HBsAg level defines different clinical phenotypes of HBeAg(-) chronic HBV infection related to HBV polymerase-specific CD8⁺ cell response quality

Background: HBe-antigen(Ag)-negative chronic hepatitis B virus (HBV) infection is characterized by little liver fibrosis progression and vigorous HBV-multispecific CD8(+) T-cell response. Aims: To assess whether HBsAg level could discriminate different HBeAg-negative chronic HBV infection subtypes with dissimilar quality of HBV-specific CD8(+) T-cell response. Methods: We recruited 63 HBeAg-negative chronic HBV infection patients in which indirect markers of liver inflammation/fibrosis, portal pressure, viral load (VL), and HBV-specific CD8(+) cell effector function were correlated with HBsAg level. Results: A positive linear trend between HBsAg level and APRI, liver stiffness (LS), liver transaminases, and HBV VL, and a negative correlation with platelet count were observed. Frequency of cases with HBV-specific CD8(+) T-cell proliferation against at least two HBV epitopes was higher in HBsAg < 1,000 IU/ml group. CD8(+) T-cell expansion after HBVpolymerase(456-63)-specific stimulation was impaired in HBsAg > 1,000 IU/ml group, while the response against HBVcore(18-27) was preserved and response against envelope(183-91) was nearly abolished, regardless of HBsAg level. Cases with preserved HBVpolymerase(456-63) CD8(+) cell response had lower LS/duration of infection and APRI/duration of infection rates. HBV-polymerase(456-63)-specific CD8(+) T-cell proliferation intensity was negatively correlated with LS/years of infection ratio. Conclusion: HBsAg > 1,000 IU/ml HBeAg-negative chronic HBV infection group shows indirect data of higher degree of inflammation, liver stiffness, and fibrosis progression speed, which are related to an impaired HBV-polymerase-specific CD8(+) T-cell response.