The Role of Alcohol Use in Incident TB Infection and Active TB Disease Among Persons Living with HIV

结核病(TB)是艾滋病毒携带者(PLWH)的主要死亡原因；#年结核病发病率 大量饮酒的PLWH是戒酒者和结核病治疗结果的2-3倍 变得更穷。结核病预防治疗(TPT)降低了从潜伏性结核病感染(LTBI)发展为结核病的风险 在许多艾滋病毒/结核病发病率较高的环境中，该病正在扩大到PLWH的范围。然而，TPT并非如此 在TPT结束后防止新的或重复的结核病感染，因此PLWH从事大量饮酒 即使在接受TPT后，感染新结核病的风险也可能增加。几乎没有什么 从进展到研究酒精使用对新的结核病感染的影响 活动性结核病；这限制了我们理解饮酒在结核病不同阶段的作用的能力 优化最适合每个人的干预策略。我们建议研究感染结核病的风险。 PLWH接受TPT治疗后重度饮酒人群感染情况及活动性肺结核发病情况 在乌干达，这是一个艾滋病毒/结核病高的国家。我们的目标是告知干预措施，以降低感染新结核病的风险 感染，包括减少饮酒的行为干预，以及TPT策略，如 重复短程TPT以预防活动性结核病。首先，我们建议研究感染新结核病的情况。 在既往结核菌素皮肤试验(TST)阴性的PLWH队列中，按酒精使用水平进行感染， 在因大量饮酒而浓缩的PLWH样本中(目标1)。我们将针对关键混杂因素进行调整，例如 吸烟、二手烟、社会经济地位、家庭拥挤、性别、年龄、最低CD4+ T细胞计数和之前的TPT接收。我们还将研究酒精使用对结核病感染风险的中介作用， 例如缺乏艾滋病毒病毒抑制，酒吧出勤，以及低体重指数，以确定是否存在 酒精干预应将这些作为额外的目标。为了实现这一目标，我们将利用 大量PLWH人群，包括50%从事高风险饮酒的人群，我们之前从 2017至2020年间，TST阴性者。我们将重新招募500人，并进行重复的TST和活动性结核病 每年筛查，超过4年，以确定获得新的结核病感染的比率。我们还将确定 酗酒和LTBI的PLWH患者进展为活动期的风险是否增加 尽管接受了TPT，但与风险较低或不饮酒的人相比，结核病的风险较低(目标2)。为 目标2，我们将利用我们之前990名PLWH和LTBI接受TPT的队列，以及超过5000人- 多年的跟踪和良好的酒精使用和TPT电子依从性测量。这两个目标 将利用专门适合这些分析的队列，并使用客观的酒精生物标记物。这些研究 将提供有效针对戒酒干预措施所需的史无前例的前瞻性证据 并告知TPT战略--如重复短程TPT--以预防新的结核病感染和减少 PLWH的高危人群：酗酒者发展为结核病的风险。

Tuberculosis (TB) is the leading cause of death among persons living with HIV (PLWH); TB disease rates for PLWH engaging in heavy alcohol use are 2-3 times those of alcohol abstainers and TB treatment outcomes are poorer. TB preventive therapy (TPT) reduces the risk of progression from latent TB infection (LTBI) to TB disease, and is being scaled up for PLWH in many high HIV/TB incidence settings. However, TPT does not prevent new or repeat TB infection after TPT has ended, therefore PLWH who engage in heavy alcohol use may be at increased risk for acquiring new TB infection even after receiving TPT. There has been little research examining the impact of alcohol use on acquiring new TB infection separately from progressing to active TB disease; this limits our ability to understand the role of alcohol use on the separate phases of TB to optimize intervention strategies most appropriate for each. We propose to examine the risk of acquiring TB infection and of incident active TB disease among PLWH with heavy alcohol use after receipt of TPT in PLWH in Uganda, a high HIV/TB country. Our goal is to inform interventions to reduce the risk for acquiring new TB infection in this group, including behavioral interventions to reduce alcohol use, and TPT strategies, such as repeat short-course TPT to prevent active TB disease. First, we propose to examine the acquisition of new TB infection by level of alcohol use among a cohort of PLWH with prior negative tuberculin skin test (TST) results, in a sample of PLWH enriched for heavy alcohol use (Aim 1). We will adjust for key confounders such as cigarette smoking, second-hand smoke, socio-economic status, household crowding, gender, age, nadir CD4+ T cell count, and prior TPT receipt. We will also examine the mediators of alcohol use on risk of TB infection, such as lack of HIV viral suppression, bar attendance, and low body mass index, to determine if existing alcohol interventions should incorporate these as additional targets. To accomplish this aim, we will leverage a large cohort of PLWH including 50% engaging in high-risk drinking, that we previously tested for LTBI from 2017 to 2020 who were TST negative. We will re-enroll 500 persons and conduct repeat TST and active TB screening yearly, over 4 years, to determine the rate of acquiring new TB infection. We will also determine whether PLWH who engage in heavy alcohol use and have LTBI are at increased risk of progressing to active TB disease, despite receipt of TPT, compared to persons engaging in lower risk or no alcohol use (Aim 2). For Aim 2, we will leverage our prior cohort of 990 PLWH with LTBI who received TPT, with over 5000 person- years of follow-up and well-characterized alcohol use and TPT electronic adherence measurement. Both aims will leverage cohorts uniquely suited for these analyses and use objective alcohol biomarkers. These studies will provide unprecedented prospective evidence needed to effectively target alcohol reduction interventions and inform TPT strategies—such as repeated short courses of TPT—to prevent new TB infection and reduce the risk of progression to TB disease for a high-risk group of PLWH: those engaging in heavy alcohol use.