discriminate a specific stage during the natural course of hepatitis B. With the introduction of HBsAg quantification in current practice, whether or not the employment of HBsAg quantification may also have a beneficial role in diagnosing the different stages of chronic hepatitis B is another issue to be further confirmed. With respect to this issue, the study by Chan et al.,20 involving 117 Chinese patients with chronic hepatitis B, investigated the changes in HBsAg level during the natural progression of disease. With a longitudinal follow-up of the untreated cohort for 99±16 months, they showed that HBsAg levels in patients at immune tolerant phase remain stable and persistently high at approximately 5 log IU/mL. Then, the levels at immune active stage or around the time of HBeAg seroconversion were comparatively lower at 3-4 log IU/mL. After achieving HBeAg seroconversion, the HBsAg level decreased progressively with time. An HBsAg reduction of >1 log IU/mL in HBeAg-negative patients resulted in a better viral control, with an increased chance of HBsAg loss during extended follow-up. In this study, however, no clear cut-off value of HBsAg serum level discriminated HBeAg-negative patients between immuno-active and -inactive diseases due to significant overlap of HBsAg levels and a highly fluctuating levels of serum HBV DNA among these patients. In contrast to the results, another study involving 209 European patients with HBeAg-negative hepatitis and genotype D indicated that quantification of both HBsAg and HBV DNA levels better discriminated between the two phases in HBeAg- negative patients, that is, a single-point combined quantification for HBsAg (<1,000 IU/mL) and HBV DNA (<2,000 IU/mL) yielded the most accurate identification of inactive carriers with a 94.3% diagnostic accuracy, comparable with that of long-term tight monitoring.21 A recent Korean study by Park et al.,19 in which 102 HBeAg-negative patients were recruited, also attempted to determine the value of HBsAg quantification for determining outcome of HBeAg-negative hepatitis. In this study, the cut-off value for HBsAg that provided the best predictive accuracy to discriminate inactive carriers from active carriers was 3.25 log IU/mL for the non-cirrhosis group and 2.57 log IU/mL for the cirrhosis group (Table 1). One key question for understanding the role of HBsAg quantification in the natural course of HBV infection is its relationship with circulating HBeAg/HBVDNAlevels, intrahepatic HBV replicative intermediates, and the significance of emerging viral variants. The study by Thompson et al.22 addressed these critical issues through a comprehensive analysis of serum and Jeong Won Jang. HBsAg during chronic HBV infection 345 liver markers of HBV replication in 149 treatment-naïve patients. There were significant differences in HBsAg expression between patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. In HBeAg-positive patients, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r=0.69-0.76). Additionally, HBeAg levels also correlated with serum HBV DNA levels (r=0.60), although the emergence of basal core promoter/precore variants decreased HBeAg levels independent of viral replication. By contrast, in HBeAg-negative patients, HBsAg correlated poorly with serum HBV DNA (r=0.28), with no correlation between HBsAg and intrahepatic HBV replicative intermediates. Similarly, HBsAg expression, as measured by quantitative immunohistochemical staining, also showed a positive correlation with viral replication only in HBeAg- positive patients, but not in HBeAg-negative patients. The disconnect between HBsAg production and HBV replication in the HBeAg-negative phase of disease implies that HBsAg might be produced from additional pathways other than HBV replication pathway from intranuclear cccDNA. HBV replication in the life cycle of HBV requires encapsidation of the pre-genomic RNA by the core particle. Under strong immune pressure associated with the HBeAg-negative phase, intracellular inhibitory cytokines more preferentially inhibit the encapsidation process, sparing the HBsAg synthesis pathway. On the other hand, HBsAg can also be produced from viral segments integrated into the host genome, which often carry the sequences of the S genes, although the integrated sequences are not able to allow for viral replication.22 In this context, HBsAg production in HBeAg-negative carriers is preserved relative to HBV replication for a quite long time, even after HBeAg seroconversion. Taken together, these findings indicate that the relationships between HBsAg, HBeAg, serum HBV DNA, and HBV replicative intermediates are not simple, but depend on the complex interplay between host and viral factors evolving over a long-lasting inflammatory process. In conclusion, quantitative HBsAg assays, which are easy to perform with low cost, would help to assess the stage of chronic hepatitis B, intrahepatic viral replicative status, and response to antiviral therapy. Despite such potential usefulness, there is extremely limited evidence to support the definitive role of HBsAg quantification as a clinical biomarker for the management of chronic hepatitis B. Studies show that the production of HBsAg likely undergoes evolutionary changes by a complex interplay between virus and host, during the natural history of chronic HBV infection. Thus, it is mandatory to further test the