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Previous Volume 357:1056-1057 September 6, 2007 Number 10 Next

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To the Editor: Study A5095 by the AIDS Clinical Trials Group (ACTG) was a randomized, double-blind, placebo-controlled, comparative study of three antiretroviral regimens for the initial treatment of human immunodeficiency virus (HIV) infection. The three regimens were zidovudine, lamivudine, and abacavir (the triple-nucleoside regimen), the triple-nucleoside regimen plus efavirenz (the four-drug regimen), and zidovudine, lamivudine, and efavirenz (the three-drug, standard-of-care regimen). The study was designed to follow patients for 120 weeks after randomization. The primary study end point was the time to virologic failure, which was defined as a confirmed HIV RNA level of more than 200 copies per milliliter at or after week 16 of the study.

At the second review of the data and safety monitoring board in February 2003, with a median of 32 weeks of study follow-up, pairwise comparisons among the three study groups showed differences that met prespecified stopping guidelines: the triple-nucleoside regimen was virologically inferior to the other two regimens. As a result, the board recommended that the triple-nucleoside regimen be stopped. They also recommended continued double-blind follow-up of the other two groups and that pooled data from these groups be presented with data from the triple-nucleoside group. These data were published in March 2004.¹

Follow-up for the two blinded groups receiving efavirenz was completed in March 2005 and showed no significant differences between the groups with respect to virologic or immunologic responses, adverse events, adherence to treatment, or drug-resistant mutations at the time of virologic failure.²

With the study completed, we feel that it is appropriate to present the unpooled data comparing the triple-nucleoside regimen with each of the efavirenz-containing regimens through the closure of blinded follow-up of the triple-nucleoside group in February 2003. Hazard ratios are presented for the triple-nucleoside group; 97.5% adjusted confidence intervals are based on an O'Brien–Fleming³ and Lan and DeMets⁴ group sequential-monitoring boundary.

With a median of 48 weeks of follow-up, 98 of 382 patients in the triple-nucleoside group had virologic failure, as compared with 50 of 383 patients in the four-drug group (hazard ratio, 2.21; 97.5% confidence interval [CI], 1.32 to 3.7) and with 60 of 382 in the three-drug, standard-of-care group (hazard ratio, 1.85; 97.5% CI, 1.14 to 3.01) (Figure 1). We conclude that this analysis confirms the findings of the review board and clearly shows that the triple-nucleoside regimen was inferior virologically to both the four-drug regimen and the three-drug, standard-of-care regimen.

View larger version (31K): [in this window] [in a new window]   Figure 1. Time to Virologic Failure for Three Initial Antiretroviral Regimens. Data are from study A5095 of the AIDS Clinical Trials Group. Virologic failure was defined as a confirmed HIV RNA level of more than 200 copies per milliliter at or after week 16 of the study. ZDV denotes zidovudine, 3TC lamivudine, ABC abacavir, and EFV efavirenz.

 

Heather J. Ribaudo, Ph.D.
Harvard School of Public Health
Boston, MA 02115
ribaudo{at}sdac.harvard.edu

Daniel R. Kuritzkes, M.D.
Brigham and Women's Hospital
Boston, MA 02115

Roy M. Gulick, M.D., M.P.H.
Weill Medical College of Cornell University
New York, NY 10021

Dr. Kuritzkes reports receiving research support and consulting and lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, and GlaxoSmithKline; and Dr. Gulick, research grants from Boehringer Ingelheim, Gilead, and Merck and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Merck. No other potential conflict of interest relevant to this letter was reported.

References

1. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004;350:1850-1861. [Free Full Text]
2. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs. four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA 2006;296:769-781. [Free Full Text]
3. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-556. [CrossRef][ISI][Medline]
4. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-663. [Free Full Text]

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