Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B
Author links open overlay panelFranziskaRinker13†Christine L.Zimmer2†ChristophHöner zu Siederdissen1Michael P.Manns134Anke R.M.Kraft1HeinerWedemeyer13Niklas K.Björkström2†MarkusCornberg134†
1
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
2
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
3
German Center for Infection Research, Partner Site Hannover-Braunschweig, Germany
4
Centre for Individualised Infection Medicine (CIIM), c/o CRC Hannover, Germany
Received 2 November 2017, Revised 2 May 2018, Accepted 3 May 2018, Available online 29 June 2018.
crossmark-logo https://doi.org/10.1016/j.jhep.2018.05.004
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Highlights
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Discontinuation of NA therapy leads to higher HBsAg loss rates in HBeAg-negative CHB patients.
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T cells from patients with subsequent HBsAg loss show a less exhausted phenotype.
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These T cells also express higher levels of activation and proliferation markers at week 12 after discontinuation of therapy.
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Relapse of active HBV replication may trigger immunological environment that enhances responsiveness of HBV-specific T cells in vitro.
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.
Lay summary
Relapse of hepatitis B virus replication after discontinuation of nucleos(t)ide analogue therapy in certain patients with chronic hepatitis B may alter the phenotype of T cells and enhance the responsiveness of hepatitis B virus-specific T cells to in vitro peptide stimulation. Blocking PD-L1 can further augment these hepatitis B virus-specific T cell responses. Interestingly, T cells of patients that subsequently achieve hepatitis B surface antigen loss are less exhausted at all time-points after stopping treatment and display a higher proliferative capacity 12-weeks after treatment discontinuation. These findings contribute to the understanding of the immunological events that occur during discontinuation of nucleos(t)ide analogue therapy.作者: StephenW 时间: 2018-12-14 12:20
