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: 10403546
• 负责人: Christine Sekaggya-Wiltshire
• 金额: $ 13.6万
• 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/10403546
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse drug effect; Adverse event; Affect; African; Age; Anti-Retroviral Agents; 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; 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; Regimen; Reporting; Risk; Risk Factors; Safety; Sampling; Standardization; Statistical Methods; Symptoms; Testing; Transferase; Tuberculosis; Uganda; Vision; World Health Organization; adverse drug reaction; adverse outcome; alternative treatment; authority; clinical predictors; cohort; drug induced liver injury; 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.

项目摘要 WHO批准了3个月的每周利福丁加上Isoniazid（3HP） 防止结核病重新激活并达到更高的完成率。乌干达的国家结核病计划是 目前从2021年1月开始从6HP过渡到3HP。 广泛用于乌干达外部临床试验中，因此其安全性在成人和成人的编程环境中 孩子们仍然不确定。可能经历3HP相关的不良药物反应的患者的准确分析 （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的安全概况，完成率以及临床，药代动力学和药物基因组学 3HP相关的ADR的决定因素，用于在程序化级别接收TPT的人。这项研究将进行 乌干达的五个医疗机构与国家结核病计划和国家药物管理局合作。 我们将进行一项队列研究 根据护理标准，设施临床医生将被录取。参与者将既受HIV感染，又 艾滋病毒未感染。参与者将每月跟踪参与者，以使用标准化的ADR评估 问卷，临床评估和实验室测试（肝功能测试）。对于300例患者的子集（150例 开发2年级及以上ADR和150个没有经历ADR的案例），我们将进行 药代动力学取样以测量利福丁和异念珠菌浓度和选定的基因分型（用于 示例N-乙酰基转移酶，细胞色素2E1）和人类白细胞抗原（HLA）键入。我们将使用 药代动力学/药物遗传学 - 药效学模型和随机梯度增强机器学习 以及常规的统计方法，以确定与ADR相关的因素和简单预测 确定ADR高风险的患者的规则。我们还将确定ADR对TPT的影响 完成率。随后将最多跟踪患者3年，并评估结核病重新激活 根据护理标准，以确定接受3HP的患者中结核病重新激活的发生率 以及为此的风险因素。 这项研究将提供有关国家推出期间3HP安全的数据，并提供有关谁可能是谁的信息 开发可能影响治疗完成的ADR，因此可能受益于替代方案。