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. 2018 Mar 28;16(1):46.
doi: 10.1186/s12916-018-1033-7.

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Conor Duncan Tweed  1 , Genevieve Helen Wills  2 , Angela M Crook  2 , Rodney Dawson  3 , Andreas H Diacon  4 , Cheryl E Louw  5 , Timothy D McHugh  6 , Carl Mendel  7 , Sarah Meredith  2 , Lerato Mohapi  8 , Michael E Murphy  6 , Stephen Murray  7 , Sara Murthy  6 , Andrew J Nunn  2 , Patrick P J Phillips  9 , Kasha Singh  10 , M Spigelman  7 , S H Gillespie  11
Affiliations

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Conor Duncan Tweed et al. BMC Med. .

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.

Keywords: Drug-induced liver injury; Hepatotoxicity; Treatment monitoring; Tuberculosis.

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Conflict of interest statement

Ethics approval and consent to participate

Ethics approval was granted for REMoxTB by the ethics board at University College London, and at each of the study sites:

  1. Kenya

    1. Kenya Medical Research Institute (KEMRI) Scientific Steering Committee

    2. KEMRI Ethical Review Committee

  2. South Africa

    1. Medicines Control Council, Pretoria

    2. Pharma Ethics, Pretoria

    3. University of Cape Town Human Research Ethics Committee, Cape Town

    4. Biomedical Research Ethics Committee, Durban

    5. Wits Human Research Ethics Committee, Johannesburg

  3. Tanzania

    1. Kilimanjaro Christian Medical College Research Ethics and Review Committee, Moshi

    2. Mbeya Ethics and Research Committee, Mbeya

    3. National Institute for Medical Research, Dar es Salaam

  4. Zambia

    1. University of Zambia Biomedical Research Ethics Committee, Lusaka

  5. China

    1. Beijing Chest Hospital of Capital Medical University Ethics Committee, Beijing

    2. Shanghai Pulmonary Hospital Ethics Committee, Shanghai

    3. Tianjin CDC Biomedical Ethics Committee, Tianjin

  6. India

    1. Biomedical Ethics Committee, New Delhi

    2. Institutional Ethics Committee, Mahatma Gandhi Medical College and Hospital, Jaipur

  7. Mexico

    1. Comité de Investigación y Ética (División de Enseñanza, Investigación, Capacitación, Ética y Calidad) Hospital General de Occidente, Jalisco

    2. National Jewish Health, Denver, USA

  8. Thailand

    1. Ethics Committees on Researches Involving Human Subjects, Rajavithi Hospital, Bangkok

    2. The Khon Kaen University Ethics Committee for Human Research Faculty of Medicine, Khon Kaen University, Muang Khon Kaen

    3. Ethical Review Committee for Research in Human Subjects, Ministry of Public Health, Nonthraburi

    4. Ethical Review Committee of Chest Disease Institute, Department of Medical Services and Ministry of Public Health, Nonthraburi

  9. Malaysia

    1. Medical Research & Ethics Committee, Ministry of Health Malaysia, Kuala Lumpur

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for time to reach peak in all patients and normalisation of elevated ALT and AST values for patients with peak ≥1 × ULN. The curves for the time to reach peak ALT and AST show for all patients the time to reach the peak enzyme level by treatment arm. The log-rank test detected a significant difference for the time to reach peak ALT between the standard arm (median time 28 days) and ethambutol arm (median time 55 days). The time for patients with peak ALT and AST > 1 × ULN to return to within the normal range from this peak is also illustrated, with no significant difference detected between the treatment arms (p > 0.10). Eleven patients were not included in the time to peak graphs, as the peak value was measured at the screening visit (visit 0). ALT alanine aminotransferase, AST aspartate aminotransferase, ULN upper limit of normal
Fig. 2
Fig. 2
Scatter plots illustrating peak values for ALT and AST in patients when peak value ≥3 × ULN. The timing in days since the first treatment dose (x-axis) and peak ALT and AST (y-axis) is illustrated for each treatment arm for those patients with a peak ≥3 × ULN. The lines on the graphs indicate the interquartile ranges for the peak ALT and AST and the timing of the peak in this subgroup, with shaded areas corresponding to the interquartile range for both time and elevation result. Four patients excluded with ALT > 19 × ULN and six patients were excluded with AST >21 × ULN. ALT alanine aminotransferase, AST aspartate aminotransferase, ULN upper limit of normal
See this image and copyright information in PMC

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