Subscribe to RSS
DOI: 10.1055/s-0032-1323629
Treatment of Chronic Delta Hepatitis
Publication History
Publication Date:
29 August 2012 (online)
Abstract
Chronic delta hepatitis (CDH) remains the most progressive form of chronic viral hepatitis and as such its successful treatment is important. However, in striking contrast to the situation in chronic hepatitis B and C, no new drugs for its treatment have been introduced in the recent past and interferons remain the only evidence-based effective treatment of CDH. However, results are far from optimal. Overall, around 25 to 30% of patients may have a sustained response after one year of conventional or pegylated interferon (Peg-INF) treatment and such treatment may favorably affect the natural history of the disease. The superiority of Peg-INF over its conventional form is possible, but has not been demonstrated in a clinical trial. Several unanswered questions remain in the context of INF treatment such as (1) the need for standardization of HDV-RNA quantitation, the most widely used surrogate marker of treatment efficacy; (2) validation of this treatment end point as an index of long-term containment of HDV; (3) optimal duration of treatment; (4) baseline and on-treatment parameters of treatment efficacy; and (5) development of new markers of treatment efficacy. Nucleos(t)ide analogs (NAs) have been widely tested in CDH, but they appear to be ineffective when used for a duration of up to 2 years. Combination treatment of NAs with INFs also proved to be disappointing. New approaches to treatment are hepatocyte entry inhibitors and prenylation inhibitors to be hopefully tested in human CDH in the not-too-distant future.
-
References
- 1 Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat 2005; 12 (1) 2-9
- 2 Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs 1994; 48 (2) 199-226
- 3 Sánchez-Tapias JM, Mas A, Costa J , et al. Recombinant alpha 2c-interferon therapy in fulminant viral hepatitis. J Hepatol 1987; 5 (2) 205-210
- 4 Yurdaydın C, Idilman R, Bozkaya H, Bozdayi AM. Natural history and treatment of chronic delta hepatitis. J Viral Hepat 2010; 17 (11) 749-756
- 5 Rizzetto M, Verme G, Recchia S , et al. Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98 (4) 437-441
- 6 Arrigoni A, Ponzetto A, Actis GC, Bonino F. Levamisole and chronic delta hepatitis. Ann Intern Med 1983; 98 (6) 1024
- 7 Trépo C, Ouzan D, Fontanges T , et al. Therapeutic potential of acyclovir and of the interferons in HBV-related chronic active hepatitis due to HBV with or without HDV superinfection. J Hepatol 1986; 3 (Suppl. 02) S129-S135
- 8 Rizzetto M. Hepatitis D: thirty years after. J Hepatol 2009; 50 (5) 1043-1050
- 9 Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol 2010; 7 (1) 31-40
- 10 Rosina F, Pintus C, Meschievitz C, Rizzetto M. A randomized controlled trial of a 12 month course of recombinant human interferonalpha in chronic delta (type D) hepatitis: a multicenter Italian study. Hepatology 1991; 13 (6) 1052-1056
- 11 Farci P, Mandas A, Coiana A , et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med 1994; 330 (2) 88-94
- 12 Gaudin JL, Faure P, Godinot H, Gerard F, Trepo C. 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 (1) 45-52
- 13 Madejón A, Cotonat T, Bartolomé J, Castillo I, Carreño V. 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 (6) 1331-1336
- 14 Günşar F, Akarca US, Ersöz G , et al. Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 2005; 10 (6) 721-726
- 15 Canbakan B, Şentürk H, Tabak F , et al. Efficacy of interferon α-2b and lamivudine combination treatment in comparison to interferon α-2b alone in chronic delta hepatitis: a randomized trial. J Gastroenterol Hepatol 2006; 21 (4) 657-663
- 16 Yurdaydın C, Bozkaya H, Önder FO , et al. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat 2008; 15 (4) 314-321
