Viral and clinical factors associated with surface gene variants among hepatitis B virus carriers.
BACKGROUND
Understanding the prevalence of potential antigenic variation of the hepatitis B virus (HBV) surface antigen (HBsAg) is fundamental for assay design and to future changes in vaccine formulation. In this study, the nature and frequency of HBsAg polymorphisms occurring in France in chronic carriers and in newly diagnosed patients were determined. We focused on variations in the major hydrophilic region (MHR), the central core of HBsAg known to be exposed on the surface and involved in antibody binding.


METHODS
Two patient groups were identified: 51 chronic HBV carriers followed at our institution for > 1 year; and 129 newly diagnosed patients (63 of whom had a first HBsAg-positive result at our hospital laboratory and 66 a first positive result in a private laboratory). DNA sequences of HBsAg were obtained from these 180 patients and compared with consensus sequences built with 168 full-length HBV sequences imported from GenBank. Polymorphisms of the MHR of HBsAg were analysed with the Mutation Master Software. Literature review and BLOSUM scores were used to define potentially altered antigenicity.


RESULTS
The global frequency of MHR variants was 27.8%. Occurrence of MHR variants was independent of viral load, HBeAg status and sex, but was associated with the chronic carriers' group, advancing age, the presence of antibodies to HBsAg, immunoprophylaxis administration, antiviral treatment and genotypic resistance to antivirals. In multivariate analysis, the independent variables associated with MHR variants were advancing age and the presence of genotypic resistance to nucleoside or nucleotide analogues.


CONCLUSIONS
Most MHR variants emerge with longer disease duration and upon indirect selective pressure. Variation of the MHR may serve to restore virus replication of resistant strains. Combined envelope and polymerase variants could impair diagnostic assays and limit treatment alternatives.
Roque-Afonso
Anne Marie
AM
INSERM U785, 94804 Villejuif, France. anne-marie.roque@pbr.aphp.fr
Férey
Marie-Pierre
MP
Ly
Thoai Duong
TD
Graube
Arielle
A
Costa-Faria
Luciana
L
Samuel
Didier
D
Dussaix
Elisabeth
E
D000367:Age Factors; D000595:Amino Acid Sequence; D002353:Carrier State; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005602:France; D006509:Hepatitis B / Q000097:blood / Q000188:drug therapy / Q000821:virology*; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000494:pharmacology; D009711:Nucleotides / Q000494:pharmacology; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D019562:Viral Load
D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D009705:Nucleosides; D009711:Nucleotides