About 180 million people worldwide are chronically infected with hepatitis C virus (HCV), with 3-4 million newly infected each year. Only 15-25% of acute HCV infections clear spontaneously, and the remainder persists as chronic HCV infection. More than 350,000 people die every year from hepatitis C-related liver failure and cancer. There is currently no vaccine and the standard-of-care therapies - peg-interferon alpha (pegIFN) plus ribavirin (RBV) - are expensive and have serious side effects. Also, they may be effective in only 40-50% of patients infected with HCV genotype 1, the most common HCV genotype in the US. Interleukin 28B (IL28B) genotype was recently and convincingly associated with response to pegIFN and RBV therapy. It has emerged as a robust pretreatment predictor of sustained virological response (SVR, i.e. virologic clearance) to pegIFN and RBV as well as to new triple therapy regimens that include a direct-acting antiviral agent with pegIFN and RBV and increase SVR rates as much as 75% in patients infected with HCV genotype 1. Testing for IL28B genotype may contribute to clinical decision-making and could inform clinical guidelines and public health policies.

Keywords:
Hepatitis C, Host genetic predisposition to disease, IL28B polymorphism, Interferon response
1.
Lavanchy D: The global burden of hepatitis C. Liver Int 2009;29(suppl 1):74-81.
2.
Wise M, Bialek S, Finelli L, Bell BP, Sorvillo F: Changing trends in hepatitis C-related mortality in the United States, 1995-2004. Hepatology 2008;47:1128-1135.
3.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD: The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156:271-278.
4.
Klevens RM, Hu DJ, Jiles R, Holmberg SD: Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis 2012;55 (suppl 1):S3-9.
5.
Spradling PR, Richardson JT, Buchacz K, Moorman AC, Finelli L, Bell BP, Brooks JT; Investigators HIVOS: Trends in hepatitis C virus infection among patients in the HIV outpatient study, 1996-2007. J Acquir Immune Defic Syndr 2010;53:388-396.
6.
Wong JB, McQuillan GM, McHutchison JG, Poynard T: Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 2000;90:1562-1569.
7.
Davis KL, Mitra D, Medjedovic J, Beam C, Rustgi V: Direct economic burden of chronic hepatitis C virus in a United States managed care population. J Clin Gastroenterol 2011;45:e17-24.
8.
Seeff LB: Natural history of chronic hepatitis C. Hepatology 2002;36(5 suppl 1):S35-S46.
9.
Kato N: Genome of human hepatitis C virus (HCV): gene organization, sequence diversity, and variation. Microb Comp Genomics 2000;5:129-151.
10.
Simmonds P, Bukh J, Combet C, Deleage G, Enomoto N, Feinstone S, Halfon P, Inchauspe G, Kuiken C, Maertens G, Mizokami M, Murphy DG, Okamoto H, Pawlotsky JM, Penin F, Sablon E, Shin IT, Stuyver LJ, Thiel HJ, Viazov S, Weiner AJ, Widell A: Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005;42:962-973.
11.
Chayama K, Hayes CN: Hepatitis C virus: how genetic variability affects pathobiology of disease. J Gastroenterol Hepatol 2011;26 (suppl 1):83-95.
12.
Feld JJ, Hoofnagle JH: Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005;436:967-972.
13.
Chen HM, Tanaka N, Mitani Y, Oda E, Nozawa H, Chen JZ, Yanai H, Negishi H, Choi MK, Iwasaki T, Yamamoto H, Taniguchi T, Takaoka A: Critical role for constitutive type I interferon signaling in the prevention of cellular transformation. Cancer Sci 2009;100:449-456.
14.
Gale M Jr, Foy EM: Evasion of intracellular host defence by hepatitis C virus. Nature 2005;436:939-945.
15.
Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for Study of Liver Diseases: an update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433-1444.
16.
McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS; IDEAL Study Team: Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-593.
17.
Howell CD, Dowling TC, Paul M, Wahed AS, Terrault NA, Taylor M, Jeffers L, Hoofnagle JH; Virahep-C Study Group: Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 2008;6:575-583.
18.
Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S; PROVE2 Study Team: Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839-1850.
19.
Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators: Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206.
20.
Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team: Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-2416.
21.
Kau A, Vermehren J, Sarrazin C: Treatment predictors of a sustained virologic response in hepatitis B and C. J Hepatol 2008;49:634-651.
22.
Thompson AJ: Genetic factors and hepatitis C virus infection. Gastroenterology 2012;142:1335-1339.
23.
Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB: Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399-401.
24.
Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M: Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105-1109.
25.
Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Gunthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Mullhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY; Swiss Hepatitis C Cohort Study; Swiss HIV Cohort Study: Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010;138:1338-1345, 1345 e1-7.
26.
Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Muller T, Bahlo M, Stewart GJ, Booth DR, George J: IL28B is associated with response to chronic hepatitis c interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100-1104.
27.
Li S, Hu P, Zhang QQ, Liu YH, Hu HD, Zhang DZ, Ren H: Single nucleotide polymorphisms of the IL28B and sustained virologic response of patients with chronic hepatitis C to PEG-interferon/ribavirin therapy: a meta-analysis: meta-analysis of IL28B. Hepat Mon 2011;11:163-172.
28.
Rangnekar AS, Fontana RJ: Meta-analysis: IL28B genotype and sustained viral clearance in HCV genotype 1 patients. Aliment Pharmacol Ther 2012;36:104-114.
29.
