, Volume 68, Issue 1, pp 27–42

Nonresponse to Treatment for Hepatitis C

Current Management Strategies
Therapy In Practice


Chronic hepatitis C affects >170 million people worldwide, causing cirrhosis and liver cancer in a sizeable proportion of patients. Substantial progress has been made in the treatment of chronic hepatitis C. More than 50% of patients can achieve sustained virological response after 24–48 weeks of interferon and ribavirin combination therapy, making chronic hepatitis C a potentially curable disease. However, a large proportion of patients with chronic hepatitis C do not clear the virus after current standard therapy. Hepatitis C virus develops two pathways to counteract the antiviral effect of interferon. Some chronic hepatitis C patients may have a virus that is more resistant to interferon therapy, while other patients appear to have defective immune responses or poor tolerance or compliance to interferon-based antiviral therapy. The possible strategies to improve antiviral efficiency in these nonresponders are to increase the dosage, prolong the duration of treatment and improve the compliance of patients. A total of 6–15% of prior nonresponders to standard interferon plus ribavirin therapy will respond to re-treatment with peginterferon plus ribavirin, while 32–50% of patients who have relapsed will respond to re-treatment. New small molecules are under development to treat chronic hepatitis C and may be important particularly in the treatment of prior nonresponders to current standard therapy.


  1. 1.
    National Institutes of Health consensus statement on management of hepatitis C: 2002. NIH Consens State Sci Statements 2002 Jun 10–12; 19(3): 1–46Google Scholar
  2. 2.
    Biggins SW, Terrault NA. Treatment of recurrent hepatitis C after liver transplantation. Clin Liver Dis 2005 Aug; 9(3): 505–23, ixPubMedCrossRefGoogle Scholar
  3. 3.
    Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology 2000 Apr; 31(4): 1014–8PubMedCrossRefGoogle Scholar
  4. 4.
    Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999 Aug 19; 341(8): 556–62PubMedCrossRefGoogle Scholar
  5. 5.
    Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004 Mar 2; 140(5): 346–55PubMedGoogle Scholar
  6. 6.
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001 Sep 22; 358(9286): 958–65PubMedCrossRefGoogle Scholar
  7. 7.
    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002 Sep 26; 347(13): 975–82PubMedCrossRefGoogle Scholar
  8. 8.
    Spiegel BM, Younossi ZM, Hays RD, et al. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005 Apr; 41(4): 790–800PubMedCrossRefGoogle Scholar
  9. 9.
    Tsuda N, Yuki N, Mochizuki K, et al. Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy. J Med Virol 2004 Nov; 74(3): 406–13PubMedCrossRefGoogle Scholar
  10. 10.
    Soriano V, Maida I, Nunez M, et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004 Dec; 9(6): 987–92PubMedGoogle Scholar
  11. 11.
    Desmond CP, Roberts SK, Dudley F, et al. Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting. J Viral Hepat 2006 May; 13(5): 311–5PubMedCrossRefGoogle Scholar
  12. 12.
    Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic hepatitis C infection: a Cochrane Hepato-Biliary Group systematic review and meta-analysis of randomized trials. Am J Gastroenterol 2006 Apr; 101(4): 842–7PubMedCrossRefGoogle Scholar
  13. 13.
    Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004 Oct; 53(10): 1504–8PubMedCrossRefGoogle Scholar
  14. 14.
    McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998 Nov 19; 339(21): 1485–92PubMedCrossRefGoogle Scholar
  15. 15.
    Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998 Oct 31; 352(9138): 1426–32PubMedCrossRefGoogle Scholar
  16. 16.
    Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004 Apr; 39(4): 1147–71PubMedCrossRefGoogle Scholar
  17. 17.
    Cornberg M, Wedemeyer H, Manns MP. Treatment of chronic hepatitis C with PEGylated interferon and ribavirin. Curr Gastroenterol Rep 2002 Feb; 4(1): 23–30PubMedCrossRefGoogle Scholar
  18. 18.
    Pedder SC. Pegylation of interferon alfa: structural and pharmacokinetic properties. Semin Liver Dis 2003; 23 Suppl. 1: 19–22PubMedCrossRefGoogle Scholar
  19. 19.
    Gale Jr M, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature 2005 Aug 18; 436(7053): 939–45PubMedCrossRefGoogle Scholar
  20. 20.
    Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003 May 16; 300(5622): 1145–8PubMedCrossRefGoogle Scholar
  21. 21.
