HBeAg Levels Vary across the Different Stages of HBV Infection According to the Extent of Immunological Pressure and Are Associated with Therapeutic Outcome in the Setting of Immunosuppression-Driven HBV Reactivation
Lorenzo Piermatteo,
Mohammad Alkhatib,
Stefano D’Anna,
Vincenzo Malagnino,
Ada Bertoli,
Eleonora Andreassi,
Elisa Basile,
Alessandra Iuvara,
Maria De Cristofaro,
Giuseppina Cappiello,
Carlotta Cerva,
Carmine Minichini,
Mariantonietta Pisaturo,
Mario Starace,
Nicola Coppola,
Carla Fontana,
Sandro Grelli,
Francesca Ceccherini-Silberstein,
Massimo Andreoni,
Upkar S. Gill,
Patrick T. F. Kennedy,
Loredana Sarmati,
Romina Salpini,
Valentina Svicher
Affiliations
Lorenzo Piermatteo
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Mohammad Alkhatib
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Stefano D’Anna
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Vincenzo Malagnino
Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Ada Bertoli
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Eleonora Andreassi
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Elisa Basile
Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Alessandra Iuvara
Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Maria De Cristofaro
Microbiology Unit, “Sandro Pertini” Hospital, 00133 Rome, Italy
Giuseppina Cappiello
Microbiology Unit, “Sandro Pertini” Hospital, 00133 Rome, Italy
Carlotta Cerva
Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Carmine Minichini
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Mariantonietta Pisaturo
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Mario Starace
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Nicola Coppola
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Carla Fontana
Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Sandro Grelli
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Francesca Ceccherini-Silberstein
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Massimo Andreoni
Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Upkar S. Gill
Barts Liver Centre, Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
Patrick T. F. Kennedy
Barts Liver Centre, Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
Loredana Sarmati
Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
Romina Salpini
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Valentina Svicher
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
HBeAg is a marker of HBV-activity, and HBeAg-loss predicts a favorable clinical outcome. Here, we characterize HBeAg-levels across different phases of HBV infection, their correlation with virological/biochemical markers and the virological response to anti-HBV therapy. Quantitative HBeAg (qHBeAg, DiaSorin) is assessed in 101 HBeAg+ patients: 20 with acute-infection, 20 with chronic infection, 32 with chronic hepatitis and 29 with immunosuppression-driven HBV-reactivation (HBV-R). A total of 15/29 patients with HBV-R are monitored for >12 months after starting TDF/ETV. qHBeAg is higher in immunosuppression-driven HBV-R (median[IQR]:930[206–1945]PEIU/mL) and declines in chronic hepatitis (481[28–1393]PEIU/mL, p = 0.03), suggesting HBeAg production, modulated by the extent of immunological pressure. This is reinforced by the negative correlation between qHBeAg and ALT in acute infection (Rho = −0.66, p = 0.006) and chronic hepatitis (Rho = −0.35; p = 0.05). Interestingly, qHBeAg strongly and positively correlates with qHBsAg across the study groups, suggesting cccDNA as a major source of both proteins in the setting of HBeAg positivity (with limited contribution of integrated HBV-DNA to HBsAg production). Focusing on 15 patients with HBV-R starting TDF/ETV, virological suppression and HBeAg-loss are achieved in 60% and 53.3%. Notably, the combination of qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL at HBV-R is the only factor predicting no HBeAg loss (HBeAg loss: 0% with vs. 72.7% without qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL, p = 0.03). In conclusion, qHBeAg varies over the natural course of HBV infection, according to the extent of immunological pressure. In the setting of HBV-R, qHBeAg could be useful in predicting the treatment response under immunosuppression.
