Biomarkers of Hepatotoxicity in Women Living with HIV and Latent TB

项目概要和摘要 感染艾滋病毒（WLWH）和潜伏性结核病（TB）感染（LTBI）的孕妇和产后妇女在 发展为活动性结核病的风险很高。在潜伏期进行安全有效的治疗， 预防活动性结核病，以及减少与结核病有关的孕产妇和婴儿发病率和死亡率。异烟肼 (INH)几十年来一直用于治疗活动性和潜伏性结核病感染， 努力扩大异烟肼预防性治疗（IPT）的使用，以应对全球结核病负担。近期大规模 妊娠期和产后WLWH的临床试验显示，IPT的严重肝毒性发生率较高（约6-7%）， vs. <1%，基于未怀孕成年人的历史数据）产后期间（IMPAACT P1078）。 现有证据表明，反应性INH代谢产物参与肝毒性的发展， INH.然而，目前还没有关于INH代谢物在妊娠或哺乳期妇女中的药代动力学数据。 产后妇女此外，在治疗期间和治疗后， 妊娠，这可能进一步使该人群在妊娠期间发生肝毒性的风险更高。 产后时期。需要机制性的见解来告知在该人群中安全使用IPT。 本提案将利用P1078研究中收集的现有样本，全面检查PK， 免疫和代谢的变化，妊娠和产后WLWH的IPT使用病例对照设计。 本研究的主要目的是：（1）定量测定妊娠期和产后WLWH患者INH代谢产物的PK （2）鉴定妊娠期和产后接受IPT的WLWH的肝毒性生物标志物， 以及（3）建立INH代谢物暴露、毒性生物标志物和 肝毒性在目标1中，将从密集和稀疏PK样本中测量INH代谢物，以定量 孕妇和产后妇女中的INH代谢物PK。在目标2中，将采用丰富的病例对照设计， 应用代谢组学和细胞因子评价肝毒性的基线和治疗中生物标志物 阵目标3将整合目标1和目标2生成的数据，以检查INH与 代谢物暴露、代谢和免疫学生物标志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，以及来自P1078研究的合作者。布鲁克斯博士还将继续 生物统计学、PK建模、代谢组学方面的重点培训和课程，以及 实验室设置。 博士布鲁克斯的职业目标是成为结核病药物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K 08申请中的拟议工作 这将为她发展成为该领域的独立调查员奠定坚实的基础。此外，委员会认为， 这项工作将解决弱势群体的关键知识差距，以帮助支持安全摄取， 在全球范围内推广结核病预防疗法。

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.