abacavir and amprenavir

Monotherapy to treat the human immunodeficiency virus (HIV) is now a thing of the past. Combination drug therapies and several new anti-HIV drugs in clinical trials offer new promise for slowing the progress and deleterious effects of this disease.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Chemistry, Pharmaceutical; Cyclopropanes; Dideoxynucleosides; Drug Approval; Furans; HIV Protease Inhibitors; Humans; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine

This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (tau), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUC(tau,ss) versus the AUC from 0 h to infinity was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA ( approximately 2 log(10) copies/ml) and increased CD4(+) cell counts ( approximately 100 cells/mm(3)) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Area Under Curve; Carbamates; CD4 Lymphocyte Count; Cross-Over Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphates; RNA, Viral; Sulfonamides

To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen.. Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs + other ART. The median follow-up was 48 weeks (range week 16-72).. Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had > or = 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): G to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) and V1081 (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the G190 mutations (OR=8.9, P<0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and 154V were de-selected, and mutations I50V, I or V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at position 10 were observed in 20/49 (41%) isolates.. Prior NNRTI and NRTI therapy influences the pathway of resistance to efavirenz. In this study, the prevalence of mutations selected by efavirenz were different from those described in less ART-experienced patients. Baseline Y181C was associated with the development of mutations at position 190, but not L100I or K103N. In this patient population, abacavir with efavirenz preferentially selected for L74V but not for thymidine analogue mutations. M184V was rarely selected and was maintained in only 77% of patients who did not add lamivudine or didanosine. Finally, amprenavir-specific mutations were selected in the background of other primary protease inhibitor mutations, confirming the distinct resistance profile of amprenavir.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Furans; Genotype; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Oxazines; Salvage Therapy; Sulfonamides

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Enfuvirtide; Female; Furans; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Peptide Fragments; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

To assess the safety and efficacy of three new drugs in patients with antiretroviral failure and to correlate retrospectively baseline factors with virological response.. Open-label, 48-week, single-arm, multi-center phase II trial conducted at nine US university or government clinics and private practices.. Patients with HIV-1 RNA > or =500 copies/ml despite > or =20 weeks of treatment with at least one protease inhibitor received abacavir 300 mg twice a day, amprenavir 1200 mg twice a day and efavirenz 600 mg once a day. Other antiretrovirals were prohibited until week 16 except for substitutions for possible abacavir hypersensitivity.. HIV RNA at weeks 16 and 48.. A total of 101 highly treatment-experienced patients enrolled; 60 were naive to non-nucleoside analog reverse transcriptase inhibitors (NNRTI). HIV RNA < 400 copies/ml was attained in 25 out of 101 (25%) patients at 16 weeks (35% of NNRTI-naive and 10% of -experienced patients) and 23 (23%) patients at 48 weeks (33% of naive and 7% of experienced patients). CD4 cells increased by a median of 15 x 10(6) and 43 x 10(6) cells/l at weeks 16 and 48, respectively. Drug-related rash occurred in 50 out of 99 (51%) of patients, and 17 out of 99 (17%) permanently discontinued one or more drugs as a result. Lower baseline viral load, fewer NNRTI-related mutations, absence of decreased abacavir (> or =4-fold) and efavirenz (> or =10-fold) susceptibility, and greater number of drugs to which virus was susceptible were associated with virological response at week 16.. Abacavir, amprenavir and efavirenz durably reduced HIV RNA and increased CD4 cell counts in a subset of treatment-experienced adults. Baseline viral load and some genotypic and phenotypic markers of resistance correlated with HIV RNA response.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Female; Furans; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Phenotype; Retrospective Studies; RNA, Viral; Safety; Sulfonamides; Treatment Failure

Topics: AIDS Vaccines; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; CD8-Positive T-Lymphocytes; Combined Modality Therapy; Defective Viruses; Dideoxynucleosides; Furans; HIV Infections; Humans; Immunotherapy, Active; Lamivudine; Lymphocyte Count; Sulfonamides; T-Lymphocyte Subsets; Vaccination; Vaccinia virus; Viral Load; Viral Vaccines; Viremia; Zidovudine

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

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

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUC(ss)) and the maximum, minimum, and average concentrations at steady state (C(max,ss), C(min,ss), and C(avg,ss), respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUC(ss)/AUC(0-->infinity) decreased linearly with dose and correlated significantly with treatment-associated decreases in alpha(1)-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i. d. provided a median amprenavir C(min,ss) (0.280 microg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 microg/ml), even after adjustment for protein binding. The median amprenavir C(min,ss) was also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 microg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C(max). The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

Topics: Adolescent; Adult; Anti-HIV Agents; Area Under Curve; Carbamates; Dideoxynucleosides; Female; Furans; HIV Protease Inhibitors; HIV Seropositivity; Humans; Male; RNA, Viral; Sulfonamides

