Inflammation and Repair in Viral Hepatitis C

  • Manuela G. Neuman
  • Kevin Sha
  • Rustan Esguerra
  • Sam Zakhari
  • Robert E. Winkler
  • Nir Hilzenrat
  • Jonathan Wyse
  • Curtis L. Cooper
  • Devanshi Seth
  • Mark D. Gorrell
  • Paul S. Haber
  • Geoffrey W. McCaughan
  • Maria A. Leo
  • Charles S. Lieber
  • Mihai Voiculescu
  • Eugenia Buzatu
  • Camelia Ionescu
  • Jozsef Dudas
  • Bernhard Saile
  • Giuliano Ramadori
Review Paper


Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host’s immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression. We aim to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. We will accomplish this task by discussion of three topics: (1) the role of cytokines in the adaptive immune response against the HCV infection; (2) the progression of fibrosis; and (3) the risk factors of co-morbidity with alcohol and human immunodeficiency virus (HIV) in HCV-infected individuals. Despite recent improvements in treating HCV infection using pegylated interferon alpha (PEGIFN-α) and ribavirin, about half of individuals infected with some genotypes, for example genotypes 1 and 4, will not respond to treatment or cannot be treated because of contraindications. This review will also aim to describe the importance of IFN-α-based therapies in HCV infection, ways of monitoring them, and associated complications.


Hepatitis C Inflammation Fibrosis Cytokines Chemokines HIV 





Acquired immunodeficiency syndrome


Alcohol dehydrogenase


Alcohol liver disease


Acetaldehyde dehydrogenase


Antigen presenting cells




antiretroviral therapy






Bone morphogenetic protein-6


Chemokines with two N-terminal cysteines


CC/CXC Receptor


Cluster of differentiation


Consensus IFN


Core protein


Chemokines presenting an amino acid between the two N-terminal cysteine residues




Extracellular matrix


Enzyme-linked immunosorbent assay


Guanisine 5′-triphosphate


Highly active antiretroviral therapy


Hepatitis C virus


Human immunodeficiency virus


Hepatocellular carcinoma


Hepatic stellate cells


Injection drug users




Interferon growth factor






Inosine monophosphate dehydrogenase


Interferon response factor


Janus kinases




Monocyte chemo-attractant protein 1




Major histocompatible complex


Macrophage inflammatory protein 1


Matrix metalloproteinases




Non-nucleoside reverse transcriptase inhibitor


Nucleoside reverse transcriptase inhibitor


Nucleoside analogue reverse transcriptase inhibitor




Platelet-derived growth factor


Polyethylene glycol


Pegylated interferon


Protease inhibitor


Regulated upon activation, normal T-cell expressed, and presumably secreted


Signal mothers against decapentaplegic


Single nucleotide polymorphisms


Suppressor of cytokine signaling


Signal transducer and activator of transcription


Tissue inhibitor of metalloproteinases


T helper


Toll-like receptors


T regulatory


Transforming growth factor beta


Transforming growth factor beta receptor


Tenofovir disoproxil fumarate


Tumor necrosis factor-alpha


Tumor necrosis factor receptor signaling





This paper was presented at the “7th International Symposium on Cytokines and Chemokines” (Montreal, Canada, 7–9 September, 2006). Dr Manuela G. Neuman, scientific organizer of the symposium is grateful for the financial support given by the Institute of Infection and Immunity of Canadian Institutes of Health Research and by the National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, USA.


