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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; Roger Detels, MD; Alfred J. Saah, MD, Mellors John W. MD
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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.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;124(12):1031-1038. doi:10.7326/0003-4819-124-12-199606150-00002
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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.


Grahic Jump Location
Figure 1.
Survival curves derived from a Cox proportional-hazards model comparing persons who changed from zidovudine monotherapy to alternate antiretroviral therapy (either combination therapy or sequential monotherapy) before reaching one of three landmarks: a CD4 lymphocyte count of 150 cells/mm3 (top), a CD4 count of 100 cells/mm3 (middle), and a CD4 count of 50 cells/mm3 (bottom).33333Pneumocystis carinii

Survival curves are based on the risk estimates for a patient who has a CD4 count of 100 cells/mm (first landmark), 60 cells/mm (second landmark), or 30 cells/mm (third landmark); a platelet count of 195 000 cells/mm (first landmark) or 190 000 cells/mm (second and third landmarks); a hemoglobin level of 127 g/L (first landmark), 123 g/L (second landmark), or 119 g/L (third landmark); and symptoms of human immunodeficiency virus infection and who is receiving acyclovir and pneumonia prophylaxis.

Grahic Jump Location




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