HIV-infected heavy drinking smokers are at high risk for coronary heart disease (CHD) and death. The mechanisms driving increased CHD risk in HIV-infected people are unclear, but are linked to inflammation. HIV, heavy drinking, and smoking are all pro-inflammatory. HIV viral suppression with antiretroviral therapy does not eliminate the elevated CHD risk nor the increased inflammation (i.e., pre-HIV infection levels are not restored). Interventions that reduce alcohol use, smoking, or both in HIV-infected people could lower inflammation, CHD and death risk. Varenicline and cytisine are proven therapies for smoking cessation. When compared to placebo, varenicline has higher cessation rates than cytisine. Human trials suggest varenicline also has efficacy for reducing alcohol consumption and craving in heavy drinking smokers. In murine models, cytisine reduces alcohol consumption. The comparative efficacy of varenicline and cytisine to reduce alcohol consumption and by extension, inflammation, CHD, and mortality risk, in humans has not been tested, nor has their comparative effectiveness been tested for smoking. Neither drug has been tested for smoking cessation against nicotine replacement therapy (NRT) in HIV-infected heavy drinking smokers. Three compelling reasons to test varenicline and cytisine in HIV-infected heavy drinking smokers are: 1) both show promise in HIV-uninfected people; 2) the morbidity caused by heavy drinking and smoking in HIV-infected persons is significant; and 3) treating heavy drinking and smoking with one medication represents a significant advance in reducing polypharmacy and improving patient care. Thus, investigators propose a 4-arm placebo-controlled randomized controlled trial (RCT) among 400 HIV-infected heavy drinking smokers. Trial arms are varenicline+NRT placebo, cytisine+NRT placebo, NRT+varenicline placebo, NRT+cytisine placebo. All participants will receive counseling (alcohol \& tobacco) and medications (placebo \& active). Specific aims will compare effects of varenicline, cytisine, and NRT at 3 months on past month % heavy drinking days and alcohol craving, cigarettes per day and smoking abstinence (verified by carbon monoxide), inflammation (hsCRP, IL-6), CHD (Reynolds risk score), and mortality (VACS index) risk. Investigators hypothesize that (1) Varenicline has greater efficacy than NRT for reducing heavy drinking, smoking, inflammation, CHD and mortality risk; (2) Cytisine has greater efficacy than NRT; and (3) Varenicline has greater efficacy than cytisine for these outcomes. Investigators will conduct an RCT, Studying Partial-agonists for Ethanol and Tobacco Elimination in Russians with HIV (St PETER HIV), in a country with an HIV epidemic and high per-capita alcohol consumption and smoking. Investigators will recruit from the ongoing Russia ARCH cohort in St. Petersburg (part of our NIAAA funded HIV/AIDS Alcohol Consortium - URBAN ARCH). If investigator hypotheses are correct, St PETER HIV could make nicotinic partial-agonists standard care for HIV+ heavy drinking smokers, and lead to reduced inflammation, CHD and mortality risk through this "one drug, two diseases" approach. This trial addresses the paucity of RCT data to guide treatment of these CHD risk factors in HIV-infected people.

The Russia ARCH Cohort and the St PETER HIV study will draw from an established cohort of HIV-infected smokers and heavy drinkers to compare the effects of two partial nicotinic receptors, varenicline and cytisine, on alcohol consumption, alcohol craving, smoking, inflammation, CHD risk and mortality risk. St PETER HIV further addresses the paucity of randomized controlled trial data to guide treatment of heavy alcohol consumption and smoking in HIV-infected people.