Development and validation of a time-varying correction factor for QT interval assessment in drug-resistant tuberculosis patients

• Standard correction factors for QT interval, such as Fridericia's, may be suboptimal in the active tuberculosis population, which is generally associated with tachycardia. • A time-varying correction factor that accounts for the change in heart rate in patients treated for tuberculosis was developed. • This novel correction factor captures natural QT-HR correlation changes during tuberculosis treatment, improving accuracy in determining QT prolongation. • Implementing this could lead to a more informative analysis of drug effects on QT in clinical trials and better treatment decisions for patients with TB. Tachycardia associated with active tuberculosis (TB) often diminishes when patients recover from TB. Elevated heart rate (HR) may lead to suboptimal correction, complicating the assessment of QT prolongation when using standard correction factors (CFs), such as Fridericia's formula (QTcF). Olliaro has proposed a CF for QT interval correction in pretreatment TB patients. However, the QT-HR correlation changes as HR decreases during treatment, indicating the need for time-varying correction. We developed an HR model to capture the HR normalisation during successful treatment. Subsequently, a time-varying CF was constructed using the estimated HR change rate. The performance of CFs to make corrected QT (QTc) independent from HR was evaluated by linear regression analyses of QTc versus HR within defined time bins. The final HR model included asymptotic change in HR attributed to time on treatment, circadian rhythm cycles, M2 (bedaquiline-metabolite) concentration, and patient covariates. The time-varying CF decreased from 0.4081 to 0.33, with a half-life of 7.74 weeks. The slope (QTc/HR vs. Time) derived from the time-varying correction was not significantly different from 0 (95% CI –0.003 to 0.002), and the intercept was not significantly different from 0 (95% CI –0.089 to 0.006), demonstrating successful QT correction from pretreatment to the end of treatment. The time-varying CF effectively captures the dynamic QT-HR relationship during TB treatment, reducing the risk of misdiagnosing QT prolongation or unnecessary discontinuation of treatment. By addressing underestimation and overestimation issues in QT interval assessment, this method enhances drug evaluation in clinical trials and supports improved treatment decisions for TB patients.