One possible explanation is that the suppression anti-PD-1 antibody inhibitor of serum HBV–DNA does not accurately reflect the host immune control and clearance of covalently closed circular DNA (cccDNA) inside the liver. Quantitative serum HBsAg has attracted a lot of research interest in recent years. Earlier reports in HBeAg-positive patients suggested that the level of serum HBsAg was associated with intrahepatic cccDNA levels, and that the

change in serum HBsAg after peg-interferon therapy could also reflect the change in cccDNA levels.7 Although HBsAg is a viral protein, the clearance of HBsAg requires host immunity. In untreated patients, HBsAg levels decline with immune clearance,8 and low HBsAg levels (< 100 IU/mL) predict spontaneous HBsAg seroclearance.9 In patients on antiviral treatment, HBsAg levels decline more dramatically with peg-interferon, an immune modulator, than nucleos(t)ide analogs, which are potent inhibitors of HBV–DNA replication.10 With this background, serum HBsAg is a logical candidate to predict and guide the response of peg-interferon therapy. Several studies, including the post-hoc analysis of the multicenter GSK-3 inhibitor review trials

on peg-interferon α-2a, have shown an association of on-treatment HBsAg level and response to peg-interferon.10 In HBeAg-positive patients, an HBsAg level of < 1500 IU/mL at weeks 12 and 24 is associated with a > 50% chance of HBeAg seroconversion, while an HBsAg level of > 20 000 IU/mL usually predicts non-response. Fenbendazole In a study in Hong Kong, a > 1 log reduction in HBsAg at week 24 was also a predictor of response.11 In HBeAg-negative patients, a reduction in HBsAg, rather than any absolute HBsAg level, is more predictive of response to peg-interferon.10 The exact reason why HBsAg is used differently in HBeAg-positive and -negative patients is unclear. This might be related to the poor

relationship between HBsAg level and cccDNA in HBeAg-negative patients, in contrast to those who are HBeAg positive.12 Even if we can predict the response to peg-interferon using on-treatment HBsAg levels, the key question is: what is next? For the 20% poor on-treatment responders, one can stop peg-interferon early and shift to an oral antiviral agent. What can we do for the remaining 80% of patients who are starting to respond? Can we further improve the response for the on-treatment responders, particularly those with intermediate HBsAg response? Combination with lamivudine does not seem to improve the sustained response to peg-interferon.3,13 More data are required before combination with entecavir or tenofovir can be recommended (a trial with telbivudine was discontinued because of unexpected toxicity). In a recent study evaluating the effect of a lower dose (90 mcg weekly) and shorter duration (24 weeks) of peg-interferon α-2a in HBeAg-positive patients, it was clear that the standard 180 mcg weekly dosing for 48 weeks is needed to achieve the best sustained response.