1932

Abstract

Hepatitis C virus (HCV) is one of the major etiologic agents of liver cancer. HCV is an RNA virus that, unlike hepatitis B virus, is unable to integrate into the host genome. Through complex interactions between viral and host proteins that induce host responses and promote inflammation, fibrosis, and ultimately cirrhosis, HCV infection can result in the development of hepatocellular carcinoma (HCC). The HCV oncogenic process involves genetic and epigenetic alterations and oncogenic effects mediated by viral proteins in the activation of cellular oncogenes, inactivation of tumor-suppressor genes, and dysregulation of multiple signal-transduction pathways. Advances in genetics and gene expression profiling have enhanced our current understanding of the pathways involved in HCV-associated liver cancer development. In this review, we summarize the current understanding of mechanisms of hepatocarcinogenesis induced by HCV infection.

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2015-01-24
2024-04-19
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Literature Cited

  1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S. 1.  et al. 2013. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, Fr: Int. Agency Res. Cancer http://globocan.iarc.fr
  2. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. 2.  2006. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J. Hepatol. 45:529–38 [Google Scholar]
  3. Altekruse SF, McGlynn KA, Reichman ME. 3.  2009. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 27:1485–91 [Google Scholar]
  4. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. 4.  2010. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127:2893–917 [Google Scholar]
  5. Parkin DM, Bray F, Ferlay J, Pisani P. 5.  2001. Estimating the world cancer burden: Globocan 2000. Int. J. Cancer 94:153–56 [Google Scholar]
  6. El-Serag HB. 6.  2007. Epidemiology of hepatocellular carcinoma in USA. Hepatol. Res. 37:Suppl. 2S88–94 [Google Scholar]
  7. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D. 7.  et al. 2014. SEER Cancer Statistics Review, 1975–2011 Bethesda, MD: Natl. Cancer Inst http://seer.cancer.gov/csr/1975_2011/
  8. Thein HH, Isaranuwatchai W, Campitelli MA, Feld JJ, Yoshida E. 8.  et al. 2013. Health care costs associated with hepatocellular carcinoma: a population-based study. Hepatology 58:1375–84 [Google Scholar]
  9. 9. WHO (World Health Organ.) 2011. Hepatitis C Rep. 164, WHO, Geneva. http://www.who.int/mediacentre/factsheets/fs164/en/
  10. Hoofnagle JH. 10.  2002. Course and outcome of hepatitis C. Hepatology 36:S21–29 [Google Scholar]
  11. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q. 11.  et al. 2002. Protection against persistence of hepatitis C. Lancet 359:1478–83 [Google Scholar]
  12. Lagging LM, Westin J, Svensson E, Aires N, Dhillon AP. 12.  et al. 2002. Progression of fibrosis in untreated patients with hepatitis C virus infection. Liver 22:136–44 [Google Scholar]
  13. Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T. 13.  et al. 1990. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. PNAS 87:6547–49 [Google Scholar]
  14. El-Serag HB. 14.  2002. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 36:S74–83 [Google Scholar]
  15. Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L. 15.  et al. 2007. Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 45:579–87 [Google Scholar]
  16. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T. 16.  et al. 1995. Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 346:1051–55 [Google Scholar]
  17. Valla DC, Chevallier M, Marcellin P, Payen JL, Trepo C. 17.  et al. 1999. Treatment of hepatitis C virus–related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Hepatology 29:1870–75 [Google Scholar]
  18. Mazzella G, Accogli E, Sottili S, Festi D, Orsini M. 18.  et al. 1996. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J. Hepatol. 24:141–47 [Google Scholar]
  19. Fattovich G, Stroffolini T, Zagni I, Donato F. 19.  2004. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127:S35–50 [Google Scholar]
  20. Zender L, Villanueva A, Tovar V, Sia D, Chiang DY, Llovet JM. 20.  2010. Cancer gene discovery in hepatocellular carcinoma. J. Hepatol. 52:921–29 [Google Scholar]
  21. Thorgeirsson SS, Grisham JW. 21.  2002. Molecular pathogenesis of human hepatocellular carcinoma. Nat. Genet. 31:339–46 [Google Scholar]
