ArticlesRandomised placebo-controlled trial of ritonavir in advanced HIV-1 disease
Introduction
Zidovudine was the first antiretroviral treatment shown to lower the rate of AIDS-related death significantly in a placebo-controlled trial of patients with advanced HIV-1 disease.1 Subsequent placebo-controlled clinical trials have shown its clinical effectiveness in the prevention of minor opportunistic infections in patients with moderate immunodeficiency2 and in those with primary HIV-1 infection.3 Compared with zidovudine monotherapy, other nucleoside analogues (alone or in combination with zidovudine) have delayed the onset of HIV-1 disease progression or death in patients with moderate immunodeficiency in relatively long clinical trials, particularly as initial therapy.4, 5, 6, 7
Ritonavir (Norvir, Abbott Laboratories, IL, USA) is a specific and potent inhibitor of HIV-1 aspartyl protease. The drug has high oral bioavailability and a long plasma half-life, which allows twice-daily dosing.8 Compared with nucleoside analogues, ritonavir has a more potent and sustained effect on plasma viraemia, cellular HIV-1- infection loads, and lymphocyte immunophenotype subsets.9, 10, 11, 12 In clinical trials on HIV-1, some surrogate- marker responses predict clinical efficacy.13, 14 However, their usefulness in assessment of protease-inhibitor therapy is not clear. Therefore, this study was designed as a simple large-scale clinical trial to investigate rapidly, in a specific subpopulation of patients with HIV-1 disease (CD4-lymphocyte counts ≤100/μL [0·1×109/L]), the safety and clinical efficacy of ritonavir. These results might be generalisable to a larger population.
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Methods
The primary objective of this randomised, double-blind, placebo-controlled, multicentre trial was to test the effectiveness of ritonavir oral solution (600 mg twice daily) in reducing the rate of death or any new, or specified recurrent, AIDS-defining illness in a population of HIV-1-infected adults with CD4-lymphocyte counts of 100/μL or less, while permitting concurrent use of licensed anti-HIV-1 therapy. Secondary objectives were to assess the effect of ritonavir on counts of CD4 and CD8
Results
Patients were recruited to the study between April, 1995, and July, 1995. 1716 patients were screened, and 626 were excluded (figure 1). Of the 1090 patients randomised (543 to ritonavir, 547 to placebo), two in each treatment group did not receive any trial medication. These patients were included in the primary, intention-to-treat analysis, but they were excluded from the analysis of adverse events attributable to study drugs.
Patients (table 1) were enrolled at 67 centres in Australia (42
Discussion
In this study ritonavir reduced the risk of AIDS complications and prolonged survival in patients with advanced HIV-1 disease. The participants in this large-scale clinical trial were representative of many patients with advanced HIV-1 disease. The effectiveness of ritonavir treatment against disease was conservatively estimated in terms of rigorously confirmed clinical outcomes. Common HIV-1-related disorders were consistently less common as first outcomes in the ritonavir group than in the
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