 visceral adipose tissue (+11 [34] cm(2); P=.01), but we also observed reduced lean limb mass (-831 [1,100] g; P=.3). Mean (SD) mtDNA content in subcutaneous fat and in PBMCs increased (+109 [274] and +45 [100] copies/cell, respectively). Improved virological control or immune recovery did not explain the results. Triglyceride, total cholesterol, estimated low-density lipoprotein cholesterol, ratio of total cholesterol to high-density lipoprotein cholesterol, and blood glucose levels deteriorated (i.e., had increased by 206%, 67%, 58%, 19%, and 6%, respectively, at week 96).. This regimen was associated with statistically significant but clinically modest increases in peripheral fat, visceral fat, and mitochondrial nucleic acid content. A predominantly adverse metabolic profile developed.

Topics: Absorptiometry, Photon; Acquired Immunodeficiency Syndrome; Adult; Body Composition; DNA, Mitochondrial; HIV Protease Inhibitors; Humans; Indinavir; Lumbar Vertebrae; Middle Aged; Mitochondria; Reverse Transcriptase Inhibitors; Ritonavir; RNA; RNA, Mitochondrial; RNA, Viral; Stavudine; Tomography, X-Ray Computed; Treatment Failure; Treatment Outcome; Viral Load; Zidovudine

This study evaluated the feasibility of reducing the indinavir (IDV) dosage in Taiwanese patients receiving the standard IDV/ritonavir (RTV) dosage of 800/100 mg twice a day who had undetectable plasma human immunodeficiency virus type 1 (HIV-1) RNA but had developed IDV-related toxicities. After dosage reduction to IDV/RTV 600/100 mg twice a day, the dose-related toxicity decreased and plasma HIV RNA remained undetectable at 24 weeks post-switch in all patients. The maximal plasma concentration (Cmax) and area under the plasma concentration-time curve of IDV decreased significantly (median, 6.3 vs 4.3 microg/mL and 1892 vs 1292 microg.min/mL, p=0.01 and 0.001, respectively) but the minimal plasma concentration remained at a similar level (median, 1.0 vs 0.8 microg/mL, p=0.12). This study found that the reduction in the dosage of IDV in HIV-1 infected patients receiving the standard IDV/RTV regimen guided by therapeutic drug monitoring decreased the Cmax, dose-related toxicity and medical cost without compromising viral control.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; HIV-1; Humans; Indinavir; Pilot Projects

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Brain; CD4 Lymphocyte Count; Cidofovir; Cytosine; Dideoxynucleosides; Encephalitis; False Negative Reactions; Fatal Outcome; Humans; Immunocompromised Host; Indinavir; JC Virus; Lamivudine; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Organophosphonates; Substance Abuse, Intravenous; Time Factors; Virus Activation; Zidovudine

HIV-1 protease inhibitors (PI) with an N-arylpyrrole moiety in the P(3) position afforded excellent antiviral potency and substantially improved aqueous solubility over previously reported variants. The rapid in vitro clearance of these compounds in human liver microsomes prompted oral coadministration with indinavir to hinder their metabolism by the cyctochrome P450 3A4 isozyme and allow for in vivo PK assessment.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Biotransformation; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Design; Drug Resistance, Viral; Drug Therapy, Combination; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Microsomes, Liver; Pyrroles; Structure-Activity Relationship

Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study.. At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed.. All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L. h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively.. Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV-1; Humans; Indinavir; Male; Oxazines; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Food-Drug Interactions; Humans; Indinavir; Randomized Controlled Trials as Topic; Ritonavir

A child with perinatally acquired AIDS and profound immunodeficiency was treated with zidovudine, lamivudine and indinavir and had excellent immunologic and virologic response. His subsequent clinical course was complicated by multisystem sarcoidosis characterized by granulomatous hepatitis, nephritis, duodenitis and a CD4+ lymphocytic alveolitis as part of the immune reconstitution syndrome.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; HIV Protease Inhibitors; Humans; Indinavir; Male; Nephritis, Interstitial; Sarcoidosis; Zidovudine

HIV protease inhibitor-related lipodystrophy is characterized by peripheral fat loss, hyperlipidemia, and insulin resistance. Increased availability of lipid to muscle may be one of the mechanisms that induce insulin resistance. Regional fat, intramyocellular lipid (by (1)H-magnetic resonance spectroscopy), serum lipids, and insulin-stimulated glucose disposal (by hyperinsulinemic-euglycemic clamp) were quantified in 10 men who had HIV-1 infection with moderate to severe lipodystrophy and a control group of 10 nonlipodystrophic men who had HIV-1 infection and were naïve to protease inhibitors to examine the effects of lipodystrophy on glucose and lipid metabolism. Lipodystrophic subjects showed lower insulin-stimulated glucose disposal than control subjects (P = 0.001) and had increased serum triglycerides (P = 0.03), less limb fat (P = 0.02), increased visceral fat as a proportion of total abdominal fat (P = 0.003), and increased intramyocellular lipid (1.90 +/- 0.15 vs. 1.23 +/- 0.16% of water resonance peak area; P = 0.007). In both groups combined, visceral fat related strongly to intramyocellular lipid (r = 0.83, P < 0.0001) and intramyocellular lipid related negatively to insulin-stimulated glucose disposal (r = -0.71, P = 0.0005). Fasting serum cholesterol and triglycerides related positively to intramyocellular lipid and visceral fat in lipodystrophic subjects only. The data indicate that lipodystrophy is associated with increased lipid content in muscle accompanying impaired insulin action. The results do not establish causation but emphasize the interrelationships among visceral fat, myocyte lipid, and insulin action.

