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The pathogenesis and prevention of cardiovascular disease in HIV positive patients
thesisposted on 2017-02-22, 02:00 authored by Trevillyan, Janine Maree
Advances in the treatment of HIV have led to dramatic improvements in life-expectancy and overall health. Yet these gains have been limited by the discovery that HIV positive individuals are at increased risk for non-AIDS related co-morbidities, and in particular cardiovascular disease (CVD) which occurs at twice the rate seen in the general population. CVD is now the leading cause of mortality in HIV positive patients on antiretroviral therapy (ART). This project aimed to extend current knowledge on the pathogenesis of CVD in people living with HIV and investigate strategies that may decrease this risk in the future. Through the performance of a retrospective case-control study the important role traditional cardiovascular risk factors (including dyslipidaemia) and current abacavir use play in promoting CVD in an Australian HIV positive population were identified. The mechanism by which abacavir may promote CVD is unknown but it is plausible that alterations in platelet function may be involved. Thus the predictive ability of a novel marker of platelet activity (soluble glycoprotein VI) was examined in HIV positive individuals. This determined that sGPVI is elevated in HIV positive individuals compared with healthy HIV negative volunteers and may be predictive of future cardiovascular events. The changes in platelet function (using a panel of markers of platelet activity including sGPVI) that occur following abacavir initiation were then investigated in a prospective open-label interventional trial. This trial did not identify a change in sGPVI with abacavir therapy (although there was a trend towards decreased levels) but did demonstrate reversible changes in other markers of platelet activation. While the clinical implications of these changes remains to be determined this provides important data to guide ongoing research in the field. The effects of ART on cardiovascular risk were further investigated using novel mass-spectrometry technology to describe the detailed lipid profile changes that occur with commencement of ART. This work identified significant, potentially pro-atherogenic, changes associated with ART, particularly with an efavirenz based regimen. Analyses of this kind may improve cardiovascular risk prediction in HIV positive patients and provide physicians and patients with individualised, detailed information when choosing an antiretroviral regimen. In an attempt to reduce the incidence of CVD locally derived guidelines for the screening and management of modifiable risk factors were developed. Implementation of these guidelines led to improved rates of screening and monitoring for CVD but as an isolated strategy did not translate into changes in the management of risk factors. This work highlights that changes in the model of HIV care provision may be needed to provide optimal management of cardiovascular risk. Cumulatively this research has contributed to understanding of the pathogenesis of CVD in HIV positive individuals, providing the basis for ongoing research and illuminating possible targets for therapeutic interventions.