Effects of HIV integrase inhibitors on cardiovascular components

Approximately 39 million people live with HIV (PLWH) today. With combination antiretroviral therapy (cART), PLWH can no longer develop AIDS and maintain an undetectable viral load, but they have been shown to acquire double the risk in developing a cardiovascular disease (CVD) compared to the general population. Several antiretrovirals have been associated with off target effects on the endothelium and platelets. In particular, integrase strand inhibitors (INSTIs), including bictegravir (BIC) and dolutegravir (DTG), are largely used in clinics today, and recent studies associated DTG with an enhanced platelet activity, highlighting the need to explore any possible impact DTG, or similar INSTIs may have on CVD risk. Here, I hypothesize that DTG affects endothelial and platelet activation more than BIC and I aimed to explore and compare the effects of the two, post in vitro treatment with clinically relevant concentrations of the drugs, alone or in therapeutical combinations and conduct some ex vivo platelet assays from PLWH to create a pilot study. Adhesion and permeability markers of Human Umbilical Vein Endothelial Cells (HUVEC) and Human Coronary Endothelial Cells (HCAEC) were measured post stimulation in flow cytometry or confocal microscopy. Platelet aggregation and surface activation markers were measured in light transmission aggregometry and flow cytometry, respectively. Additionally, platelet adhesion to collagen was measured under physiological conditions upon in vitro treatment with INSTIs. Major findings show no effects of DTG or BIC on HUVEC or HCAEC. A higher platelet aggregation profile is displayed in samples treated with INSTIs (especially DTG) versus vehicle control, however this was not extended in ex vivo assays from patients. A neutral effect of INSTIs on the endothelium was demonstrated, though clinical relevance of this yet to be determined. This pilot study offers a template for future patient and pathophysiological studies to allow personalized treatments with lower CVD risk.