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

二线抗结核药物在 HIV 感染儿童中的药代动力学和毒性

• 批准号: 8450641
• 负责人: Anneke Catharina Hesseling
• 金额: $ 39.05万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450641
• 关键词: 15 year old; 2 year old; Acids; Adult; Adverse drug effect; Adverse effects; Age; Amikacin; Anti-Retroviral Agents; Antitubercular Agents; CD4 Lymphocyte Count; Capromycin; Cartilage; Chemoprophylaxis; Chest; Child; Child health care; Childhood; Clinical; Data; Diagnostic; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Resistant Tuberculosis; Drug resistance in tuberculosis; Drug usage; Enrollment; Ensure; Epidemic; Equilibrium; Ethionamide; Ethnic Origin; Exanthema; Extreme drug resistant tuberculosis; Fluoroquinolones; Genotype; Goals; HIV; HIV Infections; Hepatotoxicity; Hospital Referrals; Hospitals; Hour; Hypothyroidism; Immunity; Incidence; Infection; Intestines; Knowledge; Lamivudine; Linezolid; Lopinavir; Measures; Medicine; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Nutritional status; Ofloxacin; Outcome; Outcome Measure; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Plasma; Population; Population Study; Prevalence; Prevention; Prophylactic treatment; Prospective Studies; Province; Reference Values; Regimen; Renal function; Resistance; Rifampin; Ritonavir; Safety; Sampling; Schedule; Severities; Simulate; South Africa; Staging; Time; Toxic effect; Tuberculosis; Viral Load result; Weight; abacavir; age effect; aged; antiretroviral therapy; base; burden of illness; chemotherapy; design; dosage; drug metabolism; efavirenz; experience; improved; interest; isoniazid; ototoxicity; pharmacokinetic model; prevent; prospective; transmission process; treatment response; tuberculosis drugs; tuberculosis treatment

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.

描述（申请人提供）：该项目的长期目标是通过研究常用二线抗结核药物在合并感染和未合并HIV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（anti-TB）药物的耐药结核（DR-TB）儿童的健康。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) 比较接受二线抗结核药物和未接受抗结核治疗的 HIV 感染儿童（< 15 岁）的血浆抗逆转录病毒（ARV）药物浓度； 3) 表征二线抗结核药物在感染艾滋病毒和未感染艾滋病毒的儿童中的耐受性和毒性。在结核病和艾滋病毒感染流行的地区，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均具有耐药性）是一种新出现的流行病，估计全球每年有 489 000 例病例。耐多药结核病患者往往会经历长时间的诊断延误，导致这些菌株传播，尤其是向幼儿传播，而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泰格伯格儿童医院）实施。 2009年，经培养确诊的结核病儿童中耐多药结核病的患病率为8.6%，结核病儿童中艾滋病毒感染的患病率为25-30%。PI环境中儿童最常用的二线抗结核药物是乙硫异烟胺、氟喹诺酮类药物、阿米卡星和特立齐酮。卷曲霉素、利奈唑胺和 PAS 通常用于治疗广泛耐药结核病。尽管二线抗结核药物常规给予并推荐用于儿童，但可用于告知幼儿和感染艾滋病毒的儿童的准确剂量的信息有限，这些儿童可能改变了药物代谢和药物相互作用。关于这些抗结核药物对儿童的毒性数据有限，儿童通常接受 18-24 个月的耐药结核治疗。 PI 将针对正在接受常规化疗或化学预防治疗或预防耐药结核病的 0-15 岁 HIV 感染和未感染儿童完成一项前瞻性、纵向、以医院为基础的观察性 PK 研究。他们将连续招募 310 名儿童，为期 3.5 年以上，在基线时对二线抗结核药物进行强化 PK 采样。 HIV 感染儿童将在基线时进行 ARV PK 采样。大约 30% 的 PI 样本将感染 HIV。将根据所需年龄层招募同等数量的接受和未接受抗结核治疗的 HIV 感染儿童（同时对照；42 名依非韦伦治疗，22 名洛匹那韦治疗），以便比较二线结核病药物对接受和未接受结核治疗的 HIV 感染儿童的 ARV 水平的影响。 PI 将跟踪接受 DR 疾病治疗的儿童，直至治疗完成，以了解临床结果，包括结核病治疗反应和药物不良反应。招生将根据艾滋病毒状况和年龄进行平衡，以确保足够数量的0-2岁儿童和艾滋病毒感染儿童。