Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

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dc.contributor.authorTweed, Conor D
dc.contributor.authorWills, Genevieve H
dc.contributor.authorCrook, Angela M
dc.contributor.authorDawson, Rodney
dc.contributor.authorDiacon, Andreas H
dc.contributor.authorLouw, Cheryl E
dc.contributor.authorMcHugh, Timothy D
dc.contributor.authorMendel, Carl
dc.contributor.authorMeredith, Sarah
dc.contributor.authorMohapi, Lerato
dc.contributor.authorMurphy, Michael E
dc.contributor.authorMurray, Stephen
dc.contributor.authorMurthy, Sara
dc.contributor.authorNunn, Andrew J
dc.contributor.authorPhillips, Patrick P J
dc.contributor.authorSingh, Kasha
dc.contributor.authorSpigelman, M
dc.contributor.authorGillespie, S H
dc.date.accessioned2018-05-07T09:50:14Z
dc.date.available2018-05-07T09:50:14Z
dc.date.issued2018-03-28
dc.date.updated2018-04-09T15:14:06Z
dc.description.abstractBackground 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.
dc.identifier.apacitationTweed, C. D., Wills, G. H., Crook, A. M., Dawson, R., Diacon, A. H., Louw, C. E., ... Gillespie, S. H. (2018). Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. <i>BMC Medicine</i>, http://hdl.handle.net/11427/27963en_ZA
dc.identifier.chicagocitationTweed, Conor D, Genevieve H Wills, Angela M Crook, Rodney Dawson, Andreas H Diacon, Cheryl E Louw, Timothy D McHugh, et al "Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study." <i>BMC Medicine</i> (2018) http://hdl.handle.net/11427/27963en_ZA
dc.identifier.citationTweed, C. D., Wills, G. H., Crook, A. M., Dawson, R., Diacon, A. H., Louw, C. E., ... & Murphy, M. E. (2018). Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. BMC medicine, 16(1), 46.
dc.identifier.ris TY - Journal Article AU - Tweed, Conor D AU - Wills, Genevieve H AU - Crook, Angela M AU - Dawson, Rodney AU - Diacon, Andreas H AU - Louw, Cheryl E AU - McHugh, Timothy D AU - Mendel, Carl AU - Meredith, Sarah AU - Mohapi, Lerato AU - Murphy, Michael E AU - Murray, Stephen AU - Murthy, Sara AU - Nunn, Andrew J AU - Phillips, Patrick P J AU - Singh, Kasha AU - Spigelman, M AU - Gillespie, S H AB - 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. DA - 2018-03-28 DB - OpenUCT DO - 10.1186/s12916-018-1033-7 DP - University of Cape Town J1 - BMC Medicine LK - https://open.uct.ac.za PB - University of Cape Town PY - 2018 T1 - Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study TI - Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study UR - http://hdl.handle.net/11427/27963 ER - en_ZA
dc.identifier.urihttp://dx.doi.org/10.1186/s12916-018-1033-7
dc.identifier.urihttp://hdl.handle.net/11427/27963
dc.identifier.vancouvercitationTweed CD, Wills GH, Crook AM, Dawson R, Diacon AH, Louw CE, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. BMC Medicine. 2018; http://hdl.handle.net/11427/27963.en_ZA
dc.language.isoen
dc.publisherBioMed Central
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rights.holderThe Author(s).
dc.sourceBMC Medicine
dc.source.urihttps://bmcmedicine.biomedcentral.com/
dc.subject.otherTuberculosis
dc.subject.otherHepatotoxicity
dc.subject.otherDrug-induced liver injury
dc.subject.otherTreatment monitoring
dc.titleLiver toxicity associated with tuberculosis chemotherapy in the REMoxTB study
dc.typeJournal Article
uct.type.filetypeText
uct.type.filetypeImage
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