Transmission of HIV-Associated XDR TB in Rural South Africa

描述(申请人提供)：广泛耐药结核病(广泛耐药结核病)已成为一种重大的全球流行病，并对艾滋病毒感染者构成特别威胁。耐药结核病主要被认为是由于耐药突变杆菌(“放大耐药性”)的选择压力而发展起来的。然而，由于接触和感染已经具有抗药性的结核菌株(“初级传播”)，也可能发生耐药结核病。耐药结核病菌株的传播在聚集环境中得到了很好的描述，例如在医院中容纳了高度免疫受损的患者，但很少有研究评估耐药结核病在人群水平的传播，而且没有一项研究在艾滋病毒高流行的环境中这样做。广泛耐药结核病和艾滋病毒在南非的碰撞为研究这两种流行病提供了一个独特的早期机会，预计这两种流行病未来将在其他国家汇聚。目前的全球耐药结核病危机既是由于扩大的耐药性，也是由于初次传播，尽管两者的相对贡献尚不清楚。在这项申请的目标1中，我们提出了一项前瞻性的、基于人群的横断面研究，以确定由于初次传播而发展的新的广泛耐药结核病病例的比例，而不是图格拉·费里区的放大耐药性，图格拉·费里区是南非的一个农村地区，广泛耐药结核病和艾滋病毒的混合感染率非常高。我们假设，超过四分之三的广泛耐药结核病病例是由原发传播引起的。在目标2中，我们将把分子基因分型与接触者追踪和社会网络分析相结合，以深入了解具有匹配菌株基因型别的广泛耐药结核病受试者(“集群”)与可能发生结核病传播的地点之间的关系。我们希望确定传播不仅发生在医疗保健中，而且发生在社区聚集环境中。这项研究的结果将有助于更好地了解Tugela Ferry社区的广泛耐药结核病传播模式，这对于针对干预措施遏制正在进行的广泛耐药结核病流行至关重要。这项拟议的研究将首次整合流行病学、分子和社会网络分析方法来研究艾滋病毒高流行环境下的结核病传播。艾滋病毒感染和耐药结核病之间的相互作用已被美国国立卫生研究院和联邦结核病工作组确定为优先研究领域，特别是流行病学研究和更多地使用基因分型以提高对艾滋病毒和耐药结核病的了解，以及实施密集的接触者追踪和暴发调查。这项申请将直接解决这些问题，并在南非农村结核病、艾滋病毒和耐药结核病集中流行的震中进行，我们的研究小组自2002年以来一直在那里工作。对广泛耐药结核病进行持续的人口一级监测，包括对Tugela Ferry区所有结核病嫌疑人进行培养和药敏试验，为研究广泛耐药结核病的传播创造了独特的机会。

DESCRIPTION (provided by applicant): Extensively drug-resistant tuberculosis (XDR TB) has emerged as a significant global epidemic and poses a particular threat to HIV-infected persons. Drug-resistant TB disease is predominantly thought to develop as a result of selection pressure for drug-resistant mutant bacilli ("amplified resistance"). Drug-resistant TB disease may also occur, however, from exposure to and infection with a TB strain which is already drug-resistant ("primary transmission"). Transmission of drug-resistant TB strains has been well-described in congregate settings, such as hospitals containing highly immunocompromised patients, but few studies have evaluated population-level transmission of drug-resistant TB, and none have done so in a high HIV prevalence setting. The collision of XDR TB and HIV in South Africa offers a unique, early opportunity to study these dual epidemics, which are anticipated to converge in other countries in the future. The current global crisis of drug-resistant TB is due to both amplified resistance and primary transmission, although the relative contribution of each is unknown. In Aim 1 of this application, we propose a prospective, population-based, cross-sectional study to determine the proportion of new XDR TB cases which develop due to primary transmission as opposed to amplified resistance in Tugela Ferry district, a rural area of South Africa with exceedingly high rates of XDR TB and HIV co-infection. We hypothesize that over three-quarters of XDR TB cases arise due to primary transmission. In Aim 2, we will combine molecular genotyping with contact tracing and social network analysis to provide insights into the relationships between XDR TB subjects with matching strain genotypes ("clusters") and the locations where TB transmission may be occurring. We expect to identify that transmission is occurring in not only healthcare, but also community congregate settings. The findings from this study will lead to a better understanding of XDR TB transmission patterns in the Tugela Ferry community, which is critical for targeting interventions to curb the ongoing XDR TB epidemic. The proposed study will be the first to integrate epidemiologic, molecular, and social network analytic methods to study TB transmission in a high HIV prevalence setting. The interactions between HIV infection and drug-resistant TB have been identified as a priority research area by the NIH and the Federal TB Task Force, specifically epidemiologic research and greater use of genotyping to improve understanding of HIV and drug-resistant TB, and implementation of intensive contact tracing and outbreak investigation. This application will address these issues directly and take place at the epicenter of the convergent epidemics of TB, HIV, and drug-resistant TB in rural South Africa, where our research group has been working since 2002. Continuous, population-level surveillance for XDR TB, including culture and drug-susceptibility testing for all TB suspects in Tugela Ferry district, creates a unique opportunity to study XDR TB transmission.