  1. 1.
    Gramenzi A, Andreone P, Loggi E, Foschi FG, Cursaro C, Margotti M et al (2005) Cytokine profile of peripheral blood mononuclear cells from patients with different outcomes of hepatitis C virus infection. J Viral Hepatitis 12:525–530Google Scholar
  2. 2.
    Farinati F, Cardin R, Bortolami M, Guido M, Rugge M (2006) Oxidative damage, pro-inflammatory cytokines, TGF-α and c-myc in chronic HCV-related hepatitis and cirrhosis. World J Gastroenterol 12:2065–2069PubMedGoogle Scholar
  3. 3.
    Zekri AR, El-Din AM, Hassan A, El-Din AH, El-Shehaby A, Abu-Shady MA (2005) Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression. World J Gastroenterol 11:6624–6630PubMedGoogle Scholar
  4. 4.
    Lau D, Luxon B, Xiao S, Beard M, Lemon S (2005) Intrahepatic gene expression profiles and alpha smooth muscle Actin patterns in Hepatitis C virus induced fibrosis. Hepatology 42:273–281PubMedGoogle Scholar
  5. 5.
    Thimme R, Lohmann V, Weber F (2006) A target on the move: Innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res 69:129–141PubMedGoogle Scholar
  6. 6.
    Ando K, Guidotti LG, Wirth S, Ishikawa T, Missale G, Moriyama T et al (1994) Class I-restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. J Immunol 152:3245–3253PubMedGoogle Scholar
  7. 7.
    Guidotti LG, Chisari FV (1996) To kill or to cure: Options in host defense against viral infection. Curr Op Immunol 8:478–483Google Scholar
  8. 8.
    Guidotti LG, Chisari FV (2001) Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19:65–91PubMedGoogle Scholar
  9. 9.
    Missale G, Bertoni R, Lamonaca V, Valli A, Massari M, Mori C et al (1996) Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Invest 98:706–14PubMedGoogle Scholar
  10. 10.
    Cerny A, Chisari FV (1999) Pathogenesis of chronic hepatitis C: Immunological features of hepatic injury and viral persistence. Hepatology 30:595–601PubMedGoogle Scholar
  11. 11.
    Ulsenheimer A, Gerlach JT, Gruener NH, Jung MC, Schirren CA, Schraut W et al (2003) Detection of functionally altered hepatitis C virus-specific CD4+ T cells in acute and chronic hepatitis C. Hepatology 37:1189–1198PubMedGoogle Scholar
  12. 12.
    Semmo N, Day CL, Ward SM, Lucas M, Harcourt G, Loughry A et al (2005) Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection. Hepatology 41:1019–1028PubMedGoogle Scholar
  13. 13.
    Prezzi C, Casciaro MA, Francavilla V, Schiaffella E, Finocchi L, Chircu LV et al (2001) Virus-specific CD8+ T cells with type 1 or type 2 cytokine profile are related to different disease activity in chronic hepatitis C virus infection. Euro J Immunol 31:894–906Google Scholar
  14. 14.
    Kamal SM, Rasenack JW, Bianchi L, Al Tawil A, El Sayed Khalifa K, Peter T et al (2001) Acute hepatitis C without and with schistosomiasis: Correlation with hepatitis C-specific CD4+ T-cell and cytokine response. Gastroenterology 121:646–656PubMedGoogle Scholar
  15. 15.
    Pachiadakis I, Pollara G, Chain BM, Naoumov NV (2005) Is hepatitis C virus infection of dendritic cells a mechanism facilitating viral persistence? Lancet Infectious 5:296–304Google Scholar
  16. 16.
    Dolganiuc A, Kodys K, Kopasz A, Marshall C, Do T, Romics L Jr et al (2003) Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol 170:5615–5624PubMedGoogle Scholar
  17. 17.
    Kanto T, Hayashi N, Takehara T, Tatsumi T, Kuzushita N, Ito A et al (1999) Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol 162:5584–5591PubMedGoogle Scholar
  18. 18.
    Kanto T, Inoue M, Miyatake H, Sato A, Sakakibara M, Yakushijin T et al (2004) Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis 190:1919–1926PubMedGoogle Scholar
  19. 19.
    Kubin M, Kamoun M, Trinchieri G (1994) Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med 180:211–222PubMedGoogle Scholar
  20. 20.
    Chang K.M, Thimme R, Melpolder JJ, Oldach D, Pemberton J, Moorhead-Loudis J et al (2001) Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection. Hepatology 33:267–276PubMedGoogle Scholar
  21. 21.
    Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY et al (1999) Analysis of a successful immune response against hepatitis C virus. Immunity 10:439–449PubMedGoogle Scholar
  22. 22.
    Oleksyk TK, Thio CL, Truelove AL, Goedert JJ, Donfield SM, Kirk GD et al (2005) Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance. Genes Immun 6:347–357PubMedGoogle Scholar
  23. 23.
    Mondelli MU, Barnaba V (2006) Viral and host immune regulatory mechanisms in hepatitis C virus infection. Euro J Gastroenterol Hepatol 18:327–331Google Scholar
  24. 24.
    Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM et al (2006) Foxp3+ CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 107:4424–4432PubMedGoogle Scholar
  25. 25.
    Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD2CD25 regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med 194:629–644PubMedGoogle Scholar
  26. 26.
    Shin EC, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel PM et al (2006) Virus induced type I interferon stimulates generation of immunoproteosomes at the site of infection. J Clin Invest 116:3006–3024PubMedGoogle Scholar
  27. 27.
    Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C et al (2004) An immunomodulatory role for CD4+ CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40:1062–1071PubMedGoogle Scholar
  28. 28.
    Thornton AM, Shevach EM (2000) Suppressor effector function of CD4CD25 immunoregulatory T cells in antigen nonspecific. J Immunol 164:183–190PubMedGoogle Scholar
  29. 29.
    Bolacchi F, Sinistro A, Ciaprini C, Demin F, Capozzi M, Carducci FC et al (2006) Increased hepatitis C virus (HCV)-specific CD4+ CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol 144: 188–196PubMedGoogle Scholar
  30. 30.
    Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C et al (2005) T cells with a CD4+ CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 79:7860–7867PubMedGoogle Scholar
