Planning for the Metformin for TB/HIV Host-directed Therapy (METHOD) Trial

 描述(由申请人提供)：结核病(TB)仍然是感染死亡的主要原因，原因是持续6个月或更长时间的多种药物方案的遵守面临挑战，以及包括合并感染艾滋病毒的患者在内的脆弱人群。结核病的缩短治疗试验一直令人失望。克服这一障碍的一种方法可能是刺激内源性防御途径，以加速和增强对抗生素的反应。抗糖尿病药物二甲双胍(MET)是一种候选的宿主导向治疗(HDT)药物，其基础是激活AMP激酶并诱导巨噬细胞自噬。我们在小鼠结核病模型中的临床前数据和对糖尿病结核病患者的现有数据的分析确立了MET的HDT潜力。值得注意的是，我们发现MET扩大了结核分枝杆菌抗原特异的CD8+T细胞，这可能对艾滋病中的结核病有特别的好处。我们计划在结核病/HIV合并感染患者中进行一项临床试验，以验证这样的假设：在标准的直接观察治疗的基础上，短程(DOTS)抗生素治疗增加了2个月后痰培养阴性患者的比例。为了验证这一假设，结核病/艾滋病毒患者将在结核病治疗期间随机服用MET或在DOTS中加入安慰剂。发现MET对2个月的痰转阴有显著影响，将证明其有潜力提高缩短结核病治疗方案的疗效。用于结核病/艾滋病毒宿主导向治疗(方法)的二甲双胍试验还将测试辅助性MET对结核病结局(治愈、失败、死亡、缺省)、放射学严重程度、肺功能以及艾滋病毒病毒载量和免疫重建炎症综合症的比率的影响。在艾滋病毒合并感染患者中进行这项HDT试验的重点是最需要更好的结核病治疗方法的人群，并提供了一种预测所有结核病患者受益的严格测试。这项试验的患者样本也将被用来解决关于HDT疗效机制的基本问题，这些机制可能包括控制有害的炎症和CD8+效应T细胞的扩张，此外还加强病变的消毒。这项研究的一个长期目标是确定具有成本效益的治疗反应生物标记物，这些标记物可在未来的HDT试验中使用，并可能在临床实践中作为最佳结核病治疗的指南针。在当前应用程序中 我们寻求R34的资金，以支持为方法试验准备令人信服的UO1申请所需的所有任务。这一临床试验开发阶段将涉及来自所有三个参与机构的未来方法试验研究人员的合作努力，并将使我们在

 DESCRIPTION (provided by applicant): Tuberculosis (TB) remains a leading cause of death from infection due to challenges of compliance with multi- drug regimens lasting 6 months or longer and vulnerable populations including patients coinfected with HIV. Treatment shortening trials for TB have been disappointing. One way past this obstacle could be stimulating endogenous defense pathways to accelerate and enhance the response to antibiotics. The anti-diabetic drug metformin (MET) is a candidate host-directed therapy (HDT) agent for TB based on its activation of AMP kinase and induction of autophagy in macrophages. Our preclinical data in the mouse TB model and analysis of existing data on diabetic TB patients establish the HDT potential of MET. Notably, we found that MET expands M. tuberculosis antigen-specific CD8+ T cells that may have particular benefit for TB in AIDS. We plan a clinical trial in TB/HIV coinfecte patients to test the hypothesis that adding MET to standard directly observed treatment, short course (DOTS) antibiotic therapy increase the proportion of patients with a negative sputum culture at 2 months. To test this hypothesis, TB/HIV patients will be randomized to MET or placebo added to DOTS for the duration of TB treatment. Finding a significant effect of MET on month-2 sputum conversion would demonstrate its potential to enhance the efficacy of shortened TB treatment regimens. The Metformin for TB/HIV Host-directed Therapy (METHOD) trial will also test the effects of adjunctive MET on TB outcomes (cure, failure, death, default), radiographic severity, lung function as well as HIV viral load and the rate of immune reconstitution inflammatory syndrome. Conducting this HDT trial in HIV-coinfected patients focuses on the population in greatest need of a better approach to TB treatment and provides a rigorous test that would predict benefit for all patients with TB. Patient samples from this trial ill also be used to address fundamental questions about the mechanisms of HDT efficacy that may include control of harmful inflammation and expansion of CD8+ effector T cells in addition to the enhancement of lesion sterilization. A long range goal of this study component is to identify cost-effective biomarkers of treatment response that could be used in future HDT trials and potentially in clinical practice as guideposts for optimal TB treatment. In the current application we seek R34 funding to support all of the tasks needed to prepare a compelling UO1 application for the METHOD trial. This clinical trial development phase will involve the collaborative effort o future METHOD trial investigators from all three participating institutions and will position us fo the