AIM:We evaluated whether community-level naloxone distribution, medication for opioid use disorder treatment and retention and incident high-risk opioid prescribing rates were associated with opioid overdose death rates. DESIGN:Observational cohort conducted using 2019 to 2023 community-level data as an exploratory analysis of the HEALing (Helping to End Addiction Long-term®) Communities Study (HCS). Exposures included: (1) community-level naloxone distribution, past 12-months, categorized as ≤1000 units per 100 000 population vs. 1001-3000 units per 100 000 population vs. >3000 units per 100 000 population; (2) individuals treated with buprenorphine per 100 000 adult population in the current quarter; (3) individuals retained on buprenorphine for ≥ 180 days per 100 000 adult population in the current quarter; and (4) incident high-risk opioid prescribing per 100 000 adult population in the current quarter. SETTING AND PARTICIPANTS:Population-based study of 67 communities with 8.2 million adults in Kentucky, Massachusetts, New York and Ohio, USA, with required annual opioid overdose death rates of > 25 per 100 000 adult population and at least 30% rural. Across the 67 communities participating in the HCS, the adult population was 31% 18-34 years, 31% 35-54 years, 38% 55 years and over, 52% female, 73% non-Hispanic White, 15% non-Hispanic Black and 7.4% Hispanic. MEASUREMENTS:Quarterly community-level opioid overdose death rates from 2020 through 2023. FINDINGS:The 2019 annual rates were 40.4 opioid overdose deaths, 1287 naloxone rescue units distributed, 977.7 people received buprenorphine treatment, 546.3 people retained for more than 180 days on buprenorphine and 1266.7 high-risk opioid prescribing incidents per 100 000 population. In models adjusted for state, community age, sex, race/ethnicity, rurality, HCS intervention group assignment, 2019 rates of opioid overdose death, naloxone distribution, buprenorphine and high-risk opioid prescribing, and the ratio of opioid overdose deaths involving fentanyl, an increase in 100 people treated with buprenorphine per 100 000 population was associated with a decrease of 0.92 [95% confidence interval (CI) = -1.30 to -0.55] in the quarterly opioid overdose death rate, while an increase of 100 people retained on buprenorphine for more than 180 days per 100 000 population was associated with a decrease of 1.3 (95% CI = -1.8 to -0. 76). There were no statistically significant associations between naloxone distribution or incident high-risk opioid prescribing with change in quarterly opioid overdose death rates. CONCLUSIONS:In this exploratory analysis, increases in both buprenorphine treatment and retention were statistically significantly associated with decreases in opioid overdose death rates, after adjusting for baseline rates of buprenorphine treatment and retention.

INTRODUCTION:Cigarette and opioid use are two leading causes of preventable death and disability in the United States and are often comorbid. Nicotinic partial agonists, such as varenicline and cytisine, are considered highly effective for Nicotine Use Disorder in the general population. However, their efficacy and safety in smokers who use opioids remain unclear, with concerns about reduced efficacy or increased opioid use. We evaluated the impact of nicotinic agonists compared to nicotine replacement therapy (NRT) on opioid and cigarette use. METHODS:We conducted a secondary analysis of the St PETER HIV study, a randomized, double-blinded, placebo-controlled trial of 400 HIV-positive individuals recruited from July 2017 to December 2020 at HIV care sites in St. Petersburg, Russia. Participants (daily smokers with risky alcohol use) were randomized to varenicline, cytisine, or NRT. Our analysis focused on the 97 participants who reported opioid use at baseline. Logistic regression assessed the relationship between treatment arms and our primary outcome of self-reported opioid use. Hochberg-adjusted p-values accounted for multiple comparisons. RESULTS:The 97 St. PETER HIV participants with baseline opioid use exhibited significant differences from non-opioid users: higher rates of HCV infection; lower CD4 counts; and higher alcohol consumption and smoking rate. Among this opioid use subgroup, there was no significant difference in self-reported opioid use between participants randomized to nicotinic partial agonists and those randomized to NRT at 1, 3, 6 or 12 months. CONCLUSIONS:Nicotinic partial agonists do not significantly impact opioid use outcomes compared to NRT in persons who use opioids. Clinicians should consider these options as part of a treatment approach to address nicotine use in this population.

