ritonavir and Acquired-Immunodeficiency-Syndrome

AIDS is one of the world's most serious public health challenges. Protease inhibitors are key components of AIDS treatment regimen. Ritonavir is a well-known protease inhibitor with low aqueous solubility belonging to BCS class II category. Some of the severe adverse effects associated with this drug restricted its use in the treatment of AIDS. However, several attempts were made by researchers in the past to enhance the oral bioavailability of Ritonavir.. The current review mainly focuses on the adverse effects of Ritonavir and recent approaches followed by researchers on the development of nanoformulations of Ritonavir. Further, various patents filed on Ritonavir have also been discussed in the current review.. Most research on nanoformulation development for Ritonavir is mainly focused on enhancing the solubility and oral bioavailability of the drug. Some of the researchers focused on the lymphatic targeting of the drug in order to bypass the hepatic metabolism of the drug. However, most of the research topics did not cover the toxicity evaluation of the developed formulation. Since the major issue of Ritonavir is not only oral bioavailability but also drug-induced toxicity, this area needs to be considered during the formulation development.

Topics: Acquired Immunodeficiency Syndrome; HIV Infections; HIV Protease Inhibitors; Humans; Ritonavir; Solubility

Selection of optimal second-line antiretroviral therapy (ART) has important clinical and programmatic implications. To inform the 2016 revision of the WHO ART guidelines, we assessed the comparative effectiveness and safety of available second-line ART regimens for adults and adolescents in whom first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens have failed.. In this systematic review and network meta-analysis, we searched for randomised controlled trials and prospective and retrospective cohort studies that evaluated outcomes in treatment-experienced adults living with HIV who switched ART regimen after failure of a WHO-recommended first-line NNRTI-based regimen. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials for reports published from Jan 1, 1996, to Aug 8, 2016, and searched conference abstracts published from Jan 1, 2014, to Aug 8, 2016. Outcomes of interest were viral suppression, mortality, AIDS-defining illnesses or WHO stage 3-4 disease, discontinuations, discontinuations due to adverse events, and serious adverse events. We assessed comparative efficacy and safety in a network meta-analysis, using Bayesian hierarchical models.. We identified 12 papers pertaining to eight studies, including 4778 participants. The network was centred on ritonavir-boosted lopinavir plus two nucleoside or nucleotide reverse transcriptase inhibitors. Ritonavir-boosted lopinavir monotherapy was the only regimen inferior to others. With the lower estimate of the 95% credible interval (CrI) not exceeding the predefined threshold of 15%, evidence at 48 weeks supported the non-inferiority of ritonavir-boosted lopinavir plus raltegravir to regimens including ritonavir-boosted protease inhibitor plus two NRTIs with respect to viral suppression (odds ratio 1·09, 95% CrI 0·88-1·35). Estimated efficacy of ritonavir-boosted darunavir (800 mg once daily) was too imprecise to determine non-inferiority. Overall, regimens did not differ significantly with respect to continuations, AIDS-defining illnesses or WHO stage 3-4 disease, or mortality.. With the exception of ritonavir-boosted lopinavir plus raltegravir, the evidence base is unable to provide strong support to alternative second-line options to ritonavir-boosted protease inhibitor plus two NRTIs, and thus more trials are warranted.. WHO.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Network Meta-Analysis; Prospective Studies; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir

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

Atazanavir is a selective and potent inhibitor of the HIV-1 protease. The drug is administered in combination with low-dose ritonavir, to boost atazanavir pharmacokinetics (i.e. ritonavir-boosted atazanavir), and other antiretroviral agents. The efficacy of once-daily ritonavir-boosted atazanavir plus background therapy (BT) in establishing virologic suppression in treatment-naive pediatric patients (aged 6 to <18 years) infected with HIV-1 was demonstrated in an ongoing, open-label, multicenter, phase I/II trial (PACTG 1020A). HIV-1 RNA levels of <50 or <400 copies/mL were achieved by the majority of patients (>70%) after 24 weeks' therapy, with these benefits maintained at week 48. Some treatment-experienced pediatric patients (aged 6 to <18 years) also achieved HIV-1 RNA levels of <50 or <400 copies/mL in the PACTG 1020A trial after 24 (≤45% of patients) and 48 (≤32%) weeks of treatment with ritonavir-boosted atazanavir plus BT, although the benefits of the regimen in this patient population appeared to be limited by as few as one or two protease inhibitor resistance mutations. Treatment-experienced pediatric patients (aged 10-19 years) infected with HIV-1 had mixed success in establishing/maintaining virologic suppression when they were switched from their current antiretroviral treatment regimen to once-daily ritonavir-boosted atazanavir plus BT in a small, single-center, observational study. However, some patients may have received atazanavir at a suboptimal dosage or had suboptimal susceptibility to BT agents. In the PACTG 1020A trial, use of atazanavir (with or without ritonavir) in pediatric patients aged 6 to <18 years was associated with a similar safety profile to that reported in adults.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Area Under Curve; Atazanavir Sulfate; Child; Clinical Trials as Topic; Drug Administration Schedule; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; HIV Protease Inhibitors; HIV-1; Humans; Multicenter Studies as Topic; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome; Viral Load; Young Adult

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Androstadienes; Bronchodilator Agents; Cushing Syndrome; Drug Interactions; Female; Fluticasone; Glucocorticoids; HIV Protease Inhibitors; Humans; Ritonavir

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

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

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Aryl Hydrocarbon Hydroxylases; Bundle-Branch Block; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Inhibitors; Heart; Heart Block; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Oxidoreductases, N-Demethylating; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Syncope; Zidovudine

The use of highly active antiretroviral therapy, the combination of at least three different antiretroviral drugs for the treatment of HIV-1 infection, has greatly improved the prognosis for HIV-1-infected patients. The efficacy of a combination of a protease inhibitor (PI) plus two nucleoside analogue reverse transcriptase inhibitors has been well established over a period of up to 3 years. However, virological treatment failure has been reported in 40-60% of unselected patients within 1 year after initiation of a PI-containing regimen. This observation may, at least in part, be attributed to the poor pharmacokinetic characteristics of the PIs. Given as a single agent the PIs have several pharmacokinetic limitations; relatively short plasma-elimination half-lives and a modest and variable oral bioavailability, which is, for some of the PIs, influenced by food. To overcome these suboptimal pharmacokinetics, high doses (requiring large numbers of pills) must be ingested, often with food restrictions, which complicates patient adherence to the prescribed regimen. Positive drug-drug interactions increase the exposure to the PIs, allowing administration of lower doses at reduced dosing frequencies with less dietary restrictions. In addition to increasing the potency of an antiretroviral regimen, combinations of PIs may enhance patient adherence, both of which will contribute to a more durable suppression of viral replication. The favourable pharmacokinetics of PIs in combination are a result of interactions through cytochrome P450 3A4 (CYP3A4) isoenzymes and, possibly, the multi-drug transporting P-glycoprotein (P-gp). Antiretroviral synergy between PIs and non-overlapping primary resistance patterns in the HIV-1 protease genome may further enhance the antiretroviral potency and durability of combinations of PIs. Many combinations contain ritonavir because this PI has the most pronounced inhibiting effects on CYP3A4. The combination of saquinavir and ritonavir, both in a dose of 400 mg twice-a-day, is the most studied double PI combination, with clinical experience extending over 3 years. Combination of a PI with a low dose of ritonavir (< or = 400 mg/day), only to boost its pharmacokinetic properties, seems an attractive option for patients who cannot tolerate higher doses of ritonavir. A recently introduced PI, lopinavir, has been co-formulated with low-dose ritonavir, which allows for a convenient three-capsules, twice-a-day dosing regimen. In an attempt t

Topics: Acquired Immunodeficiency Syndrome; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Monitoring; Drug Resistance, Viral; Drug Therapy, Combination; HIV Protease Inhibitors; HIV-1; Humans; Mixed Function Oxygenases; Ritonavir

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; Alprazolam; Animals; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; HIV Protease Inhibitors; Humans; Hypnotics and Sedatives; Metabolic Clearance Rate; Microsomes, Liver; Oxidoreductases, N-Demethylating; Ritonavir; Triazolam

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

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

AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized.. Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV.. Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV.. The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.

Topics: 2-Naphthylamine; Acquired Immunodeficiency Syndrome; Adult; Anilides; Antiviral Agents; Coinfection; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Raltegravir Potassium; Ritonavir; Sulfonamides; Uracil; Valine

Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection.. We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S.. Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4.. We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.

Topics: 2-Naphthylamine; Acquired Immunodeficiency Syndrome; Adult; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Female; Hepatitis C, Chronic; Humans; Kinetics; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; United States; Uracil; Valine; Viral Load

To access the costs of care for Ivoirian children before and after initiating LPV/r-based antiretroviral therapy (ART) before the age of two.. We assessed the direct costs of care for all HIV-infected children over the first 12 months on LPV/r-based ART initiated <2 years of age in Abidjan. We recorded all drug prescriptions, ART and cotrimoxazole prophylaxis delivery, medical analyses/examinations and hospital admissions. We compared these costs to those accrued in the month prior to ART initiation. Costs and 95% confidence intervals (95%CI) were estimated per child-month, according to severe morbidity.. Of the 114 children screened, 99 initiated LPV/r-based ART at a median age of 13.5 months (IQR: 6.8-18.6); 45% had reached World Health Organization stage 3 or 4. During the first 12 months on ART, 5% died and 3% were lost to follow-up. In the month before ART initiation, the mean cost of care per child-month reached $123.39 (95%CI:$121.02-$125.74). After ART initiation, it was $42.53 (95%CI:$42.15-$42.91); 50% were ART costs. The remaining costs were non-antiretroviral drugs (18%) and medical analyses/examinations (14%). Mean costs were significantly higher within the first three months on ART ($48.76, 95%CI:$47.95-$49.56) and in children experiencing severe morbidity ($49.76, 95%CI:$48.61-50.90).. ART reduces the overall monthly cost of care of HIV-infected children < 2 years. Because children were treated at an advanced HIV disease stage, the additional costs of treating severe morbidity on ART remain substantial. Strategies for treating HIV-infected children as early as possible must remain a priority in Côte d'Ivoire.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Cote d'Ivoire; Female; Follow-Up Studies; Health Care Costs; HIV Infections; Humans; Infant; Lopinavir; Lost to Follow-Up; Male; Outcome Assessment, Health Care; Prospective Studies; Ritonavir; Survival Rate

Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202.. Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms.. Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10).. Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Creatinine; Cyclopropanes; Dideoxynucleosides; Female; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Ritonavir; Tenofovir

Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.. Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available.. Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance.. Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Bilirubin; Female; Genome-Wide Association Study; Glucuronosyltransferase; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Male; Middle Aged; Multivariate Analysis; Oligopeptides; Polymorphism, Single Nucleotide; Prospective Studies; Pyridines; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Atazanavir Sulfate; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; Guideline Adherence; HIV Infections; HIV Protease Inhibitors; Humans; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P < 0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL, and COXIV were significantly down-regulated in the EFV arm compared to the LPV/r arm (P < 0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms and between CEBP/A or COXIV change and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial [LIPOTAR study] registered at ClinicalTrials.gov under identifier NCT00759070.).

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adipogenesis; Adiponectin; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Body Composition; CCAAT-Enhancer-Binding Proteins; Cyclopropanes; Deoxycytidine; Drug Combinations; Emtricitabine; Energy Metabolism; Female; Gene Expression; Glucose; Glucose Transporter Type 4; HIV-1; Humans; Inflammation; Lipid Metabolism; Lipoprotein Lipase; Lopinavir; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Ritonavir; Subcutaneous Fat; Tenofovir

Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants.. At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms.. Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons.. With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.

