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: 8271547
• 负责人: Annelies T.A. Van Rie
• 金额: $ 59.39万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271547
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Multidrug resistant tuberculosis (MDR-TB) is an important public health problem. Xpert MTB/RIF is a novel rapid diagnostic that simultaneously detects M. tuberculosis and rifampicin resistance. We will characterize the phenotypic and genotypic anti- tuberculosis drug resistance profiles in 474 patients with rifampicin resistant TB in South Africa, and quantify the impact of Xpert MTB/RIF on treatment outcomes of patients with drug resistant TB.

描述（由申请人提供）：结核病仍然是一个重要的公共卫生问题，2009年估计有940万病例，170万人死亡。耐多药结核病（MDR-TB，定义为至少对异烟肼和利福平具有耐药性）以及与艾滋病毒相关的结核病对结核病控制构成重要威胁。艾滋病毒相关耐多药结核病的高致死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敏试验（DST）的实验室能力，这对防治耐多药结核病构成了重大挑战。2008年，在全世界估计的44万耐多药结核病病例中，只有7%被发现。Xpert MTB/RIF是一种新的快速诊断方法，可在两小时内同时检测结核分枝杆菌和利福平耐药性，最近（2010年12月）被世卫组织推荐作为耐多药结核病或艾滋病毒相关结核病疑似患者的初始检测方法。该方法检测利福平耐药性的灵敏度为95.1%，特异性为98.4%，阴性预测值较高（99%），但在耐多药结核病检测前概率较低的人群中，阳性预测值相对较低。虽然快速诊断利福平耐药性可能会彻底改变耐多药结核病的防治工作，但只有将快速诊断与快速获得最佳治疗联系起来，这种快速诊断方面的技术进步才会改善患者的治疗结果。2008年，只有11%的耐多药结核病病例得到适当治疗。为了确保最佳的治疗效果并避免耐药性的扩大，需要了解完整的耐药性概况。使用Xpert MTB/RIF，临床医生将需要仅根据对利福平耐药性的了解做出治疗决策，因此有可能启动次优方案。为了指导Xpert MTB/RIF检测利福平耐药的初步规范化管理，我们将对大量（n=474）利福平耐药结核病患者的表型和基因型耐药谱进行综合表征。为了评估专家MTB/RIF对患者预后的影响，我们将在南非卫生部（DOH）分阶段实施专家MTB/RIF的过程中进行实施研究。我们将记录一组利福平耐药结核病病例的治疗决策，并比较237例经Xpert MTB/RIF诊断为利福平耐药的患者和237例经培养- dst检测为利福平耐药的患者（未常规使用Xpert MTB/RIF的患者）在治疗前6个月的结局（培养转化时间、耐药性扩增、药物毒性和生存率）。拟议的实施研究旨在改变目前筛查、诊断和治疗耐多药结核病的范式，方法是建立一个关于在Xpert MTB/RIF上诊断为利福平耐药结核病患者的耐药谱的强大知识库，量化该检测对耐药结核病患者的耐药扩增和治疗结果的影响。所产生的证据将有助于在资源有限、结核病/艾滋病毒负担高的国家成功地将这种新的检测方法应用到常规实践中。