A Phase II clinical trial was designed to evaluate the efficacy and tolerability of twice-daily abacavir, amprenavir, and zidovudine (ZDV)/lamivudine (3TC) in HIV-1-infected study subjects naive to protease inhibitors and 3TC. Plasma and cerebrospinal fluid (CSF) HIV-1 RNA levels and T-cell subsets were measured. In all, 27 newly diagnosed and 12 chronically HIV-1-infected study subjects are included in the analysis. Week 48 plasma HIV-1 RNA levels were <500 copies/ml in 100% of study subjects, and <50 copies/ml in 80% of chronically infected and 100% of newly infected study subjects. The mean change in CD4 was (+)150 cells/microl (newly infected, p <.001), and (+)155 cells/microl (chronically infected, p <.001). At Week 48, evidence of cellular activation persisted in both cohorts. A twice-daily regimen of amprenavir, abacavir, and ZDV/3TC affords potent viral suppression and significant increases in total CD4(+) cells in HIV-1--infected study subjects. Patient intolerance may limit the efficacy of this combination.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS Dementia Complex; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Chronic Disease; Dideoxynucleosides; Digestive System; Drug Synergism; Ethnicity; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Lymphocyte Subsets; Male; Pregnancy; Research Design; RNA, Viral; Sulfonamides; Treatment Refusal; Zidovudine

To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults.. Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial.. Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1,200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively.. At week 4, amprenavir monotherapy (900, 1,050, or 1,200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1,050 mg twice daily (118 x 10(6) cells/mm3) or 1,200 mg twice daily (114 x 10(6) cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138 x 10(6) cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy.. The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1,050 and 1,200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Maximum Tolerated Dose; Phenotype; Sulfonamides; Time Factors; Treatment Outcome

Patients with plasma viral RNA >50,000 copies/mL, despite a protease-inhibitor regimen, received abacavir, amprenavir, and efavirenz to assess efavirenz-amprenavir drug interactions and to evaluate safety and antiviral response. Patients first received amprenavir with abacavir and other nucleoside analogs. Amprenavir levels were measured before and after adding efavirenz. Patients then received a second protease inhibitor. There was evidence of genotypic and phenotypic resistance at study entry. No patient had study drugs discontinued because of toxicity. Efavirenz decreased the steady-state area under the curve, maximum plasma concentration, and minimum plasma concentration of amprenavir by 24%, 33%, and 43%, respectively. Three of 10 patients had >1.5 log10 viral response to abacavir and amprenavir. All 8 patients who added efavirenz had >0.5 log10 decline in viral load, and this response lasted >24 weeks for 3 of the patients. A combination regimen that included abacavir, amprenavir, and efavirenz was well tolerated and had sustained activity in some patients. Concomitant efavirenz therapy decreases amprenavir concentrations.

Topics: Adult; Alkynes; Antiviral Agents; Area Under Curve; Base Sequence; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Furans; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Oxazines; Phenotype; Pilot Projects; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

To evaluate the immunological and virological responses to highly active antiretroviral therapy (HAART) in blood and lymphoid compartments of HIV-1-infected patients at an early stage of infection.. An open-label, observational, non-randomized, prospective trial of outpatients attending the Centre of Clinical Investigation in Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland.. Forty-one antiretroviral-naive HIV-1-infected adults with 400 CD4 T cells/microl or greater and 5000 plasma HIV-1-RNA copies/ml or greater were enrolled, and 32 finished the study. Forty-nine HIV-negative individuals were included as controls. All subjects gave written informed consent.. All patients received abacavir 300 mg by mouth every 12 h and amprenavir 1200 mg by mouth every 12 h for 72 weeks.. The extent of immune reconstitution in blood and lymph nodes after 72 weeks of HAART was evaluated, and compared with immunological measures of 49 HIV-negative subjects.. Virus replication was effectively suppressed (-3.5 log10 at week 72). Substantial increments of CD4 T cell count in blood and percentage in lymph nodes were observed over time, and these measures were comparable to HIV-negative subjects by week 24 in blood and by week 48 in lymph nodes. The increase was equally distributed between naive and memory CD4 T cells. Recovery of HIV-specific CD4 responses occurred in 40% of patients.. The initiation of HAART at an early stage of established HIV infection induces systemic quantitative normalization of CD4 T cells, a partial recovery of HIV-specific CD4 cell responses, and effective and durable suppression of virus replication.

Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; Carbamates; CD4 Lymphocyte Count; CD4-CD8 Ratio; Dideoxynucleosides; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lymph Nodes; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Sulfonamides; Viral Load

