Hepatitis B Viral Surface Mutations in Patients with Adefovir Resistant Chronic Hepatitis B with A181T/V Polymerase Mutations

The hepatitis B virus (HBV) polymerase gene has overlapping reading frames with surface genes, which allows to alter the amino acid codon of the surface genes. In adefovir (ADV) treated chronic hepatitis B patients carrying rtA181T/rtA181V mutations, overlap with surface gene mutations such as sW172stop/sL173F has been reported. However, the clinical consequences of such surface mutations have not been determined. The aim of this study was to determine the surface gene sequence in ADV-resistant patients carrying the A181T/V mutation and to describe the clinical significance. Of the 22 patients included in this study, 13 were ADV-resistant with rtA181T/V mutations (polymerase mutation group, Group P) and nine were antiviral treatment-naïve (control group, Group C). The Pre-S1 gene mutation, V60A, was detected in 11 patients (Group P=8, Group C=3). A start codon mutation in the Pre-S2 gene was found in five patients (Group P=3, Group C=2). An S gene mutation, sA184V, was found in nine patients, all of whom were in group P. Although sW172stop and sL173F mutations were detected, reduced HBsAg titer was not observed. Further study of these mutations and their clinical implications are needed.

[1]  Y. Kook,et al.  The prevalence of hepatitis B virus preS deletions occurring naturally in Korean patients infected chronically with genotype C , 2008, Journal of medical virology.

[2]  Sheng-Nan Lu,et al.  Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients. , 2007, Gastroenterology.

[3]  C. Muller,et al.  Hepatitis B virus genotype E surface antigen detection with different immunoassays and diagnostic impact of mutations in the preS/S gene , 2007, Medical Microbiology and Immunology.

[4]  M. Choi,et al.  Clinical significance of pre‐S mutations in patients with genotype C hepatitis B virus infection , 2007, Journal of viral hepatitis.

[5]  Y. Liaw,et al.  Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HBsAg seroclearance. , 2007, Gastroenterology.

[6]  S. Yu,et al.  Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil , 2006, Gut.

[7]  Ding‐Shinn Chen,et al.  High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. , 2006, Gastroenterology.

[8]  S. Locarnini,et al.  Cellular and virological mechanisms of HBV drug resistance. , 2006, Journal of hepatology.

[9]  S. Locarnini,et al.  Hepatitis B virus mutations associated with antiviral therapy , 2006, Journal of medical virology.

[10]  M. Choi,et al.  Overlapping Gene Mutations of Hepatitis B Virus in a Chronic Hepatitis B Patient with Hepatitis B Surface Antigen Loss during Lamivudine Therapy , 2005, Journal of Korean medical science.

[11]  Tatiana A. Tatusova,et al.  A web-based genotyping resource for viral sequences , 2004, Nucleic Acids Res..

[12]  G. Raimondo,et al.  Non-sequencing molecular approaches to identify preS2-defective hepatitis B virus variants proved to be associated with severe liver diseases. , 2004, Journal of hepatology.

[13]  F. Sugauchi,et al.  Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease , 2003, Journal of medical virology.

[14]  Angeline Bartholomeusz,et al.  Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. , 2003, Gastroenterology.

[15]  J. Torresi The virological and clinical significance of mutations in the overlapping envelope and polymerase genes of hepatitis B virus. , 2002, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[16]  Heather L. Stang,et al.  Mutations in the conserved woodchuck hepatitis virus polymerase FLLA and YMDD regions conferring resistance to lamivudine. , 2002, Antiviral research.

[17]  D. Jackson,et al.  Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy. , 2002, Virology.

[18]  S. Günther,et al.  Complex HBV populations with mutations in core promoter, C gene, and pre‐S region are associated with development of cirrhosis in long‐term renal transplant recipients , 2002, Hepatology.

[19]  H. Lei,et al.  Prevalence and significance of hepatitis B virus (HBV) pre‐S mutants in serum and liver at different replicative stages of chronic HBV infection , 2001, Hepatology.

[20]  H. Sakai,et al.  Analysis of HBs antigen negative variant of hepatitis B virus: unique substitutions, Glu129 to Asp and Gly145 to Ala in the surface antigen gene. , 2000, Medical science monitor : international medical journal of experimental and clinical research.

[21]  E. Tanzi,et al.  Pre‐S2 defective hepatitis B virus infection in patients with fulminant hepatitis , 1997, Hepatology.

[22]  H. Kohno,et al.  Mutations in the envelope gene of hepatitis B virus variants co-occurring with antibody to surface antigen in sera from patients with chronic hepatitis B. , 1996, The Journal of general virology.

[23]  H. Okamoto,et al.  Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen , 1994, Journal of virology.

[24]  M. Sakamoto,et al.  Allelic subtypic determinants of hepatitis B surface antigen (i and t) that are distinct from d/y or w/r , 1993, Journal of virology.

[25]  H. Miyazaki,et al.  Mutations within the S Gene of Hepatitis B Virus Transmitted from Mothers to Babies Immunized with Hepatitis B Immune Globulin and Vaccine , 1992, Pediatric Research.

[26]  A. Zuckerman,et al.  Vaccine-induced escape mutant of hepatitis B virus , 1990, The Lancet.

[27]  P. Hofschneider,et al.  A trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Tiollais,et al.  Structure and expression of the hepatitis B virus genome , 1987, Hepatology.

[29]  J. Summers,et al.  Genome of hepatitis B virus: restriction enzyme cleavage and structure of DNA extracted from Dane particles. , 1975, Proceedings of the National Academy of Sciences of the United States of America.