Journal of Hepatology
Volume 50, Issue 2 , Pages 402-411 , February 2009

Ribavirin: Current role in the optimal clinical management of chronic hepatitis C

  • K. Rajender Reddy

      Affiliations

    • GI Division, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 215 662 4276; fax: +1 215 614 0925.
  • ,
  • David R. Nelson

      Affiliations

    • Division of Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, Gainesville, FL, USA
  • ,
  • Stefan Zeuzem

      Affiliations

    • Department of Medicine I, JW Goethe University Hospital, Frankfurt, Germany

References 

  1. Fernandez H, Banks G, Smith R. Ribavirin: a clinical overview. Eur J Epidemiol. 1986;2:1–14
  2. Zoulim F, Haem J, Ahmed SS, Chossegros P, Habersetzer F, Chevallier M, et al. Ribavirin monotherapy in patients with chronic hepatitis C: a retrospective study of 95 patients. J Viral Hepat. 1998;5:193–198
  3. Bodenheimer HC, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology. 1997;26:473–477
  4. Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, Yurdaydin C, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:897–903
  5. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol. 1996;25:591–598
  6. Hoofnagle JH, Lau D, Conjeevaram H, Kleiner D, Di Bisceglie AM. Prolonged therapy of chronic hepatitis C with ribavirin. J Viral Hepat. 1996;3:247–252
  7. Schalm SW, Hansen BE, Chemello L, Bellobuono A, Brouwer JT, Weiland O, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers. J Hepatol. 1997;26:961–966
  8. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, 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;339:1485–1492
  9. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, 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;352:1426–1432
  10. Barbaro G, Di Lorenzo G, Soldini M, Giancaspro G, Pellicelli A, Grisorio B, et al. Evaluation of long-term efficacy of interferon alpha-2b and ribavirin in combination in naive patients with chronic hepatitis C: an Italian multicenter experience. Ribavirin-Interferon in Chronic Hepatitis Italian Group Investigators. J Hepatol. 2000;33:448–455
  11. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965
  12. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FLJ, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982
  13. Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–355
  14. Reddy KR, Shiffman ML, Morgan TR, Zeuzem S, Hadziyannis S, Hamzeh FM, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124–129
  15. von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005;129:522–527
  16. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2005;352:2609–2617
  17. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124–134
  18. Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, et al. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut. 2007;56:553–559
  19. Bronowicki JP, Ouzan D, Asselah T, Desmorat H, Zarski JP, Foucher J, et al. Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin. Gastroenterology. 2006;131:1040–1048
  20. Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis. 1999;19(Suppl. 1):17–24
  21. Lindahl K, Schvarcz R, Bruchfeld A, Stahle L. Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia. J Viral Hepat. 2004;11:84–87
  22. Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004;432:922–924
  23. Enomoto M, Nishiguchi S, Kohmoto M, Tamori A, Habu D, Takeda T, et al. Effects of ribavirin combined with interferon-alpha 2b on viral kinetics during first 12 weeks of treatment in patients with hepatitis C virus genotype 1 and high baseline viral loads. J Viral Hepat. 2004;11:448–454
  24. Herrmann E, Lee JH, Marinos G, Modi M, Zeuzem S. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology. 2003;37:1351–1358
  25. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967–972
  26. Dixit NM, Perelson AS. The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus. Cell Mol Life Sci. 2006;63:832–842
  27. Parker WB. Metabolism and antiviral activity of ribavirin. Virus Res. 2005;107:165–171
  28. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JY, Hong Z, et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med. 2000;6:1375–1379
  29. Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci USA. 2001;98:6895–6900
  30. Vo NV, Young KC, Lai MM. Mutagenic and inhibitory effects of ribavirin on hepatitis C virus RNA polymerase. Biochemistry. 2003;42:10462–10471
