Zidovudine for asymptomatic human immunodeficiency virus infection
ACP J Club. 1994 Jan-Feb;120:11. doi:10.7326/ACPJC-1994-120-1-011
Cooper DA, Gatell JM, Kroon S, et al. Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter. N Engl J Med. 1993 Jul 29;329:297-303.
To study the efficacy and safety of zidovudine treatment in patients with asymptomatic human immunodeficiency virus (HIV) infection and CD4+ counts > 400 cells/mm3.
Randomized, double-blind, placebo-controlled trial with interim analysis and median follow-up of 93 weeks.
56 clinical centers in Europe and Australia.
984 patients (mean age, 31 y; 86% men) with asymptomatic HIV infection or persistent generalized lymphadenopathy. Inclusion criteria were age > 18 years, HIV antibody seropositivity, and a CD4+ count > 400 cells/mm3 within 4 weeks of study entry.
495 patients were assigned to receive zidovudine, 500 mg orally every 12 hours for 3 years, and 489 patients to receive placebo. Early in the study, before the primary end point was changed, patients could withdraw if CD4+ counts fell to ≤ 200 cells/mm3
Main Outcome Measures
The original outcomes were the acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. During the study, however, the main outcome measure was changed to progression of disease defined either as 2 CD4+ counts < 350 cells/mm3 or the development of the Centers for Disease Control and Prevention (CDC) group IV disease, which includes recurrent oral candidiasis, oral hairy leukoplakia, herpes zoster, and progressive diarrhea.
The study was terminated early after interim analysis (median follow-up, 1.8 y). 308 patients withdrew from blinded treatment during the study. Patients receiving zidovudine, compared with patients receiving placebo, had less overall disease progression (relative risk [RR], 0.56; 95% CI, 0.43 to 0.75; P < 0.001), less progression to CDC group IV disease (RR, 0.49; CI, 0.24 to 1.01; P = 0.049), and less progression to a CD4+ count < 350 cells/mm3 (RR, 0.60; CI, 0.44 to 0.81, P < 0.001). The probability of disease progression at 2 years was 0.19 for patients receiving zidovudine and 0.34 for those receiving placebo (CI for the difference, -0.21 to -0.08). The groups did not differ for progression to AIDS or severe AIDS-related complex. Severe side effects were rare.
Patients with asymptomatic human immunodeficiency virus infection and CD4+ counts > 400 cells/mm3 who received zidovudine had reduced disease progression and less frequently showed decreases in CD4+ counts to < 350 cells/mm3. Zidovudine was well tolerated.
Source of funding: Wellcome Foundation.
For article reprint: Dr. D.A. Cooper, National Centre in HIV Epidemiology and Clinical Research, 2nd Floor, 376 Victoria Street, Sydney NSW 2010, Australia. FAX 61-2-332-1837.
It is important to compare the results of this study with 2 other large randomized trials of zidovudine in adults who were asymptomatic and to contrast the duration of follow-up and the end points chosen. The AIDS Clinical Trials Group (ACTG) 019 study (1), with an entry CD4+ count < 500 cells/mm3, randomized 1338 patients to receive either zidovudine (500 mg/d or 1500 mg/d) or placebo and, after a mean follow-up of 55 weeks, showed that progression to AIDS was reduced in patients receiving zidovudine. The Concorde study (2) randomized 1749 patients to receive immediate or delayed therapy with zidovudine (250 mg, 4 times daily); 41% had CD4+ counts > 500 cells/mm3. After a mean follow-up of 3 years, no difference in progression to AIDS or death was seen between those treated at entry and those who received deferred treatment, suggesting that the benefit of zidovudine seen after 1 year may diminish over time. Patients in the study by Cooper and colleagues had higher CD4+ cell counts than those in either the Concorde or ACTG 019 studies. Hence, it is not surprising that after a median follow-up of 1.8 years, a benefit was seen when HIV disease progression, as defined by development of HIV-related symptoms (the most common end points were herpes zoster, oral hairy leukoplakia, and oral candidiasis) or a delay in the decrease of CD4+ counts to < 350 cells/mm3, was used as the outcome measure rather than progression to AIDS or survival. In the context of the preliminary results of the Concorde study, I would not recommend initiation of zidovudine therapy for patients with CD4+ counts > 500 cells/mm3 unless a more substantial benefit is shown.
Judith S. Currier, MD
Harvard Medical School Boston, Massachusetts, USA