IL-21R polymorphisms have been identified as potential predictors of virological outcomes in Western chronic hepatitis C (CHC) patients receiving interferon-based treatment. We aimed to examine the associations of IL-21R genotypes and serum IL-21 levels with virological responses to interferon-based treatment in Asian CHC patients.
Methods
Genomic and clinical data were collected from 178 consecutive Taiwanese HCV genotype 1 patients who received interferon-based therapy and 72 non-HCV healthy subjects. Among them, serum IL-21 levels, IL-21R and IL-28B genotypes were determined in 124 CHC patients and healthy controls.
Results
Among patients with IL28B rs8099917 non-TT genotypes, patients with IL-21R rs3093390 CC genotype had a higher sustained virological response rate than those with non-CC genotypes (CC versus non-CC 14/24 versus 0/4; P=0.031). Compared with non-HCV controls, CHC patients had higher serum IL-21 levels (mean ±sd HCV versus non-HCV 377.8 ±780.9 versus 70.5 ±33.2 pg/ml; P=0.001). Patients with sustained virological response had higher pretreatment serum IL-21 levels than those without (adjusted OR 0.23, 95% CI 0.07, 0.80; P=0.021).
Conclusions
CHC patients have higher serum IL-21 levels than healthy adults. Higher pretreatment serum IL-21 levels and IL-21R polymorphisms may serve as potential factors predictive of treatment outcomes in CHC patients with interferon-based therapy.
References
1.
WilliamsR.Global challenges in liver disease. Hepatology2006; 44: 521–526.
2.
StraderD.B., WrightT., ThomasD.L., SeeffL.B.Diagnosis, management, and treatment of hepatitis C. Hepatology2004; 39: 1147–1171.
3.
FriedM.W.Side effects of therapy of hepatitis C and their management. Hepatology2002; 36: S237–S244.
4.
HsuC.S., LiuC.H., LiuC.J.Factors affecting early viral load decline of Asian chronic hepatitis C patients receiving pegylated interferon plus ribavirin therapy. Antivir Ther2009; 14: 45–54.
5.
FanX., MaoQ., ZhouD.High diversity of hepatitis C viral quasispecies is associated with early virological response in patients undergoing antiviral therapy. Hepatology2009; 50: 1765–1772.
6.
HsuS.J., HsuC.S., LiuC.H.HCV core gene polymorphisms correlate with liver fibrosis but not sustained virological response in patients with genotype 1 infection. Antivir Ther2011; 16: 227–235.
7.
BergT., SarrazinC., HerrmannE.Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology2003; 37: 600–609.
8.
BackusL.I., BoothroydD.B., PhillipsB.R., MoleL.A.Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology2007; 46: 37–47.
9.
RamcharranD., WahedA.S., ConjeevaramH.S.Associations between serum lipids and hepatitis C antiviral treatment efficacy. Hepatology2010; 52: 854–863.
10.
BresslerB.L., GuindiM., TomlinsonG., HeathcoteJ.High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology2003; 38: 639–644.
11.
PersicoM., CapassoM., PersicoE.Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy. Hepatology2007; 46: 1009–1015.
12.
HeathcoteE.J., ShiffmanM.L., CooksleyW.G.Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med2000; 343: 1673–1680.
13.
PattonH.M., PatelK., BehlingC.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol2004; 40: 484–490.
14.
FriedM.W., HadziyannisS.J., ShiffmanM., MessingerD., ZeuzemS.Rapid viral response is a more important predictor of sustained virological response (SVR) than genotype in patients with chronic hepatitis C virus infection. J Hepatol2008; 48Suppl 2: 5A.
15.
National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: 2002 – June 10–12, 2002. Hepatology2002; 36Suppl 5B: S3–S20.
16.
ThomasD.L., ThioC.L., MartinM.P.Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature2009; 461: 798–801.
17.
GeD., FellayJ., ThompsonA.J.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature2009; 461: 399–401.
18.
SuppiahV., MoldovanM., AhlenstielG.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet2009; 41: 1100–1104.
19.
TanakaY., NishidaN., SugiyamaM.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet2009; 41: 1105–1109.
20.
O'BrienT.R.Interferon-alfa, interferon-lambda and hepatitis C. Nat Genet2009; 41: 1048–1050.
21.
HsuC.S., HsuS.J., ChenH.C.Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy. Proc Natl Acad Sci USA2011; 108: 3719–3724.
22.
ElsaesserH., SauerK., BrooksD.G.IL-21 is required to control chronic viral infection. Science2009; 324: 1569–1572.
23.
YiJ.S., DuM., ZajacA.J.A vital role for interleukin-21 in the control of a chronic viral infection. Science2009; 324: 1572–1576.
24.
FröhlichA., KisielowJ., SchmitzI.IL-21R on T-cells is critical for sustained functionality and control of chronic viral infection. Science2009; 324: 1576–1580.
25.
MaS.W., HuangX., LiY.Y.High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. J Hepatol2012; 56: 775–781.
26.
NaggieS., OsinusiA., KatsounasA.Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response. Hepatology2012; 56: 444–454.
27.
GhanyM.G., StraderD.B., ThomasD.L., SeeffL.B.Diagnosis, management, and treatment of hepatitis C: an update. Hepatology2009; 49: 1335–1374.
28.
KimH.C., NamC.M., JeeS.H., HanK.H., OhD.K., SuhI.Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ2004; 328: 983.
29.
PratiD., ShiffmanM.L., DiagoM.Viral and metabolic factors influencing alanine aminotransferase activity in patients with chronic hepatitis C. J Hepatol2006; 44: 679–685.
30.
HsuC.S., LiuC.J., LiuC.H.High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C. Liver Int2008; 28: 271–277.
31.
YehS.H., TsaiC.Y., KaoJ.H.Quantification and genotyping of hepatitis B virus in a single reaction by realtime PCR and melting curve analysis. J Hepatol2004; 41: 659–666.
32.
HsuC.S., LiuC.J., LaiM.Y., ChenP.J., KaoJ.H., ChenD.S.Early viral kinetics during treatment of chronic hepatitis C virus infection with pegylated interferon alpha plus ribavirin in Taiwan. Intervirology2007; 50: 310–315.
33.
KaoJ.H., LinH.H., ChenP.J.Serotyping of hepatitis C virus in chronic type C hepatitis in Taiwan: correlation with genotypes. J Gastroenterol1996; 31: 224–227.
34.
OhnoO., MizokamiM., WuR.R.New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol1997; 35: 201–207.
35.
LaggingM., RomeroA.I., WestinJ.IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology2006; 44: 1617–1625.
36.
AskariehG., AlsioA., PugnaleP.Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C. Hepatology2010; 51: 1523–1530.
37.
BassoM., GianniniE.G., TorreF., BlanchiS., SavarinoV., PicciottoA.Elevations in alanine aminotransferase levels late in the course of antiviral therapy in hepatitis C virus RNA-negative patients are associated with virological relapse. Hepatology2009; 49: 1442–1448.