    Lin W, Choe WH, Hiasa Y, et al. Hepatitis C virus expression suppresses interferon signaling by degrading STAT 1. Gastroenterology 2005 Apr; 128(4): 1034–41PubMedCrossRefGoogle Scholar
  22. 22.
    Taylor DR, Shi ST, Romano PR, et al. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 1999 Jul 2; 285(5424): 107–10PubMedCrossRefGoogle Scholar
  23. 23.
    Simmonds P, Holmes EC, Cha TA, et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol 1993 Nov; 74 (Pt 11): 2391–9PubMedCrossRefGoogle Scholar
  24. 24.
    Gale Jr MJ, Korth MJ, Tang NM, et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997 Apr 14; 230(2): 217–27PubMedCrossRefGoogle Scholar
  25. 25.
    Gale Jr M, Blakely CM, Kwieciszewski B, et al. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 1998 Sep; 18(9): 5208–18PubMedGoogle Scholar
  26. 26.
    Gale Jr M, Katze MG. Molecular mechanisms of interferon resistance mediated by viral-directed inhibition of PKR, the interferon-induced protein kinase. Pharmacol Ther 1998 Apr; 78(1): 29–46PubMedCrossRefGoogle Scholar
  27. 27.
    Gale Jr M, Blakely CM, Hopkins DA, et al. Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK. Mol Cell Biol 1998 Feb; 18(2): 859–71PubMedGoogle Scholar
  28. 28.
    Pflugheber J, Fredericksen B, Sumpter Jr R, et al. Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci U S A 2002 Apr 2; 99(7): 4650–5PubMedCrossRefGoogle Scholar
  29. 29.
    Herion D, Hoofnagle JH. The interferon sensitivity determining region: all hepatitis C virus isolates are not the same. Hepatology 1997 Mar; 25(3): 769–71PubMedCrossRefGoogle Scholar
  30. 30.
    Chung RT, Monto A, Dienstag JL, et al. Mutations in the NS5A region do not predict interferon-responsiveness in American patients infected with genotype 1b hepatitis C virus. J Med Virol 1999 Aug; 58(4): 353–8PubMedCrossRefGoogle Scholar
  31. 31.
    Enomoto N, Sakuma I, Asahina Y, et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996 Jan 11; 334(2): 77–81PubMedCrossRefGoogle Scholar
  32. 32.
    Schinkel J, Spoon WJ, Kroes AC. Meta-analysis of mutations in the NS5A gene and hepatitis C virus resistance to interferon therapy: uniting discordant conclusions. Antivir Ther 2004 Apr; 9(2): 275–86PubMedGoogle Scholar
  33. 33.
    Nainan OV, Alter MJ, Kruszon-Moran D, et al. Hepatitis C virus genotypes and viral concentrations in participants of a general population survey in the United States. Gastroenterology 2006 Aug; 131(2): 478–84PubMedCrossRefGoogle Scholar
  34. 34.
    Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. Hepatology 1999 Sep; 30(3): 787–93PubMedCrossRefGoogle Scholar
  35. 35.
    Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in Blacks and non-Hispanic Whites. N Engl J Med 2004 May 27; 350(22): 2265–71PubMedCrossRefGoogle Scholar
  36. 36.
    Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 2006 Aug; 131(2): 470–7PubMedCrossRefGoogle Scholar
  37. 37.
    Layden-Almer JE, Ribeiro RM, Wiley T, et al. Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin. Hepatology 2003 Jun; 37(6): 1343–50PubMedCrossRefGoogle Scholar
  38. 38.
    Everson GT, Hoefs JC, Seeff LB, et al. Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial. Hepatology 2006 Dec; 44(6): 1675–84PubMedCrossRefGoogle Scholar
  39. 39.
    Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 2004 Mar 2; 140(5): 370–81PubMedGoogle Scholar
  40. 40.
    Anand BS, Currie S, Dieperink E, et al. Alcohol use and treatment of hepatitis C virus: results of a national multicenter study. Gastroenterology 2006 May; 130(6): 1607–16PubMedCrossRefGoogle Scholar
  41. 41.
    Conjeevaram HS, Kleiner DE, Everhart JE, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology 2007 Jan; 45(1): 80–7PubMedCrossRefGoogle Scholar
  42. 42.
    Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003 Jul; 38(1): 75–85PubMedCrossRefGoogle Scholar
  43. 43.
    Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 2005 May; 128(5): 1437–44PubMedCrossRefGoogle Scholar
  44. 44.
