Hepatitis C virus: How genetic variability affects pathobiology of disease

Journal of Gastroenterology and Hepatology (Australia)

Volumn 26, Issue SUPPL. 1, 2011, Pages 83-95

  Chayama, Kazuaki ^a,b   Hayes, C Nelson ^a,b  

^a HIROSHIMA UNIVERSITY   (Japan)

^b Liver Research Project Center   (Japan)

Author keywords

Core amino acid substitution; IL28B; ISDR; Peg interferon; Ribavirin; Single nucleotide polymorphism

Indexed keywords

INTERFERON; NONSTRUCTURAL PROTEIN 5A; PEGINTERFERON; PEGINTERFERON ALPHA2A PLUS RIBAVIRIN; PEGINTERFERON ALPHA2B PLUS RIBAVIRIN; RIBAVIRIN;

AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ANTIVIRAL RESISTANCE; DISEASE DURATION; GENETIC VARIABILITY; GENOTYPE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN GENOME; NONHUMAN; NUCLEOTIDE SEQUENCE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; TREATMENT DURATION; VIRUS IDENTIFICATION; VIRUS RESISTANCE; VIRUS TYPING;

EID: 78650766355     PISSN: 08159319     EISSN: 14401746     Source Type: Journal    
DOI: 10.1111/j.1440-1746.2010.06550.x     Document Type: Review

References (139)

