Novel clinic-based TB diagnostics and testing algorithms for persons with HIV

项目总结/摘要 结核病（TB）是撒哈拉以南非洲艾滋病毒感染者（PWH）死亡的主要原因，部分原因是 延误诊断和及时治疗。虽然艾滋病毒感染者往往首先在外围诊所寻求治疗， 位于中心实验室的结核病诊断检测设备需要耗时的标本运输 和处理，导致延误诊断和病人辍学的照顾。使用基于尿液的即时护理 一种检测分枝杆菌脂阿拉伯甘露聚糖（LAM）的试验成功地降低了医院的死亡率 设置，但现有的测试是不敏感的门诊病人。未确诊结核病的最大负担是在 非医院环境中的PWH，以及基于临床的测试分析和改进的算法是迫切需要的。一 一种有前途的新型、快速、尿基测试（nuLAM）已经开发出来，它可能会克服结核病的许多障碍 诊断，但尚未在临床环境中进行测试。我的核心假设是合理使用next- 第二代POC LAM测试将是南非威尔斯亲王医院的有效干预措施。我将检验这个假设 具体目标如下：1）开发一种优化的临床算法来识别HIV感染的门诊患者 用于使用POC uLAM的TB测试和指导nuLAM的评估。2)为了确定诊断的准确性， 下一代LAM检测，以检测在农村诊所就诊的HIV感染门诊患者中的结核病， 南非，与严格的TB培养和GeneXpert验证标准相比。3)估计 通过成本计算和决策分析对门诊PWH进行nuLAM检测的人群水平影响。我的职业生涯 目标是成为一名医生，科学家，专注于开发和实施诊断方法， 最终降低艾滋病毒相关结核病的发病率和死亡率。我将利用K23奖的机会， 在预测建模、实施科学和诊断科学方面获得指导。这些技能是 与我在流行病学方法和临床研究方面的强大背景高度互补，并将使 我将流行病学研究结果转化为工具，以帮助临床医生和政策制定者改善 结核病的诊断方法。在完成研究和指导概述，我将很好地定位 开展独立的研究事业，最终目标是改善诊断，治疗和护理 撒哈拉以南非洲的艾滋病毒相关结核病。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading cause of mortality in people with HIV (PWH) in sub-Saharan Africa, due in part to delays in diagnosis and timely treatment. While HIV-infected persons often first seek care at peripheral clinics, TB diagnostic testing equipment located in centralized laboratories require time-consuming specimen transport and processing, resulting in delayed diagnosis and patient drop-out from care. Use of a point-of-care urine-based test detecting mycobacterial lipoarabinomannan (LAM) has been successful in reducing mortality in a hospital setting, but the existing test is insensitive in ambulatory patients. The largest burden of undiagnosed TB is in PWH in non-hospital settings, and clinic-based testing assays and improved algorithms are urgently needed. A promising novel, rapid, urine-based tests (nuLAM) has been developed that may overcome many barriers to TB diagnosis, but has not yet been tested in a clinical setting. My central hypothesis is that rational use of next- generation POC LAM testing will be an effective intervention for PWH in South Africa. I will test this hypothesis with the following specific aims: 1) To develop an optimized clinical algorithm to identify HIV-infected outpatients for TB testing using POC uLAM and guide evaluation of nuLAM. 2) To determine the diagnostic accuracy of the next-generation LAM tests to detect TB in a population of HIV-infected outpatients attending a rural clinic in South Africa, compared to rigorous validation standards of TB culture and GeneXpert. 3) To estimate the population-level impact of nuLAM testing of outpatient PWH through costing and decision analysis. My career goal is to become a physician-scientist with a focus on developing and implementing diagnostic approaches to ultimately reduce morbidity and mortality from HIV-associated TB. I will use the opportunity of the K23 award to obtain mentorship in predictive modeling, implementation science, and diagnostics science. These skills are highly complementary to my strong background in epidemiologic methods and clinical research, and will enable me to translate epidemiologic research findings into tools to help clinicians and policymakers improve approaches to TB diagnosis. At the completion of the research and mentoring outlined, I will be well-positioned to launch an independent research career with the ultimate goal of improving diagnosis, treatment, and care of HIV-associated TB in sub-Saharan Africa.