Hepatitis B virus mutants associated with hepatitis b surface antigen loss: Chicken or egg?
Authors: Tai-Chung Tseng, Jia-Horng Kao
Journal: Hepatology (2011)

We read with great interest the article entitled "Emergence of Hepatitis B Virus S Gene Mutants in Patients Experiencing Hepatitis B Surface Antigen Seroconversion After Peginterferon Therapy" by Hsu and Yeh in the July 2011 issue of HEPATOLOGY.1 Peginterferon is one of the preferred agents for the treatment of chronic hepatitis B, with a higher incidence of hepatitis B surface antigen (HBsAg) loss than nucleos(t)ide analogues, which is closest to the cure of hepatitis B virus (HBV) infection.2 Hsu and Yeh found that two patients achieved HBsAg loss after receiving peginterferon therapy but retained high serum HBV DNA levels nevertheless.1 They identified two new HBV variants, sT125A and sW74*, from the serum samples at HBsAg-negative phase, and these mutant HBsAg proteins could not be detected in in vitro studies. They therefore concluded that these S gene mutations were responsible for the failure of detecting HBsAg. Although Hsu and Yeh's findings are interesting, several issues need to be addressed further. First, the variant of sT125A was shown to be a minor strain of the total viral population (14.3%) in patient 1 according to the cloning results. If HBsAg loss is caused by viral mutation, this HBsAg loss–related viral strain is supposedly the major strain; otherwise, we cannot explain why patients achieving HBsAg loss still harbor more than 50% of viral strains, which are competent for producing detectable HBsAg. In other words, proving the in vitro phenotype of a minor viral strain does not explain the loss of circulating HBsAg in these patients. Second, the variant sW74* was shown to represent 83.1%-100% of viral strains in a patient with HBsAg loss. It is noteworthy that the S ORF is overlapped with polymerase ORF in the HBV genome.3 Assuming the deletion of sW74* from nucleotide 1284-1744 (W64 to the end of S ORF), this deletion mutant also destroys amino acids 429-581 of polymerase, an important part of the reverse-transcriptase domain. This viral strain is therefore supposed to not replicate by itself. Virologically, other viral strains with competent replication must become the major strain. However, the results derived from the cloning and pyrosequencing failed to confirm this inference. In other words, if the pyrosequencing results are correct, the viral strain is supposed to not replicate profoundly, and this patient is unlikely to have such a high viral load. On the contrary, if the pyrosequencing results are not valid, the authors need to document the existence of other competent viral strains and prove that the HBsAg produced by this viral strain could not be detected by common HBsAg antibody. Taken together, these observations suggest that the peginterferon-related HBsAg loss reported by Hsu and Yeh may not be attributed to these viral mutants, but may instead be caused by certain epigenetic or genetic modifications in hepatocytes that are driven by host immunity. These mutant strains are merely the products selected by host immune pressure. In conclusion, HBsAg loss after peginterferon therapy cannot be convincingly explained by these viral mutants. Further studies are required to examine the underlying mechanisms involved in peginterferon-induced HBsAg loss. Tai-Chung Tseng M.D.* , Jia-Horng Kao Ph.D. , * Division of Hepatogastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan, Division of Gastroenterology, Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.