Statin-dependent and -independent pathways are associated with major adverse cardiovascular events in people with HIV

BACKGROUND. Statin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond LDL-cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin-responsive and other inflammatory and metabolic pathways with MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). METHODS. Cox proportional hazards models were used to assess the relationship between MACE and proteomics measurements at study entry and year 2, adjusting for time-updated statin use and the baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine-learning (ML) model to predict MACE using baseline protein values with significant associations. RESULTS. For 765 individuals (age: 50.8 ± 5.9 years, 82% men, 18% women), among 7 proteins changing with statin versus placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (adjusted HR [aHR]: 2.31 per 2-fold-higher levels; 95% CI: 1.11–4.80; P = 0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins that did not change in response to statin therapy, 26 were associated with MACE at a FDR below 0.05. These proteins represented a predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomics ML model achieved a 10-fold cross-validated concordance index (C-index) of 0.74 ± 0.11 to predict MACE, improving on models using traditional risk prediction scores only (C-index: 0.61 ± 0.18). CONCLUSIONS. ANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C. TRIAL REGISTRATION. ClinicalTrials.gov: NCT02344290. FUNDING. NIH, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare.