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Comparative Study
. 2009 Apr 30;360(18):1815-26.
doi: 10.1056/NEJMoa0807252. Epub 2009 Apr 1.

Effect of early versus deferred antiretroviral therapy for HIV on survival

Mari M Kitahata  1 , Stephen J Gange, Alison G Abraham, Barry Merriman, Michael S Saag, Amy C Justice, Robert S Hogg, Steven G Deeks, Joseph J Eron, John T Brooks, Sean B Rourke, M John Gill, Ronald J Bosch, Jeffrey N Martin, Marina B Klein, Lisa P Jacobson, Benigno Rodriguez, Timothy R Sterling, Gregory D Kirk, Sonia Napravnik, Anita R Rachlis, Liviana M Calzavara, Michael A Horberg, Michael J Silverberg, Kelly A Gebo, James J Goedert, Constance A Benson, Ann C Collier, Stephen E Van Rompaey, Heidi M Crane, Rosemary G McKaig, Bryan Lau, Aimee M Freeman, Richard D Moore; NA-ACCORD Investigators
Collaborators, Affiliations
Comparative Study

Effect of early versus deferred antiretroviral therapy for HIV on survival

Mari M Kitahata et al. N Engl J Med. .

Abstract

Background: The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.

Methods: We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group).

Results: In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001).

Conclusions: The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

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Conflict of interest statement

Dr. Saag reports receiving consulting fees from Ardea Biosciences, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Monogram Biosciences, Pain Therapeutics, Panacos, Pfizer, Progenics, Roche Laboratories, Tibotec, Tobira Therapeutics, and Vicro and research support from Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, GlaxoSmithKline, Merck, Panacos, Pfizer, Progenics, Theratechnologies, and Tibotec; Dr. Hogg, receiving grant support from Merck; Dr. Deeks, receiving consulting fees from GlaxoSmithKline, Roche, Gilead, and Boehringer Ingelheim and grant support from Merck, Gilead, Bristol-Myers Squibb, and Pfizer; Dr. Eron, receiving consulting fees from Tibotec, Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Pfizer, lecture fees from Roche, Bristol-Myers Squibb, Tibotec, and Merck, and grant support from GlaxoSmithKline, Merck, and Boehringer Ingelheim; Dr. Gill, receiving consulting fees from Gilead, GlaxoSmithKline, Abbott, Merck, Boehringer Ingelheim, Tibotec, and Pfizer and grant support from GlaxoSmithKline, Abbott, Tibotec, and Pfizer; Dr. Klein, receiving consulting fees from GlaxoSmithKline, Abbott, Pfizer, and Boehringer Ingelheim, lecture fees from Abbott, Gilead, Tibotec, Bristol-Myers Squibb, and GlaxoSmithKline, and research support from the Canadian HIV Trials Network, the Ontario HIV Treatment Network, and Schering-Plough Canada; Dr. Rodriguez, receiving consulting fees from Gilead and Bristol-Myers Squibb, lecture fees from Bristol-Myers Squibb, and grant support from STERIS; Dr. Rachlis, receiving consulting and lecture fees from GlaxoSmithKline, Abbott, Merck, Pfizer, Bristol-Myers Squibb, Gilead, and Tibotec and grant support from GlaxoSmithKline, Tibotec, Boehringer Ingelheim, Abbott, Merck, Pfizer, and Roche; Dr. Horberg, receiving grant support from Gilead, Abbott, and Bristol-Myers Squibb; Dr. Silverberg, receiving grant support from Pfizer, Merck, Gilead, the University-wide AIDS Research Program, and Community Benefit/Kaiser Permanente; Dr. Gebo, receiving consulting fees from Tibotec and grant support from the Johns Hopkins University Richard Ross Award; Dr. Benson, receiving consulting fees from GlaxoSmithKline, Pfizer, Merck, and Achillion and grant support from Gilead; Dr. Collier, receiving consulting fees from Merck, Pfizer, and GlaxoSmithKline and grant support from Schering-Plough, Tibotec-Virco, Gilead, Koronis, and Merck and having an equity interest in Bristol-Myers Squibb and Abbott; and Dr. Moore, receiving consulting fees from Bristol-Myers Squibb and GlaxoSmithKline, lecture fees from Gilead, and grant support from Pfizer, Merck, and Gilead. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Results of Sensitivity Analyses Examining the Effect of Possible Unmeasured Confounding Factors on the Association between Deferral of Antiretroviral Therapy and Death
The contour plot shows that a confounding factor with a relative risk for death of 4.0 and an odds ratio for deferral of therapy of 4.0 after adjustment for all included variables would reduce the estimated relative risk for deferred therapy to approximately 1.30.
See this image and copyright information in PMC

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