Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PREEMPT)

摘要 结核病是导致全球死亡的主要原因之一。世界上近三分之一的人口是 感染结核分枝杆菌，估计每年新增结核病病例1040万例，其中140万例 人们死于这种疾病。艾滋病毒大流行和结核病/艾滋病毒混合感染加剧了结核病发病率的上升， 和复杂的结核病管理和控制。多药耐药(MDR)的出现和广泛 耐药结核病(XDR)加剧了对公共卫生的威胁，并重新产生了紧迫感 来控制这种疾病。耐多药结核病的治疗导致6%-20%的人出现额外的耐药性 正在接受治疗的病人。我们建议调查分枝杆菌耐药性出现的原因。 一项观察性队列研究--耐药结核病患者耐药评估的预测因素 治疗(先发制人)研究。这项建议利用了印度和印度现有的两项结核病队列研究 巴西(结核病区域前瞻性观察研究：印度报告和巴西报告)， 分别由NIAID和印度政府和巴西政府共同出资。 在Preempt研究中，我们将在印度和巴西招募400名耐多药结核病患者，为期24个月 并前瞻性地跟踪它们3年。该建议有以下具体目标： 目的1：确定低血清抗分枝杆菌药物浓度是否与 耐多药结核病患者耐药性的出现以及HIV血清阳性是否是危险因素 对于低血清药物浓度和/或出现耐药性。 目的2：确定增加的DNA突变的贡献(由先天的 结核分枝杆菌菌株的特性或通过FQ治疗)对临床出现耐药性的影响 病人被隔离。 目的3：确定是否可以及早发现导致耐药的突变 在治疗期间，在可能采取干预措施预防广泛耐药结核病的情况下。 这项建议建立在现有结核病研究框架的基础上，以研究结核病出现的机制 耐多药结核病治疗过程中的耐药性。类似的机制很可能会解释 对药物敏感的结核病治疗过程中的耐药性。所提出的每一种涌现机制 我们将调查的耐药性对新的方案设计，新的药物管理有直接的影响 可防止出现耐药性的算法和新的药物敏感性监测战略 感染和不感染艾滋病毒的结核病患者。

Abstract Tuberculosis (TB) is a leading causes of global mortality. Nearly one-third of the world's population is infected with M. tuberculosis, an estimated 10.4 million new cases of TB develop annually, and 1.4 million persons die from the disease. The HIV pandemic and TB/HIV co-infection have fueled escalating TB incidence, and complicated TB management and control. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB has exacerbated the threat to public health and created a renewed sense of urgency to control the disease. Treatment of MDR-TB leads to emergence of additional drug resistance in 6-20% of patients on treatment. We propose to investigate the causes of emergence of mycobacterial drug resistance in an observational cohort study, the Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PREEMPT) Study. This proposal takes advantage of two existing TB cohort studies in India and Brazil (Regional Prospective Observational Research for Tuberculosis: RePORT India and RePORT Brazil), co-funded by NIAID and the Indian and Brazilian governments, respectively. In the PREEMPT study, we will enroll 400 patients with MDR-TB in India and Brazil over a 24-month period and follow them prospectively for 3 years. The proposal has the following Specific Aims: Aim 1: To determine whether low serum antimycobacterial drug concentrations contribute to the emergence of drug resistance in MDR TB patients, and whether HIV seropositivity is a risk factor for low serum drug concentrations and/or the emergence of resistance. Aim 2: To determine the contribution of increased DNA mutation (caused either by an intrinsic property of the M. tuberculosis strain or by FQ treatment) to clinical emergence of drug resistance in patient isolates. Aim 3: To determine whether mutations responsible for drug resistance can be detected early during treatment, when an intervention to prevent XDR-TB might be possible. This proposal builds on an existing TB research framework to study mechanisms of emergence of TB drug resistance during MDR-TB treatment. It is very likely that similar mechanisms will explain emergence of TB drug resistance during treatment for drug-susceptible TB. Each of the proposed mechanisms of emergence of resistance that we will investigate has direct implications for new regimen designs, new drug administration algorithms and new drug susceptibility monitoring strategies that could prevent emergence of resistance in patients with TB with and without HIV.