Current Hepatitis Reports

, Volume 11, Issue 3, pp 172–180 | Cite as

Second Generation Protease Inhibitors and Nucleotide Inhibitors

Hepatitis C: Therapeutics (E Lawitz and M Manns, Section Editors)

Abstract

The hepatitis C virus (HCV) protease and polymerase inhibitors are in rapid phases of development. Following closely behind the approval of the inhibitors of the HCV RNA NS3/4A protease, boceprevir and telaprevir, include both a) more potent protease inhibitors and b) the development of the viral NS5B RNA-dependent RNA polymerase inhibitors. Protease inhibitors generally have a low barrier to resistance and extensive cross-resistance between agents. NS5B polymerase inhibitors are generally considered to have a high barrier to resistance and the potential for use across all genotypes. However, in the absence of ribavirin or of other direct-acting antivirals these agents may predispose to the selection of resistant variants or for viral relapse following treatment completion. Optimal combination of agents and therapy durations remain major challenges in clinical research.

Keywords

Direct-Acting Antivirals Hepatitis C Protease inhibitor Polymerase inhibitor 

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-alfa2a and ribavirin combination therapy in chronic hepatitis C. A randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55.PubMedGoogle Scholar
  2. 2.
    Lohmann V, Körner F, Koch JO, et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 1999;285:110–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med. 2005;11:791–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007;132:1979–98.PubMedCrossRefGoogle Scholar
  5. 5.
    Choo QL, Richman KH, Han JH, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci. 1991;88:2451–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Thimme R, Lohmann V, Weber F. A target on the move: innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res. 2006;69:129–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Li K, Foy E, Ferreon JC, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci. 2005;102:2992–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Kwo P, Vinayek R. The therapeutic approaches for hepatitis C virus: protease inhibitors and polymerase inhibitors. Gut Liver. 2011;5:406–17.PubMedCrossRefGoogle Scholar
  9. 9.
    McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–38.PubMedCrossRefGoogle Scholar
  10. 10.
    McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292–303.PubMedCrossRefGoogle Scholar
  11. 11.
    Sullivan JC, De Meyer S, Bartels DJ, et al. Evolution of treatment-emergent resistant variants in Telaprevir phase 3 clinical trials. J Hepatol. 2011;54:S4.CrossRefGoogle Scholar
  12. 12.
    Foster GR, Hezode C, Bronowicki JP, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology. 2011;141:881–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Asselah T, Benhamou Y, Marcellin P. Protease and polymerase inhibitors for the treatment of hepatitis C. Liver Int. 2009;29:57–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Asselah T, Marcellin P. New direct-acting antivirals' combination for the treatment of chronic hepatitis C. Liver International. 2011;31:68–77.PubMedCrossRefGoogle Scholar
  15. 15.
    Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376:705–16.PubMedCrossRefGoogle Scholar
  16. 16.
    Poordad F, McCone Jr J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. SPRINT-2 Investigators. N Engl J Med. 2011;364:1195–206.PubMedCrossRefGoogle Scholar
  17. 17.
    Sarrazin C, Hézode C, Zeuzem S, et al. Antiviral strategies in hepatitis C virus infection. J Hepatol. 2012;56:S88–S100.PubMedCrossRefGoogle Scholar
  18. 18.
    Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology. 2010;138:447–62.PubMedCrossRefGoogle Scholar
  19. 19.
    Rabiee A, Tillmann HL, Poordad F, et al. Influence of hepatitis C virus (HCV) genotype-1 (G1) subtype, baseline viral load and IL28B genotype on peginterferon(PEG)/ribavirin (RBV) treatment response: results of the IDEAL study. Hepatol. 2011;54:998A–9A.Google Scholar
  20. 20.
    Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatol. 2007;46:631–9.CrossRefGoogle Scholar
  21. 21.
    Susser S, Schelhorn S, Lange CM, et al. Importance of newly described rare hepatitis C virus NS3 protease resistance mutations in patients treated with telaprevir or boceprevir. Hepatol. 2011;54:1353A–4A.Google Scholar
  22. 22.
    Anton ED, Rivera AA, Tan Y, et al. Validation of an HCV NS3/4a sequencing assay for evaluating resistance to boceprevir, telaprevir and protease inhibitor candidates in a clinical reference laboratory setting. Hepatol. 2011;54:1441A–2A.Google Scholar
  23. 23.
    McHutchison JG, Manns MP, Muir AJ, PROVE3 Study Team, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292–303.PubMedCrossRefGoogle Scholar
  24. 24.
    Susser S, Welsch C, Wang Y, Zettler M, Domingues F, Karey U, et al. Characterization of resistance to the protease inhibitor Boceprevir in hepatitis C virus-infected patients. Hepatol. 2009;50:1709–18.CrossRefGoogle Scholar
  25. 25.
    He Y, King M, Kempf D, et al. Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus NS3 protease mutants in the HCV genotype 1b replicon system. Antimicrob Agents Chemother. 2008;52:1101–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Fusco Dahlene N, Chung Raymond T. New protease inhibitors for HCV—help is on the way. J Hepatol. 2011;54:S1087–9.CrossRefGoogle Scholar
  27. 27.
    Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. J Hepatol. 2010;50:S380.CrossRefGoogle Scholar
  28. 28.
    Gane E, Rouzier R, Stedman C, et al. Ritonavir boosting of low dose RG7227/ITMN-191, HCV NS3/4A protease inhibitor, results in robust reduction in HCV RNA at lower exposures than provided by unboosted regimens. J Hepatol. 2010;52:S16–7.Google Scholar
  29. 29.
    Gane E, Roberts S, Stedman C, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1467–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Everson G, Cooper C, Hézode C, et al. Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/Peg-IFNa-2a/RBV in HCV genotype 1 or 4 patients: DAUPHINE week 12 interim analysis. J Hepatol. 2012;56:S466.CrossRefGoogle Scholar
  31. 31.
    Gane EJ, Pockros P, Zeuzem S. Interferon-free treatment with a combination of mercitabine and danoprevir/r with or without ribavirin in treatment-naïve HCV genotype-1 infected patients. J Hepatol. 2012;56:S555–6.CrossRefGoogle Scholar
  32. 32.
    Reesink HW, Fanning GC, Farha KA, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138:913–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Marcellin P, Reesink H, Berg T, et al. Antiviral activity and safety of TMC435 combined with peginterferon alpha-2a and ribavirin in patients with genotype 1 hepatitis C infection who failed previous IFN-based therapy. J Hepatol. 2009;50:S385.CrossRefGoogle Scholar
  34. 34.
    Fried M, Buti M, Dore GJ, et al. Efficacy and safety of TMC435 in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype-1 HCV patients: 24-weeks interim results from the PILLAR study. Hepatology. 2010;52:403A–4A.Google Scholar
  35. 35.
    Lenz O, Fevery B, Vijgen L, et al. TMC435 in combination with peginterferon alpha-2A/ribavirin in treatment naive patients infected with HCV genotype 1: virology análysis of the PILLAR study. Hepatology. 2011;54:985A.Google Scholar
  36. 36.
    Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the ASPIRE trial. J Hepatol. 2012;56:S1–2.CrossRefGoogle Scholar
  37. 37.
    Sulkowski MS, Ferenci P, Emanoil C, et al. SILEN-C1: early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype 1 HCV infection. Hepatology. 2009;50:90A.Google Scholar
  38. 38.
    Sulkowski MS, Ceasu E, Asselah T, et al. SILEN-C1: Sustained virologic response and safety of BI201335 combined with pegintereron alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV infection. J Hepatol. 2011;54:S27.CrossRefGoogle Scholar
  39. 39.
    Sulkowski MS, Asselah T, Ferenci P, et al. Treatment with the second generation HCV protease inhibitor BI201335 results in high and consistent SVR rates—results from SILEN-C1 in treatment naïve patients across different baseline factors. Hepatol. 2011;54:473A.Google Scholar
