Effectiveness and Cardiac Safety of Bedaquiline-Based Therapy for Drug-Resistant Tuberculosis: A Prospective Cohort Study

• Type of Material: Article
• Authors: James CM Brust, Albert Einstein College of Medicine; Neel Gandhi, Emory University; Sean Wasserman, University of Cape Town; Gary Maartens, University of Cape Town; Shaheed Omar, National Institute for Communicable Diseases, Johannesburg; Nazir A Ismail, National Institute for Communicable Diseases, Johannesburg; Angela Campbell, Emory University; Lindsay Joseph, Albert Einstein College of Medicine; Alexandria Hahn, Albert Einstein College of Medicine; Salim Allana, Emory University; Alfonso C Hernandez-Romieu, Emory University; Chenshu Zhang, Albert Einstein College of Medicine; Koleka Mlisana, National Health Laboratory Services; Charle A Viljoen, University of Cape Town; Benjamin Zalta, Montefiore Medical Center; Ismaeel Ebrahim, University of Cape Town; Meghan Franczek, Emory University; Iqbal Master, King Dinuzulu Hospital Complex, Durban; Limpho Ramangoaela, Jose Pearson Hosp; Julian te Riele, Brooklyn Chest Hosp; Graeme Meintjes, University of Cape Town
• Language: English
• Date: 2021-12-06
• Publisher: OXFORD UNIV PRESS INC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/cid/ciab335
• Title of Journal or Parent Work: CLINICAL INFECTIOUS DISEASES
• Volume: 73
• Issue: 11
• Start Page: 2083
• End Page: 2092
• Grant/Funding Information: This study was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants R01AI114304, R01AI145679, and K24AI155045 to J. C. M. B. and K24AI114444 to N. R. G.), Einstein-Rockefeller-CUNY Center for AIDS Research (grant P30AI124414), Emory Center for AIDS Research (grant P30AI050409), Emory Tuberculosis Research Unit (grant U19AI111211), Einstein/Montefiore Institute for Clinical and Translational Research (grant UL1TR001073), the Atlanta Clinical and Translational Science Institute (grant UL1TR000454), the European & Developing Countries Clinical Trials Partnership (grant CDF1018 to S. W.), Wellcome Trust (grant 203135/Z/16/Z to S. W. and grants 098316, 214321/Z/18/Z, and 203135/Z/16/Z to G. Meintjes), and the National Institutes of Health (grant K43TW011421 to S. W.), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (grant 64787 to G. Meintjes), and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme (grant RFA# SAMRC-RFA-CC TB/HIV/AIDS-01-2014, funded by the National Department of Health). This research was funded in whole, or in part, by the Wellcome Trust [098316, 214321/Z/18/Z, and 203135/Z/16/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
• Keywords: Microbiology; NEVIRAPINE; Science & Technology; HIV; QT interval; HIV-INFECTED PATIENTS; CLOFAZIMINE; multidrug-resistant tuberculosis; Life Sciences & Biomedicine; antiretroviral therapy; LOPINAVIR/RITONAVIR; clofazimine; Immunology; Infectious Diseases; extensively drug-resistant tuberculosis; bedaquiline
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Epidemiology; Health Sciences, Radiology

Abstract

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant (RR) tuberculosis but prolongs the QT interval and carries a black-box warning from the US Food and Drug Administration. The World Health Organization recommends that all patients with RR tuberculosis receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published. Methods: We conducted an observational cohort study of patients with RR tuberculosis from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, which included obtaining electrocardiograms in triplicate at 4 time points during bedaquiline therapy. Participants were followed up until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT interval prolongation (QT prolongation), defined as any QT interval corrected by the Fridericia method (QTcF) >500 ms or an absolute change from baseline (ΔQTcF) >60 ms. Results: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant tuberculosis. Most participants (97%) received concurrent clofazimine. Of the participants, 74% were cured or successfully completed treatment, and outcomes did not differ by human immunodeficiency virus status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase (standard deviation) of 23.7 (22.7) ms from baseline to month 6. Four participants experienced a QTcF >500 ms and 19 experienced a ΔQTcF >60 ms. Older age was independently associated with QT prolongation. QT prolongation was neither more common nor more severe in participants receiving concurrent lopinavir-ritonavir. Conclusions: Severe QT prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close monitoring of the QT interval may be advisable in older patients.