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

项目摘要 对抗结核药物的抗药性使治疗复杂化，并使患有结核病的患者的预后恶化 结核病是全球主要的传染病死亡原因。南非正在使用新的抗结核病药物 贝达奎兰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治疗效果有所改善 以贝达奎兰为基础的治疗结果，治疗反应差的预测因素(定义为阳性 诊断后两个月、四个月或六个月的培养)和不良的治疗结果不能很好地表征 程序性设置。令人担忧的是，在临床分枝杆菌中已经检测到对贝达奎兰的耐药性。 结核病分离株。组成治疗方案的新药和旧药的背景抗药性， 结合观察到的贝达奎兰治疗前表型易感性的变化，引起了人们的关注 不良治疗反应和结果的风险可能比预期的要高。要解决这些问题 为了解决这些问题，我们将利用南非国家卫生实验室系统的强大基础设施 电子耐药结核病登记簿用于评估患者的程序性不良治疗反应 在南非感染了RR-TB。我们将进行贝达奎兰和贝达奎林的最低抑菌浓度测试 南非豪登省常规采集的标本上的配套药物 在对贝达奎兰敏感的表型中，贝达奎兰的最低抑菌浓度是否升高 前处理分离株与不良的治疗反应或结果有关。全基因组测序 常规收集的样本将允许同时表征潜在的分子 RR-TB的流行病学研究。我们还将使用一种新的方法，使用不同浓度的药物 程序确定的半衰期和药代动力学模型以评估与时间的相关性 培养阳性和治疗结果。我们将结合分枝杆菌因子，药物浓度数据， 和临床数据来开发治疗反应和结果较差的预测模型。我们的发现将 指导针对治疗反应差的高危人群的有针对性的干预策略，告知快速药物 在新的治疗中纳入贝达奎兰和配套药物的基因数据的药敏试验 RR-TB的治疗方案，并探讨在疗程早期测量药物浓度的潜在重要性 关于RR-TB治疗的建议。关于基因和表型变异与治疗相关的见解 RR-TB的结果不仅对南非的结核病项目非常有价值，而且对高风险人群也很有价值。 全球范围内的负担和资源不足的环境。我们的研究团队包括全球公认的内容专家 并将使南非在耐药结核病研究方面取得关键进展。

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.