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Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

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Tweed_2018_BMCMedicine_Livertoxicity_CC.pdf (894.5Kb)
Date
28/03/2018
Author
Tweed, Conor Duncan
Wills, Genevieve Helen
Crook, Angela M.
Dawson, Rodney
Diacon, Andreas H.
Louw, Cheryl E.
McHugh, Timothy D.
Mendel, Carl
Meredith, Sarah
Mohapi, Lerato
Murphy, Michael E.
Murray, Stephen
Murthy, Sara
Nunn, Andrew J.
Phillips, Patrick P. J.
Singh, Kasha
Spigelman, M.
Gillespie, S. H.
Keywords
Tuberculosis
Hepatotoxicity
Drug-induced liver injury
Treatment monitoring
RA0421 Public health. Hygiene. Preventive Medicine
E-DAS
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Abstract
Background:  Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. Methods: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. Results: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14–56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). Conclusions: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.
Citation
Tweed , C D , Wills , G H , Crook , A M , Dawson , R , Diacon , A H , Louw , C E , McHugh , T D , Mendel , C , Meredith , S , Mohapi , L , Murphy , M E , Murray , S , Murthy , S , Nunn , A J , Phillips , P P J , Singh , K , Spigelman , M & Gillespie , S H 2018 , ' Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study ' , BMC Medicine , vol. 16 , 46 . https://doi.org/10.1186/s12916-018-1033-7
Publication
BMC Medicine
Status
Peer reviewed
DOI
https://doi.org/10.1186/s12916-018-1033-7
ISSN
1741-7015
Type
Journal article
Rights
© The Author(s). 2018. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Description
This work was supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership (grant IP.2007.32011.011), the US Agency for International Development, the UK Department for International Development, the Directorate General for International Cooperation of the Netherlands, Irish Aid, the Australia Department of Foreign Affairs and Trade, and the National Institutes of Health, AIDS Clinical Trials Group (ACTG). It was further supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu-Natal, South Africa, ACTG site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/13046

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