Emerging therapies for the treatment of hepatitis C

EMBO Molecular Medicine

Volumn 6, Issue 1, 2014, Pages 4-15

  Lange, Christian M ^a   Jacobson, Ira M ^b   Rice, Charles M ^c   Zeuzem, Stefan ^a  

^a UNIVERSITY HOSPITAL FRANKFURT   (Germany)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

^c ROCKEFELLER UNIVERSITY   (United States)

Author keywords

Directly acting antiviral agents; Hepatitis C virus; Interferon free; NS3 4A protease inhibitor; NS5B polymerase inhibitor

Indexed keywords

ABT 267; ABT 333; ABT 450; ALISPORIVIR; ALPHA INTERFERON; ANTIVIRUS AGENT; ASUNAPREVIR; BI 207127; BMS 791325; BOCEPREVIR; CILUPREVIR; DACLATASVIR; DANOPREVIR; FALDAPREVIR; FILIBUVIR; LEDIPASVIR; LOMIBUVIR; MERICITABINE; PEGINTERFERON ALPHA; PPI 461; RIBAVIRIN; RITONAVIR; SAMATASVIR; SETROBUVIR; SIMEPREVIR; SOFOSBUVIR; TELAPREVIR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALOPICITABINE; VANIPREVIR;

ANTIVIRAL ACTIVITY; ANTIVIRAL THERAPY; ARTICLE; GENETIC ASSOCIATION; GENOTYPE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; LIFE CYCLE; PRIORITY JOURNAL; RNA REPLICATION;

ANTIVIRAL AGENTS; DRUG THERAPY, COMBINATION; HEPACIVIRUS; HEPATITIS C; HUMANS; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84891913566     PISSN: 17574676     EISSN: 17574684     Source Type: Journal    
DOI: 10.1002/emmm.201303131     Document Type: Article

References (81)