  22. Takano S, Yokosuka O, Imazeki F, Tagawa M, Omata M. 22.  1995. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. Hepatology 21:650–55 [Google Scholar]
  23. Oka H, Kurioka N, Kim K, Kanno T, Kuroki T. 23.  et al. 1990. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 12:680–87 [Google Scholar]
  24. Seki S, Sakaguchi H, Kitada T, Tamori A, Takeda T. 24.  et al. 2000. Outcomes of dysplastic nodules in human cirrhotic liver: a clinicopathological study. Clin. Cancer Res. 6:3469–73 [Google Scholar]
  25. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Okazaki N. 25.  et al. 1990. Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 336:1150–53 [Google Scholar]
  26. Brechot C. 26.  1998. Molecular mechanisms of hepatitis B and C viruses related to liver carcinogenesis. Hepato-Gastroenterology 45:Suppl. 31189–96 [Google Scholar]
  27. Grisham JW. 27.  2001. Molecular genetic alterations in primary hepatocellular neoplasms: hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. The Molecular Basis of Human Cancer WB Coleman, GJ Tsongalis 269–346 Totowa, NJ: Humana [Google Scholar]
  28. Diao J, Garces R, Richardson CD. 28.  2001. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev. 12:189–205 [Google Scholar]
  29. Kawakita N, Seki S, Sakaguchi H, Yanai A, Kuroki T. 29.  et al. 1992. Analysis of proliferating hepatocytes using a monoclonal antibody against proliferating cell nuclear antigen/cyclin in embedded tissues from various liver diseases fixed in formaldehyde. Am. J. Pathol. 140:513–20 [Google Scholar]
  30. Paradis V, Dargere D, Bonvoust F, Rubbia-Brandt L, Ba N. 30.  et al. 2000. Clonal analysis of micronodules in virus C–induced liver cirrhosis using laser capture microdissection (LCM) and HUMARA assay. Lab. Investig. 80:1553–59 [Google Scholar]
  31. Okuda T, Wakasa K, Kubo S, Hamada T, Fujita M. 31.  et al. 2001. Clonal analysis of hepatocellular carcinoma and dysplastic nodule by methylation pattern of X-chromosome-linked human androgen receptor gene. Cancer Lett. 164:91–96 [Google Scholar]
  32. Toshikuni N, Nouso K, Higashi T, Nakatsukasa H, Onishi T. 32.  et al. 2000. Expression of telomerase-associated protein 1 and telomerase reverse transcriptase in hepatocellular carcinoma. Br. J. Cancer 82:833–37 [Google Scholar]
  33. Ide T, Tahara H, Nakashio R, Kitamoto M, Nakanishi T, Kajiyama G. 33.  1996. Telomerase in hepatocellular carcinogenesis. Hum. Cell 9:283–86 [Google Scholar]
  34. Karachristos A, Liloglou T, Field JK, Deligiorgi E, Kouskouni E, Spandidos DA. 34.  1999. Microsatellite instability and p53 mutations in hepatocellular carcinoma. Mol. Cell Biol. Res. Commun. 2:155–61 [Google Scholar]
  35. Kawai H, Suda T, Aoyagi Y, Isokawa O, Mita Y. 35.  et al. 2000. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology 31:1246–50 [Google Scholar]
  36. Roncalli M, Bianchi P, Grimaldi GC, Ricci D, Laghi L. 36.  et al. 2000. Fractional allelic loss in non-end-stage cirrhosis: correlations with hepatocellular carcinoma development during follow-up. Hepatology 31:846–50 [Google Scholar]
  37. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. 37.  2007. Genomics and signaling pathways in hepatocellular carcinoma. Semin. Liver Dis. 27:55–76 [Google Scholar]
  38. Blanc P, Etienne H, Daujat M, Fabre I, Zindy F. 38.  et al. 1992. Mitotic responsiveness of cultured adult human hepatocytes to epidermal growth factor, transforming growth factor α, and human serum. Gastroenterology 102:1340–50 [Google Scholar]
  39. Hoffmann B, Piasecki A, Paul D. 39.  1989. Proliferation of fetal rat hepatocytes in response to growth factors and hormones in primary culture. J. Cell. Physiol. 139:654–62 [Google Scholar]
  40. Tonjes RR, Lohler J, O'Sullivan JF, Kay GF, Schmidt GH. 40.  et al. 1995. Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. Oncogene 10:765–68 [Google Scholar]
  41. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY. 41.  et al. 2008. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359:1995–2004 [Google Scholar]
  42. Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T. 42.  et al. 2008. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 299:53–60 [Google Scholar]
  43. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I. 43.  et al. 2011. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 17:589–95 [Google Scholar]
