Pegylated IFN-α2a and ribavirin in the treatment of hepatitis C

Expert Review of Anti-Infective Therapy

Volumn 7, Issue 8, 2009, Pages 925-935

  Aghemo, Alessio ^a   Rumi, Maria Grazia ^a   Colombo, Massimo ^a  

^a UNIVERSITY OF MILAN   (Italy)

Author keywords

Chronic hepatitis C; HCV; PegIFN 2a; Ribavirin; Sustained virological response

Indexed keywords

ALPHA2A INTERFERON; INTERFERON; PEGINTERFERON ALPHA2A; PEGINTERFERON ALPHA2B; RIBAVIRIN; ANTIVIRUS AGENT; MACROGOL DERIVATIVE; PEGINTERFERON ALFA-2A; VIRUS RNA;

ABNORMAL LABORATORY RESULT; ANEMIA; ANTIVIRAL ACTIVITY; ASTHENIA; CLINICAL TRIAL; DRUG CLEARANCE; DRUG DOSE COMPARISON; DRUG RESPONSE; DRUG SAFETY; DRUG STABILITY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FEVER; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; LOW DRUG DOSE; MYALGIA; NEUTROPENIA; NONHUMAN; OUTCOME ASSESSMENT; RETREATMENT; REVIEW; THROMBOCYTOPENIA; TREATMENT DURATION; VIRUS GENE; VIRUS LOAD; BLOOD; DRUG COMBINATION; DRUG EFFECT; GENETICS; PHASE 3 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; TREATMENT OUTCOME; VIROLOGY;

ANTIVIRAL AGENTS; CLINICAL TRIALS, PHASE III AS TOPIC; DRUG THERAPY, COMBINATION; HEPACIVIRUS; HEPATITIS C; HEPATITIS C, CHRONIC; HUMANS; INTERFERON ALFA-2A; POLYETHYLENE GLYCOLS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RIBAVIRIN; RNA, VIRAL; TREATMENT OUTCOME;

EID: 70350614356     PISSN: 14787210     EISSN: 17448336     Source Type: Journal    
DOI: 10.1586/ERI.09.70     Document Type: Review

References (65)

