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

项目总结 结核病(TB)仍然是全球主要的死亡原因，特别是在艾滋病毒阳性者中。 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 变速箱。随着抗逆转录病毒药物推广的进展，服用抗逆转录病毒药物对结核病传播的贡献是否 增长是未知的。社区结核病调查一直显示，大约一半的感染性结核病患者 不报告症状，因此大多数当前的结核病筛查工作都忽略了这一点。这样做的目的是 该项目定义了如何针对结核病病例发现工作，在保持成本效益的同时最大限度地发挥影响， 艾滋病毒高流行率的环境和成熟的抗逆转录病毒治疗方案。我们的中心假设是，人口和 可以定义这样的设置，即“症状不可知”的结核病筛查(即不限于有症状的人)具有 对结核病传播有重大影响，而且具有成本效益。该项目的目的是(1)比较传染病的传染性 接受抗逆转录病毒疗法的艾滋病毒阳性者与未接受抗逆转录病毒疗法的人的比较；(2)评估 “行走良好”，即患有无症状结核病的人；(3)模拟症状的影响和成本效益- 在卫生系统的不同级别进行不可知的筛查。该项目将在以下背景下进行 非洲卫生研究所S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疗法覆盖率都很高，使用大规模放射照片进行的人口调查 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，测量 与儿童有家庭接触的儿童感染结核病的比例，根据 指标结核病患者的特征。对于目标1，我们将比较儿童接触者与结核病的比例 HIV阳性指标结核病患者与未接受抗逆转录病毒治疗的患者之间的感染情况。对于目标2，我们将比较 未报告的无症状指标结核病患者与儿童接触者感染结核病的比例 任何症状(由AHRI的人口结核病调查确定)与症状指数结核病患者相比。这给了我们一个 调查未报告结核病症状的人的结核病传播的独特机会，这些人 大多数结核病筛查项目都忽略了这一点。在目标3中，我们将使用一个新的数学模型，结合新的 从目标1和目标2获得对结核病自然历史和传播的见解，以确定情况 在什么情况下，症状不可知的筛查对结核病的发病率和死亡率影响最大，并探索 不同健康水平诊断途径干预措施的成本-效果比较 系统。通过将基于人口的流行病学与数学和经济模型相结合，我们的项目 将勾勒出(I)应否拨出更多资源，以便及早在市民中发现结核病 接受ART；(2)是否应考虑对“行走良好”进行症状不可知的筛查；以及(3)在 什么条件。这可能会推动结核病病例发现战略的范式转变。

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.