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AS003
Serum and intrahepatic HBV markers and HBV-specific CD8 T cell
responses after nucleos(t)ide analog therapy discontinuation in
HBeAg-negative chronic hepatitis B patients
Mireia García-López1, Sabela Lens1, Laura J. Pallett2, Barbara Testoni3,
Zoe Mariño1, Sergio Rodriguez-Tajes1, Concepció Bartres1,
Ester García-Pras1, Thais Leonel1, Elena Perpiñan1, Juanjo Lozano4,
Francisco Rodríguez-Frías5, George Koutsoudakis1, Fabien Zoulim3,
Mala Maini2, Xavier Forns1, Sofía Pérez-del-Pulgar1. 1Liver Unit,
Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona,
Spain; 2Division of Infection and Immunity, Institute of Immunity and
Transplantation, University College London, London, United Kingdom;
3Cancer Research Center of Lyon (CRCL), University of Lyon, UMR_S1052,
UCBL, INSERM, U1052, Lyon, France; 4Bioinformatics Platform, CIBERehd,
Barcelona, Spain; 5Liver Pathology Unit, Department of Biochemistry and
Microbiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma
de Barcelona, CIBERehd, Barcelona, Spain
Email: [email protected]
Background and Aims: Previous studies have reported that up to 20%
of patients with chronic hepatitis B (CHB) may achieve functional
cure (HBsAg loss) after nucleos(t)ide analog (NA) treatment withdrawal.
CD8 T cells play an important role in the immune control of
HBV infection. The objective of this study was to analyze HBV-specific
CD8 responses in parallel with peripheral and intrahepatic virological
markers after NUC discontinuation in patients with HBeAg-negative
(HBeAg-) CHB.
Method: Twenty-seven HBeAg- CHB patients with complete viral
suppression (>3 years) and without cirrhosis were prospectively
studied. A liver biopsy was taken at the time of treatment withdrawal
(baseline). PBMC and serum samples were collected at baseline and
various time-points during follow-up. Intrahepatic HBV-DNA (iHBVDNAiHBVDNA),
covalently closed circular DNA (cccDNA) and serum HBV-DNA,
HBsAg, core-related antigen (HBcrAg) and pregenomic RNA (pgRNA)
levels were determined. HBV-specific T cell responses (IFNy, TNF and
CD107a) were analyzed by multiparametric flow cytometry after in
vitro expansion in the presence of overlapping peptides (OLP)
spanning core, envelope and polymerase.
Results: After a median follow-up of 34 months (IQR 26–37), 22 (81%)
patients remain off-therapy, with 8 (30% of the total cohort) losing
HBsAg; whilst 5 (19%) required NA reintroduction due to relapse.
Although all patients were iHBV-DNA and cccDNA positive at
baseline, only 41% and 48% had detectable serum pgRNA and
HBcrAg, respectively. Baseline HBsAg levels correlated significantly
with iHBV-DNA (r = 0.7, p < 0.0001) and both markers were lower in
patients who lost HBsAg (p < 0.001). Baseline intrahepatic (iHBVDNA,
cccDNA) or serum (HBsAg, HBcrAg or pgRNA) viral markers did
not show any association with peripheral CD8 T cell responses.
Importantly, degranulating CD8 T cells (CD107a+) or those coproducing
IFNy and TNF in response to stimulation with core OLP
were significantly higher (p = 0.05 and p = 0.039, respectively) at
baseline in patients remaining off-therapy compared to those
requiring NA reintroduction. Interestingly, the enhanced frequency
of CD8 T cells co-producing IFNy and TNF persisted up to 1 year of
follow-up (p = 0.009). Notably, CD8 T cell responses to polymerase or
envelope failed to associate with outcome as robustly as those against
core.
Conclusion: NA discontinuation is feasible in a high proportion of
HBeAg- patients, particularly in those with low HBsAg levels. Higher
frequencies of CD8 T cells with cytotoxic and non-cytolytic anti-HBV
(core) reactivity are detectable at baseline in those patients who
maintain viral control after therapy withdrawal. These data support
HBsAg levels and HBV-specific CD8 T cell frequencies as correlates of
HBV control off-therapy, requiring validation in larger studies. |
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发表于 2020-8-23 12:59