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 已发现WHO批准的每周3个月利福喷丁加异烟肼（3 HP）在以下方面不劣于6 H： 防止结核病复发，并实现更高的完成率。乌干达的国家结核病规划是 目前正在从6 HP过渡到3 HP，并将于2021年1月开始扩大规模。利福喷丁还没有 在乌干达广泛用于临床试验之外，因此其在成人方案环境中的安全性特征， 孩子们还不确定。准确分析可能发生3 HP相关药物不良反应的患者 药物不良反应（ADR）有可能提高TPT完成率，进而提高结核病控制。我们的建议是 描述3 HP的安全性特征、完成率以及临床、药代动力学和药物基因组学 在方案层面接受TPT的人的3 HP相关ADR的决定因素。这项研究将在 与国家结核病规划署和国家药品管理局合作，在乌干达的五个卫生设施中开展工作。 我们将进行一项队列研究，纳入614名已开始接受3 HP TPT的成人和>2岁的儿童 将由机构临床医生根据护理标准进行入组。参与者将是艾滋病毒感染者， 未感染艾滋病毒将每月对参与者进行随访，使用标准化的 问卷调查、临床评估和实验室检查（肝功能检查）。对于300例患者的子集（150 发生2级及以上ADR的病例和150例未发生ADR的对照），我们将进行 药代动力学采样以测量利福喷丁和异烟肼浓度，以及选择的基因分型（用于 例如N-乙酰基转移酶、细胞色素2 E1）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-药效学模型和随机梯度增强的机器学习 结合传统的统计学方法，确定与ADR相关的因素， 确定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，并评估结核病复发情况 根据治疗标准，确定接受3 HP治疗的患者中结核病复发的发生率 和风险因素。 本研究将提供关于3 HP在全国推广期间的安全性数据，并提供关于谁可能 发生可能影响治疗完成的ADR，因此可能从替代方案中获益。