Amprenavir in Combination with Lamivudine and Zidovudine versus Lamivudine and Zidovudine Alone in HIV-1-Infected Antiretroviral-Naive Adults (original) (raw)
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The Journal of Infectious Diseases, 1999
Amprenavir is a human immunodeficiency virus (HIV) protease inhibitor with a favorable pharmacokinetic profile and good in vitro activity. Ninety-two lamivudine-and protease inhibitor-naive individuals with у50 CD4 cells/mm 3 and у5000 HIV RNA copies/mL were assigned amprenavir (1200 mg) alone or with zidovudine (300 mg) plus lamivudine (150 mg), all given every 12 h. After a median follow-up of 88 days, the findings of a planned interim review resulted in termination of the amprenavir monotherapy arm. Among 85 subjects with confirmed plasma HIV RNA determination, 15 of 42 monotherapy versus 1 of 43 tripletherapy subjects had an HIV RNA increase above baseline or 1 log 10 above nadir (P ϭ). For subjects taking triple therapy at 24 weeks, the median decrease in HIV RNA was .0001 2.04 log 10 copies/mL, and 17 (63%) of 27 evaluable subjects had !500 HIV RNA copies/mL. Treatment with amprenavir, zidovudine, and lamivudine together reduced the levels of HIV RNA significantly more than did amprenavir monotherapy.
Clinical Infectious Diseases, 2000
Patients with plasma viral RNA 150,000 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 11.5 log 10 viral response to abacavir and amprenavir. All 8 patients who added efavirenz had 10.5 log 10 decline in viral load, and this response lasted 124 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.
Antimicrobial Agents and Chemotherapy, 2004
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 (), 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 ,ss versus the AUC from 0 h to ؕ 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 (ϳ2 log 10 copies/ml) and increased CD4 ؉ cell counts (ϳ100 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.
The Journal of Infectious Diseases, 2001
This prospective, multicenter, open-label study was designed to determine the antiretroviral activity and safety of a 4-drug regimen: 1000 mg indinavir every 8 h with 200 mg nevirapine, 40 mg stavudine, and 150 mg lamivudine, each given twice daily in amprenavir-experienced subjects. The primary end points of the study were the human immunodeficiency virus (HIV) RNA level and CD4 cell count responses. Fifty-six subjects were enrolled and were changed from amprenavir-containing regimens to the 4-drug regimen. Overall, at week 48, 33 (59%) of 56 subjects had HIV RNA levels !500 copies/mL (intent-to-treat analysis, where missing values equal у500 copies/mL) and CD4 cell counts increased by 94 cells/mm 3 from baseline. Subjects who had previously taken amprenavir combination therapy were more likely to experience virologic failure than those who had taken amprenavir monotherapy (odds ratio, 7.7;). In this study, most subjects who had taken amprenavir-based regimens and P p .0012 who changed to a 4-drug regimen achieved subsequent durable virologic suppression. Current guidelines for the treatment of human immunodeficiency virus (HIV) infection suggest approaches for choosing new antiretroviral regimens for patients experiencing virologic failure on an HIV protease inhibitor (PI)-based regimen [1, 2]. However, there are few data from prospective clinical trials to support specific treatment recommendations for therapy-experienced patients. The recently approved PI, amprenavir, was studied both as monotherapy and as part of a combination antiretroviral regimen in AIDS Clinical Trials Group (ACTG)
Clinical infectious …, 2004
The pharmacokinetics, antiviral activity, and safety of an amprenavir-ritonavir (APV-RTV) 600/100 mg b.i.d. regimen and an APV-RTV 1200/200 mg q.d. regimen were studied in a human immunodeficiency virus (HIV)-infected population. The geometric least-square mean ratio (90% confidence interval) of steady-state trough concentrations, compared with that of the amprenavir 1200 mg b.i.d. regimen, was 6.08 (4.94-7.49) for the twice-daily APV-RTV regimen, and it was 4.19 (2.90-6.08) for the daily APV-RTV regimen. The regimens were well tolerated, which supports APV-RTV as an option for twice-daily or daily therapy for HIV. Amprenavir (APV; Agenerase; GlaxoSmithKline) is an HIV protease inhibitor with potent antiretroviral activity [1-3] and a favorable safety [4] and cross-resistance profile [5-7] when administered as part of a combination regimen. Ritonavir (RTV; Norvir; Abbott Laboratories) is frequently coadministered with HIV protease inhibitors at subtherapeutic doses be
BMC infectious diseases, 2003
Low-dose ritonavir (RTV) boosts plasma amprenavir (APV) exposure. Little has been published on the efficacy, tolerability, and safety of APV 600 mg/RTV 100 mg (APV600/RTV) twice daily (BID) compared to APV 1200 mg BID (APV1200). ESS40011 was a 24-week, multicenter, open-label, clinical trial in which antiretroviral therapy-naïve and -experienced HIV-1-infected adults were randomized 3:1 to receive either APV600/RTV BID or APV1200 BID, in combination with > or = 2 non-protease inhibitor antiretroviral drugs. Non-inferiority of the APV600/RTV regimen to the APV1200 regimen was established if the 95% lower confidence limit for the difference in proportion of patients achieving HIV-1 RNA <200 copies/mL at week 24 with APV 600/RTV minus APV1200 was > or =-0.12. Late in the conduct of the trial, patients not yet completing 24 weeks of therapy were given the option of continuing treatment for an additional 24-week period. 211 patients were randomized, 158 to APV600/RTV and 53 to A...