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

HIV、抗逆转录病毒治疗和结核病基因型对耐多药结核病患者生存的影响

• 批准号: 8289466
• 负责人: Neel Rajnikant Gandhi
• 金额: $ 89.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289466
• 关键词: AIDS/HIV problem; Address; Adherence; Adherence Syndrome; Adverse effects; Adverse event; Adverse reactions; Advisory Committees; Affect; Area; Attenuated; Body mass index; Clinical Research; Cohort Studies; Combined Modality Therapy; Communities; Complex; Complication; Control Groups; Data; Disease; Disease Outbreaks; Drug Resistant Tuberculosis; Enrollment; Epidemic; Epidemiologic Studies; Failure; Future; Genotype; HIV; HIV Seropositivity; HIV drug resistance; Health; Health Policy; Immune; Immunosuppression; Incidence; Individual; Infection; Inflammatory; Integration Host Factors; International; Intervention Studies; Lead; Life; Measures; Mediating; Multidrug-Resistant Tuberculosis; National Institute of Allergy and Infectious Disease; Outcome; Patients; Persons; Pharmaceutical Preparations; Prevalence; Prospective Studies; Public Health; Research; Research Priority; Resistance; Retrospective Studies; Risk; Rural; Severe Adverse Event; Severity of illness; South Africa; Southern Africa; Study Subject; Survival Rate; Syndrome; Treatment Failure; Treatment outcome; Tuberculosis; United States National Institutes of Health; Virulent; Work; antiretroviral therapy; clinical practice; cohort; evidence base; experience; improved; microbial; microbial host; mortality; prospective; public health relevance; reconstitution; sound; treatment duration; tuberculosis treatment

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.

描述（由申请人提供）：多药耐药性结核病（MDR TB）已成为一个重大的全球威胁，每年有近50万例新案件。南非是全球艾滋病毒的最高负担，也有迅速扩大的MDR结核病流行，引起了人们对这两种疾病的灾难性融合的担忧。在南非和其他地区，MDR TB/HIV共同感染与一年的死亡率高至80％有关。但是，大多数死亡率估计是在抗逆转录病毒疗法（ART）的可用性之前得出的。目前尚不清楚接受ART治疗的MDR TB/HIV共同感染者的死亡率。 ART明显改善了可易药的TB/HIV共同感染的人的生存。尽管希望在MDR结核病治疗中增加ART，希望同样提高MDR TB/HIV共感染的人的生存率，但这种益处可能会受到微生物或宿主因素的衰减，这些因素可能在MDR TB/HIV共同感染中更普遍。受HIV感染的人可能由于感染更具毒性的结核病菌株而产生MDR结核病疾病，尽管有艺术，但仍导致更高的死亡率。同样，在HIV中更常见的某些宿主因素，例如传播的结核病，免疫抑制或低体重指数，与MDR结核病结果差是独立的，尽管ART和MDR TB治疗综合，但生存率可能会恶化。除了提高生存率外，ART和MDR结核病的联合治疗还可能导致并发症（即，不良反应和免疫重建炎症综合征[IRIS]或较低的依从性的发生率更大），从而损害了MDR TB和HIV结果。具体而言，它可能导致MDR TB培养转化率和MDR TB治疗失败或HIV病毒学衰竭的率较低。识别和理解这些潜在的并发症将为MDR TB/HIV共同感染的未来干预研究提供信息。在此应用中，我们将组装一组MDR TB/HIV受试者，并前瞻性地检查并发的MDR TB治疗和ART对生存的影响（AIM 1）。将检查宿主因素对生存的影响。此外，我们将基因型所有MDR TB分离株确定TB应变患病率，以确定这是否介导了生存的差异（AIM 2）。我们将进一步研究MDR结核病和HIV共同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，虹膜和依从性（目标3和4）。 HIV与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，以提高人们对抗HIV和耐药性结核病的了解，以及评估患有疾病和经过并发治疗的患者的临床研究。该申请将直接解决这些问题，并将在南非农村地区的结核病，艾滋病毒和耐药结核病的融合流行病的震中进行，我们的国际研究小组一直在努力改善自2002年以来TB/HIV共同感染的结果。 公共卫生相关性：虽然MDR TB/HIV共同感染以前是死亡率极高的特征，但这是在挽救生命的抗逆转录病毒疗法之前。调查结果将有助于改善受MDR结核病流行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的MDR TB/HIV疾病治疗的合理临床实践和公共卫生政策。