When to start highly active antiretroviral therapy (HAART) in asymptomatic chronically HIV-1-infected subjects with CD4 cell counts of 300 x 10(6)-500 x 10(6)/l is debated extensively. Retrospective analyses of virological and immunological responses following HAART have been evaluated in both blood and lymph nodes according to pre-treatment levels of CD4 cells either above or below 500 x 10(6)/l.. Open-label, observational, non-randomized, prospective study.. Outpatients attending the Centre of Clinical Investigation in Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland.. Fifty-four HIV-1-infected antiretroviral-naive subjects with CD4 cell count > or = 250 x 10(6)/l and plasma viraemia > or = 5000 copies/ml who had been treated with HAART for at least 48 weeks. Controls were 49 HIV-negative subjects.. All patients received abacavir, nelfinavir, saquinavir soft gel capsules, and amprenavir in varying combinations for 72 weeks.. The extent of immune reconstitution following HAART in 43 and 11 subjects with either more or fewer than 500 x 10(6) CD4 cells/l at baseline was evaluated in blood and lymph node, and compared with immunological measures observed in 49 HIV-negative controls.. After 48 weeks of therapy, plasma viraemia was suppressed effectively in both groups of patients. Normalization of both CD4 cell count in blood, divided equally between memory and naive cells, and percentage of CD4 cells in lymph nodes occurred in the two groups. Consistently, the net increase over baseline in CD4 cell count and in memory and naive CD4 subsets was greater in patients with fewer than 500 x 10(6) CD4 cells/l at baseline. Recovery of HIV-specific responses was similar in the two groups.. This study suggests that virological and immunological responses are comparable in asymptomatic therapy-naive HIV-1-infected subjects with CD4 cell counts above or below 500 x 10(6)/l.

Topics: Adult; Anti-HIV Agents; Antigens, Fungal; Antigens, Viral; Antiretroviral Therapy, Highly Active; Candida albicans; Carbamates; CD4 Lymphocyte Count; Chronic Disease; Cytomegalovirus; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nelfinavir; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Simplexvirus; Sulfonamides; T-Lymphocyte Subsets

To establish the feasibility of using ultrasound-guided lymph node needle aspiration as a means to obtain lymphoid tissue cells for the determination of a series of immunologic and virologic measures in HIV-infected patients.. First, a comparison of the characteristics of cell populations obtained by simultaneous needle aspiration and standard excisional biopsy in six patients. Second, use of lymph node needle aspiration to assess longitudinally T-cell subset changes in patients initiating highly effective antiretroviral treatment.. T-cell subsets (CD4 and CD8) and percentage Ki67+ cycling T cells were measured in lymph node cell populations harvested by ultrasound-guided aspiration or standard biopsy by flow cytometry. Cellular RNA content was assessed by a modification of the Roche Amplicor HIV-1 Monitor test.. CD4 and CD8 T-cell percentage and HIV RNA cell content of lymph node cell suspensions obtained from the simultaneous performance of ultrasound-guided needle aspiration and excisional biopsy in the same patients were correlated (n = 6). Among the 87 aspiration sessions reported here, mononuclear cell suspensions were obtained in 100% of the sessions, in numbers ranging between 4x10(4) to 6.7x10(6) cells (median: 7x10(5)). This limited number of cells did not allow to perform all type of analyses in all patients. By prioritizing the cells for the determination of T-cell subsets and proliferation rate, this approach was instrumental for demonstrating the normalization of the T-cell subset ratio and the kinetic of normalization of proliferating rates of CD4 and CD8 T cells, as well as the decrease in HIV-1 viral load in the lymph node following HAART initiation.. Ultrasound-guided aspiration appears to be a non-invasive and ad libitum, safe and repeatable procedure for the longitudinal monitoring of changes in lymph nodes.

Topics: Anti-HIV Agents; Biopsy, Needle; Carbamates; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Therapy, Combination; Flow Cytometry; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Longitudinal Studies; Lymph Nodes; Lymphocyte Activation; Reverse Transcriptase Inhibitors; RNA, Viral; Sulfonamides; Ultrasonography

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

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. TDM is useful to determine the best dosage regimen adapted to each patient. Here, we apply MALDI-TOF/TOF technology to quantify abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine in the plasma of HIV-infected patients, by standard additions analysis. Regression of standard additions was linear over the whole anti-HIV concentration range explored (1.00 x 10(-2)-1.00 pmol/microL). The absolute recovery ranged between 80% and 110%. Values of the drug concentration determined by MALDI-TOF/TOF were in the range of 1.00 x 10(-2)-1.00 pmol/microL. The limit of quantification value was 1.00 x 10(-2)pmol/microL for abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Monitoring; Feasibility Studies; Furans; Humans; Molecular Structure; Nevirapine; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrophotometry, Ultraviolet; Stavudine; Sulfonamides

We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed

To determine the extent to which genotype (GT) or phenotype (PT) methods provide HIV-1 drug resistance information that is overlapping or complementary, both tests were performed on 1378 patient plasma samples. Discordance, defined as determination of reduced susceptibility measured by PT but sensitivity by GT (PT-R/GT-S), or vice versa (PT-S/GT-R), was common: 83, 62, 43, and 28% of samples with evidence of drug resistance had at least 1, 2, 3, or 4 drugs discordant, respectively. Three types of discordance were observed: PT-R/GT-S, and PT-S/GT-R with or without the presence of mixtures at resistance-associated positions (25%, 34%, and 41% of all discordance, respectively). After accounting for mixtures, results for didanosine (30%), zalcitabine (18%), tenofovir (17%), abacavir (14%), lamivudine (12%), and amprenavir (11%) were discordant in >or= 10% of samples. PT-S/GT-R results were most common for didanosine and zalcitabine, whereas PT-R/GT-S results were most common for lamivudine and amprenavir. PT provided quantitative assessment of the degree of reduced susceptibility and identified reduced susceptibility (PT-R/GT-S) or normal susceptibility (PT-S/GT-R) that was not recognized by the GT interpretation algorithm. GT provided valuable information when mixtures were present and minor populations of drug resistant virus were not detected by phenotyping (PT-S/GT-R results). This demonstrates the complementary nature of information provided by PT and GT tests and suggests that their combined use can provide additional clinically-relevant information.

