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

描述(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耐药)和艾滋病毒相关结核病对结核病控制构成重大威胁。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有重大影响。在资源有限的情况下，缺乏结核分枝杆菌培养和药敏试验(DST)的实验室能力，对抗击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，只发现了7%。Xpert MTB/RIF是一种新的快速诊断方法，可以在两小时内同时检测出结核分枝杆菌和利福平耐药性，最近(2010年12月)被世界卫生组织推荐作为疑似耐多药结核病或艾滋病毒相关结核病的初始检测。该方法检测利福平耐药性的敏感度为95.1%，特异度为98.4%，阴性预测值较高(99%)，但在MDR-TB预检概率较低的人群中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抗击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联系，这种快速诊断方面的技术进步只会导致患者预后的改善。2008年，只有11%的耐多药结核病病例得到了适当的治疗。为了确保最佳的治疗结果并避免扩大耐药性，需要了解完整的耐药性图谱。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的初步标准化管理，我们将全面分析大量(n=474)利福平耐药结核病患者的表型和基因耐药谱。为了评估Xpert MTB/RIF对患者预后的影响，我们将进行嵌套在南非卫生部(DOH)分阶段实施Xpert MTB/RIF的实施研究。我们将记录一组利福平耐药结核病病例的治疗决定，并比较237名在Xpert MTB/RIF上被诊断为利福平耐药的患者和237名在基于DST的培养上检测到的利福平耐药患者(未常规进入Xpert MTB/RIF的患者)在前6个月的治疗结果(培养转化时间、耐药性放大、药物毒性和存活率)。这项拟议的实施研究旨在改变目前的耐多药结核病筛查、诊断和治疗模式，方法是根据Xpert MTB/RIF上诊断出的耐利福平结核病患者的耐药情况建立一个强大的知识库，量化该检测对耐药结核病患者的耐药性放大和治疗结果的影响。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将这一新的检测方法成功地应用于常规做法。

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.