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 万例病例和 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），而艾滋病毒相关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病死率对撒哈拉以南非洲地区具有重大影响。在资源有限的环境下，缺乏结核分枝杆菌培养和药敏试验 (DST) 实验室能力，这给抗击耐多药结核病带来了重大挑战。 2008 年，全世界估计有 440,000 例耐多药结核病例，只有 7% 被发现。 Xpert MTB/RIF 是一种新型快速诊断方法，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 WHO 推荐作为疑似耐多药结核病或 HIV 相关结核病患者的初始检测。该检测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%)，但对于耐多药结核病预检测概率较低的人群，阳性预测值相对较低。虽然利福平耐药性的快速诊断可能会彻底改变耐多药结核病的斗争，但如果快速诊断与快速获得最佳治疗相结合，快速诊断方面的技术进步只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了适当治疗。为了确保最佳治疗结果并避免耐药性放大，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利福平耐药性的知识做出治疗决定，因此存在启动次优治疗方案的风险。为了指导 Xpert MTB/RIF 检测到的利福平耐药性的初步标准化管理，我们将全面描述大量（n = 474）利福平耐药结核病患者的表型和基因型耐药性特征。为了评估 Xpert MTB/RIF 对患者治疗结果的影响，我们将在南非卫生部 (DOH) 分阶段实施 Xpert 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 名诊断为利福平耐药的患者在治疗前 6 个月的结果（培养转化时间、耐药​​性扩增、药物毒性和生存率）。 Xpert MTB/RIF 和 237 名通过基于培养的药敏试验检测到利福平耐药的患者（无法常规使用 Xpert MTB/RIF 的患者）。拟议的实施研究旨在改变当前耐多药结核病筛查、诊断和治疗的范式，方法是通过在 Xpert MTB/RIF 上诊断出利福平耐药结核病患者的耐药谱建立强大的知识库，量化 MDR-TB 的影响。耐药结核病患者耐药性放大和治疗结果的测定。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颖的检测方法应用到常规实践中。

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