Virologic Cure of Hepatitis C: Impact on Hepatic Fibrosis and Patient Outcomes

Liver (S Cotler and E Kallwitz, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Liver


Treatment with direct-acting antiviral agents has revolutionized the approach to hepatitis C. We are now able to obtain high sustained virological response (SVR) rates, even in the historically difficult-to-treat patient populations. SVR translates into improved clinical outcomes, particularly overall and liver-related mortality, and benefits are more striking in patients with cirrhosis. A 2.5- to 5-fold risk reduction in the incidence of hepatocellular carcinoma and improvement in complications derived from portal hypertension have been reported as well. It is hypothesized that the benefits from SVR occur largely due to regression of fibrosis, which arises from the halt on the fibrogenic stimuli and activation of extracellular matrix reabsorption signals. Non-invasive markers of fibrosis are being utilized to assess regression, but it is still unclear how accurate they are in this clinical scenario. Interventions aiming to improve liver wellness and screening for cirrhosis-related complications should continue to be the norm after SVR.


Hepatitis C cure Sustained virologic response Fibrosis regression Non-invasive markers of fibrosis Liver-related outcomes 



The authors would like to thank Dr. M. Katherine Rude for her critical review of the manuscript and Dr. Laura W. Lamps for contributing to our figure. This work is partially supported by the University of Arkansas for Medical Sciences College of Medicine Clinician Scientist Program.

