Virologic escape during danoprevir (ITMN-191/RG7227) monotherapy is hepatitis C virus subtype dependent and associated with R155K substitution.

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.