Importance: Cigarette smoking and risky alcohol consumption co-occur and are undertreated. Nicotine receptor partial agonists and nicotine replacement therapy (NRT) treat smoking but are unproven for alcohol, and clinical trials rarely include individuals with HIV, substance use, and mental health conditions.

Question: Are varenicline and cytisine more efficacious than nicotine to treat alcohol and smoking among individuals who smoke daily, have HIV, and engage in risky drinking?

Findings: This randomized clinical trial of 400 individuals with HIV who engaged in risky drinking and daily smoking found that alcohol consumption at 3 months was decreased in all groups (active varenicline and placebo nicotine replacement therapy [NRT], placebo varenicline and active NRT, active cytisine and placebo NRT, and placebo cytisine and active NRT) but heavy drinking days did not differ significantly by group. Smoking abstinence at 6 months did not differ by group, but abstinence rates were high.

Meaning: This study found that varenicline and cytisine were not more efficacious than nicotine to treat risky drinking and smoking but that rates of behavior change for alcohol consumption and smoking were high in all treatment groups, suggesting a role for these medications in individuals who report risky drinking and smoking.