Background:Ending the HIV epidemic requires achieving HIV viral load (HVL) suppression for key populations including those with risky drinking. Gabapentin can decrease alcohol use and thus holds potential for improving medication adherence and HIV viral load suppression for individuals with HIV and risky drinking. Methods:To describe the protocol for arandomized, double-blinded, placebo-controlled trial, (GRAIL [Gabapentin to Reduce Alcohol and Improve viral Load suppression]), to test the efficacy of gabapentin versus placebo on achieving undetectable HIV viral load among people with HIV with risky drinking. We recruit and randomize 300 people with detectable HIV viral loads (>= 200 copies/ml) and risky drinking. Participants are randomized 1:1 to receive either gabapentin (1800 mg/day target dose) or placebo for 3 months in a double blind design. Both arms receive a 5-minute evidence-based counseling session aimed at reducing alcohol use. The primary outcome is undetectable viral load (<200 copies/ml) at 3 months. Other secondary outcomes include undetectable viral load at 6 and 12 months, biomarker-confirmed recent alcohol consumption, antiretroviral therapy (ART) adherence, engagement in HIV care and pain severity. This study takes place in Mbarara, Uganda, as the country ranks among the top five for alcohol consumption globally and has 1.4 million people living with HIV. Discussion:GRAIL tests the efficacy of gabapentin, a medication to decrease alcohol use to achieve HIV viral load suppression. This trial may identify a treatment strategy to prevent the transmission of HIV and improve health outcomes among a high risk HIV population, specifically those with risky drinking. Trial registration:This trial has been registered at ClinicalTrials.gov (NCT05443555) on June 29, 2022. https://clinicaltrials.gov/study/NCT05443555?term=NCT05443555&rank=1.

BackgroundStress and financial concerns due to the COVID-19 pandemic are well documented, with mixed evidence regarding their relationship with substance use. This mixed-methods study describes the prevalence of pandemic-related stress and financial worry, and their association with changes in substance use among people with HIV with a history of injection drug use in Russia.MethodsWe conducted a secondary analysis of survey and qualitative data collected from two trials between May 2020 and July 2021. We used multivariable logistic regression to assess associations between pandemic-related stress and financial worry, and reported changes in illicit opioids (primary), cigarettes (secondary), and alcohol (exploratory) use. The outcome was defined as any change (increase, decrease, or stopping) in substance use. A thematic analysis of semi-structured interviews explored experiences of stress and substance use during the pandemic.Results and conclusionsAmong 132 survey participants, 52% reported high pandemic financial worry and 31% reported high pandemic stress. Overall, 22% reported changes in opioid use (20% decrease, 2% increase), 21% in cigarette smoking (18% decrease, 3% increase), and 15% in alcohol use (9% decrease, 6% increase). High stress was associated with reporting any change in opioid use due to the pandemic (AOR 2.98; 95%CI: 1.20, 7.40; p = 0.02). Financial worry showed a similar but imprecise association (AOR 2.45; 95%CI: 0.96, 6.21; p = 0.06). No associations were observed for cigarette or alcohol use. Qualitative findings indicated that pandemic-related stressors and disruptions in drug access may have been linked to substance use patterns for some participants, although changes in use were not a dominant theme. Most participants did not report changes in substance use; among those who did, changes were primarily decreases. Pandemic-related stress was associated with opioid use change, though direction varied. These findings suggest that stress-related responses are context-specific and may not uniformly lead to increased substance use among PWH.

Background:HIV-1 infection and hazardous levels of alcohol consumption have been independently linked to gut dysbiosis affecting beneficial butyrate-producing bacteria. However, sex-based differences in the composition and function of gut microbiome of People With HIV (PWH) with a history of heavy alcohol drinking remain undetermined, which is the focus of this study. Methods:Cross-sectional study examining structural and functional features of the gut microbiome in PWH between men and women with a history of hazardous alcohol drinking recruited at St. Petersburg, Russia. 16S rDNA sequencing information was used for metataxonomic, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2) and Linear Discriminant Analysis Effect Size (LEfSe) analyses. Group-wise comparisons were done using Mann-Whitney U-test. Further, linear and logistic regression models were used to evaluate the association between sex and measures of gut microbial dysbiosis and Firmicutes/Bacteroidota (F/B) ratio, respectively. Data were adjusted for confounding covariates particularly, HIV-viral load, Anti-retroviral Therapy (ART) and alcohol usage. Results:Metataxonomic analysis demonstrated that women depicted significantly higher microbial diversity (Operational Taxonomic Units, OTUs and Shannon Index), higher percent relative abundance (%RA) of Firmicutes, lower %RA of Bacteroidota and higher F/B ratio. Importantly, logistic regression revealed that women had twice the odds of having F/B ratio > 1. Notably, women demonstrated significantly higher %RA of butyrate-producing bacterial families, i.e., Lachnospiraceae, Oscillospiraceae, Rikenellaceae and Marinifilaceae and genera. Correspondingly, significantly greater expression of bacterial genes involved in butyrate synthesis in women was demonstrated by PICRUSt2 analysis. Additionally, women depicted lower %RA of pathobiont, Prevotellaceae particularly, Prevotella_9 genus. Conclusion:Overall, we observed significant sex-based differences in the relative abundances of beneficial bacterial communities such as butyrate producers and potential pathogenic Prevotella community in the gut microbiome of PWH with a history of heavy alcohol consumption. The observed sex-based differences are clinically relevant and could inform therapeutic strategies with evidence-based probiotics.

