Treatment and prevention of hepatitis D virus infection
- Francesco Negro, MD
Francesco Negro, MD
- Professor of Gastroenterology and hepatology
- University Hospitals, Geneva, Switzerland
- Anna SF Lok, MD
Anna SF Lok, MD
- Professor of Medicine
- University of Michigan Medical School
The clinical manifestations of hepatitis D virus (HDV) infection vary from benign acute hepatitis to fulminant hepatitis and from an asymptomatic carrier state to rapidly progressive chronic liver disease. HDV is a defective virus requiring the simultaneous presence of hepatitis B virus (HBV) to fully express its pathogenicity; thus, hepatitis D always occurs in the presence of HBV. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
In most cases of HDV infection, HBV replication is suppressed to low levels by HDV [1,2]. Liver damage in these patients is essentially due to HDV only. Occasionally, HBV and HDV replicate simultaneously, each virus contributing to the liver damage, thereby resulting in more severe liver disease .
CLINICAL COURSE OF HDV INFECTION
The clinical course is influenced by several factors, including the HDV genotype . This issue is discussed in detail elsewhere but a brief review is warranted to provide the rationale for antiviral therapy. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
The predominant genotype in the Western world is genotype I. Once chronic HDV infection is established, it usually exacerbates the preexisting liver disease due to HBV. Progression towards cirrhosis may be rapid, but does not occur in all patients. HDV-associated chronic liver disease may run an indolent course and asymptomatic HDV carriers have been found in some geographical areas.
Patients who are currently referred for HDV infection appear to represent cohorts infected many years ago in whom the HDV-related disease rapidly developed to cirrhosis, but whose subsequent disease progression has been slow. This was illustrated in a report from Italy in which the estimated 5- and 10-year probability of survival free of liver transplantation in patients who had already developed clinically overt cirrhosis was 49 and 40 percent, respectively . A more ominous course toward liver decompensation has been documented in patients with active HBV and HDV replication . In the Far East, where the predominant genotype is genotype II, there is a less frequent association of chronic HDV infection with progressive liver disease .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Krogsgaard K, Kryger P, Aldershvile J, et al. Delta-infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology 1987; 7:42.
- Farci P, Karayiannis P, Lai ME, et al. Acute and chronic hepatitis delta virus infection: direct or indirect effect on hepatitis B virus replication? J Med Virol 1988; 26:279.
- Smedile A, Rosina F, Saracco G, et al. Hepatitis B virus replication modulates pathogenesis of hepatitis D virus in chronic hepatitis D. Hepatology 1991; 13:413.
- Wu JC, Choo KB, Chen CM, et al. Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D. Lancet 1995; 346:939.
- Rosina F, Conoscitore P, Cuppone R, et al. Changing pattern of chronic hepatitis D in Southern Europe. Gastroenterology 1999; 117:161.
- Negro F, Shapiro M, Satterfield WC, et al. Reappearance of hepatitis D virus (HDV) replication in chronic hepatitis B virus carrier chimpanzees rechallenged with HDV. J Infect Dis 1989; 160:567.
- Abbas Z, Khan MA, Salih M, Jafri W. Interferon alpha for chronic hepatitis D. Cochrane Database Syst Rev 2011; :CD006002.
- 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; 166:1164.
- McNair AN, Cheng D, Monjardino J, et al. Hepatitis delta virus replication in vitro is not affected by interferon-alpha or -gamma despite intact cellular responses to interferon and dsRNA. J Gen Virol 1994; 75 ( Pt 6):1371.
- Pugnale P, Pazienza V, Guilloux K, Negro F. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 2009; 49:398.
- Lau JY, King R, Tibbs CJ, et al. Loss of HBsAg with interferon-alpha therapy in chronic hepatitis D virus infection. J Med Virol 1993; 39:292.
- Battegay M, Simpson LH, Hoofnagle JH, et al. Elimination of hepatitis delta virus infection after loss of hepatitis B surface antigen in patients with chronic delta hepatitis. J Med Virol 1994; 44:389.
- Lau DT, Kleiner DE, Park Y, et al. Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology 1999; 117:1229.
- Rosina F, Pintus C, Meschievitz C, Rizzetto M. 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.
- Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med 1994; 330:88.
- 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; 126:1740.
- Borghesio E, Rosina F, Di Marco V, et al. Long-term treatment of chronic hepatitis D with lymphoblastoid interferon: 10 MU vs. 5 MU. An interim report of a randomized controlled trial. Proceedings of the Fifth International Symposium on Hepatitis Delta Virus and Liver Disease. Brisbane, August 28-29, 1995; D47.
- Gaudin JL, Faure P, Godinot H, et al. 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.
- 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; 44:713.
- Castelnau C, Le Gal F, Ripault MP, et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology 2006; 44:728.
- Ferenci P, Formann E, Romeo R. Successful treatment of chronic hepatitis D with a short course of peginterferon alfa-2a. Am J Gastroenterol 2005; 100:1626.
- Ormeci N, Bölükbaş F, Erden E, et al. Pegylated interferon alfa-2B for chronic delta hepatitis: 12 versus 24 months. Hepatogastroenterology 2011; 58:1648.
