PHARMACOKINETICS AND TOXICITY OF 2ND LINE ANTI-TB DRUGS IN HIV-INFECTED CHILDREN

项目描述（由申请人提供）：该项目的长期目标是通过研究常用的二线抗结核药物在合并和未合并艾滋病毒感染的儿童中的药代动力学（PK）、安全性和毒性，改善需要二线抗结核药物的耐药结核病（DR-TB）儿童的健康状况。具体目的是：1)按年龄比较二线抗结核药物在< 15岁儿童中的PK；2)比较接受二线抗结核药物治疗与未接受抗结核治疗的艾滋病毒感染儿童（< 15岁）的血浆抗逆转录病毒药物浓度；3)确定hiv感染和未感染儿童对二线抗结核药物的耐受性和毒性。在结核病和艾滋病毒感染流行的环境中，儿童结核病占疾病负担的15-20%。耐多药结核病（MDR-TB，即对利福平和异烟肼的耐药性）是一种新出现的流行病，估计全球每年有48.9万例病例。耐多药结核病患者往往经历长时间的诊断延误，导致这些菌株传播，特别是传播给幼儿，同时接受耐多药结核病治疗和预防的儿童人数急剧增加。这项以医院为基础的研究将在南非西开普省开普敦的两家转诊医院——布鲁克林胸部疾病医院和Tygerberg儿童医院实施。2009年，结核病儿童中耐多药结核病的流行率为8.6%，结核病儿童中艾滋病毒感染的流行率为25-30%。在pi环境中，儿童最常用的二线抗结核药物是乙硫胺、氟喹诺酮类药物、阿米卡星和特立酮。卷曲霉素、利奈唑胺和PAS通常用于治疗广泛耐药结核病。虽然在儿童中常规给予和推荐二线抗结核药物，但对于可能改变药物代谢和药物-药物相互作用的青少年和感染艾滋病毒的儿童，可获得的准确剂量信息有限。关于这些抗结核药物对儿童的毒性的数据有限，儿童治疗耐药结核病通常需要18-24个月。pi将完成一项前瞻性、纵向、基于医院的观察性PK研究，研究对象为0-15岁接受常规化疗或化学预防治疗或预防耐药结核病的hiv感染和未感染儿童。他们将在3.5年的时间里连续招募310名儿童，在基线时对二线抗结核药物进行密集的PK抽样。感染艾滋病毒的儿童将在基线时进行抗逆转录病毒药代动力学抽样。大约30%的pi样本将感染艾滋病毒。将根据所需的年龄层招募同等数量的接受和未接受抗结核治疗的艾滋病毒感染儿童（同时对照；42人接受依非韦伦治疗，22人接受洛匹那韦治疗），以便比较二线结核病药物对接受和未接受结核病治疗的艾滋病毒感染儿童抗逆转录病毒水平的影响。pi将跟踪儿童的耐多药性疾病治疗，直到治疗完成，以了解临床结果，包括结核病治疗反应和药物不良反应。报名人数将根据艾滋病毒状况和年龄进行平衡，以确保0-2岁儿童和感染艾滋病毒的儿童人数充足。

DESCRIPTION (provided by applicant): The long-term goal of the project is to improve the health of children with drug-resistant tuberculosis (DR-TB) in need of second-line anti-tuberculosis (anti-TB) drugs, through studying the pharmacokinetics (PK), safety profile and toxicity of commonly used second-line anti-TB drugs in children with and without HIV co-infection. The specific aims are: 1) to compare the PK of second-line anti-tuberculosis drugs in children (< 15 years) by age; 2) to compare the plasma concentrations of antiretroviral (ARV) drugs in HIV-infected children (< 15 years) on second-line anti-TB drugs to those not on anti-TB therapy; and 3) to characterize the tolerability and toxicity of second-line anti-TB drugs in HIV-infected and uninfected children. Childhood TB represents 15-20% of the disease burden in settings where TB and HIV infection is prevalent. Multidrug-resistant TB (MDR-TB; i.e. resistance to both rifampin and isoniazid) is an emerging epidemic, with an estimated 489 000 global cases annually. MDR-TB patients often experience prolonged diagnostic delay, resulting in transmission of these strains especially to young children with a sharp increase in the numbers of children on treatment and prophylaxis for MDR-TB. This hospital-based study will be implemented in Cape Town, Western Cape Province, South Africa at 2 referral hospitals - Brooklyn Hospital for Chest Diseases and Tygerberg Children's Hospital. The prevalence of MDR-TB amongst children with culture-confirmed TB was 8.6% and the prevalence of HIV infection in children with TB was 25-30% during 2009. The most frequently used second-line anti-TB drugs in children in the PIs' setting are ethionamide, fluoroquinolones, amikacin and terizidone. Capreomycin, linezolid and PAS are typically used for treatment of extensively drug-resistant TB. Although second-line anti-TB drugs are routinely given and recommended in children, there is limited information available to inform the accurate dosing in young and in HIV-infected children, who may have altered drug metabolism and drug-drug interactions. There are limited data on toxicity of these anti-TB drugs in children, who are typically treated for 18-24 months for DR-TB. The PIs will complete a prospective, longitudinal, hospital-based, observational PK study in HIV-infected and uninfected children aged 0-15 years who are receiving routine chemotherapy or chemoprophylaxis for the treatment or prevention of DR-TB. They will enroll 310 total children consecutively over 3.5 years for intensive PK sampling of second-line anti-TB drugs at baseline. HIV-infected children will have ARV PK sampling done at baseline. Approximately 30% of the PIs' sample will be HIV-infected. An equal number of HIV-infected children with and without anti-TB therapy (concurrent controls; 42 on efavirenz and 22 on lopinavir) will be enrolled based on the required age strata to allow for comparison of the effect of second-line TB drugs on ARV levels in HIV-infected children with and without TB treatment. The PIs will follow children on treatment for DR disease until treatment completion for clinical outcomes including TB treatment response and drug adverse effects. Enrolment will be balanced by HIV status and age to ensure adequate number of the children 0-2 years of age and HIV-infected children.