  44. Zona L, Lupberger J, Sidahmed-Adrar N, Thumann C, Harris HJ. 44.  et al. 2013. HRas signal transduction promotes hepatitis C virus cell entry by triggering assembly of the host tetraspanin receptor complex. Cell Host Microbe 13:302–13 [Google Scholar]
  45. Diao J, Pantua H, Ngu H, Komuves L, Diehl L. 45.  et al. 2012. Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry. J. Virol. 86:10935–49 [Google Scholar]
  46. Fuchs BC, Hoshida Y, Fujii T, Wei L, Yamada S. 46.  et al. 2014. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 59:1577–90 [Google Scholar]
  47. Pollak M. 47.  2008. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 8:915–28 [Google Scholar]
  48. Sachdev D, Yee D. 48.  2007. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol. Cancer Ther. 6:1–12 [Google Scholar]
  49. Breuhahn K, Longerich T, Schirmacher P. 49.  2006. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25:3787–800 [Google Scholar]
  50. Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY. 50.  et al. 2010. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J. Hepatol. 52:550–59 [Google Scholar]
  51. Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P. 51.  et al. 1997. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. PNAS 94:701–6 [Google Scholar]
  52. Vejchapipat P, Tangkijvanich P, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. 52.  2004. Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma. J. Gastroenterol. 39:1182–88 [Google Scholar]
  53. Lutterbach B, Zeng Q, Davis LJ, Hatch H, Hang G. 53.  et al. 2007. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res. 67:2081–88 [Google Scholar]
  54. Liu L, Cao Y, Chen C, Zhang X, McNabola A. 54.  et al. 2006. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851–58 [Google Scholar]
  55. Zaret KS. 55.  2008. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat. Rev. Genet. 9:329–40 [Google Scholar]
  56. Zaret KS, Grompe M. 56.  2008. Generation and regeneration of cells of the liver and pancreas. Science 322:1490–94 [Google Scholar]
  57. Thompson MD, Monga SP. 57.  2007. WNT/β-catenin signaling in liver health and disease. Hepatology 45:1298–305 [Google Scholar]
  58. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P. 58.  et al. 2008. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68:6779–88 [Google Scholar]
  59. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S. 59.  et al. 2007. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45:42–52 [Google Scholar]
  60. Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y. 60.  et al. 2006. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27:748–57 [Google Scholar]
  61. Tada M, Kanai F, Tanaka Y, Tateishi K, Ohta M. 61.  et al. 2008. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin. Cancer Res. 14:3768–76 [Google Scholar]
  62. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K. 62.  et al. 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–24 [Google Scholar]
  63. Elsharkawy AM, Mann DA. 63.  2007. Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46:590–97 [Google Scholar]
  64. Li XM, Tang ZY, Zhou G, Lui YK, Ye SL. 64.  1998. Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 17:13–17 [Google Scholar]
  65. Poon RT, Ho JW, Tong CS, Lau C, Ng IO, Fan ST. 65.  2004. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br. J. Surg. 91:1354–60 [Google Scholar]
  66. Imura S, Miyake H, Izumi K, Tashiro S, Uehara H. 66.  2004. Correlation of vascular endothelial cell proliferation with microvessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in hepatocellular carcinoma. J. Med. Investig. 51:202–9 [Google Scholar]
  67. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R. 67.  et al. 2002. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 35:834–42 [Google Scholar]
  68. Campbell JS, Johnson MM, Bauer RL, Hudkins KL, Gilbertson DG. 68.  et al. 2007. Targeting stromal cells for the treatment of platelet-derived growth factor C–induced hepatocellular carcinogenesis. Differentiation 75:843–52 [Google Scholar]
  69. Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS. 69.  et al. 2005. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. PNAS 102:3389–94 [Google Scholar]
  70. Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY. 70.  et al. 2009. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J. Clin. Investig. 119:465–77 [Google Scholar]
