Effectiveness of Varenicline and Cytisine for Alcohol Use Reduction Among People With HIV and Substance Use: A Randomized Clinical Trial.

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. Objective: To compare the effects on drinking and smoking of nicotinic acetylcholine receptor partial agonists varenicline and cytisine with those of NRT. Design, Setting, and Participants: This 4-group randomized, double-blinded, placebo-controlled clinical trial was conducted from July 2017 to December 2020 in St Petersburg, Russia. Included participants were 400 individuals with HIV who engaged in risky drinking (≥5 prior-month heavy-drinking days [HDDs]) and daily smoking; they were followed up for 12 months after enrollment. Data were analyzed from May 2021 through June 2022. Interventions: Participants received alcohol and tobacco counseling, 1 active medication, and 1 placebo in 1 of 4 groups: active varenicline and placebo NRT (group 1), placebo varenicline and active NRT (group 2), active cytisine and placebo NRT (group 3), or placebo cytisine and active NRT (group 4). Main Outcomes and Measures: The primary outcome was number of prior-month HDDs at 3 months. Secondary outcomes included biochemically validated abstinence from alcohol at 3 months and smoking at 6 months. Results: Among 400 participants (263 [65.8%] men; mean [SD] age, 39 [6] years), 97 individuals (24.3%) used opioids and 156 individuals (39.1%) had depressive symptoms. These individuals had a mean (SD) CD4 count of 391 (257) cells/mm3, smoked a mean (SD) of 21 [8] cigarettes/d, and reported a mean (SD) of 9.3 (5.8) HDDs in the prior 30 days. At 3 months, the mean (SD) number of HDDs was decreased vs baseline across all groups (group 1: 2.0 [3.8] HDDs vs. 9.5 [6.1] HDDs; group 2: 2.1 [4.3] HDDs vs 9.3 [5.7] HDDs; group 3: 1.5 [3.3] HDDs vs 8.9 [5.0] HDDs; group 4: 2.4 [5.2] HDDs vs 9.6 [6.3] HDDs). There were no significant differences at 3 months between groups in mean (SD) HDDs, including group 1 vs 2 (incident rate ratio [IRR], 0.94; 95% CI, 0.49-1.79), 3 vs 4 (IRR, 0.60; 95% CI, 0.30-1.18), and 1 vs 3 (IRR, 1.29; 95% CI, 0.65-2.55). There were no significant differences at 6 months between groups in smoking abstinence, including group 1 vs 2 (15 of 100 individuals [15.0%] vs 17 of 99 individuals [17.2%]; odds ratio [OR],0.89; 95% CI, 0.38-2.08), 3 vs 4 (19 of 100 individuals [19.0%] vs 19 of 101 individuals [18.8%]; OR, 1.00; 95% CI, 0.46-2.17), and 1 vs 3 (OR, 0.79; 95% CI, 0.35-1.78). Post hoc analyses suggested lower mean (SD) HDDs (eg, at 3 months: 0.7 [1.8] HDDs vs 2.3 [4.6] HDDs) and higher alcohol abstinence (eg, at 3 months: 30 of 85 individuals [35.3%] vs 54 of 315 individuals [17.1%]) among those who quit vs continued smoking. Conclusions and Relevance: This study found that among individuals with HIV who engaged in risky drinking and smoking, varenicline and cytisine were not more efficacious than NRT to treat risky drinking and smoking but that behavior change rates were high in all groups. Trial Registration: ClinicalTrials.gov Identifier: NCT02797587.

Stigma and ART initiation among people with HIV and a lifetime history of illicit drug use in Saint-Petersburg, Russia-A prospective cohort analysis.

