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 本申请建议饮酒者接受结核病预防治疗(ADEPT-TB) 这项研究是乌干达艾滋病毒酒精研究合作(ARCH)艾滋病毒感染者队列的延续 乌干达的酗酒者。结核病是艾滋病毒携带者死亡的主要原因。异烟肼 (INH)预防疗法(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% 除了抗逆转录病毒治疗(ART)之外的好处。基于这些发现，世界卫生组织 世界卫生组织(WHO)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 对“经常大量饮酒”者的预防IPT，原因是担心 在肝酶没有常规监测的情况下，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治疗的安全性。因此，ADEPT-TB研究的目的是确定 以及对感染艾滋病毒的饮酒者进行结核病预防治疗的耐受性，并检查在预防结核病方面是否有好处 胜过风险。坚持结核病预防治疗会影响受益水平，并可能对 肝脏毒性。酒精使用是抗逆转录病毒药物治疗依从性降低和积极治疗结核病的既定风险因素 停药，但尚不清楚每天服用抗逆转录病毒药物的艾滋病毒感染者是否会感染结核病 预防性治疗。标准的IPT包括6-9个月的每日INH；较短的疗程，如3个月 异烟肼加利福平，可提高依从性。 ADEPT-TB研究将检查6个月每日服药的安全性、耐受性和依从性。 在乌干达，380名感染艾滋病毒的饮酒者服用异烟肼(6H)和3个月的异烟肼加利福平(3hr)。我们会 将参与者随机分成两种方案之一(每组190人)。我们的首要目标是评估其安全性和 在每种养生法中的耐受性和酒精使用水平。我们的第二个目标是比较遵守情况 方案；我们假设，与6H组相比，3hr组的粘附性更强。自我报告 酒精的生物标志物--磷脂酰乙醇(Peth)将增加酒精使用的衡量标准 使用。遵守的客观措施将包括电子药瓶监测和一种新的异烟肼措施 暴露，头发中的异烟肼浓度。我们将使用美国的护理标准积极监测肝脏毒性 用于对酗酒者进行结核病预防治疗。我们将使用安全性、耐受性和依从性结果， 连同已知的结核病预防治疗对南沙地区艾滋病毒感染者的疗效和死亡益处， 以及建立的结核病预防治疗决策分析模型来执行我们的第三个目标：确定 在资源方面，结核病预防治疗的好处是否大于对感染艾滋病毒的饮酒者的毒性风险 有限的设置。这些数据将为#年结核病预防治疗指南提供重要的见解。 在艾滋病毒和酒精使用普遍的结核病流行地区，使用酒精的艾滋病毒感染者。

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.