    Harvey CE, Post JJ, Palladinetti P, et al. Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation. J Leukoc Biol 2003 Sep; 74(3): 360–9PubMedCrossRefGoogle Scholar
  45. 45.
    Lagging M, Romero AI, Westin J, et al. IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology 2006 Dec; 44(6): 1617–25PubMedCrossRefGoogle Scholar
  46. 46.
    Romero AI, Lagging M, Westin J, et al. Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection. J Infect Dis 2006 Oct 1; 194(7): 895–903PubMedCrossRefGoogle Scholar
  47. 47.
    Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003 Sep; 38(3): 645–52PubMedCrossRefGoogle Scholar
  48. 48.
    Morishima C, Morgan TR, Everhart JE, et al. HCV RNA detection by TMA during the hepatitis C antiviral long-term treatment against cirrhosis (Halt-C) trial. Hepatology 2006 Aug; 44(2): 360–7PubMedCrossRefGoogle Scholar
  49. 49.
    Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998 Oct 2; 282(5386): 103–7PubMedCrossRefGoogle Scholar
  50. 50.
    Layden JE, Layden TJ, Reddy KR, et al. First phase viral kinetic parameters as predictors of treatment response and their influence on the second phase viral decline. J Viral Hepat 2002 Sep; 9(5): 340–5PubMedCrossRefGoogle Scholar
  51. 51.
    Lam NP, Neumann AU, Gretch DR, et al. Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology 1997 Jul; 26(1): 226–31PubMedCrossRefGoogle Scholar
  52. 52.
    Layden TJ, Layden JE, Ribeiro RM, et al. Mathematical modeling of viral kinetics: a tool to understand and optimize therapy. Clin Liver Dis 2003 Feb; 7(1): 163–78PubMedCrossRefGoogle Scholar
  53. 53.
    Cotler SJ, Layden JE, Neumann AU, et al. First phase hepatitis C viral kinetics in previous nonresponder patients. J Viral Hepat 2003 Jan; 10(1): 43–9PubMedCrossRefGoogle Scholar
  54. 54.
    McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002 Oct; 123(4): 1061–9PubMedCrossRefGoogle Scholar
  55. 55.
    Shiftman ML, Ghany MG, Morgan TR, et al. Impact of reducing peginterferon alfa-2a and rebavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology 2007 Jan; 132(1): 103–12CrossRefGoogle Scholar
  56. 56.
    Shiftman ML, Di Bisceglie AM, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004 Apr; 126(4): 1015–23; discussion 947CrossRefGoogle Scholar
  57. 57.
    Shiftman M, Morgan TR, Ghany MG, et al. The impact of Peginterferon (PEG) and ribavirin (RBV) dosing on sustained virological response (SVR) in patients undergoing retreatment in the HALT-C trial [abstract]. Hepatology 2004; 40 Suppl. 1: 314AGoogle Scholar
  58. 58.
    Sherman KE, Peters M, Koziel MJ. HIV and liver disease forum: conference proceedings. Hepatology 2007 Jun; 45(6): 1566–77PubMedCrossRefGoogle Scholar
  59. 59.
    Sherman KE, Rouster SD, Chung RT, et al. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis 2002 Mar 15; 34(6): 831–7PubMedCrossRefGoogle Scholar
  60. 60.
    Cooper CL. Natural history of HIV and HCV coinfection. J Int Assoc Physicians AIDS Care (Chic Ill) 2003 Oct–Dec; 2(4): 147–51Google Scholar
  61. 61.
    Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004 Jul 29; 351(5): 451–9PubMedCrossRefGoogle Scholar
  62. 62.
    Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004 Jul 29; 351(5): 438–50PubMedCrossRefGoogle Scholar
  63. 63.
    Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004 Dec 15; 292(23): 2839–48PubMedCrossRefGoogle Scholar
  64. 64.
    Kim A, Dorn A, Bouajram R, et al. The treatment of chronic hepatitis C in HIV-infected patients: a meta-analysis. HIV Med 2007 Jul; 8(5): 312–21PubMedCrossRefGoogle Scholar
  65. 65.
    Shiftman ML. Retreatment of patients with chronic hepatitis C. Hepatology 2002 Nov; 36 (5 Suppl. 1): S128–34Google Scholar
  66. 66.
    Taliani G, Gemignani G, Ferrari C, et al. Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients. Gastroenterology 2006 Apr; 130(4): 1098–106PubMedCrossRefGoogle Scholar
  67. 67.
    Jacobson IM, Gonzalez SA, Ahmed F, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol 2005 Nov; 100(11): 2453–62PubMedCrossRefGoogle Scholar
  68. 68.
    Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998 Nov 19; 339(21): 1493–9PubMedCrossRefGoogle Scholar
  69. 69.
    Layden TJ, Layden JE, Reddy KR, et al. Induction therapy with consensus interferon (CIFN) does not improve sustained virologic response in chronic hepatitis C. J Viral Hepat 2002 Sep; 9(5): 334–9PubMedCrossRefGoogle Scholar
  70. 70.
    Tassopoulos NC, Tsantoulas D, Raptopoulou M, et al. A randomized trial to assess the efficacy of interferon alpha in combination with ribavirin in the treatment of interferon alpha nonresponders with chronic hepatitis C: superior efficacy of high daily dosage of interferon alpha in genotype 1. J Viral Hepat 2003 May; 10(3): 189–96PubMedCrossRefGoogle Scholar
  71. 71.
    Gross JB, Therneau TM, Johnson SM, et al. The RENEW trial: a national multi-center study of high dose peginterferon alfa-2b + ribavirin for non-responders with hepatitis C [abstract]. Hepatology 2003; 38: 312ACrossRefGoogle Scholar
  72. 72.
    Lawitz EJ, Bala NS, Becker S, et al. Pegylated alfa-2b and ribavirin for hepatitis C patients who were non-responders to previous therapy [abstract]. Gastroenterology 2003; 124 Suppl. 1: A783CrossRefGoogle Scholar
  73. 73.
    Lee WM, Dienstag JL, Lindsay KL, et al. Evolution of the HALT-C trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders. Control Clin Trials 2004 Oct; 25(5): 472–92PubMedCrossRefGoogle Scholar
  74. 74.
    White CL, Malet P, Wentworth C, et al. The TARGET trial: 48 wk HCV RNA results of a randomized trial of 1.5 μg/kg vs 3.0 μg/kg pegylated interferon alfa-2b (PEG) plus ribavirin (RBV) for naive chronic hepatitis C [abstract]. Hepatology 2004; 40 Suppl. 1: 400AGoogle Scholar
  75. 75.
    Malet P, White CL, Wentworth C, et al. The TARGET trial: 48 wk HCV RNA results of a randomized trial of 1.5 μg/kg vs 3.0 μg/kg pegylated interferon alfa-2b (PEG) plus ribavirin (RBV) for non-responders (NR) and relapsers (Rs) to previous therapy [abstract]. Hepatology 2004; 40 Suppl. 1: 400AGoogle Scholar
  76. 76.
    von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005 Aug; 129(2): 522–7CrossRefGoogle Scholar
  77. 77.
    Dalgard O, Bjoro K, Helium KB, et al. Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004 Dec; 40(6): 1260–5PubMedCrossRefGoogle Scholar
  78. 78.
    Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005 Jun 23; 352(25): 2609–17PubMedCrossRefGoogle Scholar
  79. 79.
    Shiftman ML, Pappas L, Nyberg L, et al. Peginterferon alpha-2a (PEGASYS) plus Rebavirin (COPEGUS) for 16 or 24 weeks in patients with HCV genotype 2 or 3. Final results of the ACCELERATE trial. J Hepatol 2006; 44 Suppl. 2: S271CrossRefGoogle Scholar
  80. 80.
    Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006 Apr; 130(4): 1086–97PubMedCrossRefGoogle Scholar
  81. 81.
    Sanchez-Tapias JM, Diago M, Escartin P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006 Aug; 131(2): 451–60PubMedCrossRefGoogle Scholar
  82. 82.
    Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006 Jan; 44(1): 97–103PubMedCrossRefGoogle Scholar
  83. 83.
    Bronowicki JP, Ouzan D, Asselah T, et al. Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin. Gastroenterology 2006 Oct; 131(4): 1040–8PubMedCrossRefGoogle Scholar
  84. 84.
    Drusano GL, Preston SL. A 48-week duration of therapy with pegylated interferon alpha 2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype-1 hepatitis C viras. J Infect Dis 2004 Mar 15; 189(6): 964–70PubMedCrossRefGoogle Scholar
  85. 85.
    Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks of peg-interferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006 May; 43(5): 954–60PubMedCrossRefGoogle Scholar
  86. 86.
    Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006 Sep; 55(9): 1350–9PubMedCrossRefGoogle Scholar
  87. 87.
