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

结核病是艾滋病毒感染者死亡的主要原因; 重度饮酒的艾滋病毒携带者是戒酒者和结核病治疗结果的2-3倍 更穷。结核病预防性治疗（TPT）降低了从潜伏性结核病感染（LTBI）进展为结核病的风险 在许多艾滋病毒/结核病高发病率的环境中，艾滋病毒/结核病感染者的治疗正在扩大。然而，TPT不 在TPT结束后预防新的或重复的结核感染，因此， 即使在接受TPT后，也可能增加获得新的TB感染的风险。几乎没有 一项研究调查了酒精使用对获得新的结核病感染的影响， 活动性结核病;这限制了我们理解酒精使用对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。我们建议检查感染结核病的风险 重度饮酒者在接受TPT治疗后感染和活动性结核病发生率 在艾滋病/结核病高发国家乌干达，我们的目标是为干预措施提供信息，以降低获得新结核病的风险 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，我们建议研究新结核病的发病情况， 在结核菌素皮肤试验（TST）结果为阴性的PLWH队列中， 在富含重醇使用的PLWH样品中（目标1）。我们将调整关键混杂因素，如 吸烟、二手烟、社会经济地位、家庭拥挤、性别、年龄、最低CD 4 + T细胞计数和既往接受TPT。我们还将研究酒精使用对结核病感染风险的介体， 例如缺乏HIV病毒抑制、酒吧出勤率和低体重指数，以确定是否存在 酒精干预措施应将这些作为额外目标。为了实现这一目标，我们将利用 一个大的PLWH队列，包括50%从事高风险饮酒，我们以前测试了LTBI从 2017年至2020年，TST阴性。我们将重新招募500人，并进行重复TST和活动性结核病 每年筛查一次，持续4年，以确定新的结核病感染率。我们还将确定 重度饮酒和LTBI的PLWH是否会增加进展为活动性 与风险较低或不饮酒的人相比，尽管接受了TPT治疗，仍存在结核病（目标2）。为 目标2，我们将利用我们之前接受TPT的990名LTBI PLWH队列，其中超过5000人- 年的随访和良好表征的酒精使用和TPT电子依从性测量。两个目标 将利用独特适合这些分析的队列，并使用客观的酒精生物标志物。这些研究 将提供前所未有的前瞻性证据，以有效地针对减少酒精的干预措施 并告知TPT策略-例如重复短期TPT-以预防新的结核感染并减少 高危人群PLWH进展为结核病的风险：重度饮酒者。

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.