title: Fibrosing cholestatic hepatitis secondary to precore/core promoter hepatitis B variant with lamivudine resistance: successful retransplantation with combination adefovir dipivoxil and hepatitis B immunoglobulin.
abstract: Fibrosing cholestatic hepatitis (FCH) is a peculiar variant of hepatitis B virus (HBV) infection in immunocompromised patients characterized by rapid viral replication. Posttransplant patients receiving lamivudine for prophylaxis or treatment of HBV infection may develop drug resistance due to viral mutants, but FCH is rare because escape mutants are usually replication deficient. We report the development of FCH due to lamivudine-resistant HBV mutants in 2 patients at 12 and 13 months after liver transplantation. Rapidly progressive graft failure, accompanied by an escalating HBV DNA level, developed within weeks of onset. Analysis of gene sequence variation by polymerase chain reaction (PCR) and direct sequencing showed that both had a core promoter variant A1762T/G1764A and 1 had a concomitant precore stop codon G1896A variant in prelamivudine and postrecurrence serum samples. Comparison of the HBV polymerase gene in the 2 serum samples revealed a single mutation with methionine-to-isoleucine substitution at codon 552 (M552I) in both patients. "Add-in" treatment with adefovir dipivoxil resulted in a more than 2 to 3log10 reduction in HBV DNA level within 2 weeks and retransplantation was performed with adefovir dipivoxil and hepatitis B immunoglobulin (HBIG) prophylaxis. Both patients were alive at 15 months and 48 months after retransplantation, with normal graft function and serum negative for HBsAg and HBV DNA by quantitative PCR (< 200 copies/mL). The current report demonstrates that recurrent graft infection by precore/core promoter variant with lamivudine-resistant escape mutation may result in FCH. With combination of adefovir and high-dose HBIG, however, long-term survival can be achieved after retransplantation.
authors.affiliation: Centre for the Study of Liver Disease, and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China. chungmlo@hkucc.hku.hk
authors.forename: Chung-Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Siu-Tim
authors.initials: ST
authors.lastname: Cheung
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.forename: Chi-Leung
authors.initials: CL
authors.lastname: Liu
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.forename: Sheung-Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy / Q000209:etiology / Q000601:surgery; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D006509:Hepatitis B / Q000150:complications / Q000188:drug therapy* / Q000601:surgery; D006512:Hepatitis B Core Antigens / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000627:therapeutic use*; D019259:Lamivudine / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D063065:Organophosphonates; D011401:Promoter Regions, Genetic / Q000235:genetics; D012086:Reoperation; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D006512:Hepatitis B Core Antigens; D007136:Immunoglobulins; D063065:Organophosphonates; D019259:Lamivudine; D000225:Adenine; C106812:adefovir dipivoxil; C045213:hepatitis B hyperimmune globulin