Investigating Multiple PK and PD Relationships for TB-HIV (IMPPRove TB-HIV)

调查 TB-HIV 的多重 PK 和 PD 关系 (IMPPRove TB-HIV)

• 批准号: 10882249
• 负责人: Kelly E. Dooley
• 金额: $ 81.73万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882249
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Affect; Antitubercular Agents; Bacteria; Biological; Biological Response Modifier Therapy; Blood; COVID-19; Cessation of life; Clinical; Cohort Studies; Collaborations; Collection; Complement; DNA; Databases; Disease; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Dryness; Enrollment; Epidemiology; Exposure to; Failure; Funding; Genes; Genetic Polymorphism; Genotype; Geography; Goals; HIV; HIV/TB; Hair; Health; Individual; Inflammation; Intermediate resistance; International; Knowledge; Lung; Lung diseases; Measures; Mediating; Minority Groups; Modeling; Mutation; Mycobacterium tuberculosis; Outcome; Participant; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Play; Prevention; Pulmonary Tuberculosis; Pyrazinamide; Recurrence; Relapse; Research; Research Design; Research Personnel; Resistance; Rifampin; Risk; Role; Sampling; Science Enrichment; Sentinel; Site; Spottings; Sputum; Toxic effect; Treatment Failure; Treatment outcome; Tuberculosis; United States National Institutes of Health; Viremia; Work; acquired drug resistance; care outcomes; co-infection; cohort; design; experience; follow-up; genome sequencing; high risk; improved; isoniazid; lung health; lung injury; mortality; patient population; pharmacokinetics and pharmacodynamics; pharmacometrics; pill; prospective; resistance mutation; respiratory; respiratory health; sociodemographic factors; sociodemographics; therapeutic target; treatment response; tuberculosis drugs; tuberculosis treatment; whole genome

PROJECT SUMMARY Tuberculosis (TB) is the leading infectious cause of mortality globally after COVID-19. TB and HIV interact synergistically, each worsening the outcomes of the other. A key driver of unfavorable TB treatment outcomes is suboptimal drug exposures. However, target drug concentrations of first-line TB drugs and cumulative exposure thresholds needed for optimal clinical outcomes, post-TB lung health, and prevention of emergence of resistance are not defined, particularly in programmatic settings. In our study entitled “Investigating Multiple PK and PD Relationships for TB-HIV (IMPPRove TB-HIV)," we will leverage the Tuberculosis Sentinel Research Network (TB SRN), a large global platform cohort study for coordinated observational TB research conducted among persons with pulmonary TB with and without HIV, within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium in six IeDEA regions, to conduct pharmacokinetic-pharmacodynamic (PK-PD) analyses, using a nested case-cohort design. We will measure individual PK via collection of dried blood spots (DBS), which are easy to collect, store, and ship, and cumulative drug exposure in hair, which reflects both adherence and PK. In Aim 1 (PK-PD aim), we will examine the impact of TB drug PK and cumulative drug exposure on risk of unfavorable TB treatment outcomes (death, failure, recurrence) among individuals with pulmonary TB, with or without HIV. In Aim 2 (PK-resistance aim), we will investigate the impact of drug exposures on emergence of TB drug resistance mutations. In Aim 3 (PK-lung health aim), we will evaluate the association between anti-TB drug exposures and post-TB lung disease and longitudinal lung health. Thus, the IMPPRove study aims to elucidate the relationships between drug exposures and unfavorable TB treatment outcomes, poor lung health, and resistance under field conditions, in a large multinational patient population, taking into account HIV status and other factors known to affect these outcomes. The goal is to inform optimization of TB treatment (right dose, right patient) to improve clinically-important outcomes for patients.

项目概要 结核病 (TB) 是继 COVID-19 之后全球范围内导致死亡的主要传染病。结核病和艾滋病毒相互作用 协同作用，每一个都会使另一个的结果恶化。结核病治疗不利的关键驱动因素 结果是次优的药物暴露。然而，一线结核病药物的目标药物浓度和 最佳临床结果、结核病后肺部健康和预防结核病所需的累积暴露阈值 阻力的出现没有被定义，特别是在程序设置中。在我们的研究中题为 “调查 TB-HIV 的多重 PK 和 PD 关系 (IMPPRove TB-HIV)”，我们将利用 结核病前哨研究网络 (TB SRN)，一个大型全球平台队列研究，旨在协调 在感染和未感染艾滋病毒的肺结核患者中进行的观察性结核病研究 国际流行病学数据库评估艾滋病 (IeDEA) 联盟在六个 IeDEA 地区开展 使用嵌套病例队列设计进行药代动力学-药效（PK-PD）分析。我们将测量 通过收集干血斑 (DBS) 进行个体 PK，干血斑易于收集、储存和运输，并且 头发中的累积药物暴露，反映了依从性和 PK。在目标 1（PK-PD 目标）中，我们将 检查结核病药物 PK 和累积药物暴露对不利结核病治疗风险的影响 患有或不患有艾滋病毒的肺结核患者的结局（死亡、失败、复发）。目标 2 （PK耐药目标），我们将研究药物暴露对结核病耐药性出现的影响 突变。在目标 3（PK-肺部健康目标）中，我们将评估抗结核药物暴露之间的关联 以及结核病后肺部疾病和纵向肺部健康。因此，IMPPRove 研究旨在阐明 药物暴露与不良结核病治疗结果、肺部健康状况不佳和 考虑到艾滋病毒状况，在现场条件下，在大量跨国患者群体中进行耐药性 以及已知影响这些结果的其他因素。目标是为结核病治疗的优化提供信息（右 剂量，正确的患者）以改善患者的临床重要结果。