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MicroRNA-122 and cytokeratin-18 have potential as a biomarkers of drug-induced liver injury in European and African patients on treatment for tuberculosis
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  • Sarah Rupprechter,
  • Derek Sloan,
  • Wilna Oosthuyzen,
  • Till Bachmann,
  • Adam Hill,
  • Kevin Dhaliwal,
  • Kate Templeton,
  • Joshua Matovu,
  • Christine Sekaggya-Wiltshire,
  • James Dear
Sarah Rupprechter
Edinburgh University

Corresponding Author:[email protected]

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Derek Sloan
University of St Andrews
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Wilna Oosthuyzen
Edinburgh University
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Till Bachmann
University of Edinburgh
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Adam Hill
NHS Lothian
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Kevin Dhaliwal
University of Edinburgh Division of Clinical and Surgical Sciences
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Kate Templeton
NHS Lothian
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Joshua Matovu
Makerere University
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Christine Sekaggya-Wiltshire
Makerere University College of Health Sciences
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James Dear
Edinburgh University
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Aim Patients on anti-tuberculosis (anti-TB) therapy are at risk of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) and cytokeratin-18 (K18) are exploratory DILI biomarkers. To explore their utility in this global context, circulating miR-122 and K18 concentrations were measured in UK and Ugandan populations on anti-TB therapy for mycobacterial infection. Methods European patients receiving anti-TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER-ClinicalTrials.gov Identifier: NCT03211208). African patients with HIV-TB coinfection, receiving anti-TB and anti-retroviral therapy (ART), were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF-NCT03982277). Serial blood samples, demographic and clinical data were collected. MiR-122 was quantified using PCR. K18 was quantified using the M65 ELISA. Results The study had 235 participants (healthy volunteers (n=28); ALISTER: active TB (n=30), latent TB (n=88), non-tuberculous mycobacterial infection (n=25); SAEFRIF: HIV-TB coinfection (n=64)). In the absence of DILI, there was no difference in miR-122 and K18 across the groups. Both miR-122 and K18 correlated with alanine transaminase activity (ALT) (miR-122: r=0.52, 95%CI=0.42-0.61, P<0.0001. K18: r=0.42, 95%CI=0.34-0.49, P<0.0001). There were two DILI cases: baseline ALT was 18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR-122 4 and 17 fM, peak miR-122 60 and 336 fM, respectively. Conclusion In European and African patients treated with anti-TB therapy miR-122 and K18 correlated with ALT and increased with DILI. Further work should determine the diagnostic and prognostic utility of miR-122 and K18 in this global context-of-use.
03 Sep 2020Submitted to British Journal of Clinical Pharmacology
04 Sep 2020Submission Checks Completed
04 Sep 2020Assigned to Editor
21 Sep 2020Reviewer(s) Assigned
24 Oct 2020Review(s) Completed, Editorial Evaluation Pending
24 Oct 2020Editorial Decision: Revise Major
21 Dec 20201st Revision Received
22 Dec 2020Submission Checks Completed
22 Dec 2020Assigned to Editor
22 Dec 2020Review(s) Completed, Editorial Evaluation Pending
28 Dec 2020Editorial Decision: Accept