1. Suzuki T, Aizaki H, Murakami K, Shoji I, Wakita T. Molecular biology of hepatitis C virus. J. Gastroenterol. 2007; 42: 411-23.
2. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997; 26: S15-S20.
3. Di Bisceglie AM. Hepatitis C. Lancet 1998; 351: 351-5.
4. Marcellin P. Hepatitis C: the clinical spectrum of the disease. J. Gastroenterol. 1999; 31: 9-16.
5. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a Cdna clone derived from a blood-borne Non-a, Non-B viral-hepatitis genome. Science 1989; 244: 359-62.
6. Kuo G, Choo QL, Alter HJ et al. An assay for circulating antibodies to a major etiologic virus of human Non-a, Non-B-Hepatitis. Science 1989; 244: 362-4.
7. Kato N, Hijikata M, Ootsuyama Y et al. Molecular-cloning of the human hepatitis-C virus genome from Japanese patients with Non-a, Non-B hepatitis. P. Natl. Acad. Sci. USA 1990; 87: 9524-8.
8. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Shimotohno K. Sequence diversity of hepatitis C viral genomes. Mol. Biol. Med. 1990; 7: 495-501.
9. Choo QL, Richman KH, Han JH et al. Genetic organization and diversity of the hepatitis C virus. Proc. Natl. Acad. Sci. USA 1991; 88: 2451-5.
10. Okamoto H, Okada S, Sugiyama Y et al. The 5′-terminal sequence of the hepatitis C virus genome. Jpn. J. Exp. Med. 1990; 60: 167-77.
11. Tanaka T, Kato N, Cho MJ, Sugiyama K, Shimotohno K. Structure of the 3′ terminus of the hepatitis C virus genome. J. Virol. 1996; 70: 3307-12.
12. Weiner AJ, Brauer MJ, Rosenblatt J et al. Variable and hypervariable domains are found in the regions of HCV corresponding to the flavivirus envelope and NS1 proteins and the pestivirus envelope glycoproteins. Virology 1991; 180: 842-8.
13. Enomoto N, Takada A, Nakao T, Date T. There Are 2 Major Types of Hepatitis-C Virus in Japan. Biochem. Biophys. Res. Commun. 1990; 170: 1021-5.
14. Chayama K, Tsubota A, Arase Y et al. Genotypic Subtyping of Hepatitis-C Virus. J. Gastroenterol. Hepatol. 1993; 8: 150-6.
15. Simmonds P, Smith DB, McOmish F et al. Identification of genotypes of hepatitis C virus by sequence comparisons in the core, E1 and NS-5 regions. J. Gen. Virol. 1994; 75: (Pt 5) 1053-61.
16. Okamoto H, Sugiyama Y, Okada S et al. Typing hepatitis-C virus by polymerase chain-reaction with type-specific primers-application to clinical surveys and tracing infectious sources. J. Gen. Virol. 1992; 73: 673-9.
17. Okamoto H, Okada S, Sugiyama Y et al. Nucleotide sequence of the genomic RNA of hepatitis C virus isolated from a human carrier: comparison with reported isolates for conserved and divergent regions. J. Gen. Virol. 1991; 72: (Pt 11) 2697-704.
18. Chayama K, Tsubota A, Koida I et al. Nucleotide sequence of hepatitis C virus (type 3b) isolated from a Japanese patient with chronic hepatitis C. J. Gen. Virol. 1994; 75: (Pt 12) 3623-8.
19. Stuyver L, Rossau R, Wyseur A et al. Typing of hepatitis-c virus isolates and characterization of new subtypes using a line probe assay. J. Gen. Virol. 1993; 74: 1093-102.
20. Ciotti M, Marcuccilli F, Guenci T et al. A multicenter evaluation of the Abbott RealTime HCV Genotype II assay. J. Virol. Methods 2010.
21. Rho J, Ryu JS, Hur W et al. Hepatitis C virus (HCV) genotyping by annealing reverse transcription-PCR products with genotype-specific capture probes. J. Microbiol. 2008; 46: 81-7.
22. Tokita H, Okamoto H, Tsuda F et al. Hepatitis-C virus variants from vietnam are classifiable into the 7th, 8th, and 9th major genetic groups. P. Natl. Acad. Sci. USA 1994; 91: 11022-6.
23. Simmonds P, Alberti A, Alter HJ et al. A proposed system for the nomenclature of hepatitis-C viral genotypes. Hepatology 1994; 19: 1321-4.
24. Simmonds P, Bukh J, Combet C et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005; 42: 962-73.
25. Murphy D, Chamberland J, Dandavino R, Sablon E. A new genotype of hepatitis C virus originating from central Africa. Hepatology 2007; 46: 623a-623a.
26. LOS Alamos National Laboratory. HCV Sequence Database. Cited 30 June 2010. Available from URL: .
27. Mizokami M. Hepatitis Virus Database. Cited 30 June 2010. Available from URL: .
28. Combet C. euHCVdb. Cited 30 June 2010. Available from URL: .
29. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997; 25: 735-9.
30. Rubbia-Brandt L, Quadri R, Abid K et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J. Hepatol. 2000; 33: 106-15.
31. Rubbia-Brandt L, Leandro G, Spahr L et al. Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology 2001; 39: 119-24.
32. Sharma P, Balan V, Hernandez J et al. Hepatic steatosis in hepatitis C virus genotype 3 infection: does it correlate with body mass index, fibrosis, and HCV risk factors? Dig. Dis. Sci. 2004; 49: 25-9.
