Overview of Direct-Acting Antiviral Drugs and Drug Resistance of Hepatitis C Virus

  • Darrick K. Li
  • Raymond T. Chung
Part of the Methods in Molecular Biology book series (MIMB, volume 1911)


The advent of direct-acting antivirals (DAAs) has brought about a sudden renaissance in the treatment of chronic hepatitis C virus (HCV) infection with SVR rates now routinely >90%. However, due to the error-prone nature of the HCV RNA polymerase, resistance-associated substitutions (RASs) to DAAs may be present at baseline and can result in a significant effect on treatment outcomes and hamper the achievement of sustained virologic response. By further understanding the patterns and nature of these RASs, it is anticipated that the incidence of treatment failure will continue to decrease in frequency with the development of drug regimens with increasing potency, barrier to resistance, and genotypic efficacy. This review summarizes our current knowledge of RASs associated with HCV infection as well as the clinical effect of RASs on treatment with currently available DAA regimens.

Key words

Direct-acting antiviral Hepatitis C virus Sustained virologic response Resistance-associated substitution 


  1. 1.
    Ray SC, Thomas DL (2015) Hepatitis C. In: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, 8th edn. Elsevier Saunders, Philadelphia, pp 1904–1927Google Scholar
  2. 2.
    Powdrill MH, Tchesnokov EP, Kozak RA, Russell RS, Martin R, Svarovskaia ES et al (2011) Contribution of a mutational bias in hepatitis C virus replication to the genetic barrier in the development of drug resistance. Proc Natl Acad Sci U S A 108:20509–20513PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST (2013) Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 57:1333–1342PubMedCrossRefGoogle Scholar
  4. 4.
    Alter HJ, Holland PV, Morrow AG, Purcell RH, Feinstone SM, Moritsugu Y (1975) Clinical and serological analysis of transfusion-associated hepatitis. Lancet 306:838–841CrossRefGoogle Scholar
  5. 5.
    Feinstone SM, Kapikian AZ, Purcell RH, Alter HJ, Holland PV (1975) Transfusion-associated hepatitis not due to viral hepatitis type A or B. N Engl J Med 292:767–770PubMedCrossRefGoogle Scholar
  6. 6.
    Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M et al (1986) Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. N Engl J Med 315:1575–1578PubMedCrossRefGoogle Scholar
  7. 7.
    Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362Google Scholar
  8. 8.
    Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perrillo RP et al (1989) Treatment of chronic hepatitis C with recombinant interferon alfa. N Engl J Med 321:1501–1506PubMedCrossRefGoogle Scholar
  9. 9.
    Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J et al (1989) Recombinant interferon alfa therapy for chronic hepatitis C. N Engl J Med 321:1506–1510PubMedCrossRefGoogle Scholar
  10. 10.
    McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK et al (1998) Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 339:1485–1492PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975–982PubMedCrossRefGoogle Scholar
  12. 12.
    Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R et al (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965PubMedCrossRefGoogle Scholar
  13. 13.
    Poynard T, Bedossa P, Chevallier M, Mathurin P, Lemonnier C, Trepo C et al (1995) A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. N Engl J Med 332:1457–1463PubMedCrossRefGoogle Scholar
  14. 14.
    Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z et al (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH et al (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2416PubMedCrossRefGoogle Scholar
  16. 16.
    Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS et al (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364:1195–1206PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M, Horsmans Y et al (2014) 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 384:414–426PubMedCrossRefGoogle Scholar
  18. 18.
    Membreno FE, Lawitz EJ (2011) The HCV NS5B nucleoside and non-nucleoside inhibitors. Clin Liver Dis 15:611–626PubMedCrossRefGoogle Scholar
  19. 19.
    Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC et al (2013) Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 368:1878–1887PubMedCrossRefGoogle Scholar
  20. 20.
    Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS et al (2013) Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 368:1867–1877PubMedCrossRefGoogle Scholar
  21. 21.
    Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E et al (2014) Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 370:1483–1493PubMedCrossRefGoogle Scholar
  22. 22.
    Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M et al (2014) Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 370:1889–1898PubMedCrossRefGoogle Scholar
  23. 23.
    Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E et al (2014) Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 370:1879–1888PubMedCrossRefGoogle Scholar
  24. 24.
    Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A et al (2014) Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 384:1756–1765PubMedCrossRefGoogle Scholar
  25. 25.
    Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D et al (2014) Treatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med 370:1594–1603PubMedCrossRefGoogle Scholar
  26. 26.
    Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K et al (2014) ABT-450/r–ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 370:1973–1982PubMedCrossRefGoogle Scholar
  27. 27.
    Sulkowski MS, Vargas HE, Di Bisceglie AM, Kuo A, Reddy KR, Lim JK et al (2016) Effectiveness of simeprevir plus sofosbuvir, with or without ribavirin, in real-world patients with HCV genotype 1 infection. Gastroenterology 150:419–429PubMedCrossRefGoogle Scholar
  28. 28.
    Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM et al (2016) Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology 151:1131–1140.e1135PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Welzel TM, Nelson DR, Morelli G, Di Bisceglie A, Reddy RK, Kuo A et al (2016) Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study. Gut 66:1844–1852PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Feld JJ, Maan R, Zeuzem S, Kuo A, Nelson DR, Di Bisceglie AM et al (2016) Effectiveness and safety of Sofosbuvir-based regimens for chronic HCV genotype 3 infection: results of the HCV-TARGET study. Clin Infect Dis 63:776–783PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Reddy KR, Lim JK, Kuo A, Di Bisceglie AM, Galati JS, Morelli G et al (2016) All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database. Aliment Pharmacol Ther 45:115–126PubMedCrossRefGoogle Scholar
  32. 32.
    Laskus T, Wilkinson J, Gallegos-Orozco JF, Radkowski M, Adair DM, Nowicki M et al (2004) Analysis of hepatitis C virus quasispecies transmission and evolution in patients infected through blood transfusion. Gastroenterology 127:764–776PubMedCrossRefGoogle Scholar
  33. 33.
    Martell M, Esteban JI, Quer J, Genesca J, Weiner A, Esteban R et al (1992) Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol 66:3225–3229PubMedPubMedCentralGoogle Scholar
  34. 34.
    Andino R, Domingo E (2015) Viral quasispecies. Virology 479-480:46–51PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Perales C, Quer J, Gregori J, Esteban J, Domingo E (2015) Resistance of hepatitis C virus to inhibitors: complexity and clinical implications. Viruses 7:5746–5766PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bartenschlager R, Lohmann V (2000) Replication of hepatitis C virus. J Gen Virol 81:1631–1648PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Neumann AU (1998) Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-therapy. Science 282:103–107PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pawlotsky J-M (2016) Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology 151:70–86PubMedCrossRefGoogle Scholar
  39. 39.
    Chevaliez S, Rodriguez C, Pawlotsky JM (2012) New virologic tools for management of chronic hepatitis B and C. Gastroenterology 142:1303–1313.e1301PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Echeverria N, Moratorio G, Cristina J, Moreno P (2015) Hepatitis C virus genetic variability and evolution. World J Hepatol 7:831–845PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Leitner T, Halapi E, Scarlatti G, Rossi P, Albert J, Fenyo EM et al (1993) Analysis of heterogeneous viral populations by direct DNA sequencing. BioTechniques 15:120–127PubMedGoogle Scholar
  42. 42.
    Fourati S, Pawlotsky J-M (2015) Virologic tools for HCV drug resistance testing. Viruses 7:6346–6359PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Ninomiya M, Ueno Y, Funayama R, Nagashima T, Nishida Y, Kondo Y et al (2011) Use of Illumina deep sequencing technology to differentiate hepatitis C virus variants. J Clin Microbiol 50:857–866CrossRefGoogle Scholar
  44. 44.
    Thomson E, Ip CLC, Badhan A, Christiansen MT, Adamson W, Ansari MA et al (2016) Comparison of next-generation sequencing technologies for comprehensive assessment of full-length hepatitis C viral genomes. J Clin Microbiol 54:2470–2484PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Halfon P, Locarnini S (2011) Hepatitis C virus resistance to protease inhibitors. J Hepatol 55:192–206PubMedCrossRefGoogle Scholar
  46. 46.
    Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D et al (2010) 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 376:705–716PubMedCrossRefGoogle Scholar
  47. 47.
    McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R et al (2009) Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 360:1827–1838PubMedCrossRefGoogle Scholar
  48. 48.
    McCauley JA, Rudd MT (2016) Hepatitis C virus NS3/4a protease inhibitors. Curr Opin Pharmacol 30:84–92PubMedCrossRefGoogle Scholar
  49. 49.
    Lenz O, Verbinnen T, Fevery B, Tambuyzer L, Vijgen L, Peeters M et al (2015) Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in phase IIb/III studies. J Hepatol 62:1008–1014PubMedCrossRefGoogle Scholar
  50. 50.
    Kieffer TL, De Meyer S, Bartels DJ, Sullivan JC, Zhang EZ, Tigges A et al (2012) Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. PLoS One 7:e34372PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J et al (2010) In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother 54:1878–1887PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Howe AYM, Black S, Curry S, Ludmerer SW, Liu R, Barnard RJO et al (2014) Virologic resistance analysis from a phase 2 study of MK-5172 combined with pegylated interferon/ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection. Clin Infect Dis 59:1657–1665PubMedCrossRefGoogle Scholar
  53. 53.
    Pilot-Matias T, Tripathi R, Cohen D, Gaultier I, Dekhtyar T, Lu L et al (2014) In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450. Antimicrob Agents Chemother 59:988–997PubMedCrossRefGoogle Scholar
  54. 54.
    Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G et al (2012) MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 56:4161–4167PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Moradpour D, Penin F (2013) Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol 369:113–142PubMedGoogle Scholar
  56. 56.
    Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S et al (2014) Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 370:222–232PubMedCrossRefGoogle Scholar
  57. 57.
    Howe JA, Long J, Black S, Chase R, McMonagle P, Curry S et al (2014) Clinical implications of detectable baseline hepatitis C virus-genotype 1 NS3/4A-protease variants on the efficacy of boceprevir combined with peginterferon/ribavirin. Open Forum Infect Dis 1.
  58. 58.
    Jensen SB, Serre SBN, Humes DG, Ramirez S, Li Y-P, Bukh J et al (2015) Substitutions at NS3 residue 155, 156, or 168 of hepatitis C virus genotypes 2 to 6 induce complex patterns of protease inhibitor resistance. Antimicrob Agents Chemother 59:7426–7436PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Jiang M, Mani N, Lin C, Ardzinski A, Nelson M, Reagan D et al (2013) In vitro phenotypic characterization of hepatitis C virus NS3 protease variants observed in clinical studies of telaprevir. Antimicrob Agents Chemother 57:6236–6245PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lawitz E, Sulkowski M, Jacobson I, Kraft WK, Maliakkal B, Al-Ibrahim M et al (2013) Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: safety, antiviral activity, resistance, and pharmacokinetics. Antivir Res 99:214–220PubMedCrossRefGoogle Scholar
  61. 61.
    McPhee F, Friborg J, Levine S, Chen C, Falk P, Yu F et al (2012) Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir. Antimicrob Agents Chemother 56:3670–3681PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Serre SBN, Jensen SB, Ghanem L, Humes DG, Ramirez S, Li Y-P et al (2016) Hepatitis C virus genotype 1 to 6 protease inhibitor escape variants: in vitro selection, fitness, and resistance patterns in the context of the infectious viral life cycle. Antimicrob Agents Chemother 60:3563–3578PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Verbinnen T, Fevery B, Vijgen L, Jacobs T, De Meyer S, Lenz O (2015) In vitro activity of simeprevir against hepatitis C virus genotype 1 clinical isolates and its correlation with NS3 sequence and site-directed mutants. Antimicrob Agents Chemother 59:7548–7557PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Sarrazin C (2016) The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 64:486–504PubMedCrossRefGoogle Scholar
  65. 65.
    Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang EZ, Spanks J et al (2013) Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. Clin Infect Dis 57:221–229PubMedCrossRefGoogle Scholar
  66. 66.