  71. Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P. 71.  1994. Geographic variation of p53 mutational profile in nonmalignant human liver. Science 264:1317–19 [Google Scholar]
  72. Kim CW, Chang KM. 72.  2013. Hepatitis C virus: virology and life cycle. Clin. Mol. Hepatol. 19:17–25 [Google Scholar]
  73. Pawlotsky JM. 73.  2003. Hepatitis C virus genetic variability: pathogenic and clinical implications. Clin. Liver Dis. 7:45–66 [Google Scholar]
  74. Schaefer EA, Chung RT. 74.  2012. Anti–hepatitis C virus drugs in development. Gastroenterology 142:1340–50.e1 [Google Scholar]
  75. Fusco DN, Chung RT. 75.  2012. Novel therapies for hepatitis C: insights from the structure of the virus. Annu. Rev. Med. 63:373–87 [Google Scholar]
  76. Pawlotsky JM, Chevaliez S, McHutchison JG. 76.  2007. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 132:1979–98 [Google Scholar]
  77. Hundt J, Li Z, Liu Q. 77.  2013. Post-translational modifications of hepatitis C viral proteins and their biological significance. World J. Gastroenterol. 19:8929–39 [Google Scholar]
  78. Khaliq S, Jahan S, Hassan S. 78.  2011. Hepatitis C virus p7: molecular function and importance in hepatitis C virus life cycle and potential antiviral target. Liver Int. 31:606–17 [Google Scholar]
  79. Welbourn S, Pause A. 79.  2006. HCV NS2/3 protease. Hepatitis C Viruses: Genomes and Molecular Biology SL Tan 151–62 Norfolk, UK: Horiz. Biosci. [Google Scholar]
  80. Pang PS, Jankowsky E, Planet PJ, Pyle AM. 80.  2002. The hepatitis C viral NS3 protein is a processive DNA helicase with cofactor enhanced RNA unwinding. EMBO J. 21:1168–76 [Google Scholar]
  81. De Francesco R, Steinkuhler C. 81.  2000. Structure and function of the hepatitis C virus NS3-NS4A serine proteinase. Curr. Top. Microbiol. Immunol. 242:149–69 [Google Scholar]
  82. Gouttenoire J, Castet V, Montserret R, Arora N, Raussens V. 82.  et al. 2009. Identification of a novel determinant for membrane association in hepatitis C virus nonstructural protein 4B. J. Virol. 83:6257–68 [Google Scholar]
  83. Shirota Y, Luo H, Qin W, Kaneko S, Yamashita T. 83.  et al. 2002. Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. J. Biol. Chem. 277:11149–55 [Google Scholar]
  84. Reyes GR. 84.  2002. The nonstructural NS5A protein of hepatitis C virus: an expanding, multifunctional role in enhancing hepatitis C virus pathogenesis. J. Biomed. Sci. 9:187–97 [Google Scholar]
  85. DeMarini DJ, Johnston VK, Konduri M, Gutshall LL, Sarisky RT. 85.  2003. Intracellular hepatitis C virus RNA-dependent RNA polymerase activity. J. Virol. Methods 113:65–68 [Google Scholar]
  86. Kiyosawa K, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K. 86.  et al. 2004. Hepatocellular carcinoma: recent trends in Japan. Gastroenterology 127:S17–26 [Google Scholar]
  87. Bosch FX, Ribes J, Cleries R, Diaz M. 87.  2005. Epidemiology of hepatocellular carcinoma. Clin. Liver Dis. 9:191–211 [Google Scholar]
  88. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P. 88.  et al. 2002. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am. J. Epidemiol. 155:323–31 [Google Scholar]
  89. Imazeki F, Yokosuka O, Fukai K, Saisho H. 89.  2003. Favorable prognosis of chronic hepatitis C after interferon therapy by long-term cohort study. Hepatology 38:493–502 [Google Scholar]
  90. Zoulim F, Chevallier M, Maynard M, Trepo C. 90.  2003. Clinical consequences of hepatitis C virus infection. Rev. Med. Virol. 13:57–68 [Google Scholar]
  91. Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK. 91.  et al. 2009. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C–related advanced liver disease. Gastroenterology 136:138–48 [Google Scholar]
  92. Hino K, Okita K. 92.  2004. Interferon therapy as chemoprevention of hepatocarcinogenesis in patients with chronic hepatitis C. J. Antimicrob. Chemother. 53:19–22 [Google Scholar]
  93. Kang SM, Kim SJ, Kim JH, Lee W, Kim GW. 93.  et al. 2009. Interaction of hepatitis C virus core protein with Hsp60 triggers the production of reactive oxygen species and enhances TNF-α-mediated apoptosis. Cancer Lett. 279:230–37 [Google Scholar]
  94. Kao CF, Chen SY, Chen JY, Wu Lee YH. 94.  2004. Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein. Oncogene 23:2472–83 [Google Scholar]
  95. Yoshida I, Oka K, Hidajat R, Nagano-Fujii M, Ishido S, Hotta H. 95.  2001. Inhibition of p21/Waf1/Cip1/Sdi1 expression by hepatitis C virus core protein. Microbiol. Immunol. 45:689–97 [Google Scholar]
