J Korean Med Sci.  2010 Feb;25(2):257-264. 10.3346/jkms.2010.25.2.257.

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

• Kim JH
• Jung YK
• Joo MK
• Kim JH
• Yim HJ
• Park JJ
• Kim JS
• Bak YT
• Yeon JE
• Byun KS

• KMID: 1779257
• DOI: http://doi.org/10.3346/jkms.2010.25.2.257

Abstract

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-naive (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.

Keyword

Hepatitis B, Chronic; Adefovir; Hepatitis B Surface Antigens

MeSH Terms

Adenine/*analogs & derivatives/therapeutic use
Adult
Aged
Amino Acid Sequence
Amino Acid Substitution
Antiviral Agents/*therapeutic use
Codon, Initiator
DNA-Directed DNA Polymerase/*genetics
Demography
Drug Resistance, Viral/genetics
Female
Genotype
Hepatitis B Surface Antigens/*genetics/metabolism
Hepatitis B, Chronic/*drug therapy
Humans
Male
Middle Aged
Molecular Sequence Data
Organophosphonates/*therapeutic use
Point Mutation
Viral Proteins/*genetics
Antiviral Agents
Codon, Initiator
Hepatitis B Surface Antigens
Organophosphonates
Viral Proteins
Adenine
DNA-Directed DNA Polymerase

Figure

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  Fig. 1 Sequence changes in the Pre-S1 regions. Twelve patients (six cases in each group) and 18 patients (nine cases in each group) had nucleotide deletions at positions '21' and '30'. Nucleotide deletions at position '59' were detected in 5 of 13 patients in Group P and in 2 of 9 patients in Group C. An H51Q mutation was detected in two patients (one case in each group). A V60A mutation was detected in 8 of 13 patients in Group P and 3 of 9 patients in Group C. L74I mutations in Group P (n=2) and T86A mutations in Group C (n=2) were detected. Three cases of an I84T mutation were found in Group C and one case in Group P. G2A, G73D, A91T, and A95T mutations were detected in Group P. A81T and A95V mutations were detected in Group C.

• 

  Fig. 2 Sequence changes in the Pre-S2 regions. Five start codon mutations were identified in the Pre-S2 region. V32A, I45T and T49I mutations were detected in HCC cases. Q2K (Group P=1, Group C=1), A11T (Group P=2, Group C=1), F22L (Group P=2, Group C=2), and F46S (Group P=2) mutations were observed. In Group C, there were following mutations: N4K, T7A, H9Q, R16P, R16G, V17P, V17A, R18S, G19S, L20Q, P54Q, nucleotide '418-423' deletion, '419' deletion, and '425' deletion. In Group P, one case each of I42T, P54L mutation and nucleotide 406 deletion were detected.

• 

  Fig. 3 Sequence changes in the S regions up to the front of 'a' determinant. An S3N mutation in Groups P (n=4) and C (n=2), and an I68T mutation in Groups P (n=3) and C (n=1) were detected. G10stop, L15V, I28V, W36L, F41S, T47A, Q51L, N59H, C69-stop, L87V, F93L, V96G, L97P, and G102C mutations were detected in Group C (one case each). F41C, A45V, P49L, Q54L, P62L, I92T, and L98V mutations were identified in Group P (one case each). An L21S mutation in Groups P (n=2) and C (n=2) and an R24Q mutation in Groups P (n=1) and C (n=1) were detected.

• 

  Fig. 4 Sequence changes in the S regions from 'a' determinant. In 10 of 13 patients in Group P, sW172stop (n=5) and sL173F (n=5) mutations were detected. A184V mutations were found in 9 of 13 patients in Group P. I126T mutations in groups P (n=4) and C (n=1) and L213I mutations in Groups P (n=6) and C (n=1) were detected. T131P, Y200F, and C221Y mutations were detected in Group C (one case each). T140S, A157V, W182stop, and S204R mutations were identified in Group P (one case each). One P203R mutation was detected in each group.

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