Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trialists' Collaborative Group

Abstract

Background: To assess the effects of zidovudine, didanosine, and zalcitabine on HIV disease progression and survival, we undertook meta-analyses of individual patient data and tabular data from all randomised trials that compared these agents.

Methods: Individual patient data were available for 7722 participants without AIDS in the nine randomised trials of immediate versus deferred zidovudine, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus zalcitabine, or zidovudine alone. The main outcomes were mortality and disease progression (new AIDS-defining event or death before any such event).

Findings: In the comparison of immediate versus deferred zidovudine, during a median follow-up of 50 months, 1908 individuals progressed, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was zidovudine monotherapy in 94%). During the first year of follow-up, immediate zidovudine halved the rate of disease progression (p<0.0001), increasing the probability of AIDS-free survival at 1 year from 96% to 98%. This early delay did not persist: after 6 years, AIDS-free survival was 54% in both groups. At no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred zidovudine (rate ratio 1.04 [95% CI 0.94-1.15]). In the comparison of zidovudine plus didanosine or zalcitabine versus zidovudine alone, during a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of didanosine to zidovudine delayed both progression (rate ratio 0.74 [0.67-0.82], p<0.0001) and death (0.72 [0.64-0.82], p<0.0001). Similarly, the addition of zalcitabine to zidovudine also delayed progression (0.86 [0.78-0.94], p=0.001) and death (0.87 [0.77-0.98], p=0.02). After 3 years, the estimated percentages alive and without a new AIDS event were 53% for zidovudine plus didanosine, 49% for zidovudine plus zalcitabine, and 44% for zidovudine alone; the percentages alive were 68%, 63%, and 59%, respectively. Five of the six trials involved randomised comparisons of zidovudine plus didanosine versus zidovudine plus zalcitabine: in these, the zidovudine plus didanosine regimen had greater effects on disease progression (p=0.004) and death (p=0.009).

Interpretation: Although immediate use of zidovudine halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term. However, the use of didanosine and, to a lesser extent, zalcitabine delayed both disease progression and death, at least when added to zidovudine. The comparative effects of these different nucleoside analogues on long-term survival should inform the choice of which to combine with other types of drug, such as protease inhibitors.