Absence of mutations in the YMDD motif/B region of the hepatitis B virus polymerase in famciclovir therapy failure.
OBJECTIVE
Nucleoside analogues such as lamivudine and famciclovir are potent drugs for treatment of chronic hepatitis B virus infection. Breakthrough infections during lamivudine therapy are associated with mutations in the YMDD motif and putative B region of the HBV polymerase. This study investigated whether failure of famciclovir therapy is also associated with presence or emergence of particular mutations in the HBV polymerase.


METHODS
We analyzed longitudinally the sequence of the priming and polymerase domain in seven patients with primary non-response to therapy and two patients with a breakthrough during therapy. Two patients who responded to therapy served as a control.


RESULTS
The YMDD motif and the B region were conserved in all isolates. V-->I changes at position 555 just downstream of the YMDD motif were observed before and during therapy in a virus subpopulation of two patients with a primary non-response. In patients with a breakthrough, 378-V-->I and 424-N-->D mutations emerged in the N terminal part of the polymerase domain during follow-up. Lamivudine rescue therapy initiated in four patients, including a patient infected with YMDD(555-V-->I) variants, efficiently reduced viremia.


CONCLUSIONS
These data indicate that failure of famciclovir therapy can occur independently of mutations in the YMDD motif or B region of the HBV polymerase and provide a rationale for rescue therapy with lamivudine.
Günther
S
S
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität, Hamburg, Federal Republic of Germany.
von Breunig
F
F
Santantonio
T
T
Jung
M C
MC
Gaeta
G B
GB
Fischer
L
L
Sterneck
M
M
Will
H
H
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D004261:DNA Replication; D000077595:Famciclovir; D015684:Gene Products, pol / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology*; D006515:Hepatitis B virus / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D016415:Sequence Alignment; D017211:Treatment Failure
D000998:Antiviral Agents; D015684:Gene Products, pol; C066027:P protein, Hepatitis B virus; D015075:2-Aminopurine; D012194:RNA-Directed DNA Polymerase; D000077595:Famciclovir