33. Gordon FD, Pomfret EA, Pomposelli JJ, Lewis WD, Jenkins RL, Khettry U. Severe steatosis as the initial histologic manifestation of recurrent hepatitis C genotype 3. Hum. Pathol. 2004; 35: 636-8.
34. Hissar SS, Goyal A, Kumar M et al. Hepatitis C virus genotype 3 predominates in north and central India and is associated with significant histopathologic liver disease. J. Med. Virol. 2006; 78: 452-8.
35. Bugianesi E, Marchesini G, Gentilcore E et al. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis. Hepatology 2006; 44: 1648-55.
36. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002; 36: 1266-72.
37. Westin J, Nordlinder H, Lagging M, Norkrans G, Wejstal R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J. Hepatol. 2002; 37: 837-42.
38. Castera L, Hezode C, Roudot-Thoraval F et al. Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis. Gut 2004; 53: 420-4.
39. Hourioux C, Patient R, Morin A et al. The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut 2007; 56: 1302-8.
40. Qiang G, Yang L, Witek RP, Jhaveri R. Recombinant adenoviruses expressing Steatosis-associated Hepatitis C virus genotype 3 Core protein produce intracellular lipid accumulation in cultured and primary hepatocytes. Virus. Res. 2009; 139: 127-30.
41. Jhaveri R, McHutchison J, Patel K, Qiang G, Diehl AM. Specific polymorphisms in hepatitis C virus genotype 3 core protein associated with intracellular lipid accumulation. J. Infect. Dis. 2008; 197: 283-91.
42. Zampino R, Ingrosso D, Durante-Mangoni E et al. Microsomal triglyceride transfer protein (MTP)-493G/T gene polymorphism contributes to fat liver accumulation in HCV genotype 3 infected patients. J. Viral. Hepat. 2008; 15: 740-6.
43. Hwang SJ, Lee SD. Hepatic steatosis and hepatitis C: Still unhappy bedfellows? J. Gastroenterol. Hepatol. 2011; 26 (Suppl. 1): 96-101.
44. Kanai K, Kako M, Okamoto H. HCV genotypes in chronic hepatitis-C and response to interferon. Lancet 1992; 339: 1543-1543.
45. Yoshioka K, Kakumu S, Wakita T et al. Detection of hepatitis-C virus by polymerase chain-reaction and response to interferon-alpha therapy-relationship to genotypes of hepatitis-C virus. Hepatology 1992; 16: 293-9.
46. Chayama K, Tsubota A, Arase Y et al. Effect of lymphoblastoid alfa-interferon in patients with chronic hepatitis-C having different genotypic subtype of hepatitis-C virus. Gastroenterol. Jpn. 1993; 28: 45-7.
47. Tsubota A, Chayama K, Arase Y et al. Factors useful in predicting the response to interferon therapy in chronic hepatitis-C. J. Gastroenterol. Hepatol. 1993; 8: 535-9.
48. National Institutes of Health. NIH consensus statement on management of hepatitis C: 2002. NIH Consens. State Sci. Statements 2002; 19: 1-46.
49. 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: 958-65.
50. 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: 975-82.
51. Hasan F, Asker H, Al-Khaldi J et al. Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4. Am. J. Gastroenterol. 2004; 99: 1733-7.
52. Bruno S, Camma C, Di Marco V et al. Peginterferon alfa-2b plus ribavirin for naive patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J. Hepatol. 2004; 41: 474-81.
53. 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: 993-9.
54. 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: 346-55.
55. Alfaleh FZ, Hadad Q, Khuroo MS et al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int. 2004; 24: 568-74.
56. Kamal SM, El Tawil AA, Nakano T et al. Peginterferon {alpha}-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response. Gut 2005; 54: 858-66.
57. Mangia A, Santoro R, Minerva N et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N. Engl. J. Med. 2005; 352: 2609-17.
58. von Wagner M, Huber M, Berg T et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522-7.
59. Derbala M, Amer A, Bener A, Lopez AC, Omar M, El Ghannam M. Pegylated interferon-alpha 2b-ribavirin combination in Egyptian patients with genotype 4 chronic hepatitis. J. Viral. Hepat. 2005; 12: 380-5.
60. El-Zayadi AR, Attia M, Barakat EM et al. Response of hepatitis C genotype-4 naive patients to 24 weeks of Peg-interferon-alpha2b/ribavirin or induction-dose interferon-alpha2b/ribavirin/amantadine: a non-randomized controlled study. Am. J. Gastroenterol. 2005; 100: 2447-52.
61. Kuboki M, Iino S, Okuno T et al. Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients. J. Gastroenterol. Hepatol. 2007; 22: 645-52.
62. Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N. Engl. J. Med. 2007; 357: 124-34.
