Journal of Gastroenterology

, Volume 45, Issue 9, pp 903–910 | Cite as

IL28B in hepatitis C virus infection: translating pharmacogenomics into clinical practice

  • Golo Ahlenstiel
  • David R. Booth
  • Jacob GeorgeEmail author


Three landmark genome-wide association studies (GWAS) published in 2009 identified the interleukin (IL) 28B gene locus as pivotal to the pathogenesis of hepatitis C virus (HCV) infection. Polymorphisms near the IL28B gene not only predicted treatment-induced and spontaneous recovery from HCV infection, but they also explained, to some extent, the difference in response rates between Caucasians and African Americans to standard therapy with pegylated interferon and ribavirin. The revelation that IL28B, an innate cytokine, plays an essential role in the pathogenesis, outcomes, and treatment responses to HCV infection has triggered a gold rush and an ever increasing number of reports on the subject are being presented at international conferences and in scientific journals. This review will summarize currently available data on the clinical impact of IL28B polymorphisms on HCV infection and the potential mechanisms for its effects. It will conclude with a discussion on how the research observations may translate into clinical practice and drug development.


HCV IL28B Interferon-α GWAS Treatment 



Alanine aminotransferase


Gamma glutamyltransferase


Hepatitis C virus




Sustained virological response



Work on this review was in part supported by research grants from the National Health and Medical Research Council of Australia and by an Australian ARC linkage grant. J.G. is supported by the Robert W. Storr bequest to the University of Sydney Medical Foundation.

Conflict of interest statement

The authors have filed a provisional patent application on the genetic variants described in this paper.


