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Protease Inhibitor Resistance

  • Johannes VermehrenEmail author
  • Christoph Welsch
  • Christoph Sarrazin
Reference work entry

Abstract

The recent development of hepatitis C virus (HCV)–specific direct-acting antivirals (DAAs) has marked a major milestone in the treatment of chronic HCV infection, allowing for viral elimination in the majority of treated patients. The first two drugs to be approved for the treatment of HCV genotype 1 infection were the HCV NS3/4A protease inhibitors telaprevir and boceprevir. However, their administration in combination with pegylated interferon alfa and ribavirin was associated with poor tolerability despite showing improved overall efficacy. In addition, as in DAAs targeting other viruses, concerns were raised with regard to the selection of drug-resistant viral variants. Selection of resistance-associated variants (RAVs) allows the virus to escape from drug pressure with subsequent treatment failure. The emergence of RAVs depends on a number of drug-, host-, and virus-related factors that are reviewed here. In addition, detailed resistance profiles of approved protease inhibitors and those that are still in clinical development are also discussed.

Keywords

Hepatitis C virus Protease inhibitor Ribavirin Pegylated interferon alfa Resistance Resistance associated variant NS3-4A Telaprevir Boceprevir Simeprevir Paritaprevir 

References

  1. Afdhal NH, Everson G, Calleja JL, McCaughan G, Symonds WT, Denning J et al (2014) 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 60:S28CrossRefGoogle Scholar
  2. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S et al (2011) Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 364(13):1207–1217CrossRefPubMedPubMedCentralGoogle Scholar
  3. Barnard RJ, Howe JA, Ogert RA, Zeuzem S, Poordad F, Gordon SC et al (2013) Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies. Virology 444(1–2):329–336CrossRefPubMedGoogle Scholar
  4. Bartels DJ, Zhou Y, Zhang EZ, Marcial M, Byrn RA, Pfeiffer T et al (2008) Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis 198(6):800–807CrossRefPubMedGoogle Scholar
  5. Bartels DJ, Sullivan JC, Zhang EZ, Tigges AM, Dorrian JL, De Meyer S et al (2013) 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(3):1544–1553CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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(7):482–496CrossRefPubMedGoogle Scholar
  7. Benhamou Y, Moussalli J, Ratziu V, Lebray P, De Backer K, De Meyer S et al (2013) Telaprevir activity in treatment-naive patients infected hepatitis C virus genotype 4: a randomized trial. J Infect Dis 208(6):1000–1007CrossRefPubMedGoogle Scholar
  8. Berger KL, Lagace L, Triki I, Cartier M, Marquis M, Lawetz C et al (2013) Viral resistance in hepatitis C virus genotype 1-infected patients receiving the NS3 protease inhibitor Faldaprevir (BI 201335) in a phase 1b multiple-rising-dose study. Antimicrob Agents Chemother 57(10):4928–4936CrossRefPubMedPubMedCentralGoogle Scholar
  9. Berger K, Sarrazin C, Ferenci P, Jensen DM, Jacobson IM, Stern JO et al (2014) NS3 Q80K did not impact efficacy or treatment-emergent resistance patterns in HCV genotype 1-infected patients receiving faldaprevir + peginterferon/ribavirin in three phase III trials. J Hepatol 60:S497CrossRefGoogle Scholar
  10. Chevaliez S, Rodriguez C, Soulier A, Ahmed-Belkacem A, Hezode C, Pawlotsky JM (2011) Molecular characterization of HCV resistance to telaprevir by means of ultra-deep pyrosequencing: preexisting resistant variants and dynamics of resistant populations. J Hepatol 54:S30CrossRefGoogle Scholar
  11. De Meyer S, Thys K, Dierynck I, Ghys A, Aerssens J, Picchio G (2012a) Deep sequencing screening for telaprevir-resistant viral variants in previous null responders fails to identify those patients at risk of failing telaprevir plus peginterferon/ribavirin therapy. J Hepatol 56:S465CrossRefGoogle Scholar
  12. De Meyer S, Dierynck I, Ghys A, Beumont M, Daems B, Van Baelen B et al (2012b) Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: results from the REALIZE trial. Hepatology 56(6):2106–2115CrossRefPubMedGoogle Scholar
  13. Dierynck I, Thys K, Bartels DJ, Ghys A, Van Rossem E, Zhang E et al (2013) Post-treatment viral evolution assessment using ultra-deep pyrosequencing in samples from patients with hepatitis C virus infection: the EXTEND study. Hepatology 58:939AGoogle Scholar
  14. Domingo E, Menendez-Arias L, Holland JJ (1997) RNA virus fitness. Rev Med Virol 7(2):87–96CrossRefPubMedGoogle Scholar
  15. Fabrycki J, Patel D, Yang G, Zhao Y, Podos S, Robison H et al (2012) Characterization of HCV NS3 protease variants from patients enrolled in a 28-day phase 2a trial of ACH-1625 daily dosing plus PegIFN-alpha 2a/RBV. J Hepatol 56:S468CrossRefGoogle Scholar
