Combination Therapy with Zidovudine and Didanosine Compared with Zidovudine Alone in HIV-1 Infection

15 October 1993 | Volume 119 Issue 8 | Pages 786-793

Objective: To assess safety, pharmacokinetics, and in-vivo virologic activity of five different combination regimens of zidovudine and didanosine compared with zidovudine alone in patients with human immunodeficiency virus type 1 (HIV-1) infection.

Design: Open-label, partially randomized, dose-ranging study.

Setting: University-affiliated, medical center clinics.

Patients: A total of 69 patients with HIV-1 infection, CD4⁺ cell counts fewer than 400 cells/mm³, and fewer than 121 days of previous zidovudine treatment.

Interventions: Fifty-five patients received combination therapy with zidovudine and didanosine, and 14 received zidovudine therapy alone (600 mg/d). Daily dosages in milligrams of zidovudine and didanosine, respectively, in the five combination groups were 150 and 90 mg, 300 and 334 mg, 600 and 334 mg, 300 and 500 mg, and 600 and 500 mg.

Measurements: CD4⁺ cell counts, HIV-1 RNA titers in plasma, and toxic effects.

Results: The combination regimens were associated with higher and more sustained increases in CD4⁺ cells than zidovudine alone, even after adjustment for initial CD4⁺ counts and previous zidovudine therapy (P < 0.001). The median increase in CD4⁺ cell counts was 166 cells/mm³ with combination therapy and 77 cells/mm³ with zidovudine alone (P = 0.001) and did not differ statistically among the five combination regimens. Human immunodeficiency virus type 1 RNA titers in plasma decreased in 15 (83%) of 18 combination-therapy recipients compared with 2 of 7 zidovudine-alone recipients (P = 0.017). No pharmacokinetic interactions were seen between zidovudine and didanosine. Toxicity rates were low among all treatment groups. A greater decrease in hemoglobin levels was seen with the regimen using zidovudine alone (–8 g/L) compared with combination regimens using the same zidovudine dose ( –1.5 g/L, P = 0.03).

Conclusions: Combination therapy with zidovudine and didanosine produced larger and more sustained increases in CD4⁺ cell counts, more frequent decreases in plasma HIV-1 RNA titers, and more stable hematologic status than zidovudine therapy alone. The effects of this combination on the progression of HIV disease merit further study, to provide information about clinical outcome, because this was a relatively small study based on surrogate markers of HIV-1 infection.

Author and Article Information

From the University of Washington School of Medicine, Seattle, Washington; the University of Miami School of Medicine, Miami, Florida; Tufts University School of Medicine and the New England Medical Center, Boston, Massachusetts; the University of California at San Francisco General Hospital, San Francisco, California; the Burroughs Wellcome Company, Research Triangle Park, North Carolina; Abbott Laboratories, North Chicago, Illinois.
Requests for Reprints: Ann C. Collier, Harborview Medical Center ZA-00, 325 Ninth Avenue, Seattle, WA 98104.
Acknowledgments: The authors thank the patients for their contributions: Dana Cummings, ARNP, Cecilia Schulte, MD, Janie Patrone-Reese, RN, BSN, and Elisa Dale for clinical support; Robert Blum, PhD, and Teresa Tartaglione, PharmD, for pharmacologic support; Eileen Rojo, Jalpa Patel, MS, Mary Ann Fletcher, PhD, and Pamela Kidd, MD, for laboratory support; Vaundeen Bachus for data support; and Nancy Coomer for assistance in the preparation of the manuscript.
Grant Support: By the University of Washington Clinical Research Center (with funding from the National Institutes of Health [RR-37]).