Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Zidovudine update

ACP J Club. 1991 May-June;114:73. doi:10.7326/ACPJC-1991-114-3-073


Source Citation

Rachlis AR. Zidovudine (Retrovir) update. Can Med Assoc J. 1177-85.


Abstract

Objective

To review the efficacy and adverse effects of zidovudine in patients with AIDS and in patients with asymptomatic and symptomatic HIV infection.

Data sources

Studies on the clinical use of zidovudine published since 1985 were identified using MEDLINE. Controlled studies, studies of long-term zidovudine therapy, and studies of the incidence and management of side effects were evaluated. Abstracts from international meetings were reviewed.

Study selection

19 studies were identified and reviewed. {Criteria for study selection were not stated.}

Data extraction

The results of each of the 19 trials were summarized emphasizing clinical efficacy and the management of adverse effects.

Main results

Trials demonstrated that zidovudine therapy delays the progression to AIDS or to AIDS-related complex in patients who have asymptomatic or mildly symptomatic HIV infection with impaired immunity (an absolute CD4 count of about 0.5 × 109/L or less). Low-dose zidovudine therapy, 500 mg/d, appears to be at least as efficacious as high-dose zidovudine therapy (1200 mg/d), but low-dose zidovudine therapy results in fewer adverse effects. In symptomatic patients, a dosage of 1200 mg/d for the first 4 weeks and then of 600 mg/d has been found efficacious, but the necessity of the "induction" phase has not been established. High-dose zidovudine therapy (1200 to 1500 mg/d) may be preferable in patients with neurologic disease. The minimum effective dosage of zidovudine remains unknown. If the hemoglobin concentration falls, the zidovudine dosage should be reduced, but transfusion may be required if the patient is symptomatic. The zidovudine dosage should also be reduced if the granulocyte count is 0.5 to 0.75 × 109/L.

Conclusion

Zidovudine prolongs survival in patients with AIDS or advanced AIDS-related complex and delays progression to AIDS or AIDS-related complex in asymptomatic patients and in those with mild symptoms. Low-dose zidovudine therapy (500 mg/d) is efficacious for asymptomatic patients and has fewer adverse effects. A dosage of 600 mg/d is recommended for symptomatic patients. The minimum effective dosage of zidovudine remains to be established.

Source of funding: Not stated.

Address for article reprint: Dr. A.R. Rachlis, Room A226, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5.


Commentary

If a therapy delays progression from A to B and from B to C, does it not follow that it delays progression from A to C? The answer is not necessarily yes. For convenience, let us define middle-stage HIV infection as asymptomatic or mildly symptomatic disease with a CD4 count between 0.2 and 0.5 × 109/L. Recent trials have shown that zidovudine delays progression from middle-stage HIV infection to AIDS or AIDS-related complex. Furthermore, other trials have demonstrated that zidovudine prolongs survival in persons with AIDS or AIDS-related complex. Unfortunately, it does not necessarily follow that early institution of zidovudine therapy in patients with middle-stage HIV infection will prolong their overall survival. One reason is that the trials of zidovudine in patients with AIDS or AIDS-related complex involved subjects who had not received zidovudine before. It is conceivable that the early benefit of zidovudine could be counterbalanced by longer-term effects, including viral resistance and cumulative toxicity. Results of ongoing trials comparing early with late institution of zidovudine therapy should resolve this fundamental issue. Meanwhile, an interim recommendation of low-dose zidovudine therapy in asymptomatic or mildly symptomatic persons with CD4 counts below 0.5 × 109/L should be cautiously endorsed, as supported by the studies reviewed by Rachlis.

The gaps between these studies are being addressed by several new trials. These trials are assessing the minimum effective dosage of zidovudine and the role of viral resistance in zidovudine therapy. They are also evaluating other antiretroviral agents used in combination or in sequence with zidovudine. Such agents were not available during the trials considered in this review and will undoubtedly force a reevaluation of current recommendations regarding therapy for HIV infection in the near future.

Martin T. Schechter, MD, PhD
University of British Columbia Vancouver, British Columbia