  31. 31.
    Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G et al (2001) Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Immunol 75:5550–5558Google Scholar
  32. 32.
    Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A et al (2004) Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection. J Clin Invest 113:963–972PubMedGoogle Scholar
  33. 33.
    Abel M, Sene D, Pol S, Bourliere M, Poynard T, Charlotte F et al (2006) Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology 44:1607–1616PubMedGoogle Scholar
  34. 34.
    Neuman MG, Benhamou JP, Marcellin P, Valla DC, Malkiewicz IM, Katz GG et al (2007) Cytokine-chemokine signature in chronic hepatitis C patients. Trans Res 149:126–138Google Scholar
  35. 35.
    Neuman MG (2003) Cytokines in Alcoholic Liver. Alcohol Res Health 27:313–322Google Scholar
  36. 36.
    Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218PubMedGoogle Scholar
  37. 37.
    Ramadori G, Saile B (2004) Portal tract fibrogenesis in the liver. Lab Invest 84:153–159PubMedGoogle Scholar
  38. 38.
    Guyot C, Lepreux S, Combe C, Doudnikoff E, Bioulac-Sage P, Balabaud C et al (2006) Hepatic fibrosis and cirrhosis: The (myo)fibroblastic cell subpopulations involved. Int J Biochem Cell Biol 38:135–151PubMedGoogle Scholar
  39. 39.
    Bhogal RK, Bona CA (2005) B cells: no longer bystanders in liver fibrosis. J Clin Invest 115:2962–2965PubMedGoogle Scholar
  40. 40.
    Neuman MG (2006) Markers of fibrosis in liver disease. Rom J Hepatology 2:56–58Google Scholar
  41. 41.
    Benlloch S, Beltran B, Moreno R, Berenguer M (2003) Fibrogenesis and liver transplantation. Gastronenterol Hepatol 26:381–395Google Scholar
  42. 42.
    Braun M, Vierling JM (2003) The clinical and immunologic impact of using interferon and ribavirin in the immunosuppressed host. Liver Transpl 9:S79–S89PubMedGoogle Scholar
  43. 43.
    Piek E, Heldin CH, ten Dijke P (1999) Specificity, diversity, and regulation in TGF-β superfamily signaling. FASEB J 13: 2105–2124PubMedGoogle Scholar
  44. 44.
    Massagué J, Wotton D (2000) Transcriptional control by the TGF-β/Smad signaling system. EMBO J 19:1745–1754PubMedGoogle Scholar
  45. 45.
    Dixon M, Agius L, Yeaman SJ, Day CP (1999) Inhibition of rat hepatocyte proliferation by transforming growth factor β and glucagon is associated with inhibition of ERK2 and p70 S6 kinase. Hepatology 29:1418–1424PubMedGoogle Scholar
  46. 46.
    Sugiyama A, Nagaki M, Shidoji Y, Moriwaki H, Muto Y (1997) Regulation of cell cycle-related genes in rat hepatocytes by transforming growth factor β1. Biochem Biophys Res Commun 238:539–543PubMedGoogle Scholar
  47. 47.
    Garcia-Trevijano ER, Iraburu MJ, Fontana L, José A, Dominguez-Rosales JA, Auster A et al (1999) Transforming growth factor β1 induces the expression of a α1(I) procollagen mRNA by a hydrogen peroxide-C/EBPβ-dependent mechanism in rat hepatic stellate cells. Hepatology 29:960–970PubMedGoogle Scholar
  48. 48.
    Demirci G, Nashan B, Pichlmayr R (1996) Fibrosis in chronic rejection of human liver allografts: expression patterns of transforming growth factor-TGF-beta1 and TGF-beta3. Transplantation 62:1776–1183PubMedGoogle Scholar
  49. 49.
    Falleti E, Fabris C, Toniutto P, Fontanini E, Cussigh A, Caldato M et al (2007) Genetic polymorphisms of inflammatory cytokines and liver fibrosis progression due to recurrent hepatitis C. J Interferon Cytokine Res 27:239–246PubMedGoogle Scholar
  50. 50.
    Schirren CA, Jung MC, Worzfeld T, Mamin M, Baretton GB, Gruener NH et al (2003) Cytokine profile of liver- and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection. Liver Transpl 6:222–228Google Scholar
  51. 51.
    Ben-Ari Z, Pappo O, Druzd T, Sulkes J, Klein T, Samra Z et al (2004) Role of cytokine gene polymorphism and hepatic transforming growth factor β1 expression in recurrent hepatitis C after liver transplantation. Cytokine 27:7–14PubMedGoogle Scholar
  52. 52.
    Huang YS, Chan CY, Wu JC, Pai CH, Chao Y, Lee SD (1996) Serum levels of interleukin-8 in alcoholic liver disease: relationship with disease stage, biochemical parameters and survival. J Hepatol 24:377–384PubMedGoogle Scholar
  53. 53.
    Adams DH, Hubscher S, Fear J, Johnston J, Shaw S, Afford S (1996) Hepatic expression of macrophage inflammatory protein-1 alpha and macrophage inflammatory protein-1 beta after liver transplantation. Transplantation 61:817–825PubMedGoogle Scholar
  54. 54.
    Li X, Klintman D, Liu Q, Sato T, Jeppsson B, Thorlacius H (2004) Critical role of CXC chemokines in endotoxemic liver injury in mice. J Leukoc Biol 75:443–452PubMedGoogle Scholar
  55. 55.
    Efsen E, Grappone C, DeFranco RM, Milani S, Romanelli RG, Bonacchi A et al (2002) Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans. J Hepatol 37:39–47PubMedGoogle Scholar
  56. 56.
    Leifeld L, Dumoulin FL, Purr I, Janberg K, Trautwein C, Wolff M et al (2003) Early up-regulation of chemokine expression in fulminant hepatic failure. J Pathol 199:335–344PubMedGoogle Scholar
  57. 57.
    Czaja MJ, Geerts A, Xu J, Schmiedeberg P, Ju Y (1994) Monocyte chemoattractant protein 1 (MCP-1) expression occurs in toxic rat liver injury and human liver disease. J Leukoc Biol 55:120–126PubMedGoogle Scholar
  58. 58.
    Schwabe RF, Bataller R, Brenner DA (2003) Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 285:G949–G958PubMedGoogle Scholar
  59. 59.
    Neubauer K, Ritzel A, Saile B, Ramadori G (2000) Decrease of platelet-endothelial cell adhesion molecule 1-gene-expression in inflammatory cells and in endothelial cells in the rat liver following CCl(4)-administration and in vitro after treatment with TNF-alpha. Immunol Lett 74:153–164PubMedGoogle Scholar
  60. 60.
    Bissell DM, Wang SS, Jarnagin WR, Roll FJ (1995) Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest 96:447–455PubMedGoogle Scholar