Topics: Absorptiometry, Photon; Acquired Immunodeficiency Syndrome; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Body Composition; HIV Protease Inhibitors; Homeostasis; Humans; Indinavir; Insulin; Leptin; Lipids; Lipodystrophy; Magnetic Resonance Imaging; Male; Middle Aged; Nelfinavir; Ritonavir; Saquinavir

To report a case of suspected extrapyramidal symptoms (EPS) in a patient initiated on ritonavir and indinavir while taking risperidone for a tic disorder.. A 35-year-old white man with AIDS received risperidone 2 mg twice daily for treatment of a Tourette's-like tic disorder. Ritonavir and indinavir were initiated, and 1 week later, he experienced significantly impaired swallowing, speaking, and breathing, and worsening of his existing tremors. Ritonavir and indinavir were discontinued. On the same day, the patient increased the risperidone dosage to 3 mg twice daily. Symptoms continued to worsen over the next 3 days. All investigations and laboratory parameters were unremarkable, and vital signs were stable. Risperidone was discontinued and clonazepam initiated. Three days later, the patient's symptoms were significantly improved.. The symptoms described herein are consistent with neuroleptic-induced acute dystonia and potentially neuroleptic-induced parkinsonism. We believe this adverse effect occurred as a result of a drug interaction between ritonavir/indinavir and risperidone. Based on the pharmacokinetics of these medications, we hypothesize that inhibition of CYP2D6 and CYP3A4 by ritonavir and indinavir may have resulted in an accumulation of the active moiety of risperidone, which may explain the occurrence of EPS in this patient.. This is the second published case report describing a suspected drug interaction with ritonavir, indinavir, and risperidone. Caution is warranted when risperidone is prescribed with ritonavir/indinavir, and possibly with other antiretrovirals that inhibit the same pathways.

Topics: Acquired Immunodeficiency Syndrome; Adult; Basal Ganglia Diseases; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Antagonism; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Male; Mixed Function Oxygenases; Risperidone; Ritonavir; Tourette Syndrome

Drug-resistant strains are rapidly selected during AIDS therapy because of the high rate of mutation in HIV. In this report, we present an evolutionary simulation method for analysis of viral mutation and its use for optimization of HIV-1 protease drugs to improve their robustness in the face of resistance mutation. We first present an analysis of the range of resistant mutants that produce viable viruses by using a volume-based viral fitness model. Then, we analyze how this range of mutant proteases allows development of resistance to an optimal inhibitor previously designed by computational coevolution techniques. Finally, we evaluate the resistance patterns of commercially available drugs, and we discuss how resistance might be overcome by optimizing the size of specific side-chains of these inhibitors.

Topics: Acquired Immunodeficiency Syndrome; Binding Sites; Biological Evolution; Computational Biology; Computer Simulation; Computer-Aided Design; Drug Design; Drug Resistance, Viral; Drug Therapy, Combination; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Models, Molecular; Mutation; Nelfinavir; Ritonavir; Saquinavir

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

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

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Bone Diseases, Metabolic; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Osteoporosis; Reverse Transcriptase Inhibitors; Rib Fractures; Spinal Fractures; Stavudine

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 identify clinical factors associated with prevalence of fat atrophy (lipoatrophy) and fat accumulation (lipoaccumulation) in HIV-1 infected patients.. Evaluation of HIV-1 infected patients seen for routine care between 1 October and 31 December 1998 in the eight HIV Outpatient Study (HOPS) clinics.. Eight clinics specializing in the care of HIV-1 infected patients.. A total of 1077 patients were evaluated for signs of fat maldistribution.. A standardized set of questions and specific clinical signs were assessed. Demographic, clinical and pharmacological data for each patient were also included in the analysis.. Demographic, immunologic, virologic, clinical, laboratory, and drug treatment factors were assessed in stratified and multivariate analyses for their relationship to the presence and severity of fat accumulation and atrophy.. Independent factors for moderate/severe lipoatrophy for 171 patients were increasing age, any use of stavudine, use of indinavir for longer than 2 years, body mass index (BMI) loss, and measures of duration and severity of HIV disease. Independent risk factors for moderate/severe fat accumulation for 104 patients were increasing age, BMI gain, measures of amount and duration of immune recovery, and duration of antiretroviral therapy (ART). The number of non-drug risk factors substantially increased the likelihood of lipoatrophy. If non-drug risk factors were absent, lipoatrophy was unusual regardless of the duration of drug use.. HIV-associated lipodystrophy is associated with several host, disease, and drug factors. While prevalence of lipoatrophy increased with the use of stavudine and indinavir, and lipoaccumulation was associated with duration of ART, other non-drug factors were strongly associated with both fat atrophy and accumulation.

Topics: Acquired Immunodeficiency Syndrome; Adult; Age Factors; Anti-HIV Agents; Body Mass Index; CD4 Lymphocyte Count; Cohort Studies; Data Interpretation, Statistical; Female; HIV Protease Inhibitors; Humans; Indinavir; Lipodystrophy; Male; Middle Aged; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Viral Load

Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study.. Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome.. A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients.. Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Cohort Studies; Drug Administration Schedule; Female; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Nelfinavir; Nevirapine; Odds Ratio; Patient Compliance; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Surveys and Questionnaires

Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4-3Delta gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass increased 160% by echocardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mM). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Cardiomyopathies; Drug Therapy, Combination; Echocardiography; Gene Expression; HIV Protease Inhibitors; Indinavir; Lactic Acid; Lamivudine; Mice; Mice, Transgenic; Microscopy, Electron; Myocardium; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Zidovudine

The aim of this retrospective study was to evaluate treatment outcome and characterize the pattern of genotype mutations in subjects with treatment failure on highly active antiretroviral therapy (HAART) containing nelfinavir or indinavir.. The database of the Swiss HIV Cohort Study was screened for all subjects naive to protease inhibitor (PI) treatment who started HAART with nelfinavir or indinavir, responded initially (HIV-RNA <400 copies/ml) and received >24 weeks of treatment. Responders with subsequent treatment failure (HIV-RNA >1000 copies/ml, bordered by HIV-RNA >400 copies/ml) were selected for genotypic analysis.. Initial treatment response, maintenance of response and subsequent virological failure were observed at a comparable frequency in 1143 nelfinavir and 1555 indinavir subjects. Of the treatment-naive patients, 13% who took nelfinavir and 16% who took indinavir had HIV-RNA >1000 copies/ml at least once. These values increased to 24 and 27%, respectively, for reverse transcriptase inhibitor-experienced subjects. Genotypic analysis in a subset of subjects with virological failure identified 30N as the only primary mutation in the nelfinavir subjects (8 out of 21, 38%) whereas isolated or combined 82A/T and 461/L mutations were detected in the indinavir subjects (9 out of 20, 45%).. In this population of previously PI-naive subjects, the rate of virological failure and the frequency of resistance mutations at the time of virological failure were comparable in subjects receiving nelfinavir- or indinavir-containing HAART. In nelfinavir subjects, 30N was the only primary mutation whereas isolated or combined 82A/T and 461/L mutations were detected in indinavir subjects.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Base Sequence; CD4 Lymphocyte Count; Drug Resistance, Viral; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Molecular Sequence Data; Mutation; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Mycobacterium Infections, Nontuberculous; Mycobacterium xenopi

