ST. PETER HIV-Alcohol, Protein Biomarkers and Cardiovascular Disease Risk

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Heavy alcohol use among human immunodeficiency virus infected (HIV+) people is common and associated with heart failure (HF) and coronary heart disease (CHD). An unexplored potential mechanism for this association involves changes in intestinal microbial populations (dysbiosis), which occur with heavy alcohol use or HIV infection. Dysbiosis may shift the balance of microbial genomes (microbiomes) to promote increased trimethylamine N-oxide (TMAO) production. Increased TMAO is associated with cardiovascular disease (CVD) events, including subclinical CHD and HF morbidity and mortality in the general population. Yet, no published studies have assessed the link between alcohol and TMAO or TMAO and subclinical HF among HIV+ people. We hypothesize that among HIV+ heavy drinkers, alcohol use is associated with higher levels of TMAO, and that higher TMAO levels are associated with subclinical measures and biomarkers of HF. We will test these hypotheses in ST. PETER HIV – CVD, an observational study that will be built on and complement St. PETER HIV, a randomized clinical trial (U01AA020780; begins enrollment Winter 2017). The St. PETER HIV clinical trial is testing the effects of varenicline vs. cytosine on simultaneous alcohol reduction and smoking cessation among 400 HIV+ heavy drinkers (≥5 heavy drinking days in prior month) and daily smokers in St. Petersburg, Russia. Major strengths of ST. PETER HIV - CVD are the existing complementary resources/infrastructure of the St. PETER HIV clinical trial including:1) participant recruitment; 2) validated self- report alcohol consumption; 3) biospecimen collection; 4) expertise and strong history of collaboration on alcohol, HIV and CVD research of the U.S. and Russia team members undertaking this study. In ST. PETER HIV – CVD, we propose to collect at baseline and 3 months the following new data: TMAO, echocardiography, B-type natriuretic peptide (BNP; biomarker of ventricular stretching), phosphatidylethanol (PEth; alcohol biomarker) and food frequency questionnaires. Echocardiography will be measured also at 6 months. With these existing and new data, we will be uniquely positioned to complete the following aims: AIM 1: To assess whether heavier alcohol use (Alcohol Use Disorders Identification Test, AUDIT≥20) is: a) cross-sectionally and b) longitudinally associated with TMAO levels among HIV+ heavy drinkers; AIM 2: To assess whether TMAO is associated with cardiac function and BNP in this population; and AIM 3: To explore whether TMAO mediates the association of alcohol use and subclinical HF risk. If confirmed, our hypotheses will identify a biomarker (TMAO) responsive to interventions that reduce alcohol- related CVD risk in HIV+ heavy drinkers. Because heavy alcohol use interventions do not succeed in all, developing new alcohol treatment strategies that reduce alcohol’s negative health impact among HIV+ people are needed. The identification of biomarkers and the pathways they represent (e.g., dysbiosis) could result in new targets for intervention studies and improve CVD risk prediction in HIV+ drinkers.