BACKGROUND: HIV-positive people who inject drugs (PWID) are stigmatized and face more challenges in accessing ART. The natural course of stigma and its role on ART initiation in this population is unclear. We examined 1] whether HIV stigma changes over time and 2] whether HIV and substance use stigma are associated with ART initiation in a prospective cohort of HIV-positive PWID in St. Petersburg, Russia. METHODS: We used data from 165 HIV-positive PWID who were ART-naïve at enrollment andgeneralized estimating equations to assess changes in HIV stigma between baseline, 12- and 24-month study visits. Logistic regression estimated associations of HIV stigma and substance use stigma with ART initiation. All models were adjusted for gender, age, CD4 count, duration of HIV diagnosis, recent (past 30-day) drug use and depressive symptoms. RESULTS: Participants characteristics were the following: median age of 34 (Q1; Q3: 30; 37) years; 30% female; 28% with CD4 count <350; 44% reported recent drug use. During the study period, 31% initiated ART and the median time between HIV diagnosis and ART initiation was 8.5 years (Q1; Q3: 4.68; 13.61). HIV stigma scores decreased yearly by 0.57 (95% CI -1.36, 0.22). More than half (27/47 [57.4%]) of participants who were eligible for ART initiation per local ART guidelines did not initiate therapy. Total HIV stigma and substance use stigma scores were not associated with ART initiation (AOR 0.99, 95%CI 0.94-1.04; AOR 1.01, 95%CI 0.96-1.05, respectively). CONCLUSION: In this Russian cohort of HIV-positive, ART-naïve PWID, stigma did not change over time and was not associated with ART initiation. Addressing stigma alone is unlikely to increase ART initiation rates in this population. Reducing further existing structural barriers, e.g., by promoting equal access to ART and the value of substance-use treatment for ART treatment success should complement stigma-reduction approaches.

Per-protocol analysis of the ZINC trial for HIV disease among alcohol users.

BACKGROUND: The Zinc for INflammation and Chronic disease in HIV (ZINC) trial randomized person who live with HIV (PLWH) who engage in heavy drinking to either daily zinc supplementation or placebo. The primary outcome was change in the Veterans Aging Cohort Study (VACS) index, a predictor of mortality, between baseline and 18 months. Because adherence and follow-up were suboptimal, the intention-to-treat analysis, which was not statistically significant, may have underestimated the effect of the zinc supplementation. OBJECTIVE: We estimated the per-protocol effect of zinc versus placebo in the ZINC trial (i.e., the effect that would have been observed if all participants had had high adherence and none was lost to follow-up). METHODS: Adherence was measured as the self-reported percentage of pills taken in the previous 6 weeks and assessed at all post-baseline visits. We used inverse probability weighting to estimate and compare the change in the VACS index at 18 months in the zinc and placebo groups, had all the trial participants had high adherence (i.e., cumulative adherence ≥80% at 18 months). To examine trends by level of adherence, we rerun the analyses using thresholds for high adherence of 70% and 90% of average self-reported pill coverage. RESULTS: The estimated (95% confidence interval) change in the VACS index was - 2.16 (- 8.07, 3.59) and 5.84 (0.73, 11.80) under high adherence and no loss to follow-up in the zinc and placebo groups, respectively. The per-protocol effect estimate of the mean difference in the change between the zinc and placebo groups was - 8.01 (- 16.42, 0.01), somewhat larger than the intention-to-treat effect difference in change (- 4.68 (- 9.62, 0.25)), but it was still not statistically significant. The mean difference in the change between individuals in the zinc and placebo groups was - 4.07 (- 11.5, 2.75) and -12.34 (- 20.14, -4.14) for high adherence defined as 70% and 90% of pill coverage, respectively. CONCLUSIONS: Overall, high adherence to zinc was associated with a lower VACS score, but confidence intervals were wide and crossed 0. Further studies with a larger sample size are needed to quantify the benefits of zinc supplementation in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01934803 . Registered on August 30, 2013.

Effect of Zinc Supplementation vs Placebo on Mortality Risk and HIV Disease Progression Among HIV-Positive Adults With Heavy Alcohol Use: A Randomized Clinical Trial.

