The epidemiologic association between abacavir and myocardial infarctions has been an unexpected and controversial finding, and no mechanism has been shown by which abacavir could lead to myocardial infarctions. We hypothesized that abacavir, as a guanosine analogue, might inhibit soluble guanylyl cyclase, leading to platelet hyperreactivity and, ultimately, to increased risk of myocardial infarction.
Our data show that ex-vivo incubation with abacavir results in increased platelet activation as assessed by P-selectin expression. Platelet measurements are notoriously difficult because they vary significantly among healthy individuals and are subject to many individual confounders (including NSAID use, smoking, platelet number, and inflammatory state) [35
], and details of the phlebotomy procedure and timing of the testing all introduce additional error. By adding drug to blood samples directly after phlebotomy, assay variability was reduced, and it was possible to detect the small changes in platelet activation that likely correspond to the increase in relative risk for myocardial infarction. One possible limitation of our method is that ex-vivo loading of platelets with abacavir may not achieve the concentrations of active metabolites found in platelets of patients receiving continuous oral dosing. However, our dose–response analysis of platelet activation found detectable effects on platelets, even after brief incubations at concentrations of abacavir similar to those measured in the plasma of patients taking the drug at standard dosages. Additionally, our enzyme inhibition measurements suggest that soluble guanylyl cyclase inhibition could be physiologically significant at intracellular carbovir triphosphate concentrations measured in patients taking abacavir [30
]. Endothelial function is also mediated by cGMP and it is possible that guanylyl cyclase inhibition may contribute to the defects in endothelial dysfunction observed in patients receiving abacavir [36
Although the mechanisms underlying drug toxicities are rarely known, three separate molecular mechanisms have been elucidated for abacavir. First, like many nucleoside reverse transcriptase inhibitors, abacavir can cause mitochondrial toxicity by inhibiting DNA polymerase-γ
resulting in a range of syndromes from lipoatrophy to neuropathy to lactic acidosis [37
]. Second, a hypersensitivity syndrome specific for abacavir has been linked to the human leukocyte antigen B*5701 haplotype [38
]. Finally, we provide evidence here for a third mechanism for abacavir toxicity: inhibition of cGMP synthesis resulting in platelet and, by extension, myocardial infarctions.
These experimental results have several clinical implications. First, they provide a plausible mechanism that would allow us to infer that the correlation between abacavir use and myocardial infarction observed in nonrandomized studies may be a causal one (they do not, however, provide any information about the magnitude of this association). Second, they provide a means for screening for cardiovascular safety of different purine analogues (and, potentially, a means to screen patients for differences in relative risk) at low cost and without exposing people to the drug. Third, the platelet mechanism suggests that patients at risk of cardiovascular disease who take abacavir might benefit from antiplatelet therapy with, for example, aspirin or clopidogrel. As a corollary, if epidemiologic analyses of abacavir risk were adjusted for antiplatelet agent use, it might be possible to resolve the inconsistent findings that have been reported to date. Finally, these results are a reminder that many of the surrogate markers used to predict cardiovascular risk in HIV-infected patients (such as lipid concentrations and intimal medial thickness measurements) may not capture all medication-related cardiovascular toxicity.