Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Autor:	G Wills, Sara Murthy, Sarah Meredith, Rodney Dawson, Angela M. Crook, Mendel Carl M, Patrick P. J. Phillips, Conor D. Tweed, Stephen H. Gillespie, Andreas H. Diacon, Lerato Mohapi, Cheryl Louw, Melvin Spigelman, Kasha P. Singh, Michael E. P. Murphy, Andrew J. Nunn, Timothy D. McHugh, SR Murray
Přispěvatelé:	Department of Medicine, Faculty of Health Sciences, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, University of St Andrews. Global Health Implementation Group, University of St Andrews. Gillespie Group, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. Infection Group
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	Male Drug-induced liver injury lcsh:Medicine E-DAS Medical and Health Sciences Gastroenterology 0302 clinical medicine RA0421 Interquartile range Moxifloxacin RA0421 Public health. Hygiene. Preventive Medicine 030212 general & internal medicine Liver Disease Standard treatment Incidence Isoniazid 1. No poverty General Medicine Middle Aged 3. Good health Infectious Diseases 6.1 Pharmaceuticals 030211 gastroenterology & hepatology Female Chemical and Drug Induced Liver Injury Infection medicine.drug Research Article Adult medicine.medical_specialty Adolescent Clinical Trials and Supportive Activities 03 medical and health sciences Young Adult Rare Diseases SDG 3 - Good Health and Well-being Clinical Research Treatment monitoring General & Internal Medicine Internal medicine medicine Humans Tuberculosis Adverse effect Ethambutol business.industry Hepatotoxicity lcsh:R Evaluation of treatments and therapeutic interventions Regimen Orphan Drug Good Health and Well Being Digestive Diseases business Complication
Zdroj:	BMC Medicine, Vol 16, Iss 1, Pp 1-10 (2018) BMC Medicine BMC medicine, vol 16, iss 1
ISSN:	1741-7015
Popis:	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). 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. Publisher PDF
Databáze:	OpenAIRE
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