PHARMACOKINETICS AND TOXICITY OF SECONDLINE ANTITUBERCULOSIS DRUGS IN HIV-INFECTE

描述(申请人提供)：该项目的长期目标是通过研究感染和不感染艾滋病毒的儿童中常用二线抗结核药物的药代动力学(PK)、安全性和毒性，改善需要二线抗结核药物的耐药结核病儿童的健康。其具体目的是：1)按年龄比较二线抗结核药物在儿童(15岁)中的PK；2)比较艾滋病毒感染儿童(15岁)服用二线抗结核药物与未接受抗结核治疗的儿童抗逆转录病毒(ARV)药物的血药浓度；以及3)表征二线抗结核药物在艾滋病毒感染儿童和未感染儿童中的耐受性和毒性。在结核病和艾滋病毒感染盛行的环境中，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都有耐药性)是一种新出现的流行病，每年全球估计有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，导致这些菌株的传播，特别是向幼儿传播，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--布鲁克林胸科医院和泰格伯格儿童医院--实施。2009年期间，文化确诊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PIs的环境中，儿童最常使用的二线抗结核病药物是乙硫酰胺、氟喹诺酮、丁胺卡那星和特利西酮。卷曲霉素、利奈唑胺和PAS通常用于治疗广泛耐药的结核病。虽然二线抗结核药物是儿童常规使用和推荐的药物，但能够为幼儿和艾滋病毒感染儿童提供准确剂量信息的信息有限，他们可能改变了药物新陈代谢和药物-药物相互作用。这些抗结核药物对儿童的毒性数据有限，他们通常要接受18-24个月的DR-TB治疗。PIs将在接受常规化疗或化学预防以治疗或预防耐药结核病的0-15岁艾滋病毒感染和未感染儿童中完成一项前瞻性的、纵向的、以医院为基础的观察PK研究。他们将在3.5年内连续招募310名儿童，在基线水平上对二线抗结核药物进行密集PK抽样。艾滋病毒感染儿童将在基线上进行抗逆转录病毒PK采样。大约30%的PIs样本将是艾滋病毒感染的。同样数量的接受和不接受抗结核治疗的艾滋病毒感染儿童(同时对照；42人接受法韦伦治疗，22人接受洛比纳韦治疗)将根据所需的年龄层进行登记，以便比较二线结核病药物对接受和不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。PIs将跟踪儿童对DR疾病的治疗，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。入学将根据艾滋病毒状况和年龄进行平衡，以确保有足够数量的0-2岁儿童和感染艾滋病毒的儿童。 公共卫生相关性：虽然儿童结核病可以通过服用药物来治疗，但一些结核病菌株对常用的结核病药物(耐药结核病)具有抗药性。这些儿童需要效果较差、副作用较多的药物，其中儿童应该接受什么剂量(量)的药物以及如何检查这些药物对幼儿和感染艾滋病毒的儿童是否安全知之甚少。通过这项研究获得的知识将有助于找出如何最好地给予正确剂量的药物，以安全地治疗和预防幼儿和艾滋病毒感染儿童的耐药结核病。

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. PUBLIC HEALTH RELEVANCE: Although childhood TB can be treated by taking medicines, some strains of TB are resistant to commonly used TB medications (drug-resistant TB). These children need medications that are less effective, have more side effects, of which little is known which dosage (amount) children should receive and how to check whether these medications are safe in young and HIV-infected children. Knowledge gained through this study will help find out how to best give the correct amount of medication to safely treat and prevent drug-resistant TB in young and HIV-infected children.