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Thromb Haemost 2014; 111(06): 1067-1076
DOI: 10.1160/TH13-11-897
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Interferon lambda 3 rs12979860 polymorphism in patients with haemophilia and HCV infection: a predictor of spontaneous viral clearance and sustained virological response

Maria Elisa Mancuso
1   Angelo Bianchi Bonomi Haemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
,
Silvia Linari
2   Haemophilia Center, A.O.U. Careggi, Florence, Italy
,
Alessio Aghemo
3   A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico and University of Milan, Milan, Italy
,
Dario Bartolozzi
4   Infectious Diseases Unit, University Hospital of Florence, Florence, Italy
,
Elena Santagostino
1   Angelo Bianchi Bonomi Haemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
,
Maria Grazia Rumi
5   Division of Hepatology, Ospedale San Giuseppe and University of Milan, Milan, Italy
,
Elisa Fognani
6   Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, and Istituto Toscano Tumori (ITT), Florence, Italy
,
Maria Rosaria Fasulo
1   Angelo Bianchi Bonomi Haemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
,
Laura Gragnani
6   Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, and Istituto Toscano Tumori (ITT), Florence, Italy
,
Raffaele Bruno
7   Department of Infectious and Tropical Diseases, Fondazione IRCCS Ospedale San Matteo and University of Pavia, Pavia, Italy
,
Massimo Morfini
2   Haemophilia Center, A.O.U. Careggi, Florence, Italy
,
Anna Linda Zignego
6   Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, and Istituto Toscano Tumori (ITT), Florence, Italy
,
Massimo Colombo
3   A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico and University of Milan, Milan, Italy
› Author Affiliations
Further Information

Publication History

Received: 03 November 2013

Accepted after minor revision: 19 February 2013

Publication Date:
21 November 2017 (online)

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Summary

Chronic hepatitis C is the main cause of morbidity and mortality in adult haemophilic patients who received non-virally inactivated plasma-derived clotting factor concentrates. Overall, spontaneous viral clearance rate is 10–25% and the only approach that can halt disease progression is hepatitis C virus (HCV) eradication by means of antiviral therapy. In non-haemophilic patients a single nucleotide polymorphism located upstream the gene of interferon lambda 3 (IFNλ3) has been associated with both spontaneous viral clearance and sustained virological response after antiviral treatment. The aim of this study was to assess whether the rs12979860 polymorphism was a predictor of spontaneous viral clearance and of sustained virological response after antiviral therapy in a large cohort of haemophilic patients with HCV infection. The rs12979860 polymorphism, defined as CC genotype or T allele, was tested in a cohort of 342 haemophilic patients and evaluated as predictor of spontaneous clearance or response to antiviral therapy. By multivariate regression analysis the IFNλ3 CC genotype was an independent predictor of spontaneous viral clearance (odds ratio: 3.7, 95% confidence interval: 2.0–6.8). Sustained virological response rates were doubled in patients with the CC genotype than in those with the T allele (78% vs 44%; p<0.001), especially in patients with HCV type 1 (67% vs 32%; p<0.001) and higher sustained response rates were observed in patients with the CC genotype who did not achieve rapid virological response (61% vs 30% in T allele patients; p=0.006).

Keywords

Haemophilia - chronic hepatitis C - interferon lambda 3 - antiviral therapy - spontaneous clearance
 