Topics: Acquired Immunodeficiency Syndrome; Adult; Female; Genetic Association Studies; HIV Protease Inhibitors; Humans; Linkage Disequilibrium; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Ritonavir

To assess the cost-effectiveness of etravirine (INTELENCE), a novel nonnucleoside reverse transcriptase inhibitor, used in combination with a background regimen that included darunavir/ritonavir, from a Canadian Provincial Ministry of Health perspective.. A Markov model with a 3-month cycle time and six health states based on CD4 cell count ranges was developed to follow a hypothetical cohort of treatment-experienced adults with HIV-1 infection through initial and subsequent treatment regimens.. Costs (in 2009 Canadian dollars), utilities, and HIV-related mortality data for each health state as well as non-HIV-related mortality data were estimated from Canadian sources and published literature. Transition probabilities between health states and first-year hospitalization and mortality rates were derived from clinical trial data. Incremental 1-year costs per additional adult with viral load less than 50 copies/ml at 48 weeks and incremental lifetime costs per quality-adjusted life-year (QALY) gained were estimated using a 5% discount rate. Sensitivity and variability analyses and model validation were performed.. Etravirine was associated with an increased probability of achieving less than 50 copies/ml at 48 weeks of 0.205 and an estimated gain of 0.66 discounted (1.48 undiscounted) QALYs over a lifetime. The incremental 1-year cost per additional person with viral load less than 50 copies/ml was $23,862. The lifetime incremental cost per QALY gained was $49,120. For the uncertainty ranges and variability scenarios tested for the lifetime horizon, the cost-effectiveness ratio was between $28,859 and 66,249.. When compared with optimized standard of care including darunavir/ritonavir, adding etravirine represents a cost-effective option for treatment-experienced adults in Canada.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Canada; CD4 Lymphocyte Count; Cost-Benefit Analysis; Darunavir; Double-Blind Method; Drug Therapy, Combination; Female; HIV-1; Humans; Male; Markov Chains; Middle Aged; Models, Economic; Nitriles; Pyridazines; Pyrimidines; Quality-Adjusted Life Years; Ritonavir; Sulfonamides; Viral Load; Young Adult

To compare 48-week changes in body fat distribution and bone mineral density (BMD) between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r.. Substudy of the prospective, randomized, open-label, multicenter SPIRAL study.. Patients were randomized (1 : 1) to continue with the PI/r-based regimen or switch to RAL, maintaining the rest of the treatment unchanged. Dual-energy X-ray absorptiometry and computed tomography scans were performed at baseline and after 48 weeks to measure body fat and bone composition, analyzing intragroup and intergroup differences.. Eighty-six patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy. Significant increases in median [interquartile range (IQR)] visceral adipose tissue (VAT) [20.7 (-2.4 to 45.6) cm(2), P = 0.002] and total adipose tissue (TAT) [21.4 (-1.3 to 55.4) cm(2), P = 0.013] were seen within the PI/r group. No significant changes in body fat were seen with RAL or between treatment groups. Regarding bone composition, total BMD [0.01 (0 to 0.02) g/cm(2), P = 0.002], total hip BMD [0.01 (0 to 0.03) g/cm(2), P = 0.015] and total hip T score [0.12 (-0.05 to 0.21) SD, P = 0.004] significantly increased with RAL, with no significant changes within the PI/r group. Differences between treatment groups were significant in femoral neck BMD [0.01 (-0.02 to 0.02) g/cm(2), P = 0.032] and T score [0.01 (-0.18 to 0.18) SD, P = 0.016].. Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT. Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups.

Topics: Absorptiometry, Photon; Acquired Immunodeficiency Syndrome; Adipose Tissue; Adult; Anti-HIV Agents; Body Composition; Body Fat Distribution; Bone Density; Female; Femur Neck; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Tomography, X-Ray Computed; Treatment Outcome

The GRACE (Gender, Race and Clinical Experience) trial enrolled treatment-experienced, HIV-1-infected patients, mainly women, in North America, to assess outcomes with a darunavir/ritonavir-based regimen, which could include etravirine (ETR). We present outcomes at week 48 for men and women receiving ETR. Virologic response (HIV-1 RNA <50 copies/ml) and safety were assessed; descriptive statistics are reported. To evaluate the independent contribution of ETR treatment, a post hoc analysis including a multivariate model assessed factors predictive of virologic response for the entire GRACE population (429 patients). Of 207 patients who received ETR (women, 57.5%; black or Hispanic, 81.7%), 71.4% of women and 79.5% of men completed the study. Week 48 virologic response rates in women and men (intent-to-treat population) were 58.0% and 61.4%, respectively. After censoring patients who discontinued treatment for reasons other than virologic failure, response rates were 79.3% and 73.0%, respectively. Overall, ETR was well tolerated. Women experienced more nausea (24.4% vs. 11.4%) and rash-related events (21.0% vs. 15.9%), but less diarrhea (15.1% vs. 21.6%), compared with men. Grade 3-4 hypertriglyceridemia was more common in men (9.3%) than women (1.1%). In total, 11 (9.2%) women and 7 (8.0%) men discontinued ETR due to adverse events. In the multivariate model of the entire GRACE population, ETR use was independently associated with improved virologic response. ETR is effective and well tolerated in treatment-experienced patients with HIV-1, with similar outcomes among women and men.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; Female; HIV Protease Inhibitors; HIV-1; Humans; Male; Nitriles; North America; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Sex Distribution; Sex Factors; Sulfonamides; Treatment Outcome; Viral Load

We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4(+) cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, -0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Atazanavir Sulfate; Biomarkers; CD4 Lymphocyte Count; Darunavir; Disease Progression; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Glomerular Filtration Rate; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Oligopeptides; Pilot Projects; Pyridines; Ritonavir; RNA, Viral; Sulfonamides; Time Factors; Treatment Outcome; Viral Load; Young Adult

A nucleoside reverse transcriptase inhibitor (NRTI) backbone is a recommended component of standard highly active antiretroviral therapy (sHAART). However, long-term NRTI exposure can be limited by toxicities. NRTI class-sparing alternatives are warranted in select patient populations. This is a 48-week single-center, open-label pilot study in which 60 HIV-infected adults with plasma HIV-1 RNA (<50 copies/ml) on sHAART were randomized (2:1) to lopinavir/ritonavir (LPV/r) 400/100 mg BID+raltegravir (RAL) 400 mg BID switch (LPV-r/RAL arm) or to continue on sHAART. The primary endpoint was the proportion of subjects with HIV-RNA<50 copies/ml at week 48. Secondary efficacy and immunologic and safety endpoints were evaluated. Demographics and baseline lipid profile were similar across arms. Mean entry CD4 T cell count was 493 cells/mm(3). At week 48, 92% [95% confidence interval (CI): 83-100%] of the LPV-r/RAL arm and 88% (95% CI: 75-100%) of the sHAART arm had HIV-RNA<50 copies/ml (p=0.70). Lipid profile (mean ± SEM, mg/dl, LPV-r/RAL vs. sHAART) at week 24 was total-cholesterol 194 ± 5 vs. 176 ± 9 (p=0.07), triglycerides 234 ± 30 vs. 133 ± 27 (p=0.003), and LDL-cholesterol 121 ± 6 vs. 110 ± 8 (p=0.27). There were no serious adverse events (AEs) in either arm. Regimen change occurred in three LPV-r/RAL subjects (n=1, due to LPV-r/RAL-related AEs) vs. 0 in sHAART. There were no differences between arms in bone mineral density, total body fat composition, creatinine clearance, or CD4 T cell counts at week 48. In virologically suppressed patients on HAART, switching therapy to the NRTI-sparing LPV-r/RAL combination produced similar sustained virologic suppression and immunologic profile as sHAART. AEs were comparable between arms, but the LPV-r/RAL arm experienced higher triglyceridemia.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

CASTLE was a randomized 96-week study that demonstrated that atazanavir/ritonavir (ATV/r) was noninferior to lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-infected patients. Analyses were carried out among patients who received ATV/r in the CASTLE study to better understand the clinical significance of unconjugated hyperbilirubinemia associated with administration of boosted ATV. Hyperbilirubinemia was defined as total bilirubin (conjugated and unconjugated) elevation greater than 2.5 times the upper limit of normal (grade 3-4). Patients in the ATV/r arm were assessed based on the presence or absence of hyperbilirubinemia through week 96. Analyses included number of confirmed virologic responders (CVR; HIV RNA<50 copies per milliliter), impact of hyperbilirubinemia on symptoms, elevations in liver enzymes, patient quality of life, and medication adherence. Through 96 weeks in the CASTLE study, 44% of patients who received ATV/r had hyperbilirubinemia at any time point, and between 12.5% and 21.6% had hyperbilirubinemia at any single study visit. At 96 weeks, 74% of patients overall and 84% and 69% of patients with and without hyperbilirubinemia, respectively, achieved CVR. Symptoms of jaundice or scleral icterus occurred in 5% of patients overall and in 11% with hyperbilirubinemia and 0% without hyperbilirubinemia. Four percent of patients with and 3% of patients without hyperbilirubinemia had grade 3-4 elevations in liver transaminases. Less than 1% of patients discontinued treatment due to hyperbilirubinemia. There were no differences in quality of life or adherence between patients with or without hyperbilirubinemia. In the CASTLE study, hyperbilirubinemia observed in the ATV/r group did not negatively impact clinical outcomes in HIV-infected patients.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Atazanavir Sulfate; Female; HIV-1; Humans; Hyperbilirubinemia; Lopinavir; Male; Medication Adherence; Oligopeptides; Pyridines; Quality of Life; Ritonavir; Surveys and Questionnaires

In the MONotherapy in Europe with Tmc114 (MONET) trial, darunavir/ritonavir (DRV/r) monotherapy showed noninferior efficacy vs. two nucleoside reverse transcriptase inhibitors (NRTIs) plus DRV/r at the primary 48-week analysis. The trial was continued to week 144 to assess the durability of the results.. A total of 256 patients with viral load < 50 HIV-1 RNA copies/mL on current highly active antiretroviral therapy (HAART) for at least 6 months switched to DRV/r 800/100 mg once daily, either as monotherapy (n=127) or with two NRTIs (n=129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/mL [time to loss of virological response (TLOVR)] by week 144, or discontinuation of study drugs.. Eighty-one per cent of patients were male and 91% were Caucasian, and they had a median baseline CD4 count of 575 cells/uL. More patients in the DRV/r monotherapy arm had hepatitis C virus coinfection at baseline than in the control arm (18% vs. 12%, respectively). By week 144, the percentage of patients with HIV RNA < 50 copies/mL [intent to treat (ITT), TLOVR, switch=failure method] was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference= -5.9%; 95% confidence interval (CI) -16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), the percentage of patients with HIV RNA < 50 copies/mL was 84% vs. 83.5%, respectively (difference= +0.5%; 95% CI -8.7%, +9.7%). Twenty-one and 13 patients had two consecutive HIV RNA results above 50 copies/mL in the DRV/r monotherapy arm and triple therapy arm, respectively, of whom 18 of 21 (86%) and 10 of 13 (77%) had HIV RNA < 50 copies/mL at week 144.. In this study, for patients with HIV RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed noninferior efficacy to DRV/r plus two NRTIs in a strict ITT (switches not considered failures) analysis, but not in a TLOVR switch equals failure analysis.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; CD4 Lymphocyte Count; Darunavir; Drug Administration Schedule; Female; HIV Protease Inhibitors; HIV-1; Humans; Male; Medication Adherence; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sulfonamides; Surveys and Questionnaires; Treatment Outcome; Viral Load

Sustained antiretroviral therapy (ART)-mediated viral suppression restores responses to vaccination in HIV-1-infected individuals. As ART interruption occur frequently in resource-constrained settings, we studied their effects on the ability to mount humoral immune responses against a neoantigen.. Treatment-naive HIV-1-infected individuals were treated with stavudine, lamuvidine and lopinavir/ritonovir. Individuals who maintained viral load less than 50  copies/ml and CD4 T-cell counts more than 450  cells/μl for 6 months received three doses of rabies vaccine, and were randomized to 72 weeks of continuous ART (arm 1) or sequential 2, 4 and 8-week ART interruptions (arm 2). An additional vaccine dose was administered at study end.. Neutralizing antibody titers to rabies virus were assessed in plasma with a rapid fluorescent focus-inhibiting test.. The proportion of participants achieving protective (>0.5 IU/ml) antibody titer after vaccination was similar (arm 1=92%; arm 2=91%), but over time the cumulative proportion of observations with protective titer was greater in arm 1 than arm 2 (P=0.0177). From week 26 after vaccination, antibody titers were lower in arm 2 than arm 1, and volunteers in arm 2 lost protective antibody titers at a greater rate (P=0.0029). After boosting, 100% of arm 1 and 95% arm 2 volunteers achieved protective antibody titer.. Our data indicate that individuals undergoing recurring ART interruption retain lower neutralizing antibody titers to a neoantigen, but maintain the ability to mount secondary responses upon boosting, suggesting that they might benefit from vaccine schedule intensification.

Topics: Acquired Immunodeficiency Syndrome; Adult; Africa South of the Sahara; Anti-HIV Agents; Antibodies, Neutralizing; Antigens, Viral; Autoantigens; CD4-Positive T-Lymphocytes; Drug Administration Schedule; Female; HIV-1; Humans; Immunity, Humoral; Lopinavir; Lymphocyte Activation; Male; Ritonavir; Stavudine; Viral Load

The effect of specific antiretrovirals on inflammation is unclear.. A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r.. Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/μl. TNF-α, soluble receptors of TNF-α (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P ≥ 0.44). At week 24, ABC/3TC had a greater high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Δ] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; Δ = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P ≥ 0.89).. Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Biomarkers; C-Reactive Protein; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; HIV-1; Humans; Inflammation; Interleukin-6; Lamivudine; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir; Tumor Necrosis Factor-alpha

No randomized study has prospectively followed subcutaneous adipose tissue mitochondrial DNA (mtDNA) changes when starting thymidine nucleoside reverse transcriptase inhibitors (tNRTIs).. The Metabolic Effects of DIfferent CLasses of AntiretroviralS study randomized HIV-positive, treatment-naive male participants to start lopinavir/ritonavir (LPVr) with either zidovudine/lamivudine (ZDV/3TC) or nevirapine (NVP).. Regional body fat was assessed by dual energy x-ray absorptiometry and abdominal computed tomography at months 0, 3, 12, 24 and 36. In a molecular substudy, subcutaneous adipose tissue (SAT) biopsies were taken, with mtDNA quantified by quantitative PCR. Data were analyzed using repeated measures linear regression analyses.. Of 50 participants recruited (23 to LPVr/ZDV/3TC), 48 started therapy, and 37 participants (19 on LPVr/ZDV/3TC) enrolled in the substudy. At 36 months, the LPVr/ZDV/3TC group had significantly lower limb fat [6.4 kg (0.26) versus 7.3 kg (0.31), P = 0.017] and a trend toward lower abdominal SAT compared to the LPVr/NVP group [131 cm (6.86) versus 146 cm (6.33), P = 0.097]. Over 36 months, mtDNA declined in the LPVr/ZDV/3TC group [mtDNA region 1: -190 (95) copies/cell, P = 0.053, region 2: -269 (106) copies/cell, P = 0.016] but not within the LPVr/NVP group [region 1: +28 (99) copies/cell, P = 0.78, region 2: +51 (111) copies/cell, P = 0.65, between-group difference P < 0.01 for both measurements]. mtDNA was significantly lower in the LPVr/ZDV/3TC group at 36 months.. This is the first randomized study to prospectively demonstrate reductions in SAT mtDNA in patients initiating ZDV/3TC-containing antiretroviral therapy (ART) but not in those initiating nucleoside reverse transcriptase inhibitor-sparing ART containing NVP and protease inhibitor. That reductions in SAT mtDNA were also accompanied by lower limb fat suggests that use of ART not containing ZDV/3TC may help prevent development of peripheral lipoatrophy.

