Emerging Antivirals in the Future

  • C. Nelson Hayes
  • Michio Imamura
  • Kazuaki ChayamaEmail author


The safety and effectiveness of antiviral therapy for chronic hepatitis C has improved markedly with the introduction of direct-acting antiviral drugs and a concomitant decrease in interferon use. Although DAAs are potent antivirals, the emergence of resistance against DAAs has spurred the development of new drugs. Second-generation NS5A inhibitors have a higher genetic barrier compared to first-generation NS5A inhibitors and are highly effective against strains that are resistant to first-generation NS5A inhibitors. While new drug development has primarily focused on DAAs, another way to counter DAA resistance is to develop combination therapies that target host factors in addition to viral factors because it is more difficult for the virus to overcome changes in the host environment. For example, miravirsen targets host microRNA-122, which is highly expressed in hepatocytes and essential for viral replication. Emergence of resistance mutations in such therapies is very low. Therefore, combined use of DAAs with other drugs is expected in the future to achieve high SVR rates while minimizing the risk of resistance.


Chronic hepatitis C Second-generation NS5A inhibitors Non-nucleoside polymerase inhibitors Miravirsen Resistance-associated variants 



Direct-acting antiviral


Hepatitis C virus


Nucleoside inhibitor


Non-nucleoside inhibitor


Pegylated interferon


Protease inhibitor


Sustained viral response


  1. 1.
    Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56(1):78–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Hayashi N, Izumi N, Kumada H, Okanoue T, Tsubouchi H, Yatsuhashi H, et al. Simeprevir with peginterferon/ribavirin for treatment-naive hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial. J Hepatol. 2014;61(2):219–27.CrossRefPubMedGoogle Scholar
  3. 3.
    Hayashi N, Mobashery N, Izumi N. Vaniprevir plus peginterferon alfa-2a and ribavirin in treatment-experienced Japanese patients with hepatitis C virus genotype 1 infection: a randomized phase II study. J Gastroenterol. 2015;50(2):238–48.CrossRefPubMedGoogle Scholar
  4. 4.
    Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59(6):2083–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, et al. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Lancet Infect Dis. 2015;15(6):645–53.CrossRefPubMedGoogle Scholar
  6. 6.
    Omata M, Nishiguchi S, Ueno Y, Mochizuki H, Izumi N, Ikeda F, et al. Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial. J Viral Hepat. 2014;21(11):762–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, Courtney LF, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899–909.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405–16.CrossRefPubMedGoogle Scholar
  9. 9.
    Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365(11):1014–24.CrossRefPubMedGoogle Scholar
  10. 10.
    Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, et al. Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C. Hepatol Res: Off J Jpn Soc Hepatol. 2010;40(12):1155–67.CrossRefGoogle Scholar
  11. 11.
    Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol. 2011;55(1):192–206.CrossRefPubMedGoogle Scholar
  12. 12.
    Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366(3):216–24.CrossRefPubMedGoogle Scholar
  13. 13.
    Wyles DL. Beyond telaprevir and boceprevir: resistance and new agents for hepatitis C virus infection. Top Antivir Med. 2012;20(4):139–45.PubMedGoogle Scholar
  14. 14.
    Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61(1):77–87.CrossRefPubMedGoogle Scholar
  15. 15.
    Wendt A, Adhoute X, Castellani P, Oules V, Ansaldi C, Benali S, et al. Chronic hepatitis C: future treatment. Clin Pharmacol: Adv Appl. 2014;6:1–17.Google Scholar
  16. 16.
    Rosenquist A, Samuelsson B, Johansson PO, Cummings MD, Lenz O, Raboisson P, et al. Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. J Med Chem. 2014;57(5):1673–93.CrossRefPubMedGoogle Scholar
  17. 17.
    Jacobson IM, Dore GJ, Foster GR, Fried MW, Radu M, Rafalsky VV, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384(9941):403–13.CrossRefPubMedGoogle Scholar
  18. 18.
    Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M, Horsmans Y, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014;384(9941):414–26.CrossRefPubMedGoogle Scholar
  19. 19.
    Forns X, Lawitz E, Zeuzem S, Gane E, Bronowicki JP, Andreone P, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology. 2014;146:1669.CrossRefPubMedGoogle Scholar
  20. 20.
    Izumi N, Hayashi N, Kumada H, Okanoue T, Tsubouchi H, Yatsuhashi H, et al. Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies. J Gastroenterol. 2014;49(5):941–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146(2):430–41.e6.CrossRefPubMedGoogle Scholar
  22. 22.
    Schneider MD, Sarrazin C. Antiviral therapy of hepatitis C in 2014: do we need resistance testing? Antiviral Res. 2014;105c:64–71.CrossRefGoogle Scholar
  23. 23.
    Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G. MK-5172: a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs. 2014;23(5):719–28.CrossRefPubMedGoogle Scholar
  24. 24.
    Sulkowski M, Hezode C, Gerstoft J, Vierling JM, Mallolas J, Pol S, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015;385(9973):1087–97.CrossRefPubMedGoogle Scholar
  25. 25.
    Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015;385(9973):1075–86.CrossRefPubMedGoogle Scholar
  26. 26.
    Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med. 2013;159(2):86–96.PubMedGoogle Scholar
  27. 27.
    Patel D, Zhao Y, Fabrycki J, Yang G, Podos S, Kocinsk H, et al. P0805: achievement of SVR12 despite the presence of HCV variants resistant to first generation NS5A inhibitors in genotype-1 hepatitis C patients after 8-week therapy of ACH-3102 in combination with sofosbuvir. J Hepatol. 62:S636.Google Scholar
  28. 28.
    Gane E, Schwabe C, Mader M, Suri V, Donohue M, Huang M, et al. LP06: sustained virologic response after ACH-3102 and sofosbuvir treatment for 8 or 6 weeks: a phase 2 “proxy” study. J Hepatol. 62:S266.Google Scholar
