Risks for sudden cardiac and undetermined cause of death among people with HIV in the reprieve primary cardiovascular prevention trial

Objective: People with HIV (PWH) are at increased risk of sudden cardiac death (SCD) but the mechanisms are unclear limiting prevention efforts. We leveraged the global REPRIEVE trial with carefully adjudicated atherosclerotic cardiovascular disease (ASCVD) outcomes to determine cardiac, behavioral, and HIV-specific risks associated with SCD and assess potential similarities to undetermined deaths (UDD). Design/Methods: REPRIEVE included 7769 PWH with low-to-moderate traditional ASCVD risk without known ASCVD randomized to pitavastatin vs placebo. Clinical features and ECGs were assessed at enrollment. Cox models assessed associations with SCD and UDD outcomes, adjusted for ASCVD risk and ART duration. Results: After a median of 5.6 years, 25 participants had SCD and 53 had UDD (incidence rate 0.61, 1.31 per1000 person-years, respectively). Of those with SCD, 84% were males, and the median 10-year ASCVD risk-score was 6.9% (IQR 3.5, 8.3) vs 5.7% (3.6, 8.8) for UDD vs 4.4% (2.1, 7.0) for participants without either outcome (n = 7691). Notably, 16.0% of the participants with SCD, 9.4% with UDD and 3.0% without either had major ECG abnormalities. In adjusted Cox models, substance abuse, and detectable HIV viral load were associated with an increased hazard of UDD but not SCD. Infarct/ischemic pattern and axis abnormalities on ECG were associated with increased hazard for SCD. Conclusion: Among PWH with low-moderate ASCVD risk, subsequent SCD is associated with a higher burden of cardiovascular risk factors and ECG findings suggestive of subclinical structural abnormalities. In contrast, UDD is associated with a unique risk profile inclusive of HIV-specific and behavioral risks.