Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double- blind, controlled trial

Background: Stavudine is a promising antiretroviral agent, but its clinical efficacy has not been determined. Objective: To evaluate the clinical effect of stavudine (2',3'-didehydro-3'-deoxythymidine) monotherapy in patients with human immunodeficiency virus (HIV) infection. Design: Randomized, controlled, double-blind trial. Setting: 56 outpatient clinics in private practices, universities, and contract research organizations in the United States, France, and Italy. Patients: 822 HIV-infected adults who had 50 to 500 CD4⁺ cells/mm³ and had previously received at least 6 months of zidovudine treatment. Intervention: Monotherapy with peroral stavudine capsules or peroral zidovudine capsules. Measurements: The primary end point was clinical progression, which was defined as all occurrences of acquired immunodeficiency syndrome (AIDS)-defining events or death. Results: Patients receiving stavudine reached clinical end points at a rate of 26 per 100 person-years, compared with 32 per 100 person-years for patients receiving zidovudine (relative risk, 0.75 [95% CI, 0.58 to 0.98]; P = 0.03). The risk for death alone was 26% lower in the stavudine group than in the zidovudine group, but the comparison was not statistically significant (relative risk, 0.74 [CI, 0.53 to 1.02]; P = 0.066). The benefit of stavudine therapy was seen in all CD4⁺ cell strata (≤ 100 cells/mm³, 101 to 300 cells/mm³, and >300 cells/mm³) and clinical stages of HIV disease (asymptomatic, symptomatic, and AIDS). Four weeks after treatment began, CO4⁺ cell counts were 30 cells/mm³ higher in the stavudine group than in the zidovudine group; this difference was sustained for 96 weeks (P < 0.001). Nausea and vomiting were more common in patients receiving zidovudine (P < 0.01), and neuropathy occurred more frequently in those receiving stavudine (12% in the stavudine group compared with 4% in the zidovudine group; P < 0.001). Neuropathy resolved completely in many patients (63%) after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose. Conclusions: Stavudine was well tolerated and delayed progression of HIV disease in patients who had previously received 6 or more months of zidovudine treatment. Benefits were apparent in all CD4⁺ cell strata and clinical stages of HIV disease. Stavudine is an important agent to consider for trials of combination chemotherapy.