    Buti M, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H et al (2015) Grazoprevir, Elbasvir, and Ribavirin for chronic hepatitis C virus genotype 1 infection after failure of pegylated interferon and ribavirin with an earlier-generation protease inhibitor: final 24-week results from C-SALVAGE: table 1. Clin Infect Dis 62:32–36PubMedCrossRefGoogle Scholar
  67. 67.
    Pawlotsky J-M (2013) NS5A inhibitors in the treatment of hepatitis C. J Hepatol 59:375–382PubMedCrossRefGoogle Scholar
  68. 68.
    Penin F, Brass V, Appel N, Ramboarina S, Montserret R, Ficheux D et al (2004) Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A. J Biol Chem 279:40835–40843PubMedCrossRefGoogle Scholar
  69. 69.
    Lambert SM, Langley DR, Garnett JA, Angell R, Hedgethorne K, Meanwell NA et al (2014) The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors. Protein Sci 23:723–734PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Love RA, Brodsky O, Hickey MJ, Wells PA, Cronin CN (2009) Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J Virol 83:4395–4403PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Tellinghuisen TL, Marcotrigiano J, Rice CM (2005) Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435:374–379PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    de Chassey B, Navratil V, Tafforeau L, Andre P, Rabourdin-Combe C, Lotteau V (2008) Hepatitis C virus infection protein network. Int J Infect Dis 12:e175CrossRefGoogle Scholar
  73. 73.
    Berger C, Romero-Brey I, Radujkovic D, Terreux R, Zayas M, Paul D et al (2014) Daclatasvir-like inhibitors of NS5A block early biogenesis of hepatitis C virus–induced membranous replication factories, independent of RNA replication. Gastroenterology 147:1094–1105.e1025PubMedCrossRefGoogle Scholar
  74. 74.
    Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100PubMedCrossRefGoogle Scholar
  75. 75.
    Fridell RA, Qiu D, Wang C, Valera L, Gao M (2010) Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother 54:3641–3650PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lee C, Ma H, Hang JQ, Leveque V, Sklan EH, Elazar M et al (2011) The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 414:10–18PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Bartenschlager R, Lohmann V, Penin F (2013) The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol 11:482–496PubMedCrossRefGoogle Scholar
  78. 78.
    Bartels DJ, Sullivan JC, Zhang EZ, Tigges AM, Dorrian JL, De Meyer S et al (2012) Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment. J Virol 87:1544–1553PubMedCrossRefGoogle Scholar
  79. 79.
    Plaza Z, Soriano V, Vispo E, del Mar Gonzalez M, Barreiro P, Seclén E et al (2012) Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor. Antivir Ther 17:921–926PubMedCrossRefGoogle Scholar
  80. 80.
    Wang C, Huang H, Valera L, Sun JH, O'Boyle DR, Nower PT et al (2012) Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052. Antimicrob Agents Chemother 56:1350–1358PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Wang C, Jia L, Huang H, Qiu D, Valera L, Huang X et al (2011) In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A. Antimicrob Agents Chemother 56:1588–1590PubMedCrossRefGoogle Scholar
  82. 82.
    Wang C, Jia L, O'Boyle DR, Sun JH, Rigat K, Valera L et al (2014) Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity. Antimicrob Agents Chemother 58:5155–5163PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Wang C, Valera L, Jia L, Kirk MJ, Gao M, Fridell RA (2012) In vitro activity of daclatasvir on hepatitis C virus genotype 3 NS5A. Antimicrob Agents Chemother 57:611–613PubMedCrossRefGoogle Scholar
  84. 84.
    Sarrazin C, Dvory-Sobol H, Svarovskaia ES, Doehle BP, Pang PS, Chuang S-M et al (2016) Prevalence of resistance-associated substitutions in HCV NS5A, NS5B, or NS3 and outcomes of treatment with ledipasvir and sofosbuvir. Gastroenterology 151:501–512.e501PubMedCrossRefGoogle Scholar
  85. 85.
