Directly acting antivirals against hepatitis C virus: Mechanisms of action and impact of resistant associated variants

Minerva Gastroenterologica e Dietologica

Volumn 62, Issue 1, 2016, Pages 76-87

  Premoli, Caterina ^a   Aghemo, Alessio ^a  

^a MAGGIORE HOSPITAL   (Italy)

Author keywords

Antiviral agents; Hepatitis C; Therapeutics

Indexed keywords

AMINO ACID; BOCEPREVIR; DACLATASVIR; DASABUVIR; HEPACIVIRIN INHIBITOR; LEDIPASVIR; NONSTRUCTURAL PROTEIN 5A; NONSTRUCTURAL PROTEIN 5A INHIBITOR; NONSTRUCTURAL PROTEIN 5B; OMBITASVIR; PARITAPREVIR; SIMEPREVIR; SOFOSBUVIR; TELAPREVIR; ANTIVIRUS AGENT; ENZYME INHIBITOR; OLIGOPEPTIDE; VIRAL PROTEIN;

AMINO ACID SUBSTITUTION; ANTIVIRAL THERAPY; DRUG MECHANISM; GENE MUTATION; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IN VITRO STUDY; IN VIVO STUDY; REVIEW; SEQUENCE ANALYSIS; ANTAGONISTS AND INHIBITORS; ANTIVIRAL RESISTANCE; CLINICAL TRIAL (TOPIC); DRUG EFFECTS; GENETICS; GENOTYPE; HEPACIVIRUS; HEPATITIS C, CHRONIC; MUTATION;

ANTIVIRAL AGENTS; CLINICAL TRIALS AS TOPIC; DRUG RESISTANCE, VIRAL; ENZYME INHIBITORS; GENOTYPE; HEPACIVIRUS; HEPATITIS C, CHRONIC; HUMANS; MUTATION; OLIGOPEPTIDES; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84961575132     PISSN: 1121421X     EISSN: 18271642     Source Type: Journal    
DOI: None     Document Type: Review

References (70)

