In vivo dynamics and pathogenicity of wild-type and resistant Hepatitis B virus during long-term lamivudine monotherapy - a clinical note

Background: Genotypic resistance of Hepatitis B virus (HBV) against lamivud ine evolves within months after onset of therapy. Objectives: To determine the longitudinal order in which resistance mutations appear and to compare the kinetics and pathogenicity of wild-type and resistant HBV. Study design : In a longitudinal study, consecutive samples were drawn over a period of 28 months from a patient with chronic hepatitis B, and resistance mutations were followed by sequencing a part of the polymerase region of HBV. These data were compared with HBV copy numbers, HBsAg and ALT levels, and results of consecutive liver biopsies. Results: After 21 weeks of treatment, a sil ent mutation at codon 528 (CTG to TTG) occurred. Significant genotypic resi stance was detectable after 68 weeks, indicated by a substitution of isoleu cine for methionine at residue 552 (M552I). Nineteen weeks later, the virus exhibited additional resistance-associated mutations (L528N and I552V). Th e resulting high-level resistance was reflected by an increase of serum HBV copies of 4.7 log(10). The turnover of wild-type and resistant HBV was 2.6 x 10(6) and 1.8 x 10(6) virions/day, respectively. HBsAg and ALT levels we re lower within the period when resistant HBV was detectable. During treatm ent the progress of liver fibrosis was arrested. Conclusions: The in vivo r eplicative capacities and dynamics of wild-type and resistant HBV were simi lar. However, resistant HBV seemed to exhibit reduced pathogenicity. (C) 20 00 Elsevier Science B.V. All rights reserved.