title: Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients.
abstract: OBJECTIVE
  Adefovir monotherapy is an established treatment modality for lamivudine-experienced patients with chronic hepatitis B, but it carries a significant risk of resistance in the long term. We assessed whether this risk could be overcome by adefovir-lamivudine combination therapy.
  
  
  METHODS
  A total of 145 lamivudine-resistant patients with chronic hepatitis B (73% cirrhotics, 86% hepatitis B e antigen negative, 92% genotype D) were treated with adefovir 10 mg in addition to lamivudine 100 mg. Liver function tests and hepatitis B virus (HBV) DNA (Versant 3.0) were assessed bimonthly, whereas adefovir-related mutations were searched by INNO-LiPA assay at baseline and at yearly intervals.
  
  
  RESULTS
  During 42 months (range, 12-74), 116 patients (80%) cleared serum HBV DNA, 67 (84%) had normalized alanine aminotransferase levels, and 145 (100%) remained free of virologic and clinical breakthroughs, independently of the degree of HBV suppression. The rtA181V/T was the only adefovir-related mutation detected, which occurred in 6 patients at baseline (4%; 1 rtA181V and 5 rtA181T) and in an additional 3 patients (2%; all rtA181T) during treatment. In all these 9 patients, HBV DNA levels progressively declined during therapy to become undetectable in 7 (78%). The 1-, 2-, 3-, and 4-year cumulative rates of de novo rtA181T were 1%, 2%, 4%, and 4%, respectively. None of the cirrhotic patients clinically decompensated, but 11 (12%) developed hepatocellular carcinoma.
  
  
  CONCLUSIONS
  Under prolonged adefovir-lamivudine therapy, patients with lamivudine-resistant hepatitis B were unlikely to develop genotypic resistance to adefovir and had durable prevention of virologic and clinical breakthrough.
authors.affiliation: "A. M. and A. Migliavacca" Center for Liver Disease, Division of Gastroenterology, Department of Medicine, Fondazione Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Lampertico
authors.forename: Mauro
authors.initials: M
authors.lastname: Viganò
authors.forename: Elena
authors.initials: E
authors.lastname: Manenti
authors.forename: Massimo
authors.initials: M
authors.lastname: Iavarone
authors.forename: Erwin
authors.initials: E
authors.lastname: Sablon
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D018450:Disease Progression; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D006509:Hepatitis B / Q000097:blood / Q000188:drug therapy*; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D000225:Adenine