Background: Cigarette smoking has been associated with liver fibrosis in the setting of hepatitis C virus (HCV) infection but has not been studied among people with HIV (PWH) who consume alcohol. Methods: This is a cross-sectional study of PWH with heavy drinking and daily smoking in St. Petersburg, Russia. The primary independent variable was past 30-day cigarettes per day (cpd), and the secondary independent variable was pack-years at study entry. Advanced liver fibrosis was defined as FIB-4 > 3.25. Analyses were adjusted for gender, body mass index (BMI), past 30-day number of heavy drinking days, HCV and CD4 count. Results: Participants (n = 400) were two-thirds male (67.3%), young (median age 38 years), lean (median BMI 22), HCV antibody positive (84.5%) and not severely immune suppressed (median CD4 count 351). The median number of past-month cpd was 20 (IQR: 15–25), and the median pack-years was 24 (IQR: 17–31.8). The prevalence of advanced liver fibrosis was 11.3% (45/400). In the adjusted logistic regression analyses, we did not observe a significant association between cpd [middle (10.1–20 cigarettes) vs. lowest (5–10 cigarettes) category (adjusted odds ratio [aOR] (95% confidence interval [CI]): 1.06 (0.40–2.83), highest (>20.0 cigarettes) vs. lowest category aOR (95% CI): 0.65 (0.21–1.99), global p-value = 0.62]. The secondary analysis with pack-years yielded similar results [middle (20.1–30 pack-years) vs. lowest category (≤20 pack-years) aOR (95% CI): 0.81 (0.33–1.99), highest category (>30 pack-years) vs. lowest category aOR (95% CI): 0.91 (0.38–2.19); global p-value = 0.58]. Conclusions: In this Russian cohort of PWH, we did not detect an association between recent cigarette use or mean pack-years and advanced liver fibrosis.

Importance:Alcohol use disorder (AUD) is common in hospital patients. AUD medications are not typically initiated in that setting. The comparative effectiveness between initiation of oral naltrexone and extended-release injectable naltrexone in the hospital is not known. Objective:To compare the effectiveness of initiating oral naltrexone vs extended-release injectable naltrexone on reduction in alcohol use and health care utilization among medical inpatients with AUD. Design, Setting, and Participants:The Alcohol Disorder Hospital Treatment (ADOPT) study is a randomized clinical trial conducted at an urban teaching hospital in the US, with enrollment between June 2016 and March 2020. Inpatients were screened for eligibility, and those with AUD and recent heavy drinking (defined as 5 or more drinks for men and 4 or more drinks for women) were enrolled. Outcomes were assessed at 3-month follow-up; assessors were not blinded to treatment assignment. Data were analyzed from May 2021 to September 2023. Interventions:Participants received either daily oral naltrexone or monthly extended-release injectable naltrexone. All received medical management with a research nurse who specialized in addiction. Main Measures and Outcomes:The primary outcome was change in percentage of heavy drinking days (HDDs) over the past 30 days from baseline to 3-month follow-up, assessed by validated instrument. The secondary outcome was any acute health care utilization (emergency department or hospitalization) at 3-month follow-up over the past 90 days. Results:Of 248 participants, 199 (80.2%) were male, and the mean (SD) age was 49.4 (10.4) years. The baseline median (IQR) percentage of HDDs in the past 30 days was 80.0% (43.3-100). At 3-month follow-up, the mean percentage of HDDs in the past 30 days was reduced in both groups (oral naltrexone: baseline, 66.7% HDDs; 3-month follow-up, 27.4% HDDs; difference, -38.4 percentage points; 95% CI, -125.0 to 48.2; extended-release injectable naltrexone: baseline, 70.7% HDDs; 3-month follow-up, 23.8% HDDs; difference, -46.4 percentage points; 95% CI, -123.4 to 30.6; P = .14). At follow-up, 59 of 109 in the oral naltrexone arm (54.1%) and 66 of 108 in the extended-release injectable naltrexone arm (61.1%) reported acute health care utilization in the prior 3 months; the odds of this utilization were not significantly different between groups (adjusted odds ratio, 1.34; 95% CI, 0.77-2.33). Conclusions and Relevance:In this randomized clinical trial, when initiated at hospital discharge, oral and extended-release injectable naltrexone did not differ in effectiveness. Participants had substantial reductions in HDDs in both treatment groups; however, there was not a significant difference in the reduction of percentage of HDDs in the past 30 days or acute health care utilization between groups. Hospitalization represents an opportunity to start AUD pharmacotherapy; choice of oral naltrexone vs extended-release injectable naltrexone should be directed by factors such as patient preference and insurance. Trial Registration:ClinicalTrials.gov Identifier: NCT02478489.