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Female; HIV Protease Inhibitors; Humans; Immunization; Indinavir; Influenza Vaccines; Male; Middle Aged

Effective antiretroviral therapy leads to rapid decrease in plasma HIV-1 RNA, frequently followed by an increase in CD4 T-helper cell counts. The improvement of immune function during highly active antiretroviral therapy has important impact on natural history of AIDS-related opportunistic disorders. Here we describe cases of unusual clinical inflammatory syndromes in CMV retinitis, hepatitis C, and atypical mycobacteriosis in HIV-1 infected patients associated with the initiation of antiretroviral therapy. Pathogenetic implications and therapeutic management of these new immunopathologic syndromes are discussed.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cytomegalovirus Retinitis; Female; Hepatitis C; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Mycobacterium avium-intracellulare Infection; Reverse Transcriptase Inhibitors; Zidovudine

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

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Area Under Curve; Blood-Brain Barrier; Drug Administration Schedule; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; RNA, Messenger; RNA, Viral

Topics: Acquired Immunodeficiency Syndrome; Colon; Diarrhea; HIV Protease Inhibitors; HT29 Cells; Humans; Indinavir; Intestinal Absorption; Intestinal Mucosa; Nelfinavir; Ritonavir; Saquinavir

We reported a patient with acquired immunodeficiency syndrome (AIDS)-associated progressive multifocal leukoencephalopathy (AIDS-PML), whose condition improved after highly active anti-retroviral therapy (HAART). A 70-year-old man was admitted to our hospital because of worsening left hemiplegia and disturbance of consciousness. During the past 30 years, he frequently traveled to the United States and southeast Asia. On neurological examination, he was somnolent and left hemiplegia with severe rigospasticity was present. The deep tendon reflexes showed hyper-reflexes with extensor plantar responses. Laboratory studies showed pancytopenia and positive HIV-1 antibodies. The CD4 cell count was 38/mm3 and his HIV viral RNA load in the blood was 9,500 copies/ml. T2-weighted magnetic resonance imaging (MRI) of the brain revealed asymmetrical high intensity white matter lesions in the right fronto-parietal, and left frontal regions and in the cerebellar hemisphere. The cerebrospinal fluid (CSF) protein elevated to 91 mg/dl with a normal cell count. The diagnosis of PML was confirmed by the detection of JC virus DNA in the CSF using a nested polymerase chain reaction assay. Three weeks after starting HAART with zidovudine, lamivudine, and indinavir, he was able to respond to simple commands. Two months later, the HIV viral RNA load decreased to less than 400 copies/mm3, and no JC virus DNA was detected in the CSF, with an increase of the CD4 cell count to 285/mm3 in the blood. A follow-up MRI of the brain showed a reduction in the cerebellar and cerebral white matter lesions. The recovering immune function by decreasing of the HIV load after HAART might suppress JC virus replication. It was suggested that HAART would become a beneficial treatment for patients with AIDS-PML.

Topics: Acquired Immunodeficiency Syndrome; Aged; Antiretroviral Therapy, Highly Active; Humans; Indinavir; JC Virus; Lamivudine; Leukoencephalopathy, Progressive Multifocal; Male; Treatment Outcome; Zidovudine

Human immunodeficiency virus type 1 (HIV-1) variants that have developed protease (PR) inhibitor resistance most often display cross-resistance to several molecules within this class of antiretroviral agents. The clinical benefit of the switch to a second PR inhibitor in the presence of such resistant viruses may be questionable. We have examined the evolution of HIV-1 PR genotypes and phenotypes in individuals having failed sequential treatment with two distinct PR inhibitors: saquinavir (SQV) followed by indinavir (IDV). In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under IDV, while few additional mutations emerged. In viruses where no SQV resistance mutations were detected before the switch to IDV, typical SQV resistance profiles emerged following the introduction of IDV. We conclude that following suboptimal exposure to a first PR inhibitor, the introduction of a second molecule of this class can lead to rapid selection of cross-resistant virus variants that may not be detectable by current genotyping methods at the time of the inhibitor switch. Viruses committed to resistance to the first inhibitor appear to bear the "imprint" of this initial selection and can further adapt to the selective pressure exerted by the second inhibitor following a pathway that preserves most of the initially selected mutations.

Topics: Acquired Immunodeficiency Syndrome; Drug Resistance; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mutation; Saquinavir

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Drug Administration Schedule; HIV Protease Inhibitors; Humans; Indinavir; Odds Ratio; Ritonavir; Saquinavir; Spain; Survival Analysis; Treatment Failure; Treatment Outcome

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

To characterize indinavir-associated rash using systematic data collection through postmarketing surveillance in a sample of HIV/AIDS patients.. HIV-infected patients identified through a medication counseling line who reported onset of a rash following initiation of indinavir therapy were included in this case series analysis. Pertinent information regarding onset, description, and management of rash; other medications initiated within two weeks of indinavir or rash onset; and medication allergy history was obtained through follow-up telephone contact. Patients were contacted weekly until the rash resolved or indinavir was discontinued.. Stadtlanders Drug Distribution Company, located in Pittsburgh, PA.. Of the 110 patients identified and followed, 67% reported rash onset within two weeks of initiating indinavir therapy. The rash was initially localized in all 110 patients and subsequently spread to other areas of the body in 77% of the patients. The rash spread to the full body in 44% (49) of the patients. The rash was accompanied by pruritus in 86% of the patients, and the majority of patients (87%) were afebrile. Eighty-one patients received treatment with medications such as antihistamines or oral or topical corticosteroids. Fifty percent of patients receiving treatment for the rash reported that these medications were helpful in relieving rash symptoms. Fifty-nine percent of the patients continued indinavir therapy despite the occurrence of rash.. Results from this study suggest that indinavir-associated rash occurs within two weeks of initiation of therapy for the majority of patients. Typically, the rash is localized with subsequent spread and is associated with pruritus. The majority of patients are able to continue indinavir therapy despite the occurrence of rash.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anti-HIV Agents; Exanthema; Female; Humans; Indinavir; Male; Middle Aged