  61. 61.
    Grappone C, Pinzani M, Parola M, Pellegrini G, Caligiuri A, DeFranco R et al (1999) Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats. J Hepatol 31:100–109PubMedGoogle Scholar
  62. 62.
    Luo B, Tang L, Wang Z, Zhang J, Ling Y, Feng W et al (2005) Cholangiocyte endothelin 1 and transforming growth factor beta1 production in rat experimental hepatopulmonary syndrome. Gastroenterology 129:682–695PubMedGoogle Scholar
  63. 63.
    Gressner AM, Weiskirchen R (2006) Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 10:76–99PubMedGoogle Scholar
  64. 64.
    Knittel T, Fellmer P, Muller L, Ramadori G (1997) Bone morphogenetic protein-6 is expressed in nonparenchymal liver cells and upregulated by transforming growth factor-beta 1. Exp Cell Res 232:263–269PubMedGoogle Scholar
  65. 65.
    Scharf JG, Knittel T, Dombrowski F, Muller L, Saile B, Braulke T et al (1998) Characterization of the IGF axis components in isolated rat hepatic stellate cells. Hepatology 27:1275–1284PubMedGoogle Scholar
  66. 66.
    Breitkopf K, Roeyen C, Sawitza I, Wickert L, Floege J, Gressner AM (2005) Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC). Cytokine 31:349–357PubMedGoogle Scholar
  67. 67.
    Salmi M, Adams D, Jalkanen S (1998) Cell adhesion and migration IV. Lymphocyte trafficking in the intestine and liver. Am J Physiol 274:G1–G6PubMedGoogle Scholar
  68. 68.
    Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S et al (2005) Attenuated liver fibrosis in the absence of B cells. J Clin Invest 115:3072–3082PubMedGoogle Scholar
  69. 69.
    Ramadori G, Saile B (2004) Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 127:997–1000PubMedGoogle Scholar
  70. 70.
    Bioulac-Sage P, Kuiper J, Van Berkel TJ, Balabaud C (1996) Lymphocyte and macrophage populations in the liver. Hepatogastroenterology 43:4–14PubMedGoogle Scholar
  71. 71.
    Schaffner F, Barka T, Popper H (1963) Hepatic mesenchymal cell reaction in liver disease. Exp Mol Pathol 31:419–441PubMedGoogle Scholar
  72. 72.
    Baloch Z, Klapper J, Buchanan L, Schwartz M, Amenta PS (1992) Ontogenesis of the murine hepatic extracellular matrix: an immunohistochemical study. Differentiation 51:209–218PubMedGoogle Scholar
  73. 73.
    Cheng PL, Chang MH, Chao CH, Wu Lee YH (2004) Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation. Oncogene 23:7821–7838PubMedGoogle Scholar
  74. 74.
    Shin JY, Hur W, Wang JS, Jang JW, Kim CW, Bae SH et al (2005) HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-β1. Exp Mol Med 37:138–145PubMedGoogle Scholar
  75. 75.
    Clemente M, Nunez O, Lorente R, Rincon D, Matilla A, Salcedo M et al (2006) Increased intrahepatic and circulating levels of endoglin, a TGF-β1 co-receptor, in patients with chronic hepatitis C virus infection. Relationship to histological and serum markers of hepatic fibrosis. J Vir Hep 13: 625–632Google Scholar
  76. 76.
    Elsammak MY, Amin GM, Khalil GM, Ragab WS, Abaza MM (2006) Possible contribution of serum activin A and IGF-1 in the development of hepatocellular carcinoma in Egyptian patients suffering from combined hepatitis C virus injection and hepatic schistosomiasis. Clin Biochem 39:623–629PubMedGoogle Scholar
  77. 77.
    Sugiyama M, Ichida T, Sato T, Ishikawa T, Matsuda Y, Asakura H (1998) Expression of activin A is increased in cirrhotic and fibrotic rat livers. Gastroenterology 114:550–558PubMedGoogle Scholar
  78. 78.
    Date M, Matsuzaki K, Matsushita M, Tahashi Y, Sakitani K, Inoue K (2000) Differential regulation of activin A for hepatocyte growth and fibronectin synthesis in rat liver injury. J Hepatol 32:251–260PubMedGoogle Scholar
  79. 79.
    Sulyok S, Alzheimer C, Werner S (2005) Activin: an important regulator of wound repair, fibrosis, and neuroprotection. Mol Cell Endocrinol 225:126–132Google Scholar
  80. 80.
    Lichtinghagen R, Michels D, Haberkorn CI, Arndt B, Bahr M, Flemming P et al (2001) Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J Hepatol 34:239–247PubMedGoogle Scholar
  81. 81.
    Leroy V, Monier F, Bottari S, Trocme C, Sturm N, Hilleret MN et al (2004) Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Am J Gastroenterol 99:271–279PubMedGoogle Scholar
  82. 82.
    Nurez O, Fernandez-Martinez A, Majano PL, Apolinario A, Gomez-Gonzalo M, Benedicto I et al (2004) Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus in infection: role of viral core and NS5A proteins. Gut 53:1665–1672Google Scholar
  83. 83.
    Eisen-Vandervelde AL, Waggoner SN, Yao ZQ, Cale EM, Hahn CS, Hahn YS (2004) Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem 279:43479–43486PubMedGoogle Scholar
  84. 84.
    McCaughan GW, George J (2004) Fibrosis progression in chronic hepatitis C virus infection. Gut 53:318–321PubMedGoogle Scholar
  85. 85.
    Hissar SS, Goyal A, Kumar M, Pandey C, Suneetha PV, Sood A et al (2006) Hepatitis C virus genotype 3 predominates in north and central India and is associated with significant histopathologic liver disease. J Med Virol 78:452–458PubMedGoogle Scholar
  86. 86.
    Westin J, Nordlinder H, Lagging M, Norkrans G, Wejstal R (2002) Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol 37:837–842PubMedGoogle Scholar
  87. 87.
    Tsukamoto H, She H, Hazra S, Cheng J, Miyahara T (2006) Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation. J Gastroenterol Hepatol 21:S102–S105PubMedGoogle Scholar
  88. 88.
    Missale G, Bertoni R, Lamonaca V, Valli A, Massari M, Mori C (1996) Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Investig 98:706–714PubMedCrossRefGoogle Scholar
  89. 89.
    Nattermann J, Nischalke HD, Feldmann G, Ahlenstiel G, Bauerbrucj T, Spengler U (2004) Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5. J Viral Hepatitis 11:519–526Google Scholar
  90. 90.