Medications for opioid use disorder (MOUD) can reduce opioid use and overdose deaths. This study examined whether the Communities That HEAL (CTH) intervention increased MOUD initiation, retention, and linkage. The HEALing Communities Study was a multi-site, 2-arm, parallel, community-level, cluster-randomized, unblinded, wait-list controlled trial conducted in 67 communities (n = 34 intervention, n = 33 control). Using Prescription Drug Monitoring Programs and Medicaid claims data, we compared mean community-level rates of MOUD outcomes during the 1-year comparison period (July 2021-June 2022) for: (a) MOUD receipt at least once; (b) continuous MOUD receipt for 180 days; and (c) MOUD linkage within 31 days following an opioid-related emergency department or hospital encounter. For intervention and control communities, adjusted rates of receiving MOUD at least once were 578 (95 % CI: 562, 594) and 596 (95 % CI: 572, 621) per 1000 Medicaid enrollees, respectively [adjusted Relative Rate (aRR)= 0.97 (95 % CI: 0.93, 1.01)]. Adjusted rates of receiving MOUD for 180 consecutive days (retention) were 614 (95 % CI: 595, 634) and 620 (95 % CI: 603, 638) per 1000 Medicaid enrollees receiving MOUD at least once for intervention and control communities, respectively [aRR= 0.99 (95 % CI: 0.95, 1.04)]. The adjusted rate of linkage was 280 (95 % CI: 254, 310) and 252 (95 % CI: 226, 281) per 1000 encounters for intervention and control communities, respectively [aRR= 1.11 (95 % CI: 0.96, 1.28). Compared to control communities, communities that received the CTH intervention did not demonstrate higher rates of MOUD use, retention, or linkage. Additional efforts are needed to improve uptake and sustained use of MOUD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04111939.