  96. Alisi A, Giambartolomei S, Cupelli F, Merlo P, Fontemaggi G. 96.  et al. 2003. Physical and functional interaction between HCV core protein and the different p73 isoforms. Oncogene 22:2573–80 [Google Scholar]
  97. Cho J, Baek W, Yang S, Chang J, Sung YC, Suh M. 97.  2001. HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation. Biochim. Biophys. Acta 1538:59–66 [Google Scholar]
  98. Aoki H, Hayashi J, Moriyama M, Arakawa Y, Hino O. 98.  2000. Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J. Virol. 74:1736–41 [Google Scholar]
  99. Hayashi J, Aoki H, Kajino K, Moriyama M, Arakawa Y, Hino O. 99.  2000. Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor α. Hepatology 32:958–61 [Google Scholar]
  100. Joo M, Hahn YS, Kwon M, Sadikot RT, Blackwell TS, Christman JW. 100.  2005. Hepatitis C virus core protein suppresses NF-κB activation and cyclooxygenase-2 expression by direct interaction with IκB kinase β. J. Virol. 79:7648–57 [Google Scholar]
  101. Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J. 101.  2005. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 41:1096–105 [Google Scholar]
  102. Peifer M, Polakis P. 102.  2000. Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 287:1606–9 [Google Scholar]
  103. Terris B, Pineau P, Bregeaud L, Valla D, Belghiti J. 103.  et al. 1999. Close correlation between β-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 18:6583–88 [Google Scholar]
  104. Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC. 104.  2000. Somatic mutations of β-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett. 152:45–51 [Google Scholar]
  105. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ. 105.  2000. WISP-1 is a Wnt-1- and β-catenin-responsive oncogene. Genes Dev. 14:585–95 [Google Scholar]
  106. Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T. 106.  et al. 2001. A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma. Oncogene 20:5525–32 [Google Scholar]
  107. Tanaka S, Sugimachi K, Kameyama T, Maehara S, Shirabe K. 107.  et al. 2003. Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma. Hepatology 37:1122–29 [Google Scholar]
  108. Shi Y, Massague J. 108.  2003. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700 [Google Scholar]
  109. Massague J, Blain SW, Lo RS. 109.  2000. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103:295–309 [Google Scholar]
  110. Nelson DR, Gonzalez-Peralta RP, Qian K, Xu Y, Marousis CG. 110.  et al. 1997. Transforming growth factor-β1 in chronic hepatitis C. J. Viral Hepat. 4:29–35 [Google Scholar]
  111. Pavio N, Battaglia S, Boucreux D, Arnulf B, Sobesky R. 111.  et al. 2005. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-β pathway. Oncogene 24:6119–32 [Google Scholar]
  112. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S. 112.  et al. 2002. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J. Exp. Med. 195:35–41 [Google Scholar]
  113. Tseng CT, Klimpel GR. 113.  2002. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med. 195:43–49 [Google Scholar]
  114. Zhao LJ, Wang L, Ren H, Cao J, Li L. 114.  et al. 2005. Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. Exp. Cell Res. 305:23–32 [Google Scholar]
  115. Zemel R, Gerechet S, Greif H, Bachmatove L, Birk Y. 115.  et al. 2001. Cell transformation induced by hepatitis C virus NS3 serine protease. J. Viral Hepat. 8:96–102 [Google Scholar]
  116. Deng L, Nagano-Fujii M, Tanaka M, Nomura-Takigawa Y, Ikeda M. 116.  et al. 2006. NS3 protein of hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence–dependent manner. J. Gen. Virol. 87:1703–13 [Google Scholar]
  117. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. 117.  2005. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. PNAS 102:17717–22 [Google Scholar]
  118. Lan KH, Sheu ML, Hwang SJ, Yen SH, Chen SY. 118.  et al. 2002. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene 21:4801–11 [Google Scholar]
  119. Majumder M, Ghosh AK, Steele R, Ray R, Ray RB. 119.  2001. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J. Virol. 75:1401–7 [Google Scholar]
  120. Ghosh AK, Majumder M, Steele R, Meyer K, Ray R, Ray RB. 120.  2000. Hepatitis C virus NS5A protein protects against TNF-alpha mediated apoptotic cell death. Virus Res. 67:173–78 [Google Scholar]
