Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Multicenter AIDS Cohort Study Group.

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Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Multicenter AIDS Cohort Study Group.

Ann Intern Med. 1996 Jun 15;124(12):1031-8. Unique Identifier : AIDSLINE MED/96233411
Graham NM; Hoover DR; Park LP; Stein DS; Phair JP; Mellors JW; Detels R; Saah AJ; Johns Hopkins University School of Hygiene and Public Health,; Department of Epidemiology, Baltimore, MD 21205, USA.

Abstract: BACKGROUND: Among patients who begin receiving zidovudine during intermediate-stage human immunodeficiency virus (HIV) infection, it is unclear whether changing to combination therapy (adding didanosine or zalcitabine) or sequential monotherapy (changing to didanosine or zalcitabine) significantly improves survival. OBJECTIVE: To determine, among patients who began receiving zidovudine during intermediate-stage HIV infection, the differential effects of changing to combination therapy (zidovudine with didanosine or zalcitabine) or sequential monotherapy (with didanosine or zalcitabine) or continuing zidovudine monotherapy. PATIENTS: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. SETTING: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. DESIGN: Longitudinal cohort study, Treatment groups and important prognostic variables were modeled as time-dependent covariates in Cox proportional hazards models. MEASUREMENTS: Progression to AIDS and death. RESULTS: Compared with patients receiving continued zidovudine monotherapy, patients receiving combination therapy had a 45% improvement in survival (relative risk, 0.55 [95% Cl, 0.41 to 0.74; P < 0.001]) and patients who changed to sequential monotherapy had a 32% improvement in survival (relative risk, 0.68 [Cl, 0.52 to 0.89; P = 0.005]). In the landmark analyses, the median prolongation of survival associated with changing therapy was, at best, 3 to 6 months. Survival curves converged at 3.5 years for the 50 cells/mm3 disease-stage landmark, at 4.4 years for the 100 cells/mm3 landmark and at 4.9 years for the 150 cells/mm3 landmark. Mortality within these periods was 100%, regardless of treatment group or landmark. CONCLUSIONS: For patients who began receiving zidovudine during intermediate-stage disease, changing to either combination therapy or sequential monotherapy was associated with a statistically significant survival benefit compared with continuation of zidovudine monotherapy. The absolute increase in survival was modest, however, and long-term survival remained poor. Simultaneous time-dependent adjustment for changes in therapy and in important prognostic variables is necessary to derive relatively unbiased estimates of treatment effects in observational studies of HIV infection.

Keywords: Antiviral Agents/*ADMINISTRATION & DOSAGE Comparative Study CD4 Lymphocyte Count Didanosine/*ADMINISTRATION & DOSAGE Disease Progression Drug Administration Schedule Drug Therapy, Combination Human HIV Seropositivity/*DRUG THERAPY/IMMUNOLOGY/*MORTALITY Longitudinal Studies Male Proportional Hazards Models Support, U.S. Gov't, P.H.S. Zalcitabine/*ADMINISTRATION & DOSAGE Zidovudine/*ADMINISTRATION & DOSAGE CLINICAL TRIAL JOURNAL ARTICLE MULTICENTER STUDY
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M9690858

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