title: No resistance to tenofovir disoproxil fumarate through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B.
abstract: OBJECTIVE
  A recent study compared the efficacy of tenofovir disoproxil fumarate (TDF) vs the combination of emtricitabine and TDF (FTC/TDF) in patients with lamivudine-resistant chronic hepatitis B who were treated for as long as 96 weeks. We report findings from resistance analyses conducted for this study.
  
  
  METHODS
  Two hundred eighty patients with chronic hepatitis B virus (HBV) infection and lamivudine resistance (confirmed by INNO-LiPA Multi-DR) were randomly assigned (1:1) to groups treated with TDF or FTC/TDF. The HBV reverse transcriptase domain from the polymerase gene from all patients was sequenced at baseline and from 18 viremic patients at week 96 or early discontinuation.
  
  
  RESULTS
  At screening for the efficacy study, 99% of patients were found to have lamivudine resistance. Prior exposure to entecavir or entecavir resistance was observed in 12% of patients, and 22% of patients had been previously exposed to adefovir; 1.8% were resistant to adefovir. Only 18 patients (6.4%) qualified for sequence analysis, including 1 patient who experienced virologic breakthrough and 17 with persistent viremia. Six of these patients did not have any sequence changes from baseline in HBV reverse transcriptase (33%), and sequence analysis could not be performed for 5 patients (28%). In 2 patients who qualified for phenotypic analysis (1 given TDF and 1 given FTC/TDF), no resistance to TDF was observed. Neither previous treatment exposure nor resistance to entecavir or adefovir affected viral kinetics. However, the mean baseline level of HBV DNA was significantly higher in viremic patients than in patients with viral suppression by week 96 (7.28 log10 IU/mL vs 5.62 log10 IU/mL; P = .0003).
  
  
  CONCLUSIONS
  No resistance to TDF was detected through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B. Prior treatment or resistance to entecavir or adefovir did not affect viral kinetics through 96 weeks. No additional benefit was observed with the addition of emtricitabine vs TDF monotherapy. ClinicalTrial.gov number: NCT00737568.
authors.affiliation: Department of Research and Development, Gilead Sciences, Inc, Foster City, California. Electronic address: amy.corsa@gilead.com.
authors.forename: Amoreena C
authors.initials: AC
authors.lastname: Corsa
authors.affiliation: Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.affiliation: Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
authors.forename: Ben
authors.initials: B
authors.lastname: Mitchell
authors.affiliation: Divisions of Gastroenterology and General Internal Medicine, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Fung
authors.affiliation: New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.affiliation: Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D006515:Hepatitis B virus / Q000201:enzymology / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D063065:Organophosphonates / Q000627:therapeutic use*; D017354:Point Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D017422:Sequence Analysis, DNA; D000068698:Tenofovir
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D003841:Deoxycytidine; D019259:Lamivudine; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase; D000068679:Emtricitabine; D000225:Adenine
keywords: Adefovir; Entecavir; Hepatitis B Virus; Resistance