title: Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
abstract: BACKGROUND
  Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase.
  
  
  METHODS
  In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations.
  
  
  RESULTS
  At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies.
  
  
  CONCLUSIONS
  Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)
authors.affiliation: Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, University of Paris 7 and INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hepatites Virales, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: E Jenny
authors.initials: EJ
authors.lastname: Heathcote
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.forename: Ed
authors.initials: E
authors.lastname: Gane
authors.forename: Robert A
authors.initials: RA
authors.lastname: de Man
authors.forename: Zahary
authors.initials: Z
authors.lastname: Krastev
authors.forename: George
authors.initials: G
authors.lastname: Germanidis
authors.forename: Sam S
authors.initials: SS
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Flisiak
authors.forename: Kelly
authors.initials: K
authors.lastname: Kaita
authors.forename: Michael
authors.initials: M
authors.lastname: Manns
authors.forename: Iskren
authors.initials: I
authors.lastname: Kotzev
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tchernev
authors.forename: Peter
authors.initials: P
authors.lastname: Buggisch
authors.forename: Frank
authors.initials: F
authors.lastname: Weilert
authors.forename: Oya Ovung
authors.initials: OO
authors.lastname: Kurdas
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Shiffman
authors.forename: Huy
authors.initials: H
authors.lastname: Trinh
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Jeff
authors.initials: J
authors.lastname: Sorbel
authors.forename: Jane
authors.initials: J
authors.lastname: Anderson
authors.forename: Andrea
authors.initials: A
authors.lastname: Snow-Lampart
authors.forename: Elsa
authors.initials: E
authors.lastname: Mondou
authors.forename: Joe
authors.initials: J
authors.lastname: Quinn
authors.forename: Franck
authors.initials: F
authors.lastname: Rousseau
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068698:Tenofovir; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; D000068698:Tenofovir; D000410:Alanine Transaminase; D000225:Adenine; C106812:adefovir dipivoxil