  1. 1.
    Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.CrossRefPubMedGoogle Scholar
  2. 2.
    Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.CrossRefPubMedGoogle Scholar
  4. 4.
    WHO. Hepatitis C. Fact Sheet No. 164. Revised October 2000. (2000).
  5. 5.
    Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006;13:34–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Burra P. Hepatitis C. Semin Liver Dis. 2009;29:53–65.CrossRefPubMedGoogle Scholar
  8. 8.
    Australia and New Zealand Liver Transplant Registry ebSVL, G.A. Balderson. ANZLT Registry Report 2008, Brisbane, Queensland, Australia, 2008.Google Scholar
  9. 9.
    NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements 2002;19:1–46.Google Scholar
  10. 10.
    Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338–45, 1345.e1–7.Google Scholar
  12. 12.
    Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, et al. IL28B polymorphism improves viral kinetics and is the strongest pre-treatment predictor of SVR in HCV-1 patients. Gastroenterology. 2010;in press.Google Scholar
  13. 13.
    McCarthy JJ, Li JH, Thompson A, Suchindran S, Lao XQ, Patel K, et al. Replicated association between an interleukin-28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology. 2010;138:2307–14.CrossRefPubMedGoogle Scholar
  14. 14.
    Montes-Cano MA, García-Lozano JR, Abad-Molina C, Romero-Gómez M, Barroso N, Aguilar-Reina J, et al. IL28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology. 2010;52:33–7.Google Scholar
  15. 15.
    Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, et al. Amino acid substitution in HCV core region and genetic variation near IL28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;in press.Google Scholar
  16. 16.
    Rallon NI, Naggie S, Benito JM, Medrano J, Restrepo C, Goldstein D, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS. 2010;24:F23–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Nischalke HD, Vogel M, Michalk M, Mauss S, Baumgarten A, Naumann U, et al. Genetic variation in IL28B rs 12979860 and response to HCV-specific treatment in HIV/HIV co-infected patients. J Hepatol. 2010;52:S453.CrossRefGoogle Scholar
  18. 18.
    Abe H, Hayes CN, Ochi H, Maekawa T, Tsuge M, Miki D, et al. Common variation of IL28 affects gamma-GTP levels and inflammation of the liver in chronically hepatitis C virus infected patients. J Hepatol. 2010;52:S449.Google Scholar
  19. 19.
    Li JH, Qian Lao X, Tillmann HL, Rowell J, Patel K, Thompson A, et al. Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection. Hepatology. 2010;51:1904–11.PubMedGoogle Scholar
  20. 20.
    Eurich D, Boas-Knoop S, Ruehl M, Schulz M, Carrillo ED, Bahra M, et al. IL-28B gene polymorphism influences histological and biochemical severity of graft hepatitis after liver transplantation for HCV-induced liver disease. J Hepatol. 2010;52:S450.CrossRefGoogle Scholar
  21. 21.
    Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801.CrossRefPubMedGoogle Scholar
  22. 22.
    Mangia A, Santoro R, Mottola L, Piazzolla V, Bacca D, Sarli R, et al. IL28B C/C polymorphism is predictive of spontaneous HCV RNA clearance in patients with thalassemia major. J Hepatol. 2010;52:S452.CrossRefGoogle Scholar
  23. 23.
    Matsuura K, Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Izumi N, et al. Identification of genetic variants of the IL28B associated with spontaneous clearance of hepatitis C virus in Japanese population. J Hepatol. 2010;52:S452.CrossRefGoogle Scholar
  24. 24.
    Li M, Liu X, Zhou Y, Su SB. Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses. J Leukoc Biol. 2009;86:23–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77.CrossRefPubMedGoogle Scholar
  26. 26.
    Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Siren J, Pirhonen J, Julkunen I, Matikainen S. IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol. 2005;174:1932–7.PubMedGoogle Scholar
  28. 28.
    Witte K, Gruetz G, Volk HD, Looman AC, Asadullah K, Sterry W, et al. Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines. Genes Immun. 2009;10:702–14.CrossRefPubMedGoogle Scholar
  29. 29.
    Goodbourn S, Didcock L, Randall RE. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol. 2000;81:2341–64.PubMedGoogle Scholar
  30. 30.
    Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC. Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling. J Biol Chem. 2004;279:32269–74.CrossRefPubMedGoogle Scholar
  31. 31.
    Doyle SE, Schreckhise H, Khuu-Duong K, Henderson K, Rosler R, Storey H, et al. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 2006;44:896–906.CrossRefPubMedGoogle Scholar
  32. 32.
    Maher SG, Sheikh F, Scarzello AJ, Romero-Weaver AL, Baker DP, Donnelly RP, et al. IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther. 2008;7:1109–15.PubMedGoogle Scholar
  33. 33.
    Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, MacDonald MR, et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006;131:1887–98.CrossRefPubMedGoogle Scholar
  34. 34.
    Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Mihm S, Frese M, Meier V, Wietzke-Braun P, Scharf JG, Bartenschlager R, et al. Interferon type I gene expression in chronic hepatitis C. Lab Invest. 2004;84:1148–59.CrossRefPubMedGoogle Scholar
  36. 36.
    Honda M, Sakai A, Yamashita T, Nakamoto E, Sakai Y, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in IL28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology. 2010;in press.Google Scholar
  37. 37.
    Abe H, Hayes CN, Ochi H, Maekawa T, Tsuge M, Miki D, et al. Common variation of IL28 affects intrahepatic expression of interferon stimulated genesis and correlates with effect of peg-interferon and ribavirin combination therapy. J Hepatol. 2010;52:S449.Google Scholar
  38. 38.
    Chen L, Borozan I, Feld J, Sun J, Tannis LL, Coltescu C, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology. 2005;128:1437–44.CrossRefPubMedGoogle Scholar
  39. 39.
    Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology. 2007;46:1548–63.CrossRefPubMedGoogle Scholar
  40. 40.
    Ank N, Iversen MB, Bartholdy C, Staeheli P, Hartmann R, Jensen UB, et al. An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol. 2008;180:2474–85.PubMedGoogle Scholar
  41. 41.
    Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med. 2006;12:1023–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Freeman JA, Zhang T, Holdren MS, Hausman DF. Peg-interferon lambda (PEG-IL-29): translation of in vitro preclinical data to clinical results. J Hepatol. 2008;48:S294.CrossRefGoogle Scholar
  43. 43.
    Dodds MG, Hausman DF, Miller DM. Viral kinetic modeling during treatment with interferon lambda-1a in genotype 1 chronic hepatitis C patients. J Hepatol. 2009;50:S342.CrossRefGoogle Scholar
  44. 44.
    Shiffman M, Lawitz E, Zaman A, Vierling J, Yoffe B, Freeman J, et al. PEG-IFN-l: antiviral activity and safety profile in a 4-week phase 1b study in relapsed genotype 1 hepatitis C infection. J Hepatol. 2009;50:S237.CrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Golo Ahlenstiel
    • 1
  • David R. Booth
    • 2
  • Jacob George
    • 1
    Email author
  1. 1.Storr Liver Unit, Westmead Millennium Institute, Westmead HospitalUniversity of SydneyWestmeadAustralia
  2. 2.Institute for Immunology and Allergy Research, Westmead Millennium Institute, Westmead HospitalUniversity of SydneySydneyAustralia

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