title: A signature for immune response correlates with HCV treatment outcome in Caucasian subjects.
abstract: Broad proteomic profiling was performed on serum samples of phase 2 studies (PROVE1, PROVE2, and PROVE3) of the direct-acting antiviral drug telaprevir in combination with peg-interferon and ribavirin in subjects with HCV. Using only profiling data from subjects treated with peg-interferon and ribavirin, a signature composed of pretreatment levels of 13 components was identified that correlated well (R(2)=0.68) with subjects' underlying immune response as measured by week 4 viral decline and was highly predictive of sustained virologic response in non-African American subjects (AUC=0.99). The signature was validated by predicting in an independent cohort of non-African American subjects treated with telaprevir, peg-interferon and ribavirin (AUC=0.854). Samples from extreme responders were over-represented in these analyses. Proteins identified as differentially-expressed between responders and non-responders to HCV treatment were quantified using multiple reaction monitoring in samples from all Caucasian subjects in the peg-interferon and ribavirin arms of PROVE1 and PROVE2, revealing 15 proteins that were significantly differentially expressed between treatment responders and non-responders. Seven of the proteins are part of focal adhesions or other macromolecular assemblies that form structural links between integrins and the actin cytoskeleton and are involved in antiviral response.
  
  
  CONCLUSIONS
  HCV is a significant health problem. We describe a novel approach for identifying markers that predicts HCV treatment response different treatment regimens and use this approach to identify a novel HCV treatment response signature. The signature has potential to guide optimization of HCV treatment regimens.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hare
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Haseltine
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Fleming
authors.affiliation: Caprion Proteomics, Montreal, Quebec H2X 3Y7, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chelsky
authors.affiliation: Caprion Proteomics, Montreal, Quebec H2X 3Y7, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: McIntosh
authors.affiliation: Caprion Proteomics, Montreal, Quebec H2X 3Y7, Canada.
authors.forename: Rene
authors.initials: R
authors.lastname: Allard
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Martyn
authors.initials: M
authors.lastname: Botfield
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000998:Antiviral Agents / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism*; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D016023:Integrins / Q000097:blood*; D008297:Male; D044465:White People
chemical_list: D000998:Antiviral Agents; D016023:Integrins
keywords: Direct-acting antiviral; Focal adhesion; Proteomic profiling; Response predictor; Telaprevir