{
  "abstract": "Background Hepatitis B surface antigen (HBsAg) circulates in three isoforms, small (S)-, medium (M)-, and large (L)-HBsAg, which reflect specific steps of HBV life cycle and particle morphogenesis. In the setting of HBV/HDV co-infection, we assessed how HBsAg isoforms relate to markers of viral activity and liver injury in HDV-RNA-positive patients according to different clinical phenotypes.Methods This study included 366 viremic patients (n = 229 [62.6%] males; median age 56, IQR 46–62 years; n = 216 [59.0%] native Italians) from the HDV Describe study cohort. Serum S-, M-, and L-HBsAg levels were quantified by ELISA (Beacle Inc., Kyoto, Japan) and correlated with HDV-RNA (Robogene v2, Roboscreen GmbH, Leipzig, Germany), HBcrAg (Fujirebio, Tokyo, Japan), ALT, and liver stiffness measurement (LSM) (Fibroscan, Echosens, Paris, France). Patients’ clinical phenotypes included liver cirrhosis, chronic hepatitis D (CHD; HDV-RNA ≥ 3 Log IU/mL), and inactive/mild disease (HDV-RNA < 3 log IU/mL), as previously defined in Caviglia et al. Liver Int 2025.Results Median (IQR) HDV-RNA was 5.1 (3.4–6.0) log IU/mL and total HBsAg was 3331 (675–9055) ng/mL, while median (IQR) levels of S-, M-, L-HBsAg were 2686 (483–7234), 538 (92–1467) and 0.75 (0.10–4.50) ng/mL, respectively. Total, S-, M-, L-HBsAg showed positive correlations with HDV-RNA (rs=0.47, 0.47, 0.47, and 0.42, respectively; all p<0.001) and HBcrAg (rs=0.57, 0.56, 0.57, and 0.44, respectively; all p<0.001). Furthermore, total, S-, M-, and L-HBsAg levels were significantly higher in patients with ALT >40U/L compared to those with ALT ≤40 U/L (all p<0.001), whereas only L-HBsAg showed a correlation (albeit modest) with LSM (rs=0.16; p=0.007).Total, S, M-, L-HBsAg levels varied according to patients’ clinical phenotype, with the highest levels observed in high-viremic CHD, followed by cirrhosis and low-viremic CHD. Notably, in multivariate analysis, higher S-HBsAg levels were significantly associated with high-viremic CHD (OR=1.58, 95% CI 1.16–2.15; p=0.003), higher M-HBsAg with liver cirrhosis (OR=1.78, 95% CI 1.04–3.03; p=0.035), while lower L-HBsAg levels were associated with low-viremic CHD (OR=0.38, 95% CI 0.25–0.58; p<0.001).Conclusions Total HBsAg levels and HBsAg isoforms correlated with the extent of HDV replication and cytolytic activity. Notably, HBsAg isoforms showed distinct associations across clinical phenotypes, suggesting a differential regulation of HBV envelope proteins in HDV-driven liver disease.",
  "authors": [
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "I Grossi"
    },
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "C Tramontozzi"
    },
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "A Magnapera"
    },
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "S D’Anna"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, University of Torino, Turin, Italy"
      ],
      "name": "E Dileo"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, University of Torino, Turin, Italy"
      ],
      "name": "A Olivero"
    },
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "L Piermatteo"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, University of Torino, Turin, Italy"
      ],
      "name": "G Mengozzi"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, University of Torino, Turin, Italy"
      ],
      "name": "A Ciancio"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy"
      ],
      "name": "M Loglio"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy"
      ],
      "name": "M Viganò"
    },
    {
      "affiliations": [
        "UOSD Hepatology, Ospedale Umberto I°, ASP 8 Siracusa, Siracusa, Italy"
      ],
      "name": "S Fagiuoli"
    },
    {
      "affiliations": [
        "Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine Unit, University of Pisa, Pisa, Italy"
      ],
      "name": "P Colombatto"
    },
    {
      "affiliations": [
        "Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine Unit, University of Pisa, Pisa, Italy"
      ],
      "name": "B Coco"
    },
    {
      "affiliations": [
        "Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine Unit, University of Pisa, Pisa, Italy"
      ],
      "name": "MR Brunetto"
    },
    {
      "affiliations": [
        "Hepatology Unit, AORN A. Cardarelli, Naples, Italy"
      ],
      "name": "D Angrisani"
    },
    {
      "affiliations": [
        "Hepatology Unit, AORN A. Cardarelli, Naples, Italy"
      ],
      "name": "A Galeota Lanza"
    },
    {
      "affiliations": [
        "Division of Infectious Diseases, ASST-FBF-Sacco, Milan, Italy"
      ],
      "name": "C Magni"
    },
    {
      "affiliations": [
        "Division of Infectious Diseases, ASST-FBF-Sacco, Milan, Italy"
      ],
      "name": "G Rizzardini"
    },
    {
      "affiliations": [
        "Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy"
      ],
      "name": "V Messina"
    },
    {
      "affiliations": [
        "Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari ‘Aldo Moro’, Bari, Italy"
      ],
      "name": "M Milella"
    },
    {
      "affiliations": [
        "Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari ‘Aldo Moro’, Bari, Italy"
      ],
      "name": "A Saracino"
    },
    {
      "affiliations": [
        "Clinica Malattie Infettive UniTo, Ospedale Amedeo di Savoia, Turin, Italy"
      ],
      "name": "L Marinaro"
    },
    {
      "affiliations": [
        "Clinica Malattie Infettive UniTo, Ospedale Amedeo di Savoia, Turin, Italy"
      ],
      "name": "G Cariti"
    },
    {
      "affiliations": [
        "Department of Clinical Medicine and Surgery, Liver and Biliary Diseases Unit, University of Naples Federico II, Naples, Italy"
      ],
      "name": "V Cossiga"
    },
    {
      "affiliations": [
        "Department of Clinical Medicine and Surgery, Liver and Biliary Diseases Unit, University of Naples Federico II, Naples, Italy"
      ],
      "name": "F Morisco"
    },
    {
      "affiliations": [
        "Infectious Diseases Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"
      ],
      "name": "S Cretella"
    },
    {
      "affiliations": [
        "Infectious Diseases Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy"
      ],
      "name": "G Verucchi"
    },
    {
      "affiliations": [
        "Infectious Diseases and Hepatology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy"
      ],
      "name": "E Biliotti"
    },
    {
      "affiliations": [
        "Infectious Diseases and Hepatology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy"
      ],
      "name": "G D’Offizi"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Galliera Hospital, Genoa, Italy"
      ],
      "name": "M Feasi"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Galliera Hospital, Genoa, Italy"
      ],
      "name": "E Pontali"
    },
    {
      "affiliations": [
        "Unit of Hepatology and Interventional Ultrasonography, Department of Internal Medicine, OORR Area Stabiese, Gragnano, Italy"
      ],
      "name": "C Coppola"
    },
    {
      "affiliations": [
        "Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy"
      ],
      "name": "R Rapetti"
    },
    {
      "affiliations": [
        "Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy"
      ],
      "name": "M Pirisi"
    },
    {
      "affiliations": [
        "UOC di malattie infettive emergenti e ad alta contagiosità, Ospedale Cotugno, Naples, Italy"
      ],
      "name": "A Izzi"
    },
    {
      "affiliations": [
        "Department of Medical and Surgical Sciences, Infectious Diseases Unit, University of Foggia, Foggia, Italy"
      ],
      "name": "T Santantonio"
    },
    {
      "affiliations": [
        "Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy"
      ],
      "name": "V Di Marco"
    },
    {
      "affiliations": [
        "Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy"
      ],
      "name": "A Marrone"
    },
    {
      "affiliations": [
        "Infectious Diseases Unit, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Naples, Italy"
      ],
      "name": "N Coppola"
    },
    {
      "affiliations": [
        "SC Infectious Diseases, ASST Papa Giovanni XXIII, Bergamo, Italy"
      ],
      "name": "M Rizzi"
    },
    {
      "affiliations": [
        "Infectious and Tropical Diseases Unit, Padua University Hospital, Padua, Italy"
      ],
      "name": "AM Cattelan"
    },
    {
      "affiliations": [
        "Gastroenterology Unit, Fondazione Casa Sollievo Della Sofferenza IRCCS, San Giovanni Rotondo, Italy"
      ],
      "name": "GA Niro"
    },
    {
      "affiliations": [
        "Hepatology and Liver Transplant Unit, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy"
      ],
      "name": "P Toniutto"
    },
    {
      "affiliations": [
        "Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy"
      ],
      "name": "FR Ponziani"
    },
    {
      "affiliations": [
        "Hepatology and Gastroenterology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy"
      ],
      "name": "LS Belli"
    },
    {
      "affiliations": [
        "Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy"
      ],
      "name": "A Federico"
    },
    {
      "affiliations": [
        "Hepatology Unit, University Hospital Policlinico G. Rodolico - San Marco, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy"
      ],
      "name": "G Bertino"
    },
    {
      "affiliations": [
        "Gastroenterology Unit, Department of Precision and Regenerative Medicine—Jonian Area—(DiMePRe-J), University of Bari Aldo Moro, Policlinic University Hospital, Bari, Italy"
      ],
      "name": "M Barone"
    },
    {
      "affiliations": [
        "Division of Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda",
        "Department of Medicine, University of Milan Bicocca, Milan, Italy"
      ],
      "name": "M Puoti"
    },
    {
      "affiliations": [
        "Teaching Hospital Duilio Casula, Azienda Ospedaliero-Universitaria di Cagliari, Cagliari, Italy"
      ],
      "name": "A Civolani"
    },
    {
      "affiliations": [
        "UOSD Hepatology, Ospedale Umberto I°, ASP 8 Siracusa, Siracusa, Italy"
      ],
      "name": "M Distefano"
    },
    {
      "affiliations": [
        "Dipartimento Di Prevenzione, Azienda Sanitaria Provinciale di Catanzaro, Centro di Medicina del Viaggiatore e delle Migrazioni, P. O. Giovanni Paolo II, Lamezia Terme, Italy"
      ],
      "name": "LA Surace"
    },
    {
      "affiliations": [
        "Gastroenterology Unit, IRCCS S. De Bellis, Castellana Grotte, Italy"
      ],
      "name": "R Cozzolongo"
    },
    {
      "affiliations": [
        "Gastroenterology Unit, Riuniti Polyclinic of Foggia, Foggia, Italy"
      ],
      "name": "EM Cela"
    },
    {
      "affiliations": [
        "Infectious Disease Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "E Teti"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy",
        "CRC A. M. and A. Migliavacca Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"
      ],
      "name": "P Lampertico"
    },
    {
      "affiliations": [
        "Department of Tropical and Infectious Diseases, Policlinico Umberto I, Rome, Italy"
      ],
      "name": "T Stroffolini"
    },
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "R Salpini"
    },
    {
      "affiliations": [
        "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
      ],
      "name": "V Svicher"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, University of Torino, Turin, Italy"
      ],
      "name": "M Rizzetto"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, University of Torino, Turin, Italy"
      ],
      "name": "GP Caviglia"
    }
  ],
  "title": "OC11 Chronic HDV infection is characterized by distinct profiles of HBsAg isoforms underlying different disease stages",
  "uid": "3e439d51-50ac-5fb3-93d4-a4b6dd16058c"
}