title: Resistance Analyses of Japanese Hepatitis C-Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies.
abstract: High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ±ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.
authors.affiliation: The Research Center for Hepatitis & Immunology, National Center for Global Health and Medicine, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mizokami
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA. Hadas.Dvory-Sobol@Gilead.com.
authors.forename: H
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Musashino Red Cross Hospital, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Izumi
authors.affiliation: Hyogo College of Medicine, Hyogo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nishiguchi
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Doehle
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: De-Oertel
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Knox
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Brainard
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: H
authors.initials: H
authors.lastname: Mo
authors.affiliation: Hokkaido University, Hokkaido, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takehara
authors.affiliation: Yamanashi Prefectural Hospital Organization, Yamanashi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Omata
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D024882:Drug Resistance, Viral; D005449:Fluorenes / Q000494:pharmacology / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007564:Japan; D017422:Sequence Analysis, DNA; D000069474:Sofosbuvir / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C000595958:ledipasvir, sofosbuvir drug combination; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV genotype 1; HCV genotype 2; direct-acting antivirals; hepatitis C virus; nucleotide inhibitor