Study Supporting Earlier Antiretroviral Treatment ‘Not Definitive,’ NEJM Editorial Says
Although the results of a study comparing early and deferred antiretroviral treatment scheduled to be published in the April 30 issue of the New England Journal of Medicine are "striking," they "cannot be considered definitive evidence that everyone with HIV should start receiving antiretroviral therapy," Paul Sax and Lindsey Baden of the Division of Infectious Diseases at Brigham and Women's Hospital write in an NEJM editorial.
According to the authors, 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." Current antiretroviral treatment guidelines state that the "optimal time to start therapy for an asymptomatic patient ... is unknown." The study found that patients who did not begin antiretroviral therapy until their CD4+ T cell counts were 350 or less had a 69% increased risk of death, while those who did not begin antiretroviral therapy until their T cell counts were 500 or less had an "increased risk of death of 94%." The authors add that although the study had a "relatively large" sample size, used "advanced statistical methods" and used "survival (rather than AIDS progression or death) as the end point," it 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 survival but were not measured."
The editorial adds that the study could not measure the "sort of 'health-seeking' behavior" of "patients who were offered and began potent combination antiretroviral therapy with a high T cell count in the late 1990s." The authors write that these patients were "ideal" because they were "highly adherent, committed to doing whatever they could to prevent AIDS, and willing to push through the sometimes punishing side effects and drug-regimen burdens of the early therapies." In addition, about 45% of patients in "each study-specified stratum of T cell counts either did not initiate antiretroviral therapy or did not have a decline in the T cell count," yet because they are not a part of the comparative analysis, "we have no way of knowing whether antiretroviral therapy would have been beneficial in this group," the authors write. They add that it "will be important" to follow up with these patients to "better understand the deleterious effects of poorly controlled HIV infection on end-organ dysfunction" and determine whether "some of the deaths might have been related to underlying differences (including lifestyle choices) between the two nonrandomized study groups."
Sax and Baden add that although the study has some "limitations," it "adds to a growing body of data supporting earlier treatment for HIV infection." The editorial concludes that "a conclusion would require data from a randomized, prospective clinical trial, and at least three such studies are either ongoing or planned" but that evidence supporting the benefits of earlier antiretroviral therapy "continues to increase, making strategies to identify patients with HIV infection before the onset of substantial immunodeficiency all the more compelling" (Sax/Baden, New England Journal of Medicine, 4/30).
The editorial is available online. The study also is available online.