Biomarkers of Hepatotoxicity in Women Living with HIV and Latent TB

项目摘要(&A) 携带艾滋病毒(WLWH)和潜在结核病(LTBI)感染的孕妇和产后妇女在 进展为活动性结核病的高风险。在潜伏期进行安全有效的治疗至关重要 预防活动性结核病，以及降低与结核病相关的母婴发病率和死亡率。异烟肼 (异烟肼)几十年来一直被用来治疗活动性和潜伏性结核病感染，国际上有几种 努力扩大异烟肼预防疗法(IPT)的使用，以应对全球结核病负担。最近的一次大规模的 妊娠和产后WLWH的临床试验显示，IPT的严重肝毒性发生率很高(~6-7% 在产后期(IMPAACT P1078)，根据历史数据，非妊娠成人的死亡率为1%。 现有证据表明，反应性异烟肼代谢产物参与了肝毒性的发展 啊哈。然而，目前没有关于异烟肼代谢物在孕妇或孕妇体内的药代动力学数据。 产后妇女。此外，在发病期间和发病后还会发生免疫学和新陈代谢变化。 怀孕，这可能进一步使这一人群在 产后时期。需要机械性的洞察力来告知在这一人群中安全使用IPT。 这项建议将利用在P1078研究下收集的现有样本来全面审查PK， 采用病例对照设计研究妊娠和产后WLWH在IPT中的免疫学和代谢变化。 目的：(1)定量测定孕期和产后WLWH中异烟肼代谢产物PK 接受IPT，(2)在接受IPT的孕妇和产后WLWH中鉴定肝毒性的生物标志物， 以及(3)模拟异烟肼代谢物暴露、毒性生物标志物和糖尿病的发展之间的关系。 肝脏毒性。在目标1中，将从密集和稀疏的PK样本中测量异烟肼代谢物以进行量化 孕产期妇女体内异烟肼代谢产物PK。在目标2中，一个丰富的病例对照设计将是 应用代谢组学和细胞因子评价肝毒性基线和治疗中的生物标志物 数组。目标3将整合目标1和目标2产生的数据，以检查异烟肼之间的关系 代谢产物暴露、代谢和免疫生物标记物，以及肝毒性的发展。这 工作将由一个由药理学、代谢组学、 免疫学和统计学，以及P1078研究的合作者。布鲁克斯博士还将继续 在生物统计学、PK建模、代谢组学和实践经验方面的重点培训和课程工作 实验室环境。 布鲁克斯博士的职业目标是成为结核病药物和临床药理学方面的专家 免疫介导的药物不良反应机制。布鲁克斯博士的K08申请中提议的工作 将为她发展成为这一领域的独立调查员提供坚实的基础。此外， 这项工作将解决弱势群体中的关键知识差距，以帮助支持安全获取和 在全球范围内扩大结核病预防治疗。

Project Summary & Abstract Pregnant and postpartum women living with HIV (WLWH) and latent tuberculosis (TB) infection (LTBI) are at high risk of progressing to active TB. Safe and effective treatment during the latent phase is critical to preventing active TB, in addition to reducing TB-related maternal and infant morbidity and mortality. Isoniazid (INH) has been used for decades to treat active and latent TB infection, and there are several international efforts to expand the use of INH preventive therapy (IPT) to address global TB burden. A recent large-scale clinical trial in pregnant and postpartum WLWH revealed high rates of severe hepatotoxicity with IPT (~6-7% vs. <1% based on historical data in non-pregnant adults) during the postpartum period (IMPAACT P1078). Available evidence suggests reactive INH metabolites are involved in the development of hepatotoxicity with INH. However, there are currently no data on the pharmacokinetics of INH metabolites in pregnant or postpartum women. Additionally, there are immunologic and metabolic changes that occur during and after pregnancy, which may further predispose this population to a higher risk of developing hepatotoxicity during the postpartum period. Mechanistic insights are needed to inform the safe use of IPT in this population. This proposal will leverage existing samples collected under the P1078 study to comprehensively examine PK, immunologic, and metabolic changes in pregnant and postpartum WLWH on IPT using a case-control design. The following aims are proposed: (1) to quantify INH metabolite PK in pregnant and postpartum WLWH receiving IPT, (2) to identify biomarkers of hepatotoxicity in pregnant and postpartum WLWH receiving IPT, and (3) to model relationships between INH metabolite exposures, toxicity biomarkers, and the development of hepatotoxicity. In Aim 1, INH metabolites will be measured from intensive and sparse PK samples to quantify INH metabolite PK in pregnant and postpartum women. In Aim 2, an enriched case-control design will be applied to evaluate baseline and on-treatment biomarkers of hepatotoxicity using metabolomics and cytokine arrays. Aim 3 will integrate data generated from Aims 1 and 2 to examine relationships between INH metabolite exposures, metabolic and immunology biomarkers, and the development of hepatotoxicity. This work will be complemented by a mentoring team comprised of experts in pharmacology, metabolomics, immunology, and statistics, in addition to collaborators from the P1078 study. Dr. Brooks will also pursue focused training and coursework in biostatistics, PK modeling, metabolomics, and hands-on experience in the laboratory setting. Dr. Brooks's career goal is to become an expert in the clinical pharmacology of TB medications and mechanisms of immune-mediated adverse drug reactions. The proposed work in Dr. Brooks's K08 application will provide her with a strong foundation to develop into an independent investigator in this field. Furthermore, this work will address critical knowledge gaps in a vulnerable population to help support the safe uptake and expansion of TB preventive therapies on a global scale.