  121. Liao QJ, Ye LB, Timani KA, She YL, Yang XJ. 121.  et al. 2005. Hepatitis C virus non-structural 5A protein can enhance full-length core protein–induced nuclear factor-κB activation. World J. Gastroenterol. 11:6433–39 [Google Scholar]
  122. Arima N, Kao CY, Licht T, Padmanabhan R, Sasaguri Y. 122.  2001. Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A. J. Biol. Chem. 276:12675–84 [Google Scholar]
  123. Street A, Macdonald A, Crowder K, Harris M. 123.  2004. The hepatitis C virus NS5A protein activates a phosphoinositide 3-kinase–dependent survival signaling cascade. J. Biol. Chem. 279:12232–41 [Google Scholar]
  124. Street A, Macdonald A, McCormick C, Harris M. 124.  2005. Hepatitis C virus NS5A-mediated activation of phosphoinositide 3-kinase results in stabilization of cellular β-catenin and stimulation of β-catenin-responsive transcription. J. Virol. 79:5006–16 [Google Scholar]
  125. Gavert N, Ben-Ze'ev A. 125.  2007. β-Catenin signaling in biological control and cancer. J. Cell. Biochem. 102:820–28 [Google Scholar]
  126. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA. 126.  et al. 1998. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. PNAS 95:8847–51 [Google Scholar]
  127. Choi SH, Hwang SB. 127.  2006. Modulation of the transforming growth factor-β signal transduction pathway by hepatitis C virus nonstructural 5A protein. J. Biol. Chem. 281:7468–78 [Google Scholar]
  128. Wakefield JG, Bonaccorsi S, Gatti M. 128.  2001. The Drosophila protein Asp is involved in microtubule organization during spindle formation and cytokinesis. J. Cell Biol. 153:637–48 [Google Scholar]
  129. Wu SC, Chang SC, Wu HY, Liao PJ, Chang MF. 129.  2008. Hepatitis C virus NS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway. J. Biol. Chem. 283:29396–404 [Google Scholar]
  130. Tardif KD, Mori K, Siddiqui A. 130.  2002. Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J. Virol. 76:7453–59 [Google Scholar]
  131. Lefkowitch JH, Schiff ER, Davis GL, Perrillo RP, Lindsay K. 131.  et al. 1993. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group. Gastroenterology 104:595–603 [Google Scholar]
  132. Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K. 132.  et al. 1997. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J. Gen. Virol. 78:Pt. 71527–31 [Google Scholar]
  133. Bach N, Thung SN, Schaffner F. 133.  1992. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis. Hepatology 15:572–77 [Google Scholar]
  134. Barba G, Harper F, Harada T, Kohara M, Goulinet S. 134.  et al. 1997. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. PNAS 94:1200–5 [Google Scholar]
  135. Koike K, Moriya K. 135.  2005. Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH. J. Gastroenterol. 40:329–36 [Google Scholar]
  136. Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K. 136.  et al. 2004. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126:840–48 [Google Scholar]
  137. Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A. 137.  et al. 2002. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 16:185–94 [Google Scholar]
  138. Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K. 138.  et al. 2002. Interaction of hepatitis C virus core protein with retinoid X receptor α modulates its transcriptional activity. Hepatology 35:937–46 [Google Scholar]
  139. Koike K. 139.  2009. Steatosis, liver injury, and hepatocarcinogenesis in hepatitis C viral infection. J. Gastroenterol. 44:Suppl. 1982–88 [Google Scholar]
  140. Okuda M, Li K, Beard MR, Showalter LA, Scholle F. 140.  et al. 2002. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366–75 [Google Scholar]
  141. Bataller R, Paik YH, Lindquist JN, Lemasters JJ, Brenner DA. 141.  2004. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 126:529–40 [Google Scholar]
  142. Schuppan D, Krebs A, Bauer M, Hahn EG. 142.  2003. Hepatitis C and liver fibrosis. Cell Death Differ. 10:Suppl. 1S59–67 [Google Scholar]
  143. Mazzocca A, Sciammetta SC, Carloni V, Cosmi L, Annunziato F. 143.  et al. 2005. Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. J. Biol. Chem. 280:11329–39 [Google Scholar]
  144. Marra F. 144.  1999. Hepatic stellate cells and the regulation of liver inflammation. J. Hepatol. 31:1120–30 [Google Scholar]
  145. Lalor PF, Shields P, Grant A, Adams DH. 145.  2002. Recruitment of lymphocytes to the human liver. Immunol. Cell Biol. 80:52–64 [Google Scholar]
