Interferon-α for Patients with Chronic Hepatitis Delta: A Systematic Review of Randomized Clinical Trials

Abstract

Background

Hepatitis delta virus (HDV) infection therapy is unclear. This systematic analysis aimed to clarify the evidence on the efficacy of interferon (IFN)-α-based therapy in HDV.

Methods

We performed a systematic search on electronic databases including MEDLINE (1970 to January 2011), Web of Science, The Cochrane Library and ClinicalTrials.gov. Randomized clinical trials (RCTs) comparing IFN-α-based therapy with either another drug, placebo or no intervention were included. We excluded paediatric studies. We calculated relative risks (RRs) for comparison of treatment options on the primary outcome measure, which was defined as undetectable levels of HDV RNA and normal alanine aminotransferase at end of treatment (EOT; 1 year).

Results

Nine RCTs were included. Seven trials evaluated the treatment with IFN-α (n=132). The remaining two trials evaluated treatment with pegylated (PEG)-IFN-α (n=45). We found that 1-year treatment with high-dose IFN-α achieved better primary outcome rates than with PEG-IFN-α (RR=4.14, 95% CI 1.00, 17.14). Data for 1-year treatment with low-dose IFN-α compared with PEG-IFN-α were similar (RR=2.83, 95% CI 0.65, 12.40), as were low-dose IFN-α versus high-dose IFN-α (RR=0.68, 95% CI 0.31, 1.50). High-dose IFN-α and PEG-IFN-α reached similar HDV RNA suppression 24 weeks after EOT (RR=1.00, 95% CI 0.51, 1.97). None of the 55 patients assigned to no intervention obtained undetectable levels of HDV RNA and only one patient achieved normalization of alanine aminotransferase level.

Conclusions

Based on available RCTs, 1-year high-dose IFN-α monotherapy appears to be more effective than PEG-IFN-α for treatment of HDV patients, with efficacy rates of approximately 30%. There is a lack of head-to-head comparisons. Combination therapies and longer treatment duration need to be investigated.

References

Rizzetto

, Canese

M.G.

, Arico

Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 1977; 18: 997–1003.

Bonino

, Negro

, Baldi

The natural history of chronic delta hepatitis. Prog Clin Biol Res 1987; 234: 145–152.

Le Gal

, Gault

, Ripault

M.P.

Eighth major clade for hepatitis delta virus. Emerg Infect Dis 2006; 12: 1447–1450.

J.C.

, Chen

C.M.

, Sheen

I.J.

, Lee

S.D.

, Tzeng

H.M.

, Choo

K.B.

Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome. Hepatology 1995; 22: 1656–1660.

Ivaniushina

, Radjef

, Alexeeva

Hepatitis delta virus genotypes I and II cocirculate in an endemic area of Yakutia, Russia. J Gen Virol 2001; 82: 2709–2718.

Sakugawa

, Nakasone

, Nakayoshi

Hepatitis delta virus genotype IIb predominates in an endemic area, Okinawa, Japan. J Med Virol 1999; 58: 366–372.

Watanabe

, Nagayama

, Enomoto

Chronic hepatitis delta virus infection with genotype IIb variant is correlated with progressive liver disease. J Gen Virol 2003; 84: 3275–3289.

J.C.

, Chiang

T.Y.

, Sheen

I.J.

Characterization and phylogenetic analysis of a novel hepatitis D virus strain discovered by restriction fragment length polymorphism analysis. J Gen Virol 1998; 79: 1105–1113.

Casey

J.L.

, Brown

T.L.

, Colan

E.J.

, Wignall

F.S.

, Gerin

J.L.

A genotype of hepatitis D virus that occurs in northern South America. Proc Natl Acad Sci U S A 1993; 90: 9016–9020.

10.

Hughes

S.A.

, Wedemeyer

, Harrison

P.M.

Hepatitis delta virus. Lancet 2011; 378: 73–85.

11.

Rizzetto

Hepatitis D: virology, clinical and epidemiological aspects. Acta Gastroenterol Belg 2000; 63: 221–224.

12.

Farci

Delta hepatitis: an update. J Hepatol 2003; 39 Suppl 1: S212–S219.

13.

Hsieh

T.H.

, Liu

C.J.

, Chen

D.S.

