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Randomised, multicentre phase III study of saquinavir plus zidovudine plus zalcitabine in previously untreated or minimally pretreated HIV-infected patients



Randomised, multicentre phase III study of saquinavir plus zidovudine plus zalcitabine in previously untreated or minimally pretreated HIV-infected patients



Clinical Drug Investigation 20(5): 295-307



Background: PISCES (SV14604) was the largest study of antiretroviral therapy to assess clinical end-points. The study data provides a repository of important information, much of which remains relevant today. This paper reviews the results of the PISCES study, placing the findings in context with today's treatment practices. Objective: To determine the antiretroviral efficacy of saquinavir hard gelatin capsule (SQV; Invirase(R)) plus two nucleoside analogues (zidovudine (ZDV) and zalcitabine (ddC)) using clinical end-points. Design: Prospective, randomised, double-blind international study. Patients: HIV-1-infected individuals (CD4 50 to 350 cells/mul) who were antiretroviral-naive or minimally pretreated with zidovudine (ZDV; ltoreq16 weeks) were randomised. Interventions: Patients received: (i) SQV + ZDV + ddC, (ii) SQV + ZDV, (iii) ZDV + ddC, or (iv) ZDV for gtoreq80 weeks or until the common closure date, at daily oral dosages of SQV 1800mg, ddC 2.25mg and ZDV 600mg. After 14 months, ZDV monotherapy patients were reallocated to receive additional SQV + ddC in a double-blinded manner. Main Outcome Measure: Time to clinical end-point of first AIDS-defining event (ADE) or death. Results: A total of 3591 patients were randomised, and 3485 received therapy. Median duration of study therapy was 58.4 to 63.3 weeks and mean duration of follow-up was 73.9 to 75.6 weeks. The time to first ADE or death was significantly reduced with triple therapy relative to ZDV + ddC (p = 0.0001, log rank test). The proportion of patients progressing to the primary clinical end-point was 8.0% for the triple therapy group compared with 15.1% for ZDV + ddC. Initiating triple therapy reduced the risk of progression by 50% relative to ZDV + ddC (risk ratio 0.502; (95% CI 0.379-0.663) p = 0.0001). Patients with prior ZDV therapy for <8 weeks achieved the greatest clinical benefit. HIV-1 RNA was reduced more by triple therapy than by either dual therapy (p = 0.0001), and this reduction explained 64% of the treatment effect. In an exploratory analysis, the primary end-point was reached by 8.0% of patients receiving immediate triple therapy, compared with 17.8% receiving initial ZDV monotherapy followed by triple therapy (p = 0.0001). Conclusions: This study was the first to show the benefit of triple therapy over dual therapy using clinical outcome measures; treatment with SQV + ZDV + ddC producing a statistically significant prolongation of time to first ADE or death in antiretroviral-naive/minimally pretreated patients, compared with combined nucleoside analogues only. The study also confirms the outcome benefit (time to first ADE or death) of immediate triple therapy over delayed triple therapy and the prognostic value of monitoring HIV-1 RNA (but not CD4 count). The potential of patient/clinician perception of therapy to influence study outcome was also demonstrated.

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Accession: 011243097

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DOI: 10.2165/00044011-200020050-00001


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