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

doi:10.3390/biomedicines9101352

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

Biomedicines. 2021 Sep 29;9(10):1352. doi: 10.3390/biomedicines9101352.

Authors

Lorenzo Piermatteo¹, Mohammad Alkhatib¹, Stefano D'Anna¹, Vincenzo Malagnino², Ada Bertoli^{1

3}, Eleonora Andreassi¹, Elisa Basile³, Alessandra Iuvara³, Maria De Cristofaro⁴, Giuseppina Cappiello⁴, Carlotta Cerva², Carmine Minichini⁵, Mariantonietta Pisaturo⁵, Mario Starace⁵, Nicola Coppola⁵, Carla Fontana³, Sandro Grelli^{1

3}, Francesca Ceccherini-Silberstein¹, Massimo Andreoni², Upkar S Gill⁶, Patrick T F Kennedy⁶, Loredana Sarmati², Romina Salpini¹, Valentina Svicher¹

Affiliations

¹ Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
² Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy.
³ Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy.
⁴ Microbiology Unit, "Sandro Pertini" Hospital, 00133 Rome, Italy.
⁵ Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy.
⁶ Barts Liver Centre, Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.

Abstract

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.

Keywords: HBV; HBV reactivation; HBeAg.

Abstract

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