  16. FDA (2011) Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf
  17. 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(17):1594–1603CrossRefPubMedGoogle Scholar
  18. Forestier N, Reesink HW, Weegink CJ, McNair L, Kieffer TL, Chu HM et al (2007) Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 46(3):640–648CrossRefPubMedGoogle Scholar
  19. Foster GR, Hezode C, Bronowicki JP, Carosi G, Weiland O, Verlinden L et al (2011) Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 141(3):881–889CrossRefPubMedGoogle Scholar
  20. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347(13):975–982CrossRefPubMedGoogle Scholar
  21. Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR (2009) Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS 23(9):1035–1046CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gish R, Jia JD, Locarnini S, Zoulim F (2012) Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis 12(4):341–353CrossRefPubMedGoogle Scholar
  23. Grammatikos G, Jabara CB, Ahmad MQ, Herrmann E, Zeuzem S, Welsch C (2014) Genetic background for development of resistance mutations within the HCV NS3 protease-helicase in patients naive to direct antivirals. Antivir Ther 19(5):455–461CrossRefPubMedGoogle Scholar
  24. Hezode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V et al (2014) Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology 147(1):132–142CrossRefPubMedGoogle Scholar
  25. Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL et al (2004) Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127(5):1347–1355CrossRefPubMedGoogle Scholar
  26. Howe JA, Long JM, Black S, Chase R, McMonagle P, Curry S et al (2013a) Pooled clinical trial analyses of detectable basline HCV NS3/4A resistance associated variants on the efficacy of boceprevir plus pegylated interferon/ribavirin. Hepatology 58:1097AGoogle Scholar
  27. Howe AY, Long JM, Thompson S, Barnard RJ, Alves K, Howe JA et al (2013b) Analysis of the durability of response and persistance of resistance associated variants during long term follow Up after boceprevir plus pegylated interferon/ribavirin therapy – 3 year analysis. Hepatology 58:1095AGoogle Scholar
  28. 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(25):2405–2416CrossRefPubMedGoogle Scholar
  29. Jacobson IM, Dore GJ, Foster GR, Fried MW, Radu M, Rafalsky VV et al. (2014) 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 384(9941):403–13CrossRefPubMedGoogle Scholar
  30. Johnson CL, Owen DM, Gale M Jr (2007) Functional and therapeutic analysis of hepatitis C virus NS3.4A protease control of antiviral immune defense. J Biol Chem 282(14):10792–10803CrossRefPubMedGoogle Scholar
  31. Kao J-H, Heo J, Yoffe B, Sievert W, Jacobson IM, Bessone F et al (2014) Efficacy and safety of daclatasvir in combination with asunaprevir (DCV+ASV) in cirrhotic and Non-cirrhotic patients with HCV genotype 1B: results of the hallmark dual study. J Hepatol 60:S527CrossRefGoogle Scholar
  32. Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW et al (2007) Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 46(3):631–639CrossRefPubMedGoogle Scholar
  33. 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-naive patients. Hepatology 48(6):1769–1778CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lagace L, White PW, Bousquet C, Dansereau N, Do F, Llinas-Brunet M et al (2012) In vitro resistance profile of the hepatitis C virus NS3 protease inhibitor BI 201335. Antimicrob Agents Chemother 56(1):569–572CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P et al (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426(6963):186–189CrossRefPubMedGoogle Scholar
  36. Lange CM, Zeuzem S (2011) IL28B single nucleotide polymorphisms in the treatment of hepatitis C. J Hepatol 55(3):692–701CrossRefPubMedGoogle Scholar
  37. 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(9956):1756–1765CrossRefPubMedGoogle Scholar
  38. 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(5):1878–1887CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lenz O, Fevery B, Vijgen L, Verbeeck J, Peeters M, Beumont M et al (2011) TMC435 in combination with peginterferon alpha-2a/ribavirin in treatment-naive patients infected with HCV genotype 1: virology analysis of the pillar study. Hepatology 54:985AGoogle Scholar
  40. Lenz O, de Bruijne J, Vijgen L, Verbinnen T, Weegink C, Van Marck H et al (2012) Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy. Gastroenterology 143(5):1176–1178.e1171-1176CrossRefPubMedGoogle Scholar
  41. Lenz O, Vijgen L, Berke JM, Cummings MD, Fevery B, Peeters M et al (2013) Virologic response and characterisation of HCV genotype 2–6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol 58(3):445–451CrossRefPubMedGoogle Scholar
