title: Virologic escape during danoprevir (ITMN-191/RG7227) monotherapy is hepatitis C virus subtype dependent and associated with R155K substitution.
abstract: Danoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log(10) reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.
authors: InterMune, Inc., Brisbane, California, USA.
authors: Sharlene R
authors: SR
authors: Lim
authors: Xiaoli
authors: X
authors: Qin
authors: Simone
authors: S
authors: Susser
authors: John B
authors: JB
authors: Nicholas
authors: Christian
authors: C
authors: Lange
authors: Eva
authors: E
authors: Herrmann
authors: Jin
authors: J
authors: Hong
authors: Ann
authors: A
authors: Arfsten
authors: Lisa
authors: L
authors: Hooi
authors: Williamson
authors: W
authors: Bradford
authors: Isabel
authors: I
authors: Nájera
authors: Patrick
authors: P
authors: Smith
authors: Stefan
authors: S
authors: Zeuzem
authors: Karl
authors: K
authors: Kossen
authors: Christophe
authors: C
authors: Sarrazin
authors: Scott D
authors: SD
authors: Seiwert
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage* / Q000627:therapeutic use; D047029:Lactams, Macrocyclic; D008958:Models, Molecular; D058889:Molecular Typing; D009154:Mutation; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000032:analysis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage* / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011392:Proline; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir