Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy

OBJECTIVE: To assess the evidence for the effectiveness of increasing numbers of drugs in antiretroviral combination therapy. DESIGN: Systematic review, meta-analysis, and meta-regression of fully reported randomised controlled trials. All studies included compared quadruple versus triple therapy, triple versus double therapy, double versus monotherapy, or monotherapy versus placebo or no treatment. PARTICIPANTS: Patients with any stage of HIV infection who had not received antiretroviral therapy. MAIN OUTCOME MEASURES: Changes in disease progression or death (clinical outcomes); CD4 count and plasma viral load (surrogate markers). SEARCH STRATEGY: Six electronic databases, including Medline, Embase, and the Cochrane Library, searched up to February 2001. RESULTS: 54 randomised controlled trials, most of good quality, with 66 comparison groups were included in the analysis. For both the clinical outcomes and surrogate markers, combinations with up to and including three (triple therapy) were progressively and significantly more effective. The odds ratio for disease progression or death for triple therapy compared with double therapy was 0.6 (95% confidence interval 0.5 to 0.8). Heterogeneity in effect sizes was present in many outcomes but was largely related to the drugs used and trial quality. CONCLUSIONS: Evidence from randomised controlled trials supports the use of triple therapy. Research is needed on the effectiveness of quadruple therapies and the relative effectiveness of specific combinations of drugs.