Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

BACKGROUND The optimal sequencing ofantiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure ofthe second three-drug regimen. RESULTS A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2. 3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure ofthe second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure ofthe second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure ofthe first regimen (hazard ratio, 0.39) and the firstvirologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the firstvirologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure ofthe first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS The efficacy ofantiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study

A Randomized Controlled Trial of a Reduced Daily Dose of Zidovudine in Patients with the Acquired Immunodeficiency Syndrome

ZIDOVUDINE (3′-azido-3′-deoxythymidine; formerly azidothymidine, or AZT) is a thymidine analogue that inhibits the replication of the human immunodeficiency virus type 1 (HIV) in vitro. 1 The administration of zidovudine to patients with advanced HIV disease over a 6-to-24-month period prolongs survival, decreases the frequency and severity of opportunistic infections, improves neurologic function, transiently improves CD4 T-lymphocyte counts, and decreases the rate of HIV antigenemia. 2 3 4 5 6 7 8 Despite these benefits, zidovudine therapy is frequently associated with adverse reactions, including both anemia and neutropenia. 2 , 9 Although the serum half-life of zidovudine is one hour, the intracellular half-life of its 5′-triphosphate form approaches three hours, suggesting that . . 

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 entry CD4+ cell count.Design and Interventions.—Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-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-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019.Patients.—A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50×109/L (500/μL).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 significant (P=.008,.004,.007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine 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 between those originally randomized to zidovudine or placebo.Conclusions.—Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30×109/L (300/μL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored.(JAMA. 1994;272:437-442