1. World Health Organization. Hepatitis C factsheet no 164. Update July 2013.
2. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 2013;10:553-62.
3. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010;8:1017-29.
4. McHutchison J, Lawitz E, Shiffman M, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa2b of alfa2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-93.
5. Pawlotsky JM, Feld JJ, Zeuzem S, Hoofnagle J. From non-A, non-B hepatitis to hepatitis C virus cure. J Hepatol 2015;62:S87-S99.
6. Alexopoulou A, Karayiannis P. Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals. Ann Gastroenterol 2015;28:55-65.
7. Pawlotsky JM, Chevaliez S, McHutchinson J. Treatment of chronic hepatitis C: current and future. Curr Top Microbiol Immunol 2013;369:321-42.
8. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999;285:110-3.
9. Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Telling Huisen TL, Liu CC, et al. Complete replication of hepatitis C virus in cell culture. Science 2005;309:623-6.
10. Fusco DN, Chung RT. Novel therapies for hepatitis C: insight from the structure of the virus. Ann Med 2012;63:373-87.
11. Martell M, Esteban JL, Quer J, Genesca J, Genescà J, Weiner A, Esteban R, et al. Hepatitis C virus circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol 1992;66:3225-9.
12. Welsch C, Shimakami T, Hartmann C, Yang Y, Domingues FS, Lengauer T, et al. Peptidomimetic escape arise due to genetic diversity in the ligand-binding site of HCV NS3/4A serine protease. Gastroenterology 2010;142:654-63.
13. Welsch C, Zeusem S. Clinical relevance of HCV antiviral drug resistance. Curr Opin Virol 2012;2:651-5.
14. Barzon L, Lavezzo E, Costanzi G, Franchin E, Toppo S, Palù G. Next-generation sequencing technologies in diagnostic virology. J Clin Virol 2013;58:346-50.
15. Morikawa K, Lange CM. Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepat 2011;18:305-15.
16. Lin C. HCV NS3-4A serine protease. In: Tan SL, editor. Source hepatitis C viruses: genomes and molecular biology. Norfolk (UK): Horizon Bioscience; 2006. Chapter 6.
17. Sarrazin C. Zeuzem S Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010;138:447-62.
18. Romano KP, Ali A, Aydin C, Soumana D, Ozen A, Deveau LM, et al. The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. PLoS Pathog 2012;8:e1002832.
19. Kieffer TL, George S. Resistance to hepatitis C virus protease inhibitors. Curr Opin Virol 2014;8:16-21.
20. Lange CM, Sarrazin C, Zeuzem S. Review article: specifically targeted anti-viral therapy for hepatitis C - a new era in therapy. Aliment Pharmacol Ther 2010;32:14-28.
21. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. ADVANCE Study Team Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16.
22. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Müh U, Welker M, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007;132:1767-77.
23. Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology 2008;48:1769-78.
24. Poordad F, Bronowicki JP, Gordon SC, Zeuzem S, Jacobson IM, Sulkowski MS, et al. SPRINT-2 and RESPOND-2 Investigators. Factors that predict response of patients with hepatitis C virus infection to boceprevir. Gastroenterology 2012;143:608-18.e1-5.
25. Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang EZ, Spanks J, et al. Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials Clin Infect Dis 2013;57:221-9.
26. Powdrill MH, Tchesnokov EP, Kozak RA, Russell RS, Martin R, Svarovskaia ES, et al. 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 2011;108:20509-13.
27. Welsch C, Zeuzem S. Clinical relevance of HCV antiviral drug resistance. Current Opinion in Virology 2012;2:651-5.
28. Lenz O, de Bruijne J, Vijgen L, Verbinnen T, Weegink C, Van Marck H. et al. Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus infected patients following TMC435 monotherapy. Gastroenterology 2012;143:1176-8.
29. Sarrazin C, Reesink HW, Zeuzem S, Weegink CJ, Luo D, Witek J, et al. Retreatment with telaprevir/PEG-IFN/RBV after a short exposure to telaprevir in phase I studies: interim results from a phase IIIB rollover trial (C219). AASLD; San Francisco; 2011.
30. Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012;56:4161-7
31. Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother 2010;54:1878-87.
32. 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;384:403-13.
33. 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;384:414-26.
34. th Annual Meeting of the American Association for the Study of Liver Disease.
35. De Luca A, Di Giambenedetto S, Lo Presti A, Sierra S, Prosperi M, Cella E, et al. Two distinct hepatitis C virus genotype 1a clades have different geographical distribution and association with natural resistance to NS3 Protease Inhibitors. Open Forum Infect Dis 2015;2.
36. The AASLD/IDSA Clinical Guidance for Hepatitis C. March 21, 2015.
37. Lenz O, Verbinnen T, Fevery B, Tambuyzer L, Vijgen L, Peeters M, et al. Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies. J Hepatol 2014;28:00881-2.
38. Feld JJ, Kowdley KV, Coakley E, Sigal S. Nelson DR Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370:1594-603.