1. Hoofnagle JH, Mullen KD, Jones DB et al. Treatment of chronic non-A, non-B hepatitis with recombinant human a interferon. A preliminary report. N. Engl. J. Med. 315(25), 1575-1578 (1986).
2. 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 352, 1426-1432 (1998).
3. McHutchison JG, Gordon SC, Schiff ER et al. Interferon α-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N. Engl. J. Med. 339, 1485-1492 (1998).
4. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436(7053), 967-972 (2005).
5. Bodenheimer HC Jr, 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 26(2), 473-477 (1997).
6. Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin. Pharmacokinet. 40(7), 539-551 (2001). (Pubitemid 32738660)
7. Glue P, Fang JW, Rouzier-Panis R et al. Pegylated interferon-α-2b: pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data. Clin. Pharmacol. Ther. 68, 556-567 (2000). (Pubitemid 30953875)
8. Bailon P, Palleroni A, Schaffer CA et al. Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon α-2a for the treatment of hepatitis C. Bioconjug. Chem. 12, 195-202 (2001). (Pubitemid 32235471)
9. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958-965 (2001).
10. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347, 975-982 (2002). • Phase III registration trial that demonstrates the superior efficacy of pegylated (Peg)IFN-α2a combined with ribavirin (RBV) over standard interferon plus RBV. The study also has the merit of introducing the currently accepted 12-week HCV RNA stopping rule.
11. Caliceti P. Pharmacokinetics of pegylated interferons: what is misleading? Dig. Liver Dis. 36(Suppl. 3), S334-S339.
12. Bruno R, Sacchi P, Ciappina V et al. Viral dynamics and pharmacokinetics of peginterferon α-2a and peginterferon α-2b in naive patients with chronic hepatitis C: a randomized, controlled study. Antivir. Ther. 9, 491-497 (2004). (Pubitemid 39150205)
13. Silva M, Poo J, Wagner F et al. A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon α-2b and peginterferon α-2a in patients with chronic hepatitis C (COMPARE). J. Hepatol. 45, 204-213 (2006).
14. Di Bisceglie AM, Ghalib RH, Hamzeh F, Rustgi VK. Early virologic response after peginterferon α-2a plus ribavirin or peginterferon α-2b plus ribavirin treatment in patients with chronic hepatitis C. J. Viral. Hep. 14, 721-729 (2007). (Pubitemid 47414932)
15. Neumann AU, Lam NP, Dahari H et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-a therapy. Science 282(5386), 103-107 (1998). (Pubitemid 28471138)
16. Frese M, Pietschmann T, Moradpour D, Haller O, Bartenschlager R. Interferon-α inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway. J. Gen. Virol. 82, 723-733 (2001). (Pubitemid 32280029)
17. Peters M. Actions of cytokines on the immune response and viral interactions: an overview. Hepatology 23, 909-916 (1996). (Pubitemid 26112009)
18. Pawlotsky JM. Therapy of hepatitis C: from empiricism to eradication. Hepatology 43(Suppl. 1), S207-S220 (2006).
19. Baron S, Tyring SK, Fleischmann WR Jr et al. The interferons. Mechanisms of action and clinical applications. JAMA 266(10), 1375-1383 (1991).
20. Carithers RL Jr, Emerson SS. Therapy of hepatitis C: meta-analysis of interferon α-2b trials. Hepatology 26, 83S-88S (1997).
21. Rumi M, Del Ninno E, Parravicini ML et al. A prospective, randomized trial comparing lymphoblastoid to recombinant interferon α 2a as therapy for chronic hepatitis C. Hepatology 24(6), 1366-1370 (1996).
22. Reddy KR. Development and pharmacokinetics and pharmacodynamics of pegylated interferon α-2a (40 kD). Semin. Liver Dis. 24(Suppl. 2), 33-38 (2004).
23. Matthews SJ, McCoy C. Peginterferon α-2a: a review of approved and investigational uses. Clin. Ther. 26(7), 991-1025 (2004). (Pubitemid 39141804)
24. Santantonio T, Wiegand J, Gerlach JT. Acute hepatitis C: current status and remaining challenges. J. Hepatol. 49(4), 625-633 (2008).
25. Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology 130, 225-230 (2006).
26. Gerlach JT, Diepolder HM, Zachoval R et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 125(1), 80-88 (2003). (Pubitemid 36799109)
27. Seeff LB. Natural history of chronic hepatitis C. Hepatology 36, S35-S46 (2002).
28. Jaeckel E, Cornberg M, Wedemeyer H et al. Treatment of acute hepatitis C with interferon α-2b. N. Engl. J. Med. 345(20), 1452-1457 (2001).
29. Deterding K, Gruner N, Wiegand J et al. Early versus delayed treatment of acute hepatitis C: the German Hep-Net Acute HCV-III study - a randomized controlled trial. J. Hepatol. 50(S1), A1047 (2009).
30. Reddy KR, Wright TL, Pockros PJ et al. Efficacy and safety of pegylated (40-kD) interferon α-2a compared with interferon α-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 33(2), 433-438 (2001).
31. Heathcote EJ, Shiffman ML, Cooksley WG et al. Peginterferon α-2a in patients with chronic hepatitis C and cirrhosis. N. Engl. J. Med. 343(23), 1673-1680 (2000).
32. Zeuzem S, Feinman SV, Rasenack J et al. Peginterferon α-2a in patients with chronic hepatitis C. N. Engl. J. Med. 343(23), 1666-1672 (2000).
33. Pockros PJ, Carithers R, Desmond P et al. Efficacy and safety of two-dose regimens of peginterferon α-2a compared with interferon α-2a in chronic hepatitis C: a multicenter, randomized controlled trial. Am. J. Gastroenterol. 99(7), 1298-1305 (2004). (Pubitemid 39062267)
34. Rumi MG, Aghemo A, Prati GM et al. Randomized study comparing peginterferon-α2a plus ribavirin and peginterferon-α2b plus ribavirin in naive patients with chronic hepatitis C: final results of the Milan safety tolerability (MIST) study. Hepatology 48(Suppl.), 404A (2008).
35. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49(4), 1335-1374 (2009).
36. Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C. J. Hepatol. 49, 634-651 (2008).