Topics: Absorptiometry, Photon; Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Atrophy; CD4 Lymphocyte Count; DNA, Mitochondrial; Drug Combinations; Drug Therapy, Combination; HIV Seropositivity; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Subcutaneous Fat; Treatment Outcome; Young Adult; Zidovudine

The side-effects of anti-retroviral drugs are different between Japanese and Caucasian patients. Severe central nerve system (CNS) side-effects to efavirenz and low rate of hypersensitivity against abacavir characterize the Japanese.. The objective of this study was to select a once daily regimen for further non-inferior study comparing the virological efficacy and safety of the first line once daily antiretroviral treatment regimens in the current HIV/AIDS guideline.. The study design was a randomized, open label, multicenter, selection study. One arm was treated with efavirenz and the other with ritonavir-boosted atazanavir. A fixed-dose lamivudine plus abacavir were used in both arms. The primary endpoint was virologic success (viral load less than 50 copies/mL) rate at 48 weeks. Patients were followed-up to 96 weeks with safety as the secondary endpoint. Clinicaltrials.Gov (NCT00280969) and the University hospital Medical Information Network (UMIN000000243).. A total of 71 participants were enrolled. Virologic success rates in both arms were similar at week 48 [efavirenz arm 28/36 (77.8%); atazanavir arm 27/35 (77.1%)], but were decreased at week 96 to 55.6% in the efavirenz arm and 68.8% in the atazanavir arm (p=0.33). At the 96-week follow-up, 52.8% of the EFV arm and 34.3% of the ATV/r arm reached total cholesterol more than 220 mg/dL and required treatment. None of the patients developed cardiovascular complications in this study by week 96.. There was no significant difference in the efficacy of efavirenz and ritonavir-boosted atazanavir combined with lamivudine plus abacavir at 48 weeks. The evaluation of safety was extended to 96 weeks, which also showed no significant difference in both arms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alanine Transaminase; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cholesterol; Cyclopropanes; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Japan; Lamivudine; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings.. In the Republic of South Africa, antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals >14 years old with a CD4 cell count <200 cells/μL or a prior AIDS diagnosis were randomized to receive efavirenz (EFV) or lopinavir/ritonavir (LPV/r) with either zidovudine (ZDV) plus didanosine (ddI) or stavudine (d4T) plus lamivudine (3TC) in an open-label, 2-by-2 factorial study and followed up for the primary outcome of AIDS or death and prespecified secondary outcomes, including CD4 cell count and viral load changes, treatment discontinuation, and grade 4 events.. In total, 1771 persons were randomized and followed up for a median of 24.7 months. AIDS or death occurred in (1) 163 participants assigned EFV and 157 assigned LPV/r (hazard ratio [HR], 1.04 [95% confidence interval {CI}, 0.84-1.30]) and in (2) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC (HR, 1.15 [95% CI, 0.93-1.44]). HIV RNA levels were lower (P < .001) and CD4 cell counts were greater (P < .01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T because of toxicity (12.6%) than other treatments (<5%).. EFV and LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy.. ClinicalTrials.gov identifier: NCT00342355.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; South Africa; Stavudine; Treatment Outcome; Zidovudine

: Direct comparison of the efficacy and safety of different agents is needed to guide selection of optimal treatment regimens for therapy-naive HIV-1-infected patients.. : Gemini was a 48-week, multicenter, open-label, noninferiority trial in treatment-naive HIV-1-infected adults randomized to either saquinavir/ritonavir (SQV/r) 1000 mg/100 mg twice a day or lopinavir/ritonavir (LPV/r) 400 mg/100 mg twice a day, each with emtricitabine/tenofovir 200 mg/300 mg every day.. : A similar proportion of participants in the SQV/r (n = 167) and LPV/r (n = 170) arms had HIV-1 RNA levels <50 copies per milliliter at week 48: 64.7% vs 63.5% and estimated difference in proportion for noninferiority: 1.14%, 96% confidence interval: -9.6 to11.9 (P < 0.012), confirming that SQV/r was noninferior to LPV/r treatment. There were no significant differences in week 48 CD4 counts between arms. The rate and severity of adverse events were similar in both groups. There were no significant differences in the median change from baseline between arms in plasma lipids except for triglyceride levels, which were significantly higher in the LPV/r at week 48.. : In treatment-naive, HIV-1-infected patients, SQV/r treatment was noninferior in virologic suppression at 48 weeks to LPV/r treatment and offered a better triglyceride profile.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Saquinavir

The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC(50)s) to the study PI were high. Median 2-week VL changes were -0.7, -0.1, and -1.0 log(10) for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, -0.39 to -0.50; P < or = 0.029). The strongest correlation with response to FPV/r was the IC(50) FC (r = 0.57; P = 0.001), which improved when only adherent subjects were included (r = 0.68; P = 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P < 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r = -0.72; P < 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed.

Topics: Acquired Immunodeficiency Syndrome; Area Under Curve; Drug Resistance, Viral; Female; HIV Protease Inhibitors; HIV-1; Humans; Male; Phenotype; Predictive Value of Tests; Ritonavir; RNA, Viral

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Diarrhea; Drug Therapy, Combination; Glucose Tolerance Test; HIV Protease Inhibitors; Humans; Lopinavir; Nausea; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

One potential concern of once-daily protease inhibitor administration is low trough concentrations and ultimately the 'forgiveness' or robustness in comparison with the originally licensed twice-daily dose. To give an estimation of 'forgiveness', we determined the length of time plasma drug concentrations were below target in HIV-infected patients receiving saquinavir/ritonavir regimens.. Seventy-seven pharmacokinetic profiles (saquinavir/ritonavir 1000/100 mg twice daily, n = 34; 1600/100 mg once daily, n = 26; 2000/100 mg once daily, n = 17) from five studies were combined, presented as twice- and once-daily percentiles (P10-P90) and compared. At percentiles where trough concentrations fell below the alleged minimum effective concentration (MEC; 100 ng/mL), the length of time below MEC was determined.. Saquinavir concentrations were below MEC at P10 for 0.7 h for twice-daily saquinavir/ritonavir when compared with 8.6 and 6.6 h for 1600/100 and 2000/100 mg once daily, respectively. At P25, 1600/100 mg once daily produced suboptimal concentrations for 5.5 h in contrast to 0.5 h for 2000/100 mg once daily.. Here, we provide substantive data that indicate once-daily saquinavir, in particular 1600/100 mg, is not as robust as the twice-daily regimen based on a population of UK patients; this raises concern over late or missed doses. However, pharmacokinetic data can only ever be a guide to the impact on long-term efficacy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Female; Humans; Male; Middle Aged; Plasma; Ritonavir; Saquinavir; Time Factors; United Kingdom

The extent to which drug-resistant human immunodeficiency virus type 1 (HIV-1) acquired through mother-to-child transmission (MTCT) or failed chemoprophylaxis populates viral reservoirs and limits responses to antiretroviral treatment in infants is unknown.. We evaluated the presence, type, and persistence of drug-resistant HIV-1 in pretreatment plasma and resting CD4(+) T cells from US infants enrolled in a multicenter, open-label, phase 1/2 treatment trial of lopinavir/ritonavir (Pediatric AIDS Clinical Trials Group Protocol 1030) in young infants.. Twenty-two consecutively enrolled infants initiating highly active antiretroviral therapy at a median age of 9.7 weeks and treated for up to 96 weeks were studied. Drug-resistant HIV-1 was present in 5 (23.8%) of 21 infants analyzed; 4 (80.0%) had nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1, only 1 of whom had a history of receiving nevirapine chemoprophylaxis. All 4 infants had NNRTI-resistant variants other than the K103N mutation. The fifth infant had the M184V mutation. Drug-resistant virus was archived in the resting CD4(+) T cell latent reservoir in all 5 infants.. The high rate, types, and early archiving of drug-resistant HIV-1 suggests that resistance testing be considered for infants, especially when an NNRTI-based regimen is planned. Furthermore, drug-resistance outcomes in infants should be an important secondary end point in MTCT trials.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; DNA, Complementary; Drug Resistance, Viral; HIV-1; Humans; Infant; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Viral; United States; Viral Load; Zidovudine

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

Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied.. To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children.. Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data.. Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children.. The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Ritonavir; Safety

The complexity of highly active antiretroviral therapy (HAART), with multiple medications, formulations, and dosing intervals, makes adherence challenging. Little is known about the adherence of children to HAART. The objective of this study was to identify correlates of adherence to HAART and the relationship between adherence and study outcomes in a pediatric clinical trial.. Pediatric AIDS Clinical Trials Group 377 is a phase I/II randomized trial of 4 HAART regimens in antiretroviral-experienced, clinically stable children aged 4 months to 17 years. The 4 treatment arms include various 3- or 4-drug combinations of d4T, 3TC, nevirapine, ritonavir, and nelfinavir. After informed consent was obtained, 193 children were enrolled between December 1997 and September 1998. Questionnaires were developed to collect subject- or caregiver-reported adherence to study medications and to identify problems associated with medication administration. Every 3 months, the number of doses of each medication missed during the 3 days preceding the study visit was recorded. Full adherence (FA) and non-full adherence were defined as missing no doses and missing at least 1 dose, respectively.. Adherence data from study week 48 or the most recent study visit were available for 125 children (week 48 for 109 children). Overall, 70% of children reported FA and 30% reported non-full adherence. Adherence did not differ by treatment arm, age, or the child's knowledge of his or her human immunodeficiency virus infection status. There was a suggestion that adherence was less for white than nonwhite children (40% vs 73% FA) and did not differ between black and Hispanic children. Rates of FA were 82% for d4T, 79% for 3TC, 83% for nevirapine, 84% for ritonavir, and 68% for nelfinavir. Despite the similar rates of FA, difficulties with taking specific medications were reported most frequently for ritonavir and nelfinavir. These included poor taste, patient refusal, and scheduling problems. Adherence was associated with the virologic response: FA was seen in 92% of children with > or =2 log10 drop in viral load and in 64% with <2 log10 drop in viral load.. In children, reported adherence predicts the virologic response to HAART therapy and is a useful measure of adherence. Interventions and regimens to increase adherence to HAART should result in an improved outcome.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Drug Administration Schedule; Humans; Lamivudine; Nelfinavir; Nevirapine; Patient Compliance; Ritonavir; RNA, Viral; Stavudine; Treatment Outcome; Viral Load

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 ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection.. Open-label study carried out at three university-affiliated AIDS Clinical Trials Units in the United States.. Thirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toxoid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored.. The LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after immunization. Eighty-three percent of patients experienced at least a four-fold rise in KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naïve CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens.. Most HIV-infected patients treated with potent combination antiretrovirals develop responses to recall and presumed neoantigens after immunization. Functional immune restoration in response to immunization is related to control of viral replication, decreased immune activation as well as to both quantitative and qualitative restoration of circulating T- lymphocyte subpopulations.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Drug Therapy, Combination; Female; Hemocyanins; Hepatitis A Vaccines; HIV-1; Humans; Hypersensitivity, Delayed; Injections, Intradermal; Lamivudine; Male; Middle Aged; Ritonavir; T-Lymphocytes; Tetanus Toxoid; Thymus Gland; Vaccination; Viral Hepatitis Vaccines; Zidovudine

The outcome of second-line protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA < 1 log10 copies/ml after > or = 2 months) and discontinuation due to intolerance/toxicity. During a median follow-up of 483 days (33-1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Cox's model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus < or = 6 months: 95% confidence interval [CI], 1.08-2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04-2.30); the negatively associated factors were advanced age (HR 0.61 > 34 years versus < or = 34 years: 95% CI, 0.42-0.88), a saquinavir-containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34-0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35-0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02-3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22-0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second-line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI-containing regimen are at risk of toxicity to other PIs and should be addressed to PI-sparing HAART.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Protease Inhibitors; HIV Seropositivity; Humans; Male; Nelfinavir; Ritonavir; RNA, Viral; Saquinavir; Time Factors; Treatment Failure; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