  146. Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y. 146.  et al. 2007. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 46:48–57 [Google Scholar]
  147. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. 147.  2005. Laminin-5 with transforming growth factor-β1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129:1375–83 [Google Scholar]
  148. Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA. 148.  et al. 2002. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359:397–401 [Google Scholar]
  149. Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL, Yamada S. 149.  et al. 2011. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 141:141–49 [Google Scholar]
  150. Yang Z, Wu Q, Shi Y, Nie Y, Wu K, Fan D. 150.  2012. Epidermal growth factor 61A>G polymorphism is associated with risk of hepatocellular carcinoma: a meta-analysis. Genet. Test. Mol. Biomark. 16:1086–91 [Google Scholar]
  151. Zhong JH, You XM, Gong WF, Ma L, Zhang Y. 151.  et al. 2012. Epidermal growth factor gene polymorphism and risk of hepatocellular carcinoma: a meta-analysis. PLOS ONE 7:e32159 [Google Scholar]
  152. Trepo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E. 152.  et al. 2011. Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 54:60–69 [Google Scholar]
  153. Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B. 153.  et al. 2011. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 53:791–99 [Google Scholar]
  154. Corradini SG, Burza MA, Molinaro A, Romeo S. 154.  2011. Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma. Hepatology 53:1776; author reply 1777 [Google Scholar]
  155. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA. 155.  et al. 2014. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am. J. Gastroenterol. 109:325–34 [Google Scholar]
  156. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R. 156.  et al. 2011. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat. Genet. 43:455–58 [Google Scholar]
  157. Miki D, Ochi H, Hayes CN, Aikata H, Chayama K. 157.  2012. Hepatocellular carcinoma: towards personalized medicine. Cancer Sci. 103:846–50 [Google Scholar]
  158. Lange CM, Bibert S, Dufour JF, Cellerai C, Cerny A. 158.  et al. 2013. Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma. J. Hepatol. 59:504–9 [Google Scholar]
  159. Llovet JM, Chen Y, Wurmbach E, Roayaie S, Fiel MI. 159.  et al. 2006. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 131:1758–67 [Google Scholar]
  160. Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S. 160.  et al. 2007. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45:938–47 [Google Scholar]
  161. Hoshida Y, Villanueva A, Sangiovanni A, Sole M, Hur C. 161.  et al. 2013. Prognostic gene expression signature for patients with hepatitis C–related early-stage cirrhosis. Gastroenterology 144:1024–30 [Google Scholar]
  162. Ambros V. 162.  2004. The functions of animal microRNAs. Nature 431:350–55 [Google Scholar]
  163. Ji J, Shi J, Budhu A, Yu Z, Forgues M. 163.  et al. 2009. MicroRNA expression, survival, and response to interferon in liver cancer. N. Engl. J. Med. 361:1437–47 [Google Scholar]
  164. Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P. 164.  et al. 2008. MicroRNA gene expression profile of hepatitis C virus–associated hepatocellular carcinoma. Hepatology 47:1223–32 [Google Scholar]
  165. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. 165.  2005. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309:1577–81 [Google Scholar]
  166. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S. 166.  et al. 2007. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 67:6092–99 [Google Scholar]
  167. Kutay H, Bai S, Datta J, Motiwala T, Pogribny I. 167.  et al. 2006. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J. Cell. Biochem. 99:671–78 [Google Scholar]
  168. Banaudha K, Kaliszewski M, Korolnek T, Florea L, Yeung ML. 168.  et al. 2011. MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. Hepatology 53:53–61 [Google Scholar]
  169. Harder J, Opitz OG, Brabender J, Olschewski M, Blum HE. 169.  et al. 2008. Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver. Int. J. Cancer 122:2800–4 [Google Scholar]
  170. Lim SO, Gu JM, Kim MS, Kim HS, Park YN. 170.  et al. 2008. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 135:2128–40.e8 [Google Scholar]
  171. Matsuda Y, Ichida T, Matsuzawa J, Sugimura K, Asakura H. 171.  1999. p16INK4 is inactivated by extensive CpG methylation in human hepatocellular carcinoma. Gastroenterology 116:394–400 [Google Scholar]
