title: Danoprevir monotherapy decreases inflammatory markers in patients with chronic hepatitis C virus infection.
abstract: Danoprevir is a potent and selective direct-acting antiviral agent that targets the protease activity of hepatitis C virus (HCV) NS3/4A. This agent results in a significant rapid decline in HCV RNA levels when it is used in monotherapy. The present study evaluated whether plasma concentrations of the inflammatory markers gamma interferon-inducible protein 10 (IP-10) and neopterin or the interferon-stimulated gene product 2'-5'-oligoadenylate synthetase (OAS-1) were correlated with the plasma HCV RNA concentration before or during 14-day danoprevir monotherapy. In contrast to pegylated interferon and ribavirin treatment, a higher baseline IP-10 concentration was positively correlated with a greater first-phase HCV RNA decline upon danoprevir administration. Changes in the IP-10 plasma concentration during danoprevir administration were also associated with categorical changes in HCV RNA concentration at days 7 and 14. The neopterin concentration appeared to be moderately decreased during danoprevir administration, although these changes were not statistically significant. However, changes in neopterin concentration showed a statistically significant correlation with changes in IP-10 concentration. Considerable variation in the OAS-1 concentration was observed before and during treatment, including in patients treated with placebo and/or patients with minimal virologic response. Overall, these results suggest that effective treatment with a direct-acting antiviral agent may reduce hepatic inflammation and that first-phase HCV RNA decline during treatment with an NS3/4A protease inhibitor is more robust in patients with high baseline IP-10 concentrations.
authors.affiliation: InterMune, Inc, Brisbane, California 94005, USA.
authors.forename: Caralee J
authors.initials: CJ
authors.lastname: Schaefer
authors.forename: Karl
authors.initials: K
authors.lastname: Kossen
authors.forename: Sharlene R
authors.initials: SR
authors.lastname: Lim
authors.forename: Jiing-Huey
authors.initials: JH
authors.lastname: Lin
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Williamson
authors.initials: W
authors.lastname: Bradford
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Scott D
authors.initials: SD
authors.lastname: Seiwert
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D054357:Chemokine CXCL10 / Q000097:blood; D003521:Cyclopropanes; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D054833:Isoindoles; D007769:Lactams / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D019798:Neopterin / Q000097:blood; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000097:blood; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D013449:Sulfonamides; D019798:Neopterin; C553752:danoprevir; D011392:Proline; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase