title: Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure.
abstract: OBJECTIVE
  In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen.
  
  
  METHODS
  In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks.
  
  
  RESULTS
  At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log10IU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed.
  
  
  CONCLUSIONS
  In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.
authors.affiliation: Hepatology Department, Hospices Civils de Lyon, INSERM U1052, INSERM, Lyon University, 151 Cours Albert Thomas, 69424, Lyon Cedex 03, France. fabien.zoulim@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Department of Infectious and Liver Diseases, Medical University of Lodz, Lodz, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Białkowska-Warzecha
authors.affiliation: Centre of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Mircea Mihai
authors.initials: MM
authors.lastname: Diculescu
authors.affiliation: Clinic of Gastroenterology, University of Medicine, Timisoara, Romania.
authors.forename: Adrian Eugen
authors.initials: AE
authors.lastname: Goldis
authors.affiliation: Leberzentrum Checkpoint, Berlin, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Heyne
authors.affiliation: Department of Gastroenterology and Hepatology, Jagiellonian University, Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Mach
authors.affiliation: Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, University of Paris 7, Paris, France.|INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hépatites Virales, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Division of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Simon
authors.affiliation: Bristol-Myers Squibb, Braine-I'Alleud, Belgium.
authors.forename: Soumaya
authors.initials: S
authors.lastname: Bendahmane
authors.affiliation: Bristol-Myers Squibb, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Klauck
authors.affiliation: inVentiv Health Clinical Poland, Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wasiak
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.|Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004279:DNA, Viral / Q000097:blood; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir / Q000008:administration & dosage*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir
keywords: Antiviral resistance; Multidrug failure; Partial response; Primary non-response; Rescue therapy; Virologic breakthrough