title: Mutations associated with the therapeutic efficacy of adefovir dipivoxil added to lamivudine in patients resistant to lamivudine with type B chronic hepatitis.
abstract: Factors influencing the therapeutic efficacy of adefovir dipivoxil added to continuing lamivudine have not been elucidated in lamivudine-resistant patients with type B chronic hepatitis. The viral mutations influencing the efficacy of treatment with adefovir dipivoxil were investigated by sequencing analysis of the whole virus genome. Thirty patients resistant to lamivudine receiving adefovir dipivoxil therapy added to lamivudine were studied. From serum samples obtained before the administration of adefovir dipivoxil, full-length viral DNA sequences were determined by PCR-direct sequencing. Susceptibility of the virus to adefovir was examined further using in vitro transfection analysis. By screening the whole viral genome, the presence of two mutations, a T-to-C/G/A mutation at nt1753 (V1753) and an A-to-C mutation at nt2189 (C2189), correlated with the higher incidence of sustained viral DNA clearance during therapy (P < 0.005 and P < 0.05). In multivariate analysis, the V1753 (P = 0.001) and the C2189 (P = 0.007) mutations, and elevated transaminase (P = 0.011) and low viral load (P = 0.008) at the baseline were selected as significant independent factors associated with improved antiviral efficacy. In vitro transfection analysis showed no differences in susceptibility to adefovir among wild-type virus and C1753 and C2189 mutant viruses, suggesting that the virus possessing these mutations may be eradicated more efficiently than the wild-type virus by treatment regardless of a direct antiviral effect of adefovir.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ohkawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Michio
authors.initials: M
authors.lastname: Kato
authors.forename: Aimi
authors.initials: A
authors.lastname: Kanada
authors.forename: Matsuo
authors.initials: M
authors.lastname: Deguchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kagita
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Akira
authors.initials: A
authors.lastname: Sasakawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kohga
authors.forename: Akio
authors.initials: A
authors.lastname: Uemura
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Sakamori
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi