Evaluation of new diagnostics for incident, active and recurrent TB (ENDx-Tb)

项目摘要：ENDx-TB提案 世卫组织结束结核病战略的一个核心组成部分是每年诊断约300万名患者 由于没有针对不同的特定需求量身定做的不充分的测试而未得到诊断或治疗 卫生保健设施的水平或能力。需要在医疗保健点进行更好的测试，在那里对低资源的患者进行分诊 环境对于优先考虑那些结核病风险最高的人提供更高水平的护理至关重要。在……上面 另一方面，针对宿主-病原体相互作用的特定阶段的更复杂、资源密集型测试， 例如在治疗结束时或在潜伏感染期间，将在较少的情况下补充基于社区的诊断 发展了能够使用中央专门实验室设施的卫生保健系统。范围广泛 诊断能力在同一国家的不同地区共存，例如在农村地区与城市地区和 因此，需要一套适用于特定设置的综合诊断测试。 要实现结核病防治战略的目标，还需要大力改进疾病预防方法 以阻止传输。由于有17亿人潜伏感染，向所有人提供预防措施并不划算。 因此，一种可以预测那些最有可能患上疾病的人的测试将使有针对性的治疗成为可能 接近了。同样，迫切需要测试以实现个性化或分层治疗策略。这个 目标是在全球范围内进行临床研究计划，以并排比较最有希望的新技术 在非洲经验丰富的临床地点(南非、冈比亚)对广泛的医疗保健环境进行测试， 东南亚(越南)和南美(秘鲁)，以及美国和欧洲的先进实验室。这个 队列包括成人、儿童、艾滋病毒携带者和2型糖尿病患者。新的化验方法 包括：1)在护理地点：无痰ASSys，包括两个基于宿主蛋白检测的分诊测试 和宿主转录本，包括手指血和高灵敏度的尿液阿拉伯甘露聚糖检测；2) 区域实验室：一种改进的提卡试剂液体培养方法，提高了灵敏度和速度 性能，以及Xpert Ultra测试的循环阈值作为结核病细菌负荷的衡量标准 治疗监测；以及3)在中心实验室：对信使核糖核酸签名进行多重qRT-PCR检测 进展为结核病，以及血液中宿主4蛋白的生物特征可预测不良治疗结果。 这些测试的性能将根据国际上建立的目标产品配置文件进行评估 适用于各自的医疗保健水平。该提案规定，今后将在 管线法和纳入专门诊断研究问题的额外队列。把这个放在一起 方法将确定不同卫生保健水平和不同感染阶段的最佳测试，并 疾病。由测试开发人员和临床科学家组成的多学科团队以及队列的选择是 非常适合确定实现末期结核病里程碑的新技术。

PROJECT SUMMARY: ENDx-TB proposal A central component of WHO’s End TB Strategy is to diagnose approximately 3 million patients annually who are not diagnosed or treated due to inadequate tests that are not tailored towards specific needs for different levels or capabilities of health care facilities. Better tests are needed at point-of-care, where triage in low-resource settings is essential to prioritize those with the highest risk for tuberculosis disease to higher levels of care. On the other hand, more complex, resource-intensive tests aimed at specific phases of host-pathogen interaction, like at the end of treatment or during latent infection would complement community-based diagnosis in less- developed health care systems that have access to central, specialized laboratory facilities. Wide-ranging diagnostic capacities co-exist in different regions of the same country, for instance in rural vs urban areas and therefore, a comprehensive battery of diagnostic tests that are appropriate for specific settings are needed. Meeting the End TB Strategy targets will also require dramatically improved prevention of disease approaches to block transmission. With 1.7 billion people latently infected, it is not cost-effective to provide prophylaxis to all. Hence a test that could predict those most at risk of developing disease would enable targeted therapeutic approaches. Similarly, tests to enable personalized or stratified treatment strategies are urgently needed. The goal is to conduct a clinical research program across the globe to compare side-by-side the most promising new tests for a wide range of health care settings in experienced clinical sites in Africa (South Africa, The Gambia), Southeast Asia (Vietnam) and South America (Peru), and advanced laboratories in the USA and Europe. The cohorts include adults, children, and people living with HIV and with type 2 diabetes mellitus. The new assays include: 1) at point-of-care: sputum-free assys, including two triage tests, based on detection of host proteins and host transcripts, both on fingerstick blood, and a high-sensitivity urinary lipoarabinomannan assay; 2) at regional laboratories: a modified liquid culture method with TiKa reagent for increased sensitivity and faster performance, and the cycle threshold value of the Xpert Ultra test as a measure of bacterial load for tuberculosis treatment monitoring; and 3) at central laboratories: a multiplex qRT-PCR test for mRNA signatures for progression to tuberculosis, and a host 4-protein biosignature in blood for prediction of poor treatmeht outcome. The performance of these tests will be evaluated according to internationally established target product profiles for the respective health care levels. The proposal makes provision for the future inclusion of additional tests in the pipleline and the inclusion of additional cohorts for specialized diagnostic research questions. Together this approach will identify the best tests for different health care levels and for different phases of infection and disease. The multi-disciplinary team of test developers and clinical scientists, and the selection of cohorts are well suited to identify novel technologies towards meeting the End TB milestones.