Development and validation of a time-varying correction factor for QT interval assessment in drug-resistant tuberculosis patients
Year: 2025
Type: article
Abstract: • 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.
Institutions: Uppsala University, Janssen (Belgium), Vanderbilt University Medical Center, Albert Einstein College of Medicine, Montefiore Medical Center, University of Cape Town, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Radboud University Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,280
Funders: City University of New York, Wellcome Trust, ViiV Healthcare, ACT Government, Vetenskapsrådet, National Institutes of Health, Institute for Clinical and Translational Research, University of Wisconsin, Madison, Uppsala Multidisciplinary Center for Advanced Computational Science, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences, Janssen Pharmaceuticals, Einstein-Rockefeller-CUNY Center for AIDS Research, Albert Einstein College of Medicine
Awards: G144555574, G186995139, Evaluation of novel therapeutic strategies to accelerate bacterial clearance and host recovery in disseminated HIV-associated tuberculosis, G3321450376, Einstein-Montefiore Clinical and Translational Science Award Hub, G4517903627, Evaluation of novel therapeutic strategies to accelerate bacterial clearance and host recovery in disseminated HIV-associated tuberculosis, Clinical and Translational Science Award, Safety, pharmacokinetics, and resistance to bedaquiline in XDR TB and HIV, G712881263, G796431723, NAISS, G9000060040, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, ERC Einstein-Rockefeller-CUNY Center for AIDS research, Mentoring Investigators in HIV and Tuberculosis Therapeutics Research, Emergence of bedaquiline and clofazimine resistance after interruption of drug-resistant TB therapy in a high HIV prevalence setting, Mentoring of multidisciplinary global health research in tuberculosis and HIV, G960969753
OpenAlex ID: W4407187618