Combination antiretroviral therapy has substantially increased the life expectancy of people living with HIV. There is now a focus on the management of non-infectious comorbidities in this population, with cardiovascular disease being one of the leading causes of mortality.
Use of the nucleoside reverse transcriptase inhibitor, abacavir, has been shown to increase the relative risk of myocardial infarction by 1.9 times versus individuals not on abacavir, though there has been no confirmation of causality, nor a credible mechanism identified.
Abacavir-induced increased platelet reactivity has been suggested as an underlying mechanism, although this has not been confirmed experimentally.
In this thesis, a randomised controlled trial was conducted to investigate the effect on platelets of switching from an abacavir containing antiretroviral therapy to an abacavir free regimen. This was combined with in vitro studies and a mouse model of thromboembolism examining the effect of abacavir and lamivudine on platelet activation in the absence of HIV infection, as well as a mechanistic investigation into the effect on nitric oxide signalling and reactive oxygen species (ROS) production.
A switch away from abacavir resulted in reduced platelet reactivity in response to collagen and increases in collagen receptor GPVI, both surface and plasma soluble forms.
Acute administration of abacavir and lamivudine in vitro, had no effect on platelet aggregation but abacavir did significantly increase expression of the activation marker CD63 following collagen addition. Collagen-evoked platelet responses were augmented in the in vivo model following abacavir administration but not with lamivudine individually or in combination. No effects of antiretrovirals on platelet nitric oxide signalling or ROS production was seen.