    Cheng G, Tian Y, Doehle B, Peng B, Corsa A, Lee Y-J et al (2016) In vitro antiviral activity and resistance profile characterization of the hepatitis C virus NS5A inhibitor ledipasvir. Antimicrob Agents Chemother 60:1847–1853PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Krishnan P, Beyer J, Mistry N, Koev G, Reisch T, DeGoey D et al (2014) In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. Antimicrob Agents Chemother 59:979–987PubMedCrossRefGoogle Scholar
  87. 87.
    Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK et al (2008) Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology 48:1769–1778PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Lahser FC, Bystol K, Curry S, McMonagle P, Xia E, Ingravallo P et al (2016) The combination of grazoprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor, demonstrates a high genetic barrier to resistance in HCV genotype 1a replicons. Antimicrob Agents Chemother 60:2954–2964PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lawitz EJ, Dvory-Sobol H, Doehle BP, Worth AS, McNally J, Brainard DM et al (2016) Clinical resistance to velpatasvir (GS-5816), a novel pan-genotypic inhibitor of the hepatitis C virus NS5A protein. Antimicrob Agents Chemother 60:5368–5378PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Liu R, Curry S, McMonagle P, Yeh WW, Ludmerer SW, Jumes PA et al (2015) Susceptibilities of genotype 1a, 1b, and 3 hepatitis C virus variants to the NS5A inhibitor elbasvir. Antimicrob Agents Chemother 59:6922–6929PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Paolucci S, Fiorina L, Mariani B, Gulminetti R, Novati S, Barbarini G et al (2013) Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients. Virol J 10:355PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Wong KA, Worth A, Martin R, Svarovskaia E, Brainard DM, Lawitz E et al (2013) Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrob Agents Chemother 57:6333–6340PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yoshimi S, Imamura M, Murakami E, Hiraga N, Tsuge M, Kawakami Y et al (2015) Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J Med Virol 87:1913–1920PubMedCrossRefGoogle Scholar
  94. 94.
    Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T, Zhang X et al (2015) Analysis of hepatitis C virus genotype 1b resistance variants in Japanese patients treated with paritaprevir-ritonavir and ombitasvir. Antimicrob Agents Chemother 60:1106–1113PubMedCrossRefGoogle Scholar
  95. 95.
    Eltahla A, Luciani F, White P, Lloyd A, Bull R (2015) Inhibitors of the hepatitis C virus polymerase; mode of action and resistance. Viruses 7:5206–5224PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Soriano V, Vispo E, de Mendoza C, Labarga P, Fernandez-Montero JV, Poveda E et al (2013) Hepatitis C therapy with HCV NS5B polymerase inhibitors. Expert Opin Pharmacother 14:1161–1170PubMedCrossRefGoogle Scholar
  97. 97.
    De Clercq E (2015) Curious (old and new) antiviral nucleoside analogues with intriguing therapeutic potential. Curr Med Chem 22:3866–3880PubMedCrossRefGoogle Scholar
  98. 98.
    Ago H, Adachi T, Yoshida A, Yamamoto M, Habuka N, Yatsunami K et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7:1417–1426PubMedCrossRefGoogle Scholar
  99. 99.
    Bressanelli S, Tomei L, Roussel A, Incitti I, Vitale RL, Mathieu M et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc Natl Acad Sci U S A 96:13034–13039PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF, Weber PC (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 6:937–943PubMedCrossRefGoogle Scholar
  101. 101.
    Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Niu C, Zennou V et al (2012) Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 56:3359–3368PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Donaldson EF, Harrington PR, O'Rear JJ, Naeger LK (2014) Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. Hepatology 61:56–65PubMedCrossRefGoogle Scholar
  103. 103.
    Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM et al (2013) Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 13:401–408PubMedCrossRefGoogle Scholar
  104. 104.
    Svarovskaia ES, Dvory-Sobol H, Parkin N, Hebner C, Gontcharova V, Martin R et al (2014) Infrequent development of resistance in genotype 1–6 hepatitis C virus–infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 59:1666–1674PubMedCrossRefGoogle Scholar
  105. 105.
    Svarovskaia ES, Gane E, Dvory-Sobol H, Martin R, Doehle B, Hedskog C et al (2015) L159F and V321A sofosbuvir-associated hepatitis C virus NS5B substitutions. J Infect Dis 213:1240–1247PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourlière M et al (2014) Retreatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med 370:1604–1614PubMedCrossRefGoogle Scholar
  107. 107.
