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

营养不良对 TB-IRIS 以及 TB 和 ARV 联合治疗的药代动力学的影响

基本信息

批准号：
7915729
负责人：
Annelies T.A. Van Rie
金额：
$ 51.92万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915729
关键词：
3 year old Acquired Immunodeficiency Syndrome Adult Advocate Affect Africa Africa South of the Sahara Animal Experiments Anti-Retroviral Agents Antiviral Agents Biological Assay Body Weight decreased CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cause of Death Cellular Immunity Characteristics Child Childhood Clinic Complex Complication Cytochrome P450 Data Development Diagnosis Diagnostic Disease Dose Drug Formulations Drug Interactions Drug Kinetics Drug toxicity Drug usage Energy Metabolism Enrollment Enzymes FDA approved Gold Guidelines HIV HIV Infections Helper-Inducer T-Lymphocyte Host Defense Mechanism Immune Immune System and Related Disorders Immunophenotyping Immunosuppression Incidence Infection Inflammatory Interferon Type II Interleukin-10 Interleukin-2 Interleukin-4 Lamivudine Lead Lopinavir/Ritonavir Lymphocyte Subset Malnutrition Measurement Measures Memory Nested Case-Control Study Nevirapine Nutritional P-Glycoprotein P-Glycoproteins Peripheral Pharmaceutical Preparations Prevention Process Production Public Health Reaction Regimen Regulatory T-Lymphocyte Rehabilitation therapy Research Resistance Resources Rifabutin Rifampin Rifamycins Risk Risk Factors Role Safety South Africa Syndrome T-Lymphocyte Subsets Time Tube Tuberculosis United States Zidovudine antiretroviral therapy cohort cytokine evidence based guidelines feeding immune function improved nutrition pathogen reconstitution response tool tuberculosis drugs tuberculosis treatment viral resistance

项目摘要

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.

描述（由申请人提供）：在撒哈拉以南非洲地区，儿童承担着结核病 (TB) 和艾滋病毒双重感染总体负担的很大一部分。 HIV感染儿童的结核病管理面临着重大挑战和未解决的问题，包括少杆菌病的诊断困难、抗逆转录病毒（ARV）药物的起始时机、药物相互作用、药物毒性重叠以及免疫重建炎症的发生综合症（IRIS）。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治疗变得更加复杂。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。目前缺乏针对儿童结核病和艾滋病毒联合治疗的循证指南，并且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。我们建议估计南非约翰内斯堡 672 名开始抗逆转录病毒治疗的儿童中 TB-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。我们将在开始抗逆转录病毒治疗时筛查患有流行性结核病的儿童是否出现矛盾的 TB-IRIS，而基线时未患结核病的儿童将在接受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。将进行一项巢式病例对照研究，以揭示 TB-IRIS 的免疫发病机制，重点是细胞因子表达测量、淋巴细胞亚群免疫表型分析和调节性 T 细胞作用评估。为了改善 TB-IRIS 的诊断，我们建议前瞻性评估 QuantiFERON 的预测和诊断价值。金管内，FDA 批准的干扰素伽马释放测定。具体来说，我们将测量所有 672 名儿童在基线和开始 ARV 后 2 周的干扰素 γ 产生，以及所有 IRIS 病例及其对照在参加巢式病例对照研究时的情况。最后，我们建议评估利福布汀的剂量、安全性和药代动力学特征，利福布汀是一种在美国用于成人的利福霉素，用于克服药物间相互作用，当幼儿（年龄 < 3 岁）与 LPV/RTV 联合给药时。拟议研究的结果有可能大大改善对有发展为活动性结核病风险或需要同时接受结核病/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，儿童承担着结核病 (TB) 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未解决的问题。我们将跟踪在南非约翰内斯堡一家诊所开始艾滋病毒治疗的 672 名儿童，以研究 TB-IRIS（结核病和艾滋病毒混合感染的一种并发症）。在这些儿童中，我们还将研究利福布丁的使用，这是一种用于美国成人结核病和艾滋病毒患者的药物。研究结果有可能大大改善结核病和艾滋病毒儿童的管理。