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

项目摘要 世界卫生组织批准的每周3个月的利福喷丁加异烟肼(3HP)在 防止结核病重新激活，并实现更高的完成率。乌干达的国家结核病计划是 目前正在从6马力过渡到3马力，将于2021年1月开始扩大规模。利福喷丁还没有被 在乌干达被广泛用于临床试验外，因此其在成人和成人方案设置中的安全性 孩子们仍然不确定。准确描述可能经历3HP相关药物不良反应的患者 (ADRs)有可能提高TPT完成率，进而改善结核病控制。我们的建议旨在 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 计划水平接受TPT治疗的3HP相关不良反应的影响因素。这项研究将在#年进行 与国家结核病计划和国家药品管理局合作，在乌干达的五个卫生设施。 我们将进行一项队列研究，614名成人和儿童&>2岁，已经开始接受3HP的TPT 由该机构的临床医生根据护理标准进行登记。参与者将既是艾滋病毒感染者，又是 艾滋病毒--未感染。将每月对参与者进行跟踪，以使用标准化的 问卷调查、临床评估和实验室检查(肝功能检查)。对于300名患者(150名)的子集 发生2级及以上不良反应的病例和未发生不良反应的150名对照)，我们将进行 用于测量利福喷丁和异烟肼浓度的药代动力学采样和选择的基因分型(用于 例N-乙酰转移酶、细胞色素2E1)和人类白细胞抗原(人类白细胞抗原)分型。我们将使用 Pharmacokinetic/pharmacogenetic-pharmacodynamic模型和随机梯度增强的机器学习 与常规统计方法一起确定与ADRs相关的因素和简单预测 药品不良反应高危患者识别规则。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，并评估是否有结核病复发。 根据护理标准确定接受3HP治疗的患者结核复活的发生率 以及造成这种情况的风险因素。 这项研究将提供3HP在全国推广期间的安全性数据，并提供谁可能 开发可能影响治疗完成并因此可能受益于替代方案的不良反应。

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.