Recent advances in hepatitis C virus treatment: Review of HCV protease inhibitor clinical trials

Reviews on Recent Clinical Trials

Volumn 5, Issue 3, 2010, Pages 158-173

  Chary, Aarthi ^a,b   Holodniy, Mark ^a,b  

^a VA PALO ALTO HEALTH CARE SYSTEM   (United States)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Antiviral agents therapeutic use; Chronic hepatitis c; Clinical trials as topic; Humans; Protease inhibitors therapeutic use; Review; Serine proteinase inhibitors; Viral nonstructural proteins

Indexed keywords

ABT 450; ACH 806; ALPHA INTERFERON; BI 201335; BMS 650032; BOCEPREVIR; CILUPREVIR; GS 9132; IDX 136; IDX 316; ITMN 191; MP 424; N [[[6 (2 CARBOXY 2,3 DIHYDRO 1H ISOINDOL 4 YL) 2,2 DIMETHYLHEXYL]OXY]CARBONYL] 3 METHYLVALYL 4 HYDROXYPROLYL 1 AMINO N (CYCLOPROPYLSULFONYL) 2 ETHYLCYCLOPROPANECARBOXAMIDE LACTONE; NARLAPREVIR; PHX 1766; PROTEINASE INHIBITOR; RG 7227; RIBAVIRIN; RO 5190591; SCH 900518; TELAPREVIR; TMC 435350; UNCLASSIFIED DRUG;

CLINICAL PRACTICE; CLINICAL RESEARCH; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG EFFICACY; DRUG RESEARCH; GENETIC POLYMORPHISM; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIVER CELL CARCINOMA; LIVER FAILURE; MONOTHERAPY; NONHUMAN; PRIORITY JOURNAL; REVIEW; SUPERINFECTION; TREATMENT RESPONSE; VIRAL GENETICS; VIRUS LOAD;

ANTIVIRAL AGENTS; CLINICAL TRIALS AS TOPIC; GENOTYPE; HEPACIVIRUS; HEPATITIS C, CHRONIC; HUMANS; PROTEASE INHIBITORS; RISK FACTORS;

EID: 78650021698     PISSN: 15748871     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488710792007293     Document Type: Review

References (81)