  • References

  • 1 Eyster ME, Diamondstone LS, Lien JM. et al. Natural history of hepatitis C infection in multitransfused haemophiliacs: effect of coinfection with human immunodeficiency virus. JAIDS 1993; 06: 602-610.
    PubMedGoogle Scholar
  • 2 Goedert JJ, Chen BE, Preiss L. et al. Reconstruction of the hepatitis C virus epidemic in the US haemophilia population, 1940-1990. Am J Epidemiol 2007; 165: 1443-1453.
    CrossrefPubMedGoogle Scholar
  • 3 Fried MW, Kroner BL, Preiss LR. et al. Haemophilic siblings with chronic hepatitis C: Familial aggregation of spontaneous and treatment-related viral clearance. Gastroenterology 2006; 131: 757-764.
    CrossrefPubMedGoogle Scholar
  • 4 Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology 2000; 31: 1014-1018.
    CrossrefPubMedGoogle Scholar
  • 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 Grebely J, Raffa JD, Lai C. et al. Factors associated with spontaneous clearance of hepatitis C virus among illicit drug users. Can J Gastroeneterol 2007; 21: 447-451.
    CrossrefPubMedGoogle Scholar
  • 7 Gerlach JT, Diepolder HM, Zachoval R. et al. Acute hepatitis C: high rate of both spontaneous and treatment induced viral clearance. Gastroenterology 2003; 125: 80-88.
    CrossrefPubMedGoogle Scholar
  • 8 Vogt M, Lang T, Frösner G. et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341: 866-870.
    CrossrefPubMedGoogle Scholar
  • 9 Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 1999; 340: 1228-1233.
    CrossrefPubMedGoogle Scholar
  • 10 Rumi MG, Colombo M, Gringeri A. et al. High prevalence of antibody to hepatitis C virus in multitransfused haemophiliacs with normal transaminase levels. Ann Intern Med 1990; 112: 379-380.
    CrossrefPubMedGoogle Scholar
  • 11 Brettler DB, Alter HJ, Dienstag JL. et al. Prevalence of hepatitis C virus antibody in a cohort of haemophilia patients. Blood 1990; 76: 254-256.
    CrossrefPubMedGoogle Scholar
  • 12 Darby SC, Kan SW, Spooner RJ. et al. Mortality rates, life expectancy, and causes of death in people with haemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110: 815-825.
    CrossrefPubMedGoogle Scholar
  • 13 Arnold DM, Julian JA, Walker IR. Mortality rates and causes of death among all HIV-positive individuals with haemophilia in Canada over 21 yers of follow-up. Blood 2006; 108: 460-464.
    CrossrefPubMedGoogle Scholar
  • 14 Posthouwer D, Makris M, Yee TT. et al. Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study. Blood 2007; 109: 3667-3671.
    CrossrefPubMedGoogle Scholar
  • 15 Goedert JJ for the Second Multicenter Haemophilia Cohort Study. Prevalence of conditions associated with human immunodeficiency and hepatits virus infections among persons with haemophilia, 2001-2003. Haemophilia 2005; 11: 516-528.
    CrossrefPubMedGoogle Scholar
  • 16 Backus LI, Boothroyd DB, Philips BR. et al. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 2011; 09: 509-516.
    CrossrefPubMedGoogle Scholar
  • 17 European Association of the Study of the Liver. 2011 European Association of the Study of the Liver hepatitis C virus clinical practice guidelines. iver Int 2012; 32: 2-8.
    PubMedGoogle Scholar
  • 18 Yee HS, Chang MF, Pocha C. et al. Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol 2012; 107: 669-689.
    CrossrefPubMedGoogle Scholar
  • 19 Manns MP, McHutchison JG, Gordon SC. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-965.
    CrossrefPubMedGoogle Scholar
  • 20 Fried MW, Shiffman ML, Reddy KR. et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982.
    CrossrefPubMedGoogle Scholar
  • 21 Hadziyannis SJ, Sette Jr H, Morgan TR. et al. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346-355.
    CrossrefPubMedGoogle Scholar
  • 22 McHutchison JG, Lawitz EJ, Shiffman ML. et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580-593.
    CrossrefPubMedGoogle Scholar
  • 23 Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350: 2265-2271.
    CrossrefPubMedGoogle Scholar
  • 24 Mancuso ME, Rumi MG, Santagostino E. et al. High efficacy of combined therapy with pegylated interferon plus ribavirin in patients with haemophilia and chronic hepatitis C. Haematologica 2006; 91: 1367-1371.
    PubMedGoogle Scholar
