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

描述（由申请人提供）：耐多药结核病（MDR TB）已成为一个重大的全球威胁，每年有近50万新病例。南非是全世界艾滋病毒负担最高的国家，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发生灾难性汇合的担忧。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有关——一年时高达80%。然而，大多数死亡率估计是在获得抗逆转录病毒治疗（ART）之前得出的。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目前尚不清楚。抗逆转录病毒治疗显著提高了药物敏感结核病/艾滋病毒合并感染者的生存率。虽然在耐多药结核病治疗中加入抗逆转录病毒治疗有望同样提高耐多药结核病/艾滋病毒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，这些因素可能在耐多药结核病/艾滋病毒合并感染中更为普遍。艾滋病毒感染者由于感染了毒性更强的结核菌株，更有可能发展为耐多药结核病，导致尽管采用抗逆转录病毒治疗，但死亡率更高。同样，某些宿主因素，如播散性结核病、免疫抑制或低体重指数（这些在艾滋病毒中更为常见）与耐多药结核病预后差独立相关，并且尽管抗逆转录病毒治疗和耐多药结核病联合治疗，仍可能使生存恶化。除了提高生存率外，抗逆转录病毒治疗和耐多药结核病联合治疗可能导致并发症（即不良反应和免疫重建炎症综合征[IRIS]的发生率更高，或依从性较低），从而损害耐多药结核病和艾滋病毒的预后。具体而言，它可能导致耐多药结核病培养物转化率降低，耐多药结核病治疗失败率或艾滋病毒病毒学失败率升高。识别和了解这些潜在的并发症将为未来耐多药结核病/艾滋病毒合并感染的干预研究提供信息。在这一应用中，我们将收集一组耐多药结核病/艾滋病受试者，并前瞻性地检查耐多药结核病治疗和抗逆转录病毒治疗同时进行对生存的影响（目的1）。我们将研究宿主因素对存活的影响。此外，我们将对所有耐多药结核分离株进行基因分型，以确定结核菌株的患病率，以确定这是否介导了生存差异（目的2）。我们将进一步研究耐多药结核病和艾滋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了解，以及临床研究，以评估患有这两种疾病并同时接受治疗的患者的结果。这项申请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集中流行的中心进行，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。

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.