  40. 40.
    Kukolj G, Legace L, Cartier M, et al. Characterization of HCV NS3 varients that emerged during virologic breakthrough and relapse from BI201335 phase 2 SILEN-C1 study. Hepatol. 2011;54:991A.Google Scholar
  41. 41.
    Sulkowski M, Bourliere M, Bronowicki JP, et al. SILEN-C2: early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin (PEGIFN/RBV) in chronic HCV genotype-1 patients with non-response to PEGIFN/RBV. J Hepatol. 2010;52:S462–3.CrossRefGoogle Scholar
  42. 42.
    Sulkowski M, Bourliere M, Bronowicki JP, et al. SILEN-C2: sustained virologic response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R. J Hepatol. 2011;54:S30.CrossRefGoogle Scholar
  43. 43.
    Dieterich D, Asselah T, Guyader D, et al. SILEN-C3: treatment for 12 or 24 weeks with BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in naive patients with chronic genotype-1 HCV infection. Hepatology. 2011;54:378A.Google Scholar
  44. 44.
    Zuezem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology. 2011;141:2047–55.CrossRefGoogle Scholar
  45. 45.
    Zeuzem S, Asselah T, Angus PW. High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI201335, polymerase inhibitor BI207127 and Ribavirin, followed by BI201335 and PegIFN/Ribavirin—the SOUND-C1 study. Hepatology. 2011;54:486A–7A.Google Scholar
  46. 46.
    Zeuzem S, Soriano V, Asselah T, et al. Virologic response to an interferon-free regimen of BI201335 and BI207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: week 12 interim results of the SOUND-C2 study. Hepatology. 2011;54:1436A.Google Scholar
  47. 47.
    Zeuzem S, Soriano V, Asselah T, et al. SVR4 and SVR12 with an interferon-free regimen of BI201335 and BI207127, +/- ribavirin in treatment-naïve patients with chronic genotype-1 HCV infection: interim results of SOUND-C2. J Hepatol. 2012;56:S45.CrossRefGoogle Scholar
  48. 48.
    Lalezari J, Hazan L, Kankam M, et al. High rapid virologic response (RVR) with ACH-1625 daily dosing plus PegIFN-alpha 2a/RBV in a 28-day phase 2ª trial. Hepatology. 2011;54:992A–3A.Google Scholar
  49. 49.
    Hayashi N, Nakamura K, Wright D, et al. Safety and efficacy of vaniprevir (MK-7009) in combination with Peg-interferon alfa-2a (PEG-IFN)/Ribavirin (RBV) in genotype 1 treatment experience HCV-infected Japanese patients. Hepatology. 2011;54:996A–7A.Google Scholar
  50. 50.
    Lawitz E, Rodriguez-Torres M, et al. A phase 2b study of MK-7009 (Vaniprevir) in patients with genotype 1 HCV infection who have failed previous Pegylated interferon and Ribavirin treatment. Hepatology. 2011;54 Suppl 1:1434A–5A.Google Scholar
  51. 51.
    Caro L, Anderson M, Du L, et al. Phamacokenetics and pharmacokinetic/pharmacodynamic relationship for MK-5172, a novel hepatitis C virus (HCV) NS3/4a protease inhibitor, in genotype 1 and genotype 3 HCV-infected patients. Hepatology. 2011;54:1005A.Google Scholar
  52. 52.
    Petry A, Fraser I, Van Dyck K. Safety and antiviral activity of MK-5172, a next generation HCV NS3/4a protease inhibitor with a broad HCV genotypic activity spectrum and potent activity against known resistance mutants, in genotype 1 and 3 HCV-infected patients. Hepatology. 2011;54:531A.Google Scholar
  53. 53.
    Yang H, Appleby T, Chen X, et al. In vitro selection of resistance to GS-9451, a novel and potent inhibitor of HCV NS3 protease. Hepatol. 2011;54:1352A.CrossRefGoogle Scholar
  54. 54.
    •• Sulkowski M, Rodriguez-Torres M, et al. High Sustained Virologic Response Rate in Treatment-Naïve HCV Genotype 1a and 1b Patients Treated for 12 Weeks with an Interferon-Free All-Oral Quad Regimen: Interim Results. J Hepatol. 2012;56: S560. This quadruple regimen all oral therapy yielded a very high 4 week sustained viral response in those achieving viral suppression by week 2. Interferon was used as a rescue for those not achieving viral response by this timepoint.Google Scholar
  55. 55.
    Vierling J, Poordad F, Lawitz E, et al. Once daily Narlaprevir (NVR; SCH 900518) and Ritonavir (RTV) in combination with Peginterferon alfa-2b/Ribavirin (PR) for 12 weeks plus 12 weeks PR in treatment-naïve patients with HCV genotype 1 (G1): SVR results from NEXT-1, a phase 2 study. Hepatology. 2011;54:1437A–8A.Google Scholar
