Emergence of bedaquiline and clofazimine resistance after interruption of drug-resistant TB therapy in a high HIV prevalence setting

项目总结 耐药结核病(TB)是一种主要的全球流行病，对艾滋病毒感染者构成特别威胁 个人。可用于治疗的有效药物很少，多药耐药和广泛耐药(M/XDR) 结核病具有很高的死亡率，威胁着全球结核病和艾滋病毒控制努力。M/XDR结核病治疗时间长(18- 24个月)，并伴随着严重的副作用。因此，10%-25%的患者过早中断 治疗失败、获得额外抵抗力和死亡的风险增加。 最近发现，新的和重新调整用途的药物可以提高存活率和治愈率。 40年来第一种新的结核病药物贝达奎林和主要用于麻风病的氯法齐明已经被 处于这场治疗革命的中心。2018年，世卫组织建议所有耐多药和广泛耐药结核病治疗 治疗方案包括贝达奎林和氯法齐明。然而，贝达奎林具有极长的半衰期(5.5 月)。中断治疗的患者可能会接受贝达奎兰单一疗法作为辅助药物。 更快地被消除--使它们处于产生贝达奎林耐药性的高风险中。氯法齐明， 其半衰期为70天，可作为配伍药物防止耐药性，但交叉耐药 贝达奎林和氯法齐明之间可能会发展。鉴于治疗中断的频率很高，有 随着贝达奎林和氯法齐明在全球范围内扩大规模，耐药性可能会变得普遍存在。 在拟议的研究中，我们试图了解贝达奎兰和氯法齐明的复杂相互作用。 在治疗中断期间耐药风险的药代动力学(PK)。我们将注册MDR和XDR TB 在中断了含有贝达奎林和氯法齐明的方案后重新接受治疗的患者。在AIM 1，我们将表征存在的表型和基因耐药贝达奎兰和 检查中断持续时间如何影响耐药风险。在目标2中，我们将测量 贝达奎兰和氯法齐明的血药浓度及细胞内贝达奎兰浓度 治疗中断。我们将使用总体PK模型来了解这些药物的药代动力学 并确定与表型或基因耐药相关的浓度。在……里面 目的3，我们将使用一种新的、深度测序的方法来鉴定少数抗药亚群(即， 微异质性抗性)，通过表型测试或全基因组测序不能检测到。我们会 追踪受试者6个月，以确定异质性耐药是否预示治疗失败或获得性耐药。 南非是全球耐药结核病和艾滋病毒负担最重的国家之一，已经发起了21,000 到目前为止，服用贝达奎林的患者。这项研究的目的将回答有关贝达奎兰的基本问题 以及氯法齐明的药理和耐药性，这将直接影响它们在南非和世界各地的使用。 我们的研究将借鉴世界上最大的贝达奎兰治疗计划，并解决研究 美国国立卫生研究院和美国联邦结核病工作组概述的优先事项。

PROJECT SUMMARY Drug-resistant tuberculosis (TB) is a major global epidemic and poses a particular threat to HIV-infected individuals. With few effective drugs available for treatment, multidrug- and extensively drug-resistant (M/XDR) TB carry a high mortality rate and threaten global TB and HIV control efforts. M/XDR TB treatment is long (18- 24 months) and associated with serious side effects. As a result, 10-25% of patients prematurely interrupt therapy, placing them at increased risk for treatment failure, acquisition of additional resistance, and death. New and repurposed medications have recently been found to improve survival and cure rates. Bedaquiline, the first new TB drug in 40 years, and clofazimine—a drug primarily used for leprosy—have been at the center of this treatment revolution. In 2018, WHO recommended that all MDR and XDR TB treatment regimens include bedaquiline and clofazimine. Bedaquiline, however, has an extremely long half-life (5.5 months). Patients who interrupt therapy are likely exposed to bedaquiline monotherapy as companion drugs are more rapidly eliminated—placing them at high risk of developing bedaquiline resistance. Clofazimine, which has a half-life of 70 days, may protect against resistance as a companion drug, but cross-resistance between bedaquiline and clofazimine may develop. Given the high frequency of treatment interruption, there is danger that as bedaquiline and clofazimine are scaled up worldwide, resistance may become widespread. In the proposed study, we seek to understand the complex interplay of bedaquiline and clofazimine’s pharmacokinetics (PK) on the risk of resistance during treatment interruption. We will enroll MDR and XDR TB patients who have returned to care after interrupting a bedaquiline- and clofazimine-containing regimen. In Aim 1, we will characterize the presence of phenotypic and genotypic drug resistance to bedaquiline and clofazimine to examine how the duration of interruption affects the risk of resistance. In Aim 2, we will measure plasma concentrations of bedaquiline and clofazimine and intracellular bedaquiline concentrations after treatment interruption. We will use population PK modeling to understand the pharmacokinetics of these drugs during interruption and determine the concentrations associated with phenotypic or genotypic resistance. In Aim 3, we will use a novel, deep sequencing assay to identify minority resistant subpopulations (i.e., microheteroresistance) which are not detectable by phenotypic testing or whole genome sequencing. We will follow subjects for 6 months to determine if heteroresistance predicts treatment failure or acquired resistance. South Africa has among the highest global burden of drug-resistant TB and HIV and has initiated >21,000 patients on bedaquiline to date. The aims of this study will answer fundamental questions about bedaquiline and clofazimine pharmacology and resistance that will directly inform their use in South Africa and worldwide. Our study will draw from the largest bedaquiline treatment program in the world and addresses research priorities outlined by the NIH and the US Federal TB Task Force.