PIRR Therapy in HCV-Related Mixed Cryoglobulinemia

  • Franco Dammacco
  • Domenico Sansonno


With few exceptions, a close association between HCV infection and mixed cryoglobulinemia (MC) has been definitively established. In HCV chronically infected patients, and hence for HCV-positive MC patients as well, pegylated interferon-α (pIFN-α) plus ribavirin (RBV) combined therapy has become the standard of care. More recently, the efficacy and safety of rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, have been shown in MC patients resistant or intolerant to combined therapy; however, enhanced HCV RNA levels have often been detected following RTX administration. Thus, we tested the effectiveness and tolerability of pIFN-α plus RBV plus RTX, a combination (PIRR). A complete response was achieved in 54.5% of MC patients treated with the PIRR combination (study arm) and in 33.3% of those receiving pIFN-α plus RBV, the standard of care (control arm). The successful response was maintained for up to 36 months in over 83% of patients in the study arm, but in only 40% of those enrolled in the control arm. No serious adverse events were recorded, although acute and medium- to long-term side effects have been described in a very few patients given RTX for MC or other indications. Additional studies addressing issues such as the pharmacokinetic behavior of RTX, the best sequence of PIRR drug administration, optimal doses of the drugs as a function of HCV genotype, and therapeutic combinations including new protease inhibitors and new anti-CD20 monoclonal antibodies, will hopefully improve the overall results.


Sustained Virological Response Sustained Virological Response Rate Mixed Cryoglobulinemia Mixed Cryoglobulinemia Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



