title: Long-term safety of lamivudine treatment in patients with chronic hepatitis B.
abstract: OBJECTIVE
  Data on the long-term safety of lamivudine are limited. The aim of this analysis was to determine the incidence of hepatitis flares, hepatic decompensation, and liver-disease-related (LDR) serious adverse events (SAE) during long-term lamivudine treatment.
  
  
  METHODS
  We reviewed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years (median, 4 years) and 200 patients who received placebo for 1 year.
  
  
  RESULTS
  Hepatitis flares occurred in 10% of the lamivudine-treated patients in year 1 and in 18%-21% in years 2-5. A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43% in year 1 to >80% in year 3. Ten hepatic decompensation events occurred in 8 (<1%) lamivudine-treated patients. Fifty-three (5%) lamivudine-treated patients experienced a total of 60 LDR SAEs. Four patients died, 2 from liver-related causes. The proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5. During each year of the study, patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations (P < 0.005). The occurrence of hepatic decompensation (0%-2%) and LDR SAEs (1%-10%) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6% (P = 0.03) and 20% (P = 0.009), respectively.
  
  
  CONCLUSIONS
  This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivudine-resistant mutations may experience worsening liver disease.
authors.affiliation: Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, 48109-0362, USA. aslok@med.umich.edu
authors.forename: Anna S F
authors.initials: AS
authors.lastname: Lok
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.forename: Nancy
authors.initials: N
authors.lastname: Leung
authors.forename: Guang-Bi
authors.initials: GB
authors.lastname: Yao
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Cui
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Schiff
authors.forename: Jules L
authors.initials: JL
authors.lastname: Dienstag
authors.forename: E Jenny
authors.initials: EJ
authors.lastname: Heathcote
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Little
authors.forename: Dorothea A
authors.initials: DA
authors.lastname: Griffiths
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gardner
authors.forename: Mary
authors.initials: M
authors.lastname: Castiglia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects*; D024882:Drug Resistance, Viral; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012189:Retrospective Studies
chemical_list: D000998:Antiviral Agents; D019259:Lamivudine