    Nischalke HD, Langhans B, Sauerbruch T, Spengler U (2006) Binding hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C. Hepatology 44:945–954PubMedGoogle Scholar
  91. 91.
    Sarobe P, Lasarte JJ, Casares N, López-Díaz de Cerio A, Baixeras E, Labarga P et al (2002) Abnormal priming of CD4+ T cells by dendritic cells expressing hepatitis C virus core and E1 proteins. J Virol 76:5062–5070PubMedGoogle Scholar
  92. 92.
    Serra MA, Rodriguez F, Del Olmo JA, Escudero A, Rodrigo JM (2003) Influence of age and date of infection on distribution of hepatitis C virus genotypes and fibrosis stage. J Viral Hepatitis 10:183–188Google Scholar
  93. 93.
    Morgan TR, Brenner D, Everhart J, French SW, Fried MW, Gretch DR et al (2003) Hepatitis C and alcohol: fundamental and translational research directions. Alcohol Clin Exp Res 27:726–731PubMedGoogle Scholar
  94. 94.
    Neuman MG, Brenner DA, Rehermann B, Taleb J, Chollet-Martin S, Cohard M et al (2001) Mechanisms of alcoholic liver disease: cytokines. Alcohol Clin Exp Res 25:251S–253SPubMedGoogle Scholar
  95. 95.
    Nevins CL, Malaty H, Velez ME, Aanad BS (1999) Interaction of alcohol and hepatitis C virus infection on severity of liver disease. Dig Dis Sci 44:1236–1242PubMedGoogle Scholar
  96. 96.
    Khan KN, Tatsuhashi H (2000) Effect of alcohol consumption on progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol 32:286–295Google Scholar
  97. 97.
    Safdar K, Schiff ER (2004) Alcohol and hepatitis C. Semin Liver Dis 24:305–315PubMedGoogle Scholar
  98. 98.
    Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, Capelli F et al (2003) Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology 38:42–49PubMedGoogle Scholar
  99. 99.
    Perlemuter G, Letteron P, Carnot F, Zavala F, Pessayre D, Nalpas B et al (2003) Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model. J Hepatol 39:1020–1027PubMedGoogle Scholar
  100. 100.
    Gao B (2002) Integration of alcohol and hepatitis viral proteins: implication in synergistic effect of alcohol drinking and viral hepatitis on liver injury. Alcohol 26:69–72Google Scholar
  101. 101.
    Chiappelli F, Kung M, Lee P, Pham L, Manfrini E, Villanueva P (1995) Alcohol modulation of human normal T cell activation, maturation and migration. Alcohol Clin Exp Res 19:539–544PubMedGoogle Scholar
  102. 102.
    Cameron RG, Neuman MG (1999) Novel morphologic findings in alcoholic liver disease. Clin Biochem 32:579–584PubMedGoogle Scholar
  103. 103.
    Seth D, Gorrell MD, Cordoba S, McCaughan GW, Haber PS (2006) Intrahepatic gene expression in human alcoholic hepatitis. J Hepatol 45:306–320PubMedGoogle Scholar
  104. 104.
    Seth D, Leo MA, McGuinness PH, Lieber CS, Brennan Y, Williams R et al (2003) Gene expression profiling of alcoholic liver disease in the baboon (Papio hamadryas) and human liver. Am J Pathol 163:2303–2317PubMedGoogle Scholar
  105. 105.
    McCaughan GW, Zekry A (2004) Mechanisms of HCV reinfection and allograft damage after liver transplantation. J Hepatol 40:368–374PubMedGoogle Scholar
  106. 106.
    Rockstroh JK (2006) Influence of viral hepatitis on HIV infection. J Hepatol 44:S25–S27PubMedGoogle Scholar
  107. 107.
    Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S et al (2002) Protection against persistence of hepatitis C. Lancet 359:1478–1483PubMedGoogle Scholar
  108. 108.
    Cribier B, Schmitt C, Rey D, Uhl G, Lang JM, Vetter D et al (1997) HIV increases hepatitis C viraemia irrespective of the hepatitis C virus genotype. Res Virol 148:267–271PubMedGoogle Scholar
  109. 109.
    Lauer GM, Nguyen TN, Day CL, Robbins GK, Flynn T, McGowan K et al (2002) Human immunodeficiency virus type-1 hepatitis C virus co-infection: Intra-individual comparison of cellular immune responses against two persistent viruses. J Virol 76:2817–2826PubMedGoogle Scholar
  110. 110.
    Blackard JT, Komurian-Pradel F, Perret M, Sodoyer M, Smeaton L, Benjamin St-Clair J et al (2006) Intraheptic cytokine expression is downregulated during HCV-HIV co-infection. J Med Virol 78: 202–207PubMedGoogle Scholar
  111. 111.
    Mocroft A, Monforte A, Kirk O, Johnson MA, Friis-Moller N, Banhegyi D, EuroSIDA study group (2004) Changes in hospital admissions across Europe: 1995-2003. Results from the EuroSIDA study. HIV Med 5(6):437–447Google Scholar
  112. 112.
    Mocroft A, Rockstroh J, Soriano V, Ledergerber B, Kirk O, (2005) EuroSIDA Study Group. Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection? Antivir Ther 10:779–790PubMedGoogle Scholar
  113. 113.
    Cooper CL, Chen Y, Garber GE (2002) Perturbation of HCV RNA levels in plasma after suppressive HAART in HIV-HCV co-infected subjects. Abstract H-1736. Presented at: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, CAGoogle Scholar
  114. 114.
    Neau D, Trimoulet P, Winnock M, Le Bail B, Schvoerer E, Legrand E et al (2001) Impact of protease inhibitors on intrahepatic hepatitis C virus viral load. AIDS 15:1736–1738PubMedGoogle Scholar
  115. 115.
    Givannetti A, Ensoli F, Mazzetta F, De Cristofaro M, Piedrominici M, Muratori DS et al (1999) CCR5 and CXCR4 chemokine receptor expression and beta-chemokine production during early T cell repopulation induced by highly active anti-retroviral therapy. Clin Exp Immunol 118:87–94Google Scholar
  116. 116.
    John M, Flexman J, French MA (1998) Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 12:2289–2293PubMedGoogle Scholar
  117. 117.
    Trimoulet P, Neau D, Le Bail B, Rullier A, Winnock M, Galperine T et al (2002) Intrahepatic HCV RNA loads in 37 HIV-HCV co-infected patients with controlled HIV infection. J Med Virol 67:143–151PubMedGoogle Scholar
  118. 118.
    Rutschmann OT, Negro F, Hirschel B, Hadengue A, Anwar D, Perrin LH (1998) Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients coinfected with HIV. J Infect Dis 177:783–785PubMedGoogle Scholar
  119. 119.
