Rapid Tests for Drug Resistance to Detect Extensively Drug-Resistant Tuberculosis

描述(由申请人提供)：广泛耐药结核病(XDR-TB)的出现对国家和国际生物安全以及结核病控制成就构成越来越大的威胁。目前的标准间接药敏试验(DST)需要长达3个月的时间来识别广泛耐药结核病，这破坏了控制广泛耐药结核病的努力。加州大学圣地亚哥分校组建了一个由学术界、公共卫生和工业界的结核病专家组成的国际团队，以推进3种快速测试(即主试条、分子信标、显微镜观察药敏分析)的开发和评估，以直接从痰中检测对6种定义XDR-TB的药物(即异烟肼、利福平、氧氟沙星、阿米卡星、卡那霉素和卷曲霉素)的耐药性。具体目标是(1)将检测广泛耐药结核病的平均时间从几个月减少到一周，(2)证明快速检测与标准DST之间的一致性，(3)确定目标2中不一致结果的遗传基础，(4)表征全球广泛耐药结核病菌株和耐药性流行病学，以及(5)研究成本效益。在第一年，将根据已公布的信息、可公开获得的基因组数据库以及来自四个研究地点(即南非、摩尔多瓦、印度、菲律宾)的现有XDR和药物敏感菌株的基因分析的新信息，为快速测试(版本1)创建新的探针和分析程序。这些研究地点将在2-4年内招募2475名结核病患者；收集临床数据、痰和培养分离株；并现场进行三项快速检测和DST。被DST鉴定为耐药但未经快速检测的菌株将通过对目标基因、邻近基因或整个基因组进行测序来进一步检查，以找到与药物敏感菌株相比的新的区域或点。通过这一过程发现的新突变将根据需要创建用于版本2快速测试的探针，以便与版本1一起进行现场测试。这项为期5年的研究将产生新的检测方法，在广泛的实验室环境中快速检测广泛耐药结核病，并为未来的研究建立各种具有良好特征的结核病毒株的资料库。长期的影响是开发能够适用于快速检测新的耐药结核病菌株和测试对其他抗结核病药物的耐药性的技术和方法。相关性(见说明)：广泛耐药结核病与高死亡率有关，具有高度传染性，如果不迅速发现和治疗，有可能在地方、国家和全球范围内对公共卫生系统和经济造成大规模破坏。这项研究建议开发和评估三种新的快速检测方法，以减少广泛耐药结核病的检测时间，以更好地指导公共卫生措施和患者管理决策。

DESCRIPTION (provided by applicant): The emergence of extensively drug-resistant tuberculosis (XDR-TB) poses a growing threat to national and international biosecurity and to TB control achievements. Current standard indirect drug susceptibility testing (DST) takes up to 3 months to identify XDR-TB, undermining efforts to control XDR-TB. The University of California at San Diego has assembled an international team of TB experts from academia, public health, and industry to advance the development and evaluation of 3 rapid tests (i.e., Main strip, molecular beacon, microscopic-observation drug-susceptibility assays) to detect resistance to 6 drugs defining XDR-TB (i.e., isoniazid, rifampin, ofloxacin, amikacin, kanamycin, and capreomycin) directly from sputa. The specific aims are (1) to reduce the average XDR-TB detection time from months to a week, (2) to demonstrate agreement between the rapid tests and standard DST, (3) to identify the genetic basis of discordant results in Aim 2, (4) to characterize global XDR-TB strains and the epidemiology of drug resistance, and (5) to study cost- effectiveness. In Year 1, creation of new probes and assay procedures for the rapid tests (Version-1) will be based on published information, publicly-available genomic databases and new information from genotypic analysis of existing XDR and drug-susceptible strains from four study sites (i.e., South Africa, Moldova, India, the Philippines). These study sites will enroll 2,475 TB patients in Years 2-4; collect clinical data, sputa, and culture isolates; and perform the three rapid tests and DST onsite. Strains identified as drug resistant by the DST but not by the rapid tests will be further examined through sequencing target genes, neighboring genes, or whole genomes to find new regions or points of difference compared to drug-susceptible strains. New mutations discovered through this process will inform creation of probes for Version-2 rapid tests, as needed, to be tested onsite along with Version-1. This 5-year study will result in novel tests to rapidly detect XDR-TB in a broad range of laboratory settings as well as a repository of diverse well-characterized TB strains for future studies. The long-term implication is the development of technologies and methods that can be adapted to rapidly detect new drug-resistant TB strains and to test for resistance to other anti-TB drugs. RELEVANCE (See instructions): XDR-TB is associated with high fatality rates, is highly communicable, and has the potential to cause massive disruption to public-health systems and economies at a local, national and global scale if not detected and treated rapidly. The study proposes to develop and evaluate three novel rapid tests to reduce XDR-TB detection time to better guide public health measures and patient management decisions.