title: No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment.
abstract: A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Corsa
authors.affiliation: Hospital General Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Buti
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Cathcart
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Flaherty
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Kitrinos
authors.affiliation: Hôpital Beaujon, University Paris-Diderot, Clichy, France.
authors.forename: P
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: Auckland City Hospital, Auckland, New Zealand.
authors.forename: E J
authors.initials: EJ
authors.lastname: Gane
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D009154:Mutation; D063065:Organophosphonates / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D000068698:Tenofovir / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; C106812:adefovir dipivoxil
keywords: chronic hepatitis B; hepatitis B virus; resistance; tenofovir; tenofovir disoproxil fumarate; viread