  31. Maag D, Castro C, Hong Z, Cameron CE. Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem. 2001;276:46094–46098
  32. Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK, et al. 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. 1973;70:1174–1178
  33. Rigopoulou EI, Abbott WG, Williams R, Naoumov NV. Direct evidence for immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus. Antiviral Res. 2007;75:36–42
  34. Martin J, Navas S, Quiroga JA, Pardo M, Carreno V. Effects of the ribavirin-interferon alpha combination on cultured peripheral blood mononuclear cells from chronic hepatitis C patients. Cytokine. 1998;10:635–644
  35. Lutchman G, Danehower S, Song BC, Liang TJ, Hoofnagle JH, Thomson M, et al. Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy. Gastroenterology. 2007;132:1757–1766
  36. Hofmann WP, Polta A, Herrmann E, Mihm U, Kronenberger B, Sonntag T, et al. Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy. Gastroenterology. 2007;132:921–930
  37. Pawlotsky JM, Dahari H, Neumann AU, Hezode C, Germanidis G, Lonjon I, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology. 2004;126:703–714
  38. Buckwold VE, Wei J, Wenzel-Mathers M, Russell J. Synergistic in vitro interactions between alpha interferon and ribavirin against bovine viral diarrhea virus and yellow fever virus as surrogate models of hepatitis C virus replication. Antimicrob Agents Chemother. 2003;47:2293–2298
  39. Zhang Y, Jamaluddin M, Wang S, Tian B, Garofalo RP, Casola A, et al. Ribavirin treatment up-regulates antiviral gene expression via the interferon-stimulated response element in respiratory syncytial virus-infected epithelial cells. J Virol. 2003;77:5933–5947
  40. Snoeck E, Wade JR, Duff F, Lamb M, Jorga K. Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin. Br J Clin Pharmacol. 2006;62:699–709
  41. Jen JF, Glue P, Gupta S, Zambas D, Hajian G. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit. 2000;22:555–565
  42. Bain VG, Lee SS, Peltekian K, Yoshida E, Deschenes M, Sherman M, et al. Exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection: analysis of the Canadian PEGASYS® Expanded Access Program. Hepatology. 2006;44:335A–336A
  43. Jacobson IM, Brown RS, Freilich B, Afdhal N, Kwo P, Santoro J, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971–981
  44. Wade JR, Snoeck E, Duff F, Lamb M, Jorga K. Pharmacokinetics of ribavirin in patients with hepatitis C virus. Br J Clin Pharmacol. 2006;62:710–714
  45. Ferenci P, Brunner H, Laferl H, Bergholz U, Rosenbeiger M, Stauber R, et al. Further reduction of ribavirin dose in HCV genotype 2/3 patients receiving peginterferon alpha-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS): interim results of a randomised controlled trial. J Hepatol. 2006;44:S37
  46. Bruchfeld A, Lindahl K, Stahle L, Soderberg M, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant. 2003;18:1573–1580
  47. Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat. 2006;13:316–321
  48. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology. 2006;130:231–264
  49. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–1171
  50. Rendina M, Schena A, Castellaneta NM, Losito F, Amoruso AC, Stallone G, et al. The treatment of chronic hepatitis C with peginterferon alfa-2a (40kDa) plus ribavirin in haemodialysed patients awaiting renal transplant. J Hepatol. 2007;46:768–774
  51. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40kd)/ribavirin therapy. Hepatology. 2006;43:954–960
  52. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, 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;44:97–103
  53. Zeuzem S, Pawlotsky JM, Lukasiewicz E, von Wagner M, Goulis I, Lurie Y, et al. International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C. J Hepatol. 2005;43:250–257
  54. F. Hoffman-La Roche Inc. COPEGUS (ribavirin USP) tablets. Prescribing information; 2007. Fr. Medication Guide (LA Roche Website).
  55. eMC. Copegus 200mg SPC; 2008. Document ID 11755.
  56. Schering-Plough Corporation. REBETOL(R) (ribavirin, USP) capsules and oral solution. Product information; 2003.
  57. eMC. Rebetol 200mg hard capsules SPC; 2004. Document ID 11755.
  58. Fried M, Jensen D, Rodriguez-Torres M, Nyberg L, Di Bisceglie A, Morgan T, et al. Improved sustained virological response (SVR) rates with higher, fixed doses of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (RBV) (COPEGUS) in patients with difficult-to-cure characteristics. Hepatology. 2008;48:1033–1043
