Heterogeneity of hepatitis B virus (HBV) basal core promotor (BCP) variants during treatment with peginterferon alfa-2a is associated with low HBV replication

Abstract

The presence of precore (PC) and BCP variants is associated with HBeAg seroconversion (SC) during treatment with PEG-IFN, but the mechanism of HBeAg SC is still unknown. We investigated the occurrence of BCP/PC variants during treatment with PEG-IFN and their association with replication and treatment response. Therefore, patients with HBeAg positive chronic hepatitis B receiving PEG-IFN for 48 weeks (39 with and 28 without HBeAg SC until week 72) were retrospectively analysed. Viral markers (HBeAg, HBcrAg, HBsAg, HBV DNA and HBV RNA) were quantified and BCP (A1762T/G1764A) and PC stop (G1896A) variants were analysed by direct sequencing on HBV DNA basis at every time point. Results revealed that in patients with HBeAg SC, BCP/PC variants were present in 23/39 (60.5%) patients before treatment and in 37/39 (94%) patients at week 72. In contrast, only 7/29 (24.1%) patients without HBeAg SC showed a mutation before treatment and additional 7 patients developed BCP/PC variants until week 72 (48%, p=0.003). BCP/PC variants were strongly associated with decreasing HBV DNA, HBV RNA and HBeAg, but not HBsAg and HBcrAg levels in both patient groups. Moreover, the occurrence of BCP/PC variants was associated with low HBV RNA levels and vice versa, independent of the treatment response. In conclusion, we found higher frequencies of BCP/PC variants in patients with HBeAg SC as compared to patients not achieving HBeAg SC. However, irrespective of HBeAg SC, the occurrence of these variants leads to a decrease in HBV replication as measured by undetectable HBV RNA and abolished HBeAg production.