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

• 批准号: 7514797
• 负责人: Annelies T.A. Van Rie
• 金额: $ 54.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/7514797
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Advocate; Affect; Africa; Africa South of the Sahara; Age; Age-Years; 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; Condition; Cytochrome P450; Data; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Drug toxicity; Drug usage; Energy Metabolism; Enrollment; Enzymes; 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; Natural Immunity; Nested Case-Control Study; Nevirapine; Nutritional; P-Glycoprotein; P-Glycoproteins; Peripheral; Pharmaceutical Preparations; Prevention; Process; Production; Public Health; Rate; Reaction; Rehabilitation therapy; Research; Resistance; Resources; Rifabutin; Rifampin; Rifamycins; Risk; Risk Factors; Role; Safety; South Africa; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic immunosuppression; Time; Treatment Protocols; Tube; Tuberculosis; United States; United States Food and Drug Administration; Viral; Week; World Health Organization; Zidovudine; antiretroviral therapy; cohort; cytokine; evidence based guidelines; feeding; immune function; improved; nutrition; pathogen; reconstitution; response; rifamycin SV; tool; tuberculosis drugs; tuberculosis treatment

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，儿童在结核病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面临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）药物的起始时间、药物-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。目前缺乏同时治疗儿童结核病和艾滋病毒的循证指南，而且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。我们建议估计南非约翰内斯堡672名接受抗逆转录病毒治疗的儿童中结核病-IRIS的发病率，测量IRIS与营养不良的关系，并揭示儿童结核病-IRIS的免疫发病机制。我们将在开始抗逆转录病毒药物治疗时对患有流行结核病的儿童进行筛查，以确定是否会发展为矛盾的结核- iris，而基线时无结核病的儿童将在抗逆转录病毒药物治疗的前6个月期间进行前瞻性评估，以确定是否会发生结核- iris。一项巢式病例对照研究将揭示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和调节性T细胞作用的评估。为了提高TB-IRIS的诊断水平，我们建议对QuantiFERON的预测和诊断价值进行前瞻性评价。试管金，FDA批准的干扰素释放试验。具体而言，我们将在基线和开始抗逆转录病毒治疗后2周测量所有672名儿童的干扰素γ分泌，并在巢式病例对照研究入组时测量所有IRIS病例及其对照。最后，我们建议评估利福丁的剂量、安全性和药代动力学特征。利福丁是一种利福霉素，在美国用于成人，以克服药物-药物相互作用，并与LPV/RTV同时给予幼儿（年龄< 3岁）。拟议的研究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。在资源贫乏的环境中，儿童承担了很大一部分结核病和艾滋病毒感染的负担。艾滋病毒感染儿童的结核病管理面临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，研究结核病- iris，这是结核病和艾滋病毒合并感染的并发症。在这些儿童中，我们还将研究利福布汀的使用，这是一种用于美国成年结核病和艾滋病患者的药物。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。