HEPATITIS-B VIRUS POLYMERASE MUTATIONS DURING ANTIVIRAL THERAPY IN A PATIENT FOLLOWING LIVER-TRANSPLANTATION

Background/Aims: 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 followi ng 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 increa se in serum HBV DNA levels and a reduced sensitivity of the virion-ass ociated DNA polymerase to penciclovir triphosphate were observed. Meth ods: The viral polymerase gene and X gene were sequenced from serum sa mples collected at representative time intervals covering the entire t reatment period. Results: No mutations were detected in the X gene. Th ree nucleotide mutations, each of which resulted in an altered amino a cid sequence, were detected in the polymerase gene after 816 days of t otal antiviral therapy (370 days of famciclovir). Two of these mutatio ns were detected by direct sequencing and the third was detected after cloning and was present in 10% of the clones. All three mutations occ urred in ''region B'' of RNA-dependent DNA polymerases. The HBV polyme rase has similarities to both RNA and DNA polymerases. These mutations in the HBV polymerase gene were located in a similar area to the penc iclovir-induced mutations observed in the herpes simplex virus DNA pol ymerase gene. Conclusions: Three mutations within the HBV polymerase g ene were detected which were associated with a reduced penciclovir sen sitivity.