Clinical Predictors of weekly Rifapentine/isoniazid related adverse drug reactions during national roll-out of tuberculosis preventive therapy

全国结核病预防治疗推广期间每周利福喷丁/异烟肼相关药物不良反应的临床预测

• 批准号: 10615125
• 负责人: Christine Sekaggya-Wiltshire
• 金额: $ 13.77万
• 依托单位: INFECTIOUS DISEASES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615125
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse drug effect; Adverse event; Affect; African; Age; Anti-Retroviral Agents; Authorization documentation; Body Weight decreased; Categories; Cessation of life; Child; Clinical; Clinical Trials; Cohort Studies; Collaborations; Coughing; Country; Cytochromes; Data; Development; Diagnosis; Disease; Drug Kinetics; Enrollment; Evaluation; Event; Exanthema; Genes; Genetic; Genetic Polymorphism; Genotype; Guidelines; HIV; Health care facility; Hypotension; Immunologics; Incidence; Individual; Informed Consent; Interruption; Laboratories; Link; Liver Function Tests; Machine Learning; Measures; Mycobacterium tuberculosis; Nested Case-Control Study; Neuropathy; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Preventive therapy; Preventive treatment; Questionnaires; Recommendation; Regimen; Reporting; Risk; Risk Factors; Safety; Sampling; Standardization; Statistical Methods; Symptoms; Testing; Transferase; Tuberculosis; Uganda; Vision; World Health Organization; adverse drug reaction; alternative treatment; authority; clinical predictors; cohort; drug induced liver injury; efficacy evaluation; experience; flu; follow-up; gradient boosting; high risk; human leukocyte antigen testing; improved; isoniazid; pharmacodynamic model; prevent; programs; reactivation from latency; research clinical testing; response; rifapentine; scale up; sex; standard of care; uptake

Project Summary The WHO approved 3 months weekly rifapentine plus isoniazid (3HP) has been found non-inferior to 6H in preventing TB reactivation and achieves higher completion rates. The National TB program in Uganda is currently transitioning from 6HP to 3HP which will be scaled up starting in Jan 2021. Rifapentine has not been widely used in Uganda outside clinical trials and therefore its safety profile in programmatic setting in adults and children is still uncertain. Accurate profiling of patients likely to experience 3HP related adverse drug reactions (ADRs) has the potential to improve TPT completion rates, and in turn improve TB control. Our proposal seeks to describe safety profiles of 3HP, completion rates and the clinical, pharmacokinetic and pharmacogenomic determinants of 3HP-related ADRs for people receiving TPT at programmatic level. This study will take place in five health facilities in Uganda in collaboration with the National TB program and the National Drug Authority. We will conduct a cohort study where 614 adults and children >2 years, who have been initiated on 3HP for TPT by the facility clinician according to standard of care will be enrolled. Participants will be both HIV-infected and HIV-uninfected. Participants will be followed up monthly for evaluation for ADRs using a standardized questionnaires, clinical evaluation and laboratory tests (liver function testing). For a subset of 300 patients (150 cases who develop grade 2 and above ADRs and 150 controls who do not experience ADRs), we will conduct pharmacokinetic sampling to measure rifapentine and isoniazid concentrations and selected genotyping (for examples N-Acetyl Transferase, Cytochrome 2E1) and Human leukocyte antigen (HLA) typing. We will use pharmacokinetic/pharmacogenetic-pharmacodynamic models and stochastic gradient boosted machine learning together with conventional statistical methods to determine factors associated with ADRs and simple prediction rules for the identification of patients at high risk for ADR. We will also determine the effect of the ADRs on TPT completion rates. Patients will subsequently be followed up for up to 3 years and assessed for TB reactivation according to standard of care to determine the incidence of TB reactivation in patients who have received 3HP and the risk factors for this. This study will provide data on the safety of 3HP during national roll-out and provide information on who is likely to develop ADRs which can affect treatment completion and therefore may benefit from alternative regimens.

项目概要 世界卫生组织批准的 3 个月每周一次的利福喷丁联合异烟肼 (3HP) 已被发现不劣于 6H 防止结核病复发并实现更高的完成率。乌干达国家结核病规划是 目前正在从 6HP 过渡到 3HP，并将于 2021 年 1 月开始扩大规模。利福喷汀尚未上市 在乌干达临床试验之外广泛使用，因此其在成人和儿童的规划环境中的安全性 孩子们还不确定。准确分析可能经历 3HP 相关药物不良反应的患者 （ADR）有可能提高 TPT 完成率，进而改善结核病控制。我们的建议寻求 描述 3HP 的安全性、完成率以及临床、药代动力学和药物基因组学 在计划层面接受 TPT 的人的 3HP 相关 ADR 的决定因素。这项研究将在 乌干达的五个卫生机构与国家结核病规划和国家药品管理局合作。 我们将开展一项队列研究，其中 614 名成人和 2 岁以上的儿童已开始接受 3HP 的 TPT 由设施临床医生根据护理标准进行登记。参与者将同时感染艾滋病毒和 未感染艾滋病毒。我们将每月对参与者进行随访，使用标准化的 ADR 评估 问卷调查、临床评估和实验室测试（肝功能测试）。对于 300 名患者的子集（150 出现 2 级及以上 ADR 的病例和 150 名未出现 ADR 的对照），我们将进行 药代动力学采样以测量利福喷汀和异烟肼浓度以及选定的基因分型（用于 例如 N-乙酰转移酶、细胞色素 2E1) 和人类白细胞抗原 (HLA) 分型。我们将使用 药代动力学/药物遗传学-药效模型和随机梯度增强机器学习 与传统统计方法一起确定与 ADR 相关的因素并进行简单预测 识别 ADR 高风险患者的规则。我们还将确定 ADR 对 TPT 的影响 完成率。随后将对患者进行长达 3 年的随访并评估结核病的再激活情况 根据护理标准确定接受 3HP 的患者结核病再激活的发生率 以及造成这种情况的风险因素。 这项研究将提供有关全国推广期间 3HP 安全性的数据，并提供有关哪些人可能会使用该药物的信息。 开发可能影响治疗完成的不良反应，因此可能受益于替代疗法。