HIV-1 isolated from patients with improved CD4+ T-cell counts despite virologic failure on a nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)-containing regimen were characterized. Five paired virus isolates from patients before and after zidovudine, lamivudine, and ritonavir treatment were tested. Human peripheral blood leukocyte-reconstituted severe combined immunodeficient (hu-PBL-SCID) mice were infected with pre-or posttreatment isolates and plasma HIV-1 RNA levels and CD4+ T cells were measured. Two of five post-treatment isolates exhibited decreased replication in hu-PBL-SCID mice compared with the paired pretreatment isolate, and both had the V82A mutation in protease associated with resistance to PI. One additional posttreatment isolate with the M184V mutation in reverse transcriptase showed diminished replication. CD4+ T-cell depletion was similar following infection with either the pre-or posttreatment isolates. Subtle losses in the replication capacity of PI-or NRTI-resistant viruses may contribute to relative preservation of CD4+ T-cell counts in persons who experience virologic failure. Cytopathic effects of viral infection for target T cells vary from patient to patient but appear not to be influenced by mutations associated with failure of therapy in this system.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antigens, Viral; Base Sequence; CD4-Positive T-Lymphocytes; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Mice; Mice, SCID; Molecular Sequence Data; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sequence Analysis, DNA; Viral Load; Zidovudine

Twelve subjects were treated with zidovudine, lamivudine, and ritonavir within 90 days of onset of symptoms of acute infection to determine whether human immunodeficiency virus type 1 (HIV-1) infection could be eradicated from an infected host. In adherent subjects, with or without modifications due to intolerance, viral replication was suppressed during the 24-month treatment period. Durable suppression reduced levels of HIV-1-specific antibodies and cytotoxic T lymphocyte responses in selected subjects. Proviral DNA in mononuclear cells uniformly persisted. The persistence of HIV-1 RNA expression in lymphoid tissues and peripheral blood mononuclear cells suggests that elimination of this residual pool of virus should be achieved before considering adjustments in antiretroviral therapeutic regimens. In addition, given the reduction in levels of virus-specific immune responses, it would seem prudent to consider enhancing these responses using vaccine strategies prior to the withdrawal of antiviral therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Drug Therapy, Combination; HIV-1; Homosexuality, Male; Humans; Lamivudine; Male; Middle Aged; Pilot Projects; Ritonavir; RNA, Viral; T-Lymphocytes, Cytotoxic; Time Factors; Viremia; Virus Replication; 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

Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability. In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm3.. In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48.. Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10 copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed.. Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Female; Genotype; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Mutation; Pilot Projects; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Severity of Illness Index; Time Factors; Viral Load; Zidovudine

Combination antiretroviral therapy with ritonavir and saquinavir has established potent and durable activity on plasma viremia. CNS HIV infection may be sequestered from drug therapy that does not penetrate the blood-brain barrier. Penetration of these protease inhibitors into the cerebrospinal fluid (CSF) and CSF HIV RNA levels on such therapy has not been well described.. In a cross-sectional study, 28 HIV1-infected study subjects were evaluated either before initiation of or before maximal response to ritonavir-saquinavir therapy, during maximal plasma virologic response, and after virologic failure. Simultaneous samples of plasma and cerebrospinal fluid were obtained from 24 study subjects to measure HIV RNA and protease inhibitor levels.. Across the treatment groups, a strong correlation was found between plasma and CSF HIV RNA levels (r = 0.870; p < .001). In each study subject with plasma HIV RNA levels below assay limit (80 copies/ml), the CSF HIV RNA level was also below the limit of quantitation. Low levels of saquinavir (<2 ng/ml) and ritonavir (<25 ng/ml) in the CSF were observed, with a CSF:plasma drug concentration ratio of < or = 0.005 (0.5%) in all study subjects evaluated (n = 11). The plasma:CSF HIV RNA ratio was high before or early in treatment (median, 38; interquartile range [IQR], 13,97), but low (median, 0.29; IQR, 0.17, 7.5) in those failing therapy (group C, p < .001).. CSF ritonavir and saquinavir levels are consistent with the estimated known fraction of unbound drug in plasma (<2%). Across these treatment response groups, suppression of plasma viremia can predict low CSF HIV RNA levels. This correlation may represent HIV RNA transport and equilibrium between CSF and plasma, or it may represent CNS anti-HIV activity of protease inhibitors. The low drug levels and inverted ratio of HIV RNA in the CSF compared with plasma early in plasma virologic breakthrough suggests CSF virologic failure may contribute to failure of plasma virologic response.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Cross-Sectional Studies; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Patient Selection; Ritonavir; RNA, Viral; Saquinavir; Treatment Failure; Treatment Outcome; Viral Load; Viremia

Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Follow-Up Studies; HIV-1; Humans; Immunologic Memory; Lamivudine; Lymphocyte Count; Lymphocytes; Reference Values; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; T-Lymphocytes; Time Factors; Viral Load; Zidovudine

Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. We undertook an international, multicentre, randomised, double-blind, placebo-controlled trial of ritonavir in patients with HIV-1 infection and CD4-lymphocyte counts of 100 cells/microL or less, who had previously been treated with antiretroviral drugs.. 1090 patients were randomly assigned twice-daily liquid oral ritonavir 600 mg (n = 543) or placebo (n = 547) while continuing treatment with up to two licensed nucleoside agents. The primary study outcome was any first new, or specified recurrent, AIDS-defining event or death. Open-label ritonavir was provided after 16 weeks in the study to any patient who had an AIDS defining event.. The baseline median CD4-lymphocyte count was 18 (IQR 10-43)/microL in the ritonavir group and 22 (10-47)/microL in the placebo group. Study medication was discontinued in 114 (21.1%) ritonavir-group patients and 45 (8.3%) placebo-group patients mainly because of initial adverse symptoms. Outcomes of AIDS-defining illness or death occurred in 119 (21.9%) ritonavir-group patients and 205 (37.5%) placebo-group patients (hazard ratio 0.53 [95% CI 0.42-0.66]; log-rank p < 0.0001) during median follow-up of 28.9 weeks, with loss to follow-up of 15 (1.4%) patients. Ritonavir was then offered to all patients; at median follow-up of 51 weeks, 87 (16%) ritonavir-group patients had died of any cause versus 126 (23%) placebo-group patients (hazard ratio 0.69 [95% CI 0.52-0.91], log-rank p = 0.0072).. Although earlier intervention with combination therapy may provide much more effective treatment, ritonavir in patients with advanced disease and extensive previous antiretroviral use is safe and effective, lowers the risk of AIDS complications, and prolongs survival.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adolescent; Adult; Aged; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Disease Progression; Double-Blind Method; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Ritonavir; RNA, Viral; Survival Rate; T-Lymphocyte Subsets; Treatment Outcome

The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h] alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (Cmax) of ZDV plasma decreased from 748 +/- 375 (mean +/- standard deviation) to 546 +/- 296, and area under the concentration-time curve from 0 to 24 h (AUC0-24) decreased from 3,052 +/- 1,007 to 2,261 +/- 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide Cmax and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3'-amino-3'-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Cross-Over Studies; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Double-Blind Method; HIV Protease Inhibitors; Humans; Male; Middle Aged; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

To assess the safety, efficacy and plasma drug levels of the combination of ritonavir plus saquinavir for the treatment of advanced HIV infection.. Multicentre pilot study.. Eighteen protease inhibitor-naive patients, with intolerance or contraindication to reverse transcriptase inhibitors, a median CD4 cell count of 12 x 10(6)/l (range, 1-50 x 10(6)/l), and a median HIV viraemia of 5.25 log10 copies/ml (range, 4.00-6.13 log10 copies/ml).. Patients received 600 mg twice daily of both ritonavir and saquinavir. Viraemia was measured at baseline and at weeks 5, 9 and 13. Response was defined as a drop of viraemia of more than 1 log10 at week 5. Plasma drug levels were determined after at least 3 weeks of combined treatment: samples were collected before and 1, 2, and 4 h after the morning ingestion of both drugs. The protease gene was sequenced at baseline and under treatment.. Among the 16 patients evaluable at week 5, 11 were responders, and among these patients, six remained responders at week 13 (two with undetectable viraemia). Study discontinuations were due to side-effects (n = 4), patient choice (n = 3), protocol violation (n = 1) and death (n = 1). Responders had higher drug levels than non-responders (P < 0.01 for saquinavir, P = 0.04 for ritonavir). In two non-responders, development of multiple new mutations at positions 10, 20, 48, 82, 84 and 90 was observed after 5-13 weeks.. The response to ritonavir plus saquinavir in advanced HIV infection is unpredictable. A minority of patients respond with disappearance of HIV viraemia. In other patients, rapid cumulative emergence of protease mutations conferring resistance to treatment cannot always be prevented by good compliance and relatively high plasma drug levels.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Cohort Studies; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Protease; HIV Protease Inhibitors; Humans; Male; Mutation; Pilot Projects; Ritonavir; Saquinavir; Viremia

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4-CD8 Ratio; Humans; Ritonavir; T-Lymphocyte Subsets; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Follow-Up Studies; HIV Protease Inhibitors; Humans; Placebos; Ritonavir; Time Factors

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Ritonavir; Saquinavir

The HIV protease inhibitor, ritonavir, reduces the risk of death by 43 percent in patients with late-stage AIDS. Study participants were randomized to ritonavir or placebo in a double-blind trial. After the first month of the study, the risk of death or development of an AIDS-defining event was reduced by 58 percent. Risk reduction was seen six months into treatment. The successful data collection in this study was in large part due to the manufacturer entering patients with extremely low CD4 counts; these patients are not eligible for many trials and are at the highest risk for death.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; CD4 Lymphocyte Count; Double-Blind Method; HIV Protease Inhibitors; Humans; Ritonavir; Survivors; Thiazoles; Valine

In January 1996, Abbott Laboratories, the manufacturer of ritonavir, will start an expanded access program to make the drug available to 2,000 people with AIDS worldwide. Participation will be determined by a lottery. International patients can enroll based on physician recommendation. Abbott will likely apply for accelerated marketing approval of ritonavir in early 1996.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; HIV Protease Inhibitors; Humans; Patient Selection; Ritonavir; Thiazoles; Valine

End-stage renal disease in the human immunodeficiency virus-positive population is increasing. Kidney transplant is the optimal therapy for this population rather than dialysis modalities if some criteria are met. These include undetectable plasma human immunodeficiency virus RNA, CD4 cell count over 200 cells/μL, and the absence of any AIDS-defining illness. Here, we describe the first living-donor kidney transplant in a human immunodeficiency virus-positive recipient in Turkey. The patient, a 52-year-old male diagnosed as human immunodeficiency virus positive, was on antiretroviral therapy, which consisted of 400 mg twice daily darunavir, 100 mg/day ritonavir, and 50 mg/day dolutegravir. He had been negative for human immunodeficiency virus RNA for the past 3 years. The patient developed renal insufficiency without any known cause and started hemodialysis. A living donor transplant from his son was performed, and the patient received ATG Fresenius-S (Neovii Biotech, Rapperswil, Switzerland) induction and a maintenance immunosuppression therapy consisting of methyl-prednisolone, mycophenolate mofetil, and tacrolimus. There were no incidences of delayed graft function or acute rejection. Because of tacrolimus and ritonavir interaction, tacrolimus trough levels were too high. With tacrolimus withdrawn, tacrolimus trough level decreased to detectable levels 2 weeks later. Antiretroviral therapy was continued on the same dosage. At month 4 posttransplant, the patient's creatinine level was 1.01 mg/dL. At present, the patient has had no complications and no episodes of rejection. Kidney transplant is the most favorable replacement therapy for HIV-positive patients who are under controlled AIDS care with highly active antiretroviral therapy. However, drug interactions should be carefully evaluated.

