Trial of Metformin for TB/HIV Host-directed Therapy

项目摘要 结核病（TB）仍然是感染导致死亡的主要原因，这是由于遵守多方面的挑战。 持续6个月或更长时间的药物治疗方案和包括艾滋病毒感染者在内的脆弱人群。 结核病治疗缩短试验令人失望。一个能克服这个障碍的人可能是令人兴奋的 内源性宿主防御途径，以加速对抗生素的反应。抗糖尿病药物二甲双胍 是TB的候选宿主导向治疗（HDT）剂，其基于其AMP激酶的活化、 巨噬细胞中的自噬，以及结核分枝杆菌抗原特异性CD8+中心 记忆T（CM）细胞。小鼠和豚鼠的临床前数据，以及来自7只 糖尿病TB患者的研究支持二甲双胍的HDT潜力。我们计划在结核病和艾滋病中进行测试 合并感染的患者，因为他们在治疗期间延迟痰清除，死亡的风险增加 和肺结核后的肺损伤。通过扩增CD8+ T细胞，二甲双胍可能在以下方面特别有效： HIV合并感染者，有依据预测二甲双胍将对HIV合并感染者具有直接HDT活性。 艾滋病。我们计划进行一项随机、安慰剂对照试验，在肺结核标准治疗基础上加用二甲双胍。 结核病和艾滋病。这项2A期试验的主要目的是测试二甲双胍是否能引起胃肠道疾病， (GI)症状，在这个脆弱的人群中是可以忍受和安全的。主要终点为3级或更高GI 二甲双胍治疗3个月期间加二甲双胍停药后4周内的不良事件。我们 预计轻度胃肠道症状将是常见的，但需要停药的严重症状将是罕见的。 该试验还将测试二甲双胍的HDT疗效，次要终点为痰菌阴转， 呼吸道健康二甲双胍的抗HIV疗效将通过病毒载量的探索性终点进行检验， CD4+ T细胞计数与免疫重建炎症综合征的发生。生物样品 将用于解决有关HDT疗效机制的基本问题，包括 调节有害炎症和扩增CD8+ TCM细胞。如果METHOD试验 表明二甲双胍在同时接受TB和HIV治疗的患者中是安全的，如果HDT疗效 支持，这将为多中心III期试验提供证据基础，并最终为 结核病治疗模式的转变。

PROJECT SUMMARY 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 people living with HIV. Treatment shortening trials for TB have been disappointing. One to get past this obstacle could be stimulating endogenous host defense pathways to accelerate the response to antibiotics. The anti-diabetic drug metformin is a candidate host-directed therapy (HDT) agent for TB based on its activation of AMP kinase, induction of autophagy in macrophages, and expansion of Mycobacterium tuberculosis antigen-specific CD8+ central memory T(CM) cells. Preclinical data in mice and guinea pigs, and retrospective clinical data from seven studies of diabetic TB patients support the HDT potential of metformin. We plan to test this in TB/HIV coinfected patients because they are at increased risk for delayed sputum clearance, death during treatment and pulmonary impairment after TB. By expanding CD8+ T cells, metformin could be particularly effective in HIV coinfected individuals and there is a basis to predict that metformin will have direct HDT activity against HIV. We plan a randomized, placebo-controlled trail of metformin added to standard treatment of pulmonary TB and HIV. The primary goal of this phase 2A trial to test whether metformin, which causes gastrointestinal (GI) symptoms, is tolerable and safe in this vulnerable population. The primary endpoint is grade 3 or higher GI adverse events in the 3-month period of metformin treatment plus 4 weeks after stopping metformin. We expect that mild GI symptoms will be common but that severe symptoms requiring discontinuation will be rare. The trial will also test the HDT efficacy of metformin with secondary endpoints of sputum conversion and respiratory health. The anti-HIV efficacy of metformin will be tested with exploratory endpoints of viral load, CD4+ T cell count and the occurrence of immune reconstitution inflammatory syndrome. Biological samples from this trial will be used to address fundamental questions about the mechanisms of HDT efficacy including the modulation of harmful inflammation and the expansion of CD8+ TCM cells. If the METHOD trial demonstrates that metformin is safe in patients treated concurrently for TB and HIV, and if HDT efficacy is supported, this would provide a basis in evidence for a multi-center phase 3 trial and ultimately inform a paradigm shift in the treatment of TB.