Current Hepatitis Reports

, Volume 10, Issue 3, pp 168–178 | Cite as

Ribavirin: How Does it Work and is it Still Needed?



Ribavirin is a synthetic guanosine analogue, which acts against hepatitis C virus (HCV) through several mechanisms that include 1) immune modulation; 2) inhibition of inosine monophosphate dehydrogenase 3) inhibition of RNA-dependent RNA polymerase; 4) induction of HCV mutagenesis; and 5) modulation of interferon-stimulated gene expression. Addition of ribavirin to peginterferon-α substantially improves sustained virologic response (SVR) and decreases relapse rates. Ribavirin can be associated with hemolytic anemia. However, recent data suggest that SVR is not negatively impacted by treatment-induce anemia. Notably, optimal dosing strategy and the proper management of anemia are crucial to achieve the best treatment outcome. Several advances have been made in the areas relevant to ribavirin, such as the discovery of inosine triphosphatase gene as a promising pharmacogenetic marker and a predictor of anemia, and the role for erythropoiesis-stimulating agent in the management of anemia related to ribavirin use. Recent observations indicate that ribavirin will remain as a critical component of HCV therapy, even in the context of direct acting antivirals.


Ribavirin Hepatitis C Virus (HCV) Treatment Sustained Virologic Response (SVR) Relapse Mechanisms of action IMPDH inhibitor Mutagenesis Ribavirin-induced anemia Hemolysis Pegylated interferon Peginterferon-alfa ITPA gene Taribavirin Interferon signaling pathway Weight-based dosing Direct Acting Anti-viral (DAA) Erythropoiesis-stimulating agent Epoetin 