Compliance with Ethical Standards

Conflict of Interest

HCG declares that he has no conflicts of interest. ADR reports grants from Vital Therapies and personal fees from Gilead Sciences, outside the submitted work.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and were in compliance with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Thorlund K, Druyts E, Mills EJ. SVR12 is higher than SVR24 in treatment-naive hepatitis C genotype 1 patients treated with peginterferon plus ribavirin. Clin Epidemiol. 2014;6:49–58.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Yoshida EM et al. Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. Hepatology. 2015;61(1):41–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Barritt AST, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology. 2012;142(6):1314–1323 e1.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lawitz E et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Foster GR et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373(27):2608–17.CrossRefPubMedGoogle Scholar
  6. 6.••
    Charlton M. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology. 2015;149(3):649–59. A study reporting the use of direct-acting antiviral agents in decompensated cirrhosis both in non-transplant patients and transplant recipients.CrossRefPubMedGoogle Scholar
  7. 7.•
    Curry MP. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618–28. A study using one of the newest combinations of antiviral agents (one active drug is not FDA approved yet) in decompensated HCV-related cirrhosis.CrossRefPubMedGoogle Scholar
  8. 8.
    van der Meer AJ et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Morgan TR et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52(3):833–44.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.•
    Nyberg LM. The association of sustained virological response and all-cause mortality after interferon-based therapy for chronic hepatitis C in a large U.S. community-based health care delivery system. Hepatology. 2015;62(1):252A. A community-based study confirming that SVR reduces all-cause mortality.CrossRefGoogle Scholar
  11. 11.
    Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol. 2012;56(5):1171–80.CrossRefPubMedGoogle Scholar
  12. 12.
    Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kisseleva T, Brenner DA. Mechanisms of fibrogenesis. Exp Biol Med (Maywood). 2008;233(2):109–22.CrossRefGoogle Scholar
  14. 14.
    Krizhanovsky V et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657–67.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Iredale JP et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest. 1998;102(3):538–49.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Perez-Tamayo R. Cirrhosis of the liver: a reversible disease? Pathol Annu. 1979;14(Pt 2):183–213.PubMedGoogle Scholar
  17. 17.
    Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39 Suppl 1:S60–3.CrossRefPubMedGoogle Scholar
  18. 18.
    Iredale JP. Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis. 2001;21(3):427–36.CrossRefPubMedGoogle Scholar
  19. 19.
    Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med. 2000;124(11):1599–607.PubMedGoogle Scholar
  20. 20.••
    Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015;64(5):830–41. A comprehensive review of fibrosis regression pathophysiology.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Castera L et al. Pain experienced during percutaneous liver biopsy. Hepatology. 1999;30(6):1529–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Gonzalez HC, Jafri SM, Gordon SC. Role of liver biopsy in the era of direct-acting antivirals. Curr Gastroenterol Rep. 2013;15(2):307.CrossRefPubMedGoogle Scholar
  23. 23.
    Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344(7):495–500.CrossRefPubMedGoogle Scholar
  24. 24.
    Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–57.CrossRefPubMedGoogle Scholar
  25. 25.
    Cholongitas E et al. A systematic review of the quality of liver biopsy specimens. Am J Clin Pathol. 2006;125:710–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Duarte-Rojo A, Altamirano JT, Feld JJ. Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice. Ann Hepatol. 2012;11(4):426–39.PubMedGoogle Scholar
  27. 27.
    Bernuth S. Early changes in dynamic biomarkers of liver fibrosis in hepatitis C virus-infected patients treated with sofosbuvir. Dig Liver Dis. 2015;48(3):291–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Martinez SM et al. Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2011;33:138–48.CrossRefPubMedGoogle Scholar
  29. 29.
    Poynard T et al. Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial. J Viral Hepat. 2002;9:128–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Poynard T et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122(5):1303–13.CrossRefPubMedGoogle Scholar
  31. 31.
    Maylin S et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology. 2008;135(3):821–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Mallet V et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med. 2008;149(6):399–403.CrossRefPubMedGoogle Scholar
  33. 33.
    Everson GT et al. The spectrum of hepatic functional impairment in compensated chronic hepatitis C: results from the Hepatitis C Anti-viral Long-term Treatment against Cirrhosis Trial. Aliment Pharmacol Ther. 2008;27(9):798–809.CrossRefPubMedGoogle Scholar
  34. 34.••
    D’Ambrosio R. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology. 2012;56(2):532–43. A morphometric analysis of the liver parenchyma after SVR paired with improvement of liver function.CrossRefPubMedGoogle Scholar
  35. 35.
    European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55(2):245–64.CrossRefGoogle Scholar
  36. 36.•
    Bernuth S. Early changes in dynamic biomarkers of liver fibrosis in hepatitis C virus-infected patients treated with sofosbuvir. Dig Liver Dis. 2016;48(3):291–7. Evaluation of fibrosis regression with transient elastography after SVR.CrossRefPubMedGoogle Scholar
  37. 37.
    Andersen ES et al. Lower liver stiffness in patients with sustained virological response 4 years after treatment for chronic hepatitis C. Eur J Gastroenterol Hepatol. 2011;23(1):41–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Calvaruso V et al. Fibrosis evaluation by transient elastography in patients with long-term sustained HCV clearance. Hepat Mon. 2013;13(5):e7176.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Hezode C et al. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther. 2011;34(6):656–63.CrossRefPubMedGoogle Scholar
  40. 40.
    Crissien AM et al. Regression of advanced fibrosis or cirrhosis measured by elastography in patients with chronic hepatitis C who achieve sustained virological response after treatment for HCV. Hepatology. 2015;62:264A–5A.Google Scholar
  41. 41.••
    D’Ambrosio R. The diagnostic accuracy of Fibroscan for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response. J Hepatol. 2013;59(2):251–6. The authors analyzed transient elastography after HCV cure and called for new cutoff thresholds to stage fibrosis after SVR.CrossRefPubMedGoogle Scholar