63. Yu ML, Dai CY, Huang JF et al. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007; 56: 553-9.
64. Kamal SM, El Kamary SS, Shardell MD et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2007; 46: 1732-40.
65. Dalgard O, Bjoro K, Ring-Larsen H et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35-42.
66. El Makhzangy H, Esmat G, Said M et al. Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J. Med. Virol. 2009; 81: 1576-83.
67. 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: 580-93.
68. Rumi MG, Aghemo A, Prati GM et al. Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology 2010; 138: 108-15.
69. Yu ML, Chuang WL. Treatment of chronic hepatitis C in Asia: when East meets West. J. Gastroenterol. Hepatol. 2009; 24: 336-45.
70. Zeuzem S, Berg T, Moeller B et al. Expert opinion on the treatment of patients with chronic hepatitis C. J. Viral. Hepat. 2009; 16: 75-90.
71. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335-74.
72. Enomoto N, Sakuma I, Asahina Y et al. Comparison of full-length sequences of interferon-sensitive and resistant hepatitis-C virus 1b-sensitivity to interferon is conferred by amino-acid substitutions in the Ns5a region. J. Clin. Invest. 1995; 96: 224-30.
73. Enomoto N, Sakuma I, Asahina Y et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N. Engl. J. Med. 1996; 334: 77-81.
74. Enomoto N, Sakuma I, Asahina Y et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N. Engl. J. Med. 1996; 334: 77-81.
75. Kurosaki M, Enomoto N, Murakami T et al. Analysis of genotypes and amino acid residues 2209 to 2248 of the NS5A region of hepatitis C virus in relation to the response to interferon-beta therapy. Hepatology 1997; 25: 750-3.
76. Chayama K, Tsubota A, Kobayashi M et al. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology 1997; 25: 745-9.
77. Khorsi H, Castelain S, Wyseur A et al. Mutations of hepatitis C virus 1b NS5A 2209-2248 amino acid sequence do not predict the response to recombinant interferon-alfa therapy in French patients. J. Hepatol. 1997; 27: 72-7.
78. Hofgartner WT, Polyak SJ, Sullivan DG, Carithers RL, Jr, Gretch DR. Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b. J. Med Virol. 1997; 53: 118-26.
79. Odeberg J, Yun Z, Sonnerborg A, Weiland O, Lundeberg J. Variation in the hepatitis C virus NS5a region in relation to hypervariable region 1 heterogeneity during interferon treatment. J. Med. Virol. 1998; 56: 33-8.
80. Frangeul L, Cresta P, Perrin M et al. Mutations in NS5A region of hepatitis C virus genome correlate with presence of NS5A antibodies and response to interferon therapy for most common European hepatitis C virus genotypes. Hepatology 1998; 28: 1674-9.
81. Squadrito G, Orlando ME, Cacciola I et al. Long-term response to interferon alpha is unrelated to "interferon sensitivity determining region" variability in patients with chronic hepatitis C virus-1b infection. J. Hepatol. 1999; 30: 1023-7.
82. Akuta N, Suzuki F, Hirakawa M et al. A matched case-controlled study of 48 and 72 weeks of peginterferon plus ribavirin combination therapy in patients infected with HCV genotype 1b in Japan: amino acid substitutions in HCV core region as predictor of sustained virological response. J. Med. Virol. 2009; 81: 452-8.
83. Mihm S, Monazahian M, Grethe S, Fechner C, Ramadori G, Thomssen R. Ratio of serum gamma-GT/ALT rather than ISDR variability is predictive for initial virological response to IFN-alpha in chronic HCV infection. J. Med. Virol. 1999; 58: 227-34.
84. Murakami T, Enomoto N, Kurosaki M, Izumi N, Marumo F, Sato C. Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection. Hepatology 1999; 30: 1045-53.
85. McKechnie VM, Mills PR, McCruden EA. The NS5a gene of hepatitis C virus in patients treated with interferon-alpha. J. Med. Virol. 2000; 60: 367-78.
86. Nousbaum J, Polyak SJ, Ray SC et al. Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy. J. Virol. 2000; 74: 9028-38.
87. Berg T, Mas Marques A, Hohne M, Wiedenmann B, Hopf U, Schreier E. Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment. Hepatology 2000; 32: 1386-95.
88. Gerotto M, Dal Pero F, Pontisso P, Noventa F, Gatta A, Alberti A. Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon. Gastroenterology 2000; 119: 1649-55.
89. Murphy MD, Rosen HR, Marousek GI, Chou S. Analysis of sequence configurations of the ISDR, PKR-binding domain, and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection. Dig. Dis. Sci. 2002; 47: 1195-205.
90. Hung CH, Lee CM, Lu SN et al. Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirin. J. Viral. Hepat. 2003; 10: 87-94.
