Development and Validation of a Nomogram for Prediction of QT Interval Prolongation in Patients Administered Bedaquiline-Containing Regimens in China: a Modeling Study

Corrected QT duration (QTc) interval prolongation is the most frequent adverse event associated with bedaquiline (BDQ) use. It may affect the safety of anti-tuberculosis therapy, which leads to the consequent demands of needing to monitor during therapy. Our objective was to establish and validate a prediction model for estimating the risk of QTc prolongation after initiation of BDQ-containing regimens to multidrug-resistant tuberculosis (MDR-TB) patients. We constructed an individualized nomogram model based on baseline demographic and clinical characteristics of each patient within a Chinese cohort during BDQ treatment. The generalizability of this model was further validated through use of externally acquired data obtained from Beijing Chest Hospital from 2019 to 2020. Overall, 1,215 and 165 patients were included in training and external validation cohorts, respectively, whereby during anti-TB drug treatment, QTc prolongation was observed in 273 (22.5%) and 29 (17.6%) patients within these respective cohorts, for whom QTc values were >500 ms in 86 (31.5%) and 10 (34.7%) patients, respectively. Next, a total of four Cox proportional hazards models were created and assessed; then, nomograms derived from the models were plotted based on independent predictors of clofazimine, baseline QTc interval, creatinine, extensive drug-resistance (XDR), moxifloxacin, levofloxacin, and sex. Nomogram analysis revealed concordance index values of 0.723 (95% confidence interval [Cl], 0.695 to 0.750) for the training cohort and 0.710 (95% CI, 0.627 to 0.821) for the external validation cohort, thus indicating relatively fair agreement between predicted and observed probabilities of QTc prolongation occurrence based on data obtained during 8-week, 16-week, and 24-week anti-TB treatment of both cohorts. Taken together, results obtained using these models demonstrated that coadministration of clofazimine and abnormal baseline QTc interval significantly contributed to QTc prolongation development during MDR-TB patient treatment with a BDQ-containing anti-TB treatment regimen.