ImportanceBuprenorphine significantly reduces opioid-related overdose mortality. From 2002 to 2022, the Drug Addiction Treatment Act of 2000 (DATA 2000) required qualified practitioners to receive a waiver from the Drug Enforcement Agency to prescribe buprenorphine for treatment of opioid use disorder. During this period, waiver uptake among practitioners was modest; subsequent changes need to be examined.ObjectiveTo determine whether the Communities That HEAL (CTH) intervention increased the rate of practitioners with DATA 2000 waivers and buprenorphine prescribing.Design, Setting, and ParticipantsThis prespecified secondary analysis of the HEALing Communities Study, a multisite, 2-arm, parallel, community-level, cluster randomized, open, wait-list–controlled comparison clinical trial was designed to assess the effectiveness of the CTH intervention and was conducted between January 1, 2020, to December 31, 2023, in 67 communities in Kentucky, Massachusetts, New York, and Ohio, accounting for approximately 8.2 million adults. The participants in this trial were communities consisting of counties (n = 48) and municipalities (n = 19). Trial arm randomization was conducted using a covariate constrained randomization procedure stratified by state. Each state was balanced by community characteristics including urban/rural classification, fatal opioid overdose rate, and community population. Thirty-four communities were randomized to the intervention and 33 to wait-list control arms. Data analysis was conducted between March 20 and September 29, 2023, with a focus on the comparison period from July 1, 2021, to June 30, 2022. Data analysis was re-run on June 6, 2024, using a revised set of data that was locked on May 31, 2024.InterventionWaiver trainings and other educational trainings were offered or supported by the HEALing Communities Study research sites in each state to help build practitioner capacity.Main Outcomes and MeasuresThe rate of practitioners with a DATA 2000 waiver (overall, and stratified by 30-, 100-, and 275-patient limits) per 100 000 adult residents aged 18 years or older during July 1, 2021, to June 30, 2022, were compared between the intervention and wait-list control communities. The rate of buprenorphine prescribing among those waivered practitioners was also compared between the intervention and wait-list control communities. Intention-to-treat and per-protocol analyses were performed.ResultsA total of 8 211 506 individuals aged 18 years or older were residents of the 67 communities studied. There was no evidence of an effect of the CTH intervention on the adjusted rate of practitioners with a DATA 2000 waiver (adjusted relative rate [ARR], 1.04; 95% CI, 0.94-1.14) or the adjusted rate of practitioners with a DATA 2000 waiver who actively prescribed buprenorphine (ARR, 1.00; 95% CI, 0.91-1.10).Conclusions and RelevanceIn this randomized clinical trial, the CTH intervention was not associated with increases in the rate of practitioners with a DATA 2000 waiver or buprenorphine prescribing among those waivered practitioners. Supporting practitioners to prescribe buprenorphine remains a critical yet challenging step in the continuum of care to treat opioid use disorder.Trial RegistrationClinicalTrials.gov Identifier: NCT04111939

IMPORTANCE Buprenorphine significantly reduces opioid-related overdose mortality. From 2002 to 2022, the Drug Addiction Treatment Act of 2000 (DATA 2000) required qualified practitioners to receive a waiver from the Drug Enforcement Agency to prescribe buprenorphine for treatment of opioid use disorder. During this period, waiver uptake among practitioners was modest; subsequent changes need to be examined. OBJECTIVE To determine whether the Communities That HEAL (CTH) intervention increased the rate of practitioners with DATA 2000 waivers and buprenorphine prescribing. DESIGN, SETTING, AND PARTICIPANTS This prespecified secondary analysis of the HEALing Communities Study, a multisite, 2-arm, parallel, community-level, cluster randomized, open, wait-list-controlled comparison clinical trial was designed to assess the effectiveness of the CTH intervention and was conducted between January 1, 2020, to December 31, 2023, in 67 communities in Kentucky, Massachusetts, New York, and Ohio, accounting for approximately 8.2 million adults. The participants in this trial were communities consisting of counties (n = 48) and municipalities (n = 19). Trial arm randomization was conducted using a covariate constrained randomization procedure stratified by state. Each state was balanced by community characteristics including urban/rural classification, fatal opioid overdose rate, and community population. Thirty-four communities were randomized to the intervention and 33 to wait-list control arms. Data analysis was conducted between March 20 and September 29, 2023, with a focus on the comparison period from July 1, 2021, to June 30, 2022. INTERVENTION Waiver trainings and other educational trainings were offered or supported by the HEALing Communities Study research sites in each state to help build practitioner capacity. MAIN OUTCOMES AND MEASURES The rate of practitioners with a DATA 2000 waiver (overall, and stratified by 30-, 100-, and 275-patient limits) per 100 000 adult residents aged 18 years or older during July 1, 2021, to June 30, 2022, were compared between the intervention and wait-list control communities. The rate of buprenorphine prescribing among those waivered practitioners was also compared between the intervention and wait-list control communities. Intention-to-treat and per-protocol analyses were performed. RESULTS A total of 8 166 963 individuals aged 18 years or older were residents of the 67 communities studied. There was no evidence of an effect of the CTH intervention on the adjusted rate of practitioners with a DATA 2000 waiver (adjusted relative rate [ARR], 1.04; 95% CI, 0.94-1.14) or the adjusted rate of practitioners with a DATA 2000 waiver who actively prescribed buprenorphine (ARR, 0.97; 95% CI, 0.86-1.10). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, the CTH intervention was not associated with increases in the rate of practitioners with a DATA 2000 waiver or buprenorphine prescribing among those waivered practitioners. Supporting practitioners to prescribe buprenorphine remains a critical yet challenging step in the continuum of care to treat opioid use disorder.

BACKGROUND Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P=0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic.