91. Cappiello G, Abbate I, Lo Iacono O et al. ISDR pattern and evolution in patients with chronic hepatitis C treated with standard or PEG-IFN plus ribavirin. Antivir. Ther. 2003; 8: 105-10.
92. Saito T, Ito T, Ishiko H et al. Sequence analysis of PePHD within HCV E2 region and correlation with resistance of interferon therapy in Japanese patients infected with HCV genotypes 2a and 2b. Am. J. Gastroenterol. 2003; 98: 1377-83.
93. Murayama M, Katano Y, Nakano I et al. A mutation in the interferon sensitivity-determining region is associated with responsiveness to interferon-ribavirin combination therapy in chronic hepatitis patients infected with a Japan-specific subtype of hepatitis C virus genotype 1B. J. Med. Virol. 2007; 79: 35-40.
94. Nagase Y, Yotsuyanagi H, Okuse C et al. Effect of treatment with interferon alpha-2b and ribavirin in patients infected with genotype 2 hepatitis C virus. Hepatol. Res. 2008; 38: 252-8.
95. Shen C, Hu T, Shen L, Gao L, Xie W, Zhang J. Mutations in ISDR of NS5A gene influence interferon efficacy in Chinese patients with chronic hepatitis C virus genotype 1b infection. J. Gastroenterol. Hepatol. 2007; 22: 1898-903.
96. Veillon P, Payan C, Le Guillou-Guillemette H, Gaudy C, Lunel F. Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy. World J. Gastroenterol. 2007; 13: 1195-203.
97. Yoon J, Lee JI, Baik SK et al. Predictive factors for interferon and ribavirin combination therapy in patients with chronic hepatitis C. World J. Gastroenterol. 2007; 13: 6236-42.
98. Yen YH, Hung CH, Hu TH et al. Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209-2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin. Aliment. Pharmacol. Ther. 2008; 27: 72-9.
99. Torres-Puente M, Cuevas JM, Jimenez-Hernandez N et al. Hepatitis C virus and the controversial role of the interferon sensitivity determining region in the response to interferon treatment. J. Med. Virol. 2008; 80: 247-53.
100. Munoz de Rueda P, Casado J, Paton R et al. Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses. J. Virol. 2008; 82: 6644-53.
101. Shirakawa H, Matsumoto A, Joshita S et al. Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 2008; 48: 1753-60.
102. Hayashi K, Katano Y, Honda T et al. Mutations in the interferon sensitivity-determining region of hepatitis C virus genotype 2a correlate with response to pegylated-interferon-alpha 2a monotherapy. J. Med. Virol. 2009; 81: 459-66.
103. Mori N, Imamura M, Kawakami Y et al. Randomized trial of high-dose interferon-alpha-2b combined with ribavirin in patients with chronic hepatitis C: correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy. J. Med. Virol. 2009; 81: 640-9.
104. Bouzgarrou N, Hassen E, Mahfoudh W et al. NS5A(ISDR-V3) region genetic variability of Tunisian HCV-1b strains: correlation with the response to the combined interferon/ribavirin therapy. J. Med. Virol. 2009; 81: 2021-8.
105. Okanoue T, Itoh Y, Hashimoto H et al. Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study. J. Gastroenterol. 2009; 44: 952-63.
106. Nakagawa M, Sakamoto N, Ueyama M et al. Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection. J. Gastroenterol. 2010; 45: 656-65.
107. Hayashi K, Katano Y, Ishigami M et al. Mutations in the core and NS5A region of hepatitis C virus genotype 1b and correlation with response to pegylated-interferon-alpha 2b and ribavirin combination therapy. J. Viral. Hepat. 2010.
108. Enomoto N, Maekawa S. HCV genetic elements determining the early response to peginterferon and ribavirin therapy. Intervirology 2010; 53: 66-9.
109. Macquillan GC, Niu X, Speers D et al. Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population? J. Gastroenterol. Hepatol. 2004; 19: 551-7.
110. Yang SS, Lai MY, Chen DS, Chen GH, Kao JH. Mutations in the NS5A and E2-PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin. Liver Int. 2003; 23: 426-33.
111. El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H. Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy. Hepatology 2008; 48: 38-47.
112. El-Shamy A, Sasayama M, Nagano-Fujii M et al. Prediction of efficient virological response to pegylated interferon/ribavirin combination therapy by NS5A sequences of hepatitis C virus and anti-NS5A antibodies in pre-treatment sera. Microbiol. Immunol. 2007; 51: 471-82.
113. Puig-Basagoiti F, Forns X, Furcic I et al. Dynamics of hepatitis C virus NS5A quasispecies during interferon and ribavirin therapy in responder and non-responder patients with genotype 1b chronic hepatitis C. J. Gen. Virol. 2005; 86: 1067-75.