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Anti-Inflammatory Agents; Antitubercular Agents; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Inflammation; Nelfinavir; Prednisone; Tuberculosis

Topics: Abdominal Pain; Acquired Immunodeficiency Syndrome; Adult; Crystallization; Humans; Indinavir; Kidney; Kidney Calculi; Male; Radiography

We evaluate the clinical, diagnostic and radiographic findings in patients on indinavir therapy who presented with renal colic, and propose appropriate treatment options for indinavir urolithiasis.. A total of 16 patients positive for human immunodeficiency virus on indinavir were evaluated for 18 episodes of severe renal colic requiring hospitalization. Laboratory evaluation was performed in all patients followed by an imaging study. Conservative treatment included intravenous hydration, narcotic analgesics and temporary cessation of indinavir. Intervention was elected only in patients with persistent fever or intractable pain. A month after hospital discharge an excretory urogram and metabolic stone evaluation were performed. Mean followup was 9.3 months and 2 patients had recurrent symptoms.. All patients presented with nausea or vomiting and hematuria. Imaging studies confirmed obstruction in all patients with 13 radiolucent (indinavir) and 3 radiopaque (calcium oxalate) stones. Patients with radiolucent and radiopaque stones demonstrated significant differences in urinary pH (p = 0.002) and serum creatinine (p = 0.03). Conservative therapy was successful in 11 patients (68.8%) within 48 hours and 4 patients (25%) with radiolucent calculi required endoscopic stenting for persistent fever. Metabolic stone evaluation demonstrated significant hypocitruria (less than 50 mg./24 hours) in all patients with radiolucent calculi.. The urologist should be familiar with this growing cause of renal colic in patients on indinavir therapy. Pure indinavir stones are radiolucent and have a soft, gelatinous endoscopic appearance. Conservative treatment is successful in most patients and if intervention is deemed medically necessary, endoscopic stent placement should be the procedure of choice.

Topics: Acquired Immunodeficiency Syndrome; Adult; Colic; Female; Follow-Up Studies; HIV Protease Inhibitors; HIV Seropositivity; Humans; Indinavir; Kidney Calculi; Kidney Diseases; Male; Middle Aged; Severity of Illness Index

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

Topics: Acquired Immunodeficiency Syndrome; Acute Kidney Injury; Adult; Alcoholism; Chemical and Drug Induced Liver Injury; Hepatitis C, Chronic; HIV Protease Inhibitors; Humans; Indinavir; Male; Rhabdomyolysis; Ritonavir

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

The authors experienced granular lymphocyte-proliferative disorder (GLPD) with increased lymphocyte and CD4 cell counts after HIV treatment with a protease inhibitor indinavir in a 51-year-old male AIDS patient. GLPD proved to be the chronic type, but we could not differentiate whether it was the T-cell type or the NK-cell type. EB virus was found to be activated and its chronic activity was suggested. We should note in this case that EB virus was involved in the GLPD onset and that GLPD followed the treatment with a protease inhibitor.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Herpesviridae Infections; Herpesvirus 4, Human; HIV Protease Inhibitors; Humans; Indinavir; Lymphoproliferative Disorders; Male; Middle Aged; Tumor Virus Infections

To explore the occurrence of, and diagnostic and therapeutic procedures for urological side-effects (e.g. micro- and macrohaematuria, and kidney stone formation) in individuals treated with indinavir for the human immunodeficiency virus (HIV).. The study comprised a retrospective follow-up of 74 individuals infected with HIV-1 and who were treated with indinavir orally at a daily dose of 2.4 g. Data were collected at the outpatient department of our institution between March 1996 and November 1997.. Of the 74 individuals treated with indinavir, 15 (20%) had indinavir-related urological side-effects (19 episodes), most commonly dull flank pain and dysuria. Microhaematuria occurred in 16 of the 19 episodes. Four patients showed urinary tract distension ultrasonographically as a possible indirect sign of urolithiasis and one patient passed a kidney stone. In four patients treatment had to be stopped permanently, but in the remaining 11 patients treatment was continued. Some patients required dose reduction and/or interruption of treatment; only conservative therapeutic measures were required, consisting of rehydration (fluid intake >1.5 L/day) and analgesics.. Urological side-effects of indinavir may be apparent in 20% of patients so treated; some (5%) may require permanent withdrawal. In addition to a history and clinical examination, urine analysis and ultrasonography were the only diagnostic procedures required. Therapy is mainly conservative, using rehydration, analgesics and a brief discontinuation of therapy, according to the severity of the symptoms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Female; Fluid Therapy; Follow-Up Studies; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Urologic Diseases

Topics: Acquired Immunodeficiency Syndrome; Adult; Anemia, Hemolytic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male

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: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; Didanosine; Drug Therapy, Combination; Humans; Indinavir; Leukoencephalopathy, Progressive Multifocal; Male

The interactions of four HIV-protease inhibitors, ritonavir (RIT), saquinavir (SAQ), indinavir (IND) and nelfinavir (NEL), were examined by in vitro metabolic studies using rat liver microsomal fractions. The substrate concentrations employed were 0.75 approximately 12 microM, and the inhibitor concentrations were 2.5 approximately 60 microM. The metabolic clearance rates of SAQ, NEL and IND as determined by V(max)/K(m) were 170.9+/-10.9, 126.0+/-4.4 and 73.0+/-2.0 microL/min/mg protein, respectively. RIT was a potent inhibitor of the other three protease inhibitors, and the inhibition constants (K(i)) were 1.64 microM for SAQ, 0.95 microM for IND and 1. 01 microM for NEL. NEL was the second strongest inhibitor with a K(i) for NEL inhibition of IND metabolism of 2.14 microM. IND was the third strongest inhibitor with K(i)s of 2.76 microM for inhibition of NEL and 3.55 microM for inhibition of SAQ. As SAQ has the highest metabolic clearance rate, the K(i) for the SAQ inhibition of IND metabolism was high, 9.50 microM. Based on these in vitro results, drug interactions between NEL and IND or RIT were studied after oral administration to rats where the dose of each drug was 20 mg/kg. The C(max) and AUC of NEL were increased 3.6- and 8.5-fold by the co-administration with RIT. However, in contrast to co-administration of NEL and RIT, the effect of IND on the pharmacokinetics of NEL was negligible and the t(1/2) of NEL was not significantly increased by IND. Therefore, the combination of NEL and IND is recommended as a combination therapy for AIDS patients.

Topics: Acquired Immunodeficiency Syndrome; Animals; Drug Interactions; Drug Therapy, Combination; HIV Protease Inhibitors; Indinavir; Male; Nelfinavir; Rats; Rats, Wistar; Ritonavir; Saquinavir

Recently, several class-related adverse events have been recognized with antiretroviral drugs. For nucleoside analogue reverse transcriptase inhibitors. (NRTI), lactic acidosis with hepatomegaly and hepatic steatosis have been reported. These appear to occur at a low frequency, but with a high fatality rate. We report a case of fatal lactic acidosis in a patient with acquired immunodeficiency syndrome (AIDS) treated with stavudine (d4T), lamivudine (3TC) and indinavir (IDV). A 48-year-old male AIDS patient was admitted with complaints of general fatigue and dyspnea. His medications at presentation included d4T, 3TC and IDV. Physical examination demonstrated icteric sclerae and abdominal tenderness with hepatomegaly. Laboratory data demonstrated a severe metabolic acidosis with an anion gap due to lactate accumulation. Despite intensive treatment, cardiorespiratory arrest occurred and this could not be resuscitated.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; Fatal Outcome; Humans; Indinavir; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine

Sequential use of antiretroviral therapy with protease inhibitors (PI) is frequently prescribed owing to failure or intolerance of the first selected agent. Controversial data exist about the virological and immunological outcome of patients in whom a change to a second PI regimen is needed. A prospective study of 113 HIV-positive patients (male, 84%; mean age 36 years; previous AIDS-defining event, 35%; previous antiretroviral therapy with nucleoside analogues, 94%) who started a saquinavir-containing regimen between March 1996 and March 1997 and had to change to indinavir (n = 79) owing to intolerance, failure or medical criteria was performed. At the time of the switch, median CD4 cell count was 221 cells/mm3 and the HIV RNA level was 3.98 log10 copies/ml. The rate of viral suppression (HIV RNA levels below 200 copies/ml) was 40% at 3 months and 28% at month 6 after indinavir was instituted. In a logistic regression analysis, only the baseline viral load [relative risk (RR), 2.85; 95% confidence interval (CI), 1.31-6.05; P = 0.007] was statistically associated with the lack of viral suppression on indinavir. Although there are not sufficient data about the best therapeutic option if a change in PI-containing regimens therapy is considered, this study supports the recommendation of an early change of the PI-containing regimens, before the HIV-1 viral load reaches high levels.

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Female; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Prospective Studies; RNA, Viral; Saquinavir

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

While CD4 cell counts are widely used to predict disease progression in human immunodeficiency virus (HIV)-infected patients, they are poorly explanatory of the progression to AIDS or death after the introduction of chemotherapy. Changes in HIV load (as measured by RNA PCR) have been shown to be a much better predictor of the risk of disease progression. Since the interrelationship of these markers is of great clinical interest, we modeled the time-averaged return of CD4 cell count and change in viral load subsequent to therapy with the HIV protease inhibitor indinavir. We found that CD4 cell return was significantly related to both the baseline CD4 count (r2 = 0.86, P < 0.001) and the decline in HIV RNA PCR-determined viral load (also referred to in this work as the HIV RNA PCR decline) (r2 = 0.60, P < 0.01). Simultaneously modeling both influences in a linked nonlinear model (r2 = 0.93, P < 0.001) demonstrated that (i) the starting number of CD4 cells accounted for the majority of the change in CD4 cell return and (ii) the return of CD4 cells attributable to viral load decrease was 50% of maximal with only a decrease of approximately 0.2 log of HIV RNA as modeled from the first 12 weeks of therapy. Much greater viral inhibition beyond that necessary for maximal CD4 cell return is possible. Given that HIV RNA PCR decline is more strongly linked to ultimate clinical course in HIV disease, our findings indicate that CD4 return is potentially misleading as an indicator of antiviral effect, since it is determined more by the starting CD4 value than by viral load decline and since near-maximal changes occur with minimal antiviral effect.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Disease Progression; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Models, Biological; Models, Theoretical; Polymerase Chain Reaction; RNA, Viral; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Adult; Anemia, Hemolytic; Drug Therapy, Combination; Fatal Outcome; HIV Protease Inhibitors; Humans; Indinavir; Male

Topics: Abdomen; Acquired Immunodeficiency Syndrome; Dilatation, Pathologic; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lipodystrophy; Male; Middle Aged

Aspergillus abscesses of the kidneys are very rare complications of AIDS which usually have fatal outcome. The 4 patients described in the literature, 2 of whom had bilateral involvement, died due to this opportunistic infection.. Case report of a 33-year-old patient with AIDS in stage C3 and aspergillus abscesses of the kidney.. Successful treatment of bilateral aspergillus abscesses of the kidneys with purely conservative antimycotic measures. This was largely due to stabilization of the immune status by supplementing antiretroviral treatment with the proteinase inhibitor indinavir.. The options now available for improving immune status in AIDS also improve the treatment chances in renal aspergillosis.

Topics: Abscess; Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Humans; Indinavir; Kidney Diseases; Tomography, X-Ray Computed

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Female; Graves Disease; Humans; Immunity; Indinavir; Lamivudine; Male; Ritonavir; Stavudine

All human immunodeficiency virus type 1 (HIV-1)-infected patients who started to use indinavir (800 mg three times a day) as part of their triple drug regimen were included in a study to determine the importance of low plasma concentrations of indinavir as a cause of virological treatment failure. The indinavir concentration and a number of patient characteristics at baseline were tested as risk factors for virological treatment failure (defined as a viral load above 200 copies/ml after 24 weeks of treatment) in univariate and multivariate analyses; 65 patients were included. Virological treatment failure occurred in 36.9% of the patients. Multivariate analysis showed that a low plasma concentration of indinavir (odds ratio 0.1), a high viral load at baseline (odds ratio 2.6) and pretreatment with another protease inhibitor (odds ratio 10.0) were independent factors related to virological treatment failure. Monitoring of indinavir plasma concentrations may be an important tool for the optimization of triple drug combination therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV-1; Humans; Indinavir; Male; Middle Aged; Treatment Failure

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; California; Clinical Trials as Topic; Drug Therapy, Combination; HIV Infections; Hotlines; Humans; Indinavir; Patient Selection

