Clinicians should no longer defer initiating antiretroviral therapy in asymptomatic adults with newly diagnosed HIV infection until their CD4+ count descends to a low threshold, according to a report presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention.
Instead, antiretroviral agents should be initiated immediately, regardless of CD4+ count.
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This report was simultaneously presented at the conference and published online in the New England Journal of Medicine (2015 July 20 [doi:10.1056/NEJMoa1506816]).
General practice has been to defer antiretroviral therapy until CD4+ counts decline to a certain threshold level – a level that has changed over time and that varies across different treatment guidelines. Such deferral was prompted by concerns that early treatment would expose patients to more of the adverse effects of antiretrovirals – particularly that today’s aging HIV-positive population would have more exposure to the detrimental effects on cardiovascular and renal health. Moreover, evidence of the potential benefit of immediate treatment has been inconsistent, noted the study’s writing group cochair Dr. Jens D. Lundgren, University of Copenhagen, and his colleagues.
To address this knowledge gap, investigators in the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) designed and conducted the Strategic Timing of Antiretroviral Therapy (START) trial, which compared the benefits and risks of immediate initiation of antiretroviral therapy in patients with CD4+ counts above 500 cells/cc (2,326 patients) against deferring therapy until CD4+ counts declined to 350 cells/cc (2,359 patients).
The study participants were in generally good health and had a median age of 36 years. They were treated at 215 medical centers in 35 countries and followed for a mean of 3 years.
The primary endpoint was a composite of any serious AIDS-related event and any serious non–AIDS-related event, such as fatal or nonfatal cardiovascular disease, end-stage renal disease, liver disease, or non–AIDS-defining cancer. The endpoint was chosen because most complications and deaths that occur in patients with high CD4+ counts are attributed to non–AIDS-related events.
The study was halted early, and all patients were offered immediate antiretroviral therapy, when an interim analysis showed that only 42 patients in the immediate-initiation group reached the composite endpoint, compared with 96 in the deferred-initiation group (hazard ratio, 0.43; P < .001). This significant treatment benefit remained consistent across all subgroups of patients, regardless of demographic and clinical characteristics, and it persisted in sensitivity analyses.
With immediate antiretroviral therapy, there was a 72% relative reduction in serious AIDS-related events, primarily tuberculosis, Kaposi’s sarcoma, and malignant lymphoma. There also was a 39% relative reduction in serious non–AIDS-related events, primarily cancers. Rates of bacterial infections also were significantly decreased with immediate antiretroviral therapy.
Rates of other serious adverse events were identical in the two study groups, affecting 73 patients in each.
This study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, and other members of the National Institutes of Health; the French Agence Nationale de Recherches sur le SIDA et les Hepatites Virales; the Australian National Health and Medical Research Council; the Danish National Research Foundation; the German Bundesministerium fur Bildung und Forschung; the European AIDS Treatment Network; the U.K. Medical Research Council, National Institute for Health Research, and National Health Service; and the University of Minnesota. Antiretroviral drugs were donated by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific, and Merck.
Dr. Lundgren reported having no relevant financial disclosures; his associates reported numerous ties to industry sources.