114. Layden-Almer JE, Kuiken C, Ribeiro RM et al. Hepatitis C virus genotype 1a NS5A pretreatment sequence variation and viral kinetics in African American and white patients. J. Infect. Dis. 2005; 192: 1078-87.
115. Sarrazin C, Kornetzky I, Ruster B et al. Mutations within the E2 and NS5A protein in patients infected with hepatitis C virus type 3a and correlation with treatment response. Hepatology 2000; 31: 1360-70.
116. Polyak SJ, Nousbaum JB, Larson AM, Cotler S, Carithers RL, Jr, Gretch DR. The protein kinase-interacting domain in the hepatitis C virus envelope glycoprotein-2 gene is highly conserved in genotype 1-infected patients treated with interferon. J. Infect. Dis. 2000; 182: 397-404.
117. Cochrane A, Orr A, Shaw ML, Mills PR, McCruden EA. The amino acid sequence of the PKR-eIF2alpha phosphorylation homology domain of hepatitis C virus envelope 2 protein and response to interferon-alpha. J. Infect. Dis. 2000; 182: 1515-18.
118. Chayama K, Suzuki F, Tsubota A et al. Association of amino acid sequence in the PKR-eIF2 phosphorylation homology domain and response to interferon therapy. Hepatology 2000; 32: 1138-44.
119. Watanabe H, Nagayama K, Enomoto N et al. Amino acid substitutions in PKR-eIF2 phosphorylation homology domain (PePHD) of hepatitis C virus E2 protein in genotype 2a/2b and 1b in Japan and interferon efficacy. Hepatol. Res. 2003; 26: 268-74.
120. Gaudy C, Lambele M, Moreau A, Veillon P, Lunel F, Goudeau A. Mutations within the hepatitis C virus genotype 1b E2-PePHD domain do not correlate with treatment outcome. J. Clin. Microbiol. 2005; 43: 750-4.
121. Ukai K, Ishigami M, Yoshioka K et al. Mutations in carboxy-terminal part of E2 including PKR/eIF2alpha phosphorylation homology domain and interferon sensitivity determining region of nonstructural 5A of hepatitis C virus 1b: their correlation with response to interferon monotherapy and viral load. World J. Gastroenterol. 2006; 12: 3722-8.
122. Koizumi K, Enomoto N, Kurosaki M et al. Diversity of quasispecies in various disease stages of chronic hepatitis C virus infection and its significance in interferon treatment. Hepatology 1995; 22: 30-5.
123. Sandres K, Dubois M, Pasquier C et al. Genetic heterogeneity of hypervariable region 1 of the hepatitis C virus (HCV) genome and sensitivity of HCV to alpha interferon therapy. J. Virol. 2000; 74: 661-8.
124. Hino K, Yamaguchi Y, Fujiwara D et al. Hepatitis C virus quasispecies and response to interferon therapy in patients with chronic hepatitis C: a prospective study. J. Viral. Hepat. 2000; 7: 36-42.
125. Grahovac B, Bingulac-Popovic J, Vucelic B et al. Hypervariable region 1 of hepatitis C virus genome and response to interferon therapy. Clin. Chem. Lab. Med. 2000; 38: 905-10.
126. Yeh BI, Han KH, Lee HW et al. Factors predictive of response to interferon-alpha therapy in hepatitis C virus type 1b infection. J. Med. Virol. 2002; 66: 481-7.
127. Abbate I, Lo Iacono O, Di Stefano R et al. HVR-1 quasispecies modifications occur early and are correlated to initial but not sustained response in HCV-infected patients treated with pegylated- or standard-interferon and ribavirin. J. Hepatol. 2004; 40: 831-6.
128. Ueda E, Enomoto N, Sakamoto N et al. Changes of HCV quasispecies during combination therapy with interferon and ribavirin. Hepatol. Res. 2004; 29: 89-96.
129. Akuta N, Suzuki F, Sezaki H et al. Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005; 48: 372-80.
130. Akuta N, Suzuki F, Sezaki H et al. Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load. J. Med. Virol. 2006; 78: 83-90.
131. Akuta N, Suzuki F, Kawamura Y et al. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J. Hepatol. 2007; 46: 403-10.
132. Akuta N, Suzuki F, Kawamura Y et al. Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J. Med. Virol. 2007; 79: 1686-95.
133. Nakamoto S, Imazeki F, Fukai K et al. Association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development. J. Hepatol. 2010; 52: 72-8.
134. Akuta N, Suzuki F, Hirakawa M et al. Amino acid substitutions in the hepatitis C virus core region of genotype 1b affect very early viral dynamics during treatment with telaprevir, peginterferon, and ribavirin. J. Med. Virol. 2010; 82: 575-82.
135. Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399-401.
136. 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: 1100-4.
137. 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: 1105-9.
138. 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: 1338-45. 1345 e1331-1337.
139. Thomas DL, Thio CL, Martin MP et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798-801.