Viral particles do not contribute significantly to serum levels of hepatitis B surface antigen which is produced mainly from integrated HBV DNA in most patients with chronic hepatitis B.

Background: The surface antigen of hepatitis B virus (HBsAg) is present on viral particles (VP) and subviral particles (SVP) and is produced from both covalently closed circular DNA (cccDNA) and HBV DNA integrated into human chromosomes.

Objective: To calculate the contribution of VP and SVP to HBsAg levels in serum, and study to what extent the source of HBsAg is cccDNA or integrated HBV DNA.

Method: Analysis of HBV DNA and HBsAg levels from subjects with chronic HBV infection and after initiation or cessation of antiviral treatment.

Results: In serum samples from 800 individuals with chronic HBV infection and no antiviral treatment, the ratio between SVP and VP was > 100 million among HBe-antigen-negative subjects with low viral load. During initiation of nucleos(t)ide analogue (NA) treatment of 12 patients, the decline of HBsAg in serum was marginal or absent despite marked second phase reductions of HBV DNA, a proxy for cccDNA decline. After discontinuation of NA treatment, no increase in HBsAg levels was observed until HBV DNA had reached very high levels.

Conclusions: Viral particles do not significantly contribute to HBsAg levels in serum and in HBeAg-negative patients, and the VP/SVP ratio is much lower than previously described. The contribution from cccDNA to HBsAg levels seems to be significant only when the HBV DNA serum levels are very high and reflect a cccDNA content in the liver that produces HBsAg in amounts that equal or are greater than from integrated HBV DNA.