Serial monotherapy and add-on regimes for treatment of
chronic hepatitis B virus (HBV)
infection may induce the accumulation of viral resistance mutations in patients, reducing the options for ongoing viral suppression. The induction of
antiviral resistance by serial application of polymerase inhibitors does not necessarily imply that the subsequent combined use of the drugs will fail. Some HIV strains resistant to one polymerase inhibitor show increased susceptibility to another polymerase inhibitor. After failure of sequential
lamivudine and
adefovir monotherapy, two patients with
hepatitis B changed to treatment with
lamivudine plus
adefovir and had renewed suppression of HBV. To study the mutational history of resistant HBV subpopulations in the two patients, a part of the
HBV polymerase gene was amplified, cloned, sequenced, and analyzed for the presence of mutations, in sequential plasma samples. In both patients serial monotherapy caused the replacement in all HBV clones of wild-type virus by classical
lamivudine resistant mutants (L180M and M204V/I), which were replaced subsequently by
adefovir resistant mutants (A181V and N236T). When finally
lamivudine was added to
adefovir, the A181V
adefovir mutation persisted in all clones and
lamivudine-related mutations did not reappear. During 18 months of combination
therapy, HBV-
DNA levels decreased 10,000, respectively, 1,000-fold, despite the earlier resistance to
lamivudine and
adefovir. Although clinically insufficient, this effect indicates that
HBV polymerase resistance mutations may be antagonistic, which is relevant if chronic HBV
infection is to be treated by a combination of polymerase inhibitors.