ritonavir and fosamprenavir

Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide.. Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations.. Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echinocandins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-Retroviral Agents; Antifungal Agents; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Drug Monitoring; Echinocandins; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Mycoses; Organophosphates; Pyrimidines; Ritonavir; Sulfonamides; Triazoles; Voriconazole

Protease inhibitor monotherapy has been shown to be effective in maintaining long-term viral suppression in a majority of patients. Withdrawal of nucleoside analogues can prevent long-term toxicity related to these drugs. Clinical trials have recently reported preliminary data on the beneficial effect of protease inhibitor monotherapy on body fat distribution and bone metabolism. Some of the uncertainties possibly associated with protease inhibitor monotherapy such as the increased risk of neurological events and a higher level of subclinical inflammation will be discussed in this review.

Topics: Adipose Tissue; Bone Density; Carbamates; Drug Combinations; Drug Resistance, Viral; Furans; HIV Infections; Humans; Lopinavir; Organophosphates; Protease Inhibitors; Ritonavir; Sulfonamides

Protease inhibitors (PIs) are potent competitive inhibitors of the human immunodeficiency virus (HIV) widely used in the treatment of the acquired immune deficiency syndrome (AIDS) and prescribed in combination with other antiretroviral drugs. So far ten PIs were approved by the United States Food and Drug Administration (FDA) for the treatment of HIV infection. In this mini review, quality control methods of each PI are discussed on the basis of analytical techniques published in the literature. Special attention is given to summarize the LC methods described for the analysis of the selected PIs in both drug substances and products with the available literature till date.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Chromatography, Liquid; Darunavir; Drug Contamination; Furans; HIV Protease Inhibitors; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Organophosphates; Pyridines; Pyrimidinones; Pyrones; Quality Control; Ritonavir; Saquinavir; Sulfonamides

Fosamprenavir is a protease inhibitor (PI) approved for the treatment of HIV-1 infection. Fosamprenavir is a prodrug of amprenavir developed to reduce the pill burden yet maintain the unique resistance pattern and efficacy associated with amprenavir. In a head-to-head, noninferiority trial in antiretroviral treatment-naive HIV-infected patients, the antiviral efficacy and tolerability of ritonavir-boosted fosamprenavir was not inferior to ritonavir-boosted lopinavir, when the PIs were combined with two other nucleoside reverse transcriptase inhibitors. There are fewer studies published about fosamprenavir use in antiretroviral treatment-experienced HIV-infected patients. The high genetic barrier to the development of resistance to fosamprenavir and the low level of cross-resistance between ritonavir-boosted fosamprenavir and other PI regimens are notable. As with amprenavir, gastrointestinal disturbance and rash are the most frequent short-term treatment-limiting events with fosamprenavir. Treatment with ritonavir-boosted fosamprenavir can produce a durable response. To date, fosamprenavir is one of the recommended preferred PI components for the treatment of antiretroviral-naive HIV-infected patients.

Topics: Carbamates; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Exanthema; Furans; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Organophosphates; Ritonavir; Sulfonamides

Amprenavir is an HIV-1 protease inhibitor, the first in vitro activity studies of which were published in 1995. During in vivo development, it became clear that the pharmacokinetics of the drug would result in patients taking a large number of pills daily. The first comparative studies of amprenavir versus other protease inhibitors showed it had comparatively weak activity. Thus, studies using low doses of ritonavir to enhance the pharmacokinetic profile of amprenavir were first communicated in 2000. Only a small number of clinical trials in HIV-1-infected patients have been published. The pharmacokinetics of amprenavir have been documented in both healthy individuals and in HIV-1-infected patients. Amprenavir trough plasma concentrations increase 3- to 10-fold and the area under the concentration-time curve (AUC) increases 2- to 3-fold when using amprenavir 450 or 600 mg combined with ritonavir 100mg twice daily. Peak concentrations of amprenavir are less influenced by ritonavir coadministration, with a 1- to 2-fold increase. As there is no pharmacokinetic advantage to increasing ritonavir doses, the combination has only been used with low doses of ritonavir (100mg twice daily or 200 mg once or twice daily). Concomitant use of currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs)--efavirenz or nevirapine--is possible when amprenavir is coadministered with ritonavir, despite the pharmacokinetic interactions described when they are used with amprenavir alone. Fosamprenavir (GW 433908) is a prodrug of amprenavir primarily metabolised to amprenavir in the epithelial cells of the intestine. At steady state, plasma trough concentrations and AUC are slightly greater with fosamprenavir (two pills of 700 mg twice daily) than amprenavir (eight soft gel capsules of 150 mg twice daily). The clinical adverse effects of amprenavir are similar whether administered unboosted or in combination with ritonavir. Skin rashes do not appear to be more frequent. With regard to lipid profiles, the addition of ritonavir to amprenavir induces an increase in cholesterol and triglyceride levels; however, prospective comparative studies are lacking. In short-term prospective trials in antiretroviral-naive individuals, virological suppression with highly active antiretroviral therapy containing amprenavir plus ritonavir is similar to or higher than with unboosted amprenavir, with a smaller pill intake. Few comparative data are available in treatment-experienced

Topics: Anti-HIV Agents; Carbamates; Drug Resistance; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Organophosphates; Ritonavir; Sulfonamides

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

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

Pharmacokinetics, safety and antiviral activity of fosamprenavir (FPV) with ritonavir (RTV) twice daily were evaluated in HIV-1-infected infants and children 4 weeks to <2 years over 48 weeks.. Results from intensive pharmacokinetic sampling of subjects enrolled in single dose visits was used to determine individualized dosing for the first 6-10 subjects in each of 2 cohorts (4 weeks to <6 months, 6 months to <2 years); steady state pharmacokinetic data were then used to select the dosage regimen for the remaining subjects recruited to the cohort. Intensive pharmacokinetic sampling was performed at week 2 or 8; predose samples were collected every 4-12 weeks thereafter. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks.. Fifty-nine subjects received study medication. FPV 45 mg/kg boosted with RTV 7 to 10 mg/kg BID achieved average plasma amprenavir area under curve(0-τ) values 26% to 28% lower and Cmax similar to historical adult data for FPV/RTV 700/100 mg BID; amprenavir Cτ values were lower in the subjects <6 months of age. At week 48, 35 of 54 (65%) subjects had achieved plasma HIV-1 RNA <400 copies/mL and 33 of 54 (61%) had plasma HIV-1 RNA values <50 copies/mL. The most common adverse events were diarrhea, upper respiratory tract infection, gastroenteritis and otitis media.. Final FPV/RTV dosing regimens achieved plasma amprenavir exposures comparable with those from regimens approved in adults, with the exception of trough exposures in the <6-month-old infants. The FPV/RTV regimens led to viral suppression in 61% of patients and were generally well tolerated.

Topics: Carbamates; Cohort Studies; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Male; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Pharmacokinetics, safety and antiviral activity of twice-daily fosamprenavir with or without ritonavir were evaluated in 2- to 18-year-old protease inhibitor-naïve and -experienced HIV-1-infected children.. Serial pharmacokinetic samples were collected at week 2 and predose samples every 4-12 weeks. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks.. Twenty protease inhibitor-naïve 2- to <6-year-old subjects received antiretroviral treatment including unboosted fosamprenavir twice-daily, whereas 89 protease inhibitor-naïve and -experienced 2- to 18-year-old subjects received fosamprenavir/ritonavir-containing therapy twice-daily. Median fosamprenavir exposure was 891 days (range 15-1805 days), with 88% exposed >48 weeks. Twice-daily doses of fosamprenavir/ritonavir 23/3 mg/kg in 2- to <6-year olds, 18/3 mg/kg in ≥6-year olds and 700/100 mg in adolescents achieved plasma amprenavir exposures comparable with or higher than 700/100 mg twice-daily in adults while fosamprenavir 30 mg/kg twice-daily in 2- to <6-year olds led to exposures higher than 1400 mg twice-daily in adults. The proportion of subjects with HIV-1 RNA <400 copies/mL at week 48 was 60% for fosamprenavir and 53-74% for fosamprenavir/ritonavir (intent-to-treat [exposed], snapshot analysis). Median increases in absolute and relative (percentage) CD4 counts from baseline to week 48 occurred in both the fosamprenavir (340 cells/mm; 8%) and fosamprenavir/ritonavir group (190 cells/mm; 8%). The most common adverse events were vomiting, cough, and diarrhea; 18 subjects experienced serious adverse events, including 9 with suspected abacavir hypersensitivity.. Fosamprenavir regimens administered to HIV-1-infected children aged 2-18 years were generally well-tolerated and provided sustained antiviral activity over 48 weeks, with plasma amprenavir exposures comparable with or higher than adults.

Topics: Adolescent; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Child; Child, Preschool; Female; Furans; HIV Infections; HIV-1; Humans; Male; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.

Topics: Adolescent; Adult; Anti-HIV Agents; Antipsychotic Agents; Benzodiazepines; Carbamates; Chromatography, Liquid; Cross-Over Studies; Drug Interactions; Female; Furans; Healthy Volunteers; Humans; Male; Middle Aged; Olanzapine; Organophosphates; Ritonavir; Serum; Spectrophotometry, Ultraviolet; Sulfonamides; Young Adult

Dolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established "no-effect" boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier NCT01209065.).

Topics: Adult; Area Under Curve; Carbamates; Drug Administration Schedule; Drug Interactions; Female; Furans; Healthy Volunteers; Heterocyclic Compounds, 3-Ring; HIV Integrase; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Organophosphates; Oxazines; Piperazines; Pyridones; Ritonavir; Sulfonamides

Fosamprenavir (FPV) is the phosphate ester prodrug of the HIV-1 protease inhibitor amprenavir (APV). A pediatric population pharmacokinetic model for APV was developed and simulation was used to identify dosing regimens for pediatric patients receiving FPV in combination with ritonavir (RTV) which resulted in concentrations similar to those in adults receiving FPV/RTV 700/100 mg BID. Pharmacokinetic data was obtained from HIV infected subjects aged 2 months to 18 years receiving either FPV or FPV/RTV. A two-compartment model with first order absorption and elimination was an appropriate structural model. Significant covariates in the model included RTV coadministration on clearance, fed status on bioavailability for the oral suspension, body weight on clearance and volume terms, black race on clearance, and age on clearance. The following FPV/RTV twice daily dosing regimens in pediatric patients delivered plasma APV exposure similar to adults: 45/7 mg/kg in patients weighing <11 kg, 30/3 mg/kg in patients weighing 11 to <15 kg, 23/3 mg/kg in patients weighing 15 to <20 kg, and 18/3 mg/kg in patients weighting ≥20 kg. Additionally children weighing ≥39 kg can receive the adult regimen.

