1/2 REPRIEVE Extension for Trial Completion

Project Summary-Abstract Globally, cardiovascular disease (CVD) burden is increasing and a major cause of mortality among people with HIV (PWH). However, data are not yet available from large trials on an effective primary CVD prevention strategy for PWH. The ongoing REPRIEVE trial will address this critical knowledge gap, hypothesizing that

statin therapy, with pleiotropic effects on LDL, immune activation and inflammatory pathways, will modify traditional and nontraditional risks and prevent major adverse cardiovascular events (MACE) in PWH. REPRIEVE is well-positioned to provide high quality, clinically actionable and generalizable information to shift

the current paradigm of HIV care, in alignment with the goals of NHLBI and OAR to reduce CVD and improve the overall health of PWH. REPRIEVE has met major challenges, anticipated for a large trial. 7,770 participants (31% female, 43% Black, 25% Latino) were enrolled from over 100 sites in 12 countries, a diverse,

generalizable population. Retention is high, >90%. Endpoint (MACE) are accumulating steadily despite a low median ASCVD risk score of 4.5%, consistent with the hypothesis that nontraditional risks contribute to CVD in HIV. The Mechanistic Substudy has met its goal, enrolling over 800 participants for serial coronary CT

angiography (CTA) and immune function. Preliminary baseline data from the substudy support our hypothesis, linking plaque to CVD risk but also independently to IL-6 and Lp-PLA2, key indices of immune function and arterial inflammation that are being targeted in REPRIEVE. Moreover, REPRIEVE is being leveraged to assess

statin effects on COVID severity, and long-term effects in PWH, critical unanswered questions for the field. REPRIEVE has executed well over 6-years and is fundamentally strong. However, with a long duration of recruitment and protocol revisions to identify the optimal at-risk group given new guidelines, median duration of

follow up is still short at 3.5-years. REPRIEVE needs additional time, projected at 2-years, plus a close out year, to collect necessary MACE to ensure adequate power, analyze, and disseminate this data. The pressing need for data from a large global primary prevention trial has only grown since REPRIEVE was initiated.

Completion of the trial will protect the value of the initial NIH investment and honor the commitment to our participants and scientific community to meet the Aims of the trial. This application for the Clinical Coordinating Center (CCC) of the REPRIEVE Extension for Trial Completion focuses on the clinical rationale and

coordination of the trial. The Data Coordinating Center (DCC) application focuses on data management, including the coronary CTA data of the Mechanistic Substudy, and the statistical rationale for the trial design.