  • 25 Mancuso ME, Rumi MG, Aghaemo A. et al. Hepatitis C virus/human immunodeficiency virus coinfection in haemophiliacs: high rates of sustained virologic response to pegylated interferon and ribavirin therapy. J Thromb Haemost 2009; 07: 1997-2005.
    CrossrefPubMedGoogle Scholar
  • 26 Posthouwer D, Yee TT, Makris M. et al. Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study. J Thromb Haemost 2007; 05: 1624-1629.
    CrossrefPubMedGoogle Scholar
  • 27 Denholm JT, Wright EJ, Street A. et al. HCV treatment with pegylated interferon and ribavirin in patients with haemophilia and HIV/HCV co-infection. Haemophilia 2009; 15: 538-543.
    CrossrefPubMedGoogle Scholar
  • 28 Thomas DL, Thio CL, Martin MP. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798-801.
    CrossrefPubMedGoogle Scholar
  • 29 Ge D, Fellay J, Thompson AJ. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399-401.
    CrossrefPubMedGoogle Scholar
  • 30 Thompson AJ, Muir AJ, Sulkowski MS. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 31 Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol 2005; 79: 3851-3854.
    CrossrefPubMedGoogle Scholar
  • 32 Marcello T, Grakoul A, Barba-Spaeth G. et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology 2006; 131: 1887-1898.
    CrossrefPubMedGoogle Scholar
  • 33 Castéra L, Le Bail B, Roudot-Thoraval F. et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009; 50: 59-68.
    CrossrefPubMedGoogle Scholar
  • 34 Galmozzi E, Del Menico B, Rametta R. et al. A tetra-primer amplification refractory mutation system polymerase chain reaction for the evaluation of rs12979860 IL28B genotype. J Viral Hepat 2011; 18: 628-630.
    CrossrefPubMedGoogle Scholar
  • 35 Lindh M, Lagging M, Arnholm B. et al. IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1. J Viral Hepat 2011; 18: e325-e331.
    CrossrefPubMedGoogle Scholar
  • 36 Scherzer TM, Stättermayer AF, Strasser M. et al. Impact of IL28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with Peginterferon alpha-2a (40KD)/ribavirin. Hepatology 2011; 54: 1518-1526.
    CrossrefPubMedGoogle Scholar
  • 37 Howell CD, Gorden A, Ryan KA. et al. Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1. J Hepatol 2012; 56: 557-563.
    CrossrefPubMedGoogle Scholar
  • 38 Rauch A, Kutalik Z, Descombes P. et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138: 1338-1345.
    CrossrefPubMedGoogle Scholar
  • 39 Zhang M, Rosenberg PS, Brown DL. et al. Correlates of spontaneous clearance of hepatitis C virus among people with haemophilia. Blood 2006; 107: 892-897.
    CrossrefPubMedGoogle Scholar
  • 40 Hanley JP, Dolan G, Day S. et al. Interaction of hepatitis B and hepatitis C infection in haemophilia. Br J Haematol 1993; 85: 611-612.
    CrossrefPubMedGoogle Scholar
  • 41 Falleti E, Bitetto D, Fabris C. et al. Role of interleukin 28B rs12979860 C/T polymorphism on the histological out come of chronic hepatitis C: relationship with gender and viral genotype. J Clin Immunol 2011; 31: 891-899.
    CrossrefPubMedGoogle Scholar
  • 42 Fabris C, Falleti E, Cussigh A. et al. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC. J Hepatol 2011; 54: 716-722.
    CrossrefPubMedGoogle Scholar
  • 43 Marabita F, Aghaemo A, De Nicola S. et al. Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection. Hepatology 2011; 54: 1127-1134.
    CrossrefPubMedGoogle Scholar
  • 44 Sarrazin C, Susser S, Doehring A. et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 2011; 54: 415-421.
    CrossrefPubMedGoogle Scholar
  • 45 Di Marco V, Bronte F, Calvaruso V. et al. IL28B polymorphisms influence stage of fibrosis and spontaneous or interferon-induced viral clearance in thalassemia patients with hepatitis C virus infection. Haematologica 2012; 97: 679-686.
    CrossrefPubMedGoogle Scholar
  • 46 Neukam K, Nattermann J, Rallòn N. et al. Different distributions of hepatitis C virus genotypes among HIV-infected patients with acute and chronic hepatitis C according to interleukin-28B genotype. HIV Medicine 2011; 12: 487-493.
    CrossrefPubMedGoogle Scholar
  • 47 Aghaemo A, De Francesco R. New horizons in hepatitis C antiviral therapy with direct-acting antivirals. Hepatology 2013; 58: 428-438.
    CrossrefPubMedGoogle Scholar