Topics: Acquired Immunodeficiency Syndrome; Drug Interactions; Graft Rejection; HIV; HIV Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Ritonavir; RNA; Tacrolimus

Studies which examine quality of life (QOL) provide important insights that are needed to understand the impacts of HIV/AIDS anti-retroviral treatment (ART), comorbid conditions and other factors on the daily activities of people living with HIV/AIDS (PLH). This study aimed to determine the inter-relationships between clinical factors, behavioural, socio-demographic variables and QOL among PLH.. The secondary analysis used data collected from 293 people living with HIV/AIDS (PLH) receiving second-line ART in Johannesburg in a clinical trial which evaluated the non-inferiority of ritonavir-boosted darunavir (DRV/r 400/100 mg) compared to ritonavir-boosted lopinavir (LPV/r) over a 48 week-period. Physical functioning, cognitive and mental QOL were measured using the Aids Clinical Trial Group questionnaire. Exploratory factor analyses were used to examine the structure, the relationships between and the construct validity of QOL items. Structural equation models which tested the a priori-hypothesised inter-relationships between QOL and other variables were estimated and goodness of fit of the models to the data was assessed.. Patients on darunavir presented with lower pill burden. Older patients and women were more likely to report lower QOL scores. Pill burden mediated the effects of age, sex and treatment regimen on physical functioning QOL and adverse effects; the effects of age, sex, treatment regimen and adverse effects on cognitive QOL; and the effects of sex on mental QOL.. QOL among PLH is associated with socio-demographic and clinical factors. Therefore, QOL could be enhanced by considering PLH characteristics, clinical factors such as regimen side-effects profile, management of comorbid conditions and mitigating risks such as potential adverse drug-to-drug interactions among patients on ART.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Darunavir; Female; HIV Infections; HIV-1; Humans; Lopinavir; Quality of Life; Ritonavir; South Africa

To report a case involving a patient with presumed panretinal ritonavir-induced retinopathy.. A 52-year-old, HIV-positive patient, with no criteria for AIDS associated with the use of ritonavir for more than 10 years, underwent clinical examination, fundus photography, spectral domain optical coherence tomography, and fundus autofluorescence imaging.. Fundus examination revealed areas of atrophy and hypertrophy in the retinal pigment epithelium throughout the retina. Laboratory tests for other diseases were all negative.. HIV-positive patients undergoing ritonavir therapy should be carefully followed in the presence of low-acuity vision complaints and retinal changes.

Topics: Acquired Immunodeficiency Syndrome; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; HIV; HIV Protease Inhibitors; Humans; Male; Middle Aged; Retinal Diseases; Retinal Pigment Epithelium; Ritonavir; Time Factors; Tomography, Optical Coherence; Visual Acuity

Immune reconstitution inflammatory syndrome (IRIS) represents paradoxical immune-mediated inflammation in response to an infecting pathogen, occurring after initiation of antiretroviral therapy (ART), concomitantly with immune system recovery. It has also been described in Kaposi's sarcoma (KS). We report a case of a 9-year-old Guinean girl, who developed Kaposi's sarcoma, following introduction of ART. KS associated with immune reconstitution inflammatory syndrome is rare, especially in children, but with the increased use of ART is becoming more prevalent.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Dideoxynucleosides; Drug Therapy, Combination; Female; Humans; Immune Reconstitution Inflammatory Syndrome; Lamivudine; Lopinavir; Ritonavir; Sarcoma, Kaposi

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Humans; Indoles; Interferon-alpha; Lopinavir; Lung; Male; Pandemics; Pneumonia, Viral; Radiography, Thoracic; Ritonavir; SARS-CoV-2; Sputum; Tomography, X-Ray Computed; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Adult; Bradycardia; Darunavir; Female; HIV Protease Inhibitors; Humans; Ritonavir

Treatment of HIV has reduced HIV/AIDS-related mortality. Sustaining >90% virologic suppression in sub-Saharan Africa requires decentralized care and prevention services to rural communities. In Zimbabwe, the number of people receiving antiretroviral treatment (ART) has increased rapidly. However, access to treatment monitoring tools such as viral load and drug resistance testing is limited. We assessed virologic treatment outcomes among ART recipients in Nyamutora, a rural community receiving bimonthly ART and prevention services. We enrolled all ART recipients (143) at 6-monthly visits in the Nyamutora community in 2014 and 2015. Whole blood samples were collected in K-EDTA tubes, transported to Harare for CD4 counts and viral load testing, and genotype was obtained in participants with viral loads >1,000 copies/ml. Ages ranged from 2 to 75 years (median 43 years) with a median 42 months on ART at follow-up. Eight of 143 (6%) had viral loads >1,000 copies/ml at one of the 3 visits, 7 on first-line nevirapine (NVP)-based ART and 1 on second-line LPV/r-based ART. Seven participants had sequence data available, and five had drug resistance mutations, K65R, T69N, K101E, K103N, Y181C/I, M184V, and G190A. Virologic failure (p = .001) and drug resistance mutations (p = .01) on first-line NVP-based ART were associated with younger age by univariate exact logistic regression. The participants had high viral suppression (94%) despite less than optimal (NVP based) ART regimens without laboratory monitoring. Virologic failure and drug resistance were higher among children and adolescents. Effective ART delivery to the community achieved high rates of virologic suppression and minimal drug resistance.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Community Health Centers; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nevirapine; Ritonavir; Rural Population; Treatment Failure; Viral Load; Young Adult; Zimbabwe

The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia.. Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models.. One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively.. LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks.. NCT00357552.

Topics: Acquired Immunodeficiency Syndrome; Adult; Africa; Antiviral Agents; Asia; Developing Countries; Drug Therapy; Female; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pilot Projects; Plasma; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Female; Humans; Lopinavir; Male; Ritonavir

To investigate the morphological and biochemical effects of lamivudine associated with ritonavir on maternal and fetal livers and kidneys throughout the pregnancy of albino rats.. Forty pregnant rats were divided into four numerically equal groups: control (C), experiment 1 (E1), experiment 2 (E2), and experiment 3 (E3). Only distilled water was given to the control group, while groups E1, E2, and E3 received, respectively, 5, 15 and 45 mg/kg of lamivudine associated with 20, 60, and 180 mg/kg of ritonavir, per day, throughout the pregnancy. On the 20th day of the pregnancy, the histological structure of the maternal and fetal livers and kidneys was analyzed by means of optical microscopy, along with the blood concentrations of AST, ALT, urea, and matrix creatinine. The numerical variables were analyzed using the Kruskal-Wallis test and Dunn's multiple comparison test.. The histological alterations occurred in both the maternal livers and the maternal kidneys, particularly in group E3, which received the greatest therapeutic dosage (nine times). The blood levels ofALT in group E3 were significantly lower than in the other groups (p = 0.0037). The urea and creatinine levels in the blood were significantly lower in group E1 (p = 0.0420 andp = 0.0108, respectively).. rhe association of lamivudine and ritonavir affected the histological structure of the kidneys of the matrices of group E3. There was a significant decrease in the blood values of urea e creatinine in group El.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-Retroviral Agents; Drug Evaluation, Preclinical; Female; Kidney; Lamivudine; Liver; Pregnancy; Pregnancy Complications, Infectious; Rats; Rats, Wistar; Ritonavir

HIV/AIDS patients are probably more predisposed to vitamin E deficiency, considering that they are more exposed to oxidative stress. Additionally, there are an extensive number of drugs in the highly active antiretroviral therapy (HAART) regimens that may interfere with vitamin E concentrations. The objective of this study was to compare serum concentrations of alpha-tocopherol in 182 HIV/AIDS patients receiving different HAART regimens. The patients were divided into three groups according to regimen: nucleoside analog reverse-transcriptase inhibitors (NRTIs) + non-nucleoside analog reverse-transcriptase inhibitors (NNRTIs); NRTIs + protease inhibitors + ritonavir; NRTIs + other classes. Alpha-tocopherol was assessed by high-performance liquid chromatography. Multiple linear regression analysis was used to evaluate the effects of HAART regimen, time of use, and compliance with the regimen on alpha-tocopherol concentrations. Alpha-tocopherol concentrations were on average 4.12 μmol/L lower for the NRTIs + other classes regimen when compared to the NRTIs + NNRTIs regimen (p = 0.037). A positive association (p < 0.001) was observed between alpha-tocopherol and cholesterol concentrations, a finding due, in part, to the relationship between liposoluble vitamins and lipid profile. This study demonstrated differences in alpha-tocopherol concentrations between patients using different HAART regimens, especially regimens involving the use of new drugs. Long-term prospective cohort studies are needed to monitor vitamin E status in HIV/AIDS patients since the beginning of treatment.

Topics: Acquired Immunodeficiency Syndrome; Adult; alpha-Tocopherol; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Vitamin E; Vitamin E Deficiency

Topics: Acquired Immunodeficiency Syndrome; Adult; HIV Protease Inhibitors; Humans; Male; Nail Diseases; Nails; Ritonavir; Thumb

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

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Genotype; HIV Protease Inhibitors; Humans; Nucleosides; Ritonavir; RNA, Viral; Sulfonamides; Time Factors; Viral Load

Atazanavir is a first-line HIV protease inhibitor commonly co-dosed with ritonavir. Ritonavir inhibits atazanavir metabolism, decreasing variability and increasing plasma concentrations. However, ritonavir use results in higher costs and increased drug-related adverse events. Elucidating atazanavir pharmacokinetics might allow for individualized ritonavir boosting. We previously demonstrated that genetically determined CYP3A5 nonexpression was associated with slower atazanavir clearance CL/F and higher trough concentrations. This effect was prominent in non-African-American men but absent in African-Americans. The present study considers additional genetic predictors of atazanavir CL/F with a focus on race differences. Nine polymorphisms in CYP3A4, ABCG2, NR1I2 (PXR), and SLCO1B1 were evaluated; 330 plasma samples from 30 HIV-negative volunteers, balanced by sex, race, and CYP3A5 expressor status, were available. Analyses were performed using nonlinear mixed-effects modeling (NONMEM). The following factors were univariately associated with atazanavir CL/F (% effect) : African-American race (decreased 35%), female sex (decreased 25%), older age (decreased 1.7%/year), CYP3A5 nonexpressors (decreased 26%), ABCB1 CGC haplotype carriers (1236C/2677G/3435C) (decreased 33%), and CYP3A4*1B carriers (decreased 31%). However, an independent genetic explanation for the differential race effect could not be identified. An interaction was observed with PXR 63396 C>T and CYP3A5 expressor status (p=0.0002). CYP3A5 nonexpressors with a PXR 63396 CC genotype had 37% slower CL/F versus those with CT or TT genotypes. For CYP3A5 expressors, those with a PXR 63396 CC genotype had 63% faster CL/F versus those with CT or TT genotypes. Although this study has as its main limitation a small overall sample size, these results nonetheless provide new leads and impetus to evaluate ways to individualize the need for ritonavir boosting using demographic and genetic predictors of atazanavir pharmacokinetics.

Topics: Acquired Immunodeficiency Syndrome; Adult; Atazanavir Sulfate; Black or African American; Cost-Benefit Analysis; Cytochrome P-450 CYP3A; Female; Genotype; Haplotypes; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oligopeptides; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyridines; Ritonavir; Treatment Outcome; White People; Young Adult

To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs).. An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000  copies/ml.. Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100  mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r.. Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400  copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40  copies/ml and 30 had levels 40-200  copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400  copies/ml.. In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Africa; Anti-HIV Agents; Deoxycytidine; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Female; Health Resources; Humans; India; Lopinavir; Male; Medication Adherence; Middle Aged; Mutation; Organophosphonates; Patient Selection; Pilot Projects; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Surveys and Questionnaires; Tenofovir; Thailand; Treatment Failure; Viral Load

To evaluate biochemical and morphological effects on rats submitted to three different doses of the association zidovudine and ritonavir administered throughout pregnancy.. Forty pregnant EPM-1 Wistar rats weighing about 200 g were randomly divided into the control group (Ctr = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of zidovudine/ritonavir (Exp1 = 10/20 mg/kg bw, n = 10; Exp2 = 30/60 mg/kg bw, n = 10; Exp3 = 90/180 mg/kg bw, n = 10) from 'day 0' up to the 20th day of pregnancy. At term (20th day) the rats were anesthetized. Blood and fetal and maternal organ samples (livers and kidneys) were taken for morphological and biochemical analyses.. Upon histological examinations fetal livers and kidneys appeared normal. In contrast the maternal samples revealed structural alterations. Maternal kidneys of the three experimental groups exhibited progressive and dose-dependent histological alterations; liver alterations were detected only in Exp3. Blood levels of AST and ALT were not significantly different from the control group but urea and creatinine levels were lower in groups Exp3 and Exp1.. The administration of zidovudine plus ritonavir throughout rat pregnancy can cause morphological as well as functional changes in maternal kidneys.

Topics: Acquired Immunodeficiency Syndrome; Analysis of Variance; Animals; Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Combinations; Female; Kidney; Liver; Pregnancy; Pregnancy Complications, Infectious; Rats; Rats, Wistar; Ritonavir; Zidovudine

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

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

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Cytochrome P-450 CYP3A; Drug Administration Schedule; Drug Antagonism; HIV Infections; HIV Protease Inhibitors; Humans; Indoles; Neoplasms; Pyrroles; Risk Factors; Ritonavir; Sunitinib

The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.

