Determining the efficacy of a novel TB diagnostic test to monitor treatment success in drug resistant TB patients

确定新型结核病诊断测试的有效性，以监测耐药结核病患者的治疗成功

• 批准号: 9926663
• 负责人: Alberto Garcia-Basteiro
• 金额: $ 22.78万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-25 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926663
• 关键词: AIDS/HIV problem; Address; Africa; African; Agar; Age; Amikacin; Antitubercular Agents; Area; Biological Assay; Capromycin; Caring; Cause of Death; Color; Communicable Diseases; Country; Data; Democratic Republic of the Congo; Detection; Diagnosis; Diagnostic; Diagnostic tests; Drug Monitoring; Drug resistance; Drug resistance in tuberculosis; Early Diagnosis; Evolution; Extreme drug resistant tuberculosis; Fluoroquinolones; Generations; Ghana; HIV; Health; Healthcare Systems; Individual; Infectious Agent; Infrastructure; Injectable; Isoniazid resistance; Ivory Coast; Kanamycin; Life; Malaria; Methods; Molecular; Monitor; Mozambique; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nigeria; Patient Care; Patients; Persons; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Predisposition; Prevention; Process; Publications; Regimen; Reporting; Research; Resistance; Resources; Rifampicin resistance; Rifampin; Rural; Sensitivity and Specificity; Series; South Africa; Specimen; Sputum; Test Result; Testing; Thinness; Time; Tuberculosis; United States National Institutes of Health; Urban Hospitals; antiretroviral therapy; base; biobank; co-infection; comparative; cost; design; diagnostic accuracy; drug testing; efficacy testing; extensive drug resistance; health care settings; indexing; instrument; interest; molecular diagnostics; novel; resistant strain; rural healthcare; success; treatment response; tuberculosis diagnostics; tuberculosis drugs; tuberculosis treatment

ABSTRACT Tuberculosis (TB) is now the leading infectious disease cause of death worldwide, killing one person every 21 seconds. The growing burden of detected rifampicin-resistant (RR) and multidrug-resistant (MDR)-TB is complicating TB prevention, surveillance and care. MDR-TB is caused by Mycobacterium tuberculosis (M.tb) strains that are resistant to isoniazid (INH) and rifampicin (RIF). Extensively drug resistant (XDR)-TB is a severe form of MDR-TB that involves MDR M.tb strains that are additionally resistant to any fluoroquinolone (FQ) and a second-line injectable drug (kanamycin, amikacin, or capreomycin). M.tb strains causing extreme drug resistant (XXDR)-TB are resistant to all 1st and 2nd line TB drugs. Under programmatic conditions in endemic countries, sputum is collected and cultured every month after drug resistant TB treatment initiation, to further perform the drug susceptibility test to determine if the patient is responding or not to the treatment. In many endemic areas (urban and rural), this process takes between 42-60 days. Here, we propose to use an agar-layer based platform (the 2nd Generation Color Plate test), that can shorten this period to 14 days. Although our agar-layer test is not a molecular based assay as some of the PCR-based instruments currently being used to diagnose drug susceptible and rifampicin resistant TB, our test can diagnose phenotypic resistance for 11 anti-TB drugs, thus making it unique for this purpose. Based in our publications and preliminary data, our premise is that our 2nd Generation culture based Color Plate test will be able to shorten the lapse time of current culture methods to determine if a drug-resistant TB patient is responding well to anti- TB treatment. This novel test is of particular interest to NIH/NIAID as it may overcome limitations such as cost and infrastructure associated with current molecular diagnostic approaches; and can provide expanded rapid drug susceptibility testing (DST) for 11 anti-TB drugs; including bedaquiline and delamanid, two newly approved anti-TB drugs to treat MDR/XDR-TB cases, with the added problem that bedaquiline and delamanid resistant XXDR-TB cases already have been reported and thus, the urgent need of DST monitoring for these two drugs. We now propose to test this novel test in real life conditions in a high TB, HIV associated TB and MDR-TB country (Mozambique). Partnering with The Manhiça Health Research Center (Centro de Investigação em Saúde de Manhiça, CISM), a well-established research center in Mozambique, we propose: i) To evaluate the diagnostic accuracy of the 2nd Generation Color Plate test in diagnosing drug resistant TB; and ii) Testing the efficacy of the 2nd Generation Color Plate test in monitoring if a patient infected with drug resistant TB is responding to the treatment. We will determine the efficacy and the turnaround of the results of this test, and compare our results with other current diagnostic tests for drug resistant TB testing (GeneXpert MTB/RIF, LPA and BACTECTM MGIT DST).

摘要 结核病现在是全世界死亡的主要传染病，每21人中就有一人死亡。 秒检测到的耐利福平（RR）和耐多药（MDR）结核病的负担日益增加， 使结核病预防、监测和护理复杂化。耐多药结核病是由结核分枝杆菌（M.tb）引起的 对异烟肼（INH）和利福平（RIF）耐药的菌株。广泛耐药结核病（XDR）是一种 一种严重的MDR-TB，涉及对任何氟喹诺酮类药物额外耐药的MDR M.tb菌株 (FQ)和二线注射药物（卡那霉素、阿米卡星或卷曲霉素）。结核分枝杆菌菌株导致极端 耐药（XXDR）-结核病对所有一线和二线结核病药物都有耐药性。在方案条件下， 在结核病流行国家，开始耐药结核病治疗后每月收集痰液并进行培养， 进一步进行药物敏感性测试以确定患者是否对治疗有反应。在 在许多流行地区（城市和农村），这一过程需要42-60天。在这里，我们建议使用 基于琼脂层的平台（第二代彩色板测试），可以将此周期缩短至14天。 虽然我们的琼脂层测试不是一个基于分子的检测，因为目前的一些基于PCR的仪器 用于诊断药物敏感和利福平耐药结核病，我们的测试可以诊断表型 11种抗结核药物的耐药性，从而使其成为这一目的的独特之处。基于我们的出版物和 初步数据，我们的前提是，我们的第二代文化为基础的彩色板测试将能够缩短 目前的培养方法，以确定是否耐药结核病患者的反应良好， 肺结核治疗。NIH/NIAID对这种新的测试特别感兴趣，因为它可以克服成本等限制 以及与当前分子诊断方法相关的基础设施;并且可以提供扩展的快速 11种抗结核药物的药物敏感性测试（DST）;包括贝达喹啉和德拉马尼，两种新的 已批准用于治疗耐多药/广泛耐药结核病病例的抗结核药物， 已经报告了耐XXDR-TB病例，因此迫切需要对这些病例进行DST监测。 两种药物。我们现在建议在高结核病、HIV相关结核病和结核病的真实的生活条件下测试这种新的测试。 耐多药结核病国家（莫桑比克）。与Manhiça健康研究中心（Centro de Investigação em Saúde de Manhiça，CISM），莫桑比克一个成熟的研究中心，我们建议： 评估第二代彩色平板检测诊断耐药结核病的准确性;以及 ii）测试第二代色板测试在监测患者是否感染药物方面的功效 耐药结核病对治疗有反应。我们将确定的有效性和结果的转折点， 这项测试，并将我们的结果与其他当前耐药结核病检测的诊断测试（GeneXpert）进行比较 MTB/RIF、LPA和BACTECTM MGIT DST）。