    Perez-Olmeda M, Garcia-Saamaniego J, Soriano V (2000) Hepatitis C viraemia in HIV-HCV co-infected patients having immune restoration with highly active antiretroviral therapy. AIDS 14:212PubMedGoogle Scholar
  120. 120.
    Zylberberg H, Chaix ML, Rabian C, Rouzioux C, Aulong B, Brechot C et al (1998) Tritherapy for human immunodeficiency virus infection does not modify replication of hepatitis C virus in co-infected subjects. Clin Infect Dis 26:1104–1106PubMedGoogle Scholar
  121. 121.
    Matsiota-Bernard P, Vrioni G, Onody C, Bernard L, de Truchis P, Peronne C (2001) Human immunodeficiency virus (HIV) protease inhibitors have no effect on hepatitis C virus (HCV) serum levels of HIV-HCV co-infected patients. Int J Antimicrob Agents 17:155–157PubMedGoogle Scholar
  122. 122.
    Benhamou Y, Di Martino V, Bochet M, Colombet G, Thibault V, Liou A et al (2001) Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-co-infected patients: impact of protease inhibitor therapy. Hepatology 34:283–287PubMedGoogle Scholar
  123. 123.
    Torre D, Tambini R, Cadario F, Barbarini G, Moroni M, Basilico C (2001) Evolution of coinfection with human immunodeficiency virus and hepatitis C virus in patients treated with highly active antiretroviral therapy. Clin Infect Dis 33:1579–1585PubMedGoogle Scholar
  124. 124.
    Aceti A, Pasquazzi C, Zechini B (2003) Alanine aminotransferase decrease in HIV-hepatitis C virus co-infected patients responding to antiretroviral therapy. AIDS 17:2141–2142PubMedGoogle Scholar
  125. 125.
    Lafeuillade A, Hittinger G, Chadapaud S (2001) Increased mitochondrial toxicity with ribavirin in HIV/HCV co-infection. Lancet 357:280–281PubMedGoogle Scholar
  126. 126.
    Salmon-Ceron D, Chauvelot-Moachon L, Abad S, Silbermann B, Sogni P (2001) Mitochondrial toxic effects and ribavirin. Lancet 357:1803–1804PubMedGoogle Scholar
  127. 127.
    Gisolf EH, Dreezen C, Danner SA, Weel JL, Weverling GJ (2000) Prometheus Study Group. Risk factors for hepatotoxicity in HIV-1-infected patients receiving ritonavir and saquinavir with or without stavudine. Clin Infect Dis 31:1234–1239PubMedGoogle Scholar
  128. 128.
    Lalezari JP, Eron JJ, Carlson M, Cohen C, DeJesus E, Arduino R et al (2003) A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 17:691–698PubMedGoogle Scholar
  129. 129.
    Lalezari JP, Henry K, O’Hearn M, Montaner J, Piliero P, Trottier B et al (2003) Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348:2175–2185PubMedGoogle Scholar
  130. 130.
    Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD (2002) Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 35:182–189PubMedGoogle Scholar
  131. 131.
    Bourezane Y, Salard D, Hoen B, Vandel S, Drobacheff C, Laurent R (1998) DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy. Clin Infect Dis 27:1321–1322PubMedGoogle Scholar
  132. 132.
    Sulkowski MS, Thomas DL, Chaisson RE, Moore RD (2000) Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 283:74–80PubMedGoogle Scholar
  133. 133.
    Walmsley S, Bernstein B, King M, Arribas J, Beall G, Peter Ruane P et al (2002) Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 346:2039–2046PubMedGoogle Scholar
  134. 134.
    Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M et al (2001) ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS 15:F1–F9PubMedGoogle Scholar
  135. 135.
    Cacoub P, Rosenthal E, Halfon P, Sene D, Perronne C, Pol S (2006) Treatment of hepatitis C virus and human immunodeficiency virus coinfection: from large trials to real life. J Viral Hepatitis 13:678–682Google Scholar
  136. 136.
    Mocroft A. Soriano V, Rockstroh J, Reiss P, Kirk O, de Wit S et al (2005) Is there evidence for an increase in the death rate from liver-related disease in patients with HIV? AIDS 19:2117–2125CrossRefGoogle Scholar
  137. 137.
    Cooper CL, Cameron DW (2005) Effect of alcohol use on the impact of effective antiretroviral therapy for HIV co-infection on plasma HCV levels. Clin Infect Dis 41:S105–S109PubMedGoogle Scholar
  138. 138.
    Neuman MG, Monteiro M, Rehm J (2006) Drug interactions between psychoactive substances and antiretroviral therapy in individuals infected with human immunodeficiency and hepatitis viruses. Subst Use Misuse 41:1395–1463PubMedGoogle Scholar
  139. 139.
    Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O (2006) Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 166:1632–1641PubMedGoogle Scholar
  140. 140.
    Aranzabal L, Casado JL, Moya J, Quereda C, Diz S, Moreno A et al (2005) Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 40:588–593PubMedGoogle Scholar
  141. 141.
    Stock PG, Roland ME, Carlson L, Freise CE, Roberts JP, Hirose R et al (2003) Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 76:370–375PubMedGoogle Scholar
  142. 142.
    Ragni MV, Belle SH, Im K, Neff G, Roland M, Stock P et al (2003) Survival of human immunodeficiency virus-infected liver transplant recipients. J Infect Dis 188:1412–1420PubMedGoogle Scholar
  143. 143.
    Prachalias AA, Pozniak A, Taylor C, Srinivasan P, Muiesan P, Wendon J et al (2001) Liver transplantation in adults coinfected with HIV. Transplantation 72:1684–1688PubMedGoogle Scholar
  144. 144.
    Neff GW, Bonham A, Tzakis AG, Ragni M, Jayaweera D, Schiff ER et al (2003) Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Liver Transpl 9:239–247PubMedGoogle Scholar
  145. 145.
    Norris S, Taylor C, Muiesan P, Portmann BC, Knisely AS, Bowles M et al (2004) Outcomes of Liver Transplantation in HIV-Infected Individuals: The Impact of HCV and HBV Infection. Liver Transpl 10:1271–1278PubMedGoogle Scholar
  146. 146.
    Isaacs A, Lindenmann J (1957) Virus interference. I. The Interferon. Proc R Soc Lond B Biol Sci 147:258–267PubMedGoogle Scholar
  147. 147.
    Billiau A (2006) Interferon the pathways of discovery I. Molecular and cellular aspects. Cytokine Growth Factor Rev 17:381–409PubMedGoogle Scholar
