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Toxicity of Combined Ganciclovir and Zidovudine for Cytomegalovirus Disease Associated with AIDS
An AIDS Clinical Trials Group Study
- Howard Hochster, MD;
- Douglas Dieterich, MD;
- Samuel Bozzette, MD;
- Richard C. Reichman, MD;
- James D. Connor, MD;
- Leonard Liebes, PhD;
- R. L. Sonke, MS;
- Stephen A. Spector, MD;
- Fred Valentine, MD;
- Carla Pettinelli, MD; and
- Douglas D. Richman, MD
Abstract
Objective: To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease.
Design: Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history.
Setting: Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).
Patients: Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed.
Interventions: Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity.
Measurements and Main Results: Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy.
Conclusion: The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion.
Article and Author Information
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From the New York University Medical Center, New York, New York; the University of California, San Diego, La Jolla, California; the University of Rochester, Rochester, New York; and the NIAID AIDS Clinical Trials Program, Bethesda, Maryland.
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Requests for Reprints: Dr. Howard Hochster, New York University Medical Center, 550 First Avenue, New York, NY 10016.
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Current Author Addresses: Drs. Hochster, Dieterich, and Valentine: New York University Medical Center, 550 First Avenue, New York, NY 10016.
Dr. Bozzette: UCSD Medical Center, 225 Dickinson Street, H-208, San Diego, CA 92103.
Dr. Richman: Infectious Diseases Section, Veterans Affairs Medical Center, 3350 LaJolla Village Drive, San Diego, CA 92161.
Dr. Reichman: University of Rochester School of Medicine, Infectious Disease Unit, 601 Elmwood Avenue, P.O. Box 689, Rochester, NY 14642.
Mr. Sonke and Dr. Connor: UCSD Medical Center, Department of Pediatrics, 4046 Basic Science Building, M009-E, La Jolla, CA 92093.
Dr. Pettinelli: AIDS Program, NIAID, 6003 Executive Boulevard, Bethesda, MD 20852.
- © 1990 American College of Physicians
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