39. Ferenci P, Bernstein D, Lalezari J, Cohen D. ABT-450/rombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;370:1983-92.
40. 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;370:1973-82.
41. Krishnan P, Tripathi R, Schnell G, Reisch T, Beyer J, Dekhtyar T, et al. Long-term follow-up of treatment emergent resistance-associated variants in NS3, NS5A and NS5B with Paritaprevir/R-, Ombitasvir- and Dasabuvir-based regimens. J Hepatol 2015;62:S213-234.
42. Biochemical Activities of the HCV NS5B RNA-Dependent RNA Polymerase. Ranjith-Kumar CT, Kao CC. Hepatitis C Viruses: Genomes and Molecular Biology. Norfolk (UK): Horizon Bioscience; 2006. Chapter 10.
43. Tomassini JE, Bosserman M, Getty K, Stahlhut MW, Eldrup AB, Bhat B, et al. Inhibition of hepatitis C virus RNA replication by 2'-modified nucleoside analogs. J Biol Chem 2003;278:11979-84.
44. Larrey D, Lohse AW, de Ledinghen V, Trepo C, Gerlach T, Zarski JP, et al. Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin. J Hepatol 2012:57;39-46.
45. Migliaccio G, Tomassini JE, Carroll SS, Tomei L, Altamura S, Bhat B, et al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J Biol Chem 2003;278:49164-70.
46. Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Niu C, Zennou V, et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 2012;56:3359-68.
47. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34-44
48. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-87
49. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. POSITRON Study; FUSION Study Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867-77
50. Donaldson EF, Harrington PR, O'Rear JJ, Naeger LK. Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. Hepatology 2015;61:56-65.
51. Svarovskaia E, Dvory-Sobol H, Doehle B, Gane E, Jacobson I, Nelson D, et al. L159F and V321A Sofosbuvir treatment-emergent HCV NS5B substitutions. Hepatology 2014;60:218A.
52. Kati W, Koev G, Irvin M, Beyer J, Liu Y, Krishnan P, et al. In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob Agents Chemother 2015;59:1505-11.
53. Brass V, Bieck E, Montserret R, Wölk B, Hellings JA, Blum HE, et al. An amino-terminal amphipathic alphahelix mediates membrane association of hepatitis C virus nonstructural protein 5A. J Biol Chem 2002;277:8130-9.
54. Appel N, Schaller T, Penin F, Bartenschlager R. From structure to function: new insight into hepatitis C virus RNA replication, J Biol Chem 2006;281:9833-6.
55. Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM. Identification of residues required for RNA replication in domain II and III of the hepatitis C virus NS5A protein. J Virol 2008;1073-83.
56. Guedj L, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yield a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci USA 2013;110-3991-6.
57. Hanoulle X, Verdegem D, Badillo A, Wieruszeski JM, Penin F, Lippens G. Domain 3 of non-structural protein 5A from hepatitis C virus is natively unfolded. Biochem Biophys Res Commun 2009;381:634-8.
58. Scheel TK, Gottwein JM, Mikkelsen LS, Jensen TB, Bukh J. Recombinant HCV variants with NS5A from genotypes 1-7 have different sensitivities to an NS5A inhibitor but not interferon alpha. Gastroenterology 2011;140:1032-42.
59. Lontok E, Harrington P, Howe P, Kieffer T, Lennerstrand J, Lenz O, et al. Hepatitis C virus Drug resistance-associated substitutions: state of the art summary. Hepatology 2015;62:1623-32.
60. Gao M. Antiviral activity and resistance of HCV NS5A replication complex inhibitors. Curr Opin Virol 2013;3:514-20.
61. Plaza Z, Soriano V, Vispo E, del Mar Gonzalez M, Barreiro P, Seclén E, et al. Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor. Antivir Ther 2012;17:921-6.
62. Manns M, Pol S, Jacobson IM, Marcellin P, Gordon SC, Peng CY, et al. HALLMARK-DUAL Study Team. Alloral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014;384:1597-605.
63. Dore GJ, Lawitz E, Hézode C, Shafran SD, Ramji A, Tatum HA, et al. Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection. Gastroenterology 2015;148:355-66.
64. Yoshimi S, Imamura M, Murakami E, Hiraga N, Tsuge M, Kawakami Y, et al. Long term persistence of NS5A Inhibitor-resistence Hepatitis C virus in patients who failed Daclatasvir and Asunaprevir therapy. J Med Virol 2015;87:1919-20.
65. Yang G, Zhao Y, Patel D. Impact of viral sequences beyond HCV NS5A domain I on viral susceptibility to NS5A inhibitors. Antiviral Ther 2013;18:59.
66. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC. Schiff Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483-93.
67. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:1889-98.
68. Dvory-Sobol H, Wyles D, Ouyang W, Chodavarapu K, McNally J, Cheng W, et al. Long term persistence of HCV NS5A variants after treatment with NS5A Inhibitor Ledipasvir. J Hepatol 2015;62:S213-S234.
69. Buti M, Riviero-Barciela M, Esteban R. Management of direct antiviral agent failures. J Hepatol 2015 [Epub ahead of print].
70. th Annual meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015.