  42. Lenz O, Fevery B, Verbinnen T, Tambuyzer L, Vijgen L, Peeters M et al (2015) Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies. Hepatology 62(5):1008–14Google Scholar
  43. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A 102(49):17717–17722CrossRefPubMedPubMedCentralGoogle Scholar
  44. Lin C, Lin K, Luong YP, Rao BG, Wei YY, Brennan DL et al (2004) In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem 279(17):17508–17514CrossRefPubMedGoogle Scholar
  45. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285(5424):110–113CrossRefPubMedGoogle Scholar
  46. 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(9286):958–965CrossRefPubMedGoogle Scholar
  47. Manns MP, Pol S, Jacobson IM, Marcellin P, Gordon SC, Peng C-Y et al (2014a) All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 384(9954):1597–1605CrossRefPubMedGoogle Scholar
  48. Manns MP, Vierling JM, Bacon BR, Bruno S, Shibolet O, Baruch Y et al (2014b) The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis. Gastroenterology 147(2):366–376CrossRefPubMedGoogle Scholar
  49. Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M, Horsmans Y et al. (2014c) 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(9941):414–26CrossRefPubMedGoogle Scholar
  50. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH et al (2010) Telaprevir for previously treated chronic HCV infection. N Engl J Med 362(14):1292–1303CrossRefPubMedGoogle Scholar
  51. 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(7):3670–3681CrossRefPubMedPubMedCentralGoogle Scholar
  52. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R et al (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437(7062):1167–1172CrossRefPubMedGoogle Scholar
  53. Moreno C, Berg T, Tanwandee T, Thongsawat S, Van Vlierberghe H, Zeuzem S et al (2012) Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study. J Hepatol 56(6):1247–1253CrossRefPubMedGoogle Scholar
  54. Morikawa K, Lange CM, Gouttenoire J, Meylan E, Brass V, Penin F et al (2011) Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepat 18(5):305–315CrossRefPubMedGoogle Scholar
  55. Pawlotsky JM (2014) New hepatitis C virus (HCV) drugs and the hope for a cure: concepts in anti-HCV drug development. Semin Liver Dis 34(1):22–29CrossRefPubMedGoogle Scholar
  56. Pilot-Matias T, Tripathi R, Dekhtyar T, Menon R, Gaultier IA, Cohen D et al (2011) Genotypic and phenotypic characterization of NS3 variants selected in HCV-infected patients treated with ABT-450. J Hepatol 54:S485CrossRefGoogle Scholar
  57. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS et al (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364(13):1195–1206CrossRefPubMedPubMedCentralGoogle Scholar
  58. Poordad F, Bronowicki JP, Gordon SC, Zeuzem S, Jacobson IM, Sulkowski MS et al (2012) Factors that predict response of patients with HCV infection to boceprevir. Gastroenterology 143(3):608–618CrossRefPubMedGoogle Scholar
  59. 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(21):1973–1982CrossRefPubMedGoogle Scholar
  60. 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(51):20509–20513CrossRefPubMedPubMedCentralGoogle Scholar
  61. Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J et al (2006) Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 131(4):997–1002CrossRefPubMedGoogle Scholar
  62. Reesink HW, Fanning GC, Farha KA, Weegink C, Van Vliet A, Van 't Klooster G et al (2010) Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 138(3):913–921CrossRefPubMedGoogle Scholar
  63. Rong L, Dahari H, Ribeiro RM, Perelson AS (2010) Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2(30):30ra32CrossRefPubMedPubMedCentralGoogle Scholar
  64. Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138(2):447–462CrossRefPubMedGoogle Scholar
  65. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M et al (2007a) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132(5):1767–1777CrossRefPubMedGoogle Scholar
  66. Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta SK et al (2007b) SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 132(4):1270–1278CrossRefPubMedGoogle Scholar
  67. Sarrazin C, Hezode C, Zeuzem S, Pawlotsky JM (2012) Antiviral strategies in hepatitis C virus infection. J Hepatol 56(Suppl 1):S88–S100CrossRefPubMedGoogle Scholar
  68. Sarrazin C, Reesink HW, Zeuzem S, Dierynck I, Luo D, Witek J et al (2013) Treatment with telaprevir/PEG-IFN/RBV after 14-day telaprevir exposure in phase I studies: results from the phase IIIB C219 rollover study. J Hepatol 58:S369CrossRefGoogle Scholar
  69. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT et al (2011a) Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 365(11):1014–1024CrossRefPubMedGoogle Scholar