  148. 148.
    Galligan CL, Murooka TT, Rahbar R, Baig E, Majchrzak-Kita B, Fish EN (2006) Interferons and viruses: signaling for supremacy. Immunol Res 35:27–40PubMedGoogle Scholar
  149. 149.
    Feld JJ, Hoofnagle JH (2005) Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436:967–972PubMedGoogle Scholar
  150. 150.
    Tilg H, Vogel W, Dinarello CA (1995) Interferon-α induces circulating tumor necrosis factor receptor p55 in humans. Blood 85:433–435PubMedGoogle Scholar
  151. 151.
    Kaser A, Novick D, Rubinstein M, Siegmund B, Enrich B, Koch RO et al (2002) Interferon-α induces interleukin-18 binding protein in chronic hepatitis C patients. Clin Exp Immunol 129:332–338PubMedGoogle Scholar
  152. 152.
    Marek B, Kajdanuik D, Mazurek U, Janczewska-Kazek E, Kos-Kudla B, Strzalka B et al (2005) TGF-β mRNA expression in liver biopsy specimens and TGF-β1 serum levels in patients with chronic hepatitis C before and after antiviral therapy. J Clin Pharmacy Therapeutics 30:271–277Google Scholar
  153. 153.
    Neuman MG, Blendis LM, Shear NH, Malkiewicz IM, Ibrahim A, Katz GG et al (2001) Cytokine network in non responding chronic hepatitis C patients with genotype 1: role of triple therapy with interferon α, ribavirin and ursodeoxycholate. Clin Biochem 34:183–188PubMedGoogle Scholar
  154. 154.
    Gentile I, Viola C, Reynaud L, Borcelli F, Cerini R, Ciampi R et al (2005) Case report: hemolytic anemia during pegylated IFN-α2b plus ribavirin treatment for chronic hepatitis C: Ribavirin is not always the culprit. J Interferon and Cytokines Res 25:283–285Google Scholar
  155. 155.
    Voiculescu M, Ionescu C, Stefan M, Hortopan M, Mandache E, Constantinescu I et al (2000) Nephrotic syndrome, idiopathic thrombocytopenic purpura and systemic lupus erythematous induced by interferon-alpha. Rom J Gastroenterology 9:12Google Scholar
  156. 156.
    McHutchison JG, Poynard T (1999) Combination therapy with interferon plus ribavirin for initial treatment of chronic hepatitis C. Semin Liver Dis 19:57–65PubMedGoogle Scholar
  157. 157.
    Crotty S, Cameron CE, Andino R (2001) RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci USA 98:6895–6900PubMedGoogle Scholar
  158. 158.
    Crotty S, Maag D, Arnold JJ, Zhong W, Lau JY, Hong Z et al (2000) The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nature Med 6:1375–1379PubMedGoogle Scholar
  159. 159.
    Huang L, Hwang J, Sharma SD, Hargittai MR, Chen Y, Arnold JJ et al (2005) Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein. J Biol Chem 280:36417–36428PubMedGoogle Scholar
  160. 160.
    Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS (2004) Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 432:922–924PubMedGoogle Scholar
  161. 161.
    Pawlotszy JM, Dahari H, Neumann AU, Hezode C, Germinidis G, Lonjon I et al (2004) Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 35:1002–1009Google Scholar
  162. 162.
    Bisceglie A, Fan X, Chambers T, Strinko J (2006) Pharmacokinetics, pharmacodynamics, and hepatitis C viral kinetics during antiviral therapy: The null responder. J Med Virol 78:446–451PubMedGoogle Scholar
  163. 163.
    Miglioresi L, Bacosi M, Russo F, Patrizi F, Saccenti P, Ursitti A et al (2003) Consensus interferon versus interferon-alpha 2b plus ribavirin in patients with relapsing HCV infection. Hepatol Res 27:253–259PubMedGoogle Scholar
  164. 164.
    Böcher W, Schuchmann M, Link R, Hillenbrand H, Rahman F, Sprinzl M et al (2006) Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-α therapy. Liver Int 26:319–325PubMedGoogle Scholar
  165. 165.
    Ozes ON, Reiter ZVI, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-con1 with natural recombinant interferons-α: antiviral, antiproliferative, and natural killer–inducing activities. J Interferon Res 12:55–59PubMedGoogle Scholar
  166. 166.
    Klein SB, Blatt LM, Taylor MW (1993) Consensus interferon induces peak mRNA accumulation at lower concentrations than interferon-a2a. J Interferon Res 13:341–347PubMedGoogle Scholar
  167. 167.
    Blatt LM, Davis JM, Klein SB, Taylor MW (1996) The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. J Interferon Cytokine Res 16:489–499PubMedCrossRefGoogle Scholar
  168. 168.
    Gupta SK, Glue P, Jacobs S, Belle D, Affrime M (2003) Single-dose pharmacokinetics and tolerability of pegylated interferon-alpha2b in young and elderly healthy subjects. Br J Clin Pharmacol 56:131–134PubMedGoogle Scholar
  169. 169.
    Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC et al (2001) A randomized, double-blind trial comparing PEGylated interferon alfa-2b to interferon α-2b as initial treatment for chronic hepatitis C. Hepatology 34:395–403PubMedGoogle Scholar
  170. 170.
    Kamal SM, Fehr J, Roesler B, Peters T, Rasenack JW (2002) Peginterferon alone or with ribavirin enhances HCV-specific CD4+ T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology 123:1070–1083PubMedGoogle Scholar
  171. 171.
    Zeuzem S (2002) Pegylated interferon plus ribavirin in chronic hepatitis C. More than half of patients show a lasting response. MMW Fortschr Med 21(144):30–34Google Scholar
  172. 172.
    Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P 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 140:346–355PubMedGoogle Scholar
  173. 173.
    Pawlotsky JM (2003) Mechanism of antiviral treatment efficacy and failure in chronic hepatitis C. Antiviral Res 59:1–11PubMedGoogle Scholar
  174. 174.
    Neuman MG, Benhamou JP, Bourliere M, Ibrahim A, Malkiewicz I, Asselah T et al (2002) Serum tumour necrosis factor-alpha and transforming growth factor-beta levels in chronic hepatitis C patients are immunomodulated by therapy. Cytokine 17:108–117PubMedGoogle Scholar
  175. 175.
    Neuman MG, Benhamou JP, Malkiewicz IM, Ibrahim A, Valla DC, Martinot-Peignoux M et al (2001) Kinetics of serum cytokines reflect changes in the severity of chronic hepatitis C presenting minimal fibrosis. J Viral Hepatitis 9:134–140Google Scholar