, Chen

P.J.

Natural course and treatment of hepatitis D virus infection. J Formos Med Assoc 2006; 105: 869–881.

14.

Romeo

, Del

N.E.

, Rumi

A 28-year study of the course of hepatitis delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009; 136: 1629–1638.

15.

Smedile

, Dentico

, Zanetti

Infection with the delta agent in chronic HBsAg carriers. Gastroenterology 1981; 81: 992–997.

16.

Smedile

, Farci

, Verme

Influence of delta infection on severity of hepatitis B. Lancet 1982; 320: 945–947.

17.

Grabowski

, Wedemeyer

Hepatitis delta: immunopathogenesis and clinical challenges. Dig Dis 2010; 28: 133–138.

18.

Niro

G.A.

, Smedile

, Ippolito

A.M.

Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol 2010; 53: 834–840.

19.

Buti

, Homs

, Rodriguez-Frias

Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study. J Viral Hepat 2011; 18: 434–442.

20.

Schaper

, Rodriguez-Frias

, Jardi

Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol 2010; 52: 658–664.

21.

Fattovich

, Giustina

, Christensen

Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut 2000; 46: 420–426.

22.

Marinucci

, Hassan

, Di Giacomo

Long term treatment of chronic delta hepatitis with alpha recombinant interferon. Prog Clin Biol Res 1991; 364: 405–410.

23.

Rosina

, Pintus

, Meschievitz

, Rizzetto

A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study. Hepatology 1991; 13: 1052–1056.

24.

Rosina

, Saracco

, Lattore

, Quarterone

, Rizzetto

, Verme

Alpha 2 recombinant interferon in the treatment of chronic hepatitis delta virus (HDV) hepatitis. Prog Clin Biol Res 1987; 234: 299–303.

25.

Porres

J.C.

, Carreno

, Bartolome

, Moreno

, Galiana

, Quiroga

J.A.

Treatment of chronic delta infection with recombinant human interferon alpha 2c at high doses. J Hepatol 1989; 9: 338–344.

26.

Di Bisceglie

A.M.

, Martin

, Lisker-Melman

Treatment of chronic delta hepatitis with interferon alfa-2b: pilot study conducted at NIH. J Hepatol 1990; 11 Suppl 1: S151–S154.

27.

Hoofnagle

, Mullen

, Peters

Treatment of chronic delta hepatitis with recombinant human alpha interferon. Prog Clin Biol Res 1987; 234: 291–298.

28.

Farci

, Mandas

, Coiana

Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med 1994; 330: 88–94.

29.

Madejón

, Cotonat

, Bartolome

, Castillo

, Carreno

Treatment of chronic hepatitis D virus infection with low and high doses of interferon-alpha 2a: utility of polymerase chain reaction in monitoring antiviral response. Hepatology 1994; 19: 1331–1336.

30.

Di Marco

, Giacchino

, Timitilli

Long-term interferon-alpha treatment of children with chronic hepatitis delta: a multicentre study. J Viral Hepat 1996; 3: 123–128.

31.

Gaudin

J.L.

, Faure

, Godinot

, Gerard

, Trepo

The French experience of treatment of chronic type D hepatitis with a 12-month course of interferon alpha-2B. Results of a randomized controlled trial. Liver 1995; 15: 45–52.

32.

Reddy

K.R.

, Wright

T.L.

, Pockros

P.J.

Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 2001; 33: 433–438.

33.

Fried

M.W.

, Shiffman

M.L.

, Reddy

K.R.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–982.

34.

Manns

M.P.

, Wedemeyer

, Cornberg

Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006; 55: 1350–1359.

35.

Lutz

H.H.

, Trautwein

Reviving pegylated interferon as a therapeutic agent for hepatitis D: no more room for nucleos(t)ides?

Hepatology 2011; 53: 2131–2134.

36.

Wedemeyer

, Yurdaydin

, Dalekos

G.N.

Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364: 322–331.

37.

Niro

G.A.

, Ciancio

, Tillman

H.L.

Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther 2005; 22: 227–232.

38.

Yurdaydin

, Bozkaya

, Onder

F.O.

Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat 2008; 15: 314–321.

39.

Yurdaydin

, Bozkaya

, Gurel

Famciclovir treatment of chronic delta hepatitis. J Hepatol 2002; 37: 266–271.

