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The Current State and Future Prospects of Chronic Hepatitis C Virus Infection Treatment

  • Transplant and Oncology (M Ison, Section Editor)
  • Published:
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Abstract

Hepatitis C virus (HCV) infection is a significant cause of chronic liver disease with substantial long-term sequelae. Until very recently, therapies to cure HCV were hindered by high nonresponse rates and severe side effects. The first-generation protease inhibitor-containing regimens provided superior cure rates for many HCV-infected patients, although their side-effect profile proved to be quite burdensome. We are now witnessing the emergence of therapies with superior cure rates, limited side effects, and broad genotypic activity. Two therapies, sofosbuvir (an NS5b polymerase inhibitor) and simeprevir (a second-generation NS3/4A protease inhibitor), were approved by the Food and Drug Administration in late 2013 for use in a number of HCV populations. This review focuses primarily upon these therapies and the key studies that support their use in practice. Furthermore, representative novel antiviral therapies, in advanced stages of testing, are also reviewed.

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References

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  1. Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Am J Med Sci. 1975;270(2):329–34.

    Article  CAS  PubMed  Google Scholar 

  2. Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med. 1989;321(22):1494–500.

    Article  CAS  PubMed  Google Scholar 

  3. Alter HJ. The road not taken or how I learned to love the liver: a personal perspective on hepatitis history. Hepatology. 2014;59(1):4–12. An interesting history regarding the difficulties in the identification and diagnosis of the Hepatitis C virus.

    Article  PubMed  Google Scholar 

  4. Walsh JH, Purcell RH, Morrow AG, et al. Posttransfusion hepatitis after open-heart operations. Incidence after the administration of blood from commercial and volunteer donor populations. JAMA. 1970;211(2):261–5.

    Article  CAS  PubMed  Google Scholar 

  5. Zaltron S, Spinetti A, Biasi L, et al. Chronic HCV infection: epidemiological and clinical relevance. BMC Infect Dis. 2012;12 Suppl 2:S2.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol. 2012;26(4):531–48.

    Article  PubMed  Google Scholar 

  7. Strassburg CP, Manns MP. Liver transplantation: indications and results. Internist (Berl). 2009;50(5):550–60.

    Article  CAS  Google Scholar 

  8. Hsu SH, Yeh ML, Wang SN. New insights in recurrent HCV infection after liver transplantation. Clin Dev Immunol. 2013;2013:890517.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis. 2011;52(7):889–900.

    Article  PubMed  Google Scholar 

  10. Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol. 1996;25(5):591–8.

    Article  CAS  PubMed  Google Scholar 

  11. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med. 1989;321(22):1501–6.

    Article  CAS  PubMed  Google Scholar 

  12. Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352(9138):1426–32.

    Article  CAS  PubMed  Google Scholar 

  13. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339(21):1485–92.

    Article  CAS  PubMed  Google Scholar 

  14. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343(23):1666–72.

    Article  CAS  PubMed  Google Scholar 

  15. Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001;34(2):395–403.

    Article  CAS  PubMed  Google Scholar 

  16. 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;358:958–65.

    Article  CAS  PubMed  Google Scholar 

  17. Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology. 2004;127(5):1347–55.

    Article  CAS  PubMed  Google Scholar 

  18. Poordad F, McCone Jr J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195–206.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Kwo P, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705–16.

    Article  CAS  PubMed  Google Scholar 

  20. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405–16.

    Article  CAS  PubMed  Google Scholar 

  21. Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839–50.

    Article  CAS  PubMed  Google Scholar 

  22. Simeprevir (Olysio) for chronic hepatitis C. Med Lett Drugs Ther. 2014;56(1433):1–3.

  23. Vaidya A, Perry CM. Simeprevir: first global approval. Drugs. 2013;73(18):2093–106.

    Article  CAS  PubMed  Google Scholar 

  24. Traynor K. Sofosbuvir approved for chronic hepatitis C infection. Am J Health Syst Pharm. 2014;71(2):90.

    Google Scholar 

  25. Lawitz E, Gane EJ. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;369(7):678–9.

    Article  CAS  PubMed  Google Scholar 

  26. A Special Meeting Review Edition. Advances in the treatment of hepatitis C virus infection from EASL 2013. The 48th Annual Meeting of the European Association for the Study of the Liver, 24–28 April 2013, Amsterdam. Gastroenterol Hepatol (N.Y.). 2013(6 Suppl 3):1–18.