Topics: Acquired Immunodeficiency Syndrome; Adult; Amniotic Fluid; Anti-HIV Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Fetal Blood; Genitalia, Female; HIV-1; Humans; Hydrocortisone; Pregnancy; Pregnancy Complications, Infectious; RNA, Viral

The Antiretroviral Pregnancy Registry was established in 1989 to collect data on birth defects after pregnancy exposures to antiretroviral therapy. Using Registry data, this study estimates the birth defect risk after pregnancy exposures to lopinavir/ritonavir.. The analysis population includes all prospective lopinavir/ritonavir-exposed pregnancies enrolled in the Registry from September 2000 through July 2007. Birth defect prevalence after pregnancy exposure is compared with rates from a population-based surveillance system, and first-trimester exposures are compared with combined second/third-trimester exposures.. Among 955 live births prenatally exposed to lopinavir/ritonavir, 23 cases with birth defects were reported [2.4%, 95% confidence interval (CI) = 1.5 to 3.6). Among 267 live births with first-trimester exposures, 5 had birth defects (1.9%, 95% CI = 0.6 to 4.3). These rates are similar to the population-based comparator rate of 2.67% and the rate in infants with second/third-trimester exposures (2.6%, 95% CI = 1.6 to 4.1). No pattern of birth defects suggestive of a common etiology was seen.. The prevalence of birth defects among infants prenatally exposed to lopinavir/ritonavir is not significantly different from internal or external comparison groups. These data provide reassuring information to patients and clinicians about the safety of lopinavir/ritonavir in the treatment of HIV-positive pregnant women.

Topics: Abnormalities, Drug-Induced; Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Female; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Registries; Ritonavir

Oral lesions (OL) have an important prognostic value for HIV/AIDS patients. However, the behavior of OL in HIV/AIDS patients undergoing highly active antiretroviral therapy including efavirenz (HAART/EFV) has not been documented. Our objective was to establish the prevalence of OL in HIV/AIDS patients undergoing HAART/EFV and to compare it with the prevalence of OL in patients undergoing antiretroviral therapy including a protease inhibitor (HAART/PI). Seventy-three HIV/AIDS patients undergoing antiretroviral treatment for at least for 6 months at "La Raza" Medical Center's Internal Medicine Unit (IMSS, Mexico City) were included. To detect OL, a detailed examination of oral soft tissues was performed in each patient. Patient records recorded gender, seropositivity time, route of contagion, antiretroviral therapy type and duration, CD4 lymphocyte count/ml, and viral load. Two groups were formed: 38 patients receiving HAART/EFV [two nucleoside analogue reverse transcriptase inhibitors (NARTI) plus efavirenz] and 35 patients receiving HAART/PI (two NARTIs plus one PI). OL prevalence was established in each study group. The Chi-square test was applied (p < 0.05(IC95%)). OL prevalence in the HAART/EFV group (32%) was lower (p < 0.007) than in the HAART/PI group (63%). Candidosis was the most prevalent OL in both groups. Herpes labialis, HIV-associated necrotizing periodontitis, xerostomia, hairy leukoplakia, and nonspecific oral sores were identified. The highest prevalence for all OL was found in the HAART/PI group. These findings suggest that HIV/AIDS patients undergoing HAART/EFV show a lower prevalence of oral lesions than patients undergoing HAART/PI.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Female; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Mouth Diseases; Prevalence; Ritonavir; Saquinavir; Viral Load

A 39-year-old man with human immunodeficiency virus infection and Kaposi sarcoma on HAART therapy and doxorubicin presented in 2007 with a hyperpigmented tongue. Physical examination also showed hyperpigmented patches on the mucosal aspects of the lips and longitudinal dark bands on multiple nails. A skin biopsy specimen showed pigmentary alteration. Such hyperpigmentation has been described in numerous case reports and case series and has been reported to resolve within weeks to months of cessation of doxorubicin.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Carbamates; Doxorubicin; Drug Combinations; Furans; Humans; Lamivudine; Lip Diseases; Male; Melanosis; Nails, Malformed; Organophosphates; Ritonavir; Sarcoma, Kaposi; Sulfonamides; Tongue Diseases; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anticoagulants; Drug Overdose; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Warfarin

A patient with human immunodeficiency virus-related posterior fossa progressive multifocal leukoencephalopathy had serial diffusion-weighted imaging using b-values of 1000 and 3000 before and during highly active antiretroviral therapy (HAART). High-b-value images provided a superior definition of the leading edge of the lesion and additional information about the integrity of white matter tracts. Following HAART, there was a marked reduction of lesional apparent diffusion coefficient and reconstitution of anisotropy in the affected middle cerebellar peduncle.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brain; Diffusion; Diffusion Magnetic Resonance Imaging; HIV Protease Inhibitors; Humans; Leukoencephalopathy, Progressive Multifocal; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; Tenofovir; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Industry; Global Health; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

This study evaluates clinical, virological and immunological responses to antiretroviral (ARV) therapy based on Lopinavir/ritonovir (LPV/r) in previously protease -inhibitor-experienced children. The study included 29 Brazilian children (median age = 5.91 years) who had failed previous ARV therapy and had begun a regimen based on LPV/r. At 12 months follow-up, a good virological response to LPV/r therapy was defined as achieving an undetectable viral load or as a decrease in plasma HIV RNA levels to > 1 log. A good immunological response was defined as an increase in CD4+ cell count from baseline sufficient to attain a better CDC immune stage classification. The number of infectious episodes 12 months before and 12 months after beginning LPV/r was assessed. Sixteen (55.2%) and 19 (65.5%) of 29 patients exhibited good virological and immunological responses, respectively. Baseline CD4+ values (>500) predicted both virological and immunological responses (p<0.05). Older children were less likely to develop an immunological response (p<0.001) than younger children. Nine children receiving 3 ARV drugs plus LPV/r showed an immunological response (100%) compared to 10/20 (50%) children receiving 2 drugs plus LPV/r (p=0.01). A lower number (n<5) of infectious episodes was noted after 12 months follow-up in children using the LPV/r regimen (p=0.006). There was a positive correlation between children whose baseline CD4+ values were greater than 500 cells/mm(3) and virological responses. Although virological responses to therapy were seen in about half the children (55.2%), the use of HAART containing LPV/r provided clinical and immmunological benefits.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Follow-Up Studies; HIV Protease Inhibitors; Humans; Longitudinal Studies; Lopinavir; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Developing Countries; Drug Combinations; Drug Industry; HIV Protease Inhibitors; Humans; International Agencies; Lopinavir; Pyrimidinones; Ritonavir

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

Topics: Acquired Immunodeficiency Syndrome; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Urologic Diseases

Cryptococcus neoformans is an opportunistic pathogen that can manifest in immunocompromised patients with acquired immune deficiency syndrome. Prevention of cryptococcosis and other opportunistic diseases is an objective in the management of human immunodeficiency virus (HIV)-infected patients. The goal of highly active antiretroviral therapy (HAART) is to reduce the viral loads and enhance CD4 counts in HIV-infected patients. These 2 mechanisms keep HIV-infected patients healthier and enhance their immune systems, thus reducing and often preventing opportunistic infections such as ocular cryptococcal infections. Discontinuation of HAART can lead to ocular opportunistic infections such as cryptococcal choroiditis.. Presented here is a case of a patient who was treated successfully with HAART of stavudine (D4T), abacavir (Ziagen), ritonavir (Norvir), and saquinavir (Invirase). His last CD4 count before HAART was discontinued was 131 cells/mm(3), and viral load was less than 50 copies/mL. He discontinued his HAART regimen for 2 years and presented to the emergency room with complaints of a severe headache with neck pain, lightheadedness, nausea, disorientation, and unsteady gait. Lumbar puncture results showed cryptococcal infection, and the patient was admitted for the treatment of cryptococcal meningitis with amphotericin B and 5-flucytosine. Cryptococcal choroiditis was diagnosed after treatment of the meningitis. After resolution, his resultant visual acuities were 10/350 in the right eye and 10/600 in the left eye. He is on a maintenance dose of antifungal therapy and has been reinitiated on HAART of abacavir/zidovudine/lamivudine (Trizivir) and lopinavir/ritonavir (Kaletra).. This case exemplifies the importance of HAART in the prevention of opportunistic infections, cryptococcal meningitis/choroiditis in particular. Eye care professionals can play a role in encouraging patients to comply with their HAART regimens.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Choroiditis; Cryptococcus neoformans; Dideoxynucleosides; Eye Infections, Fungal; Follow-Up Studies; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Ritonavir; Saquinavir; Stavudine

Topics: Acquired Immunodeficiency Syndrome; CCR5 Receptor Antagonists; Clinical Trials as Topic; Darunavir; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Ritonavir; Salvage Therapy; Sulfonamides

We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.

Topics: Acquired Immunodeficiency Syndrome; Drug Resistance, Viral; Evolution, Molecular; Gene Products, gag; Genotype; Heteroduplex Analysis; HIV Protease; HIV Protease Inhibitors; Humans; Phenotype; Ritonavir; Virus Replication

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Bradycardia; Drug Combinations; Dyspnea; Electrocardiography; Female; HIV Protease Inhibitors; Humans; Lopinavir; Middle Aged; Pyrimidinones; Ritonavir; Syndrome; Tachycardia

Topics: Acquired Immunodeficiency Syndrome; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Male; Ritonavir; Saquinavir; Tablets

Topics: Acquired Immunodeficiency Syndrome; Drug Costs; Drug Industry; National Institutes of Health (U.S.); Ritonavir; United States

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Costs; Drug Industry; Humans; National Institutes of Health (U.S.); Patents as Topic; Patient Advocacy; Ritonavir; United States

Oropharyngeal candidiasis decreased when protease inhibitors were included with other antiretrovirals to treat HIV infection. We tested oral yeast isolates of Brazilian HIV-infected individuals receiving antiretroviral therapy for protease secretion and susceptibility to ritonavir and some antifungals.. We collected oral samples and identified yeasts from 19 HIV-infected patients receiving highly active antiretroviral therapy (HAART) and suspected of having oral candidiasis. Ritonavir and its excipients' effects on the isolated yeasts were tested for protease secretion by Rüchel's technique. The yeasts' susceptibility to amphotericin B (AnB), fluorocitosine (5FC), fluconazole (FZL), ketoconazole (KZL), and itraconazole (IZL) was determined by E-test (AB Biodisk). Chi-squared test determined the statistical differences.. Twenty-five different positive isolates were obtained. Sixty-eight percent were C. albicans. Other isolates included C. famata (16%), C. glabrata (4%), C. tropicalis (4%), T. capitatum (4%), and 1 isolate not identified. High protease secretion was observed for most of the isolates (20/25). Ritonavir only altered enzyme secretion in 6/20 of the protease-secreting isolates. All isolates were highly sensitive to both AnB and 5FC. Antifungal activity did not change when ritonavir was added to the culture media. Some isolates were highly resistant to studied antifungals (52.2% KZL, 30.4% FZL, and 26% IZL). Resistance significantly decreased when ritonavir was added to the medium with KZL and IZL (P <.5 by chi-squared). A trend to decreased resistance was also observed with FZL but the results were not statistically significant.. Candida continues to be the most prevalent fungus in the oral cavity. Although oral candidal isolates secrete protease, ritonavir does not inhibit all protease-secreting oral yeast isolates. There seems to be a synergistic effect between ritonavir and oral antifungals against fungal resistance.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antifungal Agents; Aspartic Acid Endopeptidases; Candida; Candidiasis, Oral; Chi-Square Distribution; Drug Resistance, Fungal; Drug Synergism; Female; HIV Protease Inhibitors; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Ritonavir

Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected patient.. To analyse virological response to lopinavir/ritonavir therapy in previously protease inhibitor (PI)-experienced HIV-1-infected children.. Sixty-seven HIV-1-children on lopinavir/ritonavir were studied in a multicentre prospective cohort observational study. The outcome variables were undetectable viral load (uVL; VL < or =400 copies/mL) and virological failure after uVL with a rebound of VL >400 copies/mL. VL and genotype of HIV-1-isolates were measured using standard assays.. 83.5% of children had a 1 log10 VL decrease including 65.6% who reached uVL. Children with >2 changes of antiretroviral therapy (ART) or >5 drugs needed a median time of 3-4 months higher than children with < or =2 changes of ART or < or =5 drugs previous to lopinavir/ritonavir, to reach those values, and the relative proportions (RP) were 2.2 (P =0.038) and 1.9 (P=0.050), respectively. Children with CD4+>15% (P=0.122), VL < or =30,000 (P < 0.001) copies/mL, and age >12 years (P=0.096) achieved an earlier control of VL during the follow-up. The children with virological failure or rebound of VL had higher baseline VL and lower CD4+ T-lymphocytes/mm3 and had taken a greater number of drugs previous to lopinavir/ritonavir. HIV-children with a new nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI) or PI plus non-nucleoside reverse transcriptase inhibitors (NNRTI) in the current regimen had a better virological response than children without these new drugs. Also, children with <6 protease mutations had an RP of 2.31 of achieving uVL.. Highly active antiretroviral therapy (HAART) including lopinavir/ritonavir induces beneficial effects in terms of virological outcome responses, and it is an effective option for salvage therapy in PI-experienced HIV-1-infected children.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Drug Therapy, Combination; HIV-1; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir; Salvage Therapy