Topics: Adolescent; Carbamates; Child; Child, Preschool; Computer Simulation; Drug Dosage Calculations; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Male; Models, Biological; Organophosphates; Prodrugs; Ritonavir; Sulfonamides

Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy.. This 96-week, open-label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg, both with ABC/3TC 600 mg/300 mg, in antiretroviral-naïve, HLA-B*5701-negative adults without major resistance mutations to study drugs. We evaluated changes from baseline to weeks 4, 12, 24, 48, and 96 in interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), d-dimer, plasminogen, and fibrinogen. Biomarker data were log-transformed before analysis, and changes from baseline were described using geometric mean ratios.. This study enrolled 101 patients (51 receiving fosamprenavir/ritonavir; 50 receiving efavirenz): 32% female, 60% African American, and 38% Hispanic/Latino; 66% (67/101) completed 96 weeks on study. At week 96, levels of IL-6, sVCAM-1, d-dimer, fibrinogen, and plasminogen were lower than baseline in both treatment groups, and the decrease was statistically significant for sVCAM-1 (fosamprenavir/ritonavir and efavirenz), d-dimer (fosamprenavir/ritonavir and efavirenz), fibrinogen (efavirenz), and plasminogen (efavirenz). Values of hs-CRP varied over time in both groups, with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group. At week 96, there was no difference between the groups in the percentage of patients with HIV-1 RNA <50 copies/mL (fosamprenavir/ritonavir 63%; efavirenz 66%) by ITT missing-equals-failure analysis. Treatment-related grade 2-4 adverse events were more common with efavirenz (32%) compared with fosamprenavir/ritonavir (20%), and median lipid concentrations increased in both groups over 96 weeks of treatment.. In this study of underrepresented patients, treatment with abacavir/lamivudine combined with either fosamprenavir/ritonavir or efavirenz over 96 weeks, produced stable or declining biomarker levels except for hs-CRP, including significant and favorable decreases in thrombotic activity (reflected by d-dimer) and endothelial activation (reflected by sVCAM-1). Our study adds to the emerging data that some cardiovascular biomarkers are decreased with initiation of ART and control of HIV viremia.. ClinicalTrials.gov identifier NCT00727597.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Biomarkers; C-Reactive Protein; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Furans; HIV Infections; Humans; Interleukin-6; Lamivudine; Male; Middle Aged; Organophosphates; Plasminogen; Prospective Studies; Ritonavir; Sulfonamides; Vascular Cell Adhesion Molecule-1; Young Adult

This open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ, Cmax, and Cτ were increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ, Cmax, and Cτ decreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Carbamates; Cyclohexanes; Drug Administration Schedule; Drug Combinations; Drug Dosage Calculations; Drug Interactions; Furans; Humans; Male; Maraviroc; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Triazoles

Steady-state pharmacokinetics in pregnant women prescribed ritonavir-boosted fosamprenavir (FPV) to prevent HIV transmission were assessed in the second trimester, third trimester, and postpartum. Compared with postpartum, geometric mean amprenavir (APV, FPVs active metabolite) area under the plasma concentration-time curves were 35% lower in the second trimester and 25% lower in the third trimester. Maternal APV concentrations were 9- to 15-fold above the mean APV protein-adjusted 50% inhibitory concentration for wild-type HIV. Median ratio of cord blood/maternal APV levels was 0.27, and all infants were HIV negative. FPV/ritonavir during pregnancy was well tolerated and led to virologic suppression.

Topics: Adult; Area Under Curve; Carbamates; Disease Transmission, Infectious; Female; Fetal Blood; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Infant, Newborn; Organophosphates; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Sulfonamides; Young Adult

This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir.. The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non-opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine.. There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine.. Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.

Topics: Anti-HIV Agents; Area Under Curve; Buprenorphine; Carbamates; Darunavir; Drug Interactions; Female; Furans; Half-Life; History, 16th Century; History, 17th Century; Humans; Male; Naloxone; Narcotic Antagonists; Opiate Substitution Treatment; Organophosphates; Protease Inhibitors; Ritonavir; Sulfonamides

Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV-coinfected patients, including those with cirrhosis.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Cohort Studies; Drug Therapy, Combination; Female; Furans; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver Cirrhosis; Male; Middle Aged; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides

Objective An open-label, three-period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF). Methods Thirty-six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty-four-hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady-state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals. Results After TDF coadministration, APV geometric mean minimum concentration (C(min)), maximum concentration (C(max)), and area under the plasma concentration-time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV C(min), C(max) and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods. Conclusions In this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.

Topics: Adenine; Adolescent; Adult; Aged; Anti-HIV Agents; Carbamates; Cross-Over Studies; Drug Administration Schedule; Drug Eruptions; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; Humans; Male; Middle Aged; Organophosphates; Organophosphonates; Prodrugs; Ritonavir; Sulfonamides; Tenofovir; Young Adult

The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4(+) counts compared to no therapy.. Participants not on continuous ART with > or = 300 CD4(+) cells/mm(3) were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4(+) counts, HIV RNA, and HIV progression events were collected monthly.. A total of 267 participants were randomized. At week 32, the mean CD4(+) count was 134 cells greater in the IL-2 alone group (p<0.001), and 133 cells greater in the IL-2 plus ART group (p<0.001) compared to the no therapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group assigned to no therapy experienced an opportunistic event or died (HR 5.84, CI: 0.59 to 43.57; p = 0.009).. IL-2 alone or with peri-cycle HAART increases CD4(+) counts but was associated with a greater number of opportunistic events or deaths compared to no therapy. These results call into question the immunoprotective significance of IL-2-induced CD4(+) cells.. ClinicalTrials.gov NCT00110812.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Carbamates; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Furans; HIV Infections; Humans; Interleukin-2; Lopinavir; Male; Nausea; Oligopeptides; Opportunistic Infections; Organophosphates; Pyridines; Pyrimidinones; Ritonavir; Sulfonamides; Treatment Outcome

Population genotyping (PG) can underestimate resistance if resistance-containing low abundance variants go undetected. PG and clonal analysis (CA) results were compared in virologic failures (VFs) from a 48-week clinical trial that evaluated once-daily fosamprenavir/ritonavir (FPV/r) 1400 mg/100 mg or atazanavir/ritonavir (ATV/r) 300 mg/100 mg, each combined with tenofovir/emtricitabine, in antiretroviral-naive patients. VF was defined as confirmed HIV-1 RNA > or =400 copies/ml at > or =24 weeks or viral rebound >400 copies/ml any time following viral suppression. All patients had baseline PG. One hundred and six patients enrolled (53/arm). Baseline resistance mutations were more prevalent in patients receiving FPV/r (10/53) than ATV/r (3/53). Seven patients (7%) were VFs-four on FPV/r and three on ATV/r. In the four FPV/r-treated VFs, baseline HIV TAMs combinations and/or PI mutations were detected in one by PG at VF (RT: L210W + T215C; PR: M46I + L76V) and three others by CA alone (RT: L210W + T215Y; RT: M41L; RT: K65R + K70R; PR: I47V); all four had study drug-associated mutations (CA detecting more HIV-1 resistance mutations than PG). In the three ATV/r VFs, no baseline drug-associated mutations were detected by PG; for one patient CA detected RT: K65R; PR: I84V. Phylogenetic analysis revealed tight clustering for FPV/r-treated VFs with highly related clones, whereas HIV-1 from ATV/r-treated VFs had no outgrowth from baseline of low abundance resistance-containing variants. In conclusion, low-abundance HIV resistance-containing variants were detected in baseline samples from patients with VF. The archived viruses that reemerged under selection pressure and acquired additional mutations were found primarily in patients in the FPV/r arm. Despite this and a baseline resistance imbalance between the two arms, FPV/r and ATV/r provided similar virologic suppression through 48 weeks; however, these findings highlight the necessity for the development of quick and inexpensive methods for detection of minority species to better guide therapy selection.

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; Atazanavir Sulfate; Carbamates; Deoxycytidine; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Emtricitabine; Furans; Genetic Variation; HIV Infections; HIV-1; Humans; Middle Aged; Oligopeptides; Organophosphates; Organophosphonates; Pyridines; Ritonavir; RNA, Viral; Sequence Analysis, RNA; Sulfonamides; Tenofovir; Treatment Failure

Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals.. HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2.. A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant.. In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.

Topics: Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Carbamates; Confidence Intervals; Drug Administration Schedule; Drug Combinations; Dyslipidemias; Furans; HIV Infections; HIV-1; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Lopinavir; Male; Organophosphates; Organophosphonates; Pyrimidinones; Ritonavir; Sulfonamides; Tenofovir

The use of protease inhibitors (PI) has led to a decrease in HIV-1-related mortality and morbidity. The objective of this study was to collect safety data on treatment with fosamprenavir/ritonavir (FPV/r) 700/100mg BID in HIV-infected patients through an expanded access program.. Prospective, multicenter, noncomparative study in HIV-1 infected adults, for whom a regimen containing FPV/r 700/100mg BID was appropriate.. A total of 678 patients were included in the intention-to-treat (ITT) and safety population. The on-treatment (OT) population contained 587 patients: 76% male, 98% Caucasian, and median age 41 years. Median CD4 cell count was 351 cells/microL, HIV-RNA was 3 log copies/mL, and 49% of patients were in CDC class C. After 24 weeks of treatment, serum viral load decreased a median of 1.3 log copies/mL and 73% of patients had <400 copies/mL (P<.0001 vs. baseline); 48-week results were similar. CD4 cell count increased a median of 49 and 62 cells/microL at 24 and 48 weeks, respectively. Adverse events (AEs) associated with the study medication occurred in 21% of patients.. Ritonavir-boosted fosamprenavir as part of antiretroviral therapy is a potent, safe treatment in real-life clinical circumstances.

