A specific deletion pattern in the preS1- and preS2-domain occurs during functional cure of chronic hepatitis B

Background and aims HBsAg consists of the S (small; SHBs), the preS2 (middle, MHBs) and the preS1 (large; LHBs) proteins, and the proportions of those proteins change during the development of HBsAg loss under nucleos(t)ide analogue (NA) treatment. We investigated whether changes in HBsAg composition during development of functional cure are associated with genomic variants in the coding s gene of HBV.

Methods Patients achieving HBsAg loss (n = 15) and matched patients without serologic response including HBeAg or HBsAg loss (w/o SR; n = 23) during NA treatment were retrospectively analyzed. The complete HBV s gene was sequenced in all available sequential serum samples (n = 164) of patients with HBsAg loss and in minimum three samples of patients w/o SR. Proportions of HBsAg proteins were quantified in sera collected before and during treatment.

Results Among patients with HBsAg loss, 53 % (n = 8) showed wildtype s gene before and during NA treatment, whereas 40 % (n = 6) developed a double deletion of aa 1-6 and aa 88-129. These deletions are located in the N-terminal regions of the preS1- (LHBs) and the preS2- (MHBs) domain and include the start ATG of both proteins. In contrast, in patients w/o SR, 74 % (n = 17) showed wildtype s genes in all analyzed samples and no patient showed the double deletion of aa 1-6 and aa 88-129. In patients with HBsAg loss, which showed the deletions aa 1-6 and aa 88-129, HBV DNA and HBsAg levels were significantly lower as compared to samples with wt s gene. The occurrence of the double deletion lead to a strong decrease of MHBs (%), but not LHBs (%). In patients with subsequent HBsAg loss LHBs and MHBs became undetectable 3.9 (0-9) and 11.4 (0-53) months before the loss of total HBsAg, whereas patient w/o SR achieved no loss of LHBs or MHBs.

Conclusion In many patients with HBsAg loss during antiviral treatment a double deletion in the start ATG of the preS1- and preS2-domain was found. Accordingly, we observed decreased MHBs ratios. The functional relevance of these mutations for HBV replication and the process of HBsAg loss need to be investigated.

Publication History

Article published online:
07 September 2021