No Risk of Myocardial Infarction Associated With Initial Antiretroviral Treatment Containing Abacavir: Short and Long-Term Results from ACTG A5001/ALLRT

Recommended first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection includes the use of two nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) combined with one or more agents from other antiretroviral drug classes (nonnucleoside reverse-transcriptase inhibitors [NNRTIs], protease inhibitors [PIs], or integrase inhibitors) [1, 2]. Lifelong treatment is required to maintain HIV suppression, improve immune function, and minimize morbidity and mortality associated with HIV disease progression. Therefore, understanding long-term risks associated with ART is paramount. The observational Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort reported that current or recent use of abacavir was associated with increased risk of myocardial infarction (MI) [3]; data from other cohort studies and clinical trials of abacavir have provided conflicting results [4–11]. For example, although analyses of the Strategies for Management of Antiretroviral Therapy (SMART) study found more than a 4-fold increase in risk [4], a GlaxoSmithKline meta-analysis of randomized trials found no increased risk [5] and an association detected in the French Agence Nationale de Recherches sur le SIDA (ANRS) cohort was not apparent after cocaine and intravenous drug users were excluded from the analysis cohort [10]. These differences may be explained by confounding and population differences, as well as differences in analytical approach. Because abacavir was considered an attractive ART for subjects with cardiovascular disease (CVD) risk [6,12–14], confounding is particularly problematic [15–17]. Recent treatment guidelines now caution against the use of abacavir in subjects with high CVD risk [1, 2], which will further confound analyses addressing this issue. Previous analyses have focused on the increased relative risk of MI associated with abacavir. When an event is rare—as is MI in this context—even very large relative risks may have limited population-level relevance, making estimation of absolute risk difference essential. We ascertained population level CVD risk associated with initiating ART with abacavir-containing regimens using a cohort of ART-naive persons randomly assigned ART through prospective clinical trials. Our unique cohort provides a means to address confounding and channeling bias issues of traditional observational cohorts. Our analytical approach and estimation of absolute risk places the CVD risk associated with abacavir for the treatment of ART-naive populations into a broader clinical context.