Optimizing the impact of Xpert MTB/RIF on treatment outcomes of drug resistant TB

优化 Xpert MTB/RIF 对耐药结核病治疗结果的影响

• 批准号: 8638891
• 负责人: Annelies T.A. Van Rie
• 金额: $ 48.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638891
• 关键词: Africa South of the Sahara; African; Aminoglycosides; Antitubercular Agents; Biological Assay; Capromycin; Case Fatality Rates; Cessation of life; Country; Cycloserine; Data; Decision Making; Detection; Diagnosis; Diagnostic; Drug Resistant Tuberculosis; Drug resistance; Drug toxicity; Ensure; Epidemic; Epidemiology; Ethambutol; Ethionamide; Extreme drug resistant tuberculosis; Fluoroquinolones; Future; Genes; Genus Mycobacterium; HIV; Health; Hour; Incidence; Individual; Isoniazid resistance; Knowledge; Laboratories; Lead; Link; Molecular; Mono-S; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Ofloxacin; Outcome; Patients; Pharmaceutical Preparations; Phase; Population; Predictive Value; Predisposition; Probability; Public Health; Pyrazinamide; Regimen; Reporting; Resistance; Resistance profile; Resolution; Resources; Rifampicin resistance; Rifampin; Risk; Sensitivity and Specificity; South Africa; Specificity; Survival Rate; Testing; Time; Toxic effect; Translations; Treatment outcome; Tuberculosis; Uncertainty; World Health; World Health Organization; base; clinical practice; cohort; fight against; implementation research; improved; isoniazid; knowledge base; member; novel; patient population; point of care; programs; rapid diagnosis; resistant strain; routine practice; screening; transmission process; tuberculosis drugs

DESCRIPTION (provided by applicant): Tuberculosis (TB) continues to be an important public health problem, with an estimated 9.4 million cases and 1.7 million deaths in 2009. Multidrug resistant TB (MDR-TB, defined as resistance to at least isoniazid and rifampicin), and HIV-associated TB pose important threats to TB control. The high case fatality rate of HIV- associated MDR-TB has major implications for sub-Saharan Africa. The lack of laboratory capacity for Mycobacterium tuberculosis culture and drug susceptibility testing (DST) in resource limited settings poses important challenges to the fight against MDR-TB. In 2008, only 7% of the estimated 440,000 MDR-TB cases worldwide were detected. Xpert MTB/RIF, a novel rapid diagnostic that simultaneously detects M. tuberculosis and rifampicin resistance within two hours, was recently (Dec. 2010) recommended by the WHO as the initial test in those suspected of MDR-TB or HIV-associated TB. The assay detects rifampicin resistance with 95.1% sensitivity and 98.4% specificity, high negative predictive value (99%) but relatively low positive predictive in people with a low pre-test probability of MDR-TB. While rapid diagnosis of rifampicin resistance could revolutionize the fight against MDR-TB, this technological advance in rapid diagnosis will only result in improved patient outcomes if the rapid diagnosis is linked to rapid access to optimal treatment. In 2008, only 11% of MDR-TB cases were appropriately treated. To ensure optimal treatment outcomes and avoid amplification of resistance, knowledge of the complete resistance profile is required. Using Xpert MTB/RIF, clinicians will need to make a treatment decision based on the knowledge of rifampin resistance only, and thus risk the initiation of a suboptimal regimen. To guide the initial standardized management of rifampicin resistance detected by Xpert MTB/RIF, we will comprehensively characterize the phenotypic and genotypic resistance profiles in a large (n=474) number of patients with rifampicin resistant TB. To evaluate the impact of Xpert MTB/RIF on patient outcomes, we will perform implementation research nested within the phased implementation of Xpert MTB/RIF by the South African Department of Health (DOH). We will document treatment decisions made in a cohort of rifampicin resistant TB cases, and compare outcomes (time to culture conversion, amplification of resistance, drug toxicity, and survival rates) during the first 6 months of treatment between 237 patients diagnosed with rifampicin resistance on Xpert MTB/RIF and 237 patients with rifampicin resistance detected on culture based-DST (patients without routine access to Xpert MTB/RIF). The proposed implementation research aims to change the current paradigm for screening, diagnosis and treatment of MDR- TB, by building a robust knowledge base on the resistance profiles of patients diagnosed with rifampicin resistant TB on Xpert MTB/RIF, by quantifying the impact of the assay on amplification of resistance and treatment outcomes in patients with drug resistant TB. The evidence generated will contribute to the successful implementation of this novel assay into routine practice in resource limited, high TB/HIV burden countries.

描述（由申请人提供）：结核病（TB）仍然是一个重要的公共卫生问题，2009年估计有940万例和170万例死亡。耐多药TB（MDR-TB（MDR-TB）（定义为对以异oni氮和利福平的抗性），以及与HIV相关的TB相关的TB pose Contorts Wisters to TB TO TB TO TB TO TB TO TB TO TB。 HIV相关的MDR-TB的高病例死亡率对撒哈拉以南非洲具有重大影响。在资源有限的环境中，缺乏结核分枝杆菌培养和药物敏感性测试（DST）的实验室能力对与MDR-TB的斗争构成了重要的挑战。 2008年，在全球估计的440,000个MDR-TB病例中，只有7％被发现。 XPERT MTB/RIF是一种新型的快速诊断，在两个小时内同时检测到结核分枝杆菌和利福平耐药性，该诊断是WHO（2010年12月）在怀疑MDR-TB或HIV相关的TB中的初步测试（2010年12月）。该测定法检测出95.1％敏感性和98.4％特异性，高阴性预测值（99％），但对MDR-TB的预测试概率较低的人的阳性预测性相对较低。虽然快速诊断利福平耐药性可以彻底改变与MDR-TB的斗争，但如果快速诊断与快速获得最佳治疗有关，这种快速诊断的技术进步只会改善患者的预后。在2008年，只有11％的MDR-TB病例得到了适当的治疗。为了确保最佳的治疗结果并避免放大电阻，需要了解完全阻力的知识。使用XPERT MTB/RIF，临床医生将需要基于利福平耐药性做出治疗决策，因此有可能启动次优方案。为了指导XPERT MTB/RIF检测到的利福平耐药性的初始标准化管理，我们将全面地表征大量（n = 474）耐利兰皮蛋白耐药蛋白TB患者的表型和基因型抗性谱。为了评估XPERT MTB/RIF对患者结局的影响，我们将进行嵌套在南非卫生部（DOH）的XPERT MTB/RIF实施中的实施研究。我们将记录在一系列抗利福平毒素抗性结核病病例中做出的治疗决定，并在237名被诊断为XPERT MTB/RIF/RIFAMPINCIAN COUPITANT coptution conture conture conture的患者的患者之间的前6个月中比较结果（培养时间转化的时间，抗药性，药物毒性和存活率），在237例治疗的患者之间进行治疗。 MTB/RIF）。拟议的实施研究旨在通过建立对XPERT MTB/RIF的耐心症患者的抗药性基础来改变筛查，诊断和治疗MDR-TB的当前范例，并通过量化对药物抗药性和抗药性药物抗药性抗药性的影响来量化XPERT MTB/RIF。产生的证据将有助于成功实施这种新颖的测定法，以在资源有限的高结核病/艾滋病毒负担国家中进行常规实践。

项目成果

Prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of Mycobacterium tuberculosis.

• DOI: 10.1016/j.tube.2016.05.003
• 发表时间: 2016-07
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Whitfield MG;Streicher EM;Dolby T;Simpson JA;Sampson SL;Van Helden PD;Van Rie A;Warren RM
• 通讯作者: Warren RM

Mycobacterium tuberculosis pncA Polymorphisms That Do Not Confer Pyrazinamide Resistance at a Breakpoint Concentration of 100 Micrograms per Milliliter in MGIT.

结核分枝杆菌 pncA 多态性在 MGIT 中的断点浓度为 100 微克/毫升时不赋予吡嗪酰胺耐药性。

• DOI: 10.1128/jcm.01001-15
• 发表时间: 2015
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4
• 作者: Whitfield,MichaelG;Warren,RobinM;Streicher,ElizabethM;Sampson,SamanthaL;Sirgel,FrikA;vanHelden,PaulD;Mercante,Alexandra;Willby,Melisa;Hughes,Kelsey;Birkness,Kris;Morlock,Glenn;vanRie,Annelies;Posey,JamesE
• 通讯作者: Posey,JamesE