Deletions in the HBV s gene are associated with altered HBsAg composition in patients with HBsAg loss during NA therapy

Question The hepatitis B surface antigen (HBsAg) consists of the components small (SHBs), middle (MHBs) and large (LHBs) HBsAg. Recently, we could show that HBsAg loss during nucleos(t)ide analogue (NA) treatment are preceded by decreases of the LHBs and MHBs ratios. In this study, we investigated the association between HBsAg composition and changes in their protein amino acids sequences within the HBV s gene during the process of HBsAg loss during NA treatment.

Methods Patients achieving HBsAg loss (n=14) during NA treatment and a population of patients without serologic response during NA treatment (including HBeAg or HBsAg loss; w/o SR; n=23) matched by HBsAg levels at baseline and duration of observation were retrospectively analyzed. HBsAg components were quantified in sera stored at -20°C collected before and during treatment. The complete HBV s gene was sequenced in all available serum samples of patients with HBsAg loss and in minimum three samples of patients w/o SR.

Results HBsAg loss occurred after a mean duration of 17 (12-53) months of NA treatment. In patients with HBsAg loss, LHBs and MHBs became undetectable at a mean of 3.9 (0-12) and 11.4 (0-53) months before HBsAg loss. In contrast, in patients w/o SR no significant changes in HBsAg composition or loss of LHBs and MHBs were detected. Of the patients with HBsAg loss, 50 % (n=7) showed a wildtype HBV s gene before and during NA treatment. In one patient a deletion of amino acids (aa) 58 to 100 occurred, which is located in the preS1-domain. Interestingly, in 43 % (n=6) a double deletion of aa 1-6 and aa 88-129 occurred, which are located in the start ATG of the preS1- (LHBs) and the preS2- (MHBs) domain. In contrast, 74 % (n=17) of patients w/o SR showed a wildtype HBV s gene in all analyzed samples and no patient achieved a double deletion of aa 1-6 and aa 88-129, respectively. Six patients w/o SR showed deletions in the preS1/2-domain, from which two include the start ATG of the preS2-domain, but showed no influence on MHBs levels in serum.

Conclusions Changes in the proportions of LHBs and MHBs that precede HBsAg loss are associated with the occurrence of a double deletion in the start ATG of the preS1- and the preS2-domain in many cases. The impact of those deletions on protein structure and the viral fitness of HBV needs to be studied more in detail.

Publication History

Article published online:
04 January 2021