  42. 42.
    Patel K et al. FibroSURE and FibroScan in relation to treatment response in chronic hepatitis C virus. World J Gastroenterol. 2011;17(41):4581–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.•
    Poynard T. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J Hepatol. 2013;59(4):675–83. A study reporting fibrosis improvement after SVR utilizing FibroTest.CrossRefPubMedGoogle Scholar
  44. 44.
    European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.CrossRefGoogle Scholar
  45. 45.
    Ioannou GN. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007;5(8):938–45, 945 e1-4.CrossRefPubMedGoogle Scholar
  46. 46.
    Yoshida H 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(3):174–81.CrossRefPubMedGoogle Scholar
  47. 47.
    Aleman S et al. A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis. Clin Infect Dis. 2013;57(2):230–6.CrossRefPubMedGoogle Scholar
  48. 48.•
    Dieperink E. All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C. Dig Dis Sci. 2014;59(4):872–80. A Veteran Administration study reporting improvement in overall and liver-related mortality after SVR.CrossRefPubMedGoogle Scholar
  49. 49.••
    Messori A, Badiani B, Trippoli S. Achieving sustained virological response in hepatitis C reduces the long-term risk of hepatocellular carcinoma: an updated meta-analysis employing relative and absolute outcome measures. Clin Drug Investig. 2015;35(12):843–50. A meta-analysis of 25 studies around the world documenting a decrease in risk for HCC after SVR.CrossRefPubMedGoogle Scholar
  50. 50.
    Bruno S et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007;45(3):579–87.CrossRefPubMedGoogle Scholar
  51. 51.
    Asahina Y et al. Alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology. 2013;58(4):1253–62.CrossRefPubMedGoogle Scholar
  52. 52.
    Lok AS. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C. Gastroenterology. 2011;140(3):840–9, quiz e12.CrossRefPubMedGoogle Scholar
  53. 53.
    Bruix J et al. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C. Gastroenterology. 2011;140(7):1990–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Sherman M et al. Screening for hepatocellular carcinoma: the rationale for the American Association for the Study of Liver Diseases recommendations. Hepatology. 2012;56(3):793–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Roberts S et al. Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis. Clin Gastroenterol Hepatol. 2007;5(8):932–7.CrossRefPubMedGoogle Scholar
  56. 56.
    D’Ambrosio R et al. The course of esophageal varices in patients with hepatitis C cirrhosis responding to interferon/ribavirin therapy. Antivir Ther. 2011;16(5):677–84.CrossRefPubMedGoogle Scholar
  57. 57.
    Bruno S et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology. 2010;51(6):2069–76.CrossRefPubMedGoogle Scholar
  58. 58.
    de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743–52.CrossRefPubMedGoogle Scholar
  59. 59.
    Kee KM et al. Improvement of thrombocytopenia in hepatitis C-related advanced fibrosis patients after sustained virological response. Dig Dis Sci. 2013;58(2):556–61.CrossRefPubMedGoogle Scholar
  60. 60.
    Taniguchi H et al. Long-term monitoring of platelet count, as a non-invasive marker of hepatic fibrosis progression and/or regression in patients with chronic hepatitis C after interferon therapy. J Gastroenterol Hepatol. 2006;21(1 Pt 2):281–7.CrossRefPubMedGoogle Scholar
  61. 61.•
    van der Meer AJ. Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis. J Gastroenterol Hepatol. 2015. doi: 10.1111/jgh.13252. The authors report improvement of platelet count as a surrogate of decreasing portal hypertension after SVR.Google Scholar
  62. 62.••
    Poordad F. Daclatasvir with sofosbuvir and ribavirin for HCV infection with advanced cirrhosis or post-liver transplant recurrence. Hepatology. 2016;63(5):1493–505. A study with new antiviral agents for advanced cirrhosis and post-transplant HCV recurrence.CrossRefPubMedGoogle Scholar
  63. 63.
    Afdhal N et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety. J Hepatol. 2014;60:S28.CrossRefGoogle Scholar
  64. 64.
    Deterding K et al. Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies. Aliment Pharmacol Ther. 2015;42(7):889–901.CrossRefPubMedGoogle Scholar
  65. 65.
    Sallie R et al. Recurrence of hepatitis C following orthotopic liver transplantation: a polymerase chain reaction and histological study. J Hepatol. 1994;21(4):536–42.CrossRefPubMedGoogle Scholar
  66. 66.
    Veldt BJ et al. Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection. Am J Transplant. 2008;8(11):2426–33.CrossRefPubMedGoogle Scholar
  67. 67.
    Selzner N et al. Antiviral treatment of recurrent hepatitis C after liver transplantation: predictors of response and long-term outcome. Transplantation. 2009;88(10):1214–21.CrossRefPubMedGoogle Scholar
  68. 68.
    Kwo PY et al. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med. 2014;371(25):2375–82.CrossRefPubMedGoogle Scholar
  69. 69.
    Pungpapong S et al. Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant. Hepatology. 2015;61(6):1880–6.CrossRefPubMedGoogle Scholar
  70. 70.
    Nair S, Satapathy SK, Gonzalez HC. Sofosbuvir and simeprevir for treatment of recurrent hepatitis C infection after liver transplant. Exp Clin Transplant. 2016. doi: 10.6002/ect.2015.0289.Google Scholar
  71. 71.
    Askgaard G et al. Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study. J Hepatol. 2015;62(5):1061–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Berzigotti A, Saran U, Dufour JF. Physical activity and liver diseases. Hepatology. 2016;63(3):1026–40.CrossRefPubMedGoogle Scholar
  73. 73.
    Macias-Rodriguez RU et al. Changes in hepatic venous pressure gradient induced by a physical exercise program in cirrhotic patients: a randomized open clinical trial. Hepatology. 2014;60(4):246–247A.Google Scholar
  74. 74.
    Hezode C et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology. 2005;42(1):63–71.CrossRefPubMedGoogle Scholar
  75. 75.
    Ranney DN et al. Marijuana use in potential liver transplant candidates. Am J Transplant. 2009;9(2):280–5.CrossRefPubMedGoogle Scholar
  76. 76.
    Feld JJ. I drink for my liver, Doc: emerging evidence that coffee prevents cirrhosis. F1000Res. 2015;4:95.PubMedPubMedCentralGoogle Scholar
  77. 77.
    George SL et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-years follow-up of 150 patients. Hepatology. 2009;49(3):729–38.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Asahina Y et al. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology. 2010;52(2):518–27.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Transplant Surgery/Center of Advanced Liver Disease, Methodist University HospitalUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Division of Gastroenterology and HepatologyUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations