Reducing Arterial Inflammation using Eplerenone and Statins to Augment Cardiovascular Health in HIV - Project Summary: Cardiovascular disease (CVD) is quickly advancing as a predominant cause of mortality in HIV and remains a key focus of longitudinal HIV clinical care. The landmark REPRIEVE trial of persons with HIV (PWH) showed a 36% hazard reduction in atherosclerotic CVD (ASCVD) events with moderate intensity statin. Based on these results, statins are now the standard of care for primary prevention among PWH ages 40-75 with ASCVD risk≥5%. We also gained valuable insight from REPRIEVE that 39% of PWH who still experienced a ASCVD event were in the statin arm, statins had minimal effect on inflammation, and that baseline inflammation was a predictor of incident MACE among PWH. Thus, there is a large group of PWH, who still present with high CVD burden and for whom statins alone may not be sufficient for CVD risk reduction due to persistent inflammatory burden. We hypothesize additional CVD benefit may be derived from an anti- inflammatory agent, and we will test this mechanism in the current proposal. Based on compelling evidence showing a physiological link of aldosterone to inflammation in HIV, we propose a mineralocorticoid receptor antagonist (MRA; aldosterone blocker) as add-on therapy to background statins to reduce this residual inflammation. We will conduct a multi-center, randomized, double-blinded, placebo-controlled trial among ART- and statin-treated PWH≥40 years with baseline arterial inflammation and test effects of eplerenone vs. placebo as add-on to background statin therapy on arterial inflammation using cardiac 18F-FDG-PET (Aim 1). We will characterize the phenotype associated with a higher burden of baseline arterial inflammation using ambulatory BP monitoring, other inflammatory measures (circulating markers, coronary inflammation via coronary CTA), and aldosterone (Aim 2), which will allow us to identify a non-invasive biomarker of arterial inflammation. We will further explore whether changes in arterial inflammation are related to changes in non-calcified plaque and high-risk plaque features using coronary CTA (Aim 3), to explore a mechanism that may drive a future trial on CV events. This study may potentially transform the standard of care to statins plus MRAs for PWH. The multi- sites (MGH, UCLA) have a track record for rapid enrollment, high retention rates, and an established relationship through NIH- and ACTG-sponsored studies. Working cardiac imaging and data transfer protocols have been implemented at MGH and UCLA in prior trials and will easily facilitate the proposed study led by a well-established team who have conducted high impact research related to CVD in HIV. The MPI design brings together experts in the fields of aldosterone physiology (Srinivasa), cardiac FDG-PET imaging (Tawakol), and inflammatory-mediated CVD (Hsue) and will be strengthen by Co-Is with expertise in coronary CTA imaging (Lu, Foldyna), HIV clinical trials (Currier), statins for CVD risk (Grinspoon), and biostatistics (Lee) to ensure the success of the study. Results obtained may have implications in treating other inflammatory-mediated processes in HIV, leveraging eplerenone as a safe, affordable, highly available, and well-tolerated agent.