    Myers RP, Poynard T. Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C. Cochrane Database Syst Rev 2002; (4): CD003617Google Scholar
  88. 88.
    Neumann AU, Lam NP, Dahari H, et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J Infect Dis 2000 Jul; 182(1): 28–35PubMedCrossRefGoogle Scholar
  89. 89.
    Pockros PJ, Shiftman ML, Schiff ER, et al. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004 Dec; 40(6): 1450–8PubMedCrossRefGoogle Scholar
  90. 90.
    Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol 2003 Nov; 98(11): 2491–9PubMedGoogle Scholar
  91. 91.
    Collantes RS, Younossi ZM. The use of growth factors to manage the hematologic side effects of PEG-interferon alfa and ribavirin. J Clin Gastroenterol 2005 Jan; 39 (1 Suppl.): S9–13PubMedCrossRefGoogle Scholar
  92. 92.
    Muir AJ, McHutchison JG. Growth factors during HCV therapy may be “cost-effective,” but are they “effective’? Hepatology 2006 Dec; 44(6): 1400–3PubMedCrossRefGoogle Scholar
  93. 93.
    Shiftman ML, Hofmann CM, Luketic VA, et al. Use of granulocyte macrophage colony stimulating factor alone or in combination with interferon-alpha-2b for treatment of chronic hepatitis C. J Hepatol 1998 Mar; 28(3): 382–9CrossRefGoogle Scholar
  94. 94.
    US FDA. Erythropoiesis-stimulating agents (ESAs) [online]. Available from URL: http://www.fda.gov/cder/drug/advisory/RHE2007.htm [Accessed 2007 Oct 19]
  95. 95.
    Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group. Ann Intern Med 1998 Jul 15; 129(2): 94–9PubMedGoogle Scholar
  96. 96.
    Saracco G, Borghesio E, Mesina P, et al. Prolonged treatment (2 years) with different doses (3 versus 6 MU) of interferon alpha-2b for chronic hepatitis type C: results of a multicenter randomized trial. J Hepatol 1997 Jul; 27(1): 56–62PubMedCrossRefGoogle Scholar
  97. 97.
    Shiftman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology 1999 Nov; 117(5): 1164–72CrossRefGoogle Scholar
  98. 98.
    Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995 Oct 21; 346(8982): 1051–5PubMedCrossRefGoogle Scholar
  99. 99.
    Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005 Jan 18; 142(2): 105–14PubMedGoogle Scholar
  100. 100.
    Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006 Jan; 130(1): 231–64; quiz 14-7PubMedCrossRefGoogle Scholar
  101. 101.
    Afdhal N, Freilich B, Levine R, et al. Colchine versus Peg-Intron long term (Copilot) trial: interim analysis of clinical outcomes at year 2 [abstract]. Hepatology 2004; 40 Suppl. 1: 239ACrossRefGoogle Scholar
  102. 102.
    Poynard T, Schiff E, Terg K, et al. High early viral response (EVR) with peg-intron/rebetol (PR) weight based dosing in previous interferon/ribavirin HCV treatment failures: early results of the EPIC3 trial [abstract]. Hepatology 2004; 40 Suppl. 1: 238AGoogle Scholar
  103. 103.
    McHutchison JG, Bartenschlager R, Patel K, et al. The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice. J Hepatol 2006 Feb; 44(2): 411–21PubMedCrossRefGoogle Scholar
  104. 104.
    Lemon SM, Yi M, Li K. “Strong reasons make strong actions”: the antiviral efficacy of NS3/4A protease inhibitors. Hepatology 2005 Mar; 41(3): 671–4PubMedCrossRefGoogle Scholar
  105. 105.
    Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 2004 Nov; 127(5): 1347–55PubMedCrossRefGoogle Scholar
  106. 106.
    Reiser M, Hinrichsen H, Benhamou Y, et al. Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 2005 Apr; 41(4): 832–5PubMedCrossRefGoogle Scholar
  107. 107.
    Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006 Oct; 131(4): 997–1002PubMedCrossRefGoogle Scholar
  108. 108.
    McHutchison JG, Everson GT, Gordon S, et al. Results of an interim analysis of a phase 2 study of Telaprevir (VX-950) with peginterferon alpha-2a and rebavirin in previously untreated subjects with hepatitis C [abstract]. J Hepatol 2007; 46 Suppl. 1: S296CrossRefGoogle Scholar
  109. 109.