- 17 Niro GA, Ciancio A, Gaeta GB , et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 2006; 44 (3) 713-720
- 18 Castelnau C, Le Gal F, Ripault MP , et al. Efficacy of Peg-interferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology 2006; 44 (3) 728-735
- 19 Erhardt A, Gerlich W, Starke C , et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int 2006; 26 (7) 805-810
- 20 Wedemeyer H, Yurdaydìn C, Dalekos GN , et al; HIDIT Study Group. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364 (4) 322-331
- 21 Gheorghe L, Iacob S, Simionov I , et al. Weight-based dosing regimen of Peg-interferon α-2b for chronic hepatitis delta: a multicenter Romanian trial. J Gastrointestin Liver Dis 2011; 20 (4) 377-382
- 22 Örmeci N, Bölükbaş F, Erden E , et al. Pegylated interferon alfa-2B for chronic delta hepatitis: 12 versus 24 months. Hepatogastroenterology 2011; 58 (110-111) 1648-1653
- 23 Farci P, Roskams T, Chessa L , et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 2004; 126 (7) 1740-1749
- 24 Le Gal F, Brichler S, Checkaraou MA , et al. Results of a French national quality control for hepatitis delta virus RNA quantification. Paper presented at: EASL Monothematic Conference on Delta Hepatitis; September 24–26, 2010; Istanbul, Turkey
- 25 Kabaçam G, Dalekos GN, Çakaloğlu Y , et al. Pegylated interferon-based treatment in patients with advanced liver disease due to chronic delta hepatitis. Turk J Gastroenterol 2012; (in press)
- 26 Everson GT, Hoefs JC, Seeff LB , et al; HALT-C Trial Group. Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial. Hepatology 2006; 44 (6) 1675-1684
- 27 Di Marco V, Giacchino R, Timitilli A , et al. Long-term interferon-α treatment of children with chronic hepatitis delta: a multicentre study. J Viral Hepat 1996; 3 (3) 123-128
- 28 Yurdaydin C, Bozkaya H, Karaaslan H , et al. A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis. J Viral Hepat 2007; 14 (11) 812-816
- 29 Kabaçam G, Yakut M, Seven G , et al. Delta hepatitis may require prolonged treatment with interferon (abstr.). Hepatology 2011; 54 (Suppl. 4) 1039A
- 30 Chang J, Nie X, Gudima S, Taylor J. Action of inhibitors on accumulation of processed hepatitis delta virus RNAs. J Virol 2006; 80 (7) 3205-3214
- 31 Ilan Y, Klein A, Taylor J, Tur-Kaspa R. Resistance of hepatitis delta virus replication to interferon-alpha treatment in transfected human cells. J Infect Dis 1992; 166 (5) 1164-1166
- 32 Pugnale P, Pazienza V, Guilloux K, Negro F. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 2009; 49 (2) 398-406
- 33 Han Z, Nogusa S, Nicolas E, Balachandran S, Taylor J. Interferon impedes an early step of hepatitis delta virus infection. PLoS ONE 2011; 6 (7) e22415
- 34 Manesis EK, Schina M, Le Gal F , et al. Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring. Antivir Ther 2007; 12 (3) 381-388
- 35 Zachou K, Yurdaydın C, Drebber U , et al; HIDT-1 Study Group. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int 2010; 30 (3) 430-437
- 36 Wolters LM, van Nunen AB, Honkoop P , et al. Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus. J Viral Hepat 2000; 7 (6) 428-434
- 37 Kaymakoğlu S, Karaca C, Demir K , et al. Alpha interferon and ribavirin combination therapy of chronic hepatitis D. Antimicrob Agents Chemother 2005; 49 (3) 1135-1138
- 38 Garripoli A, Di Marco V, Cozzolongo R , et al. Ribavirin treatment for chronic hepatitis D: a pilot study. Liver 1994; 14 (3) 154-157
- 39 Patterson JL, Fernandez-Larsson R. Molecular mechanisms of action of ribavirin. Rev Infect Dis 1990; 12 (6) 1139-1146
- 40 Yurdaydın C, Bozkaya H, Gürel S , et al. Famciclovir treatment of chronic delta hepatitis. J Hepatol 2002; 37 (2) 266-271
- 41 Lau DT-Y, Doo E, Park Y , et al. Lamivudine for chronic delta hepatitis. Hepatology 1999; 30 (2) 546-549
