Insights into the Role of Rifampicin Exposure and Clinical Baseline Covariates on the Response to Pulmonary Tuberculosis Treatment

BACKGROUND: Quantitative markers of tuberculosis disease burden are essential for assessing treatment response and optimizing therapeutic strategies. This study evaluated the impact of antimicrobial plasma drug levels on time-to-positivity (TTP) trajectories in patients with drug-susceptible tuberculosis and explored the relationship between bacillary clearance and treatment outcomes. METHODS: Patients with drug susceptible pulmonary tuberculosis initiating treatment were recruited in Worcester, South Africa. Weekly sputum samples were collected for 12 weeks, with bacterial load quantified using Mycobacterial Growth Indicator Tubes, yielding TTP. Nonlinear mixed-effects modeling was used to empirically describe longitudinal TTP, assessing rifampicin exposure and other participant characteristics as covariates. TTP trajectories were stratified by treatment outcomes to identify trends between change in TTP and outcome. RESULTS: A total of 402 participants were included, of whom 60% were male. Median age was 37 years (interquartile ratio 26-48) and 90% had successful treatment outcomes (were cured or completed treatment) at 6 months with 3% who experienced treatment failure, 2% died, 1% transferred, and 4% were lost to follow-up. Baseline smear grade and lung cavitation decreased baseline TTP. Higher rifampicin concentration area under the curve was associated with faster longitudinal change in TTP, whereas lung cavitation and older age were associated with slower longitudinal change. Furthermore, slower change in TTP during the first 12 weeks of treatment was linked to treatment failure at 6 months. CONCLUSIONS: Our findings highlight the role of rifampicin plasma exposure in optimizing bacillary clearance and improving treatment outcomes, even within standard dosing regimens for drug-susceptible tuberculosis.