Digestive Diseases and Sciences

, Volume 56, Issue 6, pp 1853–1861 | Cite as

Eradication of Hepatitis C Virus Reduces the Risk of Hepatocellular Carcinoma in Patients with Compensated Cirrhosis

  • José Velosa
  • Fátima Serejo
  • Rui Marinho
  • Joana Nunes
  • Helena Glória
Original Article



The effect of a sustained virological response (SVR) to interferon (IFN) on clinical outcomes of hepatitis C virus (HCV)–related cirrhosis is controversial. Aims: Evaluate the effect of SVR to IFN on the incidence of hepatocellular carcinoma (HCC) and mortality in patients with compensated HCV-induced cirrhosis.


A cohort of 130 consecutive patients (92 men, mean age 51.7 years) with histologically proven cirrhosis who received one or more courses of IFN monotherapy or combination therapy with ribavirin were analyzed. SVR was defined as undetectable serum HCV RNA by real-time polymerase chain reaction (PCR) 24 weeks after IFN discontinuation. HCC was assessed by alfa-fetoprotein and ultrasound every 6 months. Predictors of clinical outcomes, defined as HCC, orthotopic liver transplantation (OLT) and mortality, were assessed by Cox regression analysis.


The mean follow-up was 6.4 ± 4.0 years (range 1–18). HCC developed in 21 patients: one with SVR versus 20 with non-SVR (P = 0.017). Logistic regression analysis showed that non-SVR (odds ratio [OR] = 27.0; confidence interval [CI], 1.6–452.1), male (OR = 11.6; CI, 1.8–75.4), and greater number of treatments (OR = 4.7; CI, 1.4–16.0) increased the probability of HCC development. Multivariate analysis found that SVR was associated with lower risk of HCC (HR 0.09; CI, 0.01–0.77), OLT (HR 0.04; CI, 0.003–0.63) and any event (HR 0.11; CI, 0.02–0.46) as compared to non-SVR.


In compensated HCV-related cirrhosis, SVR markedly reduces the risk of HCC and improves survival. Clearance of the virus should be intensively attempted in these patients.


Hepatitis C virus Cirrhosis Interferon Sustained virological response Hepatocellular carcinoma Mortality 



Hepatocellular carcinoma


Hepatitis B virus


Hepatitis C virus




Ribonucleic acid


Sustained virological response



We would like to thank Dr. Carlos Ferreira for his inestimable technical assistance in the preparation of the manuscript.

Potential financial conflicts of interest

Consultancies: J. Velosa (Roche, Gilead, Bristol-Myers Squibb), F. Serejo (Schering-Plough), R. Marinho (Roche, Gilead, Bristol-Myers Squibb).


