Introduction

Chronic hepatitis B infection is a global health problem affecting more than 350 million people worldwide.1 Prolonged liver inflammation caused by active infection with the hepatitis B virus (HBV) may result in progression to liver fibrosis, cirrhosis and ultimately hepatocellular carcinoma and death.1

Since the 1960s, hepatitis B virus surface antigen (HBsAg) has been the hallmark of HBV infection with concentrations reaching several hundred micrograms per millilitre.2 Recently, studies with newly available automated quantitative assays have shown that serum HBsAg levels vary significantly during the different phases of chronic HBV infection and are inversely correlated with the immune control of HBV: the higher control, the lower HBsAg level.3–6 These findings are consistent with the hypothesis that serum levels of HBsAg reflect the complex interplay between virus and immune system and provide complementary information to viral load as measured using HBV DNA levels. In fact, serum HBsAg levels result not only from virions (42 nm, Dane particles) but mainly from non-infectious HBsAg particles (20 nm diameter filaments of variable length and 20–22 nm spheres) which do not contain viral nucleic acids and exceed virions by a factor ranging between 10² and 10⁵. The ratios between defective HBsAg particles and virions are not stable, but change over time. Filaments and spherical particles are produced in large excess in highly viraemic hepatitis B ‘e’ antigen (HBeAg)-positive carriers. While filaments decline in parallel with virions, spherical particles remain in moderate excess in low viraemic HBeAg-negative carriers.7 8 Thus, HBsAg production varies both quantitatively and qualitatively over time and appears to be dynamically regulated during different phases of the infection. HBsAg derives mainly from the intrahepatic viral minichromosome (cccDNA) by translation of specific RNAs that are distinct from pregenomic RNA, and HBsAg synthesis follows a pathway that is distinct from …