• 1
    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: 97582.
  • 2
    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: 95865.
  • 3
    McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339: 148592.
  • 4
    Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40: 9939.
  • 5
    Hadziyannis SJ, Sette H, Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 34655.
  • 6
    Kim JL, Morgenstern KA, Lin C, et al. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 1996; 87: 34355.
  • 7
    Kim JL, Morgenstern KA, Griffith JP, et al. Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure 1998; 6: 89100.
  • 8
    Lindenbach BD, Evans MJ, Syder AJ, et al. Complete replication of hepatitis C virus in cell culture. Science 2005; 309: 6236.
  • 9
    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: 1103.
  • 10
    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: 7916.
  • 11
    Bartenschlager R, Frese M, Pietschmann T. Novel insights into hepatitis C virus replication and persistence. Adv Virus Res 2004; 63: 71180.
  • 12
    Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol 2007; 5: 45363.
  • 13
    Sarrazin C, Zeuzem S. Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection. Gastroenterology 2009; 138: 44762.
  • 14
    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: 183950.
  • 15
    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: 182738.
  • 16
    Kwo P, Lawitz E, McCone J, et al. HCV SPRINT-1 final results: SVR 24 from a phase 2 study of boceprevir plus peginterferon alfa-2b/ribavirin in treatment-naive subjects with genotype-1 chronic hepatitis C. J Hepatol 2009; 50(Suppl. 1): 4.
  • 17
    Flisiak R, Horban A, Gallay P, et al. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008; 47: 81726.
  • 18
    Khattab MA. Targeting host factors: a novel rationale for the management of hepatitis C virus. World J Gastroenterol 2009; 15: 34729.
  • 19
    Rossignol JF, Kabil SM, El-Gohary Y, Keeffe EB. Randomized controlled trial of nitazoxanide-peginterferon-ribavirin, nitazoxanide-peginterferon and peginterferon-ribavirin in the treatment of patients with chronic hepatitis C genotype 4. J Hepatol 2008; 48: 30.
  • 20
    Rossignol JF, Elfert A, Keeffe EB. Evaluation of a 4 week lead-in phase with nitazoxanide prior to nitazoxanide+peginterferon in treating chronic hepatitis C. J Hepatol 2008; 48: 311.
  • 21
    Schinazi RF, Bassit L, Gavegnano C. HCV drug discovery aimed at viral eradication. J Viral Hepat 2010; 17: 7790.
  • 22
    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: 176777.
  • 23
    Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426: 1869.
  • 24
    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: 134755.
  • 25
    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: 8325.
  • 26
    Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA. Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res 2006; 70: 2838.
  • 27
    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: 106982.
  • 28
    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: 176978.
  • 29
    Le Pogam S, Seshaadri A, Kang H, et al. Low level of resistance, low viral fitness and absence of resistance mutations at baseline quasispecies may contribute to high barrier to R1626 resistance in vivo. J Hepatol 2008; 48: 10A.
  • 30
    Lin C, Gates CA, Rao BG, et al. In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J Biol Chem 2005; 280: 3678491.
  • 31
    Lin K, Kwong AD, Lin C. Combination of a hepatitis C virus NS3-NS4A protease inhibitor and alpha interferon synergistically inhibits viral RNA replication and facilitates viral RNA clearance in replicon cells. Antimicrob Agents Chemother 2004; 48: 478492.
  • 32
    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: 22606.
  • 33
    Reesink HW, Zeuzem S, Weegink CJ, 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: 9971002.
  • 34
    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: 6408.
  • 35
    Lawitz E, Rodriguez-Torres M, Muir AJ, et al. Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients. J Hepatol 2008; 49: 1639.
  • 36
    Marcellin P, Forns X, Goeser T, et al. Virological analysis of patients receiving telaprevir administered q8h or q12h with peginterferon-alfa-2a or -alfa2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C: study C208. Hepatology 2009; 50(Suppl 1): 395.
  • 37
    Benhamou Y, Moussalli J, Ratziu V, et al. Results of a prove of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 4 HCV patients. J Hepatol 2009; 50(Suppl. 1): 6.
  • 38
    Foster GR, Hezode C, Bronowicki JP, et al. Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 2 and 3 hepatitis-C patients: interim results of study C209. J Hepatol 2009; 50(Suppl. 1): 22.
