Sekaggya-Wiltshire Christine, Mbabazi Irene, Nabisere Ruth Mirembe, Alinaitwe Lucy, Otaalo Brian, Aber Florence, Nampala Juliet, Owori Rogers, Bayigga Josephine, Mayito Jonathan, Banturaki Grace, Laker Eva Agnes Odongpiny, Castelnuovo Barbara, Sekadde Moorine Penninah, Pasipanodya Jotam, Dooley Kelly E, Stavia Turyahabwe, Zawedde-Muyanja Stella
Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Central, Uganda
Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Central, Uganda.
BMJ Open. 2024 Dec 31;14(12):e088389. doi: 10.1136/bmjopen-2024-088389.
Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for TB preventive therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings.
This is an observational cohort study with a nested case-control study. We enrolled consecutive patients who had been initiated on TPT using the 3HP regimen. These are followed up biweekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2, AADAC and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes.
The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. χ tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modelling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.
Ethical approval of this study inclusive of all the appropriate documents was obtained from the Infectious Diseases Institute Research and Ethics Committee and the Uganda National Council of Science and Technology. The study adheres to legal, ethical and Good Clinical Practice (GCP) guidelines. Deidentified genotype data from 300 patients will be shared after publication. The protocol and phenotype data will be publicly accessible. Abstracts will be submitted to conferences, and a manuscript will be published poststudy.
结核病（TB）是全球主要的感染性致死原因。尽管世界卫生组织推荐了结核病预防性治疗（TPT），但挑战依然存在，包括治疗未完成以及药物不良反应（ADR）。关于3个月异烟肼和利福喷汀（3HP）的药代动力学、药物基因组学及其与ADR的关系的数据有限。我们的研究旨在描述用于TPT的3HP的药代动力学和药物基因组学、ADR及其与完成率的关联以及TPT结局，为资源有限环境下的结核病控制策略提供重要见解。
这是一项包含嵌套病例对照研究的观察性队列研究。我们纳入了连续接受3HP方案TPT治疗的患者。在治疗的活跃期，每两周对他们进行一次随访，然后每月随访一次；在TPT完成后的2年里，每3个月随访一次。ADR评估包括临床评估和肝功能检查。病例从发生ADR的患者中选取，对照从未发生ADR的患者中选取。测量血清异烟肼和利福喷汀浓度，并对NAT2、AADAC和CYP2E1基因多态性进行药物基因组学分析。对参与者随访2年以确定TPT结局。
将使用描述性统计评估3HP的安全性概况，包括发生ADR的患者比例以及与治疗相关的3级或以上事件。χ检验和回归模型将确定ADR的预测因素及其对治疗完成的影响。药代动力学-药效学建模将确定群体参数以及影响利福喷汀和异烟肼浓度的因素。
本研究已获得传染病研究所研究与伦理委员会以及乌干达国家科学技术委员会的伦理批准，包括所有适当的文件。该研究遵循法律、伦理和良好临床实践（GCP）指南。300名患者的去识别基因型数据将在发表后共享。方案和表型数据将公开获取。摘要将提交至会议，并在研究结束后发表一篇手稿。