1. Afdhal N, O'Brien C, Godofsky E (2007) Valopicitabine alone or with PEG-interferon/ribavirin retreatment in patients with HCV-1 infection and prior non-reponse to PEGIFN/RBV: one-year results. J Hepatol 46: 5
2. Alter HJ, Purcell RH, Holland PV, Popper H (1978) Transmissible agent in non-A, non-B hepatitis. Lancet 1: 459-463
3. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, et al (2011) Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 364: 1207-1217
4. Bartenschlager R, Frese M, Pietschmann T (2004) Novel insights into hepatitis C virus replication and persistence. Adv Virus Res 63: 71-180
5. 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: 482-496
6. Berg T, Sarrazin C, Herrmann E, Hinrichsen H, Gerlach T, Zachoval R, Wiedenmann B, Hopf U, Zeuzem S (2003) Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology 37: 600-609
7. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244: 359-362
8. Chu TW, Kulkarni R, Gane EJ, Roberts SK, Stedman C, Angus PW, Ritchie B, Lu XY, Ipe D, Lopatin U, et al (2012) Effect of IL28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C. Gastroenterology 142: 790-795
9. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW (2010) Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 138: 513-521
10. Di Bisceglie AM, Shindo M, Fong TL, Fried MW, Swain MG, Bergasa NV, Axiotis CA, Waggoner JG, Park Y, Hoofnagle JH (1992) A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 16: 649-654
11. Everson G, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M, Loustaud-Ratti V, Rustgi V, Schwartz R, Tatum HA, et al (2013) Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. J Hepatol 58: 573
12. Feld JJ, Hoofnagle JH (2005) Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436: 967-972
13. Feld JJ, Jacobson I, Jensen DM, Foster G, Pol S, Tam E, Berak H (2012) Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine (MCB) and ribavirin (R) +/- peginterferon alfa-2a (P) in HCV gentoype 1-infected partial and null responders: results from the Matterhorn study. Hepatology 56: 231
14. Ferenci P, Asselah T, Foster G, Zeuzem S, Sarrazin C, Moreno C, Ouzan D, Maevskaya M, Calinas F, Morano L, et al (2013) Faldaprevir plus pegylated interferon alfa-2a and ribavirin in chronic HCV genotype 1 treatment naive patients: final results from STARTVerso1, a randomized, double-blind, placebo-controlled phase III trial. J Hepatol 58: 569-570
15. Flisiak R, Feinman SV, Jablkowski M, Horban A, Kryczka W, Pawlowska M, Heathcote JE, Mazzella G, Vandelli C, Nicolas-Metral V, et al (2009) The cyclophilin inhibitor Debio 025 combined with PEG IFN alpha 2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology 49: 1460-1468
16. Fridell RA, Wang C, Sun JH, O'Boyle DR II, Nower P, Valera L, Qiu D, Roberts S, Huang X, Kienzle B, et al (2011) Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations. Hepatology 54: 1924-1955
17. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347: 975-982
18. Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, Ipe D, Morcos PN, Baher L, Najera I, et al (2010) 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 376: 1467-1475
19. Gane E, Pockros P, Zeuzem S, Marcellin P, Shikhman A, Bernaards C, Yetzer ES, Shulman N, Tong X (2012) Interferon-free treatment with a combination of mericitabine and danoprevir with or without ribavirin in treatment-naive HCV genotype 1-infected patients. J Hepatol 56: 555-556
20. Gane E, Stedman C, Hyland RH, Pang P, Ding X, Symonds WT, McHutchison JG (2013a) All-oral sofosbuvir-based 12-week regimes for the treatment of chronic HCV infection: the ELECTRON study. J Hepatol 58: 6-7
21. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (2013b) Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 368: 34-44
22. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O'Boyle DR II, et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465: 96-100
23. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H Jr, Bernstein D, Rizzetto M, et al (2004) Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140: 346-355
24. Hoofnagle JH (2009) A step forward in therapy for hepatitis C. N Engl J Med 360: 1899-1901
25. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y, Jones EA (1986) Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 315: 1575-1578
26. Innes HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Delahooke TE, Dillon JF, Forrest E, Fraser A, Gillespie R, et al (2011) Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care. Hepatology 54: 1547-1558
27. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, et al (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364: 2405-2416
28. Jacobson I, Sulkowski MS, Gane E, Koziel MJ, De Souza C, Kieffer T, Penney MS (2012) VX-222, telaprevir and ribavirin in treatment-naive gentoype 1 chronic hepatitis C: results of the ZENITH study interferon-free regimen. Hepatology 56: 308
29. Jacobson I, Dore GJ, Foster G, Fried M, Radu M, Rafalskiy VV, Moroz L, Craxi A, Peeters M, Lenz O, et al (2013a) Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronich HCV gentoype 1 infection in treatment-naive patients: results from QUEST-1, a phase III trial. J Hepatol 58: 574
30. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz E, Everson G, Bennett M, et al (2013b) Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 368: 1867-1877
31. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, et al (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368: 1685-1694
32. Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD, Landro JA, Chambers SP, Markland W, Lepre CA, O'Malley ET, et al (1996) Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87: 343-355
33. Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, Demicco M, Bernstein DE, Afdhal N, Vierling JM, Gordon SC, et al (2013a) Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 381: 2100-2107
34. Kowdley KV, Lawitz E, Poordad F, Cohen D, Nelson DR, Zeuzem S, Everson G, Kwo P, Foster G, Sulkowski M, et al (2013b) Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol 58: 2
35. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bos M, Cameron DR, Cartier M, Cordingley MG, et al (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426: 186-189
36. Landford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Orum H (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327: 198-201
37. Lange CM, Zeuzem S (2011) IL28B single nucleotide polymorphisms in the treatment of hepatitis C. J Hepatol 55: 692-701
38. Lange CM, Zeuzem S (2012) Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J Hepatol 58: 583-592
39. Lange CM, Kutalik Z, Morikawa K, Bibert S, Cerny A, Dollenmaier G, Dufour JF, Gerlach TJ, Heim MH, Malinverni R, et al (2012) Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy. Hepatology 55: 1038-1047
