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Combination and Monotherapy with Zidovudine and Zalcitabine in Patients with Advanced HIV Disease

Margaret A. Fischl, MD; Kenneth Stanley, PhD; Ann C. Collier, MD; Jean Marie Arduino, MS; Daniel S. Stein, MD; Judith E. Feinberg, MD; J. Davis Allan, MD; Jonathan C. Goldsmith, MD; William G. Powderly, MD, The NIAID AIDS Clinical Trials Group*
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Requests for Reprints: Margaret A. Fischl, MD, Department of Medicine R-60A, P.O. Box 016960, Miami, FL 33101. Acknowledgments: The authors thank the patients and the many staff members who contributed to the study; and Hoffmann-La Roche, Inc. and Burroughs Wellcome Company, who contributed study medication. Grant Support: In part by grants and contracts from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;122(1):24-32. doi:10.7326/0003-4819-122-1-199501010-00004
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Objective: To compare the safety and efficacy of continuing zidovudine therapy with that of zalcitabine alone or zalcitabine and zidovudine used together.

Design: A randomized, double-blind, controlled trial.

Setting: AIDS Clinical Trials units and National Hemophilia Foundation sites.

Patients: 1001 patients with symptomatic human immunodeficiency (HIV) disease and 300 or fewer CD4 cells/mm3 or asymptomatic HIV disease and 200 or fewer CD4 cells/mm3 who had tolerated zidovudine therapy for 6 months or more.

Intervention: Patients were randomly assigned to receive zidovudine, 600 mg/d; zalcitabine, 2.25 mg/d; or zidovudine, 600 mg/d, and zalcitabine, 2.25 mg/d.

Measurements: The primary end point was time to disease progression or death.

Results: The median follow-up time was 17.7 months. The estimated 12-month event-free rates were 70%, 67%, and 73%, respectively, for the zidovudine, zalcitabine, and combination groups (P =0.26). A trend analysis showed significantly lower progression rates for combination therapy compared with zidovudine therapy as the pretreatment CD4 cell count increased (P = 0.027). For patients with 150 or more CD4 cells/mm3, those receiving combination therapy were less likely to have disease progression or to die than were those receiving zidovudine (relative risk, 0.51; 95% CI, 0.28 to 0.93; P = 0.029). We observed no difference between the zalcitabine and zidovudine groups (relative risk, 0.74; CI, 0.40 to 1.36; P = 0.33). For patients with 50 to 150 CD4 cells/mm3 or fewer than 50 CD4 cells/mm3, we found no differences among the treatment groups (P = 0.69 and P = 0.57, respectively). Severe toxic effects occurred less frequently among patients with 150 or more CD4 cells/mm3.

Conclusions: We found no overall benefits of zalcitabine used alone or with zidovudine. However, a trend analysis suggested a better outcome for combination therapy compared with zidovudine as the pretreatment CD4 cell count increased.

*Other members of the AIDS Clinical Trials Group who participated in this study are listed in the Appendix.


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Figure 1.
Estimated distributions of time until disease progression.(A)3(B)3(C)3(D)

Proportion of patients with disease progression or death, whichever occurred first, by treatment group overall and for patients with 150 or more CD4 cells/mm , 50 to 150 CD4 cells/mm , and fewer than 50 cells/mm .

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Figure 2.
Hazard ratio comparisons and 95% confidence intervals for time to clinical progression and survival.(A)(B)(C)

Hazard ratio comparisons and 95% confidence intervals of combination therapy compared with zidovudine , zalcitabine compared with zidovudine , and combination therapy compared with zalcitabine .

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Figure 3.
Median CD4 cell count trends.

Median CD4 cell count changes from pretreatment CD4 cell counts categorized by treatment group.

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