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

项目摘要/摘要 监测耐多药结核病治疗的新一代测序方法 艾滋病病毒感染的背景 耐多药结核病(MDR-TB)是日益恶化的全球公共卫生危机，也是 在我们的有生之年实现消除结核病。目前耐多药结核病的治疗需要较长的疗程 几十年前的二线药物，有毒且效果不佳。特别是在艾滋病毒合并感染的背景下， 耐多药结核病的治疗复杂于超乎寻常的药物负担、重叠的药物毒性、劣质药物 而且往往会导致较高的早期死亡率。二线抗结核药物耐药的程度 治疗是不良结果的有力预测因素，但这种耐药性只能通过现有的分子测试来检测到。 当它已经根深蒂固的时候。来自我们的初步研究和其他人的证据表明，小抗性 结核分枝杆菌(M.tb)亚群可能是临床耐药的常见前驱。检测和 监测微异质电阻(占总结核分枝杆菌种群的5%，低于常用的阈值 结核病分子检测)可以通过个体化治疗方案和提示改变临床管理 重新评估无效的治疗方法(即，次治疗性药物水平或不充分的方案)。巨大的 财政和科学资源被用于研究治疗耐多药结核病的新药，但努力 由于对暴露反应的了解不足，优化和缩短治疗受到严重阻碍 多种药物方案中每种药物的关系，以及如何最好地识别那些将有反应的患者 治疗不充分。我们提出这项工作的目的是为了全面描述 结核分枝杆菌微异质电阻的相关性，并确定微结核分枝杆菌的检测程度 异质性耐药提高了临床医生预测合并和不合并艾滋病毒感染的耐多药结核病患者的能力， 他们有特别高的可能会出现糟糕的结果。为了达到我们的目标，我们将利用 通过两项主要的耐多药结核病临床试验建立的基础设施，现有的NIH/NIAID R01奖，以及 一个大型国际非营利组织的协调努力，其使命是促进发展和 提供与贫困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.