  176. 176.
    Polyak SJ, Khabar KS, Rezeiq M, Gretch DR (2001) Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. J Virol 75:6209–6211PubMedGoogle Scholar
  177. 177.
    Charlton M, Seaberg E, Wiesner R, Everhart J, Zetterman R, Lake J et al (1998) Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology 28:823–830PubMedGoogle Scholar
  178. 178.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975–982PubMedGoogle Scholar
  179. 179.
    Yaginuma R, Ikejima K, Okumura K, Kon K, Suzuki S, Takei Y et al (2006) Hepatic steatosis is a predictor of poor response to interferon alpha-2b and ribavirin combination therapy in Japanese patients with chronic hepatitis C. Hepatol Res 35:19–25PubMedGoogle Scholar
  180. 180.
    Patton HM, Patel K, Behling C, Bylund LM, Blatt LM, Vallee M et al (2004) The impact of steatosis on disease progression and early sustained response in chronic hepatitis C patients. J Hepatol 40:484–490PubMedGoogle Scholar
  181. 181.
    Lam NP, Pitrak D, Speralakis R, Lau AH, Willey TA, Layden TJ (1997) Effect of obesity on pharmacokinetics and biologic effect of interferon-alpha in hepatitis C. Dig Dis Sci. 42:178–185PubMedGoogle Scholar
  182. 182.
    Conjeevaram HS, Fried MW, Jeffers LJ, Terrault N, Willey-Lucas T, Afdhal N et al (2006) Pegintron and Ribavirin treatment in African American and Caucasians American patients with chronic hepatitis C genotype 1. Gastroenterology 131:470–477PubMedGoogle Scholar
  183. 183.
    Taylor MW, Tsukahara T, Brodsky L, Schaley J, Sanda C, Stephens MJ (2007) Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy. J Virol 81:3391–3401PubMedGoogle Scholar
  184. 184.
    Yee LJ (2004) Host genetic determinants in hepatitis C virus infection. Genes Immun 5:237–245PubMedGoogle Scholar
  185. 185.
    Risch N (2006) Dissecting racial and ethnic differences. N Engl J Med 354:408–411PubMedGoogle Scholar
  186. 186.
    Lindenbach BD, Rice CM (2005) Unravelling hepatitis C virus replication from genome to function. Nature 436:933–938PubMedGoogle Scholar
  187. 187.
    Esteban J, Ferrari C, Germanidis G, Haagmans B, Hellstrand K, Lurie Y et al (2002) HCV early viral kinetics report: novel decline patterns in genotype 1 but not genotypes 2 and 3 patients with peg-interferon alfa-2a and ribavirin. J Hepatol 36:121Google Scholar
  188. 188.
    Pawlotsky JM, Hezode C, Pellegrin B, Soulier A, Von Wagner M, Brouwer JT et al (2002) Early HCV genotype 4 replication kinetics during treatment with peginterferon alpha-2a (Pegasys)-ribavirin combination: a comparison with HCV genotypes 1 and 3 kinetics. Hepatology 36:291AGoogle Scholar
  189. 189.
    Toyoda H, Kumada T, Nakano S, Takeda I, Sugiyama K, Osada T et al (1997) Quasispecies nature of hepatitis C virus and response to alpha interferon: significance as a predictor of direct response to interferon. J Hepatol 26:6–13PubMedGoogle Scholar
  190. 190.
    Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK et al (1973) Mechanism of action of 1-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole) a new broad spectrum antiviral agent. Proc Natl Acad Sci USA 70:1174PubMedGoogle Scholar
  191. 191.
    Markland W, McQuaid J, Jain J, Kwong AD (2000) Broad spectrum of antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother 44:859PubMedGoogle Scholar
  192. 192.
    Firpi RJ, Nelson DR, Davis GL (2003) Lack of antiviral effect of a short course of microphenolate mofetil in patients with chronic hepatitis C viral infection. Liver Transpl 9:57–65PubMedGoogle Scholar
  193. 193.
    Schiff ER (2007) Emerging strategies for pegylated interferon combination therapy. Nat Clin Pract Gastroenterol Hepatol. Suppl 1:S17–S21Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Manuela G. Neuman
    • 1
    • 2
  • Kevin Sha
    • 1
    • 2
  • Rustan Esguerra
    • 1
    • 2
  • Sam Zakhari
    • 3
  • Robert E. Winkler
    • 4
  • Nir Hilzenrat
    • 5
  • Jonathan Wyse
    • 5
  • Curtis L. Cooper
    • 6
  • Devanshi Seth
    • 7
    • 8
  • Mark D. Gorrell
    • 8
    • 9
  • Paul S. Haber
    • 7
    • 8
    • 9
  • Geoffrey W. McCaughan
    • 8
    • 9
  • Maria A. Leo
    • 10
  • Charles S. Lieber
    • 10
  • Mihai Voiculescu
    • 11
  • Eugenia Buzatu
    • 11
  • Camelia Ionescu
    • 11
  • Jozsef Dudas
    • 12
  • Bernhard Saile
    • 12
  • Giuliano Ramadori
    • 12
  1. 1.In Vitro Drug Safety and Biotechnology, Department of Pharmacology, Biophysics and Global Health, Institute of Drug Research, and Centre for International HealthUniversity of TorontoTorontoCanada
  2. 2.In Vitro Drug Safety and Biotechnology, Toxicology and Biotechnology, South Tower of the MaRS Discovery CentreTorontoCanada
  3. 3.Division of Metabolism and Health EffectsNational Institute on Alcohol Abuse and Alcoholism, NIHBethesdaUSA
  4. 4.HepatologySchering-Plough CorporationKenilworthUSA
  5. 5.Division of Gastroenterology, Department of MedicineSMBD-Jewish General Hospital, McGill UniversityMontrealCanada
  6. 6.Division of Infectious Diseases, The Ottawa Hospital-General CampusUniversity of Ottawa HospitalOttawaCanada
  7. 7.Drug Health Services & A.W. Morrow Gastroenterology and Liver Centre Royal Prince Alfred HospitalCamperdownAustralia
  8. 8.Centenary Institute & Discipline of Medicine, The University of SydneySydneyAustralia
  9. 9.Discipline of MedicineThe University of SydneySydneyAustralia
  10. 10.Alcohol Research CenterJ. J. Peters Veteran Administration Hospital and Mount Sinai HospitalRdBronxUSA
  11. 11.Centre of Internal Medicine—Fundeni Clinical InstituteBucharestRomania
  12. 12.Department of Internal Medicine, Section of Gastroenterology and EndocrinologyGeorg-August-University GoettingenGoettingenGermany

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