  70. Sherman KE, Sulkowski MS, Zoulim F, Alberti A, Wei LJ, Sullivan J et al (2011b) Follow-up of SVR durability and viral resistance in patients with chronic hepatitis C treated with telaprevir-based regimens: interim analysis of the extend study. Hepatology 54:485ACrossRefGoogle Scholar
  71. Shimakami T, Welsch C, Yamane D, McGivern DR, Yi M, Zeuzem S et al (2011) Protease inhibitor-resistant hepatitis C virus mutants with reduced fitness from impaired production of infectious virus. Gastroenterology 140(2):667–675CrossRefPubMedGoogle Scholar
  72. Silva MO, Treitel M, Graham DJ, Curry S, Frontera MJ, McMonagle P et al (2013) Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3. J Hepatol 59(1):31–37CrossRefPubMedGoogle Scholar
  73. Strizki JM, Barnard RJO, Cheney C, McHale C, Graham D, Himmelberger A et al (2012) Evaluation of NS3 amino acid variants in a phase 1b study of genotype 1 (Gt1) and Gt3 infected patients with the Hcv protease inhibitor, MK-5172. J Hepatol 56:S479CrossRefGoogle Scholar
  74. Sulkowski MS, Asselah T, Lalezari J, Ferenci P, Fainboim H, Leggett B et al (2013a) Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV: SILEN-C1 trial. Hepatology 57(6):2143–2154CrossRefPubMedGoogle Scholar
  75. Sulkowski MS, Bourliere M, Bronowicki JP, Asselah T, Pawlotsky JM, Shafran SD et al (2013b) Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 57(6):2155–2163CrossRefPubMedGoogle Scholar
  76. Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang E, Spanks J et al (2011) Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. J Hepatol 54:S4CrossRefGoogle Scholar
  77. 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(2):221–229CrossRefPubMedGoogle Scholar
  78. 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(8):4161–4167CrossRefPubMedPubMedCentralGoogle Scholar
  79. Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U et al (2009) Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 50(6):1709–1718CrossRefPubMedGoogle Scholar
  80. Susser S, Vermehren J, Forestier N, Welker MW, Grigorian N, Fuller C et al (2011) Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir. J Clin Virol 52(4):321–327CrossRefPubMedGoogle Scholar
  81. Susser S, Schelhorn SE, Lange CM, Welsch C, Vermehren J, Perner D et al (2012) 454 deep sequencing analysis of hepatitis C virus NS3 protease resistance mutations A87T, R117H, and S174F in patients treated with telaprevir or boceprevir. Hepatology 56:714ACrossRefGoogle Scholar
  82. Susser S, Flinders M, Reesink HW, Zeuzem S, Lawyer A, Ghys A et al (2015) Re-treatment with telaprevir-based triple therapy after telaprevir exposure in phase 1 studies: deep sequence analysis for persistence of resistant variants. Antimicrob Agents Chemother 59(5):2746–55Google Scholar
  83. Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA (2006) Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antivir Res 70(2):28–38CrossRefPubMedGoogle Scholar
  84. Vermehren J, Susser S, Lange CM, Forestier N, Karey U, Hughes E et al (2012) Mutations selected in the hepatitis C virus NS3 protease domain during sequential treatment with boceprevir with and without pegylated interferon alfa-2b. J Viral Hepat 19(2):120–127CrossRefPubMedGoogle Scholar
  85. Welsch C (2014) Genetic barrier and variant fitness in hepatitis C as critical parameters for drug resistance development. Drug Discov Today Technol 11:19–25CrossRefPubMedGoogle Scholar
  86. Welsch C, Schweizer S, Shimakami T, Domingues FS, Kim S, Lemon SM et al (2012a) Ketoamide resistance and hepatitis C virus fitness in val55 variants of the NS3 serine protease. Antimicrob Agents Chemother 56(4):1907–1915CrossRefPubMedPubMedCentralGoogle Scholar
  87. Welsch C, Shimakami T, Hartmann C, Yang Y, Domingues FS, Lengauer T et al (2012b) Peptidomimetic escape mechanisms arise via genetic diversity in the ligand-binding site of the hepatitis C virus NS3/4A serine protease. Gastroenterology 142(3):654–663CrossRefPubMedGoogle Scholar
  88. Yi M, Hu F, Joyce M, Saxena V, Welsch C, Chavez D et al (2014) Evolution of a cell culture-derived genotype 1a hepatitis C virus (H77S.2) during persistent infection with chronic hepatitis in a chimpanzee. J Virol 88(7):3678–3694CrossRefPubMedPubMedCentralGoogle Scholar
  89. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S et al (2011) Telaprevir for retreatment of HCV infection. N Engl J Med 364(25):2417–2428CrossRefPubMedGoogle Scholar
  90. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourliere M et al (2014) Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 370(17):1604–1614CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Johannes Vermehren
    • 1
    Email author
  • Christoph Welsch
    • 1
  • Christoph Sarrazin
    • 1
  1. 1.Medizinische Klinik 1UniversitätsklinikumFrankfurtGermany

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