URBAN ARCH (3/5) Uganda Cohort TB preventive therapy for HIV-infected alcohol users in Uganda: an evaluation of safety tolerability and adherence

摘要 该申请提出了酒精饮酒者暴露于结核病预防治疗（ADEPT-TB） 乌干达艾滋病毒酒精研究合作组织（UNAIDS）艾滋病毒感染者队列研究的延续 乌干达的酗酒者结核病是艾滋病毒感染者死亡的主要原因。异烟肼 (INH)预防性治疗（IPT）将艾滋病毒感染者的全因死亡率和活动性结核病降低30 - 50% 远远超出了抗逆转录病毒疗法（ART）本身的好处。根据这些发现，世界卫生组织 世卫组织建议在资源有限的情况下对所有艾滋病毒感染者进行IPT，但警告说， 由于担心肝毒性增加， 在肝酶没有常规监测的环境中酗酒者。大约四分之一的艾滋病毒- 撒哈拉以南非洲（SSA）的感染者是酗酒者，但没有研究系统地评估 酒精使用者结核病预防性治疗的安全性。因此，ADEPT-TB研究旨在确定 和耐受性的结核病预防性治疗艾滋病毒感染的饮酒者，并检查是否有利于预防结核病 超过了风险坚持结核病预防性治疗会影响获益水平， 肝毒性饮酒是降低抗逆转录病毒疗法依从性和积极结核病治疗的既定风险因素 但目前尚不清楚每天接受抗逆转录病毒治疗的艾滋病毒感染饮酒者是否会坚持结核病 预防性治疗标准IPT包括6 - 9个月的每日INH;较短疗程，如3个月 INH加利福平可提高依从性。 ADEPT-TB研究将检查6个月每日一次给药的安全性、耐受性和依从性。 INH（6H）和3个月的每日INH加利福平（3HR）在380艾滋病毒感染的饮酒者在乌干达。我们将 将参与者随机分配至两种方案之一（每组n = 190）。我们的首要目标是评估安全性， 每种治疗方案内的耐受性和酒精使用水平。我们的第二个目标是通过以下方式比较依从性： 方案;我们假设3HR组的依从性高于6H组。 磷脂酰乙醇（PEth）是一种已确定的酒精生物标志物， 使用.依从性的客观指标将包括电子药瓶监测和一种新的INH指标 暴露，毛发中INH浓度。我们将使用美国标准治疗积极监测肝毒性 为酗酒者提供结核病预防治疗。我们将使用安全性、耐受性和依从性结果， 加上撒哈拉以南非洲艾滋病毒感染者结核病预防治疗的已知疗效和死亡率效益， 建立了结核病预防治疗决策分析模型，以实现我们的第三个目标： 结核病预防性治疗的益处是否超过艾滋病毒感染者饮酒的毒性风险 有限的设置。这些数据将提供重要的见解，为结核病预防治疗指南提供信息， 在艾滋病毒和酒精使用普遍的结核病流行地区，

ABSTRACT This application proposes the Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPT-TB) study, a continuation of the Uganda Alcohol Research Collaboration on HIV (ARCH) cohort of HIV-infected alcohol users in Uganda. Tuberculosis (TB) is the leading cause of mortality in persons with HIV. Isoniazid (INH) preventive therapy (IPT) decreases all-cause mortality and active TB in persons with HIV by 30-50% above and beyond the benefits of antiretroviral therapy (ART) alone. Based on these findings, the World Health Organization (WHO) recommends IPT for all persons with HIV in resource constrained settings, but warns against IPT for persons with “regular and heavy alcohol use” due to concern for increased hepatotoxicity in heavy drinkers in settings where liver enzymes are not routinely monitored. Approximately one quarter of HIV- infected persons in sub-Saharan Africa (SSA) are heavy drinkers, but no studies have systematically assessed the safety of TB preventive therapy in alcohol users. Thus, the ADEPT-TB study aims to determine the safety and tolerability of TB preventive therapy for HIV-infected drinkers, and examine if the benefits in preventing TB outweigh the risks. Adherence to TB preventive therapy impacts the level of benefit and may also impact hepatotoxicity. Alcohol use is an established risk factor for decreased ART adherence and active TB treatment discontinuation, but it is not known whether HIV-infected drinkers on daily ART can be adherent to TB preventive therapy. Standard IPT is comprised of daily INH for 6-9 months; a shorter-course, such as 3 months of INH plus rifampicin, could improve adherence. The ADEPT-TB study will examine the safety and tolerability of, and adherence to, 6 months of daily INH (6H) and 3 months of daily INH plus rifampicin (3HR) in 380 HIV-infected drinkers in Uganda. We will randomize participants to one of the two regimens (n=190 per arm). Our first aim is to evaluate the safety and tolerability within each regimen and by level of alcohol use. Our second aim is to compare adherence by regimen; we hypothesize that adherence will be greater in the 3HR arm compared to the 6H arm. Self-reported measures of alcohol use will be augmented by phosphatidylethanol (PEth), an established biomarker of alcohol use. Objective measures of adherence will include electronic pill bottle monitoring and a novel measure of INH exposure, INH concentration in hair. We will actively monitor for hepatotoxicity using the U.S. standard of care for TB preventive therapy for heavy drinkers. We will use the safety, tolerability, and adherence results, together with the known efficacy and mortality benefit of TB preventive therapy in HIV-infected persons in SSA, and an established decision analytic model of TB preventive therapy to conduct our third aim: to determine whether the benefits of TB preventive therapy outweigh the toxicity risks for HIV-infected drinkers in resource limited settings. These data will provide critical insights to inform the guidelines for TB preventive therapy for alcohol-using, HIV-infected persons in TB endemic areas where HIV and alcohol use are common.