Importance: Zinc supplementation can reduce alcohol-related microbial translocation and inflammation. Objective: To assess whether zinc supplementation reduces markers of mortality and risk of cardiovascular disease, reduces levels of inflammation and microbial translocation, and slows HIV disease progression in people with heavy alcohol use who are living with HIV/AIDS. Design, Setting, and Participants: This study is a double-blinded placebo-controlled randomized clinical trial of zinc supplementation among participants recruited from 2013 to 2015. Participants were recruited from HIV and addiction clinical and nonclinical care sites in St Petersburg, Russia. Participants were adults (aged 18-70 years) with documented HIV infection who were antiretroviral therapy-naive at baseline and had past 30-day heavy alcohol consumption. Data analysis was performed from February 2017 to February 2020. Intervention: Pharmacy-grade zinc gluconate supplementation (15 mg for men and 12 mg for women, taken daily by mouth for 18 months) was compared with a placebo. Main Outcomes and Measures: The primary outcome was mortality risk measured as a change in Veterans Aging Cohort Study (VACS) Index score between baseline and 18 months. The VACS Index scores range from 0 to 164, with higher scores indicating higher mortality risk. Secondary outcomes were change in CD4 cell count between baseline and 18 months, the assessment of cardiovascular disease risk (Reynolds Risk Score, which ranges from 0% to 100%, with higher scores indicating higher risk), and changes in inflammatory or microbial translocation biomarkers at 18 months. Adjusted linear regression analyses were performed. Results: A total of 254 participants (184 men [72%]; mean [SD] age, 34 [6] years) were enrolled in the trial; 126 were randomized to receive zinc, and 128 were randomized to receive placebo. Participants had high CD4 cell counts (mean [SD], 521 [292] cells/mm3), and 188 (74%) reported heavy drinking in the past week. In the main analyses, zinc supplementation did not affect changes in the VACS Index score at 18 months (change for zinc, mean [SD], 0.49 [14.6]; median [interquartile range], 0.0 [-7.0 to 6.0]; change for placebo, mean [SD], 5.5 [17.2]; median [interquartile range], 6.0 [-6.0 to 14.0]; adjusted mean difference [AMD], -4.68; 95% CI, -9.62 to 0.25; P = .06) or any secondary outcomes, including change in CD4 cell count (AMD, 41.8 cells/mm3; 95% CI, -20.3 to 103.8 cells/mm3; P = .19), Reynolds Risk Score (AMD, -0.014; 95% CI, -0.167 to 0.139; P = .85), interleukin-6 level (AMD, -0.13 pg/mL; 95% CI, -0.38 to 0.11 pg/mL; P = .30), dimerized plasmin fragment D level (AMD, -0.21 µg/mL fibrinogen equivalent units; 95% CI, -0.48 to 0.07 µg/mL fibrinogen equivalent units; P = .14), soluble CD14 level (AMD, -38.01 ng/mL; 95% CI, -166.90 to 90.88 ng/mL; P = .56), intestinal fatty acid binding protein level (AMD, 0.08 pg/mL; 95% CI, -0.07 to 0.22 pg/mL; P = .32), and lipopolysaccharide binding protein level (AMD, -0.09 ng/mL; 95% CI, -0.23 to 0.06 ng/mL; P = .24). In the per-protocol analyses, zinc supplementation statistically significantly affected changes in the VACS Index score at 18 months (AMD, -7.49; 95% CI, -13.74 to -1.23; P = .02); however, the adherence rate to zinc supplementation was 51%. Conclusions and Relevance: Zinc supplementation did not reduce mortality risk, CD4 cell counts, cardiovascular disease risk, and levels of inflammation or microbial translocation in people with heavy alcohol use who are living with HIV/AIDS. Zinc supplementation did not change the VACS Index score but may have been limited by low adherence. Trial Registration: ClinicalTrials.gov Identifier: NCT01934803.

Design of a randomized controlled trial of smoking cessation medications for alcohol reduction among HIV-positive heavy drinkers and daily smokers in St. Petersburg, Russia.

BACKGROUND: HIV, heavy drinking, and smoking are all pro-inflammatory and increase risk for coronary heart disease (CHD). Interventions that reduce alcohol use, smoking, or both in HIV-positive people could lower inflammation, CHD and death risk. Varenicline and cytisine are proven therapies for smoking cessation and may also reduce alcohol consumption. The comparative efficacy of varenicline and cytisine to reduce alcohol consumption has not been tested, nor has their comparative effectiveness been reported for smoking. OBJECTIVE: This paper describes the protocol of the Studying Partial agonists for Ethanol and Tobacco Elimination in Russians with HIV (St PETER HIV), a four-arm parallel-group randomized controlled trial comparing effects of varenicline, cytisine, and nicotine replacement therapy (NRT). METHODS: The study is recruiting four hundred HIV-positive heavy drinking smokers interested in cutting down on alcohol and/or tobacco in St. Petersburg, Russia. Participants are randomly assigned to receive either active varenicline + NRT placebo, varenicline placebo + active NRT, active cytisine + NRT placebo, cytisine placebo + active NRT. All participants receive evidence-based counseling for alcohol and tobacco use, one active medication, and one placebo. Outcomes are: 1) % heavy drinking days in the past month (primary study outcome at three months) and alcohol craving; 2) cigarettes per day (primary smoking outcome at 3 months) and 7-day point prevalence abstinence and; 3) inflammation, CHD risk, and mortality risk. CONCLUSION: St PETER HIV addresses the paucity of randomized controlled trial data to guide treatment of alcohol consumption and smoking in HIV-positive heavy drinking smokers.

