Chronic HDV Infection Shows Higher HBsAg Isoform Levels than HBV Infection, Paralleling HDV Replicative Activity
Background & Aim: The entry of Hepatitis D Virus (HDV) depends on HBV surface proteins (HBsAg) composed of three isoforms: large-, middle, and small HBsAg. Here, we investigate the levels of total HBsAg and HBsAg isoforms and their correlations with HDV-RNA, HBcrAg, and transaminases in the setting of untreated chronic hepatitis D (CHD). Methods: This study includes 316 HBeAg-negative patients: 192 CHD and 124 with chronic hepatitis B (CHB) as a control group. HBsAg isoforms were quantified by ad hoc-designed ELISAs. Results: The composition of HBsAg isoforms varied between the two groups of patients, with remarkably higher small HBsAg, middle-HBsAg, and large HBsAg in CHD than in CHB. This data was confirmed by multivariable analysis (p < 0.0001). Among CHD, HBsAg isoforms positively correlated with HDV-RNA (p < 0.0001) and HBcrAg (p < 0.0001) but not with HBV-DNA. The results were confirmed by stratifying patients according to HDV-RNA (< or >1000 IU/mL) and HBcrAg (< or >3 logU/mL). Furthermore, CHD patients with ALT > upper limit of normal presented significantly higher S-HBsAg and M-HBsAg levels. Conclusions: CHD is characterized by a more elevated HBsAg isoform production, paralleling HDV-RNA and HBcrAg release. This may suggest a preferential recruitment of HBsAg isoforms in HDV virions at the expense of HBV virions. The association of HBsAg isoforms with higher ALT also suggests their potential contribution in supporting HDV-induced pro-inflammatory stimuli.
Authors
- Sandro Grelli (ORCID: https://orcid.org/0000-0003-1028-3203)
- Gian Paolo Caviglia (ORCID: https://orcid.org/0000-0002-0529-9481)
- Elisabetta Teti (ORCID: https://orcid.org/0000-0002-0785-9120)
- Antonella Olivero (ORCID: https://orcid.org/0000-0003-0327-3875)
- Leonardo Duca (ORCID: https://orcid.org/0009-0008-2970-2037)
- S. Francioso
- Ada Bertoli (ORCID: https://orcid.org/0000-0003-0663-2503)
- Romina Salpini (ORCID: https://orcid.org/0000-0002-2488-2082)
- Stefano D’Anna (ORCID: https://orcid.org/0009-0003-9334-8582)
- Lorenzo Piermatteo (ORCID: https://orcid.org/0000-0002-3500-0858)
- Pierpaolo Paba
- Andrea Di Lorenzo (ORCID: https://orcid.org/0009-0008-1772-196X)
- Leonardo Baiocchi (ORCID: https://orcid.org/0000-0003-3672-4505)
- Giulia Torre
- Valentina Svicher (ORCID: https://orcid.org/0000-0002-2377-504X)
- Ilaria Grossi
- Caterina Tramontozzi
- Giuseppina Brancaccio (ORCID: https://orcid.org/0000-0001-5643-0139)
- Alessia Magnapera
- V Malagnino
- L Sarmati
- M Iannetta
- Annalisa Saracino
- Pietro Lampertico (ORCID: https://orcid.org/0000-0002-1026-7476)
- Michele Milella
- Mario Rizzetto
- Alessia Ciancio (ORCID: https://orcid.org/0000-0002-9026-6181)
- Ilaria Lenci (ORCID: https://orcid.org/0000-0001-5704-9890)
- Francesca Ceccherini-Silberstein
Institutions
- University of Rome Tor Vergata (IT)
- University of Milan (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Ospedale Maggiore (IT)
- Policlinico Tor Vergata (IT)
- Link Campus University (IT)
- University of Turin (IT)
- University of Bari Aldo Moro (IT)
Publication Details
- Journal
- Viruses
- Published
- 2026-04-30
- DOI
- https://doi.org/10.3390/v18050515
- Primary Topic
- Hepatitis B Virus Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Federation of Pharmaceutical Industries and Associations
- Innovative Health Initiative
- European Commission