The search for data on when to start treatment for HIV infection.

The question of when to start antiretroviral therapy (ART) for infection with HIV has been much discussed, and treatment management guidelines have oscillated from the “hit hard, hit early” philosophy to conservative approaches of deferring treatment in asymptomatic patients until CD4 cell counts are 200 cells/ L [1, 2], despite their being few data on the subject [3]. In this issue of the Journal, results from a subgroup analysis [4] of a randomized trial, the Strategies for Management of Antiretroviral Therapy (SMART) study, are presented that provide some insight into this question. Major reasons why, in recent years, guidelines have tended to be more conservative and have recommended deferring treatment until CD4 cell counts are 200 cells/ L include the following [5]: the low absolute risk of AIDS-defining clinical events at higher CD4 cell counts; the negative impact of side effects on quality of life as well as the occasional occurrence of life-threatening adverse effects, including ones that have been associated with long-term use of ART (such as myocardial infarction); and the inconvenience of drug regimens, leading to reduced adherence, an increased risk of drug resistance, and limitations on future drug options. Revisiting these issues, Phillips et al. [5] recently concluded that advances in drug development and an improved understanding of the durability and adverse effects of specific drugs has led to renewed interest in the possibility that initiation of ART at CD4 cell counts 200 cells/ L might be preferable. The SMART study [6] enrolled HIVinfected subjects with CD4 cell counts 350 cells/ L (including subjects with prior AIDS events) and randomized participants to a continuous ART strategy versus a CD4 cell count– guided strategy for interrupting therapy during periods of higher CD4 cell counts. The study population was predominantly and extensively ART experienced. In this issue, results are presented for a subgroup of SMART participants not receiving ART at the time of enrollment [4]. Specifically, participants who were ART naive (n 249) or who had not received ART for at least 6 months (n 228) were included. Per the SMART study design, the subjects in the continuous ART arm were in effect randomized to (re)initiate ART immediately, and those in the CD4 cell count– guided arm were randomized to defer (re)initiation until their CD4 cell count fell to 250 cells/ L. Follow-up was for a mean of 18 months. In this subgroup, as in the overall SMART population, subjects who immediately (re)initiated ART experienced fewer grade 4 symptomatic adverse events than did those deferring (re)initiation. In addition, also as in the overall study population, fewer subjects randomized to (re)initiate ART immediately experienced opportunistic disease (OD) events or died (5 vs. 15 participants; P .02) or experienced major cardiovascular, renal, or hepatic events (the so-called serious non-AIDS events; 2 vs. 12 participants; P .01). Of importance, this comparison was driven primarily by events among subjects who had previously received ART (for a median of 4 years). The data that more truly address the question of when first to start ART were limited. Of the 249 ART-naive participants, 1 versus 4 participants experienced OD events or died in the immediate versus deferred ART arms, and 1 versus 4 experienced serious non-AIDS events. That use of ART at higher CD4 cell counts might reduce the incidence of OD is not surprising: randomized trials conducted in the early 1990s showed a benefit [7], and observational studies have suggested that this is true for regimens in use more recently [8]. What is more important is that this subgroup analysis raises Received 11 January 2008; accepted 11 January 2008; electronically published 26 March 2008. Potential conflicts of interest: M.D.H. currently has consultancy agreements with the following companies that have anti-HIV products: Boehringer Ingelheim, Tibotec, and Virionyx. H.R. R. reports no potential conflicts. Financial support: National Institutes of Health (grant AI068634). Reprints or correspondence: Dr. Michael Hughes, Harvard University, School of Public Health, Center for Biostatistics in AIDS Research, 655 Huntington Ave., Boston, MA 02115 (mhughes@sdac.harvard.edu). The Journal of Infectious Diseases 2008; 197:1084–6 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19708-0003$15.00 DOI: 10.1086/586712 E D I T O R I A L C O M M E N T A R Y