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In chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion often indicates host immune clearance. Approximately 30 % of patients, however, still have active viremia and fluctuating alanine aminotransferase (ALT) levels in the HBeAg-negative phase [1]. These patients with HBeAg-negative chronic hepatitis B probably have an immune escape by the virus; a further attempt of immune modulator therapy by interferon might be difficult and the post-treatment relapse rate is high. Early experience in Europe using 12-month interferon-alpha combined with lamivudine only yielded a sustained viral suppression (undetectable by nonpolymerase chain reaction assay) rate of approximately 15 % at 6–12 months post-treatment [2, 3]. With 12-month peginterferon alfa-2a with/without lamivudine combination in the phase III international trial for HBeAg-negative chronic hepatitis B, approximately 22.6 % of patients could achieve sustained viral suppression to B10,000 copies/ml at 3-year post-treatment [4]. Owing to the inconvenient subcutaneous route of administration, potential adverse effects, and a high drug cost of peginterferon, one should select patients who have a higher chance of response to the peginterferon therapy. On the other hand, peginterferon is not preferred or should be stopped earlier if the chance of response is too low. On post hoc analysis of the phase III trial of peginterferon alfa-2a (with/without lamivudine combination), HBeAg-negative patients at a younger age and those who had lower HBV DNA at baseline had a higher chance of achieving a response, which was defined as HBV DNA B20,000 copies/ml at 24-week post-treatment [5]. Patients infected by genotype C HBV also have a better response than those infected by genotype D HBV. Nonetheless, the differences in response between patients with different baseline predictive factors were too small to guide patient selection for treatment. For example, the mean baseline HBV DNA was 7.1 log copies/ml among responders versus 7.5 log copies/ml among relapsers. Better response predictors for peginterferon treatment are therefore warranted. Serum hepatitis B surface antigen (HBsAg) quantification is a very hot topic of research in recent years. The level of serum HBsAg has been shown to reflect the level and transcriptional activity of covalently closed circular (ccc) DNA [6]. However, among HBeAg-negative patients, the relationship between serum HBsAg level and cccDNA is much weaker than that in HBeAg-positive patients [7]. The exact reason for this observation is uncertain, but could be related to the production of HBsAg by integrated HBV surface gene fragments in the host chromosome or the uncoupling on the regulation of HBsAg and HBV DNA production after HBeAg seroconversion. Nonetheless, in natural history studies, a lower HBsAg level is associated with inactive hepatitis [8, 9] and a higher chance of spontaneous seroclearance of HBsAg [10], suggesting that a lower HBsAg level is associated with better immune control of the virus. In this issue of the Journal, Marcellin et al. [11] reported the use of serum HBsAg as the on-treatment response predictor to peginterferon alfa-2a with/without lamivudine combination in HBeAg-negative patients. This was a subgroup analysis of 120 patients who had HBsAg levels available for analysis among the original cohort of 230 patients in the phase III trial. Efficacy in terms of HBV H. L. Y. Chan (&) Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 NganShing Street, Shatin, Hong Kong, People’s Republic of China e-mail: hlychan@cuhk.edu.hk

Are we ready to use the hepatitis B surface antigen level to guide peginterferon treatment in HBeAg-negative chronic hepatitis B?