D. Sansonno is supported by the AIRC (Italian Association for Cancer Research), Milan, Italy.


  1. 1.
    Ferri C, Greco F, Longombardo G et al (1991) Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum 34:1606–1610PubMedCrossRefGoogle Scholar
  2. 2.
    Dammacco F, Sansonno D (1992) Antibodies to hepatitis C virus in essential mixed cryoglobulinaemia. Clin Exp Immunol 87:352–356PubMedCrossRefGoogle Scholar
  3. 3.
    Misiani R, Bellavita P, Fenili D et al (1992) Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573–577PubMedCrossRefGoogle Scholar
  4. 4.
    Agnello V, Chung RT, Kaplan LM (1992) A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490–1495PubMedCrossRefGoogle Scholar
  5. 5.
    Marcellin P, Descamps V, Martinot-Peignoux M et al (1993) Cryoglobulinemia with vasculitis associated with hepatitis C virus infection. Gastroenterology 104:272–277PubMedGoogle Scholar
  6. 6.
    Bonomo L, Casato M, Afeltra A et al (1987) Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med 83:726–730PubMedCrossRefGoogle Scholar
  7. 7.
    Casato M, Laganà B, Antonelli G et al (1991) Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia. Blood 78:3142–3147PubMedGoogle Scholar
  8. 8.
    Ferri C, Marzo E, Longombardo G et al (1993) Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 81:1132–1136PubMedGoogle Scholar
  9. 9.
    Misiani R, Bellavita P, Fenili D et al (1994) Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751–756PubMedCrossRefGoogle Scholar
  10. 10.
    Dammacco F, Sansonno D, Han JH et al (1994) Natural interferon-alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study. Blood 84:3336–3343PubMedGoogle Scholar
  11. 11.
    Glue P, Rouzier-Panis R, Raffanel C et al (2000) A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group. Hepatology 32:647–653PubMedCrossRefGoogle Scholar
  12. 12.
    Scott LJ, Perry CM (2002) Interferon-alpha-2b plus ribavirin: a review of its use in the management of chronic hepatitis C. Drugs 62:507–556PubMedCrossRefGoogle Scholar
  13. 13.
    Hadziyannis SJ, Sette H Jr, Morgan TR et al (2004) Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140:346–355PubMedCrossRefGoogle Scholar
  14. 14.
    Strader DB, Wright T, Thomas DL et al (2004) Diagnosis, management, and treatment of hepatitis C. Hepatology 39:1147–1171PubMedCrossRefGoogle Scholar
  15. 15.
    Mangia A, Andriulli A (2010) Tailoring the length of antiviral treatment for hepatitis C. Gut 59:1–5PubMedCrossRefGoogle Scholar
  16. 16.
    Calleja JL, Albillos A, Moreno-Otero R et al (1999) Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinaemia. Aliment Pharmacol Ther 13:1179–1186PubMedCrossRefGoogle Scholar
  17. 17.
    Cacoub P, Saadoun D, Limal N et al (2005) PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 52:911–915PubMedCrossRefGoogle Scholar
  18. 18.
    Levine JW, Gota C, Fessler BJ et al (2005) Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol 32:1164–1167PubMedGoogle Scholar
  19. 19.
    Landau DA, Saadoun D, Halfon P et al (2008) Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum 58:604–611PubMedCrossRefGoogle Scholar
  20. 20.
    Sansonno D, De Vita S, Iacobelli AR et al (1998) Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol 160:3594–3601PubMedGoogle Scholar
  21. 21.
    Racanelli V, Sansonno D, Piccoli C et al (2001) Molecular characterization of B cell clonal expansions in the liver of chronically hepatitis C virus-infected patients. J Immunol 167:21–29PubMedGoogle Scholar
  22. 22.
    Sansonno D, Lauletta G, De Re V et al (2004) Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur J Immunol 34:126–136PubMedCrossRefGoogle Scholar
  23. 23.
    Vallat L, Benhamou Y, Gutierrez M et al (2004) Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum 50:3668–3678PubMedCrossRefGoogle Scholar
  24. 24.
    Sansonno D, De Re V, Lauletta G et al (2003) Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 101:3818–3826PubMedCrossRefGoogle Scholar
  25. 25.
    Zaja F, De Vita S, Mazzaro C et al (2003) Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827–3834PubMedCrossRefGoogle Scholar
  26. 26.
    Cacoub P, Delluc A, Saadoun D et al (2008) Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis 67:283–287PubMedCrossRefGoogle Scholar
  27. 27.
    Petrarca A, Rigacci L, Caini P et al (2010) Safety and efficacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinemia and severe liver disease. Blood 116:335–342PubMedCrossRefGoogle Scholar
  28. 28.
    Terrier B, Launay D, Kaplanski G et al (2010) Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French autoimmunity and rituximab registry. Arthritis Care Res 62(12):1787–1795, Aug 25 [Epub ahead of print]CrossRefGoogle Scholar
  29. 29.
    Dammacco F, Sansonno D, Piccoli C et al (2001) The cryoglobulins: an overview. Eur J Clin Invest 31:628–638PubMedCrossRefGoogle Scholar
  30. 30.
    Dammacco F, Tucci FA, Lauletta G et al (2010) Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study. Blood 116:343–353, Epub 2010 Mar 22PubMedCrossRefGoogle Scholar
  31. 31.
    Lake-Bakaar G, Dustin L, McKeating J et al (2007) Hepatitis C virus and alanine aminotransferase kinetics following B lymphocyte depletion with rituximab: evidence for a significant role of humoral immunity in the control of viremia in chronic HCV liver disease. Blood 109:845–846PubMedCrossRefGoogle Scholar
  32. 32.
    Terrier B, Saadoun D, Sene D et al (2009) Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus-related vasculitis: a long-term followup study of thirty-two patients. Arthritis Rheum 60:2531–2540PubMedCrossRefGoogle Scholar
  33. 33.
    Wink F, Houtman PM, Jansen TL (2011) Rituximab in cryoglobulinaemic vasculitis, evidence for its effectivity: a case report and review of literature. Clin Rheumatol 30(2):293–300, Epub 2010 Oct 31PubMedCrossRefGoogle Scholar
  34. 34.
    Terrier B, Saadoun D, Sène D et al (2009) Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus-related vasculitis: a long-term followup study of thirty-two patients. Arthritis Rheum 60:2531–2540PubMedCrossRefGoogle Scholar
  35. 35.
    Saadoun D, Resche Rigon M, Sene D et al (2010) Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood 116:326–334PubMedCrossRefGoogle Scholar
  36. 36.
    Ruch J, McMahon B, Ramsey G et al (2009) Catastrophic multiple organ ischemia due to an anti-Pr cold agglutinin developing in a patient with mixed cryoglobulinemia after treatment with rituximab. Am J Hematol 84:120–122PubMedCrossRefGoogle Scholar
  37. 37.
    Ardelean DS, Gonska T, Wires S et al (2010) Severe ulcerative colitis after rituximab therapy. Pediatrics 126:e243–e246, Epub 2010 Jun 21PubMedCrossRefGoogle Scholar
  38. 38.
    Sène D, Ghillani-Dalbin P, Amoura Z et al (2009) Rituximab may form a complex with IgMkappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis. Arthritis Rheum 60:3848–3855PubMedCrossRefGoogle Scholar
  39. 39.
    Tuccori M, Focosi D, Blandizzi C et al (2010) Inclusion of rituximab in treatment protocols for non-Hodgkin’s lymphomas and risk for progressive multifocal leukoencephalopathy. Oncologist 15:214–1219, Epub 2010 Nov 1CrossRefGoogle Scholar
  40. 40.
    Regazzi MB, Iacona I, Avanzini MA et al (2005) Pharmacokinetic behavior of rituximab: a study of different schedules of administration for heterogeneous clinical settings. Ther Drug Monit 27:785–792PubMedCrossRefGoogle Scholar
  41. 41.
    Mangia A (2011) Individualizing treatment duration in hepatitis C virus genotype 2/3-infected patients. Liver Int 31:36–41PubMedCrossRefGoogle Scholar
  42. 42.
    Pearlman BL (2011) The IL-28 genotype: how it will affect the care of patients with hepatitis C virus infection. Curr Gastroenterol Rep 13(1):78–86, 2010 Nov 16 [Epub ahead of print]PubMedCrossRefGoogle Scholar
  43. 43.
    Asselah T, Estrabaud E, Bieche I et al (2010) Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin. Liver Int 30:1259–1269PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Department of Internal Medicine and Clinical OncologyUniversity of Bari Medical SchoolBariItaly
  2. 2.Liver Unit, Department of Biomedical Sciences and Clinical OncologyUniversity of Bari Medical SchoolBariItaly

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