Journal
JOURNAL OF HEPATOLOGY
Volume 69, Issue 3, Pages 584-593Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2018.05.004
Keywords
Chronic hepatitis B; Nucleos(t)ide analogue (NA); Discontinuation of treatment; T cell phenotype; HBV-specific T cell response; PD-L1 blockade
Categories
Funding
- German Center for Infection Research (DZIF)
- Swedish Research Council
- Swedish Cancer Society
- Swedish Foundation for Strategic Research
- Swedish Society for Medical Research
- Cancer Research Foundations of Radiumhemmet
- Knut and Alice Wallenberg Foundation
- Novo Nordisk Foundation
- Ake Wiberg's Foundation
- Center for Innovative Medicine at Karolinska Institutet
- Stockholm County Council
- Karolinska Institutet
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Background & Aims: Treatment with nucleos(t)ide analogues (NA) leads to hepatitis B virus (HBV) DNA suppression in most patients with chronic hepatitis B (CHB), but HBV surface antigen (HBsAg) loss rates are low. Upon NA discontinuation, HBV DNA can return rapidly with ensuing alanine aminotransferase flares and induction of cytokines. Several studies reported higher HBsAg loss rates after stopping therapy, but at present it is unclear if cell-mediated immune responses are altered after treatment discontinuation. The aim of this study was to characterise T cell responses during the early phase of virological relapse, following discontinuation of NA therapy in HBeAg-negative patients. Methods: A total of 15 HBeAg-negative patients with CHB on long-term NA treatment were included in a prospective study and subjected to structured NA discontinuation. T cell responses were studied at the end of NA therapy and 4, 8 and 12 weeks thereafter. Results: The T cell phenotype of patients with CHB on long-term NA therapy was markedly different compared to healthy individuals, but was only slightly altered after discontinuation of therapy. T cells from patients with HBsAg loss expressed low levels of KLRG1 and PD-1 at all time-points and high levels of Ki-67 and CD38 at week 12 after treatment cessation. In vitro peptide stimulated HBV-specific T cell responses were increased in several patients after NA cessation. Blocking of PD-L1 further enhanced HBV-specific T cell responses, especially after discontinuation of therapy. Conclusion: Relapse of active HBV replication after stopping therapy may trigger an immunological environment that enhances the responsiveness of HBV-specific T cells in vitro. Together with other immune interventions, this approach might be of interest for the development of novel therapeutic options to induce HBsAg loss in CHB. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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