  56. 56.
    Lok AS, Gardiner DF, Lawitz E, et al. Quadruple therapy with BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders. J Hepatol. 2011;54:S536.CrossRefGoogle Scholar
  57. 57.
    Bronowicki JP, Pol S, Thuluvath P. Asunaprevir (ASV; BMS-650032), an NS3 protease inhibitor, in combination with Peginterferon and Ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C Infection. J Hepatol. 2012;56:431–2.Google Scholar
  58. 58.
    Zeuzem S, Buggisch P, Agarwal P, et al. Dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190). Hepatology. 2010;52:400A.Google Scholar
  59. 59.
    Hebner C, Martin R, Miller MD, et al. The effects of combining two direct acting antivirals. Ribavirin and Pegylated interferon on the detection of drug resistance mutations early in treatment of HCV. Hepatol. 2011;54:997A.Google Scholar
  60. 60.
    Nelson DR, Lawitz E, Bain V. High SVR12 with 16 weeks of Tegobuvir and GS-9256 with Peginterferon-alfa 2a and Ribavirin in treatment-naïve genotype 1 HCV patients. J Hepatol. 2012;56:S6–7.CrossRefGoogle Scholar
  61. 61.
    Lawitz E, Poordad F, DeJesus E, et al. ABT-450/ritonavir (ABT-450/r) combined with pegylated interferon alpha-2a/ribavirin after 3-day monotherapy in genotype 1 (GT1) HCV-infected treatment-naïve subjects: 12-week sustained virologic response. J Hepatol. 2012;56:S470.Google Scholar
  62. 62.
    •• Lawitz E, Poordad F, Kowdley KV, et al. A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV IL28B-CC Genotype-1-Infected Subject. J Hepatol. 2012;56:S7. Study demonstrated an effective all-oral therapy using an NS3 protease inhibitor with ritanovir boost, an NS5B polymerase inhibitor and ribavirin to treat select hepatitis C patients with powerful early results in the absence of interferon.Google Scholar
  63. 63.
    Poordad F, Lawitz E, Kowdley KV. 12-week interferon-free regimen of ABT-450/r+ABT-333+Ribavirin achieved SVR12 in more than 90% of treatment-naïve HCV genotype-1-infected subjects and 47% of previous non-responders. J Hepatol. 2012;56:S549–550.CrossRefGoogle Scholar
  64. 64.
    Betzi S, Eydoux C, Bussetta C, et al. Identification of allosteric inhibitors blocking the hepatitis C virus polymerase NS5B in the RNA synthesis initiation step. Antiviral Res. 2009;84:48–59.PubMedCrossRefGoogle Scholar
  65. 65.
    McGowan D, Nyanguile O, Cummings MD, et al. 1,5-Benzodiazepine inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett. 2009;19:2492–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Reddy R, Rodriguez-Torres M, Gane E, et al. Antiviral activity, pharmacokinetics, safety and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy. Hepatology. 2007;46:862A.Google Scholar
  67. 67.
    Lalezari J, Gane E, Rodriguez-Torres M, et al. Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and ribavirin: interim results of R7128 500 mg bid for 28 days. J Hepatol. 2008;48:S29.CrossRefGoogle Scholar
  68. 68.
    Gane EJ, Rodriguez-Torres M, Nelson DE, et al. Sustained virologic response (SVR) following RG7128 1500mg BID/PEG-IFN/RBV for 28 days in HCV genotype 2/3 prior non-responders. J Hepatol. 2010;52:S16.Google Scholar
  69. 69.
    Pockros P, Jensen D, Tsai N, et al. First SVR data with the nucleoside analogue polymerase inhibitor mericitabine (RG7128) combined with peginterferon/ribavirin in treatment-naive HCV G1/4 patients: interim analysis from the JUMP-C trial. J Hepatol. 2011;54:S538.CrossRefGoogle Scholar
  70. 70.
    Pockros P, Jensen D, Tsai N, et al. SVR-12 among G1/4 treatment naive patients receiving mercitabine in combination with Peg-IFNa-2a/RBV: interim analysis from the JUMP-C study. Hepatol. 2012;56:S477–8.Google Scholar
  71. 71.
    Wedemeyer H, Jensen D, Herring R. Efficacy and safety of mercitabine (MCB) in combination with Peg-IFNa-2a/RBV in G1/4 treatment naïve HCV patients: final analysis from the PROPEL study. J Hepatol. 2012;56:S481–2.CrossRefGoogle Scholar
  72. 72.
