Poor Treatment Response and Outcomes in Bedaquiline-Based Treatment Regimens for Drug-Resistant Tuberculosis in South Africa

项目摘要 对抗结核药物的耐药性使护理复杂化，并使患有结核病的个人的结果恶化。 结核病是世界范围内导致死亡的主要传染病。南非正在使用新的抗结核药物 药物贝达喹啉作为利福平患者较短和较长全口服治疗方案的一部分- 耐药结核病（RR-TB）。虽然临床试验和观察性研究表明， 基于贝达喹啉治疗的结局，治疗反应不良（定义为阳性）的预测因子 诊断后2个月、4个月或6个月的培养物）和治疗结果不佳， 编程设置。令人担忧的是，临床分枝杆菌中已检测到对贝达喹啉的耐药性 结核病分离株。对组成治疗方案的新旧药物的背景耐药性， 结合观察到的贝达喹啉治疗前表型敏感性的变化，引起了人们的担忧， 治疗反应和结果不佳的风险可能高于预期。解决这些 我们将利用南非国家卫生实验室系统的强大基础设施， 耐药结核病电子登记册用于评估患者的计划性治疗反应不佳 南非的RR-TB患者。我们将对贝达喹啉进行最低抑菌浓度检测， 南非豪登省常规采集的标本上的伴随药物，以确定 在表型贝达喹啉敏感的患者中， 治疗前分离株与不良治疗反应或结果相关。全基因组测序 将允许同时表征潜在的分子 RR-TB的流行病学。我们还将使用一种新的方法，使用不同浓度的药物， 通过编程确定半衰期，并进行药代动力学建模，以评价与至 文化积极性和治疗结果。我们将结合联合收割机分枝杆菌学因素，药物浓度数据， 和临床数据，以开发用于不良治疗反应和结果的预测模型。我们的发现将 指导针对治疗反应不良高危人群的有针对性的干预策略， 在新治疗中纳入贝达喹啉和伴随药物的基因型数据的敏感性试验 RR-TB的治疗方案，并探讨在病程早期测量药物浓度的潜在重要性 RR-TB治疗。获得了与治疗相关的基因型和表型变异的见解 RR-TB的结果不仅对南非的结核病项目非常有价值，而且对高 负担和资源不足的情况下。我们的研究团队包括全球公认的内容专家 这将使南非的耐药结核病研究取得重大进展。

Project Summary Resistance to anti-tuberculosis drugs complicates the care and worsens the outcomes of individuals with tuberculosis, the leading infectious cause of death worldwide. South Africa is using the new anti-tuberculosis drug bedaquiline as part of both shorter and longer all-oral treatment regimens for patients with rifampicin- resistant tuberculosis (RR-TB). While clinical trials and observational studies demonstrate improved treatment outcomes with bedaquiline-based treatment, the predictors of poor treatment response (defined as positive cultures two, four, or six months after diagnosis) and poor treatment outcomes are not well-characterized in programmatic settings. Alarmingly, resistance to bedaquiline has been detected in clinical Mycobacterium tuberculosis isolates. The background resistance to both new and old drugs that compose treatment regimens, combined with observed variation in pretreatment phenotypic susceptibility to bedaquiline, raise concerns that the risks of poor treatment response and outcomes may be higher than anticipated. To address these concerns, we will use the robust infrastructure of the South African National Health Laboratory system and the electronic drug-resistant tuberculosis register to assess programmatic poor treatment response among patients with RR-TB in South Africa. We will perform minimum inhibitory concentration testing of bedaquiline and companion drugs on routinely collected specimens in the Gauteng Province of South Africa to determine whether elevated minimum inhibitory concentrations of bedaquiline in phenotypically bedaquiline-susceptible pretreatment isolates are associated with poor treatment response or outcomes. Whole genome sequencing on routinely collected specimens will allow simultaneous characterization of the underlying molecular epidemiology of RR-TB. We will also use a novel approach of using the concentration of drugs with different half-lives determined programmatically and pharmacokinetic modeling to evaluate association with time to culture positivity and treatment outcomes. We will combine mycobacteriologic factors, drug concentration data, and clinical data to develop a prediction model for poor treatment response and outcomes. Our findings will guide targeted intervention strategies for individuals at high risk for poor treatment response, inform rapid drug susceptibility tests that incorporate genotypic data for bedaquiline and companion drugs in new treatment regimens of RR-TB, and explore the potential importance of measuring drug concentrations early in the course of RR-TB treatment. The insights gained about genotypic and phenotypic variation in relation to treatment outcomes of RR-TB will be highly valuable not only for South African tuberculosis programs, but also for high- burden and under-resourced settings worldwide. Our study team includes globally recognized content experts from South Africa and the US and will allow critical progress in drug-resistant TB research in South Africa.