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

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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.