1. WHO. WHO Initiative for Vaccine Research. Available from: http://www.who.int/vaccine_research/viral_cancers/en/index2.html [Accessed November 21, 2009]
2. 2008 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1998-2007. Rockville, MD: U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation 2008; Available from: http://optn.transplant.hrsa.gov/ar2008/ [Accessed November 23, 2009]
3. Zeuzem S, Berg T, Moeller B, et al. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepatitis 2009; 16(2): 75-90.
4. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006; 44(1): 97-103.
5. Ferenci P, Fried M, Shiffman M, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005; 43(3): 425-33.
6. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43(5): 954-60.
7. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferonalpha therapy. Ann Intern Med 1997; 127(10): 875-81.
8. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358(9286): 958-65.
9. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347(13): 975-82.
10. Zeuzem S. Heterogeneous virologic response rates to interferonbased therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 2004; 140(5): 370-81.
11. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351(5): 451-9.
12. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351(5): 438-50.
13. Opravil M, Sasadeusz J, Cooper DA, et al. Effect of baseline CD4 cell count on the efficacy and safety of peginterferon Alfa-2a (40KD) plus ribavirin in patients with HIV/hepatitis C virus coinfection. J Acquir Immune Defic Syndr 2008; 47(1): 36-49.
14. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461(7262): 399-401.
15. Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41(10):1100-4.
16. Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41(10): 1105-9.
17. Rallon NI, Naggie S, Benito JM, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS 2010; 24(8): F23-9.
18. Forns X, Bukh J. The molecular biology of hepatitis C virus. Genotypes and quasispecies. Clin Liver Dis 1999; 3(4): 693-716, vii.
19. Cummings KJ, Lee SM, West ES, et al. Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: a meta-analysis of randomized trials. JAMA 2001; 285(2): 193-9.
20. Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003; 300(5622): 1145-8.
21. Loo Y-M, Owen D, Li K, et al. Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA 2006; 103(15): 6001-6.
22. Foy E, Li K, Sumpter R, Jr., et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene- I signaling. Proc Natl Acad Sci USA 2005; 102(8): 2986-91.
23. Breiman A, Grandvaux N, Lin R, et al. Inhibition of RIG-Idependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J Virol 2005; 79(7): 3969-78.
24. Kato H, Sato S, Yoneyama M, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 2005; 23(1): 19-28.
25. Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005; 437(7062): 1167-72.
26. Sumpter R, Jr., Loo YM, Foy E, et al. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 2005; 79(5): 2689-99.
27. 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 USA 2005; 102(8): 2992-7.
28. Llinas-Brunet M, Bailey M, Fazal G, et al. Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg Med Chem Lett 1998; 8(13): 1713-8.
29. Steinkuhler C, Biasiol G, Brunetti M, et al. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry. 1998; 37(25): 8899-905.
30. Lamarre D, Anderson P, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426(6963): 186-9.
31. Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 2004; 127(5): 1347-55.
32. Reiser M, Hinrichsen H, Benhamou Y, et al. Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 2005; 41(4): 832-5.
33. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 2006; 50(3): 899-909.
34. Lin K, Perni RB, Kwong AD, Lin C. VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells. Antimicrob Agents Chemother 2006; 50(5): 1813-22.
35. Reesink H, Zeuzem S, Weegink C, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo- controlled, randomized study. Gastroenterology 2006; 131(4): 997-1002.
36. Lawitz E, Rodriguez-Torres M, Muir A, et al. Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients. J Hepatol 2008; 49(2): 163-9.
37. 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(18): 1827-38.
38. Forestier N, Reesink HW, Weegink CJ, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 2007; 46(3): 640-8.
39. Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360(18): 1839-50.
40. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362(14): 1292-303.
41. Njoroge FG, Chen K, Shih N-Y, Piwinski J. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc Chem Res 2008; 41(1): 50-9.
42. Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanismbased inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 2006; 50(3): 1013-20.
43. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 2007; 132(4): 1270-8.
44. Kwo P, Lawitz EJ, McCone J, et al. HCV SPRINT-1: Final results SVR 24 Boceprevir plus peginterferon alfa-2B/ribavirin HCV 1 treatment naive patients. 44th Annual Meeting of the European Association For The Study Of The Liver. Copenhagen, Denmark 2009.
45. Kwo P, Lawitz E, McCone J. High Sustained Virologic Response (SVR) in Genotype 1 (G1) Null Responders to Peg-Interferon alfa-2b (P) plus Ribavirin (R) When Treated with Boceprevir (Boc) Combination Therapy. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston, MA 2009.
46. Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009; 51(3): 1085-6.
47. Schiff E, Poordad F, Jacobson I, et al. Role of interferon response during RE-treatment of null responders with Boceprevir combination therapy: results of Phase II Trial. Gastroenterology 2008; 134(4, Suppl 1): A-755.
48. Kwo P, Lawitz E, McCone J. Response-Guided Therapy (RGT) for Boceprevir (Boc) Combination Treatment? - Results from HCV SPRINT-1. 60th Annual Meeting of the American Association for the Study of Liver Diseases AASLD 2009. Boston, MA 2009.
49. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361(6): 580-93.
50. Scotto G, Fazio V, Fornabaio C, et al. Early and sustained virological response in non-responders with chronic hepatitis C: a randomized open-label study of pegylated interferon-alpha-2a versus pegylated interferon-alpha-2b. Drugs 2008; 68(6): 791-801.