Topics: Adult; Carbamates; CD4 Lymphocyte Count; Comorbidity; Drug Therapy, Combination; Female; Fever; Furans; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Hypercholesterolemia; Hypertriglyceridemia; Male; Organophosphates; Ritonavir; RNA, Viral; Spain; Sulfonamides; Viral Load; Viremia

The long-term efficacy of once-daily (qd) fosamprenavir (FPV) 1400 mg boosted by ritonavir 100 mg (FPV/r100) has not been evaluated previously. A 96-week open-label, randomized, multicenter study compared the efficacy/safety of FPV/r100 with FPV 1400 mg boosted by ritonavir 200 mg qd (FPV/r200), plus abacavir/lamivudine 600 mg/300 mg qd, in antiretroviral-naive, HIV-infected patients with viral load (VL)> or =1000 copies/ml. Primary endpoints were proportion of patients achieving VL <400 copies/ml or discontinuing for drug-related reasons. In the intent-to-treat:exposed (ITT-E) population, missing = failure (M = F), and observed approaches were used to assess between-arm differences in VL responses by Cochran-Mantel-Haenszel test and CD4(+) count by Wilcoxon rank-sum test. One hundred and fifteen (115) patients enrolled, with 58 on FPV/r100 (median VL 4.7 log(10) copies/ml; CD4(+) count 259 cells/mm(3)) and 57 on FPV/r200 (median VL 4.9 log(10) copies/ml; CD4(+) count 179 cells/mm(3)). Fewer FPV/r100-treated patients discontinued treatment prematurely (12 vs. 24) and experienced virologic failure (5 vs. 8, none developing major protease inhibitor resistance mutations). At week 96, more FPV/r100-treated patients had VL <400 copies/ml [ITT-E,M = F: 78% (45/58) vs. 53% (30/57), p = 0.006; observed: 98% (45/46) vs. 94% (30/32)] and VL<50 copies/ml [ITT-E,M = F: 66% (38/58) vs. 53% (30/57); observed: 83% (38/46) vs. 94% (30/32)]. The FPV/r100 and FPV/r200 arms were similar at week 96 regarding median change from baseline in CD4(+) count (+265 vs. +260 cells/mm(3)) and total cholesterol (+33 vs. +35 mg/dl), and in total-cholesterol:HDL-cholesterol ratio (4.0 vs. 4.1) and type/frequency of treatment-related grade 2-4 adverse events, although FPV/r100 was associated with a lower elevation in triglycerides (+27 vs. +48 mg/dl). In conclusion, through 96 weeks, FPV/r100 was more effective and prompted less elevation in triglycerides than FPV/r200.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphates; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

We evaluate the efficacy and tolerability of ritonavir-boosted dual protease inhibitor as a nucleoside reverse transcriptase inhibitor-sparing regimen in a prospective open-label randomized pilot trial in antiretroviral-naive patients.. Thirty patients received fosamprenavir/atazanavir/ritonavir (Group 1) and 31 patients received saquinavir/atazanavir/ritonavir (Group 2). The primary endpoint for efficacy was the rate of early virological success, defined as plasma viral load <50 copies/mL at week 16. The study is registered with ClinicalTrials.gov (NCT00122603).. At baseline, median (range) viral load was 4.8 log(10) copies/mL (4.0-5.7) and the median CD4 cell count was 271/mm(3) (197-740). Viral load was <50 copies/mL in 12/30 patients [40%, 95% confidence interval (CI) 23%-58%] and 13/31 patients (42%, 95% CI 25%-59%) at week 16 in Groups 1 and 2, respectively. Patients with failing regimens (viral load >or=400 copies/mL at week 16 or >or=50 copies/mL at week 24) were switched to a standard antiretroviral regimen. At week 48, by an intention-to-treat analysis, 23/30 patients (77%) and 26/31 patients (84%) had plasma HIV-1 RNA <50 copies/mL in Groups 1 and 2, respectively. Four patients discontinued treatment for adverse events, all before week 4. No major changes in the protease gene were detected at treatment failure relative to baseline. Baseline viral load <50 000 copies/mL was the only predictor of virological success at week 16.. Ritonavir-boosted dual protease inhibitor regimens targeting only one step of viral replication were insufficient to rapidly suppress plasma HIV RNA to <50 copies/mL in antiretroviral-naive patients with high viral load at baseline.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Asparagine; Atazanavir Sulfate; Carbamates; CD4 Lymphocyte Count; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Oligopeptides; Organophosphates; Pyridines; Quinolines; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

APV102002 was an open-label study comparing a dual-boosted HIV-1 protease inhibitor (PI) [fosamprenavir/lopinavir/ritonavir (FPV/LPV/RTV; 1400 mg/533 mg/133 mg twice daily)] and a high dose of FPV/RTV 1400 mg/100 mg twice daily (HD-FPV/RTV) versus the standard FPV/RTV 700 mg/100 mg twice-daily (STD-FPV/RTV) regimen for 24 weeks.. Adult patients with prior failure to two or more PI-based regimens and on a failing PI regimen were randomized to STD-FPV/RTV (n = 24), HD-FPV/RTV (n = 25) or FPV/LPV/RTV (n = 25). The primary aim was to test week 24 superiority of HD-FPV/RTV and FPV/LPV/RTV over STD-FPV/RTV as measured by plasma HIV-1 RNA average area under the curve minus baseline (AAUCMB).. There was no difference in the week 24 AAUCMB between the regimens. The proportion of patients with <50 copies/mL of plasma HIV RNA was 21%, 24% and 20%, respectively, by time to loss of virological response (TLOVR) analysis. High baseline drug resistance provided some explanation for the low efficacy. A lower baseline background drug resistance and higher fosamprenavir genotypic inhibitory quotient led to better antiviral responses. The plasma amprenavir trough concentartion (C(tau)) was 49% higher in the HD-FPV/RTV arm than in the STD-FPV/RTV arm and similar in the FPV/LPV/RTV and STD-FPV/RTV arms. The plasma lopinavir C(tau) was similar to historical data with standard LPV/RTV 400 mg/100 mg twice daily. All regimens were relatively well tolerated, although diarrhoea was more frequent in the HD-FPV/RTV and FPV/LPV/RTV arms, and hypertriglyceridaemia and increased total cholesterol were more common in the FPV/LPV/RTV arm.. While the strategies of higher dose FPV/RTV and dual FPV/LPV/RTV were relevant at the time of study initiation, new therapies for antiretroviral-experienced patients make such strategies of limited interest. In addition, this study failed to demonstrate antiviral superiority of the HD-FPV/RTV or FPV/LPV/RTV regimen over the STD-FPV/RTV twice-daily regimen in highly treatment-experienced patients.

Topics: Adult; Aged; Anti-HIV Agents; Carbamates; Drug Resistance, Viral; Female; Furans; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

To quantify the pharmacokinetics of amprenavir and atazanavir (administered as the prodrug fosamprenavir) alone and in combination in human immunodeficiency virus (HIV)-negative subjects.. Randomized, open-label, three-way crossover study.. Research facility.. Eleven men and 10 women who were seronegative for HIV.. Subjects were randomized to 14-day treatment periods of fosamprenavir 1400 mg once/day, atazanavir 400 mg once/day, or fosamprenavir 1400 mg plus atazanavir 400 mg once/day; after a washout period of at least 21 days between each treatment, they received the other two treatments.. Subjects underwent 24-hour pharmacokinetic sampling at baseline and on day 14 of each treatment period. Primary outcome measures were area under the plasma concentration-time curve (AUC) and maximum concentration (C(max)) for amprenavir and atazanavir. Atazanavir significantly enhanced the exposure of amprenavir. When fosamprenavir was given alone, the geometric mean of amprenavir's AUC was 20.2 microg x hour/ml (95% confidence interval [CI] 19.1-21.2 microg x hr/ml). When given in combination with atazanavir, amprenavir had an AUC of 39.8 microg x hour/ml (95% CI 38.7-40.9 microg x hr/ml). Similarly, the C(max) for amprenavir increased from 4193 ng/ml (95% CI 3927-4459 ng/ml) to 6621 ng/ml (95% CI 6427-6814 ng/ml) when given in combination with atazanavir. In contrast, AUC and C(max) for atazanavir significantly decreased when atazanavir was coadministered with fosamprenavir; AUC decreased from 17.6 microg x hour/ml (95% CI 16.6-18.7 microg x hr/ml) to 11.8 microg x hour/ml (95% CI 11.3-12.3 microg x hr/ml), and C(max) decreased from 2507 ng/ml (95% CI 2379-2635 ng/ml) to 1832 ng/ml (95% CI 1752-1911 ng/ml). Adverse events were assessed at each study visit and 1 month after the subjects completed the three treatments. Both drugs were well tolerated. One serious adverse event (grade 3 acute pancreatitis) occurred and resolved without further incident.. Atazanavir 400 mg/day plus fosamprenavir 1400 mg/day significantly decreased concentrations of atazanavir compared with standard dosing regimens of each drug alone. This dosing scheme is not a recommended combination of dual, fully active protease inhibitors.

Topics: Adolescent; Adult; Aged; Atazanavir Sulfate; Carbamates; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; HIV Seronegativity; Humans; Male; Middle Aged; Oligopeptides; Organophosphates; Prodrugs; Pyridines; Ritonavir; Sulfonamides

The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (C(max)), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0-tau)], similar values for the concentration at the end of the dosing interval (C(tau)), and 114% higher unbound C(tau) values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir C(max) values, 27% lower AUC(0-24) values, 57% lower C(tau) values, and 21% higher unbound amprenavir C(tau) values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir C(max) values, 23% lower AUC(0-24) values, 38% lower C(tau) values, and similar unbound amprenavir C(tau) values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.

