Current State of Interferon Therapy in the Treatment of Chronic Hepatitis B

ABSTRACT

Interferon alpha (IFN) has been used in the treatment of chronic hepatitis B for approximately 25 years. Predictors of response include high pretreatment serum levels of alanine aminotransferase (ALT), low serum hepatitis B virus (HBV) DNA levels, and infection in adulthood. However, only one third of patients achieve a durable response to a course of IFN therapy. Predictors of nonresponse include normal serum ALT levels, high serum HBV DNA levels, hepatitis B e antigen (HBeAg)-negative infection, childhood infection, and immunosuppression. IFN is contraindicated in patients with decompensated liver disease. In addition, the need for parenteral administration and a significant incidence of difficult-to-tolerate side effects limit the suitability of IFN for long-term therapy. For most patients with chronic hepatitis B, including those infected neonatally and those with HBeAg-negative disease, safe, tolerable, and effective alternatives to IFN are needed.

KEYWORDS

Hepatitis - chronic hepatitis B - interferon - immunomodulators - antiviral agents

REFERENCES

• 1 Greenberg H B, Pollard R B, Lutwick L I. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis.  N Engl J Med . 1976;  295 517-522
• 2 Waked I, Amin M, Abd el Fattah S, Osman L M, Sabbour M S. Experience with interferon in chronic hepatitis B in Egypt.  J Chemother . 1990;  2 310-318
• 3 Alexander G JM, Brahm J, Fagan E A. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection.  Lancet . 1987;  2 66-69
• 4 Di Bisceglie M A, Fong T-L, Fried M W. A randomized, controlled trial of recombinant α-interferon therapy for chronic hepatitis B.  Am J Gastroenterol . 1993;  88 1887-1892
• 5 Fevery J, Elewaut A, Michielsen P. Efficacy of interferon alfa-2b with or without prednisone withdrawal in the treatment of chronic viral hepatitis B. A prospective double-blind Belgian-Dutch study.  J Hepatol . 1990;  11(Suppl 1) S108-S112
• 6 Hoofnagle J H, Peters M, Mullen K D. Randomized, controlled trial of recombinant human α-interferon in patients with chronic hepatitis B.  Gastroenterology . 1988;  85 1318-1325
• 7 Lok A SF, Lai C-L, Wu P-C, Leung E KY. Long-term follow-up in a randomised controlled trial of recombinant alpha₂-interferon in Chinese patients with chronic hepatitis B infection.  Lancet . 1988;  2 298-302
• 8 Lok A SF, Wu P-C, Lai C-L. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B.  Gastroenterology . 1992;  102 2091-2097
• 9 Muller R, Baumgarten R, Markus R. Treatment of chronic hepatitis B with interferon alfa-2b.  J Hepatol . 1990;  11(Suppl 1) S137-S140
• 10 Perez V, Tanno H, Villamil F, Fay O. Recombinant interferon alfa-2b following prednisone withdrawal in the treatment of chronic type B hepatitis.  J Hepatol . 1990;  11(Suppl 1) S113-S117
• 11 Perrillo R P, Regenstein F G, Peters M G. Prednisone withdrawal followed by recombinant alpha interferon in the treatment of chronic type B hepatitis: a randomized, controlled trial.  Ann Intern Med . 1988;  109 95-100
• 12 Perrillo R P, Schiff E R, Davis G L. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B.  N Engl J Med . 1990;  323 295-301
• 13 Saracco G, Mazzella G, Rosina F. A controlled trial of human lymphoblastoid interferon in chronic hepatitis B in Italy.  Hepatology . 1989;  10 336-341
• 14 Malik A H, Lee W M. Chronic hepatitis B virus infection: treatment strategies for the next millennium.  Ann Intern Med . 2000;  132 723-731
• 15 Wong D KH, Cheung A M, O'Rourke K. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis.  Ann Intern Med . 1993;  119 312-323
• 16 Williams S J, Craig P I, Cooksley W G. Randomised controlled trial of recombinant human interferon-α A for chronic active hepatitis B.  Aust NZ J Med . 1990;  20 9-19
• 17 Brook M G, McDonald J A, Karayiannis P. Randomised controlled trial of interferon alfa 2A (rbe) (Roferon-A) for the treatment of chronic hepatitis B virus (HBV) infection: factors that influence response.  Gut . 1989;  30 1116-1122
• 18 Brook M G, Chan G, Yap I. Randomised controlled trial of lymphoblastoid interferon alfa in Europid men with chronic hepatitis B virus infection.  BMJ . 1989;  299 652-656
• 19 Realdi G, Fattovich G, Pastore G. Problems in the management of chronic hepatitis B with interferon: experience in a randomized multicentre study.  J Hepatol . 1990;  11(Suppl 1) S129-S132
• 20 Porres J C, Carreno V, Mora I. Different doses of recombinant alpha interferon in the treatment of chronic hepatitis B patients without antibodies against the human immunodeficiency virus.  Hepatogastroenterology . 1988;  35 300-303
• 21 Pastore G, Santantonio T, Monno L. Permanent inhibition of viral replication induced by low dosage of human leukocyte interferon in patients with chronic hepatitis B.  Hepatogastroenterology . 1988;  35 57-61
• 22 Carreno V, Porres J C, Mora I. A controlled study of treatment with recombinant interferon alpha in chronic hepatitis B virus infection: induction and maintenance schedules.  Antiviral Res . 1987;  8 125-137
• 23 Schiff E R. Treatment algorithms for hepatitis B and C.  Gut . 1993;  34(Suppl 2) S148-S149
• 24 Shaw T, Locarnini S. Combination chemotherapy for hepatitis B virus: the path forward?.  Drugs . 2000;  60 517-531
• 25 Gervais A, Boyer N, Marcellin P. Tolerability of treatments for viral hepatitis.  Drug Safety . 2001;  24 375-384
• 26 Schalm S W, Heathcote J, Cianciara J. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.  Gut . 2000;  46 562-568
• 27 Niederau C, Heintges T, Lange S. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.  N Engl J Med . 1996;  334 1422-1427
• 28 Lok A SF, McMahon B J. Chronic hepatitis B.  Hepatology . 2001;  34 1225-1241
• 29 Lin S M, Sheen I S, Chien R N, Chu C M, Liaw Y F. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.  Hepatology . 1999;  29 971-975
• 30 Lau D T, Everhart J, Kleiner D E. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa.  Gastroenterology . 1997;  113 1660-1667
• 31 Lok A S, Chung H T, Liu V WS, Ma O CK. Long-term follow-up of chronic hepatitis B patients treated with interferon alpha.  Gastroenterology . 1993;  105 1833-1838
• 32 Korenman J, Baker B, Waggoner J. Long-term remission of chronic hepatitis B after alpha-interferon therapy.  Ann Intern Med . 1991;  114 629-634
• 33 Krogsgaard K. The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B. The Long-Term Follow-up Investigator Group. The European Study Group on Viral Hepatitis (EURHEP) Executive Team on Anti-Viral Treatment.  J Viral Hepatol . 1998;  5 389-397
• 34 Manesis E K, Hadziyannis S J. Interferon α treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.  Gastroenterology . 2001;  121 101-109
• 35 Brunetto M R, Oliveri F, Colombatto P. Treatment of chronic anti-HBe-positive hepatitis B with interferon-alpha.  J Hepatol . 1995;  22(Suppl 1) 42-44
• 36 Hadziyannis S, Bramou T, Makris A. Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B.  J Hepatol . 1990;  11(Suppl 1) S133-S136
• 37 Pastore G, Santantonio T, Milella M. Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon.  J Hepatol . 1992;  14 221-225
• 38 Brunetto M R, Oliveri F, Coco B. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.  J Hepatol . 2002;  36 263-370
• 39 Lampertico P, Del Ninno E, Manzin A. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.  Hepatology . 1997;  26 1621-1625
• 40 Lok A S, Heathcote E J, Hoofnagle J H. Management of hepatitis B: 2000-summary of a workshop.  Gastroenterology . 2001;  120 1828-1853
• 41 Papatheodoridis G V, Manesis E, Hadziyannis S J. The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B.  J Hepatol . 2001;  34 306-313
• 42 Yuen M-F, Hui C-K, Cheng C-C. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.  Hepatology . 2001;  34 139-145
• 43 Camma C, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach.  J Hepatol . 2001;  34 593-602
• 44 International Interferon-α/Hepatocellular Carcinoma Study Group. Effect of interferon-α on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study.  Lancet . 1998;  351 1535-1539
• 45 Hoofnagle J H, Di Bisceglie M A. The treatment of chronic viral hepatitis.  N Engl J Med . 1997;  336 347-356
• 46 Brook M G, Karayiannis P, Thomas H C. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy?.  <~>A statistical analysis of predictive factors. Hepatology . 1989;  10 761-763
• 47 Manns M P, Rambusch E G. Autoimmunity and extrahepatic manifestations in hepatitis C.  J Hepatol . 1999;  31(Suppl 1) 39-42
• 48 Manns M P. Syllabus. AASLD Single Topic Conference; April, 2002; Chicago, Illinois

1 *These studies used various assays for HBV DNA, and in some instances the LLQ was not specified. At the time the studies were conducted, however, more precise quantitative assays were not commonly used