Slow-release naltrexone implant versus oral naltrexone for improving treatment outcomes in people with HIV who are addicted to opioids: a double-blind, placebo-controlled, randomised trial.

BACKGROUND: Untreated opioid addiction in people with HIV is associated with poor HIV treatment outcomes. Slow-release, long-acting, implantable naltrexone might improve these outcomes. Here, we present results of a study aimed to test this hypothesis. METHODS: We did a 48 week double-blind, double-dummy, placebo-controlled, phase 3, randomised trial with men and women addicted to opioids who were starting antiretroviral therapy (ART) for HIV and whose viral loads were higher than 1000 copies per mL. Participants were seeking treatment at two HIV and two narcology programme centres in Saint Petersburg, Russia, and the surrounding Leningrad region. The Pavlov statistical department created a table with stratification on gender distribution, viral load, and CD4 cell count. We stratified participants according to gender, viral load, and CD4 cells per µL, and randomly assigned (1:1) them to addiction treatment with a naltrexone implant and oral naltrexone placebo (implant group) or oral naltrexone and placebo implant (oral group). The primary outcome was plasma viral load of less than 400 copies per mL at 24 weeks and 48 weeks. We included all randomly assigned participants in outcome analyses (intention to treat). Treatment staff and patients were masked to group assignment. The study is complete and registered at ClinicalTrials.gov, NCT01101815. FINDINGS: Between July 14, 2011, and April 14, 2014, 238 potential participants were recruited and screened, 35 were excluded for not meeting inclusion criteria, three declined to participate, and 200 were randomly assigned to treatment (100 to each group). At week 24, 38 (38) participants in the implant group and 35 (35%) in the oral group had viral loads less than 400 copies per mL (risk ratio 1·1, 95% CI 0·76-1·56; p=0·77). At week 48, 66 participants in the implant group and 50 in the oral group had viral loads less than 400 copies per mL (risk ratio 1·32, 95% CI 1·04-1·68; p=0·045). There were seven serious adverse events: three deaths in the implant group (one due to heart disease, one trauma, and one AIDS), and four in the oral group (two overdoses, one pancreatic cancer, and one AIDS). The overdose deaths occurred 9-10 months after the last naltrexone dose. INTERPRETATION: The longer the blockade of opioid effects, the more protection an individual gets from missed ART doses and impulsive behaviours that lead to relapse and poor, even fatal, outcomes. Commercial development of implants could result in a meaningful addition to addiction treatment options. FUNDING: National Institutes of Health, National Institute on Drug Abuse, Penn Centre for AIDS Research, and Penn Mental Health AIDS Research Centre.

Design of a randomized controlled trial of zinc supplementation to improve markers of mortality and HIV disease progression in HIV-positive drinkers in St. Petersburg, Russia.

Background Russia continues to have an uncontrolled HIV epidemic and its per capita alcohol consumption is among the highest in the world. Alcohol use among HIV-positive individuals is common and is associated with worse clinical outcomes. Alcohol use and HIV each lead to microbial translocation, which in turn results in inflammation. Zinc supplementation holds potential for lowering levels of biomarkers of inflammation, possibly as a consequence of its impact on intestinal permeability. This paper describes the protocol of a double-blinded randomized placebo-controlled trial of zinc supplementation in St. Petersburg, Russia. Methods Participants (n = 254) were recruited between October 2013 and June 2015 from HIV and addiction clinical care sites, and non-clinical sites in St. Petersburg, Russia. Participants were randomly assigned, to receive either zinc (15 mg for men; 12 mg for women) or placebo, daily for 18 months. The following outcomes were assessed at 6, 12, and 18 months: (1) mortality risk (primary outcome at 18 months); (2) HIV disease progression; (3) cardiovascular risk; and (4) microbial translocation and inflammation. Adherence was assessed using direct (riboflavin) and indirect (pill count, self-report) measures. Conclusion Given the limited effectiveness of current interventions to reduce alcohol use, zinc supplementation merits testing as a simple, low-cost intervention to mitigate the consequences of alcohol use in HIV-positive persons despite ongoing drinking.

Use of an android phone application for automated text messages in international settings: A case study in an HIV clinical trial in St. Petersburg, Russia.