    Lang L. Interim results presented at EASL from PROVE 1 clinical trial of investigational drug telaprevir in patients with genotype 1 hepatitis C. Gastroenterology 2007 Jun; 132(7): 2283–4PubMedCrossRefGoogle Scholar
  110. 110.
    Zeuzem S, Sarrazin C, Wagner F, et al. Combination therapy with the HCV protease inhibitor, SCH 503034, plus Peg-Intron in hepatitis C genotype-1 Peg-Intron non-responders: phase Ib results [abstract]. Hepatology 2005; 42 (4 Suppl. 1): 276ACrossRefGoogle Scholar
  111. 111.
    Malcolm BA, Zeuzem S, Gupta S, et al. Modeling of hepatitis C viral dynamics during combination therapy with peginterferon alfa-2b (Peg-Intron) and the NS3 protease inhibitor SCH 503034 [abstract]. Hepatology 2005; 42 (4 Suppl. 1): 697AGoogle Scholar
  112. 112.
    Toniutto P, Fabris C, Bitetto D, et al. Valopicitabine dihydrochloride: a specific polymerase inhibitor of hepatitis C virus. Curr Opin Investig Drugs 2007 Feb; 8(2): 150–8PubMedGoogle Scholar
  113. 113.
    Bain VG, Kaita KD, Yoshida EM, et al. A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 2006 Apr; 44(4): 671–8PubMedCrossRefGoogle Scholar
  114. 114.
    Blatt LM, Davis JM, Klein SB, et al. The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. J Interferon Cytokine Res 1996 Jul; 16(7): 489–99PubMedCrossRefGoogle Scholar
  115. 115.
    Ozes ON, Reiter Z, Klein S, et al. A comparison of interferon-Con1 with natural recombinant interferons-alpha: antiviral, antiproliferative, and natural killer-inducing activities. J Interferon Res 1992 Feb; 12(1): 55–9PubMedCrossRefGoogle Scholar
  116. 116.
    Barbara G, Barbarini G. Consensus interferon for chronic hepatitis C patients with genotype 1 who failed to respond to, or relapsed after, interferon alpha-2b and ribavirin in combination: an Italian pilot study. Eur J Gastroenterol Hepatol 2002 May; 14(5): 477–83CrossRefGoogle Scholar
  117. 117.
    da Silva LC, Bassit L, Ono-Nita SK, et al. High rate of sustained response to consensus interferon plus ribavirin in chronic hepatitis C patients resistant to alpha-interferon and ribavirin: a pilot study. J Gastroenterol 2002; 37(9): 732–6PubMedCrossRefGoogle Scholar
  118. 118.
    Cornberg M, Hadem J, Herrmann E, et al. Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study. J Hepatol 2006 Feb; 44(2): 291–301PubMedCrossRefGoogle Scholar
  119. 119.
    Heathcote EJ, James S, Mullen KD, et al. Chronic hepatitis C virus patients with breakthroughs during interferon treatment can successfully be retreated with consensus interferon. The Consensus Interferon Study Group. Hepatology 1999 Aug; 30(2): 562–6Google Scholar
  120. 120.
    Kaiser S, Hass H, Lutze R, et al. Higher susceptibility of peginterferon alfa 2a versus peginterferon 2b nonresponder patients with chronic hepatitis C to retreatment with consensus interferon daily dosing and rebavirin [abstract]. Gastroenterology 2006; 130 (4 Suppl. 2): S1061Google Scholar
  121. 121.
    Kaiser S, Hass H, Lutze B, et al. Comparison of daily consensus interferon versus peginterferon alfa 2a extended therapy of 72 weeks for peginterferon/rebavirin relapse patients with chronic hepatitis C [abstract]. Gastroenterology 2006; 130 (4 Suppl. 2): S1060Google Scholar
  122. 122.
    Gish RG, Arora S, Nelson D, et al. End-of-treatmentresponse in therapy-naive patients treated for chronic hepatitis C with viramidine in combination with pegylated interferon alpha-2a [abstract]. Hepatology 2004; 40 (4 Suppl. 1): 388AGoogle Scholar
  123. 123.
    Gish R, Arora S, Nelson D, et al. Safety and efficacy of viramidine in combination with pegylated interferon alfa-2a for treatment of hepatitis C in therapy-naive patients. J Hepatol 2004; 40 Suppl. 1: 141–2CrossRefGoogle Scholar
  124. 124.
    Gish RG. Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother 2006 Jan; 57(1): 8–13PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Division of Digestive and Liver Diseases, L5-210University of Texas Southwestern Medical SchoolDallasUSA

Personalised recommendations