  59. Lindahl K, Stahle L, Bruchfeld A, Schvarcz R. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology. 2005;41:275–279
  60. Sulkowski MS, Wasserman R, Brooks L, Ball L, Gish R. Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepat. 2004;11:243–250
  61. McHutchison JG, Manns MP, Brown RS, Reddy KR, Shiffman ML, Wong JB. Strategies for managing anemia in hepatitis C patients undergoing antiviral therapy. Am J Gastroenterol. 2007;102:880–889
  62. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology. 2003;124:1711–1719
  63. De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology. 2000;31:997–1004
  64. Spangler C, Han S, Morrissey Kwasny M, Cohen S, Jensen D. Early predictors of hemoglobin reduction during first four weeks of peginterferon alpha-2a/ribavirin therapy in chronic hepatitis C. Gastroenterology. 2006;130:A844
  65. Reau N, Jensen D, Hadziyannis S, Messinger D, Fried M. Early predictors of anemia in patients with HCV genotype 1 treated with peginterferon alfa-2a (40KD) plus ribavirin 1000–1200mg/day. Am J Gastroenterol. 2008;103:1981–1988
  66. Dieterich DT, Wasserman R, Brau N, Hassanein TI, Bini EJ, Bowers PJ, 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;98:2491–2499
  67. Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. 2004;126:1302–1311
  68. Shiffman ML, Salvatore J, Hubbard S, Price A, Sterling RK, Stravitz RT, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. 2007;46:371–379
  69. Ortho Biotech Products LP. Procrit Prescribing Information. Available from: http://www.procrit.com/procrit/shared/OBI/PI/ProcritBooklet.pdf#page=1; 2007.
  70. Marcellin P, Lurie Y, Rodriguez-Torres M, Chasen R, Xu Y, Murphy B. The safety and efficacy of taribavirin plus pegylated interferon alfa-2a versus ribavirin plus pegylated interferon alfa-2a in therapy-naive patients infected with HCV: phase 3 results. J Hepatol. 2007;46:S7
  71. Benhamou Y, Pockros P, Rodriguez-Torres M, Gordon S, Shiffman M, Lurie Y, et al. The safety and efficacy of viramidine plus PegIFN alfa-2b versus ribavirin plus PegIFN alfa-2b in therapy-naïve patients infected with HCV: phase 3 results (VISER1). J Hepatol. 2006;44;[Abstract 751]
  72. Marcellin P, Horsmans Y, Nevens F, Grange JD, Bronowicki JP, Vetter D, et al. Phase 2 study of the combination of merimepodib with peginterferon-alpha2b, and ribavirin in nonresponders to previous therapy for chronic hepatitis C. J Hepatol. 2007;47:476–483
  73. Hezode C, Ferenci P, Dusheiko GM, Pol S, Goeser T, Bronowicki JP, et al. PROVE2: phase II study of VX950 (telaprevir) in combination with peginterferon alfa 2a with or without ribavirin in subjects with chronic hepatitis C, first interim analysis. Hepatology. 2007;46(Suppl. 1):268A
  74. Jacobson IM, Everson GT, Gordon SC, Kauffman R, McNair L, Muir A, et al. Interim analysis results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C. Hepatology. 2007;46:315A–316A
  75. Klumpp K, Leveque V, Le Pogam S, Ma H, Jiang WR, Kang H, et al. The novel nucleoside analog R1479 (4′-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture. J Biol Chem. 2006;281:3793–3799
  76. Roberts S, Cooksley G, Dore G, Robson R, Shaw D, Berns H, et al. Results of a phase 1B multiple dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV genotype 1 patients. Hepatology. 2008;48:398–406
  77. Pockros PJ, Nelson D, Godofksy E, Rodriguez-Torres M, Everson G, Fried MW, et al. Robust synergistic antiviral effect of R1626 in combination with peginterferon alfa-2a (40KD) with or without ribavirin – interim analysis results of phase 2a study. Hepatology. 2008;48:385–397

 The authors declared that they have a relationship with the manufacturers of ribavirin. They received funding from the manufacturers to carry out research for this manuscript. S.Z. declared that he is on the speakers bureau, does consultancy and clinical investigation for La Roche and Schering Plough. He received support for literature search and editorial assistance from La Roche. D.R.N. declared he has a relationship with the manufacturers of the drugs involved. He did not receive funding from the manufacturers to carry out this study.

PII: S0168-8278(08)00717-4

doi: 10.1016/j.jhep.2008.11.006

Journal of Hepatology
Volume 50, Issue 2 , Pages 402-411 , February 2009