Chen Y, Xu HX, Wang LJ, Liu XX, Mahato RI, Zhao YR: Meta-analysis: IL28B polymorphisms predict sustained viral response in HCV patients treated with pegylated interferon-alpha and ribavirin. Aliment Pharmacol Ther 2012;36:91-103.
30.
Jiménez-Sousa MA, Fernández-Rodríguez A, Guzmán-Fulgencio M, García-Álvarez M, Resino S: Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C. BMC Med 2013;11:6.
31.
Lai M, Afdhal NH: Clinical utility of interleukin-28B testing in patients with genotype 1. Hepatology 2012;56:367-372.
32.
Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798-801.
33.
Tillmann HL, Thompson AJ, Patel K, Wiese M, Tenckhoff H, Nischalke HD, Lokhnygina Y, Kullig U, Göbel U, Capka E, Wiegand J, Schiefke I, Güthoff W, Grüngreiff K, König I, Spengler U, McCarthy J, Shianna KV, Goldstein DB, McHutchison JG, Timm J, Nattermann J; German Anti-D Study Group: A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology 2010;139:1586-1592, 1592 e1.
34.
Zheng MH, Li Y, Xiao DD, Shi KQ, Fan YC, Chen LL, Liu WY, Luo YW, Chen YP: Interleukin-28B rs12979860C/T and rs8099917T/G contribute to spontaneous clearance of hepatitis C virus in Caucasians. Gene 2013;518:479-482.
35.
Rallón NI, Soriano V, Naggie S, Restrepo C, Goldstein D, Vispo E, McHutchison J, Benito JM: IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin. AIDS 2011;25:1025-1033.
36.
Sajadi MM, Shakeri N, Talwani R, Howell CD, Pakyz R, Redfield RR, Parsa A: IL28B genotype does not correlate with HIV control in African Americans. Clin Transl Sci 2011;4:282-284.
37.
Salgado M, Kirk GD, Cox A, Rutebemberwa A, Higgins Y, Astemborski J, Thomas DL, Thio CL, Sulkowski MS, Blankson JN: Protective interleukin-28B genotype affects hepatitis C virus clearance, but does not contribute to HIV-1 control in a cohort of African-American elite controllers/suppressors. AIDS 2011;25:385-387.
38.
Martin MP, Qi Y, Goedert JJ, Hussain SK, Kirk GD, Hoots WK, Buchbinder S, Carrington M, Thio CL: IL28B polymorphism does not determine outcomes of hepatitis B virus or HIV infection. J Infect Dis 2010;202:1749-1753.
39.
O'Brien TR: Interferon-alfa, interferon-lambda and hepatitis C. Nat Genet 2009;41:1048-1050.
40.
Muir AJ, Shiffman ML, Zaman A, Yoffe B, de la Torre A, Flamm S, Gordon SC, Marotta P, Vierling JM, Lopez-Talavera JC, Byrnes-Blake K, Fontana D, Freeman J, Gray T, Hausman D, Hunder NN, Lawitz E: Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology 2010;52:822-832.
41.
Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, Urban T, Afdhal NH, Jacobson IM, Esteban R, Poordad F, Lawitz EJ, McCone J, Shiffman ML, Galler GW, Lee WM, Reindollar R, King JW, Kwo PY, Ghalib RH, Freilich B, Nyberg LM, Zeuzem S, Poynard T, Vock DM, Pieper KS, Patel K, Tillmann HL, Noviello S, Koury K, Pedicone LD, Brass CA, Albrecht JK, Goldstein DB, McHutchison JG: Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010;139:120-129 e18.
42.
Hsu CS, Hsu SJ, Chen HC, Tseng TC, Liu CH, Niu WF, Jeng J, Liu CJ, Lai MY, Chen PJ, Kao JH, Chen DS: 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 USA 2011;108:3719-3724.
43.
Clark PJ, Thompson AJ: Host genomics and HCV treatment response. J Gastroenterol Hepatol 2012;27:212-222.
44.
Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, Toyota J, Nakamura Y, Kamatani N, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H: IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis 2011;204:84-93.
45.
Thompson AJ, McHutchison JG: Will IL28B polymorphism remain relevant in the era of direct acting antiviral agents for HCV? Hepatology 2012;56:373-381.
46.
Smith BD, Morgan RL, Beckett GA, Falck- Ytter Y, Holtzman D, Teo CG, Jewett A, Baack B, Rein DB, Patel N, Alter M, Yartel A, Ward JW; Centers for Disease Control and Prevention: Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep 2012;61:1-32.
47.
Smith BD, Morgan RL, Beckett GA, Falck- Ytter Y, Holtzman D, Ward JW: Hepatitis C virus testing of persons born during 1945-1965: Recommendations from the centers for disease control and prevention. Ann Intern Med 2012;157:817-822.
48.
US Department of Health and Human-Services: Combating the silent epidemic of viral hepatitis: action plan for the prevention, care and treatment of viral hepatitis. 2011. http://www.liver.stanford.edu/resources/HHSactionplanintro.pdf.
49.
Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD: New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis. Ann Intern Med 2012;156:279-290.
50.
Gao X, Stephens JM, Carter JA, Haider S, Rustgi VK: Impact of adverse events on costs and quality of life in protease inhibitor-based combination therapy for hepatitis C. Expert Rev Pharmacoecon Outcome Res 2012;12:335-343.
51.
Lewden C, Salmon D, Morlat P, Bévilacqua S, Jougla E, Bonnet F, Héripret L, Costagliola D, May T, Chêne G; Mortality 2000 Study Group: Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol 2005;34:121-130.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.