title: The sequential occurrence of viral mutations in a liver transplant recipient re-infected with hepatitis B: hepatitis B immune globulin escape, famciclovir non-response, followed by lamivudine resistance resulting in graft loss.
abstract: OBJECTIVE
  The purpose of this study was to characterize the clinical, histological and virological events in an orthotopic liver transplant (OLT) recipient with recurrent hepatitis B infection who was initially managed with hepatitis B immune globulin (HBIg) and when viral recurrence occurred, with nucleoside analogue salvage therapy. The aims were to document the mutations occurring in the hepatitis B virus (HBV) polymerase gene as a consequence of HBIg escape, famciclovir non-response and subsequent lamivudine resistance.
  
  
  METHODS
  Throughout the follow-up of 796 days, the patient was seen at least at 4-week intervals. Clinical, biochemical and virological data were registered according to protocol. HBV DNA was quantified throughout the treatment period. The viral polymerase gene was sequenced from serum samples collected at representative time intervals. Consecutive liver biopsies were scored according to the modified Knodell classification.
  
  
  RESULTS
  Clinically, the patient was in excellent condition until the development of acute hepatitis during the lamivudine therapy period, 765 days post-OLT. Until this terminal event, serum transaminase activity was only 1-2 times the upper limit of normal with serum bilirubin and prothrombin time within the normal range. Subsequent liver biopsies showed chronic active hepatitis with no signs of fibrosis. The post-mortem biopsy showed severe acute hepatitis B with massive necrosis. The HBV polymerase gene was sequenced during HBIg, famciclovir and lamivudine treatment. One mutation I533L was detected during HBIg treatment. No amino acid changes were selected during famciclovir treatment. Three amino acid changes were selected while the patient was on lamivudine treatment, which include L533I, S559T and M550I.
  
  
  CONCLUSIONS
  We have documented HBV recurrence in a liver transplant recipient with the emergence of a multidrug resistant HBV which caused graft loss. The primary resistance to famciclovir in spite of therapeutic penciclovir levels may be as a result of a combination of the mutations found in the polymerase region. After 300 days of lamivudine treatment, a drug-resistant population emerged which was associated with a greater than three log increase in HBV DNA and contributed to loss of graft function. This is the first report of such an adverse clinical outcome due to the emergence of a mutant virus as a consequence of immunoprophylactic and antiviral therapy in a liver transplant recipient.
authors.affiliation: Department of Hepatogastroenterology, Erasmus University Hospital, Rotterdam, The Netherlands. MAN@INW2.AZR.NL
authors.forename: R A
authors.initials: RA
authors.lastname: de Man
authors.forename: A I
authors.initials: AI
authors.lastname: Bartholomeusz
authors.forename: H G
authors.initials: HG
authors.lastname: Niesters
authors.forename: P E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: S A
authors.initials: SA
authors.lastname: Locarnini
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D004351:Drug Resistance; D000077595:Famciclovir; D006509:Hepatitis B / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D007116:Immunization, Passive; D007136:Immunoglobulins; D019259:Lamivudine / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012008:Recurrence; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D007136:Immunoglobulins; D014764:Viral Proteins; D019259:Lamivudine; D015075:2-Aminopurine; D004259:DNA-Directed DNA Polymerase; D000077595:Famciclovir; C045213:hepatitis B hyperimmune globulin