Hepatitis B virus polymerase mutations during antiviral therapy in a patient following liver transplantation.
OBJECTIVE
The purpose of this study was to investigate possible resistance mutations which arose in the polymerase gene of hepatitis B virus (HBV) in a patient with severe recurrent HBV infection following liver transplantation. The patient's management included antiviral chemotherapy for almost 4 years comprising ganciclovir, foscarnet and famciclovir. In the last 2.5 years of famciclovir treatment, an increase in serum HBV DNA levels and a reduced sensitivity of the virion-associated DNA polymerase to penciclovir triphosphate were observed.


METHODS
The viral polymerase gene and X gene were sequenced from serum samples collected at representative time intervals covering the entire treatment period.


RESULTS
No mutations were detected in the X gene. Three nucleotide mutations, each of which resulted in an altered amino acid sequence, were detected in the polymerase gene after 816 days of total antiviral therapy (370 days of famciclovir). Two of these mutations were detected by direct sequencing and the third was detected after cloning and was present in 10% of the clones. All three mutations occurred in "region B" of RNA-dependent DNA polymerases. The HBV polymerase has similarities to both RNA and DNA polymerases. These mutations in the HBV polymerase gene were located in a similar area to the penciclovir-induced mutations observed in the herpes simplex virus DNA polymerase gene.


CONCLUSIONS
Three mutations within the HBV polymerase gene were detected which were associated with a reduced penciclovir sensitivity.
Aye
T T
TT
Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, Melbourne, Australia.
Bartholomeusz
A
A
Shaw
T
T
Bowden
S
S
Breschkin
A
A
McMillan
J
J
Angus
P
P
Locarnini
S
S
D015075:2-Aminopurine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D004247:DNA / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D000077595:Famciclovir; D006515:Hepatitis B virus / Q000201:enzymology*; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011184:Postoperative Period
D000998:Antiviral Agents; D015075:2-Aminopurine; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D000077595:Famciclovir