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Detailed and Updated Results From Protocol 019 of the AIDS Clinical Trials Group

Matthew A. Koch, MD, PhD; Paul A. Volberding, MD; Stephen W. Lagakos, phD; David K. Booth, PA; Carla Pettinelli, MD, PhD; Maureen W. Myers, PhD

Arch Intern Med. 1992;152(11):2286-2292.

Abstract
• Background.—
Protocol 019 of the AIDS Clinical Trails Group is a multicenter, double-blind, placebo-controlled trial of zidovudine (3'-azido-3'-deoxythymidine; formerly AZT) in human immunodeficiency virus-infected asymptomatic individuals. The initial results in the stratum of subjects entering with CD4<R>⁺</R> cell counts of 0.50x10<R>⁹</R>/L or less have been reported, but without a detailed a analysis of toxic effects.

Methods.—
This detailed and updated report analyzes the toxic effects that occurred in 1567 subjects (91% men; 89% white) in this stratum of protocol 019 who received placebo (494 subjects), a 500-mg daily dose of zidovudine (544 subjects), or a 1500-mg daily dose of zidovudine (529 subjects). Hematologic, hepatic, and renal effects and patientreported symptoms and clinical signs were monitored.

Results.—
Severe anemia (hemoglobin level, <80 g/L was associated with both the 500-mg zidovudine group and the 1500-mg500-mg group compared with placebo. The estimated 18month risks of severe anemia were 0.4%, 2.0%, and 9.7% for the placebo, 500-mg zidovudine, and d 1500-mg zi zidovudine groups, respectively. Predictive baseline measures were lower hemoglobin level in the e 1500-mg group and the two zidovudine groups combined and lower platelet count in the 500-mg zidovudine group. The risk of a first severe anemia developing was greatest in months 3 through 8 of treatment. Of the 44 subjects with severe anemia in the zidovudine groups, 18 (41%) progressed from mild anemia (hemoglobin level, 95 to 109 g/L to severe anemia on consecutive visits (usually 2 to 4 weeks apart). Severe neutropenia (absolute neutrophil count, <750x10<R>⁶</R>/L) did not occur significantly more often in the 500-mg zidovudine group but did in the 1500-mg zidovudine group. Moderate neutropenia (absolute neutrophil count, <1300x10<R>⁶<R/>/L did develop significantly more often in the 500-mg zidovudine group (165 subjects) than in the placebo group (71 subjects). Mild (or worse) elevations of bilirubin levels were uncommon but occurred more often with zidovudine. Severe nausea (and/or vomiting) was rare (2.8% of subjects) but was associated with zidovudine. Milder patientreported events were common, and a number were associated with zidovudine.

Conclusion.—
Zidovudine at the 500-mg/d dosage appears to be tolerable in many patients with asymptomatic human immunodeficiency virus infection and CD4<R>⁺</R> cell counts of 0.50 x 10<R>⁹</R>/L or less. Increased clinical surveillance for anemia may be warranted in certain patients.

(Arch Intern Med. 1992;152:2286-2292)

Author Affiliations
From the Centers for Medical, Environmental and Energy Statistics (Dr Koch) and Epidemiologic and Medical Studies (Mr Booth), Research Triangle Institute, Research Triangle Park, NC; Department of Medicine, University of California, San Francisco (Dr Volberding); Department of Biostatistics, Harvard School of Public Health, Boston, Mass (Dr Lagakos); and Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md (Drs Pettinelli and Myers). Dr Myers is now with the Department of Clinical Research, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Conn.

Footnotes
Accepted for publication April 10, 1992.

Reprint requests to Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194 (Dr Koch).

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