K. Rajender Reddy received grants from Merck, Roche, Vertex, Tiboec, BMS and Gilead. He has received payment for development of educational presentations from CME activites-ViralEd and Rush University, and has also received payment from the American Board of Internal Medicine, Gastroenterology, Uptodate, and the Chronic Liver Disease Foundation; Chalermrat Bunchorntavakul reported no potential conflicts of interest relevant to this article.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic hepatitis C. Cochrane Database Syst Rev 2009:CD005527.Google Scholar
  2. 2.
    Schalm SW, Hansen BE, Chemello L, 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;26:961–6.PubMedCrossRefGoogle Scholar
  3. 3.
    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;339:1485–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352:1426–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–65.PubMedCrossRefGoogle Scholar
  6. 6.
    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55.PubMedGoogle Scholar
  8. 8.
    Wade JR, Snoeck E, Duff F, Lamb M, Jorga K. Pharmacokinetics of ribavirin in patients with hepatitis C virus. Br J Clin Pharmacol. 2006;62:710–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Reddy KR, Nelson DR, Zeuzem S. Ribavirin: current role in the optimal clinical management of chronic hepatitis C. J Hepatol. 2009;50:402–11.PubMedCrossRefGoogle Scholar
  10. 10.
    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;37:1351–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Dahari H, Ribeiro RM, Perelson AS. Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology. 2007;46:16–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Rehermann B, Hepatitis C. virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009;119:1745–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Hofmann WP, Herrmann E, Sarrazin C, Zeuzem S. Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms. Liver Int. 2008;28:1332–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov NV. Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology. 2000;118:346–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Cornberg M, Hinrichsen H, Teuber G, et al. Mycophenolate mofetil in combination with recombinant interferon alfa-2a in interferon-nonresponder patients with chronic hepatitis C. J Hepatol. 2002;37:843–7.PubMedCrossRefGoogle Scholar
  17. 17.
    McHutchison JG, Shiffman ML, Cheung RC, et al. A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-α in previously untreated patients with chronic hepatitis C. Antivir Ther. 2005;10:635–43.PubMedGoogle Scholar
  18. 18.
    Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology. 2002;35:1002–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Crotty S, Maag D, Arnold JJ, et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med. 2000;6:1375–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Hofmann WP, Polta A, Herrmann E, et al. Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy. Gastroenterology. 2007;132:921–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut. 2008;57:516–24.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen L, Borozan I, Sun J, et al. Cell-type specific gene expression signature in liver underlies response to interferon therapy in chronic hepatitis C infection. Gastroenterology 2010;138:1123–33 e1-3.Google Scholar
  23. 23.
    •• Feld JJ, Nanda S, Huang Y, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology 2007;46:1548–63. The recent proposed mechanism of ribavirin in HCV therapy has been well studied in this research work. The authors found that induction of interferon-stimulated cytokines correlated with viral kinetics following ribavirin therapy, suggesting that ribavirin promotes interferon signaling pathway. PubMedCrossRefGoogle Scholar
  24. 24.
    • Thomas E, Feld JJ, Li Q, Hu Z, Fried MW, Liang TJ. Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models. Hepatology 2011;53:32–41. Recent meta-analysis demonstrated the importance of adding ribavirin to interferon-based therapy for HCV by significantly improved SVR and reduced virological relapse. PubMedCrossRefGoogle Scholar
  25. 25.
    Feld JJ, Lutchman GA, Heller T, et al. Ribavirin improves early responses to peginterferon through improved interferon signaling. Gastroenterology 2010;139:154–62 e4.Google Scholar
  26. 26.
    Brok J, Gluud LL, Gluud C. Meta-analysis: ribavirin plus interferon vs. interferon monotherapy for chronic hepatitic C - an updated Cochrane review. Aliment Pharmacol Ther. 2010;32:840–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Jacobson IM, Brown Jr RS, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971–81.PubMedCrossRefGoogle Scholar
  29. 29.
    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;41:275–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Ferenci P, Brunner H, Laferl H, et al. A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3. Hepatology. 2008;47:1816–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Singal AK, Anand BS. Tailoring treatment duration to 12 to 16 weeks in hepatitis C genotype 2 or 3 with rapid virologic response: systematic review and meta-analysis of randomized controlled trials. J Clin Gastroenterol. 2010;44:583–7.PubMedGoogle Scholar
  32. 32.
    Russmann S, Grattagliano I, Portincasa P, Palmieri VO, Palasciano G. Ribavirin-induced anemia: mechanisms, risk factors and related targets for future research. Curr Med Chem. 2006;13:3351–7.PubMedCrossRefGoogle Scholar
  33. 33.
    De Franceschi L, Fattovich G, Turrini 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.PubMedCrossRefGoogle Scholar
  34. 34.
    Grattagliano I, Russmann S, Palmieri VO, et al. Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C. Hepatology. 2004;39:1248–55.PubMedCrossRefGoogle Scholar
  35. 35.
    Balan V, Schwartz D, Wu GY, et al. Erythropoietic response to anemia in chronic hepatitis C patients receiving combination pegylated interferon/ribavirin. Am J Gastroenterol. 2005;100:299–307.PubMedCrossRefGoogle Scholar
  36. 36.
    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;98:2491–9.PubMedGoogle Scholar
  37. 37.
    Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. 2004;126:1302–11.PubMedCrossRefGoogle Scholar
  38. 38.
    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;131:1040–8.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Reddy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol 2007;5:124–9. Large retrospective analysis suggesting that ribavirin dose reduction to less than 60% of expected accumulative dose has negative impact on SVR. PubMedCrossRefGoogle Scholar
  40. 40.
    McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–93.PubMedCrossRefGoogle Scholar
  41. 41.
    •• Sulkowski MS, Shiffman ML, Afdhal NH, et al. Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 2010;139:1602–11, 11 e1. An important retrospective analysis from the IDEAL study that made the observation that anemia was a predictor of response and that early anemia treated with ESA had high SVR. PubMedCrossRefGoogle Scholar
  42. 42.
    Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin α. Hepatology. 2007;46:371–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373:1532–42.PubMedCrossRefGoogle Scholar
  44. 44.
    Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98.PubMedCrossRefGoogle Scholar
  45. 45.
    •• Fellay J, Thompson AJ, Ge D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 2010;464:405–8. Landmark paper on the promising genetic variants (ITPA gene) related to ribavirin-induced anemia. PubMedCrossRefGoogle Scholar
  46. 46.
    Thompson AJ, Fellay J, Patel K, et al. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology. 2010;139:1181–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Kurosaki M, Tanaka K, Suzuki Y, et al. The ITPA genotype correlated with hemolytic anemia and outcome after treatment with pegylated-interferon and ribavirin in genotype 1b chronic hepatitis C [abstract 469]. In: 46th Annual Meeting of the European Association for Study of the Liver (EASL). Berlin, Germany.Google Scholar
  48. 48.
    Shields WW, Pockros PJ. Ribavirin analogs. Clin Liver Dis. 2009;13:419–27.PubMedCrossRefGoogle Scholar
  49. 49.
    Benhamou Y, Afdhal NH, Nelson DR, et al. A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment-naive patients with chronic hepatitis C: ViSER1 results. Hepatology. 2009;50:717–26.PubMedCrossRefGoogle Scholar
  50. 50.
    Marcellin P, Gish RG, Gitlin N, et al. Safety and efficacy of viramidine versus ribavirin in ViSER2: randomized, double-blind study in therapy-naive hepatitis C patients. J Hepatol. 2010;52:32–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Poordad F, Lawitz E, Shiffman ML, et al. Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C. Hepatology. 2010;52:1208–15.PubMedCrossRefGoogle Scholar
  52. 52.
    Rustgi VK, Lee WM, Lawitz E, et al. Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders. Hepatology. 2009;50:1719–26.PubMedCrossRefGoogle Scholar
  53. 53.
    •• Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–50. An important and randomized clinical trial that demonstrated the importance of ribavirin in DDA-based treatment regimen. PubMedCrossRefGoogle Scholar
  54. 54.
    Kwo PY, Lawitz EJ, McCone J, et al. 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. 2010;376:705–16.PubMedCrossRefGoogle Scholar
  55. 55.
    McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292–303.PubMedCrossRefGoogle Scholar
  56. 56.
    Pockros PJ, Nelson D, Godofsky E, et al. R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin. Hepatology. 2008;48:385–97.PubMedCrossRefGoogle Scholar
  57. 57.
    Zeuzem S, Buggisch P, Agarwal K, et al. Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin or peginterferon/ribavirin for up to 28 days in treatment naive, genotype 1 HCV subjects. Hepatology. 2010;52:400A.Google Scholar
  58. 58.
    Sulkowski MS, Reddy KR, Afdhal NH, et al. Anemia had no effect on efficacy outcomes in treatment-naive patients who recieved telaprevir-based regimen in the ADVANCE and ILLUMINATE Phase 3 studies [abstract 477]. In: 46th Annual Meeting of the European Association for Study of the Liver (EASL). Berlin, Germany.Google Scholar
  59. 59.
    Sulkowski MS, Poordad F, Manns M, et al. Anemia during treatment with peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previous treatment failure patients [abstract 476]. In: 46th Annual Meeting of the European Association for Study of the Liver (EASL) March 30 - April 3, 2011; Berlin, Germany.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Chalermrat Bunchorntavakul
    • 1
    • 2
  • K. Rajender Reddy
    • 1
    • 2
  1. 1.Division of Gastroenterology and HepatologyHospital of the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of MedicineHospital of the University of PennsylvaniaPhiladelphiaUSA

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