Background: Abacavir has been linked with cardiovascular disease but the mechanism by which this may occur is unknown. Alterations in platelet function may be involved as the active anabolite of abacavir, carbovir triphosphate, affects intra-platelet guanylyl cyclase activity. This pilot study was performed to determine the impact of abacavir on known and novel markers of platelet function.
Methods: An open label trial was performed in 20 HIV positive adult males on a stable non-abacavir containing regimen for more than 6 months with an undetectable HIV viral load. Patients taking antiplatelets, with known platelet disorders or who were at high cardiovascular risk (Framingham risk score >20%) were excluded. Abacavir (600mg once daily) was added to their usual antiretroviral regimen for 15 days. Blood samples were drawn at baseline, day 15 and day 43 (at completion of 28 day washout). Platelet function was assessed using the FACS-based phosphorylated vasodilator stimulated phosphoprotein (p-VASP) assay and through measurement of the expression and shedding of the pro-thrombotic platelet-specific collagen reception, glycoprotein VI (GPVI). Platelet surface GPVI (pGPVI) was assessed using a fluorescent, phycoerythrin (PE)-conjugated anti-GPVI monoclonal antibody (PE-1G5), plasma levels of shed soluble GPVI (sGPVI) by ELISA.
Results: Participants were 90% Caucasian, mean age 42.2 years (range 29-62), median CD4+ T cell count 660 (IQR 576 – 863). 4 (20%) current smokers. Baseline median platelet count: 198 x 109/L (IQR 177-224) with no change over the study period. There was a statistically significant decrease in p-VASP index from baseline to day 15 (median at baseline; 79.1 (95%CI 59.7 – 87.4) vs day 15; 32.6 (95%CI -2.15 – 50.8) p=0.01) which returned to baseline following the 28 day washout period (day 43; 76.3 (95% CI43.7 – 86.8, p=0.71). There was no statistically significant change between baseline and day 15 sGPVI (baseline; 72.5 ng/ml (95% CI 58.3 -81.5) vs Day 15; 45.0 ng/ml (95% CI 33.0 – 98.2) p=0.79) or pGPVI (baseline: 8.38 (95%CI 5.3 – 15.7) vs 7.8 (95%CI 5.7 – 9.7) p=0.81). These results were unaffected by baseline ART (9 on NNRTI, 9 Raltegravir, 6 Protease inhibitor).
Conclusions: Abacavir administration was associated with alterations in the platelet cAMP/cGMP inhibitory pathway which were reversed by cessation and an appropriate washout period. These results require confirmation in a larger heterogeneous population and further work to determine the clinical implications.