Past, Present, and Future Hepatitis C Treatments

Conventional interferon (IFN) alfa has been used for many years in the treatment of chronic hepatitis C. However, few patients achieve sustained virological responses with IFN. Combining IFN with ribavirin improves efficacy considerably, but at the expense of diminished tolerability attributable to ribavirin. Pegylated interferons have improved pharmacokinetic profiles, may be administered once weekly, and are more effective than IFN is alone or in combination with ribavirin. In addition to enhanced efficacy, pegylated interferon alfa-2a (40 kD) also improves health-related quality of life during therapy compared with IFN-based therapy. New adjuvant agents have the potential to further improve sustained response rates and tolerability; however, pegylated interferons will likely remain the backbone of therapy in the foreseeable future.

Therapies under development and evaluation for patients with HCV infection include adjunctive use of the antiviral agent amantadine and the immunomodulatory agent thymalfasin. Novel small molecules include the ribavirin analogues, viramidine and levovirin, and BILN 2061, an inhibitor of HCV serine protease. Other therapeutic strategies that have reached the clinic include antisense oligonucleotides (ISIS 14803), nuclease-resistant ribozymes targeting HCV RNA (Heptazyme), human monoclonal antibodie, and human antibody fragments directed at HCV helicase.

Hepatitis C - therapy - pegylated interferon

REFERENCES

• 1 NIH Consensus Development Conference Panel Statement . Management of hepatitis C.  Hepatology. 1997;  26(suppl 1) 2S-10S
• 2 Centers for Disease Control . Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related disease.  MMWR Morb Mortal Wkly. 1998;  47(RR-19) 1-40
• 3 Davis G L et al.. Projecting the future healthcare burden from hepatitis C in the United States.  Hepatology. 1998;  28 390A
• 4 Foster G R, Goldin R D, Thomas H C. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis.  Hepatology. 1998;  27 209-212
• 5 Wong J B, McQuillan G M, McHutchison J G, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States.  Am J Public Health. 2000;  90 1562-1569
• 6 Tong M J, Blatt L M, McHutchison J G, Co R L, Conrad A. Prediction of response during interferon alfa 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: a comparison.  Hepatology. 1997;  26 1640-1645
• 7 Brouwer J T, Hansen B E, Niesters H G, Schalm S W. Early prediction of response in interferon monotherapy and in interferon-ribavirin combination therapy for chronic hepatitis C: HCV RNA at 4 weeks versus ALT.  J Hepatol. 1999;  30 192-198
• 8 Carithers Jr R L, Emerson S S. Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials.  Hepatology. 1997;  26(Suppl 1) 83S-88S
• 9 Keefe E B, Hollinger F B. Therapy of hepatitis C: consensus interferon trials. Consensus Interferon Study Group.  Hepatology. 1997;  26(Suppl 1) 101S-107S
• 10 McHutchison J G, Gordon S C, Schiff E R 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
• 11 Poynard T, Marcellin P, Lee S S 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.  Lancet. 1998;  352 1426-1432
• 12 Van Thiel D H, Caraceni P, Molloy P J et al.. Chronic hepatitis C in patients with normal or near normal alanine aminotransferase levels: the role of interferon alpha 2b therapy.  J Hepatol. 1995;  23 503-508
• 13 Serfaty L, Chazouilleres O, Pawlotsky J M, Andreani T, Pellet C, Poupon R. Interferon alfa therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity.  Gastroenterology. 1996;  110 291-295
• 14 Silverman A L, Piquette D L, Filipiak C L, Neill J S, Bayati N, Gordon S C. Alfa interferon treatment of hepatitis C virus RNA-positive patients with normal or near-normal alanine aminotransferase levels.  Am J Gastroenterol. 1997;  92 1793-1795
• 15 Sangiovanni A, Morales R, Spinzi G et al.. Interferon alfa treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study.  Hepatology. 1998;  27 853-856
• 16 Van Thiel D H, Colantoni A, De Maria N. Treatment of HCV positive individuals with normal serum ALT levels.  Hepatogastroenterology. 1998;  45 321-324
• 17 Gordon S C, Fang J W, Silverman A L, McHutchison J G, Albrecht J K. The significance of baseline serum alanine aminotransferase on pretreatment disease characteristics and response to antiviral therapy in chronic hepatitis C.  Hepatology. 2000;  32 400-404
• 18 Lee S S, Sherman M. Pilot study of interferon-alpha and ribavirin treatment in patients with chronic hepatitis C and normal transaminase values.  J Viral Hepat. 2001;  8 202-205
• 19 Schalm S W, Fattovich G, Brouwer J T. Therapy of hepatitis C: patients with cirrhosis.  Hepatology. 1997;  26(suppl 1) 128S-132S
• 20 Heathcote E J, Shiffman M L, Cooksley W G et al.. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.  N Engl J Med. 2000;  343 1723-1724
• 21 Kim W R, Poterucha J J, Hermans J E et al.. Cost-effectiveness of 6 and 12 months of interferon-alpha therapy for chronic hepatitis C.  Ann Intern Med. 1997;  127 866-874
• 22 Bonkovsky H L, Woolley J M. Outcomes research in chronic viral hepatitis C: effects of interferon therapy.  Can J Gastroenterol. 2000;  14(suppl B) 21B-29B
• 23 Davis G L, Balart L A, Schiff E R et al.. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile.  Clin Ther. 1994;  16 334-343
• 24 Bonkovsky H L, Woolley J M. Consensus Interferon Study Group . Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy.  Hepatology. 1999;  29 264-270
• 25 Ware Jr J E, Bayliss M S, Mannocchia M, Davis G L. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response.  Hepatology. 1999;  30 550-555
• 26 McHutchison J G, Ware Jr J E, Bayliss M S et al.. The effects of interferon alpha-2b in combination with ribarivin on health related quality of life and work productivity.  J Hepatology. 2001;  34 140-147
• 27 Nishiguchi S, Kuroki T, Nakatani S et al.. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis.  Lancet. 1995;  346 1051-1055
• 28 Benvegnu L, Chemello L, Noventa F, Fattovich G, Pontisso P, Alberti A. Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis.  Cancer. 1998;  83 901-909
• 29 International Interferon-Alfa Hepatocellular Carcinoma Study Group . Effect of interferon-alfa on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study.  Lancet. 1998;  351 1535-1539
• 30 Serfaty L, Aumaitre H, Chazouilleres O et al.. Determinants of outcome of compensated hepatitis C virus-related cirrhosis.  Hepatology. 1998;  27 1435-1440
• 31 Malaguarnera M, Di Fazio I, Restuccia S et al.. Interferon alpha-induced depression in chronic hepatitis C patients: comparison between different types of interferon alpha.  Neuropsychobiology. 1998;  37 93-97
• 32 Treadwell J R, Kearney D, Davila M. Health profile preferences of hepatitis C patients.  Dig Dis Sci. 2000;  45 345-350
• 33 Buti M et al.. The combination of interferon plus ribavirin is the therapy of choice for naive patients with chronic hepatitis C, based on economic grounds.  Hepatology. 1999;  30(suppl) 366
• 34 Sostegni R, Ghisetti V, Pittaluga F et al.. Sequential versus concomitant administration of ribavirin and interferon alfa-n3 in patients with chronic hepatitis C not responding to interferon alone: results of a randomized, controlled trial.  Hepatology. 1998;  28 341-346
• 35 Davis G, Esteban-Mur R, Rustgi V et al.. Interferon Alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C.  N Engl J Med. 1998;  339 1493-1499
• 36 Dusheiko G. Side effects of alpha interferon in chronic hepatitis C.  Hepatology. 1997;  26(suppl 1) 112-121
• 37 Bodenheimer Jr H C, Lindsay K L, Davis G L, Lewis J H, Thung S N, Seeff L B. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial.  Hepatology. 1997;  26 473-477
• 38 Reddy K R. Development and pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a (40 kD).  Semin Liver Dis. 2004;  24(suppl 2) 33-38
• 39 Lindsay K L, Trepo C, Heintges T et al.. A randomised, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.  Hepatology. 2001;  34 395-403
• 40 Manns M P, McHutchison J G, Gordon S C 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
• 41 Zeuzem S, Feinman S V, Rasenack J et al.. Peginterferon alfa-2a in patients with chronic hepatitis C.  N Engl J Med. 2000;  343 1666-1672
• 42 Fried M W, Shiffman M L, Reddy K R et al.. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;  347 975-982