    Di Maio VC, Cento V, Mirabelli C, Artese A, Costa G, Alcaro S et al (2014) Hepatitis C virus genetic variability and the presence of NS5B resistance-associated mutations as natural polymorphisms in selected genotypes could affect the response to NS5B inhibitors. Antimicrob Agents Chemother 58:2781–2797PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Krishnan P, Tripathi R, Schnell G, Reisch T, Beyer J, Irvin M et al (2015) Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir. Antimicrob Agents Chemother 59:5445–5454PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Berger KL, Sarrazin C, Nelson DR, Scherer J, Sha N, Marquis M et al (2016) Resistance analyses of HCV NS3/4A protease and NS5B polymerase from clinical studies of deleobuvir and faldaprevir. PLoS One 11:e0160668PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kati W, Koev G, Irvin M, Beyer J, Liu Y, Krishnan P et al (2014) In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob Agents Chemother 59:1505–1511PubMedCrossRefGoogle Scholar
  111. 111.
    Lu L, Dekhtyar T, Masse S, Pithawalla R, Krishnan P, He W et al (2007) Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro. Antivir Res 76:93–97PubMedCrossRefGoogle Scholar
  112. 112.
    Ji H, Kozak RA, Biondi MJ, Pilon R, Vallee D, Liang BB et al (2015) Next generation sequencing of the hepatitis C virus NS5B gene reveals potential novel S282 drug resistance mutations. Virology 477:1–9PubMedCrossRefGoogle Scholar
  113. 113.
    Kukolj G, McGibbon GA, McKercher G, Marquis M, Lefèbvre S, Thauvette L et al (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase. J Biol Chem 280:39260–39267PubMedCrossRefGoogle Scholar
  114. 114.
    Abergel A, Asselah T, Metivier S, Kersey K, Jiang D, Mo H et al (2016) Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis 16:459–464PubMedCrossRefGoogle Scholar
  115. 115.
    Abergel A, Metivier S, Samuel D, Jiang D, Kersey K, Pang PS et al (2016) Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection. Hepatology 64:1049–1056PubMedCrossRefGoogle Scholar
  116. 116.
    Bourlière M, Bronowicki J-P, de Ledinghen V, Hézode C, Zoulim F, Mathurin P et al (2015) Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 15:397–404PubMedCrossRefGoogle Scholar
  117. 117.
    Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown RS Jr et al (2015) Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 149:649–659PubMedCrossRefGoogle Scholar
  118. 118.
    Gane EJ, Hyland RH, An D, Svarovskaia E, Pang PS, Brainard D et al (2015) Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 149:1454–1461.e1451PubMedCrossRefGoogle Scholar
  119. 119.
    Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H et al (2014) 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 383:515–523PubMedCrossRefGoogle Scholar
  120. 120.
    Mizokami M, Dvory-Sobol H, Izumi N, Nishiguchi S, Doehle B, Svarovskaia ES et al (2016) Resistance analyses of Japanese hepatitis C-infected patients receiving sofosbuvir or ledipasvir/sofosbuvir containing regimens in phase 3 studies. J Viral Hepat 23:780–788PubMedCrossRefGoogle Scholar
  121. 121.
    Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM et al (2015) Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 373:2618–2628PubMedCrossRefGoogle Scholar
  122. 122.
    Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N et al (2015) Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 373:2599–2607PubMedCrossRefGoogle Scholar
  123. 123.
    Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S et al (2015) Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 373:2608–2617PubMedCrossRefGoogle Scholar
  124. 124.
    Pianko S, Flamm SL, Shiffman ML, Kumar S, Strasser SI, Dore GJ et al (2015) Sofosbuvir plus velpatasvir combination therapy for treatment-experienced patients with genotype 1 or 3 hepatitis C virus infection. Ann Intern Med 163:809PubMedCrossRefGoogle Scholar
  125. 125.
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I et al (2014) Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 370:211–221PubMedCrossRefGoogle Scholar
  126. 126.
    Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR et al (2015) Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 373:714–725PubMedCrossRefGoogle Scholar
  127. 127.
    Leroy V, Angus P, Bronowicki J-P, Dore GJ, Hezode C, Pianko S et al (2016) Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: a randomized phase III study (ALLY-3+). Hepatology 63:1430–1441PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Sarrazin C, Lathouwers E, Peeters M, Daems B, Buelens A, Witek J et al (2015) Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region. Antivir Res 116:10–16PubMedCrossRefGoogle Scholar
  129. 129.
    Kwo P, Gitlin N, Nahass R, Bernstein D, Etzkorn K, Rojter S et al (2016) Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology 64:370–380PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Lawitz E, Matusow G, DeJesus E, Yoshida EM, Felizarta F, Ghalib R et al (2016) Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: a phase 3 study (OPTIMIST-2). Hepatology 64:360–369PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    AASLD/IDSA HCV Guidance Panel (2015) Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 62:932–954CrossRefGoogle Scholar
  132. 132.
    Krishnan P, Tripathi R, Schnell G, Reisch T, Beyer J, Irvin M et al (2014) Pooled analysis of resistance in patients treated with ombitasvir/ABT-450/r and dasabuvir with or without ribavirin in Phase 2 and Phase 3 clinical trials. Hepatology 60:1134a–1135aGoogle Scholar
  133. 133.
    Schnell G, Tripathi R, Beyer J, Reisch T, Krishnan P, Lu L et al (2015) Hepatitis C virus genotype 4 resistance and subtype demographic characterization of patients treated with ombitasvir plus paritaprevir/ritonavir. Antimicrob Agents Chemother 59:6807–6815PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ari ZB, Zhao Y et al (2015) Grazoprevir–Elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection. Ann Intern Med 163:1–13PubMedCrossRefGoogle Scholar
  135. 135.
    Kwo P, Gane EJ, Peng C-Y, Pearlman B, Vierling JM, Serfaty L et al (2017) Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology 152:164–175.e164PubMedCrossRefGoogle Scholar
  136. 136.
    Jacobson IM, Asante-Appiah E, Wong P, Black TA, Howe AYM, Wahl J et al (2015) Prevalence and impact of baseline NSA resistance associated variants (RAVs) on the efficacy of elbasvir/grazoprevir (EBR/GZR) against GT1a infection. Hepatology 62:1393AGoogle Scholar
  137. 137.
    Komatsu TE, Boyd S, Sherwat A, Tracy L, Naeger LK, O’Rear JJ et al (2017) Regulatory analysis of effects of hepatitis C virus NS5A polymorphisms on efficacy of elbasvir and grazoprevir. Gastroenterology 152:586–597PubMedCrossRefGoogle Scholar
  138. 138.
    Zeuzem S, Rockstroh JK, Kwo P, Roth D, Lawitz E, Sulkowski M et al (2015) Predictors of response to grazoprevir/elbasvir among HCV genotype 1 (GT1)–infected patients: integrated analysis of phase 2-3 trials. Hepatology 62:554AGoogle Scholar
  139. 139.
    Krishnan P, Schnell G, Tripathi R, Ng T, Reisch T, Beyer J et al (2017) Pooled resistance analysis in HCV genotype 1–6-infected patients treated with glecaprevir/pibrentasvir in phase 2 and 3 clinical trials. J Hepatol 66:S500CrossRefGoogle Scholar
  140. 140.
    Reau N, Nguyen MH, Kowdley KV, Gane E, Dvory-Sobol H, Svarovskaia E et al (2016) Integrated resistance analyses of HCV-infected patients treated with sofosbuvir, velpatasvir, and voxilaprevir for 8 and 12 weeks from phase 2 studies. Hepatology 64:415A–416AGoogle Scholar
  141. 141.
    Bourliere M, Gordon SC, Flamm SL, Cooper CL, Ramji A, Tong M et al (2017) Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 376:2134–2146PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineMassachusetts General HospitalBostonUSA
  2. 2.Liver Center and Division of Gastroenterology, Department of MedicineMassachusetts General HospitalBostonUSA

Personalised recommendations