Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response.
Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients.


CONCLUSIONS
When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation.
University of North Carolina, Chapel Hill, NC 27599, USA.
Jama M
JM
Darling
Jeroen
J
Aerssens
Gregory
G
Fanning
John G
JG
McHutchison
David B
DB
Goldstein
Alexander J
AJ
Thompson
Kevin V
KV
Shianna
Nezam H
NH
Afdhal
Michael L
ML
Hudson
Charles D
CD
Howell
Willem
W
Talloen
Jacques
J
Bollekens
Mieke
M
De Wit
Annick
A
Scholliers
Michael W
MW
Fried
D000328:Adult; D001741:Black or African American / Q000235:genetics; D054357:Chemokine CXCL10 / Q000097:blood*; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D044465:White People / Q000235:genetics; D000095022:Interferon Lambda
D054357:Chemokine CXCL10; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a
Hepatology. 2010 May;51(5):1523-30
20186843
Nature. 2009 Sep 17;461(7262):399-401
19684573
Gastroenterology. 2006 Dec;131(6):1887-98
17087946
N Engl J Med. 2004 May 27;350(22):2265-71
15163776
Hepatology. 2008 Nov;48(5):1440-50
18798334
Nature. 2009 Oct 8;461(7265):798-801
19759533
Hepatology. 2006 Aug;44(2):352-9
16871572
J Infect Dis. 2006 Oct 1;194(7):895-903
16960776
Hepatology. 2007 Nov;46(5):1548-63
17929300
Gastroenterology. 2010 Aug;139(2):499-509
20434452
Ann Intern Med. 2000 Feb 15;132(4):296-305
10681285
Nat Genet. 2009 Oct;41(10):1100-4
19749758
Hepatology. 2007 Aug;46(2):350-8
17659573
Hepatology. 2007 Jan;45(1):80-7
17187406
Blood. 2005 Aug 15;106(4):1175-82
15860662
Gut. 2006 Mar;55(3):374-9
16150856
Ann Intern Med. 2004 Mar 2;140(5):346-55
14996676
Lancet. 2001 Sep 22;358(9286):958-65
11583749
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9
18467494
J Virol. 2007 Apr;81(7):3391-401
17267482
J Immunol. 1997 Jun 1;158(11):5536-44
9164978
Gastroenterology. 2010 Apr;138(4):1338-45, 1345.e1-7
20060832
J Hepatol. 2005 Sep;43(3):425-33
15990196
N Engl J Med. 2002 Sep 26;347(13):975-82
12324553
Nat Immunol. 2003 Jan;4(1):63-8
12469119
Hepatology. 2006 Dec;44(6):1617-25
17133471
J Acquir Immune Defic Syndr. 2007 Jul 1;45(3):262-8
17414926
Nat Immunol. 2003 Jan;4(1):69-77
12483210
Hepatology. 2004 Jun;39(6):1702-8
15185312
Nat Genet. 2009 Oct;41(10):1105-9
19749757
Hepatology. 2003 Sep;38(3):645-52
12939591
Gastroenterology. 2006 Aug;131(2):470-7
16890601
Genes Immun. 2007 Mar;8(2):177-80
17252004