• 43 Hadziyannis S J, Sette Jr H, Morgan T R et al.. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C. A randomized study of duration and ribavirin dose.  Ann Intern Med. 2004;  140 346-355
• 44 McHutchinson J, 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 1061-1069
• 45 Ferenci P et al.. Early prediction of response to 40 KDA peginterferon alfa-2A (Pegasys) plus ribavirin (RBV) in patients with chronic hepatitis C (CHC).  Hepatology. 2001;  34 351A
• 46 Davis G L. Monitoring of viral levels during therapy of hepatitis C.  Hepatology. 2002;  36(suppl 1) 145-151
• 47 Andant C, Lamoril J, Deybach J C, Jouet P, Soule J C. Amantadine for chronic hepatitis C: pilot study in 14 patients.  Eur J Gastroenterol Hepatol. 2000;  12 1319-1322
• 48 Goff J S, Reveille R M, Johnson J. Treatment of chronic hepatitis C with amantadine.  Dig Dis Sci. 2000;  45 1389-1391
• 49 Zeuzem S, Teuber G, Naumann U et al.. Randomized, double-blind, placebo-controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C.  Hepatology. 2000;  32 835-841
• 50 Mangia A, Minerva N, Annese M et al.. A randomized trial of amantadine and interferon versus interferon alone as initial treatment for chronic hepatitis C.  Hepatology. 2001;  33 989-993
• 51 Tabone M, Laudi C, Delmastro B et al.. Interferon and amantadine in combination as initial treatment for chronic hepatitis C patients.  J Hepatol. 2001;  35 517-521
• 52 Berg T, Naumann U, Wiedenmann B, Hopf U. Pilot study of interferon-alpha high-dose induction therapy in combination with ribavirin plus amantadine for nonresponder patients with chronic hepatitis C.  Z Gastroenterol. 2001;  39 145-151
• 53 Brillanti S, Levantesi F, Masi L, Foli M, Bolondi L. Triple antiviral therapy as a new option for patients with interferon nonresponsive chronic hepatitis C.  Hepatology. 2000;  32 630-634
• 54 Zilly M, Lingenauber C, Desch S, Vath T, Klinker H, Langmann P. Triple antiviral re-therapy for chronic hepatitis C with interferon- alpha, ribavirin and amantadine in nonresponders to interferon-alpha and ribavirin.  Eur J Med Res. 2002;  7 149-154
• 55 Brillanti S. Role of amantadine and other adjuvant therapies in the treatment of hepatitis C.  Semin Liver Dis. 2004;  24(suppl 2) 89-96
• 56 Iftikar R et al.. HCV RNA and immunological responses to thymalfasin in combination with peginterferon alfa-2a in HCV non-responders: a 12-week kinetic study.  Hepatology. 2002;  364 260A
• 57 Yeh L-T et al.. Determination of viramidine/ribavirin in human RBC following single oral dosing of viramidine in a phase I study.  Hepatology. 2002;  36 345A
• 58 Arora S et al.. Phase I clinical studies of viramidine-a liver targeting prodrug of ribavirin.  Hepatology. 2002;  36 356A
• 59 McHutchison J G, Patel P. Future therapy of hepatitis C.  Hepatology. 2002;  36(suppl 1) 245-252
• 60 Narjes H et al.. Tolerability and pharmacokinetics of BILN 2061, a novel HCV serine protease inhibitor, after oral single doses of 5 to 2400 mg in healthy male subjects.  Hepatology. 2002;  36 363A
• 61 McHutchinson J G et al.. A phase 1B dose escalation trial of ISIS 14803, an antisense inhibitor of HCV, in patients with chronic HCV: final report.  Hepatology. 2002;  36 303AQ23
• 62 Soler M et al.. Treatment of chronic hepatitis C with ISIS 14803, an antisense oligonucleotide inhibitor of HCV. Effect of target region sequence on antiviral activity.  Hepatology. 2002;  36 280A
• 63 Gordon S C et al.. A phase II, 12-week study of ISIS 14803, an antisense inhibitor of HCV for the treatment of chronic hepatitis C.  Hepatology. 2002;  36 362A
• 64 Tong M et al.. Preliminary analysis of a phase II study of hepatazyme, a nuclease resistant ribozyme targeting hepatitis C virus (HCV).  RNA Hepatology. 2002;  36 360A
• 65 Eren R et al.. Development and clinical evaluation of human monoclonal antibodies for treating HCV infection.  Hepatology. 2002;  36 287A
• 66 Feagan B G et al.. The impact of pegylated interferon alfa 2B on health-related quality of life in chronic hepatitis C patients.  Hepatology. 2000;  32 307A
• 67 Bernstein D, Kleinman L, Barker C M, Revicki D A, Green J. Relationship of health-related quality of life to treatment adherence and sustained response in chronic hepatitis C patients.  Hepatology. 2002;  35 704-708