600 mg/d of zidovudine was effective and less toxic than higher doses in AIDS
ACP J Club. 1991 Jan-Feb;114:4. doi:10.7326/ACPJC-1991-114-1-004
Fischl MA, Parker CB, Pettinelli C, et al., and the AIDS Clinical Trials Group. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1990;323:1009-14.
To determine the efficacy and safety of zidovudine, 100 mg every 4 hours compared with 250 mg every 4 hours, in patients with a first episode of Pneumocystis carinii pneumonia.
Randomized, unblinded, controlled trial with a median follow-up of 25.6 months.
18 AIDS Clinical Trials Group units in the United States.
Patients were included if they had a first episode of histologically confirmed P. carinii pneumonia at least 2 weeks before enrollment. Patients were excluded if they had previously received zidovudine, had had multiple episodes of P. carinii pneumonia, or had any other infection or neoplasm indicating the presence of AIDS other than minimal Kaposi sarcoma. Of the 560 patients enrolled, (94%) were followed until death or to the end of the study period.
Zidovudine was given in one 250-mg capsule every 4 hours (standard-treatment group, n = 262) or in one 200-mg capsule every 4 hours for 4 weeks, followed by 100 mg every 4 hours (low-dose group, n = 262).
Main outcome measures
Survival and disease progression.
Survival rates at 18 and 24 months were higher in the low-dose group than in the standard treatment group (63% vs 52%, P = 0.001; 34% vs 27%, P = 0.03, respectively). A second AIDS-defining opportunistic infection developed in 82% of patients in each treatment group. The difference in the time to development of the infection was not significant. Zidovudine was withdrawn earlier because of toxic reactions in more patients in the standard-treatment group than in the low-dose group (40% vs 29%, P < 0.001). Headache was the only symptom reported more frequently in the low-dose group (78% vs 68%, P = 0.006). However, severe anemia and neutropenia, common in both groups, were significantly less common in the low-dose group.
A lower daily dose of zidovudine (600 mg after 4 weeks) was at least as effective as the initially tested dose (1500 mg) for survival up to 24 months and was less toxic in treating patients after a first episode of P. carinii pneumonia.
Sources of funding: The AIDS Clinical Trials Group; National Institute Of Allergy and Infectious Diseases; National Institutes of Health.
Address for article reprint: Dr. M. A. Fischl, University of Miami School of Medicine, Department of Medicine R-60A, P. 0. Box 01 6960, Miami, FL 33101, USA.
In 1986, zidovudine at 1500 mg per day was shown to prolong survival and improve the quality of life in persons with advanced HIV disease (1). This dose was selected on the basis of serum pharmacokinetics, but the intracellular half-life is now known to be considerably longer. Thus, it was plausible that lower doses of zidovudine might be equally effective. The present study confirms that zidovudine, 100 mg every 4 hours (following a 4-week induction phase), is at least as effective as 250 mg every 4 hours in terms of survival after an initial episode of P. carinii pneumonia, and produces significantly less anemia and neutropenia, the two main dose-limiting adverse reactions necessitating zidovudine withdrawal. The present findings support a recommendation of 600 mg per day of zidovudine for persons with advanced HIV disease without central nervous system involvement.
Martin T. Schechter, MD, MSc, PhD
University of British ColumbiaVancouver, British Columbia, Canada
1. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med. 1987;317:185-91.