37. 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 131(2), 470-477 (2006).
38. Chen L, Borozan I, Feld J et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128, 1437-1444 (2005). (Pubitemid 40712193)
39. Sarasin-Filipowicz M, Oakeley EJ, Duong FH et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl Acad. Sci. USA 105, 7034-7039 (2008).
40. 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 57, 516-524 (2008).
41. Hadziyannis SJ, Sette H Jr, 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. 140, 346-355 (2004).
42. Ferenci P, Fried MW, Shiffman ML et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon α-2a (40 kD)/ribavirin. J. Hepatol. 43(3), 425-433 (2005).
43. Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon α-2a (40 kD)/ribavirin therapy. Hepatology 43, 954-960 (2006).
44. Zeuzem S, Pawlotsky JM, Lukasiewicz E et al. International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C. J. Hepatol. 43(2), 250-257 (2005). (Pubitemid 40956877)
45. von Wagner M, Huber M, Berg T et al. Peginterferon-α-2a (40kD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 129, 522-527 (2005). (Pubitemid 41096640)
46. Shiffman ML, Suter F, Bacon BR et al. Peginterferon α-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N. Engl. J. Med. 357, 124-134 (2007). (Pubitemid 47057730)
47. 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-α- 2a plus ribavirin. Gastroenterology 130, 1086-1097 (2006).
48. Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology 46, 1688-1694 (2007).
49. Buti M, Lurie Y, Zakharova NG et al. Extended treatment duration in chronic hepatitis C genotype 1-infected slow responders: final results of the SUCCESS study. J. Hepatol. 50 (S2), S58 (2009).
50. McHutchison JG, Bartenschlager R, Patel K, Pawlotsky JM. 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. 44(2), 411-421 (2006). (Pubitemid 43069225)
51. 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 123, 1061-1069 (2002).
52. Shiffman ML, Di Bisceglie AM, Lindsay KL et al. Peginterferon α-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 126(4), 1015-1023 (2004).
53. Jensen DM, Marcellin P, Freilich B et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-α2b: a randomized trial. Ann. Intern. Med. 150(8), 528-540 (2009).
54. Shiffman 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 117(5), 1164-1172 (1999).
55. Afdhal N, Freilich B, Levine R et al. Colchicine versus peg-intron long term (COPILOT) trial: interim analysis of clinical outcomes at year 2. Hepatology 40(4 Suppl. 1), 239A (2004).
56. Bruix J, Poynard T, Colombo M et al. Pegintron maintenance therapy in cirrhotic (metavir f4) HCV patients, who failed to respond to interferon/ribavirn (IR) therapy: final results of the EPIC3 cirrhosis maintenance trial. J. Hepatol. 50(S1), 22 (2009).
57. Di Bisceglie AM, Shiffman ML, Everson GT et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N. Engl. J. Med. 359(23), 2429-2441 (2008). • Demonstrated that low-dose PegIFN-α2a maintenance therapy does not modify the natural history of chronic hepatitis C or cirrhosis. While the COPILOT and the EPIC3 studies have shown a small benefit in terms of rates of esophageal varices enlargement and bleeding in patients receiving low-dose maintenance therapy, currently this therapeutic strategy cannot be recommended in clinical practice.
58. McHutchison JG, Lawitz ML, Shiffman ML et al. PegInterferon α-2b or α-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361, 580-593 (2009).
59. Ascione A, De Luca M, Tartaglione MT et al. Peginterferon α-2a plus ribavirin versus peginterferon α-2b plus ribavirin in naive patients with chronic hepatitis C virus infection: results of a prospective randomised trial. J. Hepatol. 48(Suppl. 2), S370 (2008).
60. McHutchison JG, Everson GT, Gordon SC et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N. Engl. J. Med. 360(18), 1827-1838 (2009). • Phase II studies on triple therapy with PegIFN plus RBV plus telaprevir show an increase in sustained virological response (SVR) rates of approximately 20% in HCV-1-naive patients over the PegIFN plus RBV standard of care treatment. Unfortunately, data regarding tolerability and safety of the protease inhibitor telaprevir are less encouraging as approximately 20% of the patients discontinued treatment for side effects. The Hézode et al. study also demonstrates that RBV is essential to achieve high SVR rates when telaprevir is given, reinforcing its role as a backbone of future therapies.
61. Hézode C, Forestier N, Dusheiko G et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N. Engl. J. Med. 360(18), 1839-1850 (2009). • Phase II studies on triple therapy with PegIFN plus RBV plus telaprevir show an increase in SVR rates of approximately 20% in HCV-1-naive patients over the PegIFN plus RBV standard of care treatment. Unfortunately, data regarding tolerability and safety of the protease inhibitor telaprevir are less encouraging as approximately 20% of the patients discontinued treatment for side effects.
62. Kwo P, Lawitz E, McCone J et al. HCV-SPRINT 1 final results: SVR 24 from a Phase II study of boceprevir plus PegIntron (PegIFN-α2b)/ribavirin in treatment-naive subjects with genotype 1 chronic hepatitis C. J. Hepatol. 50(S1), A4 (2009).
63. 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 131(4), 997-1002 (2006). (Pubitemid 44498690)
64. Sarrazin C, Kieffer TL, Bartels D et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132(5), 1767-1777 (2007). (Pubitemid 46677938)
65. Pegasys. Procedural steps taken and scientific information after the authorisation. Changes made after 01/04/2005 www.emea.europa.eu/humandocs/PDFs/ EPAR/pegasys/H-395-en8b.pdf