Defining drivers of TB transmission in the era of universal ART, and implications for finding the walking well

项目摘要 结核病（TB）仍然是全球死亡的主要原因，特别是在艾滋病毒阳性人群中。 了解抗逆转录病毒治疗（ART）时代结核病传播的动态是遏制结核病的关键 传输随着抗逆转录病毒疗法推广的进展，接受抗逆转录病毒疗法的人对结核病传播的贡献是否 增长是未知的。社区结核病调查一致表明，大约一半的传染性结核病患者 没有报告症状，因此被目前大多数结核病筛查工作所遗漏。的目的 该项目旨在确定如何确定结核病病例发现工作的目标，以最大限度地发挥影响，同时保持成本效益， 艾滋病毒高流行率和成熟的抗逆转录病毒治疗方案的背景下。我们的中心假设是人口和 可以定义“结核病不可知”结核病筛查（即不限于有症状的人）的设置， 对结核病传播有重大影响，而且具有成本效益。本项目的目的是（1）比较 （2）与未接受抗逆转录病毒治疗的人相比，艾滋病毒阳性者接受抗逆转录病毒治疗的比例; “走得好”，即无症状结核病患者;（3）模拟症状的影响和成本效益， 在各级卫生系统进行不可知的筛查。该项目将在联合国 非洲卫生研究所（AHRI）在南非夸祖鲁-纳塔尔的人口监测区， 结核病发病率、艾滋病毒流行率和抗逆转录病毒治疗覆盖率都很高， 结核病筛查已经开始。我们将通过家庭接触研究来实现我们的目标， 家庭接触者中感染结核病的儿童比例，根据 结核病患者的特征。对于目标1，我们将比较儿童结核病接触者的比例 感染之间的艾滋病毒阳性指标结核病患者谁是与不服用抗逆转录病毒治疗。为目标2，我们将比较 未报告的无症状指示结核病患者与结核病感染儿童接触的比例 任何症状（由AHRI的人口结核病调查确定）与有症状的索引结核病患者。这给了我们一个 这是一个调查结核病从没有报告结核病症状的人传播的独特机会， 被大多数结核病筛查项目遗漏。在目标3中，我们将使用一种新的数学模型， 从目标1和2中获得对结核病自然史和传播的深入了解，以确定具体情况 在这种情况下，结核病不可知筛查对结核病发病率和死亡率的影响最大，并探讨 在不同的健康水平上，干预措施沿着诊断途径的成本效益比较 系统通过将基于人群的流行病学与数学和经济模型相结合，我们的项目 （i）应否投放更多资源，以及早识别结核病 （二）是否应考虑对“走得好”的患者进行不可知的筛查;以及（三） 什么条件。这可能为结核病病例发现策略的范式转变提供信息。

PROJECT SUMMARY Tuberculosis (TB) remains a leading cause of death globally, particularly among HIV-positive people. Understanding the dynamics of TB transmission in the era of antiretroviral therapy (ART) is key to halting TB transmission. As ART roll-out progresses, whether the contribution of people taking ART to TB transmission is increasing is unknown. Community TB surveys consistently show that about half of people with infectious TB do not report symptoms, and are therefore missed by most current TB screening efforts. The objective of this project is define how to target TB case-finding efforts to maximise impact while retaining cost-effectiveness, in settings of high HIV prevalence and mature ART programs. Our central hypothesis is that populations and settings can be defined where "symptom-agnostic" TB screening (i.e. not limited to symptomatic people) has a major impact on TB transmission, and is cost-effective. The project aims are (1) to compare the infectiousness of HIV-positive people taking ART compared to those not taking ART; (2) to assess the infectiousness of the "walking well", i.e. people with asymptomatic TB; (3) to model the impact and cost-effectiveness of symptom- agnostic screening at different levels of the health system. The project will be conducted in the context of the Africa Health Research Institute (AHRI)'s demographic surveillance area in KwaZulu-Natal, South Africa where TB incidence, HIV prevalence and ART coverage are high, and a population survey using mass radiographic screening for TB has started. We will accomplish our aims through a household contact study, measuring the proportion of child household contacts who have TB infection, comparing groups of households according to characteristics of the index TB patient. For Aim 1, we will compare the proportion of child contacts with TB infection between HIV-positive index TB patients who are vs. are not taking ART. For Aim 2, we will compare the proportion of child contacts with TB infection between asymptomatic index TB patients who do not report any symptoms (identified by AHRI's population TB survey) vs. symptomatic index TB patients. This gives us a unique opportunity to investigate TB transmission from people who do not report TB symptoms, who are missed by most TB screening programs. In Aim 3 we will use a novel mathematical model, incorporating new insights into TB natural history and transmission gained from Aims 1 and 2, to determine the circumstances under which symptom-agnostic screening would have most impact on TB incidence and mortality, and explore comparative cost-effectiveness of interventions along the diagnostic pathway at different levels of the health system. By combining population-based epidemiology with mathematical and economic modelling, our project will delineate (i) whether more resources should be dedicated to earlier identification of TB among people taking ART; (ii) whether symptom-agnostic screening of the "walking well"; should be considered and (iii) under what conditions. This could inform a paradigm shift in TB case-finding strategy.