Topics: Adolescent; Adult; Aged; Carbamates; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Young Adult

Rosuvastatin (RSV) is a potent statin with a lower potential for drug interactions. However, recent data have revealed unexpected increases in RSV concentrations with lopinavir/ritonavir. The objective is to study the pharmacokinetic interaction of RSV with atazanavir/ritonavir (ATV/RTV) or fosamprenavir/ritonavir (FPV/RTV).. In a prospective pharmacokinetic drug interaction study, six HIV-seronegative, healthy adult volunteers received single 10-mg doses of RSV at baseline and after 6 days of ATV/RTV and FPV/RTV, with 6-day washout periods. Plasma concentrations of RSV and its metabolites, N-desmethyl-RSV and RSV-lactone, were measured by using a internally validated tandem mass spectrometric (LC-MS/MS) method over 24 hours.. Compared to baseline, the area under the plasma concentration-time curve (AUC 0-24h) and maximum plasma concentration (Cmax) of RSV increased by 213% and 600%, respectively, and the time to reach Cmax was shorter (1.75 h vs. 2.91 h) when given with ATV/RTV (P < 0.05). However, coadministration with FPV/RTV did not significantly affect the pharmacokinetics of RSV. The AUC 0-24h of N-desmethyl-RSV was not significantly affected by either combinations, but that of RSV-lactone increased (P < 0.05) by 61% and 76% after coadministration with ATV/RTV and FPV/RTV, respectively.. ATV/RTV significantly increases the plasma concentrations of rosuvastatin, most likely by increasing rosuvastatin's oral bioavailability. Dose limitations of RSV with ATV/RTV may be needed.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Atazanavir Sulfate; Carbamates; Drug Combinations; Drug Interactions; Female; Fluorobenzenes; Furans; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Oligopeptides; Organophosphates; Prospective Studies; Pyridines; Pyrimidines; Ritonavir; Rosuvastatin Calcium; Sulfonamides

To compare steady-state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg-ritonavir 100 mg twice/day.. Open-label, single-sequence, two-period crossover, drug-interaction study.. Two university-affiliated research centers.. Twenty-six opioid-dependent, methadone-maintained, healthy adults.. Subjects received their usual daily dose of methadone alone for 4 days (period 1). Subjects then received the same daily dose of methadone plus fosamprenavir 700 mg-ritonavir 100 mg twice/day for 14 days (period 2).. Blood was collected on days 1-4 (period 1) and on days 11-14 (period 2) for plasma R- and S-methadone concentrations; amprenavir concentrations were assessed during period 2. Opioid-effect measures were assessed in each study period. Subjects served as their own controls for comparison of period 1 with period 2. Coadministration of fosamprenavir-ritonavir with methadone reduced plasma total R-methadone area under the plasma concentration-time curve over the dosing interval at steady state (AUC tau-ss) by 18%, maximum concentration at steady state (Cmax-ss) by 21%, and concentration at the end of the dosing interval at steady state (Ctau-ss) by 11%; time to reach Cmax-ss (Tmax) was delayed by 1.75 hours. Coadministration of fosamprenavir-ritonavir with methadone also reduced plasma total S-methadone AUC tau-ss and Cmax-ss by 43% each, Ctau-ss by 41%, and delayed Tmax by 0.85 hours. Fosamprenavir-ritonavir administered with methadone did not alter plasma amprenavir pharmacokinetics compared with historical control data; nor did it alter the unbound R-methadone at 2 and 6 hours after methadone dosing. Pharmacodynamic indexes remained essentially unchanged after adding fosamprenavir-ritonavir to methadone. No subject demonstrated opioid intoxication or withdrawal, or requested methadone dosage modification.. No adjustment in the dosages of either methadone or fosamprenavir 700 mg-ritonavir 100 mg twice/day is required during coadministration, on the basis of the small reduction in total R-methadone exposure, no change in unbound R-methadone, no clinically important opioid effects, and no change in amprenavir exposure.

Topics: Adult; Anti-HIV Agents; Carbamates; Cross-Over Studies; Drug Interactions; Female; Furans; Humans; Male; Methadone; Narcotics; Organophosphates; Prodrugs; Ritonavir; Stereoisomerism; Sulfonamides

Recent data indicate that fosamprenavir/ritonavir as part of an initial antiretroviral regimen in HIV-1-infected patients is associated with favourable efficacy and tolerability and in the KLEAN study (kaletra versus lexiva with epivir and abacavir in antiretroviral-naive patients) it was found to be non-inferior to lopinavir/ritonavir in association with abacavir/lamivudine. In our open-label, observational study conducted in 82 therapy-nasmall yi, Ukrainianve HIV-1-infected patients followed-up for 18 months, virological and immunological efficacy was comparable in subjects receiving a fosamprenavir/ritonavir-based and a lopinavir/ritonavir-based treatment (proportions of patients with HIV RNA <50 copies/mL at month 18 were 76.9% and 74.4%, respectively, when discontinuations were counted as failures). At the same time, frequency of treatment discontinuations and adverse events were similar in both groups, whereas incidence of diarrhoea and hypertriglyceridaemia was significantly higher in lopinavir-treated patients than in fosamprenavir-treated ones (53.5% vs. 25.6% and 69.8% vs. 43.6%, respectively; P < 0.01). In subjects with virological failure, no viral protease resistance mutations were detected by genotype analysis.

Topics: Adult; Anti-HIV Agents; Carbamates; Diarrhea; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease; HIV-1; Humans; Hypertriglyceridemia; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Failure; Treatment Outcome

The aim of this study was to identify human immunodeficiency virus (HIV) protease mutations associated with virological response (VR) to fosamprenavir-ritonavir (FPV/r) in 113 protease inhibitor (PI)-experienced patients randomized in both CONTEXT and TRIAD clinical trials and receiving the same dose (700/100 mg twice daily) of FPV/r. The impact of each protease mutation on the VR to FPV/r, defined as the decrease in HIV RNA at week 12, was investigated with nonparametric analyses. A step-by-step procedure was done using a Jonckheere-Terpstra (JT) test that retains the group of mutations most strongly associated with the VR. Mutations at the following 14 codons were associated with a reduced VR to FPV/r: 10, 15, 33, 46, 54, 60, 62, 63, 72, 73, 82, 84, 89, and 90. The JT procedure led to selecting the CONTEXT/TRIAD genotypic set of mutations, I15V, M46I/L, I54L/M/V, D60E, L63P/T, and I84V, as providing the strongest association with the VR (P = 1.45 x 10(-11)). In the nine patients with zero mutations within this set, the median decrease in HIV RNA was -2.63 log copies/ml, and was -2.22 (n = 45), -1.50 (n = 26), -0.58 (n = 23), -0.47 (n = 6), -0.13 (n = 3), and 0.04 (n = 1) log copies/ml in those with one, two, three, four, five, and six mutations, respectively. This study identified six mutations associated with VR to FPV/r. Some of these mutations are shared with the current FPV/r Agence Nationale de Recherches sur le SIDA (ANRS) resistance score, which has been cross-validated in the CONTEXT/TRIAD data set, suggesting that the current ANRS FPV/r score is a useful tool for the prediction of VR to FPV/r in PI-experienced patients.

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Resistance, Viral; Female; Furans; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Male; Mutation; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC(0-48)) and a 14% decrease in the maximum concentration of drug in plasma (C(max)), whereas the AUC(0-48) and C(max) of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC(0-48). Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC(0-tau)) and C(max) were increased approximately 35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by > or =75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).

Topics: Adult; Antitubercular Agents; Area Under Curve; Carbamates; Cross-Over Studies; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Furans; Humans; Male; Middle Aged; Organophosphates; Rifabutin; Ritonavir; Sulfonamides

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

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

Human immunodeficiency virus-infected patients have an increased risk for depression. Despite the high potential for drug-drug interactions, limited data on the combined use of antidepressants and antiretrovirals are available. Theoretically, ritonavir-boosted protease inhibitors may inhibit CYP2D6-mediated metabolism of paroxetine. We wanted to determine the effect of fosamprenavir-ritonavir on paroxetine pharmacokinetics and vice versa and to evaluate the safety of the combination. Group A started with 20 mg paroxetine every day for 10 days; after a wash-out period of 16 days, subjects received paroxetine (20 mg every day) plus fosamprenavir-ritonavir (700/100 mg twice a day) from days 28 to 37. Group B received the regimens in reverse order. On days 10 and 37, pharmacokinetic curves were recorded. Twenty-six healthy subjects (18 females, 8 males) were included. Median (range) age and weight were 44.4 (18.2 to 64.3) years and 68.8 (51.0 to 89.4) kg. Three subjects were excluded (two because of adverse events; one for nonadherence). Addition of fosamprenavir-ritonavir to paroxetine resulted in a significant decrease in paroxetine exposure: the geometric mean ratios (90% confidence intervals) of paroxetine plus fosamprenavir-ritonavir to paroxetine alone were 0.45 (0.41 to 0.49) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (C(max)), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (t(1/2)). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC(0-12), C(max), C(min), and t(1/2) of amprenavir and ritonavir were similar to those of historical controls. No serious adverse events occurred. Fosamprenavir-ritonavir reduced total paroxetine exposure by 55%. This is partly explained by protein displacement of paroxetine. We think that this interaction is clinically relevant and that titration to a higher dose of paroxetine may be necessary to accomplish the needed antidepressant effect.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antidepressive Agents, Second-Generation; Area Under Curve; Carbamates; Drug Interactions; Female; Furans; Genotype; Humans; Male; Metabolic Clearance Rate; Middle Aged; Organophosphates; Paroxetine; Ritonavir; Sulfonamides

Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (Cmax), the area under the plasma concentration-time curve over the dosing period (AUC0-tau), and trough concentrations (Ctau) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC0-tau (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and Cmax (0.97 [90% CI, 0.91 to 1.04]). The APV Ctau was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV Ctau observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV Ctau was 2.5 times higher than the historical Ctau for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; Female; Furans; HIV Infections; Humans; Male; Middle Aged; Organophosphates; Prodrugs; Ritonavir; Sulfonamides

Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

Topics: Adolescent; Adult; Antifungal Agents; Area Under Curve; Carbamates; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; Humans; Ketoconazole; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Treatment Outcome

The effect of tenofovir disoproxil fumarate (TDF) in combination with two boosted fosamprenavir regimens on amprenavir pharmacokinetic parameters was assessed in this prospective phase I crossover study with 30 healthy volunteers. The co-administration of TDF 300 mg once a day with fosamprenavir/ritonavir 1400/200 mg or 1400/100 mg once a day has no effect on the pharmacokinetics of amprenavir and results in non-significant increases of ritonavir pharmacokinetic parameters, suggesting that no dose modification is necessary when combining fosamprenavir/ritonavir with TDF.

Topics: Adenine; Anti-Retroviral Agents; Area Under Curve; Carbamates; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; HIV Seronegativity; Humans; Male; Organophosphates; Organophosphonates; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Tenofovir

Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions.. Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2).. In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06 microg/ml, P = 0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34 microg x h/ml, P = 0.22) or maximum concentration (Cmax; 2.61 versus 4.33 microg/ml, P = 0.08); for LPV there was no difference in Cmin, (median: 3.66 versus 6.18 microg/ml, P = 0.20), AUC (81.84 versus 93.75 microg x h/ml, P = 0.37) or Cmax (10.36 versus 10.93 microg/ml, P = 0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 microg/ml, P = 0.0001), AUC by 76% (19.41 versus 34.24 micorg x h/ml, P = 0.0001), and Cmax by 75% (3.50 versus 6.14, P = 0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up).. EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Ritonavir; Sulfonamides

High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval (tau) at steady state [AUC(0-tau)], maximum concentration of drug in plasma (C(max)), and plasma concentration at the end of tau at steady state (C(tau)) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC(0-tau), C(max), and C(tau) were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.

Topics: Adolescent; Adult; Carbamates; Clinical Trials as Topic; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; HIV Seronegativity; Humans; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides

To compare the effect of ritonavir on plasma amprenavir pharmacokinetics, healthy adults received either fosamprenavir (700 mg twice a day [BID]) or amprenavir (600 mg BID) alone and in combination with ritonavir (100 mg BID). Ritonavir increased plasma amprenavir pharmacokinetic parameters to a similar extent when coadministered with either fosamprenavir or amprenavir.

Topics: Adult; Area Under Curve; Carbamates; Cross-Over Studies; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; Humans; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides

In the SOLO study (APV30002), once-daily antiretroviral treatment with the protease inhibitor fosamprenavir (FPV) 1,400 mg boosted by ritonavir (r) 200 mg plus abacavir/lamivudine (ABC/3TC) was found to be noninferior to nelfinavir plus ABC/3TC over 48 weeks in treatment-naive patients with HIV -1 infection.. This interim report presents antiviral efficacy and tolerability data from 211 patients who received FPV/r QD for at least 48 weeks in SOLO and continued this treatment in the follow-on study (APV30005) for up to 120 weeks.. APV30005 is an international, multicenter, uncontrolled, open-label, follow-on study conducted to provide continued access to FPV in patients with HIV-1 infection who had participated in previous FPV studies, including SOLO, and to obtain longer-term data on the antiviral response and tolerability of an FPV-containing regimen. Patients who had completed at least 48 weeks of FPV/r therapy in the SOLO study were eligible to enter the follow-on study and continue receiving FPV/r 1,400/200 QD, with study visits every 12 weeks. Their background regimens were chosen at the investigators' discretion and could be changed at any time. Antiviral response end points included plasma HIV-1 RNA levels <400 and <50 copies/mL, median plasma HIV-1 RNA levels, median and absolute changes from baseline in the CD4 cell count, and the frequency of HIV disease progression. Genotype and phenotype analyses were performed for patients meeting the criterion for virologic failure (defined as plasma HIV -1 RNA >1,000 copies/mL on 2 consecutive occasions on or after week 12). Tolerability was assessed in terms of adverse-event reports evaluated by the primary investigator and changes in laboratory values. Assessments were conducted at 12-week intervals during the follow-on study. Data from the baseline visit (day 1 of SOLO) were compared with data from the follow-on study through March 31, 2004, when all patients had completed at least 120 weeks of therapy with FPV/r QD. Because this was a rollover study, no significance testing was performed and all reported results are descriptive.. The demographic and baseline characteristics of the patients who received FPV/r QD in this follow on study (N = 211) were similar to those of the 322 patients randomized to receive FPV/r QD in the SOLO study. Their median age was 36 years, 72% were male, 49% were white, and 39% were black. The median baseline plasma HIV 1 RNA level was 4.82 log(10) copies/ mL, and the median baseline CD4+ cell count was 168 cells/mm(3). The median duration of exposure to FPV/r QD from SOLO baseline through the cutoff date was 996 days (142 weeks), ranging from 372 to 1,226 days (53-175 weeks). At week 120, plasma HIV-1 RNA levels <400 and <50 copies/mL were achieved and maintained in 75% (159) and 66% (139) of patients, respectively, when missing data and discontinuations were counted as failures. The median CD4+ cell count at week 120 was 451 cells/mm(3), a median change from baseline of 292 cells/mm(3). In 14 patients with no baseline resistance who met the criterion for virologic failure, no viral protease resistance mutations were detected. Extended treatment was generally well tolerated. The most frequently reported drug-related grade 2-4 adverse events were diarrhea (22 [10%]), nausea (17 [8%]), drug hypersensitivity (14 [7%], all cases attributed to ABC, which was a study drug in SOLO), and increased triglycerides (14 [7%]). The nature of adverse events reported after 48 weeks of therapy was comparable to that reported before week 48. Adverse events occurred at a similar or lower frequency between weeks 48 and 120 compared with before week 48. Similarly, laboratory abnormalities seen by week 120 were comparable to those seen by week 48, although they were less frequent.. Extended treatment (120 weeks) with FPV/r QD in these antiretroviral therapy-naive, HIV-1-infected patients was associated with sustained antiviral response and immunologic improvement. Adverse events had generally developed by 48 weeks of therapy and did not occur at a higher frequency through 120 weeks of treatment.

Topics: Adult; Aged; Carbamates; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Time

Previous investigations have shown a significant negative two-way drug interaction between fosamprenavir (FPV) and lopinavir/ritonavir (LPV/RTV) in both human immunodeficiency virus (HIV)-infected patients and seronegative volunteers. This randomized, nonblinded, three-way crossover study of HIV-seronegative adult volunteers investigated dose separation and increased doses of RTV as a means to overcome the interaction between FPV and LPV/RTV. Eleven HIV-seronegative volunteers were given FPV plus LPV/RTV at 700 mg plus 400/100 mg every 12 hours (q12h) simultaneously for 10 days and then randomized to receive each of three 7-day treatments in one of six possible sequences, as follows: FPV plus LPV/RTV at 700 mg plus 400 mg/100 mg q12h simultaneously, FPV/RTV at 700 mg/100 mg q12h plus LPV/RTV at 400 mg/100 mg q12h, with doses separated by 4 h, and FPV/RTV at 1,400 mg/200 mg in the morning plus LPV/RTV at 800 mg/200 mg in the evening. Pharmacokinetic sampling was performed on day 8 of each treatment, and samples were analyzed for FPV, amprenavir (APV), LPV, and RTV concentrations by high-performance liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR [with 95% confidence intervals]) for the 4- and 12-h dose separation strategies compared to simultaneous administration were calculated for the areas under the concentration-time curves from 0 to 24 h. Compared to simultaneous administration, RTV exposures increased with both 4-h and 12-h dose separation strategies (GMR, 5.30 [3.66 to 7.67] and 4.45 [3.09 to 6.41], respectively). LPV exposures also significantly increased with both 4-h and 12-h dose separation strategies (GMR, 1.76 [1.34 to 2.32] and 1.43 [1.02 to 2.01], respectively). However, both the 4- and 12-h strategies resulted in greater reductions in APV exposure (0.67 [0.54 to 0.83] and 0.77 [0.59 to 0.99], respectively) compared to simultaneous administration. Additional investigations are warranted to determine the optimal dosing of FPV with LPV/RTV.

Topics: Adolescent; Adult; Area Under Curve; Carbamates; Clinical Trials as Topic; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; HIV Seronegativity; Humans; Lopinavir; Male; Organophosphates; Pyrimidinones; Ritonavir; Sulfonamides

Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients.. This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943.. At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir.. Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Topics: Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

Fosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Interactions; Female; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Male; Nevirapine; Organophosphates; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk.. Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects.. A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001).. Amprenavir mean area under the curve over 12 h (AUC0-12 h) and concentration at 12 h (C12 h) (microg/ml) were, respectively, 42.7 microg x h/ml (range, 33.1-55.1) and 2.4 microg/ml (range, 1.4-3.2) in arm B and 17.4 microg x h/ml (range, 4.6-41.3) and 0.9 microg/ml (range, 0.2-2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P < or = 0.0001). Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 microg x h/ml (range, 60.3-119.3) and 6.3 microg/ml (range, 2.2-9.2) in arm A and 54.4 microg x h/ml (range, 23.5-112.2) and 3.0 microg/ml (range, 0.4-7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P < or = 0.0008). Ritonavir exposure was not significantly different between arms.. APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

Topics: Adult; Carbamates; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Ritonavir; Salvage Therapy; Sulfonamides; Treatment Outcome

To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV).. In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period.. Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents.. When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.

Topics: Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Carbamates; Cholesterol; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Female; Furans; Humans; Linear Models; Male; Middle Aged; Organophosphates; Oxazines; Prodrugs; Ritonavir; Sulfonamides; Triglycerides

To investigate the emergence of resistance to GW433908 (908), a protease inhibitor (PI) with demonstrated antiviral efficacy, safety and tolerability, when administered once daily (q.d.) with low dose ritonavir (908/r).. A 48-week Phase III open-label study (SOLO, APV30002) in which antiretroviral therapy-naive patients (n = 649) were treated with 908/r, (1400 mg/200 mg, q.d.) or nelfinavir [1250 mg, twice daily (b.i.d.)] with two nucleoside reverse transcriptase inhibitors (NRTI), abacavir (300 mg, b.i.d.) and lamivudine (150 mg, b.i.d.).. Viral genotype and phenotype were analysed at baseline and on treatment up to 48 weeks and beyond.. Emergence of genotypic resistance was significantly different between the 908/r q.d. and the nelfinavir b.i.d. treatment arms for both PIs (0 versus 50%; P < 0.001) and the NRTI (13% versus 69%; P < 0.001) received. In the nelfinavir arm the key protease mutations D30N and/or L90M were frequently observed. The absence of protease resistance mutations and reduced incidence of NRTI resistance mutations in the 908/r q.d. arm was confirmed by phenotyping, which showed a lack of PI cross-resistance.. The absence of resistance to 908 or cross-resistance to other PIs, and reduced NRTI resistance, following a 908/r q.d. regimen supports the use of this boosted PI early in therapy.

Topics: Antiretroviral Therapy, Highly Active; Carbamates; Drug Resistance; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Follow-Up Studies; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Mutation; Organophosphates; Phenotype; Ritonavir; Sulfonamides

To compare the magnitude and durability of the antiviral response to fosamprenavir (FPV) plus ritonavir (RTV) once-daily (FPV/r QD) with nelfinavir twice-daily (NFV BID), each administered with abacavir and lamivudine twice-daily.. An international, phase III, randomized, open-label study in antiretroviral therapy-naive, HIV-infected adults.. Patients with advanced HIV disease received FPV/r QD (n = 322) or NFV BID (n = 327). At week 48, 69% of patients in the FPV/r QD group and 68% in the NFV BID group had plasma HIV-1 RNA (vRNA) < 400 copies/ml, whereas 55% of patients in the FPV/r QD group and 53% in the NFV BID group had vRNA < 50 copies/ml (intent to treat, rebound/discontinuation = failure). More patients in the NFV BID group (17%) experienced virological failure than in the FPV/r QD group (7%). Efficacy of FPV/r QD was maintained in patients with CD4+ cell counts < 50 x 10 cells/l or vRNA >/= 100 000 copies/ml at entry. At week 48, median CD4+ cell counts were increased to 203 x 10 cells/l (FPV/r QD group) and 207 x 10 cells/l (NFV BID group). Both regimens were generally well tolerated. Diarrhea was more common on NFV BID than on FPV/r QD (16 versus 9%; P = 0.008). Fasting lipid profile results were generally favorable in both treatment arms. FPV/r QD maintained plasma amprenavir (APV) trough concentrations above the mean phenotypic drug-susceptibility (IC50) for wild-type virus for APV.. As a first choice protease inhibitor with a low daily pill burden, FPV/r QD was well tolerated and provided potent, durable antiviral suppression.

Topics: Adolescent; Adult; Aged; Carbamates; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Nelfinavir; Organophosphates; Patient Compliance; Ritonavir; Sulfonamides

Safety and tolerability evaluation of adapted dose regimens containing fosamprenavir/ritonavir (FPV/r) in HIV-infected subjects with viral hepatitis co-infection.. A retrospective multicohort analysis was conducted. Subjects from three European cohorts who started FPV/r or lopinavir/ritonavir (LPV/r) as a comparator contributed data to a centralized database. Subjects were divided into five groups by treatment regimen and level of hepatic impairment (aspartate aminotransferase [AST] platelet ratio index [APRI] score < or ≥2). Multivariable Cox regression analyses controlling for demographic factors, baseline CD4 count, FIB-4 score, use of antiretroviral therapy, and laboratory markers (bilirubin and platelet count) were performed to identify factors independently associated with risk of developing adverse events or safety events (eg, drug discontinuation, alanine aminotransferase (ALT) elevation, hepatic decompensation/death).. A total of 1096 patients contributed data to the study. Fosamprenavir/ritonavir (except in subjects with APRI ≥2 receiving standard dose) was associated with a higher two-year risk of drug discontinuation compared with LPV/r. Restricting the analysis to discontinuations due to adverse events (AEs), only subjects who received the reduced dose were more likely to discontinue ≥1 drug in the FPV/r regimen. There were no statistical differences in ALT elevation between groups. Incidence of hepatic decompensation events was similar among groups except for subjects who received non standard doses of FPV, though the number of events was small.. Fosamprenavir/ritonavir discontinuation rate due to AEs or ALT elevation was similar across all European-approved FPV/r doses and to that of LPV/r subjects.  Although liver tolerated antiretrovirals, such as integrase inhibitor and entry inhibitor, the use of FPV/r is acceptable in HIV infected patients with viral hepatitis.

Topics: Adult; Antiretroviral Therapy, Highly Active; Carbamates; Cause of Death; CD4 Lymphocyte Count; Coinfection; Female; Furans; Hepatitis; HIV Infections; Humans; Liver Function Tests; Male; Middle Aged; Mortality; Organophosphates; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Factors; Ritonavir; Sulfonamides; Treatment Failure; Treatment Outcome; Viral Load

Metabolic abnormalities associated with cumulative exposure to antiretroviral therapy have been linked to an increased risk of myocardial infarction in HIV positive individuals. The aim of this study was to evaluate whether the switch from lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) to darunavir/ritonavir (DRV/r) is able to improve the lipid profile. A total of 13 Caucasian subjects (7 from LPV/r and 6 from FPV/r) were enrolled in the study and received DRV/r at the dose of 800/100 mg, without change in their NRTI backbone. Viro-immunological parameters, triglycerides (TGs), total cholesterol (TCh), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, fasting glucose, HOMA-IR, indexes of hepatic and renal functionality, microalbuminuria and cystatin C were measured at baseline (T0), 3 months (T3), 6 months (T6), and 12 months (T12). The switch to DRV/r reduced levels of TCh, LDL, and TGs at T3. Similar improvements were confirmed further at T6 and at T12. A 14% increase in CD4+ count cells (P < 0.05) was observed. Serum cystatin C values showed a statistically significant decrease. After 12 months of switching to DRV/r from LPV/r or FPV/r, patients infected with HIV with TGs above 200 mg/dl, showed a 49% decrease in TGs, along with a 16% reduction of LDL and 19% reduction of TCh. Switching to DRV/r also improved immunological parameters, such as CD4+ cells count and cystatin C plasmatic levels, which may translate into a reduction of the cardiovascular risk. In conclusion, a switch to DRV/r should be considered in those HIV positive patients undergoing antiretroviral therapy, who also present abnormal lipid profiles.

Topics: Adult; Anti-HIV Agents; Blood Chemical Analysis; Carbamates; CD4 Lymphocyte Count; Darunavir; Dyslipidemias; Female; Follow-Up Studies; Furans; HIV Infections; Humans; Kidney Function Tests; Liver Function Tests; Male; Metabolome; Middle Aged; Organophosphates; Prospective Studies; Protease Inhibitors; Ritonavir; Sulfonamides; White People

Left ventricular hypertrophy (LVH) is a predictor of overall mortality in the general population. The most sensitive diagnostic method is transthoracic echocardiography (TTE). In this study, we describe the prevalence of LVH, and the factors associated with it, in a group of patients with HIV infection.. TTE was offered to all patients attending the outpatient clinic of the Hospital Costa del Sol (Marbella, Spain) between 1 December 2009 and 28 February 2011. The corresponding demographic and clinical data were obtained. The left ventricular mass (LVM) was calculated and indexed by height(2.7). LVH was defined as LVM >48g/m(2.7) in men or >44g/m(2.7) in women.. We examined 388 individuals (75.5% male, mean age 45.38years). Of these, 76.1% were receiving HAART; 11.9% had hypertension, 6.2% had diabetes mellitus, 23.2% had dyslipidaemia and 53.6% were tobacco users. The risk of cardiovascular disease at 10years (RV10) was 12.15% (95%CI: 10.99-13.31%). 19.1% of these patients had a high RV10. A total of 69 patients (19.8%) presented high LVM. Age, hypertension, dyslipidaemia, RV10 and the use of nevirapine were associated with a greater presence of LVH in the univariate analysis. In the logistic regression analysis performed, the factors retained in the model were the presence of high RV10 (OR: 2.92, 95%CI: 1.39-6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18-4.14).. In this group of patients, the use of nevirapine and the presence of high RV10 were associated with LVH. The use of nevirapine might be related to its prescription for patients with higher RV10.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Comorbidity; Cross-Sectional Studies; Cyclopropanes; Diabetes Mellitus; Drug Combinations; Dyslipidemias; Echocardiography; Female; Furans; HIV Infections; Humans; Hypertension; Hypertrophy, Left Ventricular; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Organophosphates; Organophosphonates; Risk Factors; Ritonavir; Smoking; Spain; Sulfonamides; Tenofovir; Zidovudine

In a retrospective database study at two HIV treatment centres, medical records were accessed to evaluate long-term efficacy and safety parameters in all HIV-infected adults who had achieved HIV-1 RNA <50 copies/mL following the initiation of fosamprenavir (FPV)/ritonavir (RTV) 1400 mg/100 mg once-daily (QD)-containing regimens between January 2004 and January 2006. Data were available for 20 antiretroviral (ARV)-naïve patients (baseline median HIV-1 RNA 5.0 log(10) copies/mL; CD4+ cell count 307 cells/mm(3)), 30 protease inhibitor (PI)-naïve, ARV-experienced patients (HIV-1 RNA 3.6 log(10) copies/mL; CD4+ count 348 cells/mm(3)) and 25 PI-experienced patients switching to FPV/RTV100 for reasons other than virological failure (HIV-1 RNA 2.7 log(10) copies/mL; CD4+ count 328 cells/mm(3)). HIV-1 RNA <50 copies/mL was achieved in 100% of the ARV-naïve cohort (median monitoring period, 2.4 years; range, 1.4-3.2 years), 87% of the PI-naïve cohort (2.4 years; range, 1.2-3.4 years) and 88% of the PI-experienced cohort (2.2 years; range, 1.0-3.2 years). Virological failure occurred in 0%, 7% and 8% of the cohorts, respectively, and median CD4+ count increased above baseline by 224, 155 and 115 cells/mm(3), respectively. Change from baseline in median fasting lipids was: total cholesterol +12, -6, -2 mg/dL; low-density lipoprotein-cholesterol 0, -5, +12 mg/dL; high-density lipoprotein-cholesterol +4, +2, +7 mg/dL; triglycerides +9, -21, -65 mg/dL, respectively. In conclusion, FPV/RTV 1400/100 mg QD-containing regimens remained effective long-term in all ARV-naïve and most PI-naïve and PI-experienced HIV-infected patients.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; CD4 Lymphocyte Count; Female; Furans; HIV Infections; Humans; Lipids; Male; Middle Aged; Organophosphates; Retrospective Studies; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