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Sulfonamides; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Adult; Female; HIV Protease Inhibitors; Humans; Indinavir; Kidney Calculi

Topics: Acquired Immunodeficiency Syndrome; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Remission Induction; Sarcoma, Kaposi; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Herpesvirus 8, Human; HIV-1; Humans; Indinavir; Leukocytes, Mononuclear; Male; Polymerase Chain Reaction; Protease Inhibitors; Sarcoma, Kaposi

To evaluate the in vivo relationship between HIV replication and circulating levels of the chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, RANTES (acronym for Regulated upon Activation, Normal T-cell Expressed and presumably Secreted), interleukin (IL)-16 and monocyte chemotactic protein (MCP)-1, which have recently been characterized as factors capable of regulating in vitro HIV replication.. We have compared changes in plasma HIV-RNA levels and circulating levels of MIP-1 alpha, MIP-1 beta, RANTES, IL-16 and MCP-1 in 20 severely immunodeficient HIV-infected individuals (CD4+ T cells = 14 +/- 3 cells x 10(6)/l; plasma HIV RNA = 4.45 +/- 0.27 log 10 copies/ml) undergoing treatment with the HIV protease inhibitor indinavir that added to pre-existing nucleoside-based therapy. At weeks 0, 2, 6 and 12, viral load was quantified using a commercial reverse-transcription polymerase chain reaction assay, peripheral blood T-cell subpopulations assessed by flow cytometry, and chemokine levels quantified using commercial sandwich enzyme-linked immunosorbent assay kits.. Following initiation of indinavir-based therapy, significant decreases in plasma HIV-RNA levels (change = 2.0 +/- 0.75 log 10 copies/ml) were observed in conjunction with significant increases in absolute CD4+ (change = 83 +/- 19 cells x 10(6)/l) and CD8+ (change = 293 +/- 96 cells x 10(6)/l) T-cell numbers. Concomitantly, significant increases in MIP-1 alpha (19% increase), MIP-1 beta (14% increase), RANTES (15% increase) and IL-16 (1213% increase) levels occurred. In contrast, MCP-1 levels decreased significantly (47% decrease).. The in vivo demonstration of an association between diminishing plasma HIV-RNA levels and the emergence of a circulating chemokine profile capable of inhibiting HIV replication corroborates recent in vitro observations and provides evidence for the restoration of chemokine capacity by HIV protease inhibitor-based therapy.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines; Female; HIV-1; Humans; Indinavir; Interleukin-16; Macrophage Inflammatory Proteins; Male; Retrospective Studies; RNA, Viral; T-Lymphocytes; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; HIV Protease Inhibitors; Humans; Indinavir; Male; Uveitis, Anterior

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; British Columbia; CD4 Lymphocyte Count; Drug Therapy, Combination; Humans; Indinavir; Lamivudine; Mortality; Saquinavir; Stavudine

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Humans; Indinavir; Kidney Diseases; Male; Middle Aged

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

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Hemophilia B; Humans; Indinavir; Male

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

Plasma viremia during HIV-1 infection is regulated by a dynamic balance between viral replication and removal of infected cells and cell-free virus. Administration of novel potent antiretroviral drugs provides an opportunity to study the consequences of perturbing this equilibrium by blocking de novo infections. In this study, we examined the expression of differentially spliced forms of HIV-1 mRNA, unspliced (US) and multiply spliced (MS), in peripheral blood mononuclear cells (PBMCs) of patients treated with HIV protease inhibitors or combination therapy. In all nine patients studied, a significant reduction in the MS/US mRNA ratio was observed after 1 week of treatment, suggesting that the majority of HIV MS mRNA in the steady-state situation prior to therapy was expressed by cells which had been infected during the previous couple of days. This idea was supported by a detailed analysis of serial PBMC specimens collected from two of the patients during the first hours and days after initiation of therapy. In both cases, a substantial decrease in MS mRNA expression was evident already after 48 hr, whereas the expression of US mRNA at this time was virtually unaffected. These data indicate that the HIV mRNA splicing pattern in vivo is mainly determined by the relative proportion of newly infected cells and suggest that examination of this pattern could be useful in evaluating the potency of antiretroviral therapies and in studying dynamics of HIV-1 infection.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; DNA Primers; Drug Therapy, Combination; HIV-1; Humans; Indinavir; Isoquinolines; Leukocytes, Mononuclear; Nelfinavir; Polymerase Chain Reaction; Ritonavir; RNA Splicing; RNA, Messenger; RNA, Viral; Sulfonic Acids; Virus Replication; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Survival Rate

Gene therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infection using intracellular immunization strategies is currently being tested in clinical trials. With the continuing development of potent antiretroviral drugs (e.g., reverse transcriptase [RT] and protease [PR] inhibitors), it is likely that HIV-1 gene therapy will be applied to humans concurrently receiving such antiretroviral medication. In this study, we assessed the in vitro antiviral efficacy of two gene therapy strategies (trans-dominant RevM10, Gag antisense RNA) in combination with clinically relevant RT (AZT, ddC) or PR (indinavir) inhibitors. Retrovirally transduced, human T cell lines expressing antiviral gene constructs were inoculated with high doses of HIV-1HXB3 in the presence or absence of inhibitors. The combination of RevM10 or Gag antisense RNA with antiviral drugs inhibited HIV-1 replication 10-fold more effectively than the single antiviral drug regimen alone. More importantly, we also addressed whether gene therapy strategies are effective against drug-resistant HIV-1 isolates. Both the RevM10 and Gag antisense RNA strategies showed antiviral efficacy against several RT inhibitor-resistant HIV-1 isolates equivalent to their inhibition of HIV-1HXB3 replication. In summary, our data demonstrate the greater than additive antiviral efficacy of gene therapy strategies and RT or PR inhibitors, and that gene therapy approaches are effective against drug-resistant HIV-1 viral isolates.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Cell Line; Combined Modality Therapy; DNA, Recombinant; Dose-Response Relationship, Drug; Gene Products, gag; Gene Products, rev; Genetic Therapy; Genetic Vectors; Genome, Viral; HIV Core Protein p24; HIV-1; Humans; Indinavir; rev Gene Products, Human Immunodeficiency Virus; RNA, Antisense; T-Lymphocytes; Zalcitabine; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; RNA, Viral; Viral Load; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; United States; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Brazil; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Indinavir; Zidovudine