  27. Witkop B. Paul Ehrlich and his magic bullets – revisited. Proc Am Philos Soc. 1999;143(4):540–57.

    CAS  PubMed  Google Scholar 

  28. Back D, Else L. The importance of drug-drug interactions in the DAA era. Dig Liver Dis. 2013;45 Suppl 5:S343–8.

    Article  CAS  PubMed  Google Scholar 

  29. Kiser J, Burton J, Everson G. Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10(10):596–606.

    Article  CAS  PubMed  Google Scholar 

  30. Jacobson I, Dore G, Foster G. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: efficacy in difficult-to-treat patient sub-populations in the QUEST 1 and 2 phase III trials. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, 1–5 November 2013; Abstract 1122.

  31. Lawitz E, Forns X, Zeuzem S. Simeprevir (TMC-435) peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in patients who relapsed after previous interferon based therapy: results from PROMISE, a phase III trial. Digestive Disease Week 2013; Abstract 869.

  32. Zeuzem S, Berg T, Gane E. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the ASPIRE trial. Proceedings of the 47th Annual Meeting of the European Association for the Study of the Liver; 18–22 April 2012; Barcelona, Spain. Abstract 2.

  33. Jacobson I, Ghalib R, Rodriguez-Torres M. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. Proceedings of the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 1–5 November 2013; Washington, DC. Abstract LB-3. Initial results of an important study utilizing both FDA-approved oral therapies together, without ribavirin or pegylated-interferon. Additionally there were strong cure rates in traditionally difficult to treat patients.

  34. American Association for the Study of Liver Diseases. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report/initial-treatment-box-summary-recommendations-patients-who-are-initiating-therapy-hcv. Accessed 13 May 2014. These are the joint recommendations of the AASLD and IDSA for the treatment of HCV, taking into account the current data on simeprevir and sofosbuvir. Note that these recommendations go even further than the FDA-approved indications for these two medications.

  35. European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60(2):392–420.

    Article  Google Scholar 

  36. Hepatitis C Online. Simeprevir (Olysio). http://hepatitisc.uw.edu/page/treatment/drugs/simeprevir-drug. Accessed 13 May 2014.

  37. Koff RS. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014;39(5):478–87.

    Article  CAS  PubMed  Google Scholar 

  38. Keating GM, Vaidya A. Sofosbuvir: first global approval. Drugs. 2014;74(2):273–82.

    Article  CAS  PubMed  Google Scholar 

  39. Sofosbuvir (Sovaldi) for chronic hepatitis C. Med Lett Drugs Ther. 2014;56(1434):5–6.

  40. Lawitz E, Mangia A, Wyles D. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878–87.

    Article  CAS  PubMed  Google Scholar 

  41. Gane E, Lawitz E, Rodriguez-Torres M. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naive GT2/3 HCV-infected patients (FISSION). Proceedings of the 48th Annual Meeting of the European Association for the Study of the Liver; 24–28 April 2013; Amsterdam. Abstract 5.

  42. Jacobson I, Yoshida E, Sulkowski M. Treatment with sofosbuvir + ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. Proceedings of the 48th Annual Meeting of the European Association for the Study of the Liver; 24–28 April 2013; Amsterdam. Abstract 61.

  43. Nelson D, Feld J, Kowdley K. All overall therapy with sofosbuvir + ribavirin for 12 or 16 weeks in treatment experienced GT2/3 HCV-infected patients: results of the phase 3 FUSION trial. Proceedings of the 48th Annual Meeting of the European Association for the Study of the Liver; 24–28 April 2013; Amsterdam. Abstract 6.

  44. Zeuzem S, Dusheiko G, Salupere R. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Proceedings of the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 1–5 November 2013; Washington, DC. Abstract 1085.

  45. Sulkowski M, Rodriguez-Torres M, Lalezari J. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Proceedings of the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 1–5 November 2013; Washington, DC. Abstract 212.

  46. 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(11):693–9.

    Article  CAS  PubMed  Google Scholar 

  47. Curry M, Forns X, Chung R. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Proceedings of the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 1–5 November 2013; Washington, DC. Abstract 213. Important study detailing the efficacy of this therapy administered before liver transplantation in achieving SVR-12 weeks after liver transplantation. Additionally, the study demonstrates important guidance on duration of therapy before liver transplantation and duration of viral negativity before liver transplantation to achieve this SVR.

