The effects of antiretroviral combinations upon platelets and cardiovascular health remain unclear. Although data have been presented on the effect of certain nucleoside reverse transcriptase inhibitors (NRTIs), third agents have not been studied in this context in isolation. Both dolutegravir (DTG) and darunavir/cobicistat (DRV/c) are effective third agents recommended by International HIV treatment guidelines.
Platelets were isolated from two populations of HIV-negative volunteers: 1) Subjects that were not taking any medication whose platelets were pre-incubated with ARVs in vitro and 2) 21 subjects enrolled on a Phase I clinical trial (NCT03094507) who were randomised to two groups. Group one received DTG (50mg, QD), DTG plus Cobi-boosted darunavir (DRV/c; 800/150mg QD) and DRV/c for 7 d with a 14 d washout period between drugs. Group two followed the same sequence but started with DRV/c and ended on DTG. Platelets were isolated pre-dose and after achieving steady-state for each drug intervention. Intra-subject analysis was performed to compare platelet function at each time point. For in vitro studies, platelets were exposed to each drug at Cmax values derived from the clinical trial. Plate-based aggregometry and flow cytometry was used to assess platelet function.
Platelet aggregation responses were reduced for subjects taking daily DTG (13.9±4.7% for 3µM ADP and 13.8±4.7% for 10µM TRAP6). This effect was lost when subjects were taking DTG/DRV/c and there was no effect of DRV on maximum platelet aggregation. Maximum aggregation values for platelets isolated from ARV-naïve volunteers were not affected by clinically-relevant concentrations of DTG or DRV. However, DTG reduced collagen-evoked alpha and dense granule release 80.6±10.1% and 71.5±13.1%, respectively. Whereas DRV increased alpha and dense granule release 2.2±0.4- and 1.2±0.2-fold, respectively.
The mechanism for reduced platelet activation in the presence of DTG may be explained by altered platelet granule release, that confers a potentially cardioprotective phenotype. Enhanced granule release following acute exposure to DRV may be important in the context of protease inhibitor-related cardiovascular risk. Further studies are required to correlate our basic science and clinical approaches to understand the potential impacts of alternative novel therapies upon cardiovascular health in people living with HIV.