    Lawitz E, Rodriguez-Torres M, Denning J, et al. Once daily dual-nucleotide combination of PSI-938 and PSI-7977 provides 94% HCV RNA <LOD at day 14: first purine/pyrimidin clinical combination data (the NUCLEAR study). J Hepatol. 2011;54:S543.CrossRefGoogle Scholar
  73. 73.
    Lawitz E, Nguyen T, Younes Z, Santoro J, et al. Clearance of HCV RNA with valopicitabine (NM283) plus PEG-interferon in treatment-naive patients with HCV-1 infection: results at 24 and 48 weeks. J Hepatol. 2007;46:9A.CrossRefGoogle Scholar
  74. 74.
    Lalezari J, Lawitz E, Rodriguez-Torres M, Sheikh A, et al. Once daily PSI-7977 plus peginterferon/ribavirin in a Phase 2b trial: rapid virologic suppression in treatment-naive patients with HCV genotype 2/3. J Hepatol. 2011;54:S28.CrossRefGoogle Scholar
  75. 75.
    Sharma P, Lok AS. Interferon-free treatment regimens for hepatitis C: are we there yet? Gastro. 2011;141:1963–7.CrossRefGoogle Scholar
  76. 76.
    •• Lawitz E, Gane E, Stedman C, et al. PSI-7977 PROTON and ELECTRON: 100% concordance of SVR4 with SVR24 in HCV GT1, GT2, GT3. J Hepatol. 2012;56:S4. The ELECTRON study provided the foundation for a potential all-oral therapy for hepatitis C. It also demonstrated the continued importance of ribavirin with the protease inhibitors.Google Scholar
  77. 77.
    Kowdley KV, Lawitz E, Crespo I, et al. ATOMIC: 97% RVR for PSI-7977 + PEG/RBV X 12 week regimen in HCV GT1: an end to response-guide therapy? J Hepatol. 2012;56:S1.CrossRefGoogle Scholar
  78. 78.
    Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100.PubMedCrossRefGoogle Scholar
  79. 79.
    Pol S, Everson G, Ghalib R, et al. Once-daily NS5A inhibitor (BMS-790052) plus peginterferon-alpha-2a and ribavirin produces high rates of extended rapid virologic response in treatment-naïve HCV-genotype 1 subjects: phase 2a trial. J Hepatol. 2010;52:S462.CrossRefGoogle Scholar
  80. 80.
    Ratziu V, Gadano A, Pol S, et al. Triple therapy with Daclatasvir (DCV; bms-790052), Peginterferon alfa-2a and Ribavirin in HCV-infeted prior null and partial responders: 12-week results of phase 2b COMMAND-2 trial. J Hepatol. 2012;56:S478–479.CrossRefGoogle Scholar
  81. 81.
    Suzuki F, Ikeda K, Toyota J, et al. Dual oral therapy with the NS5A inhibitor Daclatasvir (BMS-790052) and NS3 protease inhibitor Asunaprevir (BMS-650032) in HCV genotype 1b-infected null responders or ineligible/intolerant to Peginterferon. J Hepatol. 2012;56:S7–8.CrossRefGoogle Scholar
  82. 82.
    Lok AS, Gardiner D, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216–24.PubMedCrossRefGoogle Scholar
  83. 83.
    Sullivan GJ, Rodriques-Torres M, Lawitz E, et al. ABT-267 combined with pegylated interferon alpha-2a/ribavirin in genotype 1 (GT1) HCV-infected treatment-naïve subjects: 12 week antiviral and safety analysis. J Hepatol. 2012;56:S480.CrossRefGoogle Scholar
  84. 84.
    Gane E, Foster GR, Cianciara J, et al. Antiviral activity, pharmacokinetics, and tolerability of AZD7295, a novel NS5A inhibitor, in a placebo-controlled multiple ascending dose study in HCV genotype 1 and 3 patients. J Hepatol. 2010;52 Suppl 1:S464.CrossRefGoogle Scholar
  85. 85.
    Brown NA, Vig P, Ruby E, et al. Safety and pharmacokinetics of PPI-461, a potent new hepatitis C virus NS5A inhibitor with pan-genotype activity. Hepatology 2010;52(Suppl.):879A-880A.Google Scholar
  86. 86.
    Nettles R, Wang XD, Quadri S, et al. BMS-824393 is a potent hepatitis C virus NS5A inhibitor with substantial antiviral activity when given as monotherapy in subjects with chronic genotype 1 HCV infection. Hepatology. 2010;52(Suppl.):1203A-1204A.Google Scholar
  87. 87.
    Lawitz E, Gruener D, Hill J, et al. A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol. 2012;57:24–31.PubMedCrossRefGoogle Scholar
  88. 88.
    Colonno R, Peng E, Bencsik M, et al. Identification and characterization of PPI-461, a potent and selective HCV NS5A inhibitor with activity against all HCV genotypes. J Hepatol. 2010;52:S14–5.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Henry Ford Health SystemDetroitUSA

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