  • 39
    McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362: 1292303.
  • 40
    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: 181322.
  • 41
    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. Hepatology 2007; 46: 6319.
  • 42
    Forestier N, Susser S, Welker MW, Karey U, Zeuzem S, Sarrazin C. Long term follow-up of patients previously treated with telaprevir. Hepatology 2008; 48(Suppl. 1): 760.
  • 43
    Adiwijaya BS, Hare B, Caron PR, et al. Rapid decrease of wild-type hepatitis C virus on telaprevir treatment. Antivir Ther 2009; 14: 5915.
  • 44
    McCown MF, Rajyaguru S, Kular S, Cammack N, Najera I. GT-1a or GT-1b subtype-specific resistance profiles for hepatitis C virus inhibitors telaprevir and HCV-796. Antimicrob Agents Chemother 2009; 53: 212932.
  • 45
    Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanism-based 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: 101320.
  • 46
    Zeuzem S, Sarrazin C, Wagner F, et al. Antiviral activity of SCH 503034, a HCV protease inhibitor, administered as monotherapy in hepatitis C genotype 1 (HCV-1) patients refractory to pegylated interferon (PEG-IFN-alpha). Hepatology 2005; 42: 276A.
  • 47
    Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009; 50: 170918.
  • 48
    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: 12708.
  • 49
    Vermehren J, Susser S, Karey U, Forestier N, et al. Clonal analysis of mutations selected in the NS3 protease domain of genotype 1 non-responders sequentially treated with boceprevir (SCH503034) and/or pegylated interferon-alfa-2b (pegIFN-α-2b). Hepatology 2009; 50(Suppl. 4): 1040.
  • 50
    Schiff E, Poordard F, Jacobson I, et al. Boceprevir combination therapy in null responders: response dependent on interferon responsiveness. J Hepatol 2008; 48(Suppl. 2): 46.
  • 51
    Susser S, Forestier N, Welker MW, et al. Detection of resistant variants in the hepatitis C virus NS3 protease gene by clonal sequencing at long-term follow-up in patients treated with boceprevir. J Hepatol 2009; 50(Suppl 1): 7.
  • 52
    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: 91321.
  • 53
    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 study. Hepatology 2008; 48(Suppl): 1132.
  • 54
    Pottage JC, Lawitz E, Mazur D, et al. Short-term antiviral activity and safety of ACH-806, an NS4A antagonist, in HCV genotype 1 infected individuals. J Hepatol 2007; 46: 2945.
  • 55
    Wyles DL, Kaihara KA, Schooley RT. Synergy of a hepatitis C virus (HCV) NS4A antagonist in combination with HCV protease and polymerase inhibitors. Antimicrob Agents Chemother 2008; 52: 18624.
  • 56
    Yang W, Zhao Y, Fabrycki J, et al. Selection of replicon variants resistant to ACH-806, a novel hepatitis C virus inhibitor with no cross-resistance to NS3 protease and NS5B polymerase inhibitors. Antimicrob Agents Chemother 2008; 52: 204352.
  • 57
    Ali S, Leveque V, Le Pogam S, et al. Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrob Agents Chemother 2008; 52: 435669.
  • 58
    Klumpp K, Leveque V, Le Pogam S, et al. The novel nucleoside analog R1479 (4′-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture. J Biol Chem 2006; 281: 37939.
  • 59
    Lalezari J, Gane J, Rodriguez-Torres M, et al. Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with peg-IFN and ribavirin: interim results of R7128 500mg bid for 28 days. J Hepatol 2008; 48: 29.
  • 60
    Le Pogam S, Jiang WR, Leveque V, et al. In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology 2006; 351: 34959.
  • 61
    Nelson D, Pockros PJ, Godofsky E, et al. High end-of-treatment response (84%) after 4 weeks of R1626, peginterferon alfa-2a (40kd) and ribavirin followed by a further 44 weeks of peginterferon alfa-2a and ribavirin. J Hepatol 2008; 48: 371.
  • 62
    Pierra C, Benzaria S, Amador A, et al. Nm 283, an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. Nucleosides Nucleotides Nucleic Acids 2005; 24: 76770.