  48. Hepatitis C Online. Sofosbuvir (Sovaldi). http://hepatitisc.uw.edu/page/treatment/drugs/sofosbuvir-drug. Accessed 13 May 2014.

  49. Sulkowski M, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211–21.

    Article  CAS  PubMed  Google Scholar 

  50. Dore G, Lawitz E, Hezode C. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with HCV genotype 2 or 3 infection: COMMAND GT2/3 study. Proceedings of the 48th Annual Meeting of the European Association for the Study of the Liver; 24–28 April 2013; Amsterdam. Abstract 1418.

  51. Kowdley K, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370(3):222–32.

    Article  CAS  PubMed  Google Scholar 

  52. Hepatitis C Online. Medications to treat HCV. http://hepatitisc.uw.edu/page/treatment/drugs. Accessed 13 May 2014.

  53. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014;383(9916):515–23.

    Article  CAS  PubMed  Google Scholar 

  54. Gilead. Gilead announces SVR12 rates from three phase 3 studies evaluating a once-daily fixed-dose combination of sofosbuvir ledipasvir for genotype 1 hepatitis C patients. Foster City, CA: Gilead Sciences. http://www.gilead.com/news/press-releases/2013/12/gilead-announces-svr12-rates-from-three-phase-3-studies-evaluating-a-oncedaily-fixeddose-combination-of-sofosbuvir-and-ledipasvir-for-genotype-1-hepatitis-c-patients. Accessed 13 May 2014. The ION trials were important in demonstrating high SVR rates in a diverse group of genotype 1 patients, including a treatment-experienced cohort. This trial also used a fixed-dose combination of sofosbuvir and daclatasvir, i.e. one pill – a significant achievement in design compared to prior therapies requiring a multitude of pills per day (and injections).

  55. Watt K, Veldt B, Charlton M. A practical guide to the management of HCV infection following liver transplantation. Am J Transplant. 2009;9(8):1707–13.

    Article  CAS  PubMed  Google Scholar 

  56. Charlton M, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study. Proceedings of the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 1–5 November 2013; Washington, DC. Abstract LB-2.

  57. ClinicalTrials.gov. An expanded access phase 2 study of sofosbuvir with ribavirin and with or without pegylated interferon for 24 weeks in subjects who have undergone liver transplantation and who have aggressive, recurrent hepatitis C infection. http://clinicaltrials.gov/ct2/show/NCT01779518. Accessed 13 May 2014.

  58. Fontana RJ, Hughes EA, Bifano M, et al. Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C. Am J Transplant. 2013;13(6):1601–5.

    Article  CAS  PubMed  Google Scholar 

  59. Fleming KM, Aithal GP, Card TR, West J. The rate of decompensation and clinical progression of disease in people with cirrhosis: a cohort study. Aliment Pharmacol Ther. 2010;32(11–12):1343–50.

    Article  CAS  PubMed  Google Scholar 

  60. Firpi RJ, Clark V, Soldevila-Pico C, et al. The natural history of hepatitis C cirrhosis after liver transplantation. Liver Transpl. 2009;15(9):1063–71.

    Article  PubMed  Google Scholar 

  61. Werner CR, Egetemeyr DP, Lauer UM, et al. Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl. 2012;18(12):1464–70.

    Article  PubMed  Google Scholar 

  62. Coilly A, Roche B, Samuel D. Current management and perspectives for HCV recurrence after liver transplantation. Liver Int. 2013;33 Suppl 1:56–62.

    Article  PubMed  Google Scholar 

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Conflict of Interest

Josh Levitsky has served as a consultant for Gilead and Abbvie, and has received honoraria from Gilead and Salix. Christopher Moore has done a fellowship at Northwestern University, Chicago, IL.

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This article does not contain any studies with human or animal subjects performed by the author.

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  1. Section of Hepatology, Department of Medicine, Northwestern University, Chicago, IL, USA

    Christopher Moore & Josh Levitsky

  2. Kovler Organ Transplantation Center, Arkes Family Pavilion, 676 North St Claire Street, Floor 19, Suite 1900, Chicago, IL, 60611, USA

    Christopher Moore & Josh Levitsky

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Correspondence to Josh Levitsky.

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Moore, C., Levitsky, J. The Current State and Future Prospects of Chronic Hepatitis C Virus Infection Treatment. Curr Infect Dis Rep 16, 413 (2014). https://doi.org/10.1007/s11908-014-0413-1

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