Topics: Adenine; Anti-HIV Agents; Carbamates; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir; Zalcitabine

To monitor changes in the numbers of CD8 lymphocytes expressing the activated CD38++ phenotype in peripheral blood samples from patients with primary HIV infection (PHI) treated with highly active antiretroviral therapy (HAART).. Zidovudine, lamivudine, abacavir and amprenavir were initiated during PHI as part of the Quest study. Absolute numbers of CD8+/CD38++ T cells were determined using three-colour flow cytometry, and plasma viral load (VL) was measured using the Roche Amplicor method.. The median, pre-therapy CD8+/CD38++ T cell count was 461/mm(3)(interquartile range 216, 974) in 131 patients compared with normal control values of less than 20 cells/mm(3). Levels fell markedly in parallel with VL within the first 2 weeks of HAART initiation, to a median of 47 cells/mm(3) at 28 weeks (median 436 cell decline; P < 0.001). At that time, 80% of patients had a VL less than 50 copies/ml, and 16.3% of all patients had less than 20 CD8+/CD38++ T cells/mm(3). A continued decrease in CD8+/CD38++ T cell count occurred in 67.2% of patients whose VL was maintained below 50 copies/ml (median change from first to last value -18 cells/mm(3); P < 0.001).. After the initiation of HAART in PHI, CD8+/CD38++ lymphocytes declined rapidly in parallel with VL, and allowed for a normalization of CD8+/CD38++ T cell numbers in a subset of patients at week 28. Cell numbers continued to decline in patients who maintained VL below 50 copies/ml, indicating that the CD8+/CD38++ T cell count may represent a marker of residual viral replication when VL falls below detectable levels after HAART intervention.

Topics: Adult; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Biomarkers; Carbamates; CD48 Antigen; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lymphocyte Count; Male; Middle Aged; Reverse Transcriptase Inhibitors; Sulfonamides; T-Lymphocyte Subsets; Treatment Outcome; Viral Load; Viremia; Zidovudine

CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5+ CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5- CD4 T lymphocytes. After antiretroviral therapy, Ki-67- CCR5- CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking and/or sequestration. In the CCR5+ subset of CD4 T cells, there was an elevation in the proliferative (Ki-67+) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5+ CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Epstein-Barr Virus Infections; Flow Cytometry; Furans; Genotype; HIV Infections; HIV-1; Humans; Immunoglobulin M; Lamivudine; Longitudinal Studies; Male; Proto-Oncogene Proteins c-bcl-2; Receptors, CCR5; Sulfonamides; Time Factors; Zidovudine

Topics: Antiretroviral Therapy, Highly Active; Carbamates; Chemistry, Pharmaceutical; Clinical Trials, Phase III as Topic; Dideoxynucleosides; Furans; HIV Protease Inhibitors; Humans; Lamivudine; Multicenter Studies as Topic; Nelfinavir; Organophosphates; Prodrugs; Randomized Controlled Trials as Topic; Sulfonamides

Topics: Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drug Resistance, Microbial; Furans; HIV; HIV Infections; Humans; Mutation; Sulfonamides

Topics: Anti-HIV Agents; Carbamates; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; Financing, Government; Furans; HIV Infections; HIV Protease Inhibitors; National Institutes of Health (U.S.); Reverse Transcriptase Inhibitors; Sulfonamides; United States

Abacavir and amprenavir, a nucleoside reverse transcription inhibitor and a protease inhibitor, respectively, are new drugs used for the treatment of HIV. Methadone blood concentrations were measured in five addict patients receiving methadone maintenance therapy before and after introduction of abacavir plus amprenavir. The administration of these two drugs for a median period of 14 days resulted in a significant reduction (P = 0.043) of methadone concentration, with a median decrease to 35% of the original concentration (range 28-87%). Two patients reported on several occasions nausea in the morning before the intake of the daily methadone dose, which is compatible with withdrawal reaction to opioids. Because amprenavir is a cytochrome P4503A4 substrate and is involved in the metabolism of methadone, reduction of methadone concentrations could be explained by an induction of cytochrome P4503A4.

Topics: Acquired Immunodeficiency Syndrome; Analgesics, Opioid; Carbamates; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; HIV-1; Humans; Methadone; Reverse Transcriptase Inhibitors; Substance-Related Disorders; Sulfonamides

Topics: Aged; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; Humans; Lopinavir; Male; Patient Compliance; Pyrimidinones; Ritonavir; Stavudine; Sulfonamides; Viral Load

Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1-infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Dideoxynucleosides; Furans; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lymph Nodes; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Stavudine; Sulfonamides; Time Factors; Viral Load; Viremia; Zidovudine

Clinical cohort studies suggest that as many as 60% of patients experience virologic failure of a first-line antiretroviral regimen. Second-line and rescue (or salvage) regimens have a poorer success record: Most studies presented to date show a short-term virologic response rate of only approximately 30% in treatment-experienced individuals. That rate will improve with better understanding of what causes initial virologic failure, continued development of new antiretroviral agents (including drugs with new mechanisms of action) and new treatment strategies (including dual-protease inhibitor regimens), and more widespread use of resistance testing. Further clinical research is needed to improve salvage options, and physicians should consider enrolling treatment-experienced patients in clinical trials.

Topics: Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Microbial Sensitivity Tests; Mutation; Nelfinavir; Practice Guidelines as Topic; Pyrimidinones; Retroviridae; Retroviridae Infections; Reverse Transcriptase Inhibitors; Sulfonamides; Time Factors; Treatment Failure; Viral Load

The delineation of optimal regimens for combinations of agents is a difficult problem, in part because, to address it, one needs to (i) have effect relationships between the pathogen in question and the drugs in the combination, (ii) have knowledge of how the drugs interact (synergy, antagonism, and additivity), and (iii) address the issue of true between-patient variability in pharmacokinetics for the drugs in the population. We have developed an approach which employs a fully parametric assessment of drug interaction using the equation of W. R. Greco, G. Bravo, and J. C. Parsons (Pharmacol. Rev. 47:331-385, 1995) to generate an estimate of effects for the two drugs and have linked this approach to a population simulator, using Monte Carlo methods, which produce concentration-time profiles for the drugs in combination. This software automatically integrates the effect over a steady-state dosing interval and produces an estimate of the mean effect over a steady-state interval for each simulated subject. In this way, doses and schedules can be easily evaluated. This software allows for a rational choice of dose and schedule for evaluation in clinical trials. We evaluated different schedules of administration for the combination of the nucleoside analogue abacavir plus the human immunodeficiency virus type 1 protease inhibitor amprenavir. Amprenavir was simulated as either 800 mg every 8 h (q8h) or 1,200 mg q12h, each along with 300 mg q12h of abacavir. Both regimens produced excellent effects over the simulated population of 500 subjects, with average percentages of maximal effect (as determined from the in vitro assays) of 90.9%+/- 11.4% and 80.9%+/-18.6%, respectively. This difference is statistically significant (P<<0.001). In addition, 68.8 and 46.0% of the population had an average percentage of maximal effect which was greater than or equal to 90% for the two regimens. We can conclude that the combination of abacavir plus amprenavir is a potent combination when it is given on either schedule. However, the more fractionated schedule for the protease inhibitor produced significantly better effects in combination. Clinicians need to explicitly balance the improvement in antiviral effect seen with the more fractionated regimen against the loss of compliance attendant to the use of such a regimen. This approach may be helpful in the preclinical evaluation of multidrug anti-infective regimens.

Topics: Anti-HIV Agents; Carbamates; Computer Simulation; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Furans; Humans; Monte Carlo Method; Sulfonamides

The effect on humoral immune responses of highly active antiretroviral therapy (HAART) commenced during primary or chronic human immunodeficiency virus type 1 (HIV-1) infection was investigated. HAART inhibited the development of anti-gp120 antibodies when initiated during primary infection and could sometimes reduce antibody titers in patients treated within 2 years of HIV-1 infection. Conversely, antibody responses in patients infected for several years were less sensitive to HAART. Administering HAART during primary infection usually did not substantially affect the development of weak neutralizing antibody responses against autologous virus. However, 2 patients treated very early after infection did not develop neutralizing responses. In contrast, 3 of 4 patients intermittently adherent to therapy developed autologous neutralizing antibodies of unusually high titer, largely coincident with brief viremic periods. The induction of strong neutralizing antibody responses during primary HIV-1 infection might require the suppression of virus replication by HAART, to allow for the recovery of immune competency, followed by exposure to native envelope glycoproteins.

Topics: Anti-HIV Agents; Carbamates; Dideoxynucleosides; Furans; HIV Antibodies; HIV Core Protein p24; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Lamivudine; Neutralization Tests; Ritonavir; Sulfonamides; Zidovudine

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

Long-term management of HIV shows that combination therapy can achieve viral loads of under 50 copies, sustainable for 3 years or more. Highly affective antiretroviral therapy (HAART) is the most effective prevention against opportunistic infections due to its ability to stimulate the immune system. Some statistics show as much as an 82 percent decline in opportunistic infections in patients on HAART. Combination therapy does not work equally well for everyone, largely due to side effects and cross resistance, but newer medications and regimens appear more effective and have fewer side effects. Updated information is given for several new anti-HIV drugs, including amprenavir and adefovir (Preveon, 1592U89). Results of recent clinical trials with these drugs, including their effectiveness in restoring immune system strength, are reviewed. Genotypic and phenotypic resistance testing are also discussed.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

More antiretroviral drugs are becoming available, increasing potential treatment regimens but also increasing the complexity of HIV treatment. The 4 newest of the 15 available antiretroviral agents are described: efavirenz (Sustiva, EFV), abacavir (Ziagen, ABC), adefovir (Preveon, ADV), and amprenavir (Agenerase, APV). Information on dosing, side effects, and interactions with other drugs is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Sulfonamides

We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.

