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.