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

项目总结 结核病是仅次于新冠肺炎的全球主要死亡传染病。结核病与艾滋病毒相互作用 在协同作用下，每一方都会恶化另一方的结果。结核病治疗不利的关键驱动因素 结果是接触不到最理想的药物。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以下疾病所需的累积暴露阈值 抵抗的出现没有被定义，特别是在方案环境中。在我们题为 “调查结核病-艾滋病毒(ImPPRove TB-HIV)的多种PK和PD关系”，我们将利用 结核病哨兵研究网络(TB SRN)，一个协调的全球大型平台队列研究 在感染和不感染艾滋病毒的肺结核病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区域进行 药代动力学-药效学(PK-PD)分析，采用嵌套病例队列设计。我们将衡量 通过收集干血点(DB)进行个人PK，这些血点易于收集、存储和运输，以及 头发中的累积药物暴露，这既反映了依从性，也反映了PK。在目标1(PK-PD目标)中，我们将 检查结核病药物PK和累积药物暴露对结核病治疗不利风险的影响 感染或不感染艾滋病毒的肺结核病患者的结果(死亡、失败、复发)。在AIM 2 (PK-耐药性目标)，我们将调查药物暴露对结核病耐药性出现的影响 突变。在目标3(PK-肺健康目标)中，我们将评估抗结核药物暴露之间的关系 以及结核病后肺部疾病和纵向肺健康。因此，IMPPRove研究旨在阐明 药物暴露与不利的结核病治疗结果、较差的肺部健康以及 在考虑到艾滋病毒状况的情况下，在大量多国患者人口中的现场条件下的耐药性 以及其他已知的影响这些结果的因素。目标是为结核病治疗的优化提供信息(右 剂量，正确的患者)，以改善对患者具有临床重要性的结果。

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.