Treatment with Amprenavir Alone or Amprenavir with Zidovudine and Lamivudine in Adults with Human Immunodeficiency Virus Infection (original) (raw)

Amprenavir in Combination with Lamivudine and Zidovudine versus Lamivudine and Zidovudine Alone in HIV-1-Infected Antiretroviral-Naive Adults

Antiviral Therapy

Objectives To compare the antiviral activity and safety of a new protease inhibitor, amprenavir (141W94) in combination with lamivudine and zidovudine, versus lamivudine and zidovudine alone in HIV-1 infected, antiretroviral-naive subjects. Design Subjects ( n=232) with a CD4 T cell count of ≥200 cells/mm3, plasma HIV-1 RNA levels of ≥10000 copies/ml, and ≤4 weeks of prior nucleoside antiretroviral therapy, were stratified according to baseline plasma HIV-1 RNA level (10000–30000; 30000–100000; or >100000 copies/ml). Subjects received double-blind treatment with either 1200 mg amprenavir twice daily in combination with lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily) (amprenavir/lamivudine/zidovudine) or matched placebo, lamivudine and zidovudine for 16 weeks. Thereafter, subjects with confirmed plasma HIV-1 RNA levels of ≥400 copies/ml could add open-label amprenavir or switch to other antiretrovirals and continue treatment for up to a minimum of 48 weeks. The...

Six-Week Randomized Controlled Trial To Compare the Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients

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.

Indinavir, Nevirapine, Stavudine, and Lamivudine for Human Immunodeficiency Virus–Infected, Amprenavir‐Experienced Subjects: AIDS Clinical Trials Group Protocol 373

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)

Combination Therapy with Amprenavir, Abacavir, and Efavirenz in Human Immunodeficiency Virus (HIV)-Infected Patients Failing a Protease-Inhibitor Regimen: Pharmacokinetic Drug Interactions and Antiviral Activity

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.

A 42-week open-label study to assess the pharmacokinetics, antiretroviral activity, and safety of amprenavir or amprenavir plus ritonavir in combination with abacavir …

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

Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

Antimicrobial Agents and Chemotherapy, 2003

The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C min,ss ) was 1.92 g/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 g/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C max,ss ) was 7.12 g/ml, the area under the concentration-time curve from 0 to 10 h (AUC 0-10 ) was 32.06 g ⅐ h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUC ss ) was 35.74 g ⅐ h/ml. Decreases in the mean values of C min,ss (29%), C max,ss (42%), AUC 0-10 (42%), and AUC ss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C min,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C min,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.