  • 63
    Pockros P, Nelson D, Godofsky E, et al. High relapse rate seen at week 72 for patients treated with R1626 combination therapy. Hepatology 2008; 48: 134950.
  • 64
    Pockros PJ, Nelson D, Godofsky E, et al. R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin. Hepatology 2008; 48: 38597.
  • 65
    Roberts SK, Cooksley G, Dore GJ, et al. Robust antiviral activity of R1626, a novel nucleoside analog: a randomized, placebo-controlled study in patients with chronic hepatitis C. Hepatology 2008; 48: 398406.
  • 66
    Koch U, Narjes F. Allosteric inhibition of the hepatitis C virus NS5B RNA dependent RNA polymerase. Infect Disord Drug Targets 2006; 6: 3141.
  • 67
    Koch U, Narjes F. Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. Curr Top Med Chem 2007; 7: 130229.
  • 68
    Beaulieu PL. Non-nucleoside inhibitors of the HCV NS5B polymerase: progress in the discovery and development of novel agents for the treatment of HCV infections. Curr Opin Investig Drugs 2007; 8: 61434.
  • 69
    Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF, Weber PC. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 1999; 6: 93743.
  • 70
    Lawitz E, Nguyen T, Younes Z. Clearance of HCV RNA with valopicitabine plus peginterferon treatment-naive patients with HCV-1 infection: Results at 24 and 48 weeks. J Hepatol 2007; 46: 9.
  • 71
    Erhardt A, Deterding K, Benhamou Y, et al. Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antivir Ther 2009; 14: 2332.
  • 72
    Shi ST, Herlihy KJ, Graham JP, et al. Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 2009; 53: 254452.
  • 73
    Cooper C, Lawitz E, Ghali P, et al. Evaluation of VCH-759 monotherapy in hepatitis C infection. J Hepatol 2009; 51: 3946.
  • 74
    Thompson PA, Patel R, Showalter RE, Li C, Appleman JR, Steffy K. In vitro studies demonostrate that combinations of antiviral agents that include HCV polymerase inhibitor ANA598 have the potential to overcome viral resistance. Hepatology 2008; 48(Suppl): 1164.
  • 75
    Kneteman NM, Howe AY, Gao T, et al. HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus. Hepatology 2009; 49: 74552.
  • 76
    Villano SA, Raible D, Harper D, et al. Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in combination with pegylated interferon alfa-2b in treatment-naive patients with chronic HCV. J Hepatol 2007; 46: 24.
  • 77
    Nettles R, Chien C, Chung E, et al. BMS-790052 is a first-in-class potent hepatitis C virus NS5A inhibitor for patients with chronic HCV infection: results from a proof-of-concept study. Hepatology 2008; 48(Suppl): 1025.
  • 78
    Einav S, Gerber D, Bryson PD, et al. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 2008; 26: 101927.
  • 79
    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 2009; 50(Suppl. 1): 380.
  • 80
    Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399401.
  • 81
    Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure - A Genome-Wide Association Study. Gastroenterology 2010; 138: 133845.
  • 82
    Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798801.
  • 83
    Barth H, Liang TJ, Baumert TF. Hepatitis C virus entry: molecular biology and clinical implications. Hepatology 2006; 44: 52735.
  • 84
    Bartosch B, Vitelli A, Granier C, et al. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J Biol Chem 2003; 278: 4162430.
  • 85
    Lozach PY, Amara A, Bartosch B, et al. C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles. J Biol Chem 2004; 279: 3203545.
  • 86
    Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science 1998; 282: 93841.
  • 87
    Clarke D, Griffin S, Beales L, et al. Evidence for the formation of a heptameric ion channel complex by the hepatitis C virus p7 protein in vitro. J Biol Chem 2006; 281: 3705768.
  • 88
    Steinmann E, Whitfield T, Kallis S, et al. Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Hepatology 2007; 46: 3308.
  • 89
    Steinmann E, Penin F, Kallis S, Patel AH, Bartenschlager R, Pietschmann T. Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. PLoS Pathog 2007; 3: e103.
  • 90
    Lorenz IC, Marcotrigiano J, Dentzer TG, Rice CM. Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. Nature 2006; 442: 8315.
  • 91
    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: 116772.
  • 92
    Tellinghuisen TL, Marcotrigiano J, Rice CM. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 2005; 435: 3749.