Topics: Adult; Aged; Anti-HIV Agents; Carbamates; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Ki-67 Antigen; Lymph Nodes; Male; Middle Aged; Reverse Transcriptase Inhibitors; Sulfonamides

The use of combinations of anti-human immunodeficiency virus (anti-HIV) agents targeted to different molecular targets will most likely result in increased viral suppression and may also delay or prevent the emergence of resistant HIV strains. The purpose of the present study was to develop information on the in vitro anti-HIV activities of combinations of the reverse transcriptase inhibitor 1592U89 and the protease inhibitor 141W94 to help guide the choice of dosages in clinical trials. Triplicate in vitro dose-response matrices were prepared with MT-2 cells infected with HIV type 1 (HIV-1) strain IIIB. In order to account for the effects of protein binding, tissue culture medium with 10% fetal bovine serum was supplemented with the human serum proteins alpha1 acid glycoprotein (1 mg/ml) and albumin (40 mg/ml). The three-dimensional drug interaction surface for 1592U89 and 141W94 was constructed with the program MacSynergy II. As analyzed relative to a Bliss Independence null reference model, this combination was synergistic, with volumes of synergy exceeding 100 (99% confidence). Analysis of the data set with a fully parametric form of an equation for the quantitation of drug interaction developed by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) resulted in an interaction term statistically significantly greater than 0.0, indicating true synergy. Both methods concur that this combination is significantly synergistic. These data, with favorable findings from phase I/II trials for each drug alone, suggest that the combination of 1592U89 plus 141W94 should be further evaluated in clinical trials.

Topics: Anti-HIV Agents; Carbamates; Cell Line; Dideoxynucleosides; Drug Synergism; Furans; HIV Protease Inhibitors; HIV-1; Humans; Sulfonamides

The transfer of abacavir, a new nucleoside inhibitor, and amprenavir, a new protease inhibitor, used for the treatment of human immunodeficiency virus, has been studied in the ex vivo human placental model.. The ex vivo human placental model used C14 antipyrine to determine the transport fraction and clearance index of these compounds at both the peak and trough serum concentrations. The clearance index accumulation and tissue concentrations were determined for each drug by high pressure liquid chromatography.. The clearance index of abacavir was 0.47 +/- 0.19 and 0.50 +/- 0.07 at peak and trough concentrations, respectively. The clearance index of amprenavir was 0.38 +/- 0.09 and 0.14 +/- 0.08 at peak and trough concentrations, respectively. There was no unusual accumulation of either drug in the media or tissue when the perfusion system was closed.. Abacavir is the first nucleoside compound studied in the perfusion system with a high clearance index. The transfer of the protease inhibitor amprenavir had a clearance index 2.75 times greater than the clearance index of ritonavir at peak concentration determined in a previous study. At trough concentration the clearance index was much less than at the peak concentration. A similar result was found with ritonavir.

Topics: Carbamates; Dideoxynucleosides; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; In Vitro Techniques; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Sulfonamides

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

Some of the latest developments in HIV treatment are described and contact information is given for people seeking further information on the topic. Clinical studies and preliminary results for interleukin-2 (IL-2), 1592U89 (abacavir), DMP-266 (efavirenz or Sustiva), and 141W94 (VX-94, Vertex) are described. Pharmaceutical companies are expected to continue developing new HIV drugs, including those in new drug classes, that will be more convenient, palatable, and less prone to resistance.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Interleukin-2; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

The 5th Conference on Retroviruses and Opportunistic Infections included 837 abstracts and oral presentations on clinical and basic science aspects of HIV. A major theme of the conference was the effectiveness of newer anti-HIV therapies, and there were many sessions dealing with combination treatments, including six-drug treatments. Results of studies with several drugs, including abacavir, efavirenz, amprenavir, PMPA Prodrug, adefovir dipivoxil, hydroxyurea, and protease inhibitors in several combinations are summarized. Treatments for opportunistic infections, including MAC, CMV retinitis, herpesvirus, and tuberculosis, are also presented.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antiviral Agents; Benzoxazines; Carbamates; Chicago; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

A Glaxo-Wellcome study of anti-HIV-drug-naive patients taking amprenavir at 1200 mg and abacavir at 300 mg twice daily reveals viral load drops to below 500 copies. Another study involving abacavir at 300 mg, amprenavir at 1200 mg, AZT at 300 mg, and 3TC at 150 mg, all taken twice daily was conducted with recently infected patients and chronically infected patients. Viral load drops and rises in CD4+ cell counts were reported in both groups after 20 weeks. A rash associated with abacavir tends to occur in about 5 percent of the patients tested. Fatigue, nausea, vomiting, and fever are also possible side effects.

