Impact of HIV, Antiretroviral Therapy and TB Genotype on Survival in MDR TB

描述（申请人提供）：耐多药结核病（MDR TB）已成为一个重大的全球威胁，每年有近50万新发病例。南非是世界上艾滋病毒负担最重的国家，而且耐多药结核病的流行也在迅速扩大，这引起了人们对这两种疾病灾难性趋同的担忧。在南非和其他地区，耐多药结核病/艾滋病毒合并感染与极高的死亡率相关--一年死亡率高达80%。然而，大多数死亡率估计数是在抗逆转录病毒疗法可用之前得出的。目前尚不清楚接受抗逆转录病毒治疗的耐多药结核病/艾滋病毒合并感染者的死亡率。抗逆转录病毒疗法显著提高了对药物敏感的结核病/艾滋病毒合并感染者的存活率。尽管在MDR TB治疗中加入ART有望类似地改善MDR TB/HIV合并感染者的生存率，但这种益处可能会因微生物或宿主因素而减弱，这些因素在MDR TB/HIV合并感染中可能更普遍。HIV感染者可能更有可能由于感染毒性更强的TB菌株而发展为MDR TB疾病，导致尽管进行ART仍有更高的死亡率。同样，某些宿主因素，如在HIV中更常见的播散性TB、免疫抑制或低体重指数，与MDR TB不良结局独立相关，尽管进行ART和MDR TB联合治疗，仍可能使生存率恶化。除了提高生存率外，联合ART和MDR TB治疗可能导致并发症（即，不良反应和免疫重建炎性综合征[IRIS]的发生率更高，或依从性更低），从而损害MDR TB和HIV结局。具体而言，它可能导致MDR TB培养转化率较低，MDR TB治疗失败或HIV病毒学失败率较高。识别和了解这些潜在的并发症将为未来的耐多药结核病/艾滋病病毒合并感染的干预研究提供信息。在本申请中，我们将组建一个MDR TB/HIV受试者队列，并前瞻性地研究同时进行MDR TB治疗和ART对生存率的影响（目标1）。将检查宿主因素对存活率的影响。此外，我们将对所有MDR TB分离株进行基因分型，以确定TB菌株的流行率，从而确定这是否介导生存率的差异（目标2）。我们将进一步研究耐多药结核病和艾滋病病毒联合治疗对每种疾病结局的影响，并严格衡量可能影响这些结局的因素，即：不良事件、IRIS和依从性（目标3和4）。艾滋病毒和耐药结核病之间的相互作用已被确定为NIH/NIAID和联邦结核病工作组的优先研究领域，特别是流行病学研究，以提高对艾滋病毒和耐药结核病的认识，以及临床研究，以评估患有这两种疾病并接受同时治疗的患者的结果。这项应用将直接解决这些问题，并将在南非农村结核病、艾滋病毒和耐药结核病的集中流行中心进行，我们的国际研究小组自2002年以来一直致力于改善结核病/艾滋病毒合并感染的结果。 公共卫生相关性：虽然耐多药结核病/艾滋病毒合并感染以前的特点是极高的死亡率，这是在挽救生命的抗逆转录病毒治疗可用之前。研究结果将有助于改善受耐多药结核病流行影响的个人和社区的健康状况，并将为指导整个发展中国家耐多药结核病/艾滋病治疗的合理临床实践和公共卫生政策建立证据基础。

DESCRIPTION (provided by applicant): Multidrug-resistant tuberculosis (MDR TB) has emerged as a significant global threat, with nearly 500,000 new cases annually. South Africa has the highest burden of HIV worldwide and also has a rapidly expanding MDR TB epidemic, raising concerns for a catastrophic convergence of these two diseases. In South Africa and in other regions, MDR TB/HIV co-infection has been associated with exceedingly high mortality-up to 80% at one year. Most mortality estimates, however, were derived prior to the availability of antiretroviral therapy (ART). Mortality rates for MDR TB/HIV co-infected persons treated with ART are currently unknown. ART has markedly improved survival in drug-susceptible TB/HIV co-infected persons. Though adding ART to MDR TB treatment is hoped to similarly improve survival in MDR TB/HIV co-infected persons, this benefit may be attenuated by microbial or host factors which may be more prevalent in MDR TB/HIV co-infection. HIV- infected persons may be more likely to develop MDR TB disease as a result of infection with more virulent TB strains, leading to higher mortality despite ART. Similarly, certain host factors, such as disseminated TB, immunosuppression, or low body mass index, which are more common in HIV, are independently associated with poor MDR TB outcomes and may worsen survival despite combined ART and MDR TB treatment. In addition to improving survival, combined ART and MDR TB treatment may result in complications (i.e., greater incidence of adverse reactions and immune reconstitution inflammatory syndrome [IRIS], or lower adherence) that compromise both MDR TB and HIV outcomes. Specifically, it may cause lower rates of MDR TB culture conversion and higher rates of MDR TB treatment failure, or HIV virologic failure. Identifying and understanding these potential complications will inform future intervention studies of MDR TB/HIV co-infection. In this application, we will assemble a cohort of MDR TB/HIV subjects and examine prospectively the impact of concurrent MDR TB treatment and ART on survival (Aim 1). The influence of host factors on survival will be examined. Additionally, we will genotype all MDR TB isolates to determine TB strain prevalence to determine whether this mediates differences in survival (Aim 2). We will further examine the effect of MDR TB and HIV co-treatment on outcomes for each disease, with rigorous measures of factors that may impact these outcomes, namely: adverse events, IRIS, and adherence (Aims 3 & 4). The interactions between HIV and drug-resistant TB have been identified as a priority research area for the NIH/NIAID and the Federal TB Task Force, specifically epidemiologic research to improve understanding of HIV and drug-resistant TB, and clinical research to assess outcomes of patients afflicted with both diseases and undergoing concurrent treatment. This application will address these issues directly, and will take place at the epicenter of the convergent epidemics of TB, HIV, and drug-resistant TB in rural South Africa, where our international research group has been working to improve outcomes in TB/HIV co-infection since 2002. PUBLIC HEALTH RELEVANCE: While MDR TB/HIV co-infection was previously characterized by extremely high mortality, this was before life- saving antiretroviral therapy was available. Findings will help improve the health of individuals and communities affected by the MDR TB epidemic and will create an evidence-base to guide sound clinical practice and public health policy for MDR TB/HIV disease treatment throughout the developing world.