In vitro synergy and complementary resistance profiles provide a strong rationale for combining fosamprenavir with saquinavir as part of a potent double-boosted protease inhibitor regimen. This study evaluated the steady-state pharmacokinetics of saquinavir 1000 mg twice daily (bid) and fosamprenavir 700 mg bid administered with 2 different doses of ritonavir (100 and 200 mg bid) in HIV-1-infected subjects.. On day 1, 12-hour pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg bid) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Fosamprenavir 700 mg bid was then added to the regimen, and pharmacokinetic sampling was repeated for all 3 agents at day 11. The ritonavir daily dose was then increased to 200 mg bid, and a 3rd pharmacokinetic profile was obtained at day 22.. The coadministration of fosamprenavir 700 mg bid with saquinavir/ritonavir 1000/100 mg bid resulted in a statistically nonsignificant decrease in saquinavir concentrations (by 14, 9, and 24%, for saquinavir area under the concentration-time curve [AUC]0-12, C(max), and C(trough), respectively). This was compensated for by an increased ritonavir dose of 200 mg bid, which resulted in a statistically nonsignificant increase in saquinavir exposure compared with baseline. Amprenavir levels did not appear to be significantly influenced by coadministration of saquinavir with fosamprenavir. Fosamprenavir significantly reduced ritonavir exposure, but the increased ritonavir dose compensated for this interaction.. Our findings showed that saquinavir/ritonavir/fosamprenavir was well tolerated over the study period. Saquinavir plasma concentrations were slightly lowered by the addition of fosamprenavir to the regimen. However, the addition of a further 100 mg ritonavir bid restored the small and insignificant decrease.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Area Under Curve; Carbamates; Drug Administration Schedule; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Metabolic Clearance Rate; Middle Aged; Organophosphates; Ritonavir; RNA, Viral; Saquinavir; Sulfonamides; Viral Load

A total of 251 venous lactate levels were obtained from 127 children with HIV/AIDS; 104 on highly active antiretroviral therapy, and 23 not on therapy. Asymptomatic hyperlactatemia (> 2 mmol/l) was found in 41 children; no hepatic dysfunction or life-threatening lactic acidosis occurred. Asymptomatic hyperlactatemia is associated with treatment with nucleoside reverse transcriptase inhibitors or protease inhibitors and with undetectable viral loads regardless of treatment regimen, suggesting that elevated lactate levels are useful in evaluating adherence.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; Child; Child, Preschool; Female; HIV Protease Inhibitors; Humans; Infant; Lactic Acid; Male; Patient Compliance; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Viral Load

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

We report a case of rapidly progressive solid lymphoma with anaplastic large cell morphology, followed by systemic Kaposi sarcoma in an adult patient with AIDS. The lymphoma cells expressed human herpesvirus 8 (HHV-8)-encoded latent and lytic proteins and Epstein-Barr virus-encoded small RNA, suggesting that this case could be categorized into HHV-8-associated solid lymphoma, a recently identified disease entity.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Cyclophosphamide; Disease Progression; Doxorubicin; Epstein-Barr Virus Infections; Fatal Outcome; Gastrointestinal Neoplasms; Herpesviridae Infections; Herpesvirus 4, Human; Herpesvirus 8, Human; HIV-1; Humans; Lamivudine; Lymphoma, AIDS-Related; Lymphoma, Large B-Cell, Diffuse; Male; Neoplasms, Second Primary; Prednisone; Ritonavir; Saquinavir; Sarcoma, Kaposi; Skin Neoplasms; Stavudine; Tumor Virus Infections; Vincristine

Tenofovir-related tubular damage, like all other recently reported cases, occurred in patients receiving the protease inhibitor (PI) ritonavir, often with lopinavir. Increased plasma concentrations of didanosine were also observed after the addition of tenofovir. It was suspected that tenofovir with PIs interacted with renal organic anion transporters, leading to nephrotoxic tubular concentrations of tenofovir and systemic accumulation of didanosine. Until there is a better understanding of these interactions, close monitoring is recommended for patients receiving tenofovir, PIs, and didanosine.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Anti-HIV Agents; Diabetes Insipidus, Nephrogenic; Didanosine; Drug Therapy, Combination; Fanconi Syndrome; Humans; Lopinavir; Male; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Ritonavir; Tenofovir

Topics: Acquired Immunodeficiency Syndrome; Carbamates; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; Humans; Organophosphates; Patient Compliance; Ritonavir; Sulfonamides; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials, Phase II as Topic; Drug Combinations; Drug Resistance, Viral; Follow-Up Studies; HIV Protease Inhibitors; HIV-1; Humans; Long-Term Care; Lopinavir; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Quality of Life; Randomized Controlled Trials as Topic; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Drug Synergism; Drug Therapy, Combination; Food-Drug Interactions; HIV Protease Inhibitors; Humans; Multicenter Studies as Topic; Nelfinavir; Randomized Controlled Trials as Topic; 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

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Cohort Studies; Drug Resistance, Multiple, Viral; Drug Synergism; Germany; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Salvage Therapy; Saquinavir

We describe 2 patients with acquired immunodeficiency syndrome who had potentially fatal bradyarrhythmia that occurred shortly after commencement of antiretroviral therapy. Lopinavir-ritonavir was the only drug that both patients were using.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Bradycardia; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

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 Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

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; Adult; Anti-HIV Agents; HIV Protease Inhibitors; HIV-1; Humans; Kidney Failure, Chronic; Male; Nevirapine; Peritoneal Dialysis, Continuous Ambulatory; Ritonavir

To study the effectiveness of anti-HIV therapy for vertical HIV-1 transmission based on the PACTG protocol 076, modified and adapted to Venezuela.. Between March 1997 and March 2000, 74 HIV-1-infected women (15-42 years old) with 77 singleton pregnancies were evaluated. Zidovudine (ZDV) 500 mg/day (average 8 weeks) was begun after Western blot confirmatory tests, independent of CD4+ count or viral load. ZDV was administered as follows: 47 patients (61 per cent) received prenatal, perinatal and postnatal therapy; 13 (17 per cent) received prenatal and postnatal therapy; two (3 per cent) received prenatal and perinatal therapy; one patient received perinatal and postnatal therapy; seven (9 per cent) received only postnatal therapy. Seven HIV-1 infected women received no treatment. Thirty-two newborns were obtained by C-section (45.7 per cent), while 38 were delivered vaginally (54.2 per cent). Due to advanced maternal illness, seven HIV-1-infected women received ZDV+3TC, two women received ZDV+ddI and one woman received ZDV+3TC+ Ritonavir. Breastfeeding was avoided in all cases.. Outcomes showed 65 term newborns and five preterm newborns; three abortions; one fetal loss and one preterm death. Two maternal/fetal deaths were secondary to complications related to AIDS at 27 and 29 weeks, respectively. Twenty-one children over 18 months old were considered uninfected. Thirty-five infants below 15 months of age were considered with the status of indeterminate HIV-1 infection (PO). Three infants fewer than 5 months of age with multiple risk factors were considered infected (P2). Two infants were asymptomatic and HIV positive at 12 months of age (P1). Eight children were lost to follow-up.. Independent of maternal status and delivery type, confirmed vertical transmission of HIV-1-infected women who received ZDV is 4.25 per cent. Prenatal care with a multidisciplinary team is necessary for good obstetric and newborn outcomes.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Ritonavir; Viral Load; Zidovudine

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

Topics: Acquired Immunodeficiency Syndrome; Adult; Cholesterol; Delavirdine; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Retinal Diseases; Retinal Vessels; Ritonavir; Saquinavir; Triglycerides; Viral Load; Zalcitabine

Lamivudine and zidovudine are proving to be an important antiretroviral combination against HIV that is superior to monotherapy. Recently, with the appearance of protease inhibitors, ritonavir has been shown to be a powerful drug when used in combination with reverse transcriptase inhibitors. The objective of this study was to observe the efficacy, adverse events, and changes in the quality of life of AIDS patients receiving treatment for the first time using AZT, 3TC and ritonavir as combination therapy. We selected 36 patients diagnosed with AIDS due to opportunistic infections and evaluated them by assessing their score on quality of life scales (Karnofsky, uniscale - Quality of Life, and Quality of Life Scale), T CD(4) and CD(8) lymphocyte counts, bodyweight and symptoms during a 6 month period. Assessments were made at 2 month intervals. One patient was excluded from the trial, therefore, 35 were assessed during 6 months.. Bodyweight increased an average of 7.2%, CD(4) increased 260 cells/mm(3) and CD(8) increased 198 cells/mm(3). The Karnofsky and uniscale QOL scales reached 100% on the fourth visit. The Quality of Life Scale showed an important increase during this study from 5.5+/-2.3 to 9.7+/-0.5. Adverse events were observed in 25.0% of the patients, most being slight. One patient had to stop taking ritonavir due to nausea and vomiting. We conclude that AZT, 3TC, and ritonavir restored the quality of life for the AIDS patients studied in terms of psychosocial aspects and overall health conditions during 6 months of treatment. The adverse events were probably related to ritonavir, but they were slight and disappeared after 2 weeks. There was a significant increase in the average number of CD(4) lymphocytes during 6 months of treatment.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Body Weight; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; Humans; Lamivudine; Male; Quality of Life; Ritonavir; Viral Load; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; United States; United States Food and Drug Administration

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Anti-HIV Agents; Carbamates; Coronary Disease; Dideoxynucleosides; Drug Therapy, Combination; Furans; Hepatitis B; HIV Protease Inhibitors; Humans; Hyperlipoproteinemias; Male; Middle Aged; Pancreatitis; Risk Factors; Ritonavir; Sulfonamides

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

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

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from lytic infection of oligodendrocytes by the papovavirus JC (JCV). PML has also been recognized as an AIDS-defining illness. The incidence of PML has increased since 1987 and it occurs in up to 4% of patients with AIDS. To date, there is no treatment available for PML and it usually results in death within 3-6 months of diagnosis. However, there are some reports of remission of PML after antiretroviral therapy. We report a 12-year-old child with hemophilia B and developing AIDS with the onset of PML. With highly active antiretroviral therapy, PML subsided with an increase of CD4 count from 10 to 300/microl in spite of about 1.0 X 10(4) human immunodeficiency virus (HIV)-1-RNA copies. He has survived more than 1 year without specific therapy against JCV. Highly active antiretroviral therapy appears to have improved his prognosis in HIV-associated PML.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Brain; CD4 Lymphocyte Count; Child; Hemophilia B; HIV Infections; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Papillomavirus Infections; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Zidovudine

Human immunodeficiency virus 1 (HIV-1) protease inhibitors have dramatically reduced the morbidity and mortality due to HIV-1 infection. However, most of these antiretrovirals are also potent inhibitors (and occasionally inducers) of hepatic and intestinal cytochrome P450 systems and, therefore, have the potential to alter the elimination of any substance that utilizes these metabolic pathways. We describe a patient infected with HIV-1 who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylenedioxymetamphetamine (MDMA or ecstacy) and a nearly fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). We also discuss the potential for HIV-1 protease inhibitors to alter the metabolism of other abusable prescribed and illicit substances.

Topics: Acquired Immunodeficiency Syndrome; Adrenergic Uptake Inhibitors; Adult; Anesthetics; Drug Synergism; Hallucinogens; HIV Protease Inhibitors; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine; Ritonavir; Saquinavir; Sodium Oxybate

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

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

We report a rare case of ergotism related to a single dose of ergotamine tartrate in a man with AIDS being treated with ritonavir. He was treated with a prostacyclin analogue and made a complete recovery.

Topics: Acquired Immunodeficiency Syndrome; Adult; Contraindications; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Administration Schedule; Ergotamine; Ergotism; HIV Protease Inhibitors; Humans; Male; Mixed Function Oxygenases; Ritonavir; Vasoconstrictor Agents

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; HIV Infections; HIV Protease Inhibitors; Hotlines; Humans; Patient Selection; Ritonavir; United States

A simple, ion-pair high-performance liquid chromatographic method has been developed and validated for the quantitative determination of the HIV protease inhibitor ritonavir in human plasma, cerebrospinal fluid and saliva. Sample pretreatment consisted of precipitation of proteins with acetonitrile prior to high-performance liquid chromatography with ultraviolet detection at 239 nm. The method has been validated over the range of 50 ng/ml to 50 microg/ml with use of 100-microl volumes of sample. The currently described assay has been used successfully for the analysis of ritonavir in plasma, cerebrospinal fluid and saliva in HIV-1 infected patients.

