Abacavir and Cardiovascular Risk
Academic Med Ctr, Univ of Amsterdam, The Netherlands
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, patientsí absolute
CVD risk in the presence of ABC should be minimized by aggressive management of
traditional CVD risk factors.