  29. 29.
    Liu M, Tuttle M, Gao M, Lemm JA. Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes. Antimicrob Agents Chemother. 2014;58(12):7416–23.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Everson GT, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014;146(2):420–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Shi N, Hiraga N, Imamura M, Hayes CN, Zhang Y, Kosaka K, et al. Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice. Gut. 2013;62(7):1055–61.CrossRefPubMedGoogle Scholar
  32. 32.
    Abe H, Hayes CN, Hiraga N, Imamura M, Tsuge M, Miki D, et al. A translational study of resistance emergence using sequential direct-acting antiviral agents for hepatitis C using ultra-deep sequencing. Am J Gastroenterol. 2013;108(9):1464–72.CrossRefPubMedGoogle Scholar
  33. 33.
    Reddy KR, Bourliere M, Sulkowski M, Omata M, Zeuzem S, Feld JJ, et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: an integrated safety and efficacy analysis. Hepatology. 2015;62:79.CrossRefPubMedGoogle Scholar
  34. 34.
    Friborg J, Zhou N, Han Z, Yang X, Falk P, Mendez P, et al. In vitro assessment of re-treatment options for patients with hepatitis C virus genotype 1b infection resistant to daclatasvir plus asunaprevir. Inf Dis Ther. 2014.Google Scholar
  35. 35.
    Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594–603.CrossRefPubMedGoogle Scholar
  36. 36.
    Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(21):1983–92.CrossRefPubMedGoogle Scholar
  37. 37.
    Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourliere M, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1604–14.CrossRefPubMedGoogle Scholar
  38. 38.
    Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(21):1973–82.CrossRefPubMedGoogle Scholar
  39. 39.
    Kumada H, Chayama K, Rodrigues Jr L, Suzuki F, Ikeda K, Toyoda H, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology. 2015;62(4):1037–46.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Fofana I, Jilg N, Chung RT, Baumert TF. Entry inhibitors and future treatment of hepatitis C. Antiviral Res. 2014;104:136–42.CrossRefPubMedGoogle Scholar
  41. 41.
    Lin LT, Chung CY, Hsu WC, Chang SP, Hung TC, Shields J, et al. Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry. J Hepatol. 2015;62(3):541–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Xiao F, Fofana I, Thumann C, Mailly L, Alles R, Robinet E, et al. Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C. Gut. 2015;64(3):483–94.CrossRefPubMedGoogle Scholar
  43. 43.
    Hopkins S, Bobardt M, Chatterji U, Garcia-Rivera JA, Lim P, Gallay PA. The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes. Antimicrob Agents Chemother. 2012;56(7):3888–97.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hopkins S, Gallay P. Cyclophilin inhibitors: an emerging class of therapeutics for the treatment of chronic hepatitis C infection. Viruses. 2012;4(11):2558–77.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Daito T, Watashi K, Sluder A, Ohashi H, Nakajima S, Borroto-Esoda K, et al. Cyclophilin inhibitors reduce phosphorylation of RNA-dependent protein kinase to restore expression of IFN-stimulated genes in HCV-infected cells. Gastroenterology. 2014;147(2):463–72.CrossRefPubMedGoogle Scholar
  46. 46.
    Chatterji U, Bobardt M, Tai A, Wood M, Gallay PA. Cyclophilin and NS5A inhibitors, but not other anti-hepatitis C virus (HCV) agents, preclude HCV-mediated formation of double-membrane-vesicle viral factories. Antimicrob Agents Chemother. 2015;59(5):2496–507.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Feher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol. 2012;13(1):210–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Mengs U, Pohl RT, Mitchell T. Legalon(R) SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol. 2012;13(10):1964–70.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ferenci P, Scherzer TM, Kerschner H, Rutter K, Beinhardt S, Hofer H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology. 2008;135(5):1561–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Polyak SJ, Ferenci P, Pawlotsky JM. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology. 2013;57(3):1262–71.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Dahari H, Shteingart S, Gafanovich I, Cotler SJ, D’Amato M, Pohl RT, et al. Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics. Liver Int: Off J Int Assoc Study Liver. 2015;35(2):289–94.CrossRefGoogle Scholar
  52. 52.
    Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science. 2005;309(5740):1577–81.CrossRefPubMedGoogle Scholar
  53. 53.
    Li YP, Gottwein JM, Scheel TK, Jensen TB, Bukh J. MicroRNA-122 antagonism against hepatitis C virus genotypes 1–6 and reduced efficacy by host RNA insertion or mutations in the HCV 5′UTR. Proc Natl Acad Sci U S A. 2011;108(12):4991–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Jopling CL, Schutz S, Sarnow P. Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. Cell Host Microbe. 2008;4(1):77–85.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Henke JI, Goergen D, Zheng J, Song Y, Schuttler CG, Fehr C, et al. microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J. 2008;27(24):3300–10.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ottosen S, Parsley TB, Yang L, Zeh K, van Doorn LJ, van der Veer E, et al. In vitro antiviral activity and preclinical and clinical resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122. Antimicrob Agents Chemother. 2015;59(1):599–608.CrossRefPubMedGoogle Scholar
  57. 57.
    Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685–94.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2017

Authors and Affiliations

  • C. Nelson Hayes
    • 1
    • 2
  • Michio Imamura
    • 1
    • 2
  • Kazuaki Chayama
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Liver Research Project CenterHiroshima UniversityHiroshimaJapan
  3. 3.Laboratory for Digestive DiseasesCenter for Genomic Medicine, RIKENHiroshimaJapan

Personalised recommendations