40. Lawitz E, Poordad F, Kowdley KV, Jensen DM, Cohen D, Siggelkow S, Wikstrom K, Larsen L (2012) 12-week interferon-free regimen of ABT-450/R, ABT-072, and ribavirin was well tolerated and achieved sustained virologic response in 91% treatment-naive HCV IL28B-CC genotype-1-infected subjects. J Hepatol 56: 7
41. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, et al (2013a) Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 13: 401-408
42. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Reddy KR, et al (2013b) Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 368: 1878-1887
43. Lindenbach BD (2013) Virion assembly and release. Curr Top Microbiol Immunol 369: 199-218
44. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, et al (2005) Complete replication of hepatitis C virus in cell culture. Science 309: 623-626
45. Lohmann V (2013) Hepatitis C virus RNA replication. Curr Top Microbiol Immunol 369: 167-198
46. 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: 110-113
47. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, et al (2012) Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 366: 216-224
48. Lorenz IC, Marcotrigiano J, Dentzer TG, Rice CM (2006) Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. Nature 442: 831-835
49. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK (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: 958-965
50. Manns M, Marcellin P, Poordad F, Evaldo S, Araujo A, Buti M, Horsmans Y, Janczewska E, Villamil F, Peeters M, et al (2013) Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronich HCV gentoype 1 infection in treatment-naive patients: results from QUEST-2, a phase III trial. J Hepatol 58: 568
51. McCown MF, Rajyaguru S, Kular S, Cammack N, Najera I (2009) GT-1a or GT-1b subtype-specific resistance profiles for hepatitis C virus inhibitors telaprevir and HCV-796. Antimicrob Agents Chemother 53: 2129-2132
52. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK (1998) Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 339: 1485-1492
53. Moradpour D, Penin F, Rice CM (2007) Replication of hepatitis C virus. Nat Rev Microbiol 5: 453-463
54. Morikawa K, Lange CM, Gouttenoire J, Meylan E, Brass V, Penin F, Moradpour D (2011) Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepatitis 18: 305-315
55. Nature Outlook N (2011) Hepatitis C. Nature 474: S1-S21
56. Niepmann M (2013) Hepatitis C virus RNA translation. Curr Top Microbiol Immunol 369: 143-166
57. Pawlotsky JM, Sarin SK, Foster G, Peng CY, Rasenack J, Flisiak R (2012) Alisporivir plus ribavirin achieves high rates of sustained HCV clearance (SVR24) as interferon (IFN)-free or IFN-add-on regimen in treatment-naive patients with HCV GT2 or GT3: Final results from VITAL-1 study. Hepatology 56: 309
58. Pol S, Ghalib RH, Rustgi VK, Martorell C, Everson GT, Tatum HA, Hezode C, Lim JK, Bronowicki JP, Abrams GA, et al (2012) Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis 12: 671-677
59. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, et al (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364: 1195-1206
60. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, et al (2013) Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 368: 45-53
61. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, et al (1998) Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 352: 1426-1432
62. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, et al (2013) A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet 45: 164-171
63. Rein DB, Smith BD, Wittenborn JS, Lesense SB, Wagner LD, Roblin DW, Patel N, Ward JW, Weinbaum CM (2012) The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med 156: 263-270
64. Romero-Brey I, Merz A, Chiramel A, Lee JY, Chlanda P, Haselman U, Santarella-Mellwig R, Habermann A, Hoppe S, Kallis S, et al (2012) Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus replication. PLoS Pathogens 8: e1003056
65. Schoggins JW, Rice CM (2013) Innate immune responses to hepatitis C virus. Curr Top Microbiol Immunol 369: 219-242
66. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy R, Hassanein T, Jacobson I, Lawitz E (2012a) High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV genotype 1, 2 or 3. Hepatology 56: LB-2
67. Sulkowski MS, Rodriguez-Torres M, Lawitz E, Shiffman M, Pol S, Herring R, McHutchison JG (2012b) Complete SVR4 rates in treatment-naïve HCV genotype 1a and 1b patients who achieved vRVR with an interferon-free all-oral regimen. Hepatology 56: 298
68. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, et al (2013) Sustained virological response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). J Hepatol 58: 570
69. Tabor E, Gerety RJ, Drucker JA, Seeff LB, Hoofnagle JH, Jackson DR, April M, Barker LF, Pineda-Tamondong G (1978) Transmission of non-A, non-B hepatitis from man to chimpanzee. Lancet 1: 463-466
70. Thimme R, Binder M, Bartenschlager R (2012) Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiol Rev 36: 663-683
71. Thomas E, Feld JJ, Li Q, Hu Z, Fried MW, Liang TJ (2011) Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models. Hepatology 53: 32-41
72. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, Duarte-Rojo A, Heathcote EJ, Manns MP, Kuske L, et al (2012) Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308: 2584-2593
73. Vermehren J, Schlosser B, Domke D, Elanjimattom S, Muller C, Hintereder G, Hensel-Wiegel K, Tauber R, Berger A, Haas N, et al (2012) High prevalence of anti-HCV antibodies in two metropolitan emergency departments in Germany: a prospective screening analysis of 28, 809 patients. PloS One 7: e41206
74. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, et al (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11: 791-796
75. Zeisel MB, Felmlee DJ, Baumert TF (2013) Hepatitis C virus entry. Curr Top Microbiol Immunol 369: 87-112
76. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, O'Grady J, Reichen J, Diago M, Lin A, et al (2000) Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 343: 1666-1672
77. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, et al (2011a) Telaprevir for retreatment of HCV infection. N Engl J Med 364: 2417-2428
78. Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Mullhaupt B, Gane E, Schuchmann M, Lohse A, Pol S, et al (2011b) Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 141: 2047-2055
79. Zeuzem S, Buggisch P, Agarwal K, Marcellin P, Sereni D, Klinker H, Moreno C, Zarski JP, Horsmans Y, Mo H, et al (2011c) The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C. Hepatology 55: 749-758
80. Zeuzem S, Soriano A, Asselah T, Bronowicki JP, Lohse A, Mullhaupt B, Schuchmann M (2012) (IFN)-free combination therapy of the NS3-4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 +/- ribavirin (RBV): final results of SOUND-C2 and predictors of response. Hepatology 56: 308
81. Zeuzem S, Asselah T, Angus PW, Zarski JP, Larrey D, Müllhaupt B, Gane E, Schuchmann M, Lohse A, Pol S, et al (2013) Faldaprevir (BI 201335), BI 207127 and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results. Antivir Ther. DOI: 10.3851/IMP2567