Novel next-generation sequencing assay for monitoring multidrug resistant tuberculosis treatment in the setting of HIV infection

项目总结/摘要 新一代测序检测用于监测耐多药结核病治疗 艾滋病毒感染的背景 耐多药结核病（MDR-TB）是一个日益恶化的全球公共卫生危机，也是 在我们有生之年消灭结核病。目前对耐多药结核病的治疗需要长期的疗程， 几十年前的、有毒的、效果不佳的二线药物。特别是在艾滋病毒合并感染的情况下， 耐多药结核病的治疗因特殊的药丸负担、重叠的药物毒性、药物不良反应、 吸收，并往往导致高早期死亡率。二线抗结核药物耐药性的程度 治疗是预后不良的一个强有力的预测因素，但这种耐药性只能通过现有的分子检测来检测 当它已经很好地建立。我们的初步研究和其他人的研究表明， M.结核分枝杆菌（M.tb）亚群可能是临床耐药性的常见前兆。检测和 监测微异源耐药性（<总结核分枝杆菌群体的5%，低于常用的 结核病分子检测）可以通过个体化治疗方案改变临床管理， 无效治疗的重新评估（即，亚治疗药物水平或不适当的方案）。巨大 财政和科学资源用于研究耐多药结核病新药，但努力 由于缺乏对疗效的理解， 多种药物治疗方案中每种药物的关系，以及如何最好地识别将产生应答的患者 不足以治疗。我们提出这项工作的目标是全面表征药理学 结核分枝杆菌微异源耐药性的相关性，并确定微异源耐药性检测的程度， 异源耐药性提高了临床医生预测耐多药结核病患者的能力，无论是否合并感染艾滋病毒， 结果不佳的可能性特别高。为了实现我们的目标，我们将利用 通过两项主要的耐多药结核病临床试验、现有的NIH/NIAID R 01奖和 一个大型国际非营利组织的协调努力，其使命是促进发展， 提供与贫穷有关的疾病的诊断测试。

PROJECT SUMMARY / ABSTRACT Novel next-generation sequencing assay for monitoring multidrug resistant tuberculosis treatment in the setting of HIV infection Multidrug resistant tuberculosis (MDR-TB) is a worsening global public health crisis and critical barrier to achieving TB elimination during our lifetimes. Current treatment of MDR-TB requires long treatment courses of decades-old, toxic, and poorly efficacious second-line drugs. In the setting of HIV co-infection, in particular, treatment of MDR-TB is complicated by extraordinary pill burden, overlapping drug toxicities, poor drug absorption, and often results in high early mortality. The extent of second-line anti-TB drug resistance during treatment is a strong predictor of poor outcome, but such resistance is only detected by existing molecular tests when it is already well-established. Evidence from our preliminary studies and others’ suggest that small resistant M. tuberculosis (M.tb) subpopulations may be common precursors to clinical resistance. Detection and monitoring of micro-heteroresistance (<5% of total M.tb population, beneath the threshold for commonly used TB molecular tests) could transform clinical management through individualized treatment regimens and prompt reassessment of ineffective treatments (i.e., sub-therapeutic drug levels or inadequate regimens). Tremendous financial and scientific resources are directed toward investigation of new drugs for MDR-TB, but efforts to optimize and shorten treatment are hindered significantly by a poor understanding of exposure-response relationships for each drug within multi-drug regimens and how to best identify those patients who will respond inadequately to treatment. Our goal in proposing this work is to comprehensively characterize the pharmacologic correlates of M.tb micro-heteroresistance, and to determine the extent to which detection of micro- heteroresistance improves clinicians’ ability to predict those MDR-TB patients, with and without HIV co-infection, who are at especially high likelihood for poor outcome. In order to achieve our Aims, we will leverage the infrastructure established through two major MDR-TB clinical trials, an existing NIH/NIAID R01 award, and the coordinated efforts of a large international non-profit organization whose mission is to enable development and delivery of diagnostic tests for poverty-related diseases.