gms | German Medical Science

Background: Chronic HBV infection can cause liver-cirrhosis or hepatocellular carcinoma. Different antiviral therapy regimens are used to influence the disease progression. An obstacle regarding sustained suppression of viral replication are emerging drug-resistances. Due to overlapping reading-frames treatment-associated polymerase mutations often influence the HBV-surface-antigen (HBsAg). Little is known about the co-evolution of both proteins.

Material & methods: We analysed HBV isolates (n=85) in the polymerase and s-Antigen reading-frame harbouring treatment-associated mutations or failing antiviral therapy. Consecutive genotypes of 15 patients could be compared. HBsAg mutants were expressed in hepatocytes and tested in diagnostic assays.

Results: 14% (10/73) of the HBV- isolates harbouring treatment-associated polymerase mutations had at least one stop codon in the s-Antigen reading frame at different positions (sW172: n=5, sW182: n=4, sW196: n=1, sW199: n=2, sL216: n=2). Moreover, in 4 of these patients two stop codons were detected. Interestingly, mutation rtM204I resulted only once in sW196* whereas 23 HBV isolates harboured sW196L. HBsAg mutations conferring immune-escape were found in 30% (22/73) of these HBV isolates. 11 HBV isolates had mutations in two epitopes (aa120-125/aa137-145) of the a-determinant potentially conferring detection-escape in commercial tests. These mutations significantly decreased the detection of in vitro expressed HBsAg with commercial test assays, which was most prominent for the test assay using monoclonal antibodies for the capture and detection phase. In some cases the detection was hampered at all. In one patient a HBsAg immune-escape mutation (sP120T) developed, whereas pre-existing resistance-associated mutations (rtL180M, rtM204I/V) maintained. Interestingly, in another patient HBV resistance profiles changed from sP120T, rtL180M, rtM204V after lamivudin failure to sQ101R, sP120S, sW172*, sT189I, rtV173F, rtQ181V, rtL215S after failure of a following adefovir therapy.

Conclusions: Treatment-associated polymerase and HBsAg mutations were often found together. Compensatory mutations in the polymerase lead to mutations in the s-Antigen, which decrease the detection of HBsAg in commercial assays. However, about 10% of HBV resistant isolates carried stop codons in the s-Antigen, which might additionally enhance viral pathogenicity.