51. Reesink H, Bergmann J, de Bruijne J, et al. Eds. Safety and antiviral activity of SCH 900518 administered as monotherapy and in combination with peginterferon alfa-2b to naive and treatmentexperienced HCV infected patients. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark, 2009.
52. Vierling J, Poordad F, Lawitz E, et al. Once daily narlaprevir (SCH900518) in combination with PegIntron (peginterferon alfa-2b)/ribavirin for treatment-naive subjects with genotype-1 CHC: interim results from NEXT-1, a phase 2a study. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009), Boston, MA 2009.
53. Manns MP, Bourliere M, Benhamou Y, et al. Safety and antiviral activity of BI 201335, a new HCV NS3 protease inhibitor, in treatment-naïve patients with chronic hepatitis C genotype 1 infection given as monotherapy and in combination with peginterferon alfa-2a (P) and ribavirin (R) 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco, CA, 2008.
54. Manns MP, Bourliere M, Benhamou Y, et al. Safety and antiviral activity of BI 201335, a new HCV NS3 protease inhibitor, in combination therapy with peginterferon alfa-2a (P) and ribavirin (R) for 28 days in P+R treatment-experienced patients with chronic hepatitis C genotype 1 infection 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008), San Francisco, CA, 2008.
55. Pol S, Berg T, Bonacini M, et al. Virological response and safety of BI 201335 protease inhibitor, peginterferon alfa 2A and ribavirin treatment of HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous peginterferon/ribavirin. 60th Annual meeting of the American Association for the Study of Liver Disease (AASLD 2009). Boston, MA, 2009.
56. Sulkowski M, Ferenci P, Emanoil C, et al. Eds. SILEN-C1: Early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV infection. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston, MA, 2009.
57. Lin TI, Lenz O, Fanning G, et al. In vitro activity and pre-clinical profile of TMC435350, a potent HCV protease inhibitor. Antimicrob Agents Chemother 2009; 53: 1377-85.
58. Reesink H, Fanning G, Farha K, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 2010; 138(3): 913-21.
59. Manns M, Reesink H, Moreno C, et al. OPERA-1 trial (Study TMC435-C201): interim analysis of safety and antiviral activity of TMC435 in treatment-naïve genotype-1 HCV patients. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark, 2009.
60. 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. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark, 2009.
61. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother 2010; 54(5): 1878-87.
62. Manns M, Gane E, Rodriguez-Torres M, et al. Early Viral Response (EVR) Rates in Treatment-naïve Patients with Chronic Hepatitis C (CHC) Genotype 1 Infection Treated with MK-7009, a Novel NS3/4a Protease Inhibitor, in Combination with Pegylated Interferon Alfa-2a and Ribavirin for 28 Days. 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30-November 3, 2009; Boston, MA.
63. Seiwert SD, Andrews SW, Jiang Y, et al. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother 2008; 52(12): 4432-41.
64. Forestier N, Larrey D, Guyader D, et al. Treatment of chronic hepatitis C virus (HCV) genotype 1 patients with the NS3/4A protease inhibitor ITMN-191 leads to rapid reductions in plasma HCV RNA: results of a phase 1b multiple ascending dose (MAD) study. Hepatology. 2008;48(Supplement 1):1132A.
65. Forestier N, Larrey D, Marcellin P, et al. Antiviral Activity and Safety of ITMN-191 (R7227) in Combination with Peginterferon alfa-2a and Ribavirin in Patients with Chronic Hepatitis C Virus (HCV). J Hepatol 2009; 50(Suppl 1): S35.
66. Seiwert S, Andrews SW, Tan H, et al. Generation and characterization of HCV replicons with reduced sensitivity to ITMN 191, a macrocyclic inhibitor of NS3/4A. Digestive Disease Week 2006 (DDW 2006). Los Angeles, CA, 2006.
67. Pottage JCJ, Lawitz E, Mazur D, et al. Eds. Short-term antiviral activity and safety of ACH-806 (GS-9132), an NS4A antagonist, in HCV genotype 1 infected individuals. 42nd Meeting of the European Association for the Study of Liver Diseases (EASL). Barcelona, Spain, 2007.
68. Lu L, Pilot-Matias TJ, Stewart KD, et al. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob Agents Chemother 2004; 48(6): 2260-6.
69. Trozzi C, Bartholomew L, Ceccacci A, et al. In vitro selection and characterization of hepatitis C virus serine protease variants resistant to an active-site peptide inhibitor. J Virol 2003; 77(6): 3669-79.
70. Kuntzen T, Timm J, Berical A, et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology 2008; 48(6): 1769-78.
71. Bartels DJ, Zhou Y, Zhang EZ, et al. Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis 2008; 198(6): 800-7.
72. Gaudieri S, Rauch A, Pfafferott K, et al. Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology 2009; 49(4): 1069-82.
73. Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138(2): 447-62.
74. Lopez-Labrador FX, Moya A, Gonzalez-Candelas F. Mapping natural polymorphisms of hepatitis C virus NS3/4A protease and antiviral resistance to inhibitors in worldwide isolates. Antivir Ther 2008; 13(4): 481-94.
75. Kieffer T, Kwong A, Picchio G. Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother 2010; 65(2): 202-12.
76. Zhou Y, Bartels DJ, Hanzelka BL, et al. Phenotypic characterization of resistant Val36 variants of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 2008; 52(1): 110-20.
77. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132(5): 1767-77.
78. He Y, King MS, Kempf DJ, et al. Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system. Antimicrob Agents Chemother 2008; 52(3): 1101-10.
79. Lallos LB, Bilello JP, Soubasakos MA, et al. Preclinical Profiles of IDX136 and IDX316, Two Novel Macrocyclic HCV Protease Inhibitors. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark, 2009.
80. Gane EJ, Roberts SK, Stedman CA, et al. Combination Therapy with a Nucleoside Polymerase (R7128) and Protease (R7227/ITMN-191) Inhibitor in HCV: Safety, Pharmacokinetics, and Virologic Results from INFORM-1. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston, MA, 2009.
81. Winters MA, Chary A, Eison R, Asmuth D, Holodniy M. Impact of highly active antiretroviral therapy on hepatitis C virus protease quasispecies diversity in HIV co-infected patients. J Med Virol 2010; 82: 791-8.