  172. Revill K, Wang T, Lachenmayer A, Kojima K, Harrington A. 172.  et al. 2013. Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma. Gastroenterology 145:1424–35.e25 [Google Scholar]
  173. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. 173.  2008. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 134:1752–63 [Google Scholar]
  174. Davila JA, Duan Z, McGlynn KA, El-Serag HB. 174.  2012. Utilization and outcomes of palliative therapy for hepatocellular carcinoma: a population-based study in the United States. J. Clin. Gastroenterol. 46:71–77 [Google Scholar]
  175. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. 175.  2008. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7:3129–40 [Google Scholar]
  176. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. 176.  2013. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann. Intern. Med. 158:329–37 [Google Scholar]
  177. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF. 177.  et al. 2012. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308:2584–93 [Google Scholar]
  178. Manns MP, McCone J Jr, Davis MN, Rossaro L, Schiff E. 178.  et al. 2014. Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials. Liver Int. 34:707–19 [Google Scholar]
  179. Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM. 179.  et al. 2010. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376:705–16 [Google Scholar]
  180. Jacobson IM, McHutchison JG, Dusheiko G. Bisceglie AM, Reddy KR. 180. , Di et al. 2011. Telaprevir for previously untreated chronic hepatitis C virus infection. N. Engl. J. Med. 364:2405–16 [Google Scholar]
  181. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS. 181.  et al. 2011. Response-guided telaprevir combination treatment for hepatitis C virus infection. N. Engl. J. Med. 365:1014–24 [Google Scholar]
  182. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM. 182.  et al. 2010. Telaprevir for previously treated chronic HCV infection. N. Engl. J. Med. 362:1292–303 [Google Scholar]
  183. Lawitz E, Gane EJ. 183.  2013. Sofosbuvir for previously untreated chronic hepatitis C infection. N. Engl. J. Med. 369:678–79 [Google Scholar]
  184. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M. 184.  et al. 2013. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 368:1867–77 [Google Scholar]
  185. Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R. 185.  et al. 2014. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N. Engl. J. Med. 370:1993–2001 [Google Scholar]
  186. Jacobson IM, Dore GJ, Foster GR, Fried MW, Radu M. 186.  et al. 2014. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 384:403–13 [Google Scholar]
  187. Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M. 187.  et al. 2014. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 384:414–26 [Google Scholar]
  188. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM. 188.  et al. 2014. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet In press. doi: 10.1016/S0140-6736(14)61036-9
  189. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE. 189.  et al. 2014. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N. Engl. J. Med. 370:1879–88 [Google Scholar]
  190. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC. 190.  et al. 2014. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N. Engl. J. Med. 370:1483–93 [Google Scholar]
  191. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N. 191.  et al. 2014. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med. 370:1889–98 [Google Scholar]
  192. Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S. 192.  et al. 2014. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N. Engl. J. Med. 370:1973–82 [Google Scholar]
  193. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F. 193.  et al. 2014. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N. Engl. J. Med. 370:1604–14 [Google Scholar]
  194. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y. 194.  et al. 2014. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N. Engl. J. Med. 370:1983–92 [Google Scholar]
  195. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR. 195.  et al. 2014. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N. Engl. J. Med. 370:1594–603 [Google Scholar]
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