Topics: Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Sulfonamides; Viral Load; Zidovudine

There are a number of new developments in the fight against the HIV epidemic. New drugs are being developed, results are being reported from a number of clinical trials, and there are some new strategies in disease management. Currently, there are eleven approved medications for HIV. Several new drugs or studies are highlighted: adefovir dipivoxil (preveon), which is now available under an expanded access program; abacavir (GW1592U89, efavirenz), which shows promise as an antiretroviral ten times more effective than AZT; amprenavir (141W94, VX-478), a new protease inhibitor nearing the end of clinical trials; Fortovase (soft-gel Saquinavir), which is proving much more effective than its earlier formulation; and Hydroxyurea (HU), a long-approved anti-cancer drug which enhances the effectiveness of other HIV medications. Several drugs under development are discussed, such as ABT-378, which show great promise in the treatment arsenal.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Carbamates; Decision Making; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Patient Compliance; Saquinavir; Sulfonamides

Since many new anti-HIV drugs are variations of currently available drugs, they may be more effective for people who are beginning treatment. One study shows favorable results when using efavirenz in triple combination therapy; however, it is recommended that this therapy be reserved for people who are treatment-naive and symptom-free. It is still unclear if all non-nucleoside RT inhibitors (NNRTIs) are as potent as efavirenz and whether the long-term potential for them is as promising as standard combinations. Researchers caution against pairing an NNRTI with a protease inhibitor in the event that resistance to the combination develops. That resistance may eliminate the option of using any other protease inhibitor or NNRTI in future therapies. Conversely, abacavir, an NARTI, has been effective in combination with many protease inhibitors. Amprenavir shows good antiviral activity; although studies show that it may not be successful as a salvage therapy with protease inhibitors. Nucleotide analogue reverse transcriptase inhibitors, such as adefovir and bis-poc PMPA, showed moderate anti-HIV potency. A study evaluating FTC alone showed a good reduction in viral load. FTC also fights hepatitis B and requires only one dose daily. Information is included about expanded access programs for abacavir, adefovir, and efavirenz.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides; United States; Zidovudine

Current treatment strategies need to be planned carefully, because there is an inadequate supply of new types of drugs available to treat people who have failed previous therapies. It is important to fully use existing therapies so as not to limit future options. Drugs in development include: ABT-378, a protease inhibitor from Abbott Laboratories; tipranavir (PNU-140690), a protease inhibitor by Pharmacia & Upjohn; and S-1153, a non-nucleoside reverse transcriptase inhibitor from Agouron Pharmaceuticals. All were effective and well-tolerated in recent trials. A warning was issued for adefovir, a nucleoside reverse transcriptase inhibitor, regarding the development of kidney toxicity for people taking the drug more than 20 weeks. Information on expanded access programs for abacavir, adefovir, amprenavir, and efavirenz is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Imidazoles; Kidney Diseases; Lopinavir; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

Glaxo Wellcome's new drug, Ziagen (abacavir), was recently recommended to the Food and Drug Administration (FDA) for accelerated approval. Ziagen appears to have significant antiviral activity, and its dosage is one pill twice a day. Data from various studies of the drug show it to be effective in previously untreated patients. Glaxo Wellcome also filed a New Drug Application for Agenerase (amprenavir), a new protease inhibitor. Preliminary data presented at ICAAC showed it to be effective in multi-drug combinations. Agenerase is taken twice daily without any food or water restrictions and is available through an expanded access program. Contact information is provided.

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

Amprenavir, abacavir, and adefovir are available at no cost during their final approval phase by the FDA. Eligibility requirements for receiving the drugs and contact information are provided.

Topics: Adenine; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Sulfonamides

New anti-HIV drugs that are expected to become available in the future are discussed. The potent protease inhibitor amprenavir (Agenerase) is expected to be available in pharmacies by early 1999. Results of a study of treatment-naive, HIV-positive people showed that those taking amprenavir as part of a three-drug combination therapy, with AZT and 3TC, had better viral reduction than those using AZT and 3TC alone. In a French study of the non-nucleoside reverse transcriptase inhibitor Nevirapine, and a similar study of Delavirdine, a majority of participants had HIV RNA levels below the limit of detection. Further comparative studies are needed between Nevirapine, Delavirdine and the more costly, highly publicized competitor, efavirenz. Several studies of regimens that include protease inhibitors compare dosing twice daily to three times a day. A Canadian study describes salvage therapies, for people who have failed previous treatment with protease inhibitors, that can include up to nine drugs. Because there is a shortage in the development of new types of HIV drugs, people are encouraged to carefully consider when to begin treatment and what medical options are available.

