Analysis of the effects on the QT interval of a gatifloxacin-containing regimen versus standard treatment of pulmonary tuberculosis.


Olliaro, PL; Merle, C; Mthiyane, T; Bah, B; Kassa, F; Amukoye, E; N' Diaye, A; Perronne, C; Lienhardt, C; Mcilleron, H; Fielding, K; (2017) Analysis of the effects on the QT interval of a gatifloxacin-containing regimen versus standard treatment of pulmonary tuberculosis. Antimicrobial agents and chemotherapy. ISSN 0066-4804 DOI: https://doi.org/10.1128/AAC.01834-16

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Abstract

: Background: The effects on ventricular repolarisation - recorded on the ECG as lengthening of the QT interval - of acute tuberculosis and those of standard and alternative anti-tuberculosis regimens are under-documented. 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.Methods: ECGs were performed pre- and 1-5 hours post-dosing (month 1, 2, end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampicin and isoniazid for 6 months, pyrazinamide and ethambutol for 2 months; &quot;control&quot;) or a test regimen with gatifloxacin, rifampicin 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 modelled the effect of individual drugs' Cmax on the Fredericia-corrected QT interval.Results: 1686 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 from 37.2 to 36.5 C. Pre-treatment, the non-linear 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.1602 patients contributed to the analysis of QTcF by treatment arm. The peak QTcF value during follow-up was &gt;480ms for 21 patients (7 and 14 in the test and control arm) and &gt;500ms for 9 (5 and 4, respectively), corresponding to a risk difference of -0.9% (95% 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. 106 (6.6%) patients had a peak measurement change from baseline &gt;60ms (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 anti-tuberculosis drugs 1 month into treatment and the length QTcF.Conclusions: Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appear to carry a sizeable risk of QT prolongation in patients with newly-diagnosed pulmonary tuberculosis. This is to-date the largest dataset studying the effects of anti-tuberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen.<br/>

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Research Centre: TB Centre
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PubMed ID: 28438924
Web of Science ID: 406257600067
URI: http://researchonline.lshtm.ac.uk/id/eprint/3820853

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