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


Therapeutics

Early zidovudine slowed progression to AIDS

ACP J Club. 1992 Sept-Oct;117:48. doi:10.7326/ACPJC-1992-117-2-048


Source Citation

Hamilton JD, Hartigan PM, Simberkoff MS, et al. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study. N Engl J Med. 1992 Feb 13;326:437-43.


Abstract

Objective

To compare early and late initiation of zidovudine treatment in patients with symptomatic human immunodeficiency virus (HIV) infections for rate of progression to the acquired immunodeficiency syndrome (AIDS) and survival.

Design

Randomized, double-blind, placebo-controlled, 4-year trial.

Setting

7 Veterans Affairs medical centers.

Patients

Patients with symptomatic HIV infection and CD4+ lymphocyte counts between 0.2 × 109/L and 0.5 × 109/L were eligible. Patients were excluded if they had AIDS, had taken antiretroviral medication, had seriously abnormal laboratory values for hemoglobin, creatinine, leukocyte count, or granulocyte count, or were clinically unstable. 99% of the patients were men, and 64% were non-Hispanic whites (mean age 40 y). Follow-up was 96%.

Intervention

Randomization was stratified based on CD4+ counts. 170 patients were assigned to zidovudine (1500 mg/d) from the start of the study (early-treatment group). 168 patients were randomized to placebo until their CD4+ counts fell to below 0.2 × 109/L or they developed AIDS. Zidovudine (1500 mg/d) was then started (late-treatment group). New evidence from other studies led to study patients being offered open-label zidovudine therapy for the last 18 months of the study: 16% of early patients and 23% of late patients chose open therapy.

Main outcome measures

Progression to AIDS and mortality.

Main results

The overall mean follow-up periods for the early- and late-treatment groups were 27.2 and 28.2 months. Blinded follow-up periods were 14.8 and 13.9 months, respectively. 28 early-treatment group patients developed AIDS compared with 48 late-treatment group patients (16.5 % vs 28.6%, P = 0.02). {This absolute risk reduction (ARR) of 12.1% means that 9 patients would need to be treated with early treatment (rather than late treatment) to prevent 1 additional patient from progressing to AIDS, 95% CI 5 to 31; the relative risk reduction was 42%, CI 13% to 62%.}* For mortality, however, the groups were similar with 23 deaths (13 AIDS-related) in the early-treatment group compared with 20 deaths (12 AIDS-related) in the late-treatment group (13.5% vs 11.9%, P > 0.2, {CI for the 1.6% ARR -8.9% to 5.6%}*). The survival rates for 1, 2, and 3 years were 97%, 93% and 77% for early therapy and 98%, 95%, and 83% for late therapy. Early therapy increased the time until CD4+ counts fell below 0.2 × 109/L but was associated with more leukopenia, anemia, nausea, and diarrhea.

Conclusion

Early zidovudine therapy slowed the progression to AIDS but did not improve overall survival compared with late zidovudine therapy.

Sources of funding: Department of Veteran Affairs and U.S. Army Medical Research and Development Command.

Address for article reprint: Dr. J.D. Hamilton, Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705, USA.

*Numbers calculated from data in article.


Commentary

The Veterans Affairs Cooperative Study compared the effects of early with late initiation of zidovudine therapy on the rate of progression to AIDS and mortality in persons with symptomatic HIV infection. Early therapy with zidovudine resulted in a marked decrease in the rate of progression to AIDS, similar to findings in previous controlled trials of early zidovudine therapy in patients with symptomatic and asymptomatic HIV infection (1).

The groups did not differ, however, in overall survival. The observation that in patients in the early treatment group the CD4+ count declined most rapidly from months 20 through 24 support a time-limited benefit of zidovudine. (Survival data from other controlled studies of early zidovudine therapy, have not confirmed a survival benefit.) Frequent side effects were probably caused by the high dose (1500 mg/d) in this trial. (The current recommended dose is 500 to 600 mg/d.)

Most patients and physicians would agree that an extended time with no serious disease is worthwhile even if death is not delayed. The findings indicate, however, that better treatment is needed than zidovudine monotherapy. Options include beginning combination therapy with multiple antiretrovirals.

Andrew T. Pavia, MD
University of Utah Health Sciences CenterSalt Lake City, Utah, USA

Andrew T. Pavia, MD
University of Utah Health Sciences Center
Salt Lake City, Utah, USA


Reference

1. Volderbring PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med. 1990;322:941-9.