Background:
People with HIV (PWH) have elevated systemic inflammation, even after HIV viral suppression, which is exacerbated by risky drinking and smoking. Nicotine receptor agonists promote smoking cessation, may reduce alcohol consumption, and may directly reduce inflammation via cholinergic stimulation. If varenicline, cytisine, or nicotine replacement therapy (NRT) differentially reduced biomarkers of inflammation and risk for coronary heart disease (CHD) and mortality independent of abstinence from smoking or alcohol this could alter treatment guidelines.
Methods:
We conducted a four-arm randomized, double-blinded, placebo-controlled trial among 400 heavy drinking (> 5 heavy-drinking days in the past month) and daily smoking PWH in St. Petersburg, Russia from 2017-2020. All participants received one active medication and one placebo: Arm 1: varenicline + placebo NRT; Arm 2: placebo varenicline + NRT; Arm 3: cytisine + placebo-NRT; and Arm 4: placebo-cytisine + NRT. Treatment regimens ranged from 25 days (cytisine) to 12 weeks (varenicline). Outcomes, assessed at 3 months, were: high sensitivity c-reactive protein (hsCRP; µg/ml) (primary), IL-6 (pg/ml), Reynolds Risk Score (10-year % risk CHD), and VACS Index (5-year all-cause mortality risk). We performed linear regression analyses controlling for randomization stratification factors (alcohol consumption, average daily cigarettes, current antiretroviral therapy).
Results:
Randomized groups were similar on baseline characteristics: 66% male, mean age 39 years, mean CD4 count 391 cells/mm3, and 57% undetectable HIV viral load. There were no significant differences in the three main comparisons for hsCRP at 3 months: arm 1 vs. 2 (adjusted ratio of means [AROM] 1.25; 95%CI 0.61, 2.54, p=0.73), arm 3 vs. 4 (AROM 1.13; 95%CI 0.55, 2.35, p=0.73), or arm 1 vs. 3 (AROM 1.21; 95%CI 0.58, 2.49, p=0.73) (Table). Similarly, 3-month IL-6, Reynolds Risk Score, and VACS Index did not differ by group (Table). In exploratory analyses, participants who quit drinking and smoking appeared to have lower 3-month hsCRP, IL-6, and VACS scores compared to those who continued both behaviors (Table).
Conclusions:
Among PWH with heavy drinking and smoking, biomarkers of inflammation and risk of CHD and mortality did not differ by treatment group. These results do not support the hypothesis that nicotine receptor partial and full agonists lower levels of inflammation independent of smoking or alcohol cessation.
Table 1. Effects on Inflammatory Biomarkers, Cardiovascular Risk and Mortality Risk among People with HIV (PWH) with Risky Drinking and Daily Smoking in Russia