Utility of Deep Sequencing for Detecting Heteroresistant Mycobacterium tuberculosis Infections among HIV-infected Persons

深度测序在检测 HIV 感染者中异抗性结核分枝杆菌感染中的应用

• 批准号: 8993375
• 负责人: Sanghyuk Sam Shin
• 金额: $ 18.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993375
• 关键词: Affect; Alleles; Botswana; Cause of Death; Clinical; Cohort Studies; Collaborations; Country; DNA; Detection; Development; Diagnosis; Diagnostic Procedure; Diagnostic tests; Drug resistance; Drug resistance in tuberculosis; Early Diagnosis; Early treatment; Enrollment; Failure; Foundations; Frequencies; Future; Genes; Genetic; Genetic study; Goals; HIV; HIV drug resistance; Health; Infection; Intermediate resistance; Lead; Life; Liquid substance; Methodology; Methods; Minority; Morbidity - disease rate; Mutation; Mycobacterium tuberculosis; Newly Diagnosed; Outcome; Parents; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Process; Public Health; Reading; Research; Research Infrastructure; Resistance; Resistance development; Resources; Rifampin; Risk; Sample Size; Sampling; Scientific Advances and Accomplishments; Specimen; Sputum; Technology; Testing; Time; Treatment outcome; Tuberculosis; Variant; clinical practice; deep sequencing; high risk; improved; innovation; insight; isoniazid; mortality; mutant; next generation; novel diagnostics; population based; prospective; public health relevance; rapid detection; rapid diagnosis; research study; response; tool; tuberculosis drugs; tuberculosis treatment

 DESCRIPTION (provided by applicant): The proposed study will help to establish methods for rapid detection of heteroresistant Mycobacterium tuberculosis (MTB) infections among HIV-infected TB patients. Heteroresistant MTB infections involve both drug-resistant and drug-susceptible types of MTB. A person with heteroresistant MTB infection is more likely to develop fully drug-resistant TB, which can cause poor treatment outcomes, increasing morbidity and mortality. People living with HIV appear to be especially at high risk for acquiring heteroresistan TB infections, and TB remains the leading cause of death among HIV-infected persons in resource poor countries, including Botswana. Recent developments in sequencing technology (deep sequencing) could be a powerful tool for rapidly detecting heteroresistant MTB infections. However, no study has systematically evaluated deep sequencing for detecting heteroresistance among TB patients in a clinical setting. Improved understanding of heteroresistance will contribute to significant improvements in TB morbidity and mortality and advance scientific understanding of TB. We propose to conduct an exploratory substudy of TB/HIV co-infected patients enrolled in an ongoing population-based TB research study in Botswana. We will identify and enroll 200 newly diagnosed TB patients on first-line therapy. We will collect sputum samples at enrollment and after 2 months of treatment. We will use deep sequencing of MTB DNA to look for heteroresistance. There are two specific aims to our proposal. Aim 1. We will determine whether direct sequencing from sputum specimen increases the detection of heteroresistant MTB infections compared to sequencing done on MTB culture samples. Aim 2. We will determine whether heteroresistant MTB infection status is predictive of response to TB treatment among patients on first-line TB therapy. This proposed research will be the first to systematically evaluate the use of deep sequencing to detect heteroresistant MTB infections, potentially improving clinical practice by allowing for rapid, early detection of heteroresistant infections and informing treatment decisions accordingly.

 描述（由申请方提供）：拟议的研究将有助于建立快速检测HIV感染的结核病患者中异质耐药结核分枝杆菌（MTB）感染的方法。异源耐药MTB感染涉及耐药和药物敏感类型的MTB。具有异源耐药MTB感染的人更有可能发展为完全耐药结核病，这可能导致治疗效果差，发病率和死亡率增加。艾滋病毒感染者似乎特别容易感染耐药性结核病，结核病仍然是包括博茨瓦纳在内的资源贫乏国家艾滋病毒感染者的主要死因。测序技术（深度测序）的最新发展可能是快速检测异源耐药MTB感染的有力工具。然而，没有研究系统地评估深度测序在临床环境中检测结核病患者中的异质耐药性。提高对异源耐药性的认识将有助于显著改善结核病发病率和死亡率，并促进对结核病的科学认识。我们建议对博茨瓦纳正在进行的基于人群的结核病研究中招募的结核病/艾滋病病毒合并感染患者进行探索性亚组研究。我们将确定并招募200名新诊断的结核病患者接受一线治疗。我们将在入组时和治疗2个月后采集痰液样本。我们将使用MTB DNA的深度测序来寻找异源耐药性。我们的建议有两个具体目标。目标1.我们将确定与对MTB培养样本进行测序相比，从痰液标本直接测序是否增加了异源耐药MTB感染的检测。目标2.我们将确定异源耐药MTB感染状态是否可预测一线TB治疗患者对TB治疗的反应。这项拟议的研究将是第一个系统地评估使用深度测序来检测异源耐药MTB感染的研究，通过允许快速，早期检测异源耐药感染并相应地告知治疗决策，可能改善临床实践。