When to start antiretroviral therapy--ready when you are?

The optimal time to start antiretroviral therapy in asymptomatic patients has been one of the central controversies in the care of patients with the human immunodeficiency virus (HIV) since the introduction of the first antiretroviral agent, zidovudine, more than two decades ago.1 Since then, periods of enthusiasm for aggressive early intervention2 have been followed by a more cautious approach.3 This slowly swinging pendulum has been pushed back and forth by the extraordinary benefits of antiretroviral therapy on one side4 and emerging data on its adverse effects on the other.5 The absence of a controlled, prospective study comparing early and deferred therapy has forced treatment guidelines to rely largely on data from observational cohort studies.6,7 Currently, these guidelines state that the optimal time to start therapy for an asymptomatic patient with a CD4+ count of more than 350 cells per cubic millimeter is unknown. In this issue of the Journal, Kitahata and colleagues present data from the one of the largest of these observational cohorts, the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).8 The combined effort of 22 North American prospective research groups, NA-ACCORD evaluated patients with HIV infection who had not undergone previous therapy and who were stratified according to their CD4+ count at baseline: 351 to 500 cells per cubic millimeter or more than 500 cells per cubic millimeter. The investigators compared survival between patients who started antiretroviral therapy within the given CD4+ stratum with those who waited until after the CD4+ count fell below the stratum. The results are striking. Among the 8362 patients with a CD4+ count of 351 to 500 cells per cubic millimeter, deferral of therapy until the CD4+ count had fallen to 350 cells or less was associated with an increase of 69% in the risk of death, as compared with patients who initiated therapy when their CD4+ count was within the designated range. Similarly, among the 9155 patients with a CD4+ count of more than 500 cells per cubic millimeter, deferral of therapy until the CD4+ count fell below 500 cells was associated with a significantly increased risk of death of 94%. The strengths of this study included its relatively large size, the use of advanced statistical methods that attempted to analyze the data in a fashion similar to that of a randomized trial, and the use of survival (rather than AIDS progression or death) as the end point. The use of death from any cause is important in evaluating patients who have higher CD4+ counts, since HIV-related opportunistic infections and cancers develop relatively infrequently in such patients.9 Indeed, in the NA-ACCORD study, the majority of deaths for which cause was available were from “non– AIDS-defining” causes. An additional strength of the study was its ability to minimize lead-time bias by having access to data for patients before antiretroviral therapy was started. In many other cohort studies, such events are either not accounted for10 or must be estimated with the use of historical data.11 The strengths of the study notwithstanding, the results of the NA-ACCORD study cannot be considered definitive evidence that everyone with HIV should start receiving antiretroviral therapy. This was not a randomized trial, and the patients who chose to begin therapy early might have differed in other important ways from those who chose to defer therapy — ways that improved