40.

Zavaglia

, Bottelli

, Smedile

A pilot study of thymosin-alpha 1 therapy for chronic hepatitis D. J Clin Gastroenterol 1996; 23: 162–163.

41.

Garripoli

, Di Marco

, Cozzolongo

Ribavirin treatment for chronic hepatitis D: a pilot study. Liver 1994; 14: 154–157.

42.

Arrigoni

, Ponzetto

, Actis

, Bonino

Levamisole and chronic delta hepatitis. Ann Intern Med 1983; 98: 1024.

43.

Higgins

J.P.H.

, Green

(Editors). Cochrane handbook for systematic reviews of interventions. Chichester, UK: John Wiley & Sons Ltd 2008.

44.

Canbakan

, Senturk

, Tabak

Efficacy of interferon alpha-2b and lamivudine combination treatment in comparison to interferon alpha-2b alone in chronic delta hepatitis: a randomized trial. J Gastroenterol Hepatol 2006; 21: 657–663.

45.

Gunsar

, Akarca

U.S.

, Ersoz

Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 2005; 10: 721–726.

46.

Niro

G.A.

, Ciancio

, Gaeta

G.B.

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 2006; 44: 713–720.

47.

Pegylated interferon to treat chronic hepatitis D; HIDIT II - PegIFN-alfa2a plus tenofovir in chronic delta hepatitis. Clinicaltrials.gov identifier NCT00932971. (Updated 23 June 2011. Accessed 1 July 2011.) Available from http://clinicaltrials.gov/ct2/show/NCT00932971.

48.

Niro

G.A.

, Rosina

, Rizzetto

Treatment of hepatitis D. J Viral Hepat 2005; 12: 2–9.

49.

Sagnelli

, Stroffolini

, Ascione

Decrease in HDV endemicity in Italy. J Hepatol 1997; 26: 20–24.

50.

Gaeta

G.B.

, Stroffolini

, Chiaramonte

Chronic hepatitis D: a vanishing disease? An Italian multicenter study. Hepatology 2000; 32: 824–827.

51.

Navascués

C.A.

, Rodriguez

, Sotorrio

N.G.

Epidemiology of hepatitis D virus infection: changes in the last 14 years. Am J Gastroenterol 1995; 90: 1981–1984.

52.

Glenn

J.S.

Prenylation of HDAg and antiviral drug development. Curr Top Microbiol Immunol 2006; 307: 133–149.

53.

Bordier

B.B.

, Ohkanda

, Liu

In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003; 112: 407–414.

54.

Proof-of-concept study evaluating the safety and efficacy of EBP921 in delta hepatitis (HDV). Clinicaltrials.gov identifier NCT01316185. (Updated 14 March 2011. Accessed 1 July 2011.) Available from http://clinicaltrials.gov/ct2/show/NCT01316185?term=Proof-of-concept+study+evaluating+the+safety+and+efficacy+of+EBP921+in+delta+hepatitis.&rank=1.

55.

Kabacam

, Yakut

, Seven

, Bozkaya

, Idilman

, Yurdaydin

Interferon treatment of delta hepatitis: the longer the duration the better the success?

J Hepatol 2011; 54 Suppl 1: S290.

56.

Mederacke

, Bremer

, Heidrich

Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. J Clin Microbiol 2010; 48: 2022–2029.

57.

Aoki

Y.H.

, Ohkoshi

, Yamagiwa

Characterization of elevated alanine aminotransferase levels during pegylated-interferon alpha-2b plus ribavirin treatment for chronic hepatitis C. Hepatol Res 2011; 41: 118–125.

58.

Rizzetto

, Rosina

, Saracco

Treatment of chronic delta hepatitis with alpha-2 recombinant interferon. J Hepatol 1986; 3 Suppl 2: S229–S233.

59.

Gaudin

J.L.

, Trepo

Therapy of chronic delta hepatitis with alpha- and beta-interferon. Prog Clin Biol Res 1993; 382: 345–352.

60.

Rosina

, Pintus

, Meschievitz

, Rizzetto

Long term interferon treatment of chronic delta hepatitis: a multicenter Italian study. Prog Clin Biol Res 1991; 364: 385–391.