Although a safety review board stopped ACTG 320 before its completion, the study showed that a three-drug combination could cut the mortality rate from AIDS in half. Study participants who were taking two nucleoside analog drugs were also given a protease inhibitor, and they developed half as many opportunistic infections as those on only two drugs. However, the study also showed that simply adding a protease inhibitor to a treatment regimen that was not working was not effective. The results of ACTG 320 show that the era of monotherapy is over, and that strong anti-HIV combinations designed to reduce viral load to undetectable levels is the preferred treatment.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Indinavir; Male; Patient Selection; United States; Zidovudine

A case study is presented of a 27-year-old male, in the late stages of AIDS, who benefitted from recent advances in HIV therapy. During recovery from his fourth episode of pneumocystis pneumonia and newly-diagnosed disseminated Mycobacterium avium (MAC) infection, he agreed to take antiretrovirals. He received treatment with indinavir, Epivir, and stavudine, and then had stavudine replaced with AZT due to adverse effects. He also received treatment for MAC. His diarrhea and fevers disappeared, his appetite returned, and he gained 50 pounds. A tinea infection on his back and face resolved, as did persistent oral candidiasis. Although HIV myelitis was suspected during treatment, it stabilized, or even improved. The patient became discouraged when his viral load rose from 2,100 to 5,700, and trying to make him understand that his initial loads were probably near a million copies did not reassure him. Referral to a clinical psychologist seemed to help, and he continues to do well on therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Counseling; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Mycobacterium avium-intracellulare Infection; Pneumonia, Pneumocystis; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; Zidovudine

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

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; HIV; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; RNA, Viral; Thiazoles; Valine; Viremia

Topics: Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Chemistry, Pharmaceutical; Controlled Clinical Trials as Topic; Drug Approval; Drug Design; Drug Industry; HIV; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; Thiazoles; United States; United States Food and Drug Administration; Valine

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Drug Therapy, Combination; Health Education; Humans; Indinavir; Lamivudine; Pyridines; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; HIV Protease Inhibitors; Humans; Indinavir; United States; United States Food and Drug Administration

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

The PWA Health Group, an AIDS buyers' club, is asking the Food and Drug Administration (FDA) to require Merck and Abbott to obtain long-term follow-up data of their drugs, indinavir and ritonavir. To obtain this information, clinical trial participants should be allowed to continue their treatment in long-term follow-up studies. Unless the FDA requires these studies, the companies could refuse to provide free drugs once they are available on the market. Call the PWA Health Group to sign the consensus letter.

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; Thiazoles; United States Food and Drug Administration; Valine

Ritonavir, a protease inhibitor, demonstrated strong antiviral activity when combined with AZT and ddC at dosage levels of 1200, 600 and 2.25 mg respectively. Six-month therapy resulted in a median CD4 count increase that was nearly double from baseline, and significant viral load reductions that were sustained throughout the study. Ritonavir was generally well tolerated. A study using AZT and 3TC with an experimental protease inhibitor, indinavir, also greatly reduced viral loads. The effects lasted throughout the six-month treatment period. A specific HIV protease gene that contributes to the emergence of resistance during treatment with ritonavir has also been identified.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Pyridines; Ritonavir; Thiazoles; Valine; Zalcitabine; Zidovudine

Merck's protease inhibitor, indinavir, has received Food and Drug Administration (FDA) approval, and is being made available under a temporary distribution system through Stadtlander's Pharmacy. Indinavir's price is significantly lower than the other FDA-approved protease inhibitors. Indinavir studies found viral load decreases and improvements in CD4 counts in patients. The drug must be taken consistently at 8-hour intervals. Detailed instructions for use and warnings of potential drug interactions are included on the package insert. A shortage in supply is expected through the end of 1996, when new manufacturing facilities are opened. Patients are advised not to discontinue treatments once indinavir therapy has begun. Merck has established a tracking system to ensure that current users will have refills available.

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; Drug Costs; HIV Protease Inhibitors; Humans; Indinavir; Pyridines

Educating patients who use protease inhibitors is essential. Both indinavir (Crixivan) and ritonavir (Norvir) interact with other drugs, and patients need to be aware of their adverse effects. Another concern is that improper use of these drugs may cause viral resistance, which would decrease future effectiveness in all patients. Both indinavir and ritonavir seem most effective when used in combination with other drugs. Further study is needed to determine which combinations and dosages are most effective. Patients are urged to delay protease inhibitor therapy until more information is available on safety and effectiveness.

Topics: Acquired Immunodeficiency Syndrome; Drug Interactions; Drug Resistance, Microbial; HIV; HIV Protease Inhibitors; Humans; Indinavir; Patient Education as Topic; Pyridines; Ritonavir; Thiazoles; Valine

Topics: Acquired Immunodeficiency Syndrome; Delivery of Health Care; Drug Industry; Economics; Health Care Rationing; HIV Seropositivity; Humans; Indinavir; Patient Care; Pharmaceutical Preparations; Pharmacists; Resource Allocation; United States

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Pyridines; Quinolines; Ritonavir; Saquinavir; Thiazoles; United States; United States Food and Drug Administration; Valine

Analysis of mutational effects in the human immunodeficiency virus type-1 (HIV-1) provirus has revealed that as few as four amino acid side-chain substitutions in the HIV-1 protease (M46I/L63P/V82T/I84V) suffice to yield viral variants cross-resistant to a panel of protease inhibitors either in or being considered for clinical trials (Condra, J. H., Schleif, W. A., Blahy, O. M., Gadryelski, L. J., Graham, D. J., Quintero, J. C., Rhodes, A., Robbins, H. L., Roth, E., Shivaprakash, M., Titus, D., Yang, T., Teppler, H., Squires, K. E., Deutsch, P. J., and Emini, E. A. (1995) Nature 374, 569-571). As an initial effort toward elucidation of the molecular mechanism of drug resistance in AIDS therapies, the three-dimensional structure of the HIV-1 protease mutant containing the four substitutions has been determined to 2.4-A resolution with an R factor of 17.1%. The structure of its complex with MK639, a protease inhibitor of the hydroxyaminopentane amide class of peptidomimetics currently in Phase III clinical trials, has been resolved at 2.0 A with an R factor of 17.0%. These structures are compared with those of the wild-type enzyme and its complex with MK639 (Chen, Z., Li, Y., Chen, E., Hall, D. L., Darke, P. L., Culberson, C., Shafer, J., and Kuo, L. C. (1994) J. Biol. Chem. 269, 26344-26348). There is no gross structural alteration of the protease due to the site-specific mutations. The C alpha tracings of the two native structures are identical with a root-mean-square deviation of 0.5 A, and the four substituted side chains are clearly revealed in the electron density map. In the MK639-bound form, the V82T substitution introduces an unfavorable hydrophilic moiety for binding in the active site and the I84V substitution creates a cavity (unoccupied by water) that should lead to a decrease in van der Waals contacts with the inhibitor. These changes are consistent with the observed 70-fold increase in the Ki value (approximately 2.5 kcal/mol) for MK639 as a result of the mutations in the HIV-1 protease. The role of the M46I and L63P substitutions in drug resistance is not obvious from the crystallographic data, but they induce conformational perturbations (0.9-1.1 A) in the flap domain of the native enzyme and may affect the stability and/or activity of the enzyme unrelated directly to binding.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Base Sequence; Binding Sites; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Crystallography, X-Ray; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Mutagenesis, Site-Directed; Point Mutation; Protein Conformation; Pyridines; Recombinant Proteins; Software

