Impact of HBV genotype and mutations on HBV DNA and qHBsAg levels in patients with HBeAg-negative chronic HBV infection.

Background: HBV DNA and quantitative (q)HBsAg levels as prognostic markers for HBV-related disease are mostly validated in Asia and their significance in Western populations is uncertain. Aim: To analyse the impact of the HBV genotype and frequent mutations in precore (PC), basal core promoter (BCP) and preS on HBV DNA and qHBsAg levels. Methods: HBV DNA and qHBsAg serum levels of 465 patients with HBeAg-negative chronic HBV infection were correlated with the HBV genotype and mutations in PC, BCP and preS. For a detailed analysis of the molecular virology, genotype A2 genomes harbouring these mutations were analysed for replication efficacy and HBsAg release in cell culture. Results: While no impact of the HBV genotype on HBV DNA levels was observed, qHBsAg levels differed up to 1.4 log among the genotypes (P < 0.001), reflected by large differences regarding the 1000 IU/mL HBsAg cut-off. While PC mutations were associated with higher (P<0.001), BCP mutations were associated with lower HBV DNA levels (P<0.001). Higher qHBsAg levels were associated with preS and lower levels with PC mutations (P<0.001 and P=0.001, respectively). The cell culture experiments revealed a higher HBsAg release and shorter filaments in case of a HBV genome harbouring a preS deletion. In contrast, a perinuclear HBsAg accumulation was detected for the PC and BCP-variants, reflecting an impaired HBsAg release. Conclusions: qHBsAg serum levels depend on the HBV genotype and together with HBV DNA levels on frequent mutations in PC, BCP and preS in HBeAg-negative patients. qHBsAg cut-offs when used as prognostic markers require genotype-dependent validation.