Although dual-boosted protease inhibitors regimen is not recommended in children with HIV infection, such a strategy could be useful in subjects with a complex resistance profile. This study was aimed at assessing the long term efficacy and safety of a double-boosted protease inhibitor combination, fosamprenavir (fAVP) and atazanavir/ritonavir (ATV/r) in a cohort of HIV-infected children and adolescents who had failed with nucleoside reverse transcriptase inhibitors.. Seven vertically infected children and adolescents who had previously failed highly active antiretroviral therapy and were resistant to nucleoside reverse transcriptase inhibitors, received a dual protease inhibitor (PI) regimen including fAVP plus ATV/r for 42 months. The patients were assessed at baseline, every month for the first 24 weeks of therapy and every 3 months until month 32. Physical examination, CD4+ cell count, HIV-RNA viral load, lipid profile and hepatic function were assessed throughout the follow up.. During the study no serious adverse events were reported. CD4 absolute number increased over-time in all subjects. At baseline the median HIV-RNA was 6562 cp/mL (ranging 1048 -102772 cp/mL) and rapidly decreased below the limit of detection (50 cp/mL) after 2 months of the new treatment and remained undetectable in all cases through the entire study period. At the beginning of the study all cases showed a normal lipid profile. During the study period, 4/7 subjects showed total cholesterol, low density lipoprotein and triglyceride levels >97th cent.le for the males and 94th cent.le for the females. HDL cholesterol showed protective values. Hepatic enzymes remained stable during the entire observation, whereas total bilirubin showed toxicity II/III grade in 6/7 subjects. No change in fat redistribution and insulin resistance was observed.. Dual-boosted protease inhibitor therapy was virologically and immunologically effective and it could be considered as a possible alternative to a rescue regimen in children and adolescents. However, hypercholesterolemia and hypertriglyceridemia need close follow-up and may limit the use of this therapeutic option.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; CD4 Lymphocyte Count; Child; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lipids; Male; Oligopeptides; Organophosphates; Pyridines; Ritonavir; RNA, Viral; Salvage Therapy; Sulfonamides; Treatment Outcome; Viral Load

The aim of the study was to evaluate the efficacy of fosamprenavir/ritonavir (FPV/r) monotherapy in plasma and reservoirs in virologically suppressed patients.. A 48-week, prospective, single-arm pilot trial was carried out (trial registration: ISRCTN78584791). Patients receiving triple therapy [FPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least the previous month], with viral load (VL) <40 HIV-1 RNA copies/mL and no previous virological failure (VF) on protease inhibitors (PIs), were included in the trial and received FPV/r monotherapy (700/100 mg/12 h). VL and FPV/r levels [by liquid chromatography-tandem mass spectrometry (LC/MS/MS); limit of detection (LOD) 0.5 ng/mL] in cerebrospinal fluid (CSF) were determined at week 24. VF was defined as VL >40 copies/mL in three consecutive samples or >500 copies/mL in two samples.. Enrolment was prematurely stopped because of a high percentage of VF. Twenty patients (45% men; median age 43.5 years) were included in the trial. Nine patients (45%) presented therapeutic failure [seven (35%) had VF, and two discontinued therapy]. Resistance testing was available in five patients. One patient presented major PI mutations (54L, 32I and 47V) in addition to one minor mutation (13V), whereas two patients had minor PI mutations (10V+36I and 71T, respectively). The patient with major PI mutations switched from FPV/r to darunavir/r and VL was re-suppressed. In the other six patients with VF, VL was re-suppressed after the reintroduction of NRTIs. VL was <40 copies/mL in all CSF samples (n=10). Median amprenavir plasma levels were 2.5 μg/mL (range 0.7-8.6 μg/mL) at week 24 and 2.5 μg/mL (range 0.4-3.8 μg/mL) at VF. The CSF amprenavir concentration was 28.1 ng/mL (range 6.39-83.6 ng/mL), exceeding the reported 50% inhibitory concentration (IC(50) ) range for CSF in nine of 11 patients.. The high percentage of patients with VF in our study suggests that the use of FPV/r in a simplification monotherapy strategy should be discouraged. Adequate amprenavir levels and undetectable VL in CSF were documented in all samples evaluated.

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Resistance, Viral; Female; Furans; HIV Infections; HIV-1; Humans; Male; Organophosphates; Pilot Projects; Prospective Studies; Ritonavir; RNA, Viral; Spectrum Analysis; Sulfonamides; Treatment Outcome; Viral Load; Virus Replication

The role of exposure to specific antiretroviral drugs on risk of myocardial infarction in human immunodeficiency virus (HIV)-infected patients is debated in the literature.. To assess whether we confirmed the association between exposure to abacavir and risk of myocardial infarction (MI) and to estimate the impact of exposure to other nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-NRTIs on risk of MI, we conducted a case-control study nested within the French Hospital Database on HIV. Cases (n = 289) were patients who, between January 2000 and December 2006, had a prospectively recorded first definite or probable MI. Up to 5 controls (n = 884), matched for age, sex, and clinical center, were selected at random with replacement among patients with no history of MI already enrolled in the database when MI was diagnosed in the corresponding case. Conditional logistic regression models were used to adjust for potential confounders.. Short-term/recent exposure to abacavir was associated with an increased risk of MI in the overall sample (odds ratios [ORs], 2.01; 95% confidence interval [CI], 1.11-3.64) but not in the subset of matched cases and controls (81%) who did not use cocaine or intravenous drugs (1.27; 0.64-2.49). Cumulative exposure to all PIs except saquinavir was associated with an increased risk of MI significant for amprenavir/fosamprenavir with or without ritonavir (OR, 1.53; 95% CI, 1.21-1.94 per year) and lopinavir with ritonavir (1.33; 1.09-1.61 per year). Exposure to all non-NRTIs was not associated with risk of MI.. The risk of MI was increased by cumulative exposure to all the studied PIs except saquinavir and particularly to amprenavir/fosamprenavir with or without ritonavir and lopinavir with ritonavir, whereas the association with abacavir cannot be considered causal.

Topics: Adult; Anti-HIV Agents; Carbamates; Case-Control Studies; Cohort Studies; Confidence Intervals; Dideoxynucleosides; Female; France; Furans; HIV Infections; Hospitals, Isolation; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Organophosphates; Regression Analysis; Risk; Ritonavir; Sulfonamides

Topics: Adenine; Carbamates; Deoxycytidine; Emtricitabine; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Immunocompromised Host; Male; Middle Aged; Organophosphates; Organophosphonates; Orthotic Devices; Osteonecrosis; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Talus; Tenofovir

We report our experience on the impact of different fosamprenavir boosted regimens on plasma lipid levels in 48 naive monoinfectd- HIV-seropositive patients. Eighteen months after starting antiretroviral therapy (ART), all patients showed a good immuno-virological response, with no statistically significant differences among the three groups; no changes in ART regimens were necessary and no adverse events were reported. On the contrary, a statistically significant difference among the three groups of patients was observed in cholesterol and triglyceride levels, since higher levels of cholesterol (including LDLs) and triglycerides were observed in patients taking the higher dose of ritonavir. (www.actabiomedica.it)

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; HIV Seropositivity; Humans; Hyperlipidemias; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Triglycerides

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Therapy, Combination; Female; Furans; HIV Infections; Humans; Lamivudine; Male; Organophosphates; Prospective Studies; Ritonavir; Sulfonamides; Zidovudine

Topics: Anti-HIV Agents; Carbamates; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Furans; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Liver Function Tests; Organophosphates; Ritonavir; Sulfonamides; 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

The influence of nevirapine or efavirenz co-administration on ritonavir-boosted amprenavir pharmacokinetics was investigated in HIV-infected patients with a population pharmacokinetic approach. The analysis was performed with a population of 61 patients treated with fosamprenavir/ritonavir (700 mg/100 mg twice daily) combined with nucleoside/nucleotide reverse transcriptase inhibitors +/- enfuvirtide and no other antiretroviral drugs (group A, n = 46) or nevirapine (group B, n = 10) or efavirenz (group C, n = 5). No significant increase in amprenavir clearance [mean +/- standard deviation: 22.49 +/- 10.32 (group A) vs. 21.57 +/- 9.62 (group B) vs. 20.15 +/- 5.18 (group C) L/h] and no significant decrease in trough amprenavir plasma concentrations [1.75 +/- 0.95 (group A) vs. 1.82 +/- 0.72 (group B) vs. 1.55 +/- 0.66 (group C) mg/L] were found in groups B and C in comparison with group A, although nevirapine and efavirenz are inductors of protease inhibitors metabolism. These results suggest that fosamprenavir/ritonavir should be used at standard doses of 700 mg/100 mg twice daily when combined with efavirenz or nevirapine.

