Trial of Metformin for TB/HIV Host-directed Therapy

项目总结 结核病(TB)仍然是感染死亡的主要原因，这是因为遵守多种疾病的挑战 持续6个月或更长时间的药物疗法和脆弱人群，包括艾滋病毒携带者。 结核病的缩短治疗试验一直令人失望。跨越这一障碍的人可能会令人兴奋 内源性宿主防御途径加速了对抗生素的反应。抗糖尿病药物二甲双胍 是一种候选的宿主导向治疗(HDT)制剂，基于其对AMP激酶的激活，诱导 巨噬细胞的自噬和结核分枝杆菌抗原特异性CD8+中心的扩增 记忆T(CM)细胞。小鼠和豚鼠的临床前数据，以及7个 对糖尿病结核病患者的研究支持二甲双胍的HDT潜力。我们计划在结核病/艾滋病毒中测试这一点 合并感染的患者，因为他们有更高的风险延迟痰清除，在治疗过程中死亡 和肺结核后的肺功能损害。通过扩增CD8+T细胞，二甲双胍对 HIV合并感染的患者，有基础预测二甲双胍将直接对HDT具有抗病毒活性 爱滋病毒。我们计划一项随机、安慰剂对照试验，在标准的肺病治疗基础上加用二甲双胍。 结核病和艾滋病毒。这项2A期试验的主要目标是测试导致胃肠道疾病的二甲双胍 (GI)症状，在这一脆弱人群中是可耐受和安全的。主要终点为3级或更高级别的GI 二甲双胍治疗3个月和停药4周期间的不良事件。我们 预计轻微的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与痰转阴次级终点的HDT疗效和 呼吸健康。二甲双胍的抗HIV效果将通过病毒载量的探索性终点进行测试， CD4+T细胞计数与免疫重建炎症综合征的发生。生物样本 这项试验将被用来解决关于HDT疗效机制的基本问题，包括 对有害炎症的调节和CD8+中医细胞的增殖。如果该方法试验 证明二甲双胍在同时治疗结核病和艾滋病毒的患者中是安全的，如果HDT的疗效是 支持，这将为多中心第三阶段试验提供证据基础，并最终为 结核病治疗的范式转变。

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.