Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection

T Barry Kelleher, MD, FRCPI
Nezam H Afdhal, MD, FRCPI
Section Editor
Adrian M Di Bisceglie, MD
Deputy Editor
Allyson Bloom, MD


Side effects are observed in almost 80 percent of patients receiving peginterferon and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection (figure 1). Care of patients with chronic HCV infection depends upon recognition of those at increased risk for side effects, anticipation (and prevention) of side effects, and appropriate response when they occur. Furthermore, the ability to achieve a sustained virologic response (SVR) to therapy depends in part upon the degree of compliance with therapy. Reduction of the dose of these agents (or their discontinuation) due to side effects can potentially compromise the outcome, depending upon when dose reduction occurs.

Although treatment paradigms for chronic hepatitis C are rapidly evolving, peginterferon and ribavirin, typically in combination with a direct-acting antiviral, remain in use for certain genotypes, particularly in resource-limited settings where newer interferon-free regimens are inaccessible or unavailable. With a few exceptions, the majority of the side effects reported in trials of such triple combination therapy are similar in nature and frequency to those seen with peginterferon and ribavirin.

This topic review will summarize the major side effects associated with regimens for the treatment of HCV infection that include peginterferon and ribavirin. A detailed discussion on treatment regimens and side effects of directly acting antivirals is presented separately. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults".)


Side effects are frequent with the use of peginterferon and ribavirin for the treatment of chronic HCV, thus patients should be evaluated regularly for toxicity during the course of therapy (table 1).

Certain laboratory and other specialized testing to assess for specific side effects are warranted at baseline and/or during HCV treatment with peginterferon and ribavirin. These include:


