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

描述(申请人提供)：在撒哈拉以南非洲，儿童在结核病和艾滋病毒混合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面临重大挑战和悬而未决的问题，包括少菌病的诊断困难、抗逆转录病毒(ARV)药物的启动时机、药物与药物的相互作用、重叠的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/艾滋病毒混合感染的管理进一步复杂化。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几项小型研究。缺乏同时治疗儿童结核病和艾滋病毒的循证指南，关于一线抗逆转录病毒药物和儿童结核病药物相互作用的药代动力学信息也很少。我们建议估计在南非约翰内斯堡发起ARV的672名儿童中结核病-IRIS的发病率，测量IRIS与营养不良的关联，并揭示儿童TB-IRIS的免疫发病机制。我们将在抗逆转录病毒治疗开始时对患有结核病流行的儿童进行筛查，以发现矛盾的TB-IRIS，而基线上没有结核病的儿童将在抗逆转录病毒治疗的前6个月接受前瞻性评估，以确定是否发生或暴露出TB-IRIS。将进行一项嵌套病例对照研究，以揭示TB-IRIS的免疫发病机制，重点是细胞因子表达的测量、淋巴细胞亚群免疫表型和调节性T细胞的作用评估。为了提高对TB-IRIS的诊断，我们建议前瞻性地评估Quantiferon的预测和诊断价值。金试管，FDA批准的干扰素伽马释放试验。具体地说，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2周后的干扰素伽马产量，以及在嵌套病例对照研究登记时所有IRIS病例及其对照的干扰素伽马产量。最后，我们建议评估利福平的剂量、安全性和药代动力学，利福平是一种在美国成人中用于克服药物相互作用的药物，当与LPV/RTV一起在幼儿(3岁)中使用时。拟议研究的结果有可能大大改善对感染艾滋病毒的儿童的管理，这些儿童有患活动性结核病的风险或需要同时接受结核病/艾滋病毒治疗。在资源匮乏的情况下，儿童承担着结核病和艾滋病毒感染的很大比例。艾滋病毒感染儿童的结核病管理是重大挑战和悬而未决的问题。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-IRIS，一种结核病和艾滋病毒混合感染的并发症。在这些儿童中，我们还将研究利福平的使用，这是一种用于美国患有结核病和艾滋病毒的成年人的药物。这项研究的结果有可能大大改善对患有结核病和艾滋病毒的儿童的管理。

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.