BACKGROUND/AIMS: Reproducible outcomes in clinical trials depend on adherence to study protocol. Short message service (also known as text message) reminders have been shown to improve clinical trial adherence in the United States and elsewhere. However, due to systematic differences in mobile data plans, languages, and technology, these systems are not easily translated to international settings. METHODS: To gauge technical capabilities for international projects, we developed SMSMessenger, an automated Android application that uses a US server to send medication reminders to participants in a clinical trial in St. Petersburg, Russia (Zinc for HIV disease among alcohol users-a randomized controlled trial in the Russia Alcohol Research Collaboration on HIV/AIDS cohort). The application is downloaded once onto an Android study phone. When it is time for the text message reminders to be sent, study personnel access the application on a local phone, which in turn accesses the existing clinical trial database hosted on a US web server. The application retrieves a list of participants with the following information: phone number, whether a message should be received at that time, and the appropriate text of the message. The application is capable of storing multiple outgoing messages. With a few clicks, text messages are sent to study participants who can reply directly to the message. Study staff can check the local phone for incoming messages. The SMSMessenger application uses an existing clinical trial database and is able to receive real-time updates. All communications between the application and server are encrypted, and phone numbers are stored in a secure database behind a firewall. No sensitive data are stored on the phone, as outgoing messages are sent through the application and not by messaging features on the phone itself. Messages are sent simultaneously to study participants, which reduces the burden on local study staff. Costs and setup are minimal. The only local requirements are an Android phone and data plan. CONCLUSION: The SMSMessenger technology could be modified to be applied anywhere in the world, in any language, script, or alphabet, and for many different purposes. The novel application of this existing low-cost technology can improve the usefulness of text messaging in advancing the goals of international clinical trials.

Alcohol Use and Food Insecurity Among People Living with HIV in Mbarara, Uganda and St. Petersburg, Russia.

Food insecurity (FI) is a documented problem associated with adverse health outcomes among HIV-infected populations. Little is known about the relationship between alcohol use and FI. We assessed whether heavy alcohol use was associated with FI among HIV-infected, antiretroviral therapy (ART)-naïve cohorts in Uganda and Russia. Inverse probability of treatment weighted logistic regression models were used to evaluate the association using cross-sectional baseline data. FI was experienced by half of the Russia cohort (52 %) and by a large majority of the Uganda cohort (84 %). We did not detect an association between heavy alcohol use and FI in either cohort (Russia: AOR = 0.80, 95 % CI 0.46, 1.40; Uganda: AOR = 1.00, 95 % CI 0.57, 1.74) or based on the overall combined estimate (AOR = 0.89, 95 % CI 0.60, 1.33). Future studies should explore the determinants of FI in HIV-infected populations to inform strategies for its mitigation.

Heat capacity of molten halides.

The heat capacities of molten salts are very important for their practical use. Experimental investigation of this property is challenging because of the high temperatures involved and the corrosive nature of these materials. It is preferable to combine experimental investigations with empirical relationships, which allows for the evaluation of the heat capacity of molten salt mixtures. The isobaric molar heat capacities of all molten alkali and alkaline-earth halides were found to be constant for each group of salts. The value depends on the number of atoms in the salt, and the molar heat capacity per atom is constant for all molten halide salts with the exception of the lithium halides. The molar heat capacities of molten halides do not change when the anions are changed.

Depression, substance use, viral load, and CD4+ count among patients who continued or left antiretroviral therapy for HIV in St. Petersburg, Russian Federation.

Antiretroviral therapy (ART) became more widely available in the Russian Federation in 2006 when the Global Fund made a contribution to purchase ART with a mandate to increase numbers of patients receiving it. Funds were distributed to AIDS Centers and selected hospitals, and numbers quickly increased. Though ART is highly effective for adherent patients, dropout has been a problem; thus understanding characteristics of patients who remain on ART vs. those who leave treatment may provide information to facilitate engagement. We retrospectively assessed depression, hopelessness, substance use, viral load, and CD4+ counts of 120 patients who dropped out of ART for ≥12 months (Lost-to-Care, LTCs) and 120 who continued for ≥12 months (Engaged-in-Care, EICs). As expected, LTCs had higher viral loads and depression, lower CD4+ counts, more alcohol, heroin, and injection drug use in the past 30 days. A binary logistic regression with Center for Epidemiologic Studies Depression score, Beck Hopelessness score, whether drugs/alcohol had ever prevented them from taking ART, and past 30 days' alcohol use [χ(2)(4) = 64.27, p = .0.000] correctly classified 74.5% of participants as LTC or EIC, suggesting that integrated treatment for substance use, psychiatric, and HIV could reduce dropout and improve outcomes.