Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection:meta-analyses of the randomised evidence

Citation
D. Abrams et al., Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection:meta-analyses of the randomised evidence, LANCET, 353(9169), 1999, pp. 2014-2025
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Journal title
LANCET
ISSN journal
0140-6736 → ACNP
Volume
353
Issue
9169
Year of publication
1999
Pages
2014 - 2025
Database
ISI
SICI code
0140-6736(19990612)353:9169<2014:ZDAZIT>2.0.ZU;2-G
Abstract
Background. To assess the effects of zidovudine, didanosine, and zalcitabin e on HIV disease progression and survival, we undertook mete-analyses of in dividual patient data and tabular data from all randomised trials that comp ared these agents. Methods. Individual patient data were available for 7722 participants witho ut AIDS in the nine randomised trials of immediate versus deferred zidovudi ne, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus zalcitabine, or zidovudine alon e, The main outcomes were mortality and disease progression (new AIDS-defin ing 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 ti me to therapy 28 months, which was zidovudine monotherapy in 94%). During t he 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 diffe rence in overall survival, which at 6 years was 64% with immediate and 65% with deferred zidovudine (rate ratio 1.04 [95% Cl 0.94-1.15]). In the compa rison of zidovudine plus didanosine or zalcitabine versus zidovudine alone, during a median follow-up of 29 months, 2904 individuals progressed, of wh om 1850 died. The addition of didanosine to zidovudine delayed both progres sion (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 del ayed 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 ne w AIDS event were 53% for zidovudine plus didanosine, 49% for zidovudine pl us zalcitabine, and 44% for zidovudine alone; the percentages alive were 68 %, 63%, and 59%, respectively. Five of the six trials involved randomised c omparisons of zidovudine plus didanosine versus zidovudine plus zalcitabine : in these, the zidovudine plus didanosine regimen had greater effects on d isease progression (p = 0.004) and death (p = 0.009). Interpretation. Although immediate use of zidovudine halved disease progres sion 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 did anosine and, to a lesser extent, zalcitabine delayed both disease progressi on and death, at least when added to zidovudine, The comparative effects of these different nucleoside analogues on long-term survival should inform t he choice of which to combine with other types of drug, such as protease in hibitors.