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Apr 12, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Nachnani JS, Rao GA, Bulchandani D, et al. Predictors of hematological abnormalities in patients with chronic hepatitis C treated with interferon and ribavirin. Ann Hematol 2010; 89:121.
  2. Hadziyannis SJ, Sette H Jr, 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; 140:346.
  3. 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.
  4. 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.
  5. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405.
  6. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195.
  7. 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.
  8. Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 2013; 58:1918.
  9. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014; 146:430.
  10. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13:401.
  11. Sulkowski MS, Poordad F, Manns MP, et al. Anemia during treatment with peginterferon Alfa-2b/ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial. Hepatology 2013; 57:974.
  12. Crismale JF, Martel-Laferrière V, Bichoupan K, et al. Diabetes mellitus and advanced liver fibrosis are risk factors for severe anaemia during telaprevir-based triple therapy. Liver Int 2014; 34:1018.
  13. Reau N, Hadziyannis SJ, Messinger D, et al. Early predictors of anemia in patients with hepatitis C genotype 1 treated with peginterferon alfa-2a (40KD) plus ribavirin. Am J Gastroenterol 2008; 103:1981.
  14. Asselah T, Pasmant E, Lyoumi S. Unraveling the genetic predisposition of ribavirin-induced anaemia. J Hepatol 2010; 53:971.
  15. 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.
  16. 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.
  17. 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.
  18. Balestrieri C, Serra G, Cauli C, et al. Treatment of chronic hepatitis C in patients with glucose-6-phosphate dehydrogenase deficiency: is ribavirin harmful? Blood 2006; 107:3409.
  19. Lin CC, Yeh LT, Vitarella D, Hong Z. Viramidine, a prodrug of ribavirin, shows better liver-targeting properties and safety profiles than ribavirin in animals. Antivir Chem Chemother 2003; 14:145.
  20. McHutchison JG, Manns MP, Longo DL. Definition and management of anemia in patients infected with hepatitis C virus. Liver Int 2006; 26:389.
  21. Homma M, Matsuzaki Y, Inoue Y, et al. Marked elevation of erythrocyte ribavirin levels in interferon and ribavirin-induced anemia. Clin Gastroenterol Hepatol 2004; 2:337.
  22. Canonico PG, Kastello MD, Spears CT, et al. Effects of ribavirin on red blood cells. Toxicol Appl Pharmacol 1984; 74:155.
  23. Cosgriff TM, Hodgson LA, Canonico PG, et al. Morphological alterations in blood and bone marrow of ribavirin-treated monkeys. Acta Haematol 1984; 72:195.
  24. 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.
  25. Sievert W, Dore GJ, McCaughan GW, et al. Virological response is associated with decline in hemoglobin concentration during pegylated interferon and ribavirin therapy in hepatitis C virus genotype 1. Hepatology 2011; 53:1109.
  26. Poordad F, Lawitz E, Reddy KR, et al. Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection--a randomized trial. Gastroenterology 2013; 145:1035.
  27. Gaetano JN, Reau N. Hepatitis C: management of side effects in the era of direct-acting antivirals. Curr Gastroenterol Rep 2013; 15:305.
  28. 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; 123:1061.
  29. Shiffman ML, Ghany MG, Morgan TR, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology 2007; 132:103.
  30. 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.
  31. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417.
  32. Dieterich DT, Wasserman R, Bräu 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.
  33. 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.
  34. Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology 2007; 46:371.
  35. Younossi Z, Ong J, Collantes R. Darbepoetin alfa for ribavirin-induced anemia in patients with chronic hepatitis C treated with pegylated interferon and ribavirin: a preliminary analysis. Gastroenterology 2004; 126 Suppl 2:AB83.
  36. 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.
  37. Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362:1255.
  38. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005; 23:5960.
  39. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007; 25:1027.
  40. Henke M, Mattern D, Pepe M, et al. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 2006; 24:4708.
  41. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346:469.
  42. Suzuki M, Inage E, Minowa K, et al. Prophylaxis for ribavirin-related anemia using eicosapentaenoic acid in chronic hepatitis C patients. Pediatr Int 2012; 54:528.
  43. Soza A, Everhart JE, Ghany MG, et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002; 36:1273.
  44. Roomer R, Hansen BE, Janssen HL, de Knegt RJ. Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. Hepatology 2010; 52:1225.
  45. Jacobson IM, Brown RS Jr, 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.
  46. Melia MT, Bräu N, Poordad F, et al. Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study. Clin Infect Dis 2014; 58:960.
  47. PEGASYS (peginterferon alfa-2a). US FDA approved product information. National Library of Medicine. http://dailymed.nlm.nih.gov/ (Accessed on November 11, 2013).
  48. PEG-Intron (peginterferon alfa-2b). US FDA approved product information. National Library of Medicine. http://dailymed.nlm.nih.gov/ (Accessed on November 11, 2013).
  49. 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; 131:470.
  50. Sulkowski MS, Cooper C, Hunyady B, et al. Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C. Nat Rev Gastroenterol Hepatol 2011; 8:212.
  51. Van Thiel DH, Faruki H, Friedlander L, et al. Combination treatment of advanced HCV associated liver disease with interferon and G-CSF. Hepatogastroenterology 1995; 42:907.
  52. Kawasaki T, Takeshita A, Souda K, et al. Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis. Am J Gastroenterol 1999; 94:1918.
  53. Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of "hypersplenic" thrombocytopenia. J Clin Invest 1966; 45:645.
