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. 2025 Dec 19:gutjnl-2024-333309.
doi: 10.1136/gutjnl-2024-333309. Online ahead of print.

Tracking B cell immunity during perturbation of hepatitis B infection induced by treatment withdrawal

Sabela Lens  1   2   3   4   5 , Alice R Burton  6 , Jessica Davies  6 , Maelle Locatelli  2   3   4   5 , Mireia García-López  2   3   4   5 , Anna Pocurull  2   3   4   5 , Anna Jeffery-Smith  6 , Nikolai Novikov  7 , Simon P Fletcher  7 , Xavier Forns  2   3   4   5 , Sofía Pérez-Del-Pulgar  2   3   4   5 , Mala K Maini  1
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Free article

Tracking B cell immunity during perturbation of hepatitis B infection induced by treatment withdrawal

Sabela Lens et al. Gut. .
Free article

Abstract

Background: Withdrawal of prolonged nucleos(t)ide analogue (NA) treatment results in hepatitis B surface antigen (HBsAg) loss in some subjects with chronic hepatitis B (CHB), potentially revealing immune correlates of functional cure.

Objective: We investigated whether baseline or longitudinal changes in humoral immunity correlated with outcome of discontinuing prolonged NA treatment.

Design: Global memory B cells (MBC) and T follicular helper cells (Tfh) were analysed by flow cytometry. HBs (small surface)/HBc (core)-MBC were quantified by ex-vivo bait staining and function assessed by cultured ELISpots (enzyme-linked immunosorbent spots). Immune parameters assessed at end-of-treatment (EOT), 12 and 48 weeks after treatment withdrawal (and at 4-8 years in a subset) were correlated with intrahepatic and longitudinal serum viral markers and alanine transaminase (ALT).

Results: Individuals on prolonged NA had comparable frequencies of HBc-MBC and HBs-MBC, although the latter were PD-1hi and functionally defective. Following treatment withdrawal, increases in class-switched HBc-MBC were frequently temporally linked with hepatic flares. Subjects achieving HBsAg loss had an increase in activated global MBC detectable at EOT that become more marked by week 48, accompanied by significant increases in plasmablasts. HBs-MBC in those with HBsAg loss showed significant reductions in PD-1, trends to increased activation (CD71) and function and a more robust correlation with Tfh, compared with HBsAg persistence. MBC changes were maintained 4-8 years after HBsAg seroconversion.

Conclusion: Differences in global and HBs-specific B cell immunity associate with HBsAg loss, whereas HBc-MBC temporally associates with flares, following withdrawal of prolonged NA treatment. Our results underscore the need to further explore the potential of B cell targets for monitoring and enhancing HBV functional cure in larger cohorts.

Keywords: B CELL; HEPATITIS B.

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Conflict of interest statement

Competing interests: SL has received speaking and consulting fees from Gilead Sciences and AbbVie, and research grants from Gilead Sciences. XF has acted as advisor for Gilead and AbbVie. MKM has received unrestricted grants from Gilead and sat on advisory boards for Gilead, Vir-Bio, Roche and GSK. SPF and NN are employees of Gilead Sciences. All other authors report no potential conflict of interest.

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