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Agents; Drug Approval; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Sarcoma, Kaposi; United States; United States Food and Drug Administration

Three key questions were addressed at the February 23-24 meeting of the National Task Force on AIDS Drugs Development: 1) what can be done to accelerate approval of the protease inhibitors, 2) can enough drug be obtained from the manufacturing process to permit expanded access programs without limiting the supply needed for phase III clinical trials, and 3) how can trials be structured to verify that positive effects on viral load (if demonstrated) will result in a measurable delay in clinical progression? While several AIDS organizations signed a consensus statement urging Abbott, Merck, and Hoffmann-La Roche to file for accelerated approval of their protease inhibitors by the second quarter of 1995, the companies are unlikely to meet that goal. However, Roche and Merck do confirm accelerated plans using U.S.-Canadian and European trials for data. Supply has largely been a problem of production lead times, but improved techniques are beginning to cut production time, as evidenced by the reduction of Roche's saquinavir production by eight months. Other manufacturers are not as aggressive in their approaches to supply. David Kessler, commissioner of the Food and Drug Administration (FDA), promised to pursue the accelerated processes to gain more access to these drugs. Meeting participants offered no easy solution on how to plan trials that will confirm clinical benefit after a drug wins accelerated approval; all agreed, however, that phase III trials or postapproval studies must be mounted to demonstrate a drug's effectiveness following approval.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Drug Approval; Drug Design; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Pyridines; Treatment Outcome; United States; United States Food and Drug Administration; Zalcitabine; Zidovudine

Hoffmann-La Roche has announced details of the Invirase International Compassionate Treatment Program, which will distribute saquinavir (brand name, Invirase), a protease inhibitor. Saquinavir will be made available to 2,280 U.S. patients with a CD4 (T-helper) count under 300 who no longer benefit from approved antiretroviral drugs (AZT, ddI, ddC, and d4T), and who meet other criteria. Sixty percent of the slots will be reserved for persons with a T-helper count under fifty. In addition, Roche has set up a lottery in case more people apply for the drug. Physicians must enter their patients by July 21, 1995. The author notes, however, that previous data on saquinavir at the suggested dosage levels to be used in this program have not been significant. The drug appears to be safe and effective, but at larger doses. Roche may make saquinavir a better drug by using new data to show doctors how to use it more effectively. There are concerns that patients using saquinavir alone are more likely to develop resistance to it, which means they may not be able to benefit from future protease inhibitors. However, Roche claims that new data shows that saquinavir does not cause resistance to other protease inhibitors, and that the development of resistance to saquinavir itself can be reduced by using it in combination with AZT.

Topics: Acquired Immunodeficiency Syndrome; Australia; Canada; CD4 Lymphocyte Count; Drug Industry; Drug Resistance, Microbial; Europe; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Patient Selection; Pyridines; Quinolines; Saquinavir; United States

Merck & Co. has announced an expanded-access program to make Crixivan (generic name, indinavir sulfate), its experimental protease inhibitor, available to persons with a CD4 (T-helper) count of 50 or below. The new program will allow 1,100 people in the U.S. and 650 people from other countries to obtain the drug, formerly known as MK-639 and L-735,524. U.S. participants must register by August 11, 1995; those registered after that date will be placed on a waiting list. To be eligible, participants must have a CD4 count less than 50, be at least 18 years old, cannot have hepatitis, and cannot be pregnant or breastfeeding. Required laboratory tests, paid for by Merck, will fulfill additional entry criteria. Patients are allowed to combine the Crixivan with most other drugs. Patients in the open-label study will be treated by their own doctors.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Industry; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Patient Selection; Pyridines; United States

A controversy has developed, initiated by a paper in the April 1995 issue of Nature, over the use of protease inhibitors among AIDS patients. The article, written by Jon Condra and Emilio Emini, reported that HIV developed resistance to indinavir (Merck & Co.'s protease inhibitor), and all other protease inhibitors as well. In response to the study on Merck's product, Roche released information suggesting that their protease inhibitor, saquinavir, does not cause resistance nearly as quickly or as much. Merck is currently studying the combination of indinavir and AZT, and Abbott Laboratories is examining the effects of AZT, ddC, and ritonavir. These studies imply that optimal multi-drug combination therapy should delay drug resistance as well as cross-resistance. The implications are promising for patients with HIV and AIDS. Pharmaceutical companies are conducting additional studies to develop new reverse transcriptase inhibitors and to determine the effectiveness of the combination of two or more protease inhibitors. Each drug trial demonstrates the relationship between dosing and resistance; patients are advised to adhere completely to dosing instructions.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Carbamates; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Lamivudine; Nelfinavir; Pyridines; Quinolines; Saquinavir; Sulfonamides; Zalcitabine; Zidovudine

Hoffman LaRoche and Merck have agreed to expand enrollment in their Invirase and Crixivan programs if the drug availability increases. The Roche program offers Invirase to HIV-positive individuals with CD4 cell counts under 300. The Merck program provides Crixivan to people with AIDS who have fifty or fewer CD4 cells. Originally, both programs were open only to individuals who were intolerant to, or had failed, standard treatments for HIV infection.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Drug Industry; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Pyridines; Quinolines; Random Allocation; Saquinavir