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，每年新增病例近50万例。南非的艾滋病毒负担是世界上最高的，而且耐多药结核病疫情也在迅速扩大，这引发了人们对这两种疾病灾难性汇聚的担忧。在南非和其他地区，耐多药结核病/艾滋病毒混合感染与极高的死亡率有关--每年高达80%。然而，大多数死亡率估计是在抗逆转录病毒治疗(ART)可用之前得出的。目前尚不清楚接受抗逆转录病毒疗法治疗的耐多药结核病/艾滋病毒混合感染者的死亡率。抗逆转录病毒疗法显著提高了对药物敏感的结核病/艾滋病毒混合感染者的存活率。虽然在耐多药结核病治疗中加入抗逆转录病毒疗法有望同样提高耐多药结核病/艾滋病毒混合感染者的存活率，但这一益处可能会被微生物或宿主因素削弱，而微生物或宿主因素可能在耐多药结核病/艾滋病毒联合感染中更为普遍。尽管抗逆转录病毒治疗，但由于感染了更多毒力的结核菌株，艾滋病毒感染者可能更有可能患上耐多药结核病，从而导致更高的死亡率。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，在艾滋病毒中更常见，与不良的耐多药结核病结局独立相关，尽管联合应用抗逆转录病毒疗法和耐多药结核病治疗，但可能会恶化存活率。除了提高存活率，抗逆转录病毒治疗和耐多药结核病联合治疗可能会导致并发症(即更多的不良反应和免疫重建炎症综合征[IRIS]，或更低的依从性)，从而损害耐多药结核病和艾滋病毒的结果。具体地说，它可能导致耐多药结核病培养转换率较低，耐多药结核病治疗失败率或艾滋病毒病毒学失败率较高。识别和了解这些潜在的并发症将为未来耐多药结核病/艾滋病毒混合感染的干预研究提供信息。在这项应用中，我们将汇集耐多药结核病/艾滋病毒受试者的队列，并前瞻性地检查同时进行耐多药结核病治疗和抗逆转录病毒疗法对生存的影响(目标1)。寄主因素对存活率的影响将被研究。此外，我们将对所有耐多药结核病分离株进行分型，以确定结核菌株的流行率，以确定这是否会影响存活率的差异(目标2)。我们将进一步审查耐多药结核病和艾滋病毒联合治疗对每种疾病结果的影响，并严格衡量可能影响这些结果的因素，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，特别是提高对艾滋病毒和耐药结核病的了解的流行病学研究，以及评估患有这两种疾病并同时接受治疗的患者结果的临床研究。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震中进行，我们的国际研究小组自2002年以来一直在那里努力改善结核病/艾滋病毒混合感染的结果。 与公共卫生相关：尽管耐多药结核病/艾滋病毒混合感染以前的特点是死亡率极高，但这是在可获得挽救生命的抗逆转录病毒治疗之前。研究结果将有助于改善受耐多药结核病疫情影响的个人和社区的健康，并将创建一个证据基础，以指导整个发展中国家耐多药结核病/艾滋病毒疾病治疗的健全临床实践和公共卫生政策。

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.