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QT prolongation in patients treated for drug-resistant tuberculosis

Hughes, Gareth; (2023) QT prolongation in patients treated for drug-resistant tuberculosis. Doctoral thesis (M.D(Res)), UCL (University College London). Green open access

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Abstract

Introduction STREAM (Standardised Treatment Regimen of Anti-TB Drugs for Patients with MDRTB) Stage 1 demonstrated non-inferior efficacy of a Short regimen for rifampicin-resistant TB compared to the WHO-recommended Long regimen. Cardiac safety of participants was a concern due to the composition of the Short (study) regimen. It was unclear how many patients would be affected, who would be affected, the best monitoring strategy and how to identify those at risk of developing QT prolongation. Methods An analysis of new data created from STREAM Stage 1 ECGs was performed to investigate cardiac safety. In total, 424 participants (282 Short: 142 Long) were randomised. Data were analysed to identify risk factors for clinically relevant QT prolongation (QT/QTcF ≥500ms), how it evolved over time, whether a monitoring strategy could be refined, if machine readings were reliable and whether differences between groups for T-wave morphology abnormalities existed. Results The risk of developing QT or QTcF prolongation ≥500ms was higher for participants on the Short regimen (11%) vs the Long regimen (5%) (HR 95% CI: 2.31 (1.02-5.26)), p=0.0470. QT/QTcF prolongation ≥500ms was more frequent in patients from Mongolia (10/22 45.5%) compared with 3.5-11.9% at other sites, as well as those with higher baseline values (QTcF ≥400ms; OR 5.99, 95% CI 2.04-17.62). Compared with manual readings, machine readings overestimated the QT interval by a mean of 22.5ms. Nearly half (90/200) of ECGs reviewed had T-wave morphology abnormalities by 3 months or more of treatment. Conclusion Though a sizeable number developed clinically relevant QT prolongation, the Short regimen in STREAM Stage 1 was safe and tolerated by most participants. This thesis has shown who was at greater risk, how they were managed and how early ECG readings can identify them for more targeted monitoring. This will inform clinicians and policy makers involved in rifampicin resistant tuberculosis (RR-TB) treatment programmes.

Type: Thesis (Doctoral)
Qualification: M.D(Res)
Title: QT prolongation in patients treated for drug-resistant tuberculosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10165894
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