Lamivudine and Famciclovir resistant hepatitis B virus associated with fatal hepatic failure

Abstract 

Background: Lamivudine (LMV) is the only nucleoside analogue approved for the treatment of chronic hepatitis B (CHB). LMV, as with other nucleoside analogues including Famciclovir (FCV), suppresses the replication of hepatitis B virus (HBV) by targeting the viral polymerase. However, prolonged antiviral therapy results in the emergence of drug resistance HBV which can contribute to virological breakthroughs and recurrent hepatitis flares. Objectives: A 38-year-old hepatitis B e antigen (HBeAg) positive Chinese female infected with genotype B HBV commenced treatment with FCV and LMV combination therapy but was later maintained on LMV monotherapy. The patient remained HBeAg positive throughout treatment. Virological breakthrough occurred with the emergence of drug resistant HBV. This coincided with worsening liver function and the patient died of subacute fulminant hepatitis. This study evaluated the virological factors that contributed to the clinical decline of the patient. Study design: Biochemical analysis and full-length HBV genomic sequencing were performed on serial serum samples collected from the patient before and during antiviral therapy. Results: Virological analysis revealed that the pre-treatment dominant HBV quasispecies in the patient had a number of non-consensus genotype B mutations which were located in the basal core promoter (BCP), polymerase, X, core and S genes. Subsequent to the instigation of antiviral therapy, the dominant drug resistant HBV which caused virological breakthrough and was associated with hepatic failure displayed a series of unique mutations particularly in the BCP (A1762T and G1764A) and in the polymerase (rtL180M, rtM204V, rtA222T and rtL336V), core (cP5T, cS26A, cV85I and cP135A), surface (sI195M and sM213I) and X (xK95Q, xN118T, xK130M and xV131I) proteins. Conclusions: Monitoring for the accumulation of unique mutations within the genome of drug resistant HBV mutants isolated during long term antiviral therapy appears warranted in the clinical management of patients with CHB.

Keywords: Hepatitis B virus, Lamivudine, Famciclovir, Drug resistance, Compensatory mutations, Subacute fulminant hepatitis

Abbreviations: CHB, chronic hepatitis B, LMV, Lamivudine, FCV, Famciclovir, HBV, hepatitis B virus, HBsAg, hepatitis B surface antigen, HBeAg, hepatitis B e antigen, anti-HBe, antibody to hepatitis B e antigen, rt, reverse transcriptase, ALT, alanine transferase, LiPA, line probe assay