Background:  The current or recent (within the last 6 months) use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease (CVD) within the setting of an observational cohort study (D:A:D) and a randomized trial (SMART). The risk was removed upon drug discontinuation. Of note, other than what has been the case for HIV PI, no association was found with the cumulative use of ABC. CVD events in both these studies were captured and validated prospectively according to predefined procedures. In contrast, an analysis of an aggregated clinical trials database maintained by the manufacturer of ABC, which includes data on CVD, but only captured as part of general reporting of adverse events, did not confirm the earlier mentioned association. The latter was also the case for an analysis performed in patients randomized to their first ART regimen in 1 of 5 ACTG studies for whom extended follow-up was available through the ALLRT long-term protocol. Interestingly, an intermediate size randomized trial which compared treatment simplification with fixed-dose combination (FDC) of tenofovir (TDF)/emtricitabine (FTC) or ABC/lamivudine (3TC) in patients with prior HIV suppression to <50 copies/mL (STEAL) did find a higher rate of CVD events (predefined as secondary endpoints) in those randomized to FDC-ABC/3TC.

Conclusions: Although differences in study design, statistical power, endpoint definitions, and procedures to capture and validate endpoints may each contribute to these discrepant findings, additional possible explanations also need to be considered. Reviewing the characteristics of the various patient populations which were studied, one could for instance speculate whether the likelihood of identifying the CVD risk associated with ABC may be greater in those who are first exposed after their HIV infection is already suppressed. Data suggest a pathogenic mechanism (possibly of a proinflammatory nature) involving acute processes, such as plaque rupture or subesquent thrombosis, rather than a chronic one affecting atheroma formation. For now, it seems prudent to withold ABC from patients with high underlying CVD risk if suitable alternative regimens are available. If not, patients’ absolute CVD risk in the presence of ABC should be minimized by aggressive management of traditional CVD risk factors.