Sputum Transcriptomic Expression Profiling in Study 31: Express 31

项目摘要/摘要 开发更短、更安全、更有效的治疗活动性结核病(TB)的药物方案是一个至关重要的公共卫生问题 优先考虑。然而，缺乏可靠的中间临床试验终点限制了准确的方案选择。 用于第三阶段试验。此外，目前的替代标记不能解释不良结果的根本原因， 即使遗传敏感、耐药结核分枝杆菌能够存活的功能适应 (MTB)亚群。我们的目标是评估痰结核分枝杆菌转录图谱作为一种新的生物标志物 预测复发并作为临床试验的替代终点。我们的中心假设是结核病治疗 结果是由结核分枝杆菌的生理变化驱动的，通过病原体靶向转录图谱可以测量到。 我们的长期目标是开发新的替代标记，并为药物提供新的生物学见解 通过在治疗期间对结核分枝杆菌种群进行直接的活体分子监测来提高耐受性。我们的科学研究 方法将是在培养确认的药物敏感的情况下进行痰结核分枝杆菌转录图谱分析 肺结核患者共同参加由美国疾病控制与预防中心结核病中心牵头的大型3期开放随机临床试验 试验联盟(TBTC)和NIAID/DAIDS艾滋病临床试验小组(ACTG)。研究31/ACTG 5349将 比较两种为期4个月的大剂量利福喷丁方案(其中一种包括氟喹诺酮)与标准方案 6个月的结核病治疗。在肯尼亚、秘鲁、乌干达和越南的地点，我们将在以下地点收集RNA保存的痰 高复发风险患者的基线和整个治疗过程，包括艾滋病毒感染患者，以及 未感染HIV的患者胸片基线上有空洞。在目标1中，我们将在全基因组范围内 结核分枝杆菌转录图谱在方案正确的患者的每个治疗臂中提供全面的 结核病治疗对结核分枝杆菌转录组的生理和药效学影响路线图， 关键耐药途径的生物学解释。具体地说，我们将测试假设 针对药物作用机制的转录改变也可作为药效标记物 作为与利福霉素和莫西沙星暴露水平相关的不同假设。在目标2中，我们将执行Mtb 在所有培养/基因确认的复发和无复发的匹配对照中进行转录图谱分析 解药。我们将建立先进的药代动力学模型，以选择可以准确预测的结核分枝杆菌转录本 复发并作为临床试验的替代终点。AIM 2还将生产一个综合系统 解释患者之间治疗结果差异的药理学模型。我们的研究项目已经 开创一个新时代的潜力，在这个时代，药物开发不是基于文化，而是基于替代药物 关于结核病治疗过程中病原体生理状态的精确的体内分子标记。

PROJECT SUMMARY/ ABSTRACT Developing shorter, safer, more effective drug regimens for active tuberculosis (TB) is a critical public health priority. However, a lack of reliable intermediate clinical trial endpoints constrains accurate regimen selection for Phase 3 trials. Moreover, current surrogate markers cannot explain the root causes of poor outcomes, namely the functional adaptations that enable survival of genetically-susceptible, drug-tolerant M. tuberculosis (Mtb) subpopulations. Our objective is to evaluate sputum Mtb transcriptional profiling as a novel biomarker for predicting relapse and as a surrogate endpoint for clinical trials. Our central hypothesis is that TB treatment outcomes are driven by Mtb physiologic changes measurable via pathogen-targeted transcriptional profiling. Our long-term objective is to develop novel surrogate markers and provide new biologic insights into drug tolerance through direct, in vivo molecular monitoring of Mtb populations during treatment. Our scientific approach will be to perform sputum Mtb transcriptional profiling in culture-confirmed, drug-susceptible pulmonary TB patients co-enrolled in a large, Phase 3, open-label, randomized clinical trial led by the CDC TB Trials Consortium (TBTC) and the NIAID/DAIDS AIDS Clinical Trials Group (ACTG). Study 31/ACTG 5349 will compare two 4-month, high-dose rifapentine-based regimens (one including a fluoroquinolone) with standard 6-month TB treatment. At sites in Kenya, Peru, Uganda, and Vietnam, we will collect RNA-preserved sputum at baseline and throughout treatment from patients at high risk of relapse, including HIV-infected patients, and HIV-uninfected patients with cavitation on baseline chest radiograph. In Aim 1, we will perform genome-wide Mtb transcriptional profiling in protocol-correct patients in each treatment arm to provide a comprehensive roadmap of physiologic and pharmacodynamic effects of TB treatment on the Mtb transcriptome, with biological interpretations of key drug-tolerance pathways. Specifically, we will test hypotheses that transcriptional changes specific to drug mechanism of action can serve as pharmacodynamic markers, as well as distinct hypotheses related to rifamycin and moxifloxacin exposure levels. In Aim 2, we will perform Mtb transcriptional profiling in all culture-/genotype-confirmed relapses and matched controls with relapse-free cure. We will build advanced pharmacokinetic models to select Mtb transcripts that can accurately predict relapse and serve as surrogate endpoints for clinical trials. Aim 2 will also produce an integrative systems pharmacology model to explain between-patient differences in treatment outcomes. Our research program has the potential to inaugurate a new era in which drug-development is based not on culture-based surrogates but on precise, in vivo molecular markers of pathogen physiologic state during TB treatment.