THE DURATION OF ZIDOVUDINE BENEFIT IN PERSONS WITH ASYMPTOMATIC HIV-INFECTION - PROLONGED EVALUATION OF PROTOCOL-019 OF THE AIDS-CLINICAL-TRIALS-GROUP

Objective.-To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV ) disease and to assess the relationship between this effect and the e ntry CD4(+) cell count. Design and Interventions.-Extended follow-up d ata from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjec ts were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Origina l treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were con ducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all sub jects, (2) analysis of all subjects but with follow-up of original pla cebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. Setting.-University-ba sed and university-affiliate AIDS research clinics participating in AI DS Clinical Trials Group protocol 019. Patients.-A total of 1565 asymp tomatic HIV-infected subjects with entry CD4(+) cell counts less than 0.50x10(9)/L (500/mu L). Main Outcome Measure.-Time to progression to AIDS or death. Results.-During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significa nt (P=.008, .004, .007) decrease in the risk of such progression. Howe ver, each of these analyses also indicated a decreasing placebo:zidovu dine relative risk with duration of use (P=.002, .08, .04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4(+) cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found be tween those originally randomized to zidovudine or placebo. Conclusion s.-Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not as sociated with an additional prolongation of survival compared with del ayed initiation. The delay in progression diminished overtime especial ly in subjects with entry CD4(+) cell counts less than 0.30x10(9)/L (3 00/mu L). Treatment strategies that alter drug regimens before the los s of zidovudine benefit should be explored.