Letter: clinical outcomes of HBsAg loss in chronic HBV infection - author's reply.

Abstract

We appreciate the interest and comments of Dr Zhao, et al.1 on our recent report on the clinical outcomes after spontaneous and nucleo(t)ide analogue (Nuc)-treated hepatitis B surface antigen (HBsAg) seroclearance in chronic HBV infection.2 They emphasised that the presence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in hepatocytes is responsible for persistent viral replication after HBsAg seroclearance, which is therefore one of the risk factors of hepatocellular carcinoma (HCC) development. Some points in our study will be clarified. Among the 422 patients with HBsAg seroclearance in our recent study,2 HBV DNA assays were performed in 215 patients (155 spontaneous and 60 Nuc-treated) at a median period of 1.2 years (<1–23 years) after HBsAg seroclearance, as described elsewhere.3 HBV DNA was detected in 51 (23.7%) patients (20–2000 IU/mL in 48 and >2000 IU/mL in three patients). Of the five patients with HCC development, HBV DNA was undetectable in all except one with a level of 340 IU/mL at the time of HCC diagnosis. The role of viraemia is still unclear although low HBV DNA levels can be detected in few patients with HCC development after HBsAg seroclearance.4 The integration of HBV genome into hepatocytes with initiation of carcinogenesis and a family history of HCC may be the possible aetiologies.5 As the definition of HBsAg seroclearance in the study, HBsAg was still seronegative in the five patients when HCC developed. We acknowledge the limitations of small sample size and potential bias by propensity score analysis and agree that more prospective studies with large sample size will certify the clinical outcomes after HBsAg seroclearance. As HBsAg seroclearance is uncommon in the nature course of chronic HBV infection and under Nuc treatment, a case–control study with propensity score analysis may be the second best choice to explore this issue. The author's declarations of personal and financial interests are unchanged from those in the original article.2