BackgroundTo estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain.MethodsWe conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks.ResultsParticipants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively. Pain interference decreased for all three arms. Mean differences in change in pain interference for gabapentin vs. placebo, and naltrexone vs. placebo was 0.16 (95% CI -1.38, 1.71; p = 0.83) and 0.40 (95% CI -1.18, 1.99; p = 0.83), respectively.ConclusionNeither gabapentin nor low-dose naltrexone appeared to improve pain more than placebo among PWH with chronic pain and past-year heavy alcohol use.Clinical trial registrationClinicalTrials.gov (NCT4052139).

Objectives. To determine whether the Communities That HEAL (CTH) intervention is effective in increasing naloxone distribution compared with usual care. Methods. The HEALing (Helping to End Addiction Long-Term) Communities Study (HCS) is a cluster-randomized, parallel-arm, wait-list controlled implementation science trial testing the impact of the CTH intervention on increasing the use of evidence-based practices to lower opioid-related overdose deaths. Communities (n = 67) highly impacted by opioid overdose in Kentucky, Massachusetts, New York, and Ohio were allocated to CTH intervention (n = 34) or wait-list comparison (usual care; n = 33) arms. The primary outcome for this study was the number of naloxone units distributed in HCS communities during the comparison period (July 1, 2021‒June 30, 2022), examined using an intent-to-treat negative binomial regression model. Results. Naloxone distribution was 79% higher in the CTH intervention versus usual care arm (adjusted relative rate = 1.79; 95% confidence interval = 1.28, 2.51; P = .001; adjusted rates of naloxone distribution 3378 vs 1884 naloxone units per 100 000 residents), when controlling for urban‒rural status, state, baseline opioid-related overdose death rate, and baseline naloxone distribution rate. Conclusions. The CTH intervention increased naloxone distribution compared with usual care in communities highly impacted by the opioid crisis. Trial Registration. ClinicalTrials.gov identifier: NCT04111939. (Am J Public Health. 2025;115(1):83-94. https://doi.org/10.2105/AJPH.2024.307845).

Introduction: Alcohol intake contributes to the pathogenesis of alcohol-related liver disease in part through the propagation of reactive oxygen species. Eight-isoprostane, a stable by-product of lipid-peroxides, is a measure of in vivo oxidative stress. Several markers of oxidative stress are elevated in people with HIV (PWH) who consume alcohol compared to their HIV-negative counterparts who also drink. However, the link between the amount of alcohol consumption and oxidative stress remains largely unknown in this population. Methods: Between 2017-2019, the Studying Partial-agonists for Ethanol and Tobacco Elimination in Russians with HIV (St PETER HIV) study collected data from 400 PWH aged 18-70 years in St. Petersburg, Russia who endorsed ≥5 heavy drinking days in the past 30 days. Participants were invited to engage in 5 in-person assessments and blood draw visits over 12 months. Linear mixed effect models were used to estimate the association between total grams of alcohol consumed within 30 days and 8-isoprostane levels at baseline and 3 months. Secondary analyses were conducted with phosphatidyl ethanol (PEth) dichotomized as positive or negative. Each analysis was adjusted for age, sex, body mass index (BMI), CD4 count, log transformed HIV viral load, diabetes, smoking, illicit drug use, history of hepatitis C infection, FIB-4, and renal dysfunction. Results: The final sample included 399 individuals, among whom the mean total grams of alcohol consumed within 30 days was 1019.0g ± 830.0g (mean ± standard deviation) and 68% had a positive PEth (124 ng/ml ± 250 ng/ml). The mean 8-isoprostane concentration (pg/ml) was 26 pg/ml ± 15.0 pg/ml. The primary adjusted analysis showed that a 1kg increase in total grams of alcohol was associated with a 5% increase in 8-isoprostane levels; however, the association was of borderline statistical significance (Ratio of means 1.05; confidence limits (CL) 1.00, 1.10; P=0.057). Secondary analyses found positive PEth was associated with higher 8-isoprostane levels (Ratio of means 1.13; 95% CL 1.04, 1.22; P=0.003). Conclusion: Among this sample of PWH, we did not observe a clear relationship between self-reported total grams of alcohol consumed within the last 30 days and oxidative stress. Testing positive for PEth however was associated with a measure of oxirectly correlated with 8-isoprostane levels and whether reducing or eliminating alcohol use correlates with lower oxidative stress.