Skip to content

Research at St Andrews

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Research output: Contribution to journalArticlepeer-review

Author(s)

Conor Duncan Tweed, Genevieve Helen Wills, Angela M. Crook, Rodney Dawson, Andreas H. Diacon, Cheryl E. Louw, Timothy D. McHugh, Carl Mendel, Sarah Meredith, Lerato Mohapi, Michael E. Murphy, Stephen Murray, Sara Murthy, Andrew J. Nunn, Patrick P. J. Phillips, Kasha Singh, M. Spigelman, S. H. Gillespie

School/Research organisations

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.
Close

Details

Original languageEnglish
Article number46
Number of pages10
JournalBMC Medicine
Volume16
DOIs
Publication statusPublished - 28 Mar 2018

    Research areas

  • Tuberculosis, Hepatotoxicity, Drug-induced liver injury, Treatment monitoring

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Toxicity related to standard TB therapy for pulmonary tuberculosis and treatment outcomes in the REMoxTB study according to HIV status

    Tweed, C. D., Crook, A. M., Dawson, R., Diacon, A. H., McHugh, T. D., Mendel, C. M., Meredith, S. K., Mohapi, L., Murphy, M. E., Nunn, A. J., Phillips, P. P. J., Singh, K. P., Spigelman, M. & Gillespie, S. H., 14 Aug 2019, In: BMC Pulmonary Medicine. 19, 9 p., 152.

    Research output: Contribution to journalArticlepeer-review

  2. Toxicity associated with tuberculosis chemotherapy in the REMoxTB study

    Tweed, C. D., Crook, A. M., Amukoye, E. I., Dawson, R., Diacon, A. H., Hanekom, M., McHugh, T. D., Mendel, C. M., Meredith, S. K., Murphy, M. E., Murthy, S. E., Nunn, A. J., Phillips, P. P. J., Singh, K. P., Spigelman, M., Wills, G. H. & Gillespie, S. H., 11 Jul 2018, In: BMC Infectious Diseases. 18, 11 p., 317.

    Research output: Contribution to journalArticlepeer-review

  3. Clinical perspectives in integrating whole genome sequencing into the investigation of healthcare and public health outbreaks – hype or help?

    Parcell, B. J., Gillespie, S. H., Pettigrew, K. A. & Holden, M. T. G., Mar 2021, In: Journal of Hospital Infection. 109, p. 1-9 9 p.

    Research output: Contribution to journalArticlepeer-review

  4. Modelling the effects of environmental heterogeneity within the lung on the tuberculosis life-cycle

    Pitcher, M. J., Bowness, R., Dobson, S. A., Eftimie, R. & Gillespie, S. H., 7 Dec 2020, In: Journal of Theoretical Biology. 506, 18 p., 110381.

    Research output: Contribution to journalArticlepeer-review

  5. Culture-free proof of Mycobacterium tuberculosis - a new assay for viable bacteria

    Heyckendorf, J., Gillespie, S. H. & Ruhwald, M., Dec 2020, In: EBioMedicine. 62, 2 p., 103117.

    Research output: Contribution to journalComment/debate

Related by journal

  1. Repeated clinical malaria episodes are associated with modification of the immune system in children

    Bediako, Y., Adams, R., Reid, A. J., Valletta, J. J., Ndungu, F. M., Sodenkamp, J., Mwacharo, J., Ngoi, J. M., Kimani, D., Kai, O., Wambua, J., Nyangweso, G., De Villiers, E. P., Sanders, M., Lotkowska, M. E., Lin, J. W., Manni, S., Addy, J. W. G., Recker, M., Newbold, C. & 4 others, Berriman, M., Bejon, P., Marsh, K. & Langhorne, J., 13 Mar 2019, In: BMC Medicine. 17, 14 p., 60.

    Research output: Contribution to journalArticlepeer-review

  2. Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study

    Murphy, M. E., Wills, G. H., Murthy, S., Louw, C., Bateson, A. L. C., Hunt, R. D., McHugh, T. D., Nunn, A. J., Meredith, S. K., Mendel, C. M., Spigelman, M., Crook, A. M., Gillespie, S. H. & REMoxTB Consortium, 17 Oct 2018, In: BMC Medicine. 16, 11 p., 189.

    Research output: Contribution to journalArticlepeer-review

  3. Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis

    Murthy, S. E., Chatterjee, F., Crook, A., Dawson, R., Mendel, C., Murphy, M. E., Murray, S. R., Nunn, A. J., Phillips, P. P. J., Singh, K. P., McHugh, T. D., Gillespie, S. H. & REMoxTB Consortium, 21 May 2018, In: BMC Medicine. 16, 11 p., 73.

    Research output: Contribution to journalArticlepeer-review

  4. A comparison of liquid and solid culture for determining relapse and durable cure in phase III TB trials for new regimens

    Phillips, P. P. J., Mendel, C. M., Nunn, A. J., McHugh, T. D., Crook, A. M., Hunt, R., Bateson, A. & Gillespie, S. H., 24 Nov 2017, In: BMC Medicine. 15, 9 p., 207.

    Research output: Contribution to journalArticlepeer-review

ID: 252649357

Top