Abstract
ABSTRACTThe 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.)
Highlights
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
It has been suggested that compounds such as gatifloxacin and moxifloxacin, both considered in antituberculosis regimens, which have a methoxy substitution at position C-8, might inhibit human ether-a-go-go-related gene (hERG) at therapeutically achievable concentrations [4]
There is no information on the appropriateness of these corrections in patients with pulmonary tuberculosis (PTB), i.e., how good they are in making the QT interval independent of the heart rate
Summary
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. Prolonged repolarization is recorded on ECG as lengthening of the QT interval [1] This condition is considered to increase the risk for ventricular arrhythmias and the potentially fatal “torsades de pointes” (TdP). With prospects of having them added to the antituberculosis armory of drugs, drugs belonging to the fluoroquinolone (FQ) family have attracted attention, as they can variably affect ventricular repolarization [2] These drugs have different affinities for binding to the rapid component of the delayed-rectifier current IKr, which is expressed by the human ether-a-go-go-related gene (hERG) [3]. There is no information on the appropriateness of these corrections in patients with pulmonary tuberculosis (PTB), i.e., how good they are in making the QT interval independent of the heart rate
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