Absence of mutations in the YMDD motif/B region of the hepatitis B virus polymerase in famciclovir therapy failure

Background/Aims: Nucleoside analogues such as lamivudine and famciclovir ar e potent drugs for treatment of chronic hepatitis B virus infection, Breakt hrough infections during lamivudine therapy are associated with mutations i n the YMDD motif and putative B region of the HBV polymerase. This study in vestigated whether failure of famciclovir therapy is also associated with p resence or emergence of particular mutations in the HBV polymerase. Methhods: We analyzed longitudinally the sequence of the priming and polyme rase 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 durin g follow-up. Lamivudine rescue therapy initiated in four patients, includin g a patient infected with YMDD(555-V-->I) variants, efficiently reduced vir emia, Conclusions: These data indicate that failure of famciclovir therapy can oc cur independently of mutations in the YMDD motif or B region of the HBV pol ymerase and provide a rationale for rescue therapy with lamivudine.