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

在艾滋病毒高流行地区耐药结核病治疗中断后出现贝达喹啉和氯法齐明耐药性

• 批准号: 9926538
• 负责人: James C M Brust
• 金额: $ 75.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-26 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926538
• 关键词: Address; Advisory Committees; Affect; Aftercare; Bacteria; Binding Proteins; Biological Assay; Caring; Cessation of life; Clinical; Companions; Complex; Development; Disease; Drug Exposure; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Early treatment; Effectiveness; Enrollment; Epidemic; Exposure to; Extreme drug resistant tuberculosis; Frequencies; Genes; Genetic; Genetic Polymorphism; Genotype; Guidelines; HIV; Half-Life; Hour; Individual; Intermediate resistance; Interruption; Leprosy; Linezolid; Measures; Meta-Analysis; Methods; Microbiology; Minority; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Play; Population; Population Heterogeneity; Prevalence; Public Health; Pump; Recommendation; Regimen; Research Priority; Resistance; Resistance profile; Risk; Role; Sampling; South Africa; Techniques; Testing; Time; Treatment Failure; Treatment Protocols; Tuberculosis; United States National Institutes of Health; base; cohort; deep sequencing; efflux pump; extensive drug resistance; genome sequencing; high risk; improved; individual patient; mortality; mortality risk; novel; novel therapeutics; pharmacokinetic model; pharmacometrics; premature; resistance mechanism; scale up; side effect; single molecule; treatment center; treatment duration; treatment program; treatment risk; tuberculosis drugs; tuberculosis treatment; whole genome

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.

项目摘要 耐药结核病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。 个体由于有效的治疗药物很少，多药耐药和广泛耐药（M/XDR） 结核病的死亡率很高，威胁着全球结核病和艾滋病毒控制工作。M/XDR结核病治疗时间长（18- 24个月），并伴有严重的副作用。因此，10-25%的患者过早中断 治疗，使他们在治疗失败，获得额外的阻力和死亡的风险增加。 最近发现新的和重新使用的药物可以提高生存率和治愈率。 贝达喹啉，40年来第一种新的结核病药物，和氯法齐明，一种主要用于麻风病的药物， 在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 治疗方案包括贝达喹啉和氯法齐明。然而，贝达喹啉具有极长的半衰期（5.5 月）。中断治疗的患者可能暴露于贝达喹啉单药治疗作为伴随药物 更快地被消除-使它们处于发展贝达喹啉耐药性的高风险中。氯法齐明， 它的半衰期为70天，可以作为一种伴随药物防止耐药性，但交叉耐药性 贝达喹啉和氯法齐明之间可能会产生鉴于治疗中断的频率很高，有 随着贝达喹啉和氯法齐明在全球范围内的推广，耐药性可能会变得普遍。 在拟议的研究中，我们试图了解贝达喹啉和氯法齐明的复杂的相互作用， 药代动力学（PK）对治疗中断期间耐药风险的影响。我们将入组MDR和XDR TB 中断含有贝达喹啉和氯法齐明的治疗方案后返回护理的患者。在Aim中 1，我们将描述对贝达喹啉的表型和基因型耐药的存在， 氯法齐明，以检查中断的持续时间如何影响耐药的风险。在目标2中，我们将测量 贝达喹啉和氯法齐明的血浆浓度和细胞内贝达喹啉浓度 治疗中断。我们将使用群体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型抗性相关的浓度。在 目的3，我们将使用一种新的深度测序测定来鉴定少数耐药亚群（即， 微异源抗性），其不能通过表型测试或全基因组测序检测到。我们将 跟踪受试者6个月，以确定异源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高的国家之一， 患者服用贝达喹啉。本研究的目的将回答有关贝达喹啉的基本问题 和氯法齐明药理学和耐药性，将直接告知他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喹啉治疗项目， 美国国家卫生研究院和美国联邦结核病工作组概述的优先事项。