Effects on the QT Interval of a Gatifloxacin-Containing Regimen versus Standard Treatment of Pulmonary Tuberculosis

Abstract

The effects on ventricular repolarization-recorded on the electrocardiogram (ECG) as lengthening of the QT interval-of acute tuberculosis and those of standard and alternative antituberculosis regimens are underdocumented. A correction factor (QTc) is introduced to make the QT independent of the heart rate, translating into the slope of the regression line between QT and heart rate being close to zero. ECGs were performed predosing and 1 to 5 h postdosing (month 1, month 2, and end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampin and isoniazid for 6 months and pyrazinamide and ethambutol for 2 months; "control") or a test regimen with gatifloxacin, rifampin, and isoniazid given for 4 months (pyrazinamide for the first 2 months) as part of the OFLOTUB study, a randomized controlled trial conducted in five African countries. Drug levels were measured at steady state (month 1) in a subset of patients. We compared treatment effects on the QTc and modeled the effect of individual drugs' maximum concentrations of drug in serum (Cmax) on the Fridericia-corrected QT interval. A total of 1,686 patients were eligible for the correction factor analysis of QT at baseline (mean age, 30.7 years; 27% female). Median heart rate decreased from 96/min at baseline to 71/min at end of treatment, and body temperature decreased from 37.2 to 36.5°C. Pretreatment, the nonlinear model estimated the best correction factor at 0.4081 in between Bazett's (0.5) and Fridericia's (0.33) corrections. On treatment, Fridericia (QTcF) was the best correction factor. A total of 1,602 patients contributed to the analysis of QTcF by treatment arm. The peak QTcF value during follow-up was >480 ms for 21 patients (7 and 14 in the test and control arms, respectively) and >500 ms for 9 patients (5 and 4, respectively), corresponding to a risk difference of -0.9% (95% confidence interval [CI], -2.0% to 2.3%; P = 0.12) and 0.1% (95% CI, -0.6% to 0.9%; P = 0.75), respectively, between the test and control arms. One hundred six (6.6%) patients had a peak measurement change from baseline of >60 ms (adjusted between-arm difference, 0.8%; 95% CI, -1.4% to 3.1%; P = 0.47). No evidence was found of an association between Cmax of the antituberculosis drugs 1 month into treatment and the length of QTcF. Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appears to carry a sizable risk of QT prolongation in patients with newly diagnosed pulmonary tuberculosis. This is to date the largest data set studying the effects of antituberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT00216385.).

Keywords: Mycobacterium tuberculosis; QT interval; cardiotoxicity; fluoroquinolones; gatifloxacin.

Copyright © World Health Organization 2017. Licensee, American Society for Microbiology.

Figures

FIG 1

Study flow diagram.

FIG 2

Plot of uncorrected data and regression line and regression lines for Bazett-corrected, Fridericia-corrected, and new-corrected QT (QTc-TB), using data at baseline (n = 1,686). QT unc-obs, QT uncorrected observed data; QT uncorrected, uncorrected regression line; QTc-F, Fridericia-corrected regression line; QTc-B, Bazett-corrected regression line; QTc-TB, regression line corrected using correction factor of 0.4081.

FIG 3

Plot of uncorrected data and QTcTB (0.4081)-corrected regression line against 1-RR (where RR = 60/heart rate), using data at baseline, by country, sex, and cavitation status.

FIG 4

Mean and 95% confidence interval (CI), by test and control arm, of QTcF values at baseline, months 1 and 2, and end of treatment (months 4 and 6, respectively).