HBsAg Seroclearance: The More and Earlier, the Better

Abstract

We read with great interest the article entitled “HBsAg Seroclearance in Chronic Hepatitis B in Asian Patients: Replicative Level and Risk of Hepatocellular Carcinoma” by Yuen et al in the October 2008 issue of Gastroenterology.1Yuen M.F. Wong D.K. Fung J. et al.HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma.Gastroenterology. 2008; 135: 1192-1199Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar Although effective vaccines have been available for >2 decades,2Kao J.H. Chen D.S. Universal hepatitis B vaccination: killing 2 birds with 1 stone.Am J Med. 2008; 121: 1029-1031Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar chronic hepatitis B virus (HBV) infection remains a leading cause of end-stage liver disease and hepatocellular carcinoma (HCC) worldwide. In clinical practice, seroclearance of hepatitis B surface antigen (HBsAg) has been recognized as an important endpoint in both natural history of HBV infection and treatment of chronic hepatitis B.3Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2156) Google Scholar, 4Kao J.H. Chen D.S. Global control of hepatitis B virus infection.Lancet Infect Dis. 2002; 2: 395-403Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar However, because of the rarity of spontaneous or treatment-induced HBsAg seroclearance, the incidence and long-term outcomes of HBV carriers experiencing this event remain disputed.5Liaw Y.F. Sheen I.S. Chen T.J. et al.Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study.Hepatology. 1991; 13: 627-631Crossref PubMed Scopus (244) Google Scholar, 6Hsu H.Y. Chang M.H. Lee C.Y. et al.Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection.Hepatology. 1992; 15: 382-386Crossref PubMed Scopus (79) Google Scholar Yuen et al analyzed 298 patients who achieved HBsAg seroclearance between 1980 and 2006. Among them, the risks of significant hepatic fibrosis and HCC were significantly lower in patients with HBsAg seroconversion at ages <50 years than at >50.1Yuen M.F. Wong D.K. Fung J. et al.HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma.Gastroenterology. 2008; 135: 1192-1199Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar Their findings suggested that earlier HBsAg seroconversion with sustained suppression of HBV DNA and remission of liver damage can bring out a better prognosis over time. Although these data are important to practicing gastroenterologists and hepatologists, some of their results deserve further discussion. In a long-term follow-up cohort in Taiwan, a total 245 patients achieving spontaneous HBsAg seroclearance were identified.7Chu C.M. Liaw Y.F. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up.Hepatology. 2007; 45: 1187-1192Crossref PubMed Scopus (278) Google Scholar The annual HBsAg seroclearance was estimated to be 1.15% on the basis of 21,267 person-years follow-up (1965 anti-HBe–positive HBsAg carriers with 10.8 ± 5.4 years of follow-up). In the current study, the number of patients achieving HBsAg seroclearance was even greater than that in the Taiwanese study. Unfortunately, the number of HBV carriers and total person-years of the entire cohort were not offered. If the authors would provide relevant data, we could understand more about the annual incidence of spontaneous HBsAg seroclearance in Asian HBV carriers. Two possible flaws were also noted in this study. First, the surveillance for HCC was to perform ultrasound of the liver in patients with elevated α-fetoprotein levels. This measure is misleading and obviously violates the recommendations of current guidelines of HCC management,3Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2156) Google Scholar and may lead to a later diagnosis of HCC in their patients. Second, intrahepatic HBV-related mRNAs were analyzed and none but X-mRNA was identified in 1 of the 11 HBsAg seroconverters. This observation is contradictory to our understanding of HBV lifecycle. It is known that all 4 HBV-related mRNAs overlapped at the open reading frame of X gene8Block T.M. Guo H. Guo J.T. Molecular virology of hepatitis B virus for clinicians.Clin Liver Dis. 2007; 11: 685-706Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar; therefore, only X-mRNA could be found by using region-specific primers seems unusual. One possibility is that the visible band on the gel might not be X-mRNA alone, but the summation of all m-RNAs. Further studies are needed to clarify this interesting observation. In summary, existing lines of evidence indicate that spontaneous or treatment-induced HBsAg seroclearance, albeit rare, does occur in chronic hepatitis B patients. The better prognosis of earlier HBsAg seroclearance is likely caused by less HBV replication as well as less liver damage. To provoke more and earlier HBsAg seroclearance in HBV carriers, a better understanding of the mechanisms involved in HBsAg seroclearance is required. ReplyGastroenterologyVol. 136Issue 5PreviewWe would like to thank Tseng and Kao for their interest in our study.1 The following are our responses to their comments. Our study was primarily aimed at examining various virologic and histologic aspects as well as clinical events for chronic hepatitis B patients with hepatitis B surface antigen (HBsAg) seroclearance. Therefore, we did not mention the size of the study population to estimate the incidence of this event. This supplementary information was mentioned in our reply to another letter to editor submitted by Chu and Liaw. Full-Text PDF