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; 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，儿童承担着结核病总负担（TB）和HIV共同感染的很大比例。艾滋病毒感染儿童中结核病的管理提出了主要的挑战和未解决的问题，包括诊断性疾病的诊断困难，抗逆转录病毒（ARV）药物的启动时间，药物相互作用，重叠的药物毒性以及免疫重构炎性综合综合征（IRIS）的发生。有限的ARV选择和高营养不良率有限，幼儿TB/HIV共同感染的管理更加复杂。我们对小儿TB-IRIS的发病率，免疫病生成和公共健康重要性的理解仅限于一些小型研究。缺乏基于证据的儿童治疗结核病和艾滋病毒的指南，几乎没有关于儿童第一线ARV和结核病药物相互作用的药代动力学信息。我们建议在南非约翰内斯堡启动ARV的672名儿童中估计TB-IRI的发生率，测量虹膜与营养不良的关联，并揭示小儿TB-IRIS的免疫发作。我们将在ARV启动时筛查患有TB的儿童，以开发矛盾的TB-IRI，并且在ARV治疗的前6个月中，将对基​​线的未经结核病儿童进行前瞻性评估。将进行一项嵌套的病例对照研究，以揭示TB-IRIS的免疫发病发生，重点是细胞因子表达测量，淋巴细胞子集免疫表型和调节T细胞作用的评估。为了改善TB-IRIS的诊断，我们提出了前瞻性评估Quantiferon的预测和诊断价值。金属块，FDA批准了干扰素伽玛释放分析。具体而言，我们将在基线和开始ARV后2周的所有672名儿童中测量干扰素伽玛的产生，以及在所有虹膜病例及其对照组进行入学时的对照。最后，我们建议评估利法布丁的剂量，安全性和药代动力学特征，利法布丁是美国成年人在美国成年人使用的利法霉素，以克服药物 - 药物相互作用，同时与幼儿（年龄<3岁）同时给予了LPV/RTV。拟议研究的结果有可能大大改善有活跃结核病或需要伴随结核病治疗的艾滋病毒感染的儿童的管理。在资源较差的情况下，儿童承担着大部分结核病负担（TB）和HIV感染。在感染HIV的儿童中，结核病的管理提出了主要的挑战和未解决的问题。我们将跟随672名儿童在南非约翰内斯堡的一家诊所发起HIV治疗，研究结核病和HIV共同感染的并发症。在这些孩子中，我们还将研究利法布丁的使用，利法布丁是一种在美国结核病和艾滋病毒的美国成年人中使用的药物。该研究的结果有可能大大改善结核病和艾滋病毒儿童的管理。