High MIG (CXCL9) plasma levels favours response to peginterferon and ribavirin in HCV-infected patients regardless of DPP4 activity.
OBJECTIVE
Sustained virological response (SVR) following peginterferon (pegIFN) and ribavirin (RBV) treatment in hepatitis C virus (HCV)-infected patients has been linked with the IL28B genotype and lower peripheral levels of the CXCR3-binding chemokine IP-10 (CXCL10). To further improve the understanding of these biomarkers we investigated plasma levels of the other CXCR3-binding chemokines and activity of the dipeptidyl peptidase IV (DPP4, CD26) protease, which cleaves IP-10, in relation to treatment response.


METHODS
African-American and Caucasian HCV genotype 1-infected patients (n = 401) were treated with pegIFN/RBV for 48 weeks (ViraHep-C cohort). Pretreatment plasma levels of MIG (CXCL9), I-TAC (CXCL11) and the type III interferon IL29 were investigated by Luminex and DPP4 activity by using a luciferase assay.


RESULTS
Patients achieving SVR had higher baseline MIG plasma levels and lower DPP4 activity than non-SVR patients. MIG was higher in Caucasians, IL28B CC (rs1297860) genotype carriers and patients with higher ALT levels. MIG correlated with IP-10 in SVR patients, but not in non-SVRs. A high DPP4 activity correlated with higher IP-10 levels, while DPP4 activity was not associated with MIG or I-TAC levels.


CONCLUSIONS
The associations of MIG with SVR status and IL28B genotype imply that higher MIG plasma levels could reflect a beneficial immunological state for response to pegIFN/RBV treatment. The correlation between MIG and IP-10 observed only in SVR patients may contribute to a better treatment response, whereas this MIG/IP-10 balance might be disrupted in non-SVR patients because of the increased DPP4 cleavage of IP-10 into a dysfunctional form.
Janssen Research and Development, Beerse, Belgium.
Susanne
http://orcid.org/0000-0002-0073-6355
S
Johansson
Janssen Research and Development, Beerse, Belgium.
Willem
W
Talloen
Janssen Research and Development, Beerse, Belgium.
Marianne
M
Tuefferd
University of North Carolina, Chapel Hill, NC, USA.
Jama
J
Darling
Janssen Research and Development, Beerse, Belgium.
Gregory
G
Fanning
University of North Carolina, Chapel Hill, NC, USA.
Michael W
MW
Fried
Janssen Research and Development, Beerse, Belgium.
Jeroen
J
Aerssens
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D054370:Chemokine CXCL9 / Q000097:blood*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006526:Hepatitis C / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007372:Interferons; D016753:Interleukin-10 / Q000097:blood; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D015854:Up-Regulation; D044465:White People / Q000235:genetics; D055815:Young Adult; D000095022:Interferon Lambda
D000998:Antiviral Agents; D015415:Biomarkers; D054370:Chemokine CXCL9; D018819:Dipeptidyl Peptidase 4; D016898:Interferon-alpha; D007372:Interferons; D016753:Interleukin-10; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C080810:CXCL9 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C508609:IL10 protein, human; C042807:DPP4 protein, human; C100416:peginterferon alfa-2a
DPP4; HCV; IP-10; Interferon; MIG