Integrating genomic and spatial approaches for targeted control of HIV-associated tuberculosis epidemics

项目总结 结核病(TB)仍然是由单一病原体引起的主要感染性死亡原因，并且是主要的 艾滋病毒携带者的死因。在艾滋病毒高流行环境中改善结核病控制需要 阻断结核病传播的新方法。最近的研究表明，在 结核病的社区危险因素，以及结核病的传播和流行，即使在高密度城市 中心设在非洲。艾滋病高发区活动性肺结核病例发现的无针对性社区干预 环境需要大量资源来实施，但还没有可靠地产生人口一级的好处。 我们假设，通过结核分枝杆菌的全基因组测序，可以更准确地针对结核病干预措施。 从所有培养阳性的结核病患者中分离出结核病，将导致更有效的结核病控制，还可能 与关注较少的以社区为基础的干预措施相比，在艾滋病毒负担较高的情况下具有效率优势 设置。基于之前的研究和我们在马拉维布兰太尔的研究现场的初步数据(那里是成年人 艾滋病毒流行率约为20%，近80%的呈报结核病病例为艾滋病毒血清阳性)，我们认为 护理场所和其他地点将被确定为结核病传播热点，那里是传染性结核病病例的聚集地 在感染控制条件较差的情况下，与高度易感的个人接触。 在这个项目中，我们建议使用从以下地点收集的数据和样本 马拉维布兰太尔市的所有诊断中心在2015年到我们开始研究期间完成 三个具体目标：(目标1)综合预期收集的人口、空间和基因组数据，以 阐明艾滋病毒高流行环境中当地结核病传播动态的模式和关键驱动因素； 2)开发和应用当地校准的数学模型，以调查潜在的影响和成本- 由地点和地点的高分辨率信息提供的空间定向结核病干预措施的有效性 艾滋病毒高流行环境中的感染源，以及(目标3)正式评估信息的价值 通过全基因组测序来提供，并估计建立局部 病原体基因组数据的测序和分析能力。

PROJECT SUMMARY Tuberculosis (TB) remains the leading infectious cause of death due to a single pathogen and is a leading cause of death among individuals living with HIV. Improved TB control in high HIV prevalence settings requires new approaches for interrupting TB transmission. Recent studies have revealed substantial heterogeneity in community risk factors for TB, as well as in TB transmission and prevalence, even within high-density urban centers in Africa. Untargeted community-based interventions for active TB case finding in high HIV prevalence settings demand substantial resources to implement yet have not reliably produced population-level benefits. We hypothesize that more precisely targeted TB interventions, informed by whole genome sequencing of M. tuberculosis isolates from all culture-positive TB patients, will result in more effective TB control, and may also have efficiency benefits when compared with less focused community-based interventions in high HIV burden settings. Based on previous studies and preliminary data from our study site in Blantyre, Malawi (where adult HIV prevalence is around 20% and nearly 80% of notified TB cases are HIV seropositive), we believe that HIV care settings and other locations will be identified as TB transmission hotspots where infectious TB cases are in contact with highly susceptible individuals under poor infection control conditions. In this project, we propose to use data and specimens that have been collected from notified TB patients from all diagnostic centers in the city of Blantyre, Malawi between 2015 and the start of our study to accomplish three specific aims: (Aim 1) To synthesize prospectively-collected demographic, spatial and genomic data to illuminate patterns and critical drivers of local TB transmission dynamics in high HIV prevalence settings; (Aim 2) To develop and apply locally-calibrated mathematical models to investigate the potential impact and cost- effectiveness of spatially-targeted TB interventions informed by high-resolution information on locations and sources of infection in high HIV prevalence settings, and (Aim 3) To formally assess the value of information afforded by whole genome sequencing and to estimate the costs and cost-effectiveness of building local capacity for sequencing and analysis of pathogen genomic data.