Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways.

BACKGROUND

We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy.

METHODS

Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured.

RESULTS

Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients.

CONCLUSIONS

Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: [e-mail].

Déclaration de conflit d'intérêts

Potential conflicts of interest. K. V. received speaker fees from Gilead and consulting fees from Antios Pharmaceuticals. K. V. is on the Advisory Board for Gilead and ViiV Health Care; A. J. T. received funding from Roche Diagnostics, which did not support the current work. A. J. T. received speaker fees from Gilead Sciences and is on their Advisory Board; P. A. R. is an executive for the Australian Centre for HIV and Hepatitis Virology and the International Coalition to Eliminate Hepatitis B Virus; G. M. received funding from Gilead Sciences, Abbvie, and ViiV Health Care. G. M. received consulting fees from Astra Zeneca and speaker fees from Janssen. G. M. is on the Gilead Advisory Board and has a leadership role in ASHM; M. S. received funding from Mallinckrodt; M. C. N. is a member for the board of directors of ANZAC Research Institute; S. I. S. received funding from Gilead, Abbvie, BMS, MSD, Eisai, Astra Zeneca, CSL Behring, Cheisi, Roche, Pfizer, and Norgine. S. I. S. has leadership roles in The Liver Foundation, GESA, and APASL; A. J. N. received speaker fees from Astra Zeneca, Roche, and Eisai. A. J. N. is on the Ipsen Advisory Board; J. S. L. is on the Advisory Board for Gilead, Abbvie, and Bayer. J. S. L. has a leadership role in GESA; M. T. L. received funding from Gilead Sciences and Abbvie. M. T. L. received speaker fees from Gilead and Falk. M. T. L. is on the Advisory Board for Abbvie, Gilead, and Ipsen. M. T. L. has a leadership role in GESA. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.