Exposure to abacavir (ABC) has been associated with increased risk of cardiovascular events with altered platelet function implicated. Glycoprotein VI (GPVI), expressed on and shed from platelets, regulates platelet activation in response to collagen exposure. We previously demonstrated increases in soluble GPVI (sGPVI) in virologically-suppressed people with HIV-1 (PWH) switching from ABC to tenofovir disoproxil fumarate (TDF) and recently showed decreased platelet reactivity in response to collagen and increases in GPVI expression on platelets upon switching from ABC / lamivudine (ABC/3TC) to tenofovir alafenamide / emtricitabine (TAF/FTC). Changes in sGPVI when switching from ABC/3TC to TAF/FTC have not been determined.
In a platelet function substudy within a randomized, double-blind, active-controlled trial of virologically suppressed PWH on ABC/3TC who were randomized to switch to TAF/FTC or remain on ABC/3TC, we quantified sGPVI in platelet-poor plasma taken at weeks 0, 4, 12, 24 and 48 by electrochemiluminescence. The primary endpoint was change in sGPVI to week 48 with the between-group difference compared using mixed effects models with repeated measures.
Of 556 subjects enrolled in the study, 545 (98%) had samples available for analysis. Mean (SD) age was 51 (9.3) years, 82% male, 72% white. Baseline CD4+ count was 712 (284) cells/mm3 and 99% had HIV-1 RNA <50 copies/ml. Baseline sGPVI (µg/mL, median [IQR]) were similar between groups: TAF/FTC 7.36 (5.2, 12.7) versus ABC/3TC 8.46 (5.27, 14.51), P=0.18. The TAF/FTC group had a significantly greater increase in sGPVI to week 48 (figure), with a +14.7%, (95% CI 4.1, 26.3) difference between groups in change in sGPVI to week 48 by mixed effects models (P=0.005).
Switching away from ABC/3TC to TAF/FTC was associated with greater increases in sGPVI. In combination with the previously demonstrated decreases in platelet reactivity and re-expression of GPVI on platelets in PWH switching from ABC/3TC to TAF/FTC, these data suggest a reversible, inherent platelet dysfunction with ABC/3TC, centered on GPVI function, which may contribute to increased risk of cardiovascular events observed in PWH exposed to ABC.