Oberhardt, Valerie, Degasperi, Elisabetta, Maas, Michelle, Borghi, Marta, Heim, Kathrin and Price, David A.  ORCID: https://orcid.org/0000-0001-9416-2737
2026.
Fate of hepatitis D virus-specific CD8+ T cells during bulevirtide monotherapy in patients with chronic hepatitis delta☆.
JHEP Reports
8
(10)
, 101970.
10.1016/j.jhepr.2026.101970
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Abstract
Background and Aims Bulevirtide reduces viremia in chronic hepatitis D virus (HDV) infection, but long-term treatment is required in most patients to prevent relapse. Sustained treatment responses may be fostered by therapy-induced amelioration of HDV-specific CD8+ T-cell responses that are exhausted due to high viremia and antigen loads during chronic HDV infection. We therefore studied the effect of bulevirtide monotherapy on HDV-specific CD8+ T-cell repertoire, phenotype, and functionality. Methods 28 HDV-infected cirrhotic patients starting bulevirtide treatment were followed for 40–120 weeks on treatment. HLA-class-I typing and HDV sequencing was performed. HDV-specific CD8+ T cells were analyzed longitudinally using optimal epitopes and overlapping peptides spanning the L-HDAg. Ex vivo high-dimensional flow cytometry analysis of peptide/HLA class I tetramer+ CD8+ T cells was performed longitudinally in selected patients. Results In 42% of patients, an HDV-specific CD8+ T-cell response was detectable at baseline, but did not substantially increase during treatment. Importantly, a large majority of HDV-specific CD8+ T-cell responses targeted viral epitopes with sequence variations consistent with viral escape mutations. Only one HLA-B*35-restricted HDV-specific CD8+ T-cell epitope was conserved and continuously targeted throughout therapy. HDV-specific CD8+ T cells targeting this conserved epitope displayed a predominant terminally exhausted phenotype at baseline that shifted longitudinally to a memory-like phenotype with suppression of HDV load. Conclusion Albeit based on small patient numbers, antiviral treatment with bulevirtide could ameliorate exhausted HDV-specific CD8+ T cells targeting conserved HDV epitopes. However, as the majority of HDV-specific CD8+ T-cell responses target escaped viral epitopes, this does not translate to a substantial improvement in overall HDV-specific CD8+ T-cell immunity. Our findings may explain in part why long-term bulevirtide treatment is required to prevent viral relapse.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Additional Information: | Full list of authors: https://doi.org/10.1016/j.jhepr.2026.101970 |
| Publisher: | Elsevier |
| ISSN: | 2589-5559 |
| Date of First Compliant Deposit: | 3 August 2026 |
| Date of Acceptance: | 14 July 2026 |
| Last Modified: | 02 Oct 2026 10:00 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/188681 |
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