Impact of malnutrition on TB-IRIS and pharmacokinetics of TB and ARV co-treatment

描述（由申请人提供）：在撒哈拉以南非洲，儿童在结核病（TB）和艾滋病毒合并感染的总体负担中占很大比例。艾滋病毒感染儿童的结核病管理提出了重大挑战和尚未解决的问题，包括少杆菌病的诊断困难，抗逆转录病毒（ARV）药物的启动时间，药物相互作用，重叠药物毒性，以及免疫重建炎症综合征（IRIS）的发生。由于抗逆转录病毒药物的选择有限和营养不良率高，幼儿结核病/艾滋病毒合并感染的管理更加复杂。我们对儿童TB-IRIS的发病率、免疫发病机制和公共卫生重要性的了解仅限于一些小型研究。缺乏儿童结核病和艾滋病毒合并治疗的循证指南，关于一线抗逆转录病毒药物和结核病药物在儿童中相互作用的药代动力学信息也很少。我们建议在南非约翰内斯堡的672名开始接受抗逆转录病毒治疗的儿童中估计TB-IRIS的发病率，测量IRIS与营养不良的相关性，并阐明儿童TB-IRIS的免疫发病机制。我们将在开始抗逆转录病毒治疗时筛查结核病流行的儿童，以确定是否发生反常的TB-IRIS，在基线时无结核病的儿童将在抗逆转录病毒治疗的前6个月内前瞻性评估是否发生或暴露TB-IRIS。将进行巢式病例对照研究，以阐明TB-IRIS的免疫发病机制，重点是细胞因子表达测量，淋巴细胞亚群免疫表型和调节性T细胞的作用评估。为了提高TB-IRIS的诊断水平，我们建议前瞻性评价QuantiFERON的预测和诊断价值。金管，FDA批准的干扰素γ释放测定。具体来说，我们将测量所有672名儿童在基线和开始抗逆转录病毒治疗后2周的干扰素γ产生，以及所有IRIS病例及其对照在巢式病例对照研究中登记时的干扰素γ产生。最后，我们建议评估利福霉素（一种在美国用于成人以克服药物相互作用的利福霉素）在幼儿（年龄< 3岁）中与LPV/RTV同时给药时的剂量、安全性和药代动力学特征。拟议研究的结果有可能大大改善对有发展活动性结核风险或需要同时接受结核/艾滋病毒治疗的艾滋病毒感染儿童的管理。在资源匮乏的环境中，儿童承担了结核病和艾滋病毒感染的很大一部分负担。艾滋病毒感染儿童的结核病管理提出了重大挑战和尚未解决的问题。我们将在南非约翰内斯堡的一家诊所跟踪672名开始接受艾滋病毒治疗的儿童，以研究结核病和艾滋病毒合并感染的并发症TB-IRIS。在这些儿童中，我们还将研究利福平的使用，利福平是一种用于美国结核病和艾滋病成人的药物。研究结果有可能大大改善结核病和艾滋病毒儿童的管理。

DESCRIPTION (provided by applicant): In sub-Saharan Africa, children carry a large proportion of the overall burden of tuberculosis (TB) and HIV co-infection. The management of TB in HIV-infected children presents major challenges and unresolved issues, including diagnostic difficulties of paucibacillary disease, timing of initiation of antiretroviral (ARV) drugs, drug-drug interactions, overlapping drug toxicities, and the occurrence of the immune reconstitution inflammatory syndrome (IRIS). The management of TB/HIV co-infection in young children is further complicated by the limited choice of ARVs and high rates of malnutrition. Our understanding of the incidence, immunopathogenesis and public health importance of pediatric TB-IRIS is limited to a few small studies. Evidence-based guidelines for concomitant treatment of TB and HIV in children are lacking, and little pharmacokinetic information is available on the interaction of first line ARV and TB drugs in children. We propose to estimate the incidence of TB-IRIS in a cohort of 672 children initiating ARV in Johannesburg, South Africa, measure the association of IRIS with malnutrition, and unravel the immunopathogenesis of pediatric TB-IRIS. We will screen children with prevalent TB at time of ARV initiation for the development of paradoxical TB-IRIS, and children free of TB at baseline will be prospectively assessed for incident or unmasking TB-IRIS during the first 6 months of ARV treatment. A nested case-control study will be performed to unravel the immunopathogenesis of TB-IRIS, with a focus on cytokine expression measurements, lymphocyte subset immunophenotyping and assessment of the role of regulatory T cells. To improve the diagnosis of TB-IRIS, we propose to prospectively evaluate the predictive and diagnostic value of QuantiFERON. Gold in-tube, an FDA approved interferon gamma release assay. Specifically, we will measure interferon gamma production in all 672 children at baseline and 2 weeks after start ARV, and in all IRIS cases and their controls at time of enrollment in the nested case-control study. Finally, we propose to assess dosing, safety and pharmacokinetic profile of rifabutin, a rifamycin used in adults in the United States to overcome drug-drug interactions, when given concomitantly with LPV/RTV in young children (age < 3 years). The results of the proposed research have the potential to substantially improve the management of HIV-infected children at risk of developing active TB or in need of concomitant TB/HIV treatment. In resource poor settings, children carry a large proportion of the burden of tuberculosis (TB) and HIV infection. The management of TB in HIV-infected children presents major challenges and unresolved issues. We will follow 672 children initiating HIV treatment in a clinic in Johannesburg South Africa to study TB-IRIS, a complication of TB and HIV co-infection. In these children, we will also study the use of rifabutin, a drug used in U.S. adults with TB and HIV. The results of the research have the potential to substantially improve the management of children with TB and HIV.