- Abbas Z, Memon MS, Mithani H, et al. Treatment of chronic hepatitis D patients with pegylated interferon: a real-world experience. Antivir Ther 2014; 19:463.
- Ouzan D, Pénaranda G, Joly H, Halfon P. Optimized HBsAg titer monitoring improves interferon therapy in patients with chronic hepatitis delta. J Hepatol 2013; 58:1258.
- Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364:322.
- Soriano V, Vispo E, Sierra-Enguita R, et al. Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients. AIDS 2014; 28:2389.
- Rasshofer R, Choi SS, Wolfl P, et al. Inhibition of HDV RNA replication in vitro by ribavirin and suramin. In: Viral Hepatitis and Liver Disease, Hollinger FB, Lemon SM, Margolis HS (Eds), Williams & Wilkins, Baltimore 1991. p.659.
- Buti M, Lopez-Talavera JC, Allende H, et al. Serological diagnosis of chronic delta infection: correlation between serological markers and hepatitis delta virus RNA in hepatic tissue. Prog Clin Biol Res 1993; 382:319.
- Garripoli A, Di Marco V, Cozzolongo R, et al. Ribavirin treatment for chronic hepatitis D: a pilot study. Liver 1994; 14:154.
- Petcu DJ, Aldrich CE, Coates L, et al. Suramin inhibits in vitro infection by duck hepatitis B virus, Rous sarcoma virus, and hepatitis delta virus. Virology 1988; 167:385.
- Ponzetto A, Negro F, Gerin JL, Purcell RH. Experimental hepatitis delta virus infection in the animal model. Prog Clin Biol Res 1991; 364:147.
- Lau DT, Doo E, Park Y, et al. Lamivudine for chronic delta hepatitis. Hepatology 1999; 30:546.
- Niro GA, Ciancio A, Tillman HL, et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther 2005; 22:227.
- 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; 7:428.
- Yurdaydin C, Bozkaya H, Onder FO, et al. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat 2008; 15:314.
- Yurdaydin C, Bozkaya H, Gürel S, et al. Famciclovir treatment of chronic delta hepatitis. J Hepatol 2002; 37:266.
- Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 1996; 65:241.
- Bordier BB, Marion PL, Ohashi K, et al. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J Virol 2002; 76:10465.
- Bordier BB, Ohkanda J, Liu P, et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003; 112:407.
- Koh C, Canini L, Dahari H, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis 2015; 15:1167.
- Ni Y, Lempp FA, Mehrle S, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 2014; 146:1070.
- Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012; 1:e00049.
- Urban S, Bogomolov P, Voronkova N, et al. A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B. Hepatology 2014;60(suppl):LB-20
- Kaneko M, Watashi K, Kamisuki S, et al. A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide. J Virol 2015; 89:11945.
- Chen TZ, Wu JC, Au LC, Choo KB. Specific inhibition of delta antigen by in vitro system by antisense oligodeoxynucleotide: implications for translation mechanism and treatment. J Virol Methods 1997; 65:183.
- Hedin G, Weiland O, Ljunggren K, et al. Treatment of fulminant hepatitis B and fulminant hepatitis B and D coinfection with foscarnet. Prog Clin Biol Res 1987; 234:309.
- Rizzetto M, Canese MG, Gerin JL, et al. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis 1980; 141:590.
- Ponzetto A, Forzani B, D'Urso N, et al. Immunization with hepatitis delta antigen does not prevent superinfection with hepatitis delta virus in the woodchuck. Gastroenterology 1989; 96:646.
- Karayiannis P, Saldanha J, Monjardino J, et al. Immunization of woodchucks with recombinant hepatitis delta antigen does not protect against hepatitis delta virus infection. Hepatology 1990; 12:1125.
- Ponzetto A, Eckart M, D'Urso N, et al. Towards a vaccine for the prevention of hepatitis delta virus superinfection in HBV carriers. Prog Clin Biol Res 1993; 382:207.
- Karayiannis P, Saldanha J, Jackson AM, et al. Partial control of hepatitis delta virus superinfection by immunisation of woodchucks (Marmota monax) with hepatitis delta antigen expressed by a recombinant vaccinia or baculovirus. J Med Virol 1993; 41:210.
- Eckart MR, Dong C, Houghton M, et al. The effects of using recombinant vaccinia viruses expressing either large or small HDAg to protect woodchuck hepadnavirus carriers from HDV superinfection. Prog Clin Biol Res 1993; 382:201.
- Bergmann KF, Casey JL, Tennant BC, Gerin JL. Modulation of hepatitis delta virus infection by vaccination with synthetic peptides: a preliminary study in the woodchuck model. Prog Clin Biol Res 1993; 382:181.
- CLINICAL COURSE OF HDV INFECTION
- AIMS OF TREATMENT
- TRIALS OF INTERFERON ALFA
- Trials of standard interferon therapy
- - Factors predicting response to standard IFNa
- Peginterferon plus adefovir dipivoxil
- HBV nucleotide inhibitors
- EXPERIMENTAL TREATMENTS
- TREATMENT OF ACUTE HEPATITIS D
- PREVENTION OF HDV INFECTION
- Vaccination against HDV
- SUMMARY AND RECOMMENDATIONS