Topics: Adult; Alkynes; Anti-HIV Agents; Bayes Theorem; Benzoxazines; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; France; Furans; HIV Infections; Humans; Male; Models, Biological; Nevirapine; Organophosphates; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Ritonavir; Sulfonamides

We developed clinically relevant genotypic scores for resistance to fosamprenavir/ritonavir in HIV-1 protease inhibitor (PI)-experienced patients.. PI-experienced patients with virological failure receiving fosamprenavir/ritonavir as the sole PI for at least 3 months and with detectable fosamprenavir plasma levels were included. The impact of baseline protease mutations on virological response (VR, i.e. decrease in plasma HIV-1 RNA between baseline and month 3) was analysed using the Mann-Whitney test. Mutations with prevalence >10% and P value <0.10 were retained. The Jonckheere-Terpstra test was used to select the combination of mutations most strongly associated with VR. The association between score and VR was assessed by multivariate backward regression.. In the 73 patients included, the median baseline HIV-1 RNA was 4.6 log(10) copies/mL (range: 2.7-6.9) and the mean decrease at month 3 was -1.07 +/- 1.40 log(10) copies/mL. Ninety per cent of the patients were infected by HIV-1 subtype B variants. Two fosamprenavir/ritonavir mutation scores were constructed: score A (L10F/I/V + L33F + M36I + I54L/M/V/A/T/S + I62V + V82A/F/C/G + I84V + L90M) was based only on mutations associated with a worse VR, whereas score B (L10FIV + L33F + M36I + I54L/M/V/A/T/S + A71V - V77I - N88S + L90M) also took into account favourable mutations. Both scores were independent predictors of VR, however, co-administration of tenofovir was associated with a worse VR and the presence of the N88S protease mutation and co-administration of enfuvirtide with a better VR.. These clinically validated mutation scores should be of interest for the clinical management of PI-experienced patients. The fosamprenavir/ritonavir score A was introduced in the 2006 ANRS algorithm along with isolated mutations I50V and V32I + I47V.

Topics: Adult; Amino Acid Substitution; Carbamates; Drug Resistance, Viral; Female; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation, Missense; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

In this study, named the Zephir study (Telzir-pharmacokinetics), 121 antiretroviral-experienced human immunodeficiency virus (HIV) patients failing on highly active antiretroviral therapy (HAART) were included in a prospective cohort and received a fosamprenavir-ritonavir (700 mg/100 mg twice a day)-based regimen. The impact of baseline HIV type 1 (HIV-1) mutations, pharmacokinetic (PK) parameters, and genotype inhibitory quotient (GIQ) on the virological response at week 12 (W12) was assessed. HIV reverse transcriptase and protease were sequenced at W0. The response at W12 was defined as<2.3 log10 HIV-1 RNA copies/ml or a virus load decrease of>or=1 log10 copies/ml. W4 amprenavir PK were determined by high-performance liquid chromatography. Patients had a median of nine previous treatments over 8 years. Median W0 values were as follows: 295 CD4+/microl, 4.4 log10 HIV-1 RNA copies/ml, and 6 protease- and 5 nucleotide reverse transcription inhibitor-related mutations. Respective values for minimum concentration of drug in serum (Cmin) and area under the concentration-time curve (AUC) from 0 to 24 h were 1,400 ng/ml and 35 mg.h/ml. At W12, 52% of the patients were successes, with a median decrease of -0.7 log10 HIV-1 RNA copies/ml. The Zephir mutation score included 12 IAS protease mutations associated with poorer virological response: L10I/F/R/V, L33F, M36I, M46I/L, I54L/M/T/V, I62V, L63P, A71I/L/V/T, G73A/C/F/T, V82A/F/S/T, I84V, L90M, and polymorphism mutations I13V, L19I, K55R, and L89M. Comparing<4 versus>or=4 mutations, HIV-1 RNA decreases were -2.3 log10 copies/ml versus -0.1 log10 copies/ml (P<10(-4)) with 93% versus 19% successes (P<10(-4)), respectively. This score predicted W12 failure with 94% sensitivity, versus 31% for the ANRS 2005 algorithm. Cmin (<1,600 ng/ml), AUC (<40 mg.h/ml), and GIQ (<300) values were associated with failure (all P values were <10(-4)). The need to test genotype-based algorithms using different patient databases before their implementation in clinical practice is highlighted. Specific mutations, PK and GIQ, provide relevant information for monitoring fosamprenavir-ritonavir-based HAART.

Topics: Antiretroviral Therapy, Highly Active; Carbamates; Cohort Studies; Drug Resistance, Viral; Drug Therapy, Combination; Furans; Genotype; HIV Infections; HIV-1; Humans; Organophosphates; Prospective Studies; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

HAART has decreased the incidence of AIDS and death among HIV-infected individuals dramatically. This approach often becomes cumbersome to patients, involving multiple drugs administered on varying schedules. We investigated the pharmacokinetics, efficacy, and tolerability of a once-daily regimen of fosamprenavir, tenofovir, emtricitabine and ritonavir in HIV-infected treatment-naive subjects. No clinically significant interaction between the drugs was noted, and the regimen showed good efficacy and tolerability over the course of 48 weeks.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; Carbamates; Deoxycytidine; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Organophosphates; Organophosphonates; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sulfonamides; Tenofovir; Treatment Outcome

Topics: Anti-HIV Agents; Carbamates; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Organophosphates; Phenotype; Ritonavir; Sulfonamides

The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment.. HIV-positive patients receiving fosamprenavir/ritonavir (700/100 mg twice daily) were included. Patients were classified into three groups: (i) chronic hepatitis; (ii) liver cirrhosis; (iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (>14 days on treatment) were collected in the fasting state before the morning dose (C(trough)) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC.. Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-infinity), C(max) and C(ss) were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C(max) and C(ss) values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found (r = 0.64, P = 0.003).. On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors (i.e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Attention; Bilirubin; Carbamates; Chromatography, High Pressure Liquid; Female; Furans; HIV Infections; Humans; Liver Diseases; Male; Middle Aged; Organophosphates; Plasma; Ritonavir; Sulfonamides; Time Factors

The aim of this study was to establish the prevalence and predictors of genotypic resistance of HIV-1 to lopinavir and fosamprenavir from patients failing protease inhibitors (PI)-based regimens. We selected 643 HIV-1-infected patients with available treatment history who underwent genotypic resistance assays for virological failure from a clinical site and from the Stanford database. According to the genotypic resistance interpretation of the Stanford algorithm, proportions of viruses showing full susceptibility to fosamprenavir and lopinavir were 32% and 34%, respectively (p =ns). Proportions of viruses fully susceptible to lopinavir/r and fosamprenavir/r according to the Agence Nationale pour la Recherche sur le SIDA (ANRS) algorithm, were 81% and 81%, respectively. According to the Rega algorithm, proportions of viruses showing full susceptibility to fosamprenavir/r and lopinavir were 80% and 70%, respectively (p<0.001). According to the ANRS and Rega interpretations, the time on therapy predicted susceptibility to lopinavir/r, while susceptibility to fosamprenavir/r according to ANRS was predicted by the number of prior PI regimens experienced. According to the Stanford interpretation, prior indinavir exposure predicted resistance to lopinavir/r and fosamprenavir/r while prior nelfinavir use predicted susceptibility to both drugs. After failing PI-based regimens, the majority of viruses retained a predicted susceptibility to fosamprenavir/r and lopinavir/r. In patients failing PIs, the interpretation of genotypic resistance to fosamprenavir may change considerably according to the different algorithms and in respect to the effect of pharmacokinetic boosting with ritonavir.

Topics: Adult; Algorithms; Antiretroviral Therapy, Highly Active; Carbamates; Drug Resistance, Multiple, Viral; Female; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Organophosphates; Prevalence; Pyrimidinones; Retrospective Studies; Ritonavir; Sulfonamides

Topics: Carbamates; Dose-Response Relationship, Drug; Drug Approval; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Organophosphates; Ritonavir; Sulfonamides; United States; United States Food and Drug Administration

To evaluate the drug interaction between fosamprenavir (FPV) and esomeprazole (ESO) after repeated doses in healthy adults.. Subjects received ESO 20 mg once daily (qd) for 7 days followed by either ESO 20 mg qd + FPV 1400 mg twice daily (bid) or ESO 20 mg qd + FPV 700 mg bid + ritonavir (RTV) 100 mg bid for 14 days in arms 1 and 2, respectively. After a 21- to 28-day washout, subjects received either FPV 1400 mg bid for 14 days (arm 1) or FPV 700 mg bid + RTV 100 mg bid for 14 days (arm 2). Pharmacokinetic sampling was conducted on the last day of each treatment.. Simultaneous coadministration of ESO 20 mg qd with either FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid had no effect on steady-state amprenavir pharmacokinetics. The only effect on plasma ESO exposure was a 55% increase in area under the plasma concentration-time curve during a dosing interval, tau[AUC0-tau], after coadministration of ESO 20 mg qd with FPV 1400 mg bid.. FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid may be coadministered simultaneously with ESO without dose adjustment. However, the impact of staggered administration of proton pump inhibitors (PPI) on plasma amprenavir exposure is unknown at present.

Topics: Administration, Oral; Adolescent; Adult; Carbamates; Diarrhea; Drug Administration Schedule; Drug Combinations; Esomeprazole; Female; Furans; Headache; Humans; Male; Middle Aged; Nausea; Organophosphates; Ritonavir; Sulfonamides

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Cyclopropanes; Furans; HIV Infections; Humans; Oligopeptides; Organic Chemicals; Organophosphates; Oxazines; Patient Compliance; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Viral Load

Topics: Anti-HIV Agents; Carbamates; Clinical Trials as Topic; Cross-Over Studies; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Organophosphates; Prodrugs; Ritonavir; Saquinavir; Sulfonamides

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

Topics: Carbamates; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Furans; HIV Infections; Humans; Nelfinavir; Organophosphates; Protease Inhibitors; Ritonavir; Sulfonamides

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Organophosphates; Pilot Projects; Pyridines; Pyrimidinones; Ritonavir; Sulfonamides; Time Factors; Viral Load

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

We compared seminal plasma pharmacokinetic data for the investigational amprenavir prodrug GW433908 with those for amprenavir and an amprenavir-ritonavir combination regimen. All 3 regimens resulted in detectable blood plasma and seminal plasma concentrations of amprenavir. The majority of these concentrations were greater than the plasma protein-corrected 50% inhibitory concentration for wild-type human immunodeficiency virus type 1.

Topics: Adult; Anti-HIV Agents; Carbamates; Chemistry, Pharmaceutical; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Organophosphates; Prodrugs; Ritonavir; Semen; Sulfonamides