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

项目摘要 结核病（TB）是COVID-19之后全球死亡的主要传染性原因。结核病和艾滋病毒相互作用 协同地，每一个都恶化了另一个的结果。结核病治疗不利的一个关键因素 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 抵抗的出现没有定义，特别是在方案背景下。在我们的研究中， “研究TB-HIV的多种PK和PD关系（IMPPRove TB-HIV）”，我们将利用 结核病哨点研究网络（TB SRN）是一个大型全球平台队列研究， 在艾滋病毒感染者和未感染者中进行的结核病观察性研究， 国际流行病学数据库评估艾滋病联合会，在六个区域开展 药代动力学-药效学（PK-PD）分析，采用嵌套病例队列设计。我们将测量 通过采集易于采集、储存和运输的干血点（DBS）进行个体PK，以及 毛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和累积药物暴露对结核病治疗不利风险的影响 结果（死亡，失败，复发）与肺结核的个人，有或没有艾滋病毒。在目标2中 （PK耐药目标），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与肺结核病之间的关系。 肺结核后肺部疾病和纵向肺部健康。因此，IMPPRove研究旨在阐明 药物暴露与不利的结核病治疗结果、肺部健康状况差以及 考虑到艾滋病毒状态，在大量多国患者人群中实地条件下的耐药性 以及其他已知会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），以改善患者的临床重要结局。

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.