Identifying Optimal Treatment Strategies for Tuberculosis Treatment

项目摘要/摘要 目前对药物敏感结核病的治疗标准是“一刀切”，将难以治疗的结核病 复发风险较高的患者和获得耐药性风险较高的分枝杆菌患者。第三阶段 治疗缩短研究TBTC/ACTG(研究31/A5349)正在评估两种新的 含有大剂量利福喷丁的短程方案。我们提案的主要目标是将 药理学和微生物学分析(PK/PD)在这项临床试验中提供详细的药物药代动力学， 麦克风反应和安全性数据-包括2000多名患者的新数据(持久者的标记)。我们的 目的是了解和量化单个药物PK/PD、MICS、新的标志物之间的相互作用 基因组负荷，持久者的新标记物，活跃的疾病严重性和早期治疗反应 患者群体，并认识它们与临床结果和安全事件的关系。通过这样做，我们将成为 能够理解和量化药理作用(多药药代动力学)和非药物作用 治疗反应的药理成分(宿主、疾病严重程度)和了解表型 难以治疗的患者，使我们能够为所有服用药物的患者得出最佳治疗策略- 敏感结核病，包括方案的选择、治疗时间和剂量。 我们提出了一个创新的假设，即感染细菌和宿主都可以被视为“低”。 和“高”风险，而正是这两种风险的结合决定了治疗 结果和所需的治疗时间，与使用的药物无关。我们的方法将分层 细菌的负担风险、最低抑菌浓度--即使是在对药物敏感的结核分枝杆菌中--以及耐药的存在 亚群。宿主风险将根据疾病严重程度、艾滋病毒状况和吸收和 代谢药物(PK)。然后，我们将使用高级分析和建模策略来开发工具和 识别可用超短程治疗的感染低风险细菌的低风险患者的算法 (=四个月)和感染高危细菌的高危患者，他们需要治疗的时间超过 六个月。通过我们的分析，我们将能够为每个患者选择效果最好的方案 治愈的可能性。我们的发现将彻底改变全球结核病临床试验和护理的未来。 这项研究将解决基本问题，如暴露-反应/安全关系是什么 有利的AUC/MIC目标是针对所有使用主要临床结果(复发)的一线结核病药物以及如何 在众多不同的患者中，对治疗的早期反应与临床结果有关。该项目已 来自TBTC/ACTG领导层和我们的行业合作伙伴(赛诺菲安万特)前所未有的支持。中国的资金 本R01请求完成研究31中未包括的药物措施和最低抑菌浓度(即，所有 利福喷丁和莫西沙星以外的药物)和全套PK/PD建模和学习 这项试验的主要目标是测试试验性四个月养生法的非劣性。

Project Summary/Abstract The current standard of care for drug-sensitive TB is a “one-size-fits-all” approach, putting hard-to-treat patients at higher risk of relapse and mycobacteria at higher risk of acquiring drug resistance. The Phase 3 treatment-shortening study TBTC/ACTG (Study 31/A5349) is evaluating the efficacy and safety of two new short-course regimens containing high-dose rifapentine. The primary aim of our proposal is to embed full pharmacology and microbiology analyses (PK/PD) in this clinical trial to provide detailed drug pharmacokinetic, MIC response and safety data - including novel data (markers of persisters) for more than 2,000 patients. Our goal is to understand and quantify the interactions among individual drug PK/PD, MICs, new markers of genome load, new markers for persisters, active disease severity and early treatment response in a diverse patient population and recognize how they relate to clinical outcome and safety events. By doing so, we will be able to understand and quantify the contributions of pharmacological (multidrug pharmacokinetic) and non- pharmacological (host, disease severity) components of treatment response and to understand the phenotypes of patients who are hard to treat, allowing us to derive optimal treatment strategies for all patients with drug- sensitive TB, including choice of regimen, treatment duration, and dose. We propose the innovative hypothesis that both the infecting bacteria and the host can be seen as “low” and “high” risk and that it is the combination of these two risks that together determine treatment outcome and the required duration of treatment, regardless of the drugs used. Our approach will stratify bacterial risk by burden, MIC - even among drug-susceptible Mtb - and the presence of drug-tolerant subpopulations. The host risk will be stratified by disease severity, HIV status and ability to absorb and metabolize drugs (PK). We will then use advanced analytic and modeling strategies to develop tools and algorithms to identify low-risk patients infected with low-risk bacteria who can be treated with ultra-short treatment (<=four months) and high-risk patients infected with high-risk bacteria who will need treatment for longer than six months. Through our analyses, we will be able to select for each patient the regimen that results in the highest likelihood of cure. Our findings will completely change the future of TB clinical trials and care worldwide. This study will address fundamental questions, such as what the exposure-response/safety relationships and favorable AUC/MIC targets are for all first-line TB drugs using a major clinical outcome (relapse) and how early response to treatment relates to clinical outcome in a large and diverse patient population. The project has unprecedented support from the TBTC/ACTG leadership and our industry partner (Sanofi Aventis). The funds in this R01 requests the budget needed to complete drug measures and MIC not included in Study 31 (i.e., all drugs other than rifapentine and moxifloxacin) and the full suite of PK/PD modeling and learnings that go beyond the trial's primary goal of testing the non-inferiority of the experimental four-month regimens.