- 42 Niro GA, Ciancio A, Tillman HL , et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther 2005; 22 (3) 227-232
- 43 Kabaçam G, Önder FO, Yakut M , et al. Entecavir treatment of chronic hepatitis D. Clin Infect Dis 2012; June 21 (Epub ahead of print)
- 44 Sheldon J, Ramos B, Toro C , et al. Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients?. Antivir Ther 2008; 13 (1) 97-102
- 45 Wursthorn K, Lutgehetmann M, Dandri M , et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology 2006; 44 (3) 675-684
- 46 Peek SF, Cote PJ, Jacob JR , et al. Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-β, L-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax). Hepatology 2001; 33 (1) 254-266
- 47 Casey J, Cote PJ, Toshkov IA , et al. Clevudine inhibits hepatitis delta virus viremia: a pilot study of chronically infected woodchucks. Antimicrob Agents Chemother 2005; 49 (10) 4396-4399
- 48 Yakut M, Seven G, Baran B , et al. Clevudine treatment of chronic delta hepatitis. Paper presented at: EASL Monothematic Conference on Delta Hepatitis; September 24–26, 2010; Istanbul, Turkey
- 49 Kim BK, Oh J, Kwon ST , et al. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol 2009; 51 (5) 829-834
- 50 Boyd A, Lacombe K, Miailhes P , et al. Longitudinal evaluation of viral interactions in treated HIV-hepatitis B co-infected patients with additional hepatitis C and D virus. J Viral Hepat 2010; 17 (1) 65-76
- 51 Schaper M, Rodriguez-Frias F, Jardi R , et al. 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 (5) 658-664
- 52 Yalcin K, Degertekin H, Yurdaydin C, Bozdayi M, Bozkaya H. The role of HBeAg seroconversion in acute exacerbation of liver disease with termination of hepatitis B and D virus infection in a chronic hepatitis D patient during alpha-interferon therapy. Eur J Gastroenterol Hepatol 2003; 15 (7) 819-823
- 53 Zavaglia C, Bottelli R, Smedile A , et al. A pilot study of thymosin-alpha 1 therapy for chronic hepatitis D. J Clin Gastroenterol 1996; 23 (2) 162-163
- 54 Rosina F, Conoscitore P, Smedile A , et al. Treatment of chronic hepatitis D with thymus-derived polypeptide thymic humoral factor-gamma 2: a pilot study. Dig Liver Dis 2002; 34 (4) 285-289
- 55 Goso C, Frasca D, Doria G. Effect of synthetic thymic humoral factor (THF-gamma 2) on T cell activities in immunodeficient ageing mice. Clin Exp Immunol 1992; 87 (3) 346-351
- 56 Katorza E, Pecht M, Apte RN , et al. Restoration of immunological responses by THF, a thymic hormone, in mice infected with murine cytomegalovirus (MCMV). Clin Exp Immunol 1987; 70 (2) 268-275
- 57 Farhat BA, Marinos G, Daniels HM, Naoumov NV, Williams R. Evaluation of efficacy and safety of thymus humoral factor-gamma 2 in the management of chronic hepatitis B. J Hepatol 1995; 23 (1) 21-27
- 58 Glenn JS. Prenylation of HDAg and antiviral drug development. Curr Top Microbiol Immunol 2006; 307: 133-149
- 59 Engelke M, Mills K, Seitz S , et al. Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology 2006; 43 (4) 750-760
- 60 Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 2007; 46 (6) 1759-1768
- 61 Petersen J, Dandri M, Mier W , et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 2008; 26 (3) 335-341
- 62 McHutchison JG, Bacon BR, Gordon SC , et al. Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus. Hepatology 2007; 46 (5) 1341-1349
- 63 Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science 1992; 256 (5061) 1331-1333
- 64 Bordier BB, Marion PL, Ohashi K , et al. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J Virol 2002; 76 (20) 10465-10472
- 65 Bordier BB, Ohkanda J, Liu P , et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003; 112 (3) 407-414
- 66 Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 1999; 17 (11) 3631-3652