  54. Maan R, van der Meer AJ, Hansen BE, et al. Effect of thrombocytopenia on treatment tolerability and outcome in patients with chronic HCV infection and advanced hepatic fibrosis. J Hepatol 2014; 61:482.
  55. Roomer R, Hansen BE, Janssen HL, de Knegt RJ. Thrombocytopenia and the risk of bleeding during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. J Hepatol 2010; 53:455.
  56. Raanani P, Ben-Bassat I. Immune-mediated complications during interferon therapy in hematological patients. Acta Haematol 2002; 107:133.
  57. Yagura M, Tanaka A, Tokita H, et al. Factors regarding increase of platelet counts in chronic hepatitis C patients with sustained virological response to interferon-Relation to serum thrombopoietin levels. Hepatol Res 2005; 33:211.
  58. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007; 357:2227.
  59. Adfdhal N, Dusheiko G, Giannini EG, et al. Final results of ENABLE 1, a phase 3 multicenter study of eltrombopag as an adjunct for antiviral treatment of hepatitis C virus-related chronic liver disease associated with thrombocytopenia. Hepatology 2011; 54:1427A.
  60. Afdhal NH, Dusheiko GM, Giannini EG, et al. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterology 2014; 146:442.
  61. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm211796.htm (Accessed on May 14, 2010).
  62. Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012; 367:716.
  63. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36:S237.
  64. Daoud MS, Gibson LE, Daoud S, el-Azhary RA. Chronic hepatitis C and skin diseases: a review. Mayo Clin Proc 1995; 70:559.
  65. Berk DR, Mallory SB, Keeffe EB, Ahmed A. Dermatologic disorders associated with chronic hepatitis C: effect of interferon therapy. Clin Gastroenterol Hepatol 2007; 5:142.
  66. Gurguta C, Kauer C, Bergholz U, et al. Tongue and skin hyperpigmentation during PEG-interferon-alpha/ribavirin therapy in dark-skinned non-Caucasian patients with chronic hepatitis C. Am J Gastroenterol 2006; 101:197.
  67. Farshidi D, Chiu MW. Lingual hyperpigmentation from pegylated interferon and ribavirin treatment of hepatitis C. J Am Acad Dermatol 2010; 62:164.
  68. Willems M, Munte K, Vrolijk JM, et al. Hyperpigmentation during interferon-alpha therapy for chronic hepatitis C virus infection. Br J Dermatol 2003; 149:390.
  69. Bachmeyer C, Pellen JC. Tongue hyperpigmentation during hepatitis C treatment. CMAJ 2012; 184:1498.
  70. Ogata K, Koga T, Yagawa K. Interferon-related bronchiolitis obliterans organizing pneumonia. Chest 1994; 106:612.
  71. Slavenburg S, Heijdra YF, Drenth JP. Pneumonitis as a consequence of (peg)interferon-ribavirin combination therapy for hepatitis C: a review of the literature. Dig Dis Sci 2010; 55:579.
  72. Kawano T, Shigehira M, Uto H, et al. Retinal complications during interferon therapy for chronic hepatitis C. Am J Gastroenterol 1996; 91:309.
  73. Manesis EK, Moschos M, Brouzas D, et al. Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 1998; 27:1421.
  74. Kuga K, Hasumura S, Nagamori S, et al. Intraocular hemorrhage developing during interferon therapy. Intern Med 1996; 35:15.
  75. Hayasaka S, Fujii M, Yamamoto Y, et al. Retinopathy and subconjunctival haemorrhage in patients with chronic viral hepatitis receiving interferon alfa. Br J Ophthalmol 1995; 79:150.
  76. Manesis EK, Petrou C, Brouzas D, Hadziyannis S. Optic tract neuropathy complicating low-dose interferon treatment. J Hepatol 1994; 21:474.
  77. Fortin E. Neurovisual complications of interferon-alpha therapy. Hepatology 1998; 27:1441.
  78. Mehta N, Murthy UK, Kaul V, et al. Outcome of retinopathy in chronic hepatitis C patients treated with peginterferon and ribavirin. Dig Dis Sci 2010; 55:452.
  79. Vujosevic S, Tempesta D, Noventa F, et al. Pegylated interferon-associated retinopathy is frequent in hepatitis C virus patients with hypertension and justifies ophthalmologic screening. Hepatology 2012; 56:455.
  80. Moriarty AP. Indocyanine green enhanced diode laser photocoagulation of subretinal neovascular membranes. Br J Ophthalmol 1994; 78:238.
  81. Kwon YS, Choe YH, Chin HS. Development of glaucoma in the course of interferon alpha therapy for chronic hepatitis B. Yonsei Med J 2001; 42:134.
  82. Isler M, Akhan G, Bardak Y, Akkaya A. Dry cough and optic neuritis: two rare complications of interferon alpha treatment in chronic viral hepatitis. Am J Gastroenterol 2001; 96:1303.
  83. Noto H, Raskin P. Hepatitis C infection and diabetes. J Diabetes Complications 2006; 20:113.
  84. Georgetson MJ, Yarze JC, Lalos AT, et al. Exacerbation of psoriasis due to interferon-alpha treatment of chronic active hepatitis. Am J Gastroenterol 1993; 88:1756.
  85. Simsek H, Savas C, Akkiz H, Telatar H. Interferon-induced vitiligo in a patient with chronic viral hepatitis C infection. Dermatology 1996; 193:65.
  86. Nagao Y, Sata M, Ide T, et al. Development and exacerbation of oral lichen planus during and after interferon therapy for hepatitis C. Eur J Clin Invest 1996; 26:1171.
  87. Nawras A, Alsolaiman MM, Mehboob S, et al. Systemic sarcoidosis presenting as a granulomatous tattoo reaction secondary to interferon-alpha treatment for chronic hepatitis C and review of the literature. Dig Dis Sci 2002; 47:1627.
  88. Tahan V, Ozseker F, Guneylioglu D, et al. Sarcoidosis after use of interferon for chronic hepatitis C: report of a case and review of the literature. Dig Dis Sci 2003; 48:169.
  89. Borghi-Scoazec G, Merle P, Scoazec JY, et al. Onset of dermatitis herpetiformis after treatment by interferon and ribavirin for chronic hepatitis C. J Hepatol 2004; 40:871.
  90. Ramos-Casals M, Mañá J, Nardi N, et al. Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases. Medicine (Baltimore) 2005; 84:69.
  91. Tosti A, Misciali C, Bardazzi F, et al. Telogen effluvium due to recombinant interferon alpha-2b. Dermatology 1992; 184:124.
  92. Kernland KH, Hunziker T. Alopecia areata induced by interferon alpha? Dermatology 1999; 198:418.
  93. Bräu N, Bini EJ, Stancic S, et al. Severe migraine headaches are caused by ribavirin but not by interferon alpha-2B in combination therapy for chronic hepatitis C. J Hepatol 2003; 38:871.
  94. Formann E, Stauber R, Denk DM, et al. Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin. Am J Gastroenterol 2004; 99:873.