Topics: Anti-HIV Agents; Carbamates; Delavirdine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nevirapine; Reverse Transcriptase Inhibitors; Salvage Therapy; Sulfonamides

Highlights from the 38th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) included a tribute to Jonathan Mann and Mary-Lou Clements Mann and a review of HIV drugs recently approved and currently in development. Information is provided about efavirenz, abacavir, amprenavir, and adefovir, including the classification, dosing, and side effects of these drugs. Data from recent trials of these new drugs can be used to determine the best course of treatment for treatment-naive and treatment-experienced patients. New nucleoside reverse transcriptase inhibitors reviewed are lodenosine (FDDA), FTC, BCH-10652, and DAPD. Non-nucleoside reverse transcriptase inhibitors described include MKC 442 and PNU 142721. Other drugs under development include bis(POC) PMPA, a nucleotide RTI, and several protease inhibitors. T-20, an enzyme that interferes with envelope fusion, is also in development.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

A chart provides profile information on Agenerase (amprenavir), Ziagen (abacavir) and Preveon (adefovir). Basic questions about drug type, storage, dosing, and benefits for people with or without previous antiviral experience are answered. Drug interactions, side effects, and pediatric use are also covered for these three drugs, which are only accessible through expanded access programs. Contact information is provided.

Topics: Adenine; Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Child; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Male; Pregnancy; Sulfonamides

Presentations at the Fifth Conference on Retroviruses and Opportunistic Infections focused on new and novel HIV treatments. Four new agents in advanced testing are described: abacavir (1592), efavirenz (DMP-266), adefovir dipivoxil (bis-POM PMEA), and amprenavir (141W94). Other new drugs are being developed; however, the drugs are not as far along in the testing and approval process. The new drugs include integrase inhibitors, zinc finger inhibitors, cyclams and bycyclams, fusion inhibitors, and CKR-5 gene therapy. A summary of each drug is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; Genetic Therapy; Heterocyclic Compounds; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Oxazines; Receptors, Chemokine; Reverse Transcriptase Inhibitors; Sulfonamides; Zinc Fingers

Ron Baker of the San Francisco AIDS Foundation discusses the presentation highlights at the Fifth Conference on Retroviruses and Opportunistic Infections with Dr. Harvey Bartnoff of the AIDS Virus Education and Research Institute, Dr. Steven Deeks of the University of California, and Dr. Stephan Follansbee of the Institute for HIV Research and Treatment. The panel discusses trends in testing and treatment, drug interactions, and studies of several therapies, including amprenavir, hydroxyurea, and adefovir. Dr. Mellors described study results of abacavir used in combination with protease inhibitors. The panel of doctors emphasize that abacavir is very effective; however, it needs to be used carefully in case a reaction occurs. If the drug is restarted, the allergic reaction may result in death.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Furans; Genetic Techniques; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

The 12th World AIDS Conference in Geneva brought together AIDS researchers, medical care providers, advocates, and people living with HIV to discuss implications related to providing global access to care. New drugs have decreased deaths and opportunistic infections in developed countries, but developing countries are becoming overwhelmed by the number of new patients. The World Health Organization estimates that the majority of the 30.6 million people infected with HIV/AIDS worldwide will die within a decade unless a cure is found or treatments are made accessible to them. Researchers are no longer optimistic about the feasibility of viral eradication, and instead are looking for strategies to overcome the virus that continues to live in latent reservoirs in the body. Descriptions are given of several new drugs currently being studied, including abacavir, amprenavir, efavirenz, ABT 378, and Hydroxyurea. Progress is also highlighted about dosing regimens, antiretroviral resistance, and reconstitution of the immune system.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Furans; Health Services Accessibility; HIV Protease Inhibitors; Humans; Hydroxyurea; Lopinavir; Oxazines; Patient Care Planning; Pyrimidinones; Remission Induction; Reverse Transcriptase Inhibitors; Sulfonamides; Switzerland; Virus Replication

Glaxo Wellcome is discussing the development of expanded access programs for its experimental nucleoside 1592 (abacavir) and its new protease inhibitor 141W94. Community representatives proposed a framework that will expand the outdated criteria of the present program. The underlying principle is to provide the drugs to patients who are otherwise unable to construct a viable treatment regimen based on the current treatment guidelines. Glaxo is willing to provide unused 1592 to patients; however, it is unclear whether the Food and Drug Administration (FDA) will support the changes. Community representatives would like to see this approach used with expanded access to 141W94. Community representatives hope that the new simplified, open-ended approaches to expanded access will serve as a model for future programs and place medical decisions about treatment back in the hands of the patient and doctor.

Topics: Anti-HIV Agents; Carbamates; Clinical Trials as Topic; Dideoxynucleosides; Drug Industry; Furans; Health Services Accessibility; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors; Sulfonamides

A phase II multicenter trial is underway to test the effectiveness of three new antiretrovirals in patients who are failing combination protease inhibitor therapy. The study, organized by Glaxo Wellcome, is testing the effectiveness of a combination of 1592, 141W94, and efavirenz (Sustiva or DMP-266). Volunteers must be at least 13 years old, with viral loads over 500 following protease inhibitor therapy. Other criteria include no AIDS-defining opportunistic infections or malignancies except Kaposi's sarcoma. Each of the drugs has side effects associated with it, and rash has been the most common reason for each drug to be discontinued.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials, Phase II as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Male; Multicenter Studies as Topic; Oxazines; Patient Selection; Reverse Transcriptase Inhibitors; Sulfonamides; Treatment Failure