Survival in HIV-Infected Patients Who Have Received Zidovudine: Comparison of Combination Therapy with Sequential Monotherapy and Continued Zidovudine Monotherapy

doi:10.1059/0003-4819-124-12-199606150-00002

Survival in HIV-Infected Patients Who Have Received Zidovudine: Comparison of Combination Therapy with Sequential Monotherapy and Continued Zidovudine Monotherapy

Neil M.H. Graham, MD;
Donald R. Hoover, PhD;
Lawrence P. Park, MSE;
Daniel S. Stein, MD;
John P. Phair, MD;
Mellors John W. MD;
Roger Detels, MD; and
Alfred J. Saah, MD

For the Multicenter AIDS Cohort Study Group* For author affiliations and current author addresses, see end of text. *For members of the Multicenter AIDS Cohort Study Group, see the Appendix. Grant Support: By U.S. Public Health Service cooperative agreements U01-AI-35042, U01-AI-35043, U01-AI-35039, U01-AI-35040, U01-AI-35041, and P30-AI-28748 from the National Institute of Allergy and Infectious Diseases and 5-M01-RR-00722 from the National Institutes of Health, General Clinical Research Center. Requests for Reprints: Neil M.H. Graham, MD, The Johns Hopkins University, School of Hygiene and Public Health, Department of Epidemiology, 624 North Broadway, Room 895, Baltimore, MD 21205. Current Author Addresses: Drs. Graham, Hoover, and Saah: The Johns Hopkins University School of Hygiene and Public Health, Department of Epidemiology, 624 North Broadway, Room 895, Baltimore, MD 21205.

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% CI, 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 [CI, 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.