title: Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial.
abstract: OBJECTIVE
  Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV.
  
  
  METHODS
  In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=45) or TDF and ETV (1 mg/day) combination therapy (n=45) for 48 weeks.
  
  
  RESULTS
  Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log10 IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs. 73%; p>0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (-3.66 vs. -3.74 log10 IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p>0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups.
  
  
  CONCLUSIONS
  TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV.
  
  
  BACKGROUND
  ClinicalTrials.gov ID NCT01639092.
authors.affiliation: Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Byun
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Yoo
authors.affiliation: Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kwon
authors.affiliation: Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yung Sang
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000068698:Tenofovir / Q000008:administration & dosage*; D017211:Treatment Failure
chemical_list: D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir
keywords: ANTIVIRAL THERAPY; HEPATITIS B