Amprenavir in Combination with Lamivudine and Zidovudine Versus Lamivudine and Zidovudine Alone in HIV-1-Infected Antiretroviral-Naive Adults
Total Page：16
File Type：pdf, Size：1020Kb
Antiviral Therapy 5: 215-225 Amprenavir in combination with lamivudine and zidovudine versus lamivudine and zidovudine alone in HIV-1-infected antiretroviral-naive adults Jeffery C Goodgame1, John C Pottage Jr2*, Helmut Jablonowski3, W David Hardy4, Allan Stein5, Margaret Fischl6, Patrick Morrow7, Judith Feinberg8, Cynthia Hanson Brothers9, Imogen Vafidis10, Pantaleo Nacci10, Jane Yeo10 and Louise Pedneault9 for the Amprenavir PROAB3001 International Study Team 1Central Florida Research Initiative, Altamonte Springs, Fla., USA (currently with Pfizer, Ohio, USA) 2Vertex Pharmaceuticals, Cambridge, Mass., USA 3Universitatsklinik Dusseldorf, Medizinische Klinik & Poliklinik, Dusseldorf, Germany 4Pacific Oaks Research, Beverly Hills, Calif., USA 5Care Resource, Coral Gables, Fla., USA 6University of Miami, AIDS Clinical Trial Unit, Miami, Fla., USA 7ID Associates, Dallas, Tex., USA (Currently with Aesculapius Medical Health Group, Dallas, Tex., USA) 8University of Cincinnati, Holmes Division, Cincinnati, Ohio, USA 9Glaxo Wellcome, Research Triangle Park, N.C., USA 10Glaxo Wellcome, Greenford, UK *Corresponding author: Tel: +1 617 577 6322; Fax: +1 617 577 6501; E-mail: [email protected] Objectives: To compare the antiviral activity and safety of plasma HIV-1 RNA of <400 copies/ml at 48 weeks. a new protease inhibitor, amprenavir (141W94) in combi- Results: At 48 weeks, a significantly greater proportion of nation with lamivudine and zidovudine, versus lamivudine amprenavir/lamivudine/zidovudine subjects had plasma and zidovudine alone in HIV-1 infected, antiretroviral- HIV-1 RNA levels <400 copies/ml than lamivudine/ zidovu- naive subjects. dine subjects in the overall population: 41 versus 3% Design: Subjects (n=232) with a CD4 T cell count of ≥200 (intent-to-treat missing equals failure analysis) (P<0.001); cells/mm3, plasma HIV-1 RNA levels of ≥10000 copies/ml, 93 versus 42% (as-treated analysis) (P<0.001); and within and ≤4 weeks of prior nucleoside antiretroviral therapy, each of the three randomization strata (P<0.001). Subjects were stratified according to baseline plasma HIV-1 RNA on amprenavir/lamivudine/ zidovudine experienced longer level (10000–30000; 30000–100000; or >100000 time to event (permanent discontinuation of randomized copies/ml). Subjects received double-blind treatment with therapy or viral rebound) than those on lamivudine/ either 1200 mg amprenavir twice daily in combination zidovudine (median of 33 versus 13 weeks; P<0.001). A with lamivudine (150 mg twice daily) and zidovudine (300 significantly greater incidence of drug-related nausea, mg twice daily) (amprenavir/lamivudine/zidovudine) or vomiting, rash and oral/perioral paresthesia was observed matched placebo, lamivudine and zidovudine for 16 weeks. with amprenavir/lamivudine/zidovudine than with lamivu- Thereafter, subjects with confirmed plasma HIV-1 RNA dine/zidovudine. levels of ≥400 copies/ml could add open-label amprenavir Conclusions: Amprenavir, in combination with lamivudine or switch to other antiretrovirals and continue treatment and zidovudine, has potent and durable antiviral activity in for up to a minimum of 48 weeks. The primary endpoint of antiretroviral-naive subjects over 48 weeks. Amprenavir the study was defined as the proportion of subjects with was safe and generally well tolerated. Introduction HIV-1 protease inhibitors in combination with other such as zidovudine, lamivudine, didanosine, antiretrovirals have been shown to achieve reduction in zalcitabine or stavudine, have been shown to suppress the levels of plasma HIV-1 RNA to levels below the viral replication in lymphoid tissue [4–8]. Because detection limit of current assays [1–3]. In addition, HIV-1 protease inhibitor-containing regimens have protease inhibitor (PI)-containing regimens including demonstrated potent antiviral activity and a dramatic indinavir, saquinavir, ritonavir or nelfinavir and two reduction in HIV-related deaths and opportunistic nucleoside reverse transcriptase inhibitors (NRTIs), infections [9,10], most HIV/AIDS treatment guidelines ©2000 International Medical Press 1359-6535/00/$17.00 215 JC Goodgame et al. [11–13] currently recommend the consideration of treatment, begin open-label amprenavir therapy, add HIV-1 PIs in the initial treatment of HIV-1 infection. abacavir, add a commercially available HIV protease Amprenavir (141W94; Agenerase), which was struc- inhibitor (except ritonavir), change NRTIs, or switch turally designed based on the 3D structure of the to a commercially available PI (including ritonavir), protease enzyme, is a newly approved and potent and continue study participation for up to a minimum inhibitor of HIV-1 protease (Ki=0.6 nM) [14] and of of 48 weeks (open-label phase). Subjects with HIV-1 HIV-1 replication in vitro (mean IC50=29 nM against RNA levels consistently below 400 copies/ml remained 216 HIV clinical isolates) [15]. Clinical data indicate on blinded, randomized study medication (randomized that amprenavir is well absorbed and can be adminis- phase). tered with or without food, although it should not be taken with a high-fat meal [16]. Twice-daily dosing is Measurements feasible with amprenavir because of its long half-life of Blood was collected at baseline, at weeks 1, 2, 4, 8, 12, between 7 and 10 h [16] compared with that of 1.8–5 16 and every 4 weeks thereafter for analysis of plasma h for currently marketed HIV-1 PIs [17]. Clinical trials HIV-1 RNA levels, absolute CD4 lymphocyte counts, with amprenavir in combination with other antiretro- clinical chemistry and haematology evaluations. Blood virals, such as abacavir, zidovudine, lamivudine, samples for most laboratory evaluations were not indinavir, saquinavir and nelfinavir, are ongoing and collected in the fasting state because subjects were have demonstrated potent antiviral activity, as required to fast overnight only for week 2 and 12 eval- evidenced by decreased plasma HIV-1 RNA levels and uations. Throughout the study period, clinical adverse increased CD4 counts [18–21]. Additionally, ampre- events and haematology or clinical chemistry labora- navir is safe, with most adverse events being transient tory abnormalities were assessed and graded according and mild-to-moderate [19–22]. to ACTG toxicity scales [23] wherever possible (grade This study was designed to evaluate the efficacy and 1 or mild, to grade 4 or very severe). Durability of the safety of amprenavir in combination with lamivudine plasma HIV-1 RNA response over 48 weeks was and zidovudine versus lamivudine and zidovudine in measured as time-to-event. An event occurred when antiretroviral-naive subjects with CD4 counts of ≥200 any one of the following conditions was met: cells/mm3, and to assess the durability of this effect confirmed plasma HIV-1 RNA levels ≥400 copies/ml, over 48 weeks of treatment. However, treatment modi- permanent discontinuation of randomized therapy fications were encouraged from week 16 onwards in (including confirmed plasma HIV-1 RNA level of ≥400 subjects whose HIV-1 RNA levels were not maintained copies/ml), progression to a new confirmed CDC cate- at ≤400 copies/ml. gory C event or death. Materials and Methods Laboratory methods A reverse transcriptase PCR assay (Amplicor HIV-1 Subjects and study design Monitor, Roche Molecular Systems, Branchburg, N.J., Male or female adults (≥18 years) with a confirmed USA) was used to measure plasma HIV-1 RNA diagnosis of HIV-1 infection gave informed consent to (Primers 1.0 Standard Assay, limit of detection=400 participate in this randomized, placebo-controlled copies/ml; Primers 1.0, Ultrasensitive Assay, limit of study (PROAB3001) which was approved by the detection=50 copies/ml). CD4 lymphocyte counts Institutional Review Board/Ethics Committee at 23 were determined using flow cytometry (FACScalibur, clinical sites, 13 in the USA and 10 in Europe. Subjects Becton Dickinson Three-Color Flow Cytometry, San with CD4 counts of ≥200 cells/mm3, who were anti- Jose, Calif., USA). All efficacy and safety laboratory retroviral-naive (≤4 weeks previous NRTI treatment) measurements were performed at Covance Central and CDC category A or B, were randomly assigned in Laboratories (Geneva, Switzerland; and Indianapolis, a double-blind manner to receive 1200 mg amprenavir Ind., USA). twice daily or matched placebo twice daily without regard to food, in combination with lamivudine (150 Statistical analyses mg twice daily) and zidovudine (300 mg twice daily) A sample size of 115 subjects per treatment group was for 16 weeks. Randomization was stratified according estimated to provide ≥85% power in detecting a 20% to screening plasma HIV-1 RNA (10000–30000, difference between treatment groups at the primary 30000–100000 or >100000 copies/ml). At week 16 endpoint, which was the proportion of subjects with and thereafter, subjects who met the protocol-defined plasma HIV-1 RNA levels of <400 copies/ml at week switch criterion (defined as two consecutive plasma 48. P-values at or below the 0.05 alpha level were HIV-1 RNA values of ≥400 copies/ml measured within considered significant. 3 weeks of one another), could remain on randomized Efficacy variables were analysed on an intent-to- 216 ©2000 International Medical Press Efficacy of amprenavir with lamivudine and zidovudine versus lamivudine and zidovudine alone treat (ITT) basis (which includes data from all random- Table 1. Demographics and baseline characteristics of ized subjects) and on an as-treated basis (which randomized subjects includes data from all subjects who remained