title: Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir.
abstract: OBJECTIVE
  Daclatasvir and asunaprevir are NS5A and NS3 protease-targeted antivirals currently under development for treatment of chronic hepatitis C virus infection. Clinical data on baseline and on-treatment correlates of drug resistance and response to these agents are currently limited.
  
  
  METHODS
  Hepatitis C virus genotype 1b Japanese patients (prior null responders to PegIFN-α/RBV [n=21] or PegIFN-α/RBV ineligible or intolerant [n=22]) were administered daclatasvir/asunaprevir for 24 weeks during a phase 2a open-label study. Genotypic and phenotypic analyses of NS3 and NS5A substitutions were performed at baseline, after virologic failure, and post-treatment through follow-up week 36.
  
  
  RESULTS
  There were three viral breakthroughs and four relapsers. Baseline NS3 polymorphisms (T54S, Q80L, V170M) at amino acid positions previously associated with low-level resistance (<9-fold) to select NS3 protease inhibitors were detected in four null responders and three ineligibles, but were not associated with virologic failure. Baseline NS5A polymorphisms (L28M, L31M, Y93H) associated with daclatasvir resistance (<25-fold) were detected in five null responders and six ineligibles. All three viral breakthroughs and 2/4 relapsers carried a baseline NS5A-Y93H polymorphism. NS3 and NS5A resistance-associated variants were detected together (NS3-D168A/V, NS5A-L31M/V-Y93H) after virologic failure. Generally, daclatasvir-resistant substitutions persisted through 48weeks post-treatment, whereas asunaprevir-resistant substitutions were no longer detectable. Overall, 5/10 patients with baseline NS5A-Y93H experienced virologic failure, while 5/10 achieved a sustained virologic response.
  
  
  CONCLUSIONS
  The potential association of a pre-existing NS5A-Y93H polymorphism with virologic failure on daclatasvir/asunaprevir combination treatment will be examined in larger studies. The persistence of treatment-emergent daclatasvir- and asunaprevir-resistant substitutions will require assessment in longer-term follow-up studies.
authors.affiliation: Sapporo Kosei General Hospital, Sapporo, Japan.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Karino
authors.forename: Joji
authors.initials: J
authors.lastname: Toyota
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Suzuki
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Yoshiiku
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D002219:Carbamates; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005814:Genes, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007546:Isoquinolines / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D013449:Sulfonamides / Q000008:administration & dosage*; D017211:Treatment Failure; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D012367:RNA, Viral; D013449:Sulfonamides; D014633:Valine; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C571889:asunaprevir