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

Background: PISCES (SV14604) was the largest study of antiretroviral therap y to assess clinical end-points. The study data provides a repository of im portant information, much of which remains relevant today. This paper revie ws the results of the PISCES study, placing the findings in context with to day's treatment practices. Objective: To determine the antiretroviral efficacy of saquinavir hard gela tin capsule (SQV; Invirase(R)) plus two nucleoside analogues [zidovudine (Z DV) 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 ant i-retroviral-naive or minimally pretreated with zidovudine (ZDV; less than or equal to 16 weeks) were randomised. Interventions: Patients received: (i) SQV + ZDV + ddC, (ii) SQV + ZDV, (iii ) ZDV + ddC, or (iv) ZDV for greater than or equal to 80 weeks or until the common closure date, at daily oral dosages of SQV 1800mg, ddC 2.25mg and Z DV 600mg. After 14 months, ZDV monotherapy patients were reallocated to rec eive additional SQV + ddC in a double-blinded manner. Main Outcome Measure: Time to clinical end-point of first AIDS-defining eve nt (ADE) or death. Results: A total of 3591 patients were randomised, and 3485 received therap y. Median duration of study therapy was 58.4 to 63.3 weeks and mean duratio n of follow-up was 73.9 to 75.6 weeks. The time to first ADE or death was s ignificantly reduced with triple therapy relative to ZDV + ddC (p = 0.0001, log rank test). The proportion of patients progressing to the primary clin ical end-point was 8.0% for the triple therapy group compared with 15.1% fo r ZDV + ddC. Initiating triple therapy reduced the risk of progression by 5 0% 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 clini cal benefit. HIV-1 RNA was reduced more by triple therapy than by either du al 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% rece iving 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 + ZD V + ddC producing a statistically significant prolongation of time to first ADE or death in antiretroviral-naive/minimally pretreated patients, compar ed with combined nucleoside analogues only. The study also confirms the out come benefit (time to first ADE or death) of immediate triple therapy over delayed triple therapy and the prognostic value of monitoring HIV-1 RNA (bu t not CD4 count). The potential of patient/clinician perception of therapy to influence study outcome was also demonstrated.