Topics: Acquired Immunodeficiency Syndrome; Chromatography, High Pressure Liquid; HIV Protease Inhibitors; HIV-1; Humans; Reproducibility of Results; Ritonavir; Saliva; Sensitivity and Specificity

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

It has long been assumed that HIV-1 evolution is best described by deterministic evolutionary models because of the large population size. Recently, however, it was suggested that the effective population size (Ne) may be rather small, thereby allowing chance to influence evolution, a situation best described by a stochastic evolutionary model. To gain experimental evidence supporting one of the evolutionary models, we investigated whether the development of resistance to the protease inhibitor ritonavir affected the evolution of the env gene. Sequential serum samples from five patients treated with ritonavir were used for analysis of the protease gene and the V3 domain of the env gene. Multiple reverse transcription-PCR products were cloned, sequenced, and used to construct phylogenetic trees and to calculate the genetic variation and Ne. Genotypic resistance to ritonavir developed in all five patients, but each patient displayed a unique combination of mutations, indicating a stochastic element in the development of ritonavir resistance. Furthermore, development of resistance induced clear bottleneck effects in the env gene. The mean intrasample genetic variation, which ranged from 1.2% to 5.7% before treatment, decreased significantly (P < 0.025) during treatment. In agreement with these findings, Ne was estimated to be very small (500-15,000) compared with the total HIV-1 RNA copy number. This study combines three independent observations, strong population bottlenecking, small Ne, and selection of different combinations of protease-resistance mutations, all of which indicate that HIV-1 evolution is best described by a stochastic evolutionary model.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Base Sequence; DNA Primers; Drug Resistance, Microbial; Evolution, Molecular; Gene Products, env; Genes, env; Genetic Variation; Genotype; HIV Protease Inhibitors; HIV-1; Humans; Molecular Sequence Data; Phylogeny; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Sequence Alignment; Sequence Homology, Amino Acid; Stochastic Processes

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV-1; Humans; Hyperlipidemias; Protease Inhibitors; Ritonavir; Saquinavir; Triglycerides

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; Fatal Outcome; Hallucinogens; Heart Arrest; Humans; Liver Diseases, Alcoholic; Male; N-Methyl-3,4-methylenedioxyamphetamine; Ritonavir

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

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Child; Child, Preschool; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Lamivudine; Ritonavir; Zidovudine

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

Michael Golk, a person with AIDS who is successfully maintaining a non-detectable viral load using Norvir combined with D4T and 3TC, describes his treatment regimen and use of nutritional supplements. Changes in Golk's nutritional supplement list (36 supplements were used) and the regimen and reasons for these changes are discussed. Changes are suggested to treat metabolic imbalances, such as high levels of triglycerides and high cholesterol, and to stimulate ATP production. The value of delavirdine vs. nevirapine in therapy is also discussed.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Dietary Fats; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Killer Cells, Natural; Lamivudine; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Triglycerides

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Humans; Product Surveillance, Postmarketing; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Analgesics, Non-Narcotic; Drug Therapy, Combination; Ergotamine; Ergotism; HIV Protease Inhibitors; Humans; Male; Middle Aged; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Canada; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Etoposide; HIV Protease Inhibitors; Humans; Isoquinolines; Nelfinavir; Prednisone; Randomized Controlled Trials as Topic; Ritonavir; Sulfonic Acids; Vincristine; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Models, Biological; Nevirapine; Pyridines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine

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; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; DNA, Viral; Herpesvirus 8, Human; HIV Protease Inhibitors; Humans; Male; Mouth Neoplasms; Ritonavir; Sarcoma, Kaposi; Skin Neoplasms

The effect of antiretroviral therapy on both T-cell numbers and T-cell function in peripheral blood was studied. CD4+ and CD8+ T-cell numbers, T-cell reactivity to CD3 monoclonal antibodies (mAb), and viral RNA load date were obtained from patients treated for at least 28 weeks with either the HIV-1 protease inhibitor ritonavir, the nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor nevirapine, or the nucleoside-analogue RT inhibitor zidovudine. Compared with both RT inhibitors, treatment with the protease inhibitor ritonavir resulted in the most significant and persistent elevation of CD4+ and CD8+ T-cell counts. However, in vitro T-cell functional improvement was of limited duration in the ritonavir-treated group and was inversely correlated with viral RNA load changes during the entire follow-up period. Thus, despite what can be assumed of responses during RT inhibitor therapy, quantitative responses on therapy did not necessarily correlate with qualitative immunologic responses, as can be seen during treatment with ritonavir. For optimal immune reconstitution, both numeric and functional immunologic improvements are essential. During antiretroviral therapy, measurement of in vitro improvement in immune function will be useful as a correlate for transient drug-induced alteration of immunodeficiency.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; HIV-1; Humans; Nevirapine; Ritonavir; RNA, Viral; T-Lymphocytes; Zidovudine

In order to test the hypothesis that a combination of protease inhibitors with nucleoside analogues-agents known to inhibit different steps of the human immunodeficiency virus (HIV) life cycle--is likely to prove more effective in reducing viral loads than either of those modalities alone, we performed a 60 week, open-label trial in 32 HIV-positive patients with depressed CD4 T lymphocyte cell counts but no active AIDS-defining illnesses. For the first 2 weeks, patients received 600 mg twice daily of liquid ritonavir, a protease inhibitor; then zidovudine 200 mg three times daily and zalcitabine 0.75 mg three times daily were added to the treatment regimen. Mononuclear blood cell fractions were analysed for infected cell levels, using a co-culture system. HIV-1 RNA in plasma was measured both by reverse transcriptase-polymerase chain reaction (RT-PCR) and reverse transcriptase quantitative PCR (QcRT-PCR); lymphocyte counts were determined by standard laboratory methods. In the 2 weeks of ritonavir therapy, both the mean count of infectious blood cells and plasma HIV RNA levels decreased dramatically. Mean CD4 cell counts increased from 173 cells/mm3 at baseline to 286 cells/mm3; CD8 cell counts rose from 951 cells/mm3 to 1,141 cells/mm3. With the introduction of the nucleoside analogues, infectious cell counts and plasma virus dropped another log unit to a nadir at 8 weeks, while CD4 T lymphocyte counts continued to rise slowly. By week 28, 12 patients had withdrawn due to adverse events, none of which were life-threatening. At week 36, infectious material could not be detected in the cells of 10 of the 17 remaining patients; by week 60, four of the seven patients with residual viraemia at week 24 had undergone viral relapse. After the introduction of a more palatable capsule formulation of ritonavir at week 52, infectious cells and plasma virus were undetectable in 50-60% of patients. The combination of protease inhibitors and nucleoside analogues significantly reduces HIV load, and in some patients may suppress viral activity for sustained periods.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Viral; Zalcitabine; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Didanosine; Drug Approval; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Ritonavir; United States; United States Food and Drug Administration; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Drug Approval; HIV Protease Inhibitors; Humans; Ritonavir; Thiazoles; Valine

Topics: Acquired Immunodeficiency Syndrome; France; HIV Protease Inhibitors; Humans; Public Opinion; Ritonavir; Thiazoles; Valine

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; Anti-HIV Agents; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Protease Inhibitors; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Time Factors; Zalcitabine; Zidovudine

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

Abbott Laboratories is providing ritonavir, a protease inhibitor, through an expanded access program. Abbott warns that the drug's use should be monitored very closely. Ritonavir blocks a liver enzyme and its use with medications that are normally metabolized by the liver may cause toxic levels to build quickly. Call Project Inform for a list of drugs which should not be taken with ritonavir.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Drug Interactions; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Liver; Ritonavir; Thiazoles; Valine

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

Abbott Laboratories' protease inhibitor, ritonavir, received Food and Drug Administration (FDA) approval in record time, and was available in pharmacies within a week of approval. Ritonavir is the only protease inhibitor to complete clinical-endpoint trials to date, and has a proven survival benefit. However, its drawbacks include strong drug interactions, resistance and cross resistance, and liver damage. Patients are cautioned to delay protease inhibitor treatment until Merck's Crixivan is available. Information from ritonavir's package insert is included, detailing usage, drug interactions, adverse events, and cost and reimbursement information. Ritonavir is the most expensive antiretroviral drug on the market.

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; HIV Protease Inhibitors; Humans; Ritonavir; Thiazoles; Valine

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

The disparity in the availability of AIDS drugs between the United States and Europe is frustrating to members of the European AIDS Treatment Group, among others. It is hoped that the newly-created European Medicines Evaluation Agency (EMEA) will streamline drug approval for the European Union overall, since previous approvals were done on a country-by-country basis. Although alternative methods of drug approval in Europe cause apprehension, it is hoped that a system will be created that will deliver drugs quickly without sacrificing the physician and patient guideline requirements.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Didanosine; Drug Costs; Europe; HIV Protease Inhibitors; Humans; Isoquinolines; Lamivudine; Quinolines; Ritonavir; Saquinavir; Thiazoles; United States; Valine; Zalcitabine; Zidovudine

The protease inhibitor ABT-538 (ritonavir) is available through a compassionate use program. Qualifications include a CD4 cell count of less than 50, and no prior experience with protease inhibitors, ketoconazole, rifabutin, tagamet, or psychotropics. Two-thirds of the 2000 participants will be from the United States. Participants will be selected by lottery. Ritonavir, manufactured by Abbott Laboratories, appears effective in reducing viral loads and increasing CD4 counts, but has significant side effects. Food and Drug Administration (FDA) approval of the drug in pill form is expected in three months.

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; HIV Protease Inhibitors; Ritonavir; Thiazoles; Valine

Saquinavir's manufacturer, Hoffmann-La Roche of Nutley, NJ, has begun a new trial that will study the effectiveness of saquinavir (Invirase) and ritonavir (Norvir) in combination. The study, which began recruitment in seven cities, will enroll 120 patients, both drug-experienced and naive, with CD4 counts between 100 and 500. According to researchers at the Aaron Diamond AIDS Research Center, in vitro studies show that they cannot grow virus in the presence of the two drugs. Of great concern is the safety issue. Researchers will closely watch toxicity levels and other possible adverse reactions. They warn patients not to experiment with the two drugs until the trial's results are known. The seven cities participating in the trial are: Pittsburgh; New York; Boston; Fairfax, VA; Los Angeles; San Francisco; and Ottawa, Canada.

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Isoquinolines; Quinolines; Ritonavir; Saquinavir; Thiazoles; Valine

Data from a multi-center study of combination therapy of two protease inhibitors is encouraging. The viral load reductions have been greater than would have been expected from either ritonavir or saquinavir alone. The two drugs are being studied in combination because ritonavir increases blood levels of saquinavir and because these protease inhibitors have somewhat different patterns of viral resistance development. Each drug alone has shown benefit in clinical trials. It is possible that this combination might work even better if combined with one or two nucleoside analogs.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Ritonavir; Saquinavir; Viral Load

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

Abbott Laboratories' refusal to provide any compassionate access to ABT-538, the company's experimental protease inhibitor, has caused U.S. AIDS organizations representatives to call for a protest. The first phase of the protest, scheduled from May 16 through May 22, involves representatives of some of the largest U.S. AIDS organizations calling and faxing Abbott's top executives. Representatives are requesting that Abbott set up a program this summer that will allow persons with a CD4 count under 50, who have failed approved treatments and have no other options, to receive ABT-538. Individuals can obtain an informative four-page packet by leaving a message on the voicemail of ACT UP/Golden Gate, (415) 252-9200.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Drug Industry; HIV Protease Inhibitors; Illinois; Pharmaceutical Services; Public Opinion; Ritonavir; Social Responsibility; Thiazoles; Valine

In early 1996, Abbott Pharmaceutical plans to establish a global compassionate use program for Ritonavir (ABT-538), its candidate protease inhibitor for the treatment of HIV/AIDS. Fifteen hundred people with advanced AIDS will be enrolled in the program, limited to patients with CD4+ counts of fifty or less who are failing other available antiretroviral drugs, and who have not enrolled in any other protease inhibitor trials. A formal announcement on the details of the program is expected in early November 1995.

Topics: Acquired Immunodeficiency Syndrome; Altruism; HIV Infections; HIV Protease Inhibitors; Humans; Ritonavir; Thiazoles; Valine

At a meeting with community treatment advocates in Chicago, Abbott Laboratories agreed to expand its access program for ritonavir (ABT-538). A complete patient eligibility profile for enrollment in the open label protocol for the drug has not yet been formulated. It appears that in vitro, ritonavir increases the concentration of saquinavir by 100-fold. Earlier reports of elevated liver enzymes from ritonavir are unfounded. Discussions between Roche and Abbott are underway for a clinical study of the double combination of ritonavir and saquinavir. Roche and Merck are also planning a double combination clinical study of Invirase plus Crixivan.

Topics: Acquired Immunodeficiency Syndrome; Dosage Forms; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Isoquinolines; Quinolines; Ritonavir; Saquinavir; Thiazoles; Valine

Descriptions and entry criteria for three expanded access programs for experimental drugs used in treating AIDS patients are provided. The programs involve use of Abbott Laboratories' protease inhibitor, ritonavir; Hoffman-La Roche's protease inhibitor, saquinavir; and Celgene Corporation's treatment for wasting, thalidomide.

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; Drugs, Investigational; HIV Protease Inhibitors; Humans; Ritonavir; Thalidomide; Thiazoles; Valine

A lottery will be used to select 2,000 participants for Abbott Laboratories' worldwide expanded access program for the protease inhibitor, ritonavir (previously known as ABT-538). The lottery will begin in January 1996. Participants must be over the age of twelve and have CD4 counts less than fifty. Other medical qualifications are also necessary.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; CD4 Lymphocyte Count; HIV Protease Inhibitors; Humans; Patient Selection; Ritonavir; Thiazoles; Valine

AIDS patients over age twelve, with CD4 counts of fifty or less, and who meet other health status-related criteria will be eligible to participate in the Abbott Laboratories' ritonavir lottery program. About 2,000 patients worldwide with advanced AIDS will participate. A new drug formulation may help diminish commonly seen adverse effects of ritonavir, such as nausea and diarrhea. There are also a significant number of other drugs which have adverse interactions with ritonavir.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; HIV Protease Inhibitors; Humans; Ritonavir; Thiazoles; Valine