  1. 1.
    Zaman SN, Melia WM, Johnson RD, et al. Risk factors in development of hepatocellular carcinoma in cirrhosis: Prospective study of 613 patients. Lancet. 1985;1:1357–1360.PubMedCrossRefGoogle Scholar
  2. 2.
    Colombo M, de Franchis R, Del Ninno E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med. 1991;325:675–680.PubMedCrossRefGoogle Scholar
  3. 3.
    Simonetti RS, Cammà C, Fiorello F, et al. Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis. A case–control study. Ann Intern Med. 1992;116:97–102.PubMedGoogle Scholar
  4. 4.
    Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: A cohort study of 297 patients. Am J Gastroenterol. 2002;97:2886–2895.PubMedCrossRefGoogle Scholar
  5. 5.
    Benvegnù L, Gios M, Boccato S, et al. Natural history of compensated viral cirrhosis: A prospective study on the incidence and hierarchy of major complications. Gut. 2004;53:744–749.PubMedCrossRefGoogle Scholar
  6. 6.
    Sangiovanni A, Prati GM, Fasani P, et al. The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients. Hepatology. 2006;43:1303–1310.PubMedCrossRefGoogle Scholar
  7. 7.
    Yu ML, Lin SM, Chuang WL, et al. A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: A nationwide, multicentre study in Taiwan. Antivir Ther. 2006;11:985–994.PubMedGoogle Scholar
  8. 8.
    Okanoue T, Itoh Y, Minami M, et al. Interferon therapy lowers the rate of progression to hepatocellular carcinoma in chronic hepatitis C but not significantly in an advanced stage: A retrospective study in 1148 patients. Viral Hepatitis Therapy Study Group. J Hepatol. 1999;30:653–659.PubMedCrossRefGoogle Scholar
  9. 9.
    Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med. 1999;131:174–181.PubMedGoogle Scholar
  10. 10.
    Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: Association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med. 2005;142:105–114.PubMedGoogle Scholar
  11. 11.
    Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–472.PubMedCrossRefGoogle Scholar
  12. 12.
    Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677–684.PubMedGoogle Scholar
  13. 13.
    Degos F, Christidis C, Ganne-Carrie N, et al. Hepatitis C virus related cirrhosis: Time to occurrence of hepatocellular carcinoma and death. Gut. 2000;47:131–136.PubMedCrossRefGoogle Scholar
  14. 14.
    Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology. 2004;127:S35–S50.PubMedCrossRefGoogle Scholar
  15. 15.
    Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;346:1051–1055.PubMedCrossRefGoogle Scholar
  16. 16.
    Mazzella G, Accogli E, Sottili S, et al. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J Hepatol. 1996;24:141–147.PubMedCrossRefGoogle Scholar
  17. 17.
    Fattovich G, Giustina G, Degos F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol. 1997;27:201–205.PubMedCrossRefGoogle Scholar
  18. 18.
    Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: A retrospective study. Hepatology. 2007;45:579–587.PubMedCrossRefGoogle Scholar
  19. 19.
    Ikeda M, Fujiyama S, Tanaka M, et al. Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C after sustained response to interferon. J Gastroenterol. 2005;40:148–156.PubMedCrossRefGoogle Scholar
  20. 20.
    Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: The relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med. 2008;149:399–403.PubMedGoogle Scholar
  21. 21.
    Valla DC, Chevallier M, Marcellin P, et al. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Hepatology 1999;29:1870–1875.PubMedCrossRefGoogle Scholar
  22. 22.
    Cammà C, Giunta M, Andreone P, et al. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: An evidence-based approach. J Hepatol. 2001;34:593–602.PubMedCrossRefGoogle Scholar
  23. 23.
    Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136:138–148.PubMedCrossRefGoogle Scholar
  24. 24.
    Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010;139:1593–1601.PubMedCrossRefGoogle Scholar
  25. 25.
    Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-α therapy. Ann Intern Med. 1997;127:875–881.PubMedGoogle Scholar
  26. 26.
    Makiyama A, Itoh Y, Kasahara A, et al. Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy. Cancer. 2004;101:1616–1622.PubMedCrossRefGoogle Scholar
  27. 27.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–2576.PubMedCrossRefGoogle Scholar
  28. 28.
    Kobayashi S, Takeda T, Enomoto M, et al. Development of hepatocellular carcinoma in patients with chronic hepatitis C who had a sustained virological response to interferon therapy: A multicenter, retrospective cohort study of 1124 patients. Liver Int. 2007;27:186–191.PubMedCrossRefGoogle Scholar
  29. 29.
    Kasahara A, Hayashi N, Mochizuki K, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group. Hepatology. 1998;27:1394–1402.PubMedCrossRefGoogle Scholar
  30. 30.
    Serfaty L, Aumaître H, Chazouillères O, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology. 1998;27:1435–1440.PubMedCrossRefGoogle Scholar
  31. 31.
    Bruno S, Zuin M, Crosignani A, et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: A long-term prospective study. Am J Gastroenterol. 2009;104:1147–1158.PubMedCrossRefGoogle Scholar
  32. 32.
    Iwasaki Y, Takaguchi K, Ikeda H, et al. Risk factors for hepatocellular carcinoma in hepatitis C patients with sustained virologic response to interferon therapy. Liver Int. 2004;24:603–610.PubMedCrossRefGoogle Scholar
  33. 33.
    Pollicino T, Squadrito G, Cerenzia G, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology. 2004;126:102–110.PubMedCrossRefGoogle Scholar
  34. 34.
    Tanaka A, Uegaki S, Kurihara H, et al. Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C. World J Gastroenterol. 2007;13:5180–5187.PubMedGoogle Scholar
  35. 35.
    Bruix J, Sherman M, Llovet JM, Panel of Experts on HCC, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–430.PubMedCrossRefGoogle Scholar
  36. 36.
    Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis. 1999;19:329–338.PubMedCrossRefGoogle Scholar
  37. 37.
    Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699.PubMedCrossRefGoogle Scholar
  38. 38.
    Sheu JC, Sung JL, Chen DS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology. 1985;89:259–266.PubMedGoogle Scholar
  39. 39.
    Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–346.PubMedCrossRefGoogle Scholar
  40. 40.
    Plentz RR, Park YN, Lechel A, et al. Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology. 2007;45:968–976.PubMedCrossRefGoogle Scholar
  41. 41.
    Arase Y, Ikeda K, Suzuki F, et al. Interferon-induced prolonged biochemical response reduces hepatocarcinogenesis in hepatitis C virus infection. J Med Virol. 2007;79:1485–1490.PubMedCrossRefGoogle Scholar
  42. 42.
    Tamori A, Nishiguchi S, Shiomi S, et al. Hepatitis B virus DNA integration in hepatocellular carcinoma after interferon-induced disappearance of hepatitis C virus. Am J Gastroenterol. 2005;100:1748–1753.PubMedCrossRefGoogle Scholar
  43. 43.
    Ikeda K, Marusawa H, Osaki Y, et al. Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: A prospective study. Ann Intern Med. 2007;146:649–656.PubMedGoogle Scholar
  44. 44.
    Stroffolini T, Almasio PL, Persico M, et al. Lack of correlation between serum anti-HBcore detectability and hepatocellular carcinoma in patients with HCV-related cirrhosis. Am J Gastroenterol. 2008;103:1966–1972.PubMedCrossRefGoogle Scholar
  45. 45.
    Bruno S, Shiffman ML, Roberts SK, et al. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 2010;51:388–397.PubMedCrossRefGoogle Scholar
  46. 46.
    Hino K, Kitase A, Satoh Y, et al. Interferon retreatment reduces or delays the incidence of hepatocellular carcinoma in patients with chronic hepatitis C. J Viral Hepat. 2002;9:370–376.PubMedCrossRefGoogle Scholar
  47. 47.
    Poynard T, Ratziu V, Charlotte F, et al. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol. 2001;34:730–739.PubMedCrossRefGoogle Scholar
  48. 48.
    George SL, Bacon BR, Brunt EM, et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: A 5-year follow-up of 150 patients. Hepatology. 2009;49:729–738.PubMedCrossRefGoogle Scholar
  49. 49.
    Jensen DM, Marcellin P, Freilich B, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-α2b: A randomized trial. Ann Intern Med. 2009;150:528–540.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • José Velosa
    • 1
  • Fátima Serejo
    • 1
  • Rui Marinho
    • 1
  • Joana Nunes
    • 1
  • Helena Glória
    • 2
  1. 1.Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Faculdade de MedicinaUniversidade de LisboaLisbonPortugal
  2. 2.Unidade Transplante Hepático, Hospital Curry CabralLisbonPortugal

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