Studies from our group and others have demonstrated that individuals with HIV infection have a higher rate of atherosclerosis compared to uninfected controls.[19
] HIV-infected patients also appear to have higher rates of myocardial infarction.[21
] The underlying mechanism for these observations are still under active investigation but have been attributed to an excess of traditional risk factors, HIV-associated inflammation,[22
] and direct antiretroviral therapy toxicity.[1
] With regard to the latter, among individuals enrolled in the D:A:D study, current treatment with abacavir (as well as didanosine) was associated with a higher rate of myocardial infarction. This effect was particularly evident among those with other risk factors for coronary artery disease.[2
] This finding—which remains controversial—was also evident in 3 other studies (French Hospital Database, SMART, and STEAL)[24
] while an effect of abacavir was not demonstrated in a retrospective analysis by GSK-sponsored studies [25
] nor in a prospective ACTG cohort (the participants in these latter studies tended to be younger).[26
] In our current study, we provide further evidence and a potential biological underpinning for a detrimental effect of abacavir on vascular function. In an unselected population of long-term antiretroviral treated patients, those on abacavir had a greater degree of endothelial dysfunction than those not on abacavir. These differences were not readily explained by differences in HIV disease-associated factors or by differences in traditional cardiovascular risk factors.
The endothelium serves to regulate vascular homeostasis by balancing the level of vasodilators and vasoconstrictors. An imbalance in these factors leads to endothelial dysfunction and eventually the development of atherosclerosis.[27
] Endothelial dysfunction can occur in response to traditional risk factors and/or inflammation.[28
] Recent studies have shown that FMD is clearly impaired in antiretroviral untreated patients, and rapidly improves in response to combination therapy. A reduction in HIV-associated inflammation has been postulated as the major mechanism accounting for this improved FMD.[12
] Our data also raise concerns about whether long-term effective antiretroviral therapy can “normalize” endothelial function, even with regimens that do not include abacavir. The median FMD across all patients was 3.5%, and the median among those not taking abacavir was 4.9%. These levels are generally lower than the levels which we have observed in healthy controls studied in our laboratory (average FMD of 6.2%, standard deviation of 1.8%, n=30). As multiple studies in a variety of patient populations and clinical settings have show that endothelial dysfunction both precedes and strongly predicts future cardiovascular events[10
], our findings provide one potential mechanism for the abacavir risk noted in D:A:D and other studies.
Our data regarding abacavir and FMD also provide a potential explanation for the recent observation suggesting that abacavir promotes platelets aggregation. Using a study design comparable to ours, Satchell and colleagues observed that abacavir exposure was associated with enhanced platelet aggregation.[31
] FMD measures the bioavailability of endothelium-derived nitric oxide (NO).[16
] Endothelium-derived NO is a multifunctional molecule that, as well as promoting vasodilation, markedly inhibits platelet aggregation and adhesion.[32
] Conversely, diseases associated with a loss of endothelium-derived NO are characterized by enhanced platelet aggregation and adhesion. In addition, platelets synthesize their own NO[33
]; its bioavailability is diminished by some of the same mechanisms that impair endothelial function. Activated platelets produce factors such thromboxane, ADP, prostacyclin, and NO[34
] which may shift the vascular homeostasis towards vasoconstriction. Thus, we propose that our finding of significantly diminished FMD in patients on abacavir is indicative of a state in which loss of NO derived from the endothelium or from platelets promotes a platelet pro-aggregatory, pro-thrombotic state.
In addition to reduced FMD, the subjects currently on abacavir also displayed larger brachial artery diameters. This may be yet another indication of increased cardiovascular risk. In that context, it is interesting that among the 2,792 elderly subjects in the Cardiovascular Health Study followed for 5 years, both reduced brachial artery FMD and increased brachial artery diameter predicted incident cardiovascular events, independently of traditional risk factors.[35
] Increased brachial artery diameter may be a consequence of outward vascular remodeling (i.e. enlargement) described previously in an atherosclerotic milieu[36
] and now potentially with abacavir.
Our study was observational and hence susceptible to many of the limitations associated with this approach. Patients who received abacavir in our clinics may have differered from those who did not receive in a number of unmeasured factors, each of which may have confounded our observations. For example, if abacavir was perceived to be a safer option than other drugs such as tenofovir for patients at risk for renal disease, then a potential “channeling” bias may have occurred. Although we have attempted to address this concern by controlling for traditional risk factors and we found no difference in traditional risk factors among the abacavir and non-abacavir treated patients, unmeasured confounders may still have been present. These same unmeasured confounders might also explain why past use of abacavir was associated with impaired FMD among participants not currently receiving abacavir. A prospective randomized study is needed to more definitively address the role of abacavir-based regimens compared to non-abacavir based regimens in causing impaired FMD. Future longitudinal studies may wish to consider carotid intima-media thickness and as well as biologic markers[37
] to better understand the mechanism underlying the impairment in FMD associated with abacavir use. In addition, in vitro studies evaluating the effect of abacavir and others NRTIs on endothelial cells may be useful in understanding and supporting the clinical results of the present study.
Whether or not to use abacavir in HIV-infected individuals with known coronary artery disease or who are at high risk for future events remains unclear. Our study may help to provide a biologic mechanism for the association between myocardial infarction and recent or current abacavir use seen in observational studies. Future studies will be needed to confirm our findings and to help determine if abacavir-associated impairment in endothelial function contributes to the clinically observed relationship between current abacavir use and myocardial infarction.