Targeting Hepatitis D

Abstract

New therapeutic strategies to treat chronic hepatitis D are directed to deprive the hepatitis D virus (HDV) of functions necessary to complete its life cycle that are provided by the hepatitis B virus (HBV) and by the host. Current options are (1) the block by the synthetic peptide Myrcludex B of HBV surface antigen (HBsAg) entry into cells through the inhibition of the sodium taurocholate cotransporting receptor; (2) the inhibition with lonafarnib of the farnesylation of the large HD antigen, required for virion assembly; (3) the presumed reduction by the nucleic acid polymer REP 2139 of the release of the HBsAg and subviral HBV particles necessary for HD virion morphogenesis. Lonafarnib and Myrcludex in monotherapy reduced serum HDV-RNA but did not reduce the HBsAg and HD viremia rebounded after therapy; they may provide additional efficacy to pegylated interferon alpha (Peg IFN-α) therapy. Treatment with REP-2139 in combination with Peg IFN-α induced a sustained clearance both of the HDV-RNA and HBsAg in 5 of 12 patients, providing the best interim results so far obtained in the therapy of chronic hepatitis D.

Keywords

hepatitis D virus - chronic hepatitis D - Lonafarnib - Myrcludex B - REP 2139 - HDV therapy

• References

• 1 Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat 2005; 12 (01) 2-9
• 2 Rizzetto M. Hepatitis D: thirty years after. J Hepatol 2009; 50 (05) 1043-1050
• 3 Lai MM. RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J Virol 2005; 79 (13) 7951-7958
• 4 Taylor JM. Virology of hepatitis D virus. Semin Liver Dis 2012; 32 (03) 195-200
• 5 Singh S, Gupta SK, Nischal A. , et al. Design of potential siRNA molecules for hepatitis delta virus gene silencing. Bioinformation 2012; 8 (16) 749-757
• 6 Yurdaydin C. Treatment of chronic delta hepatitis. Semin Liver Dis 2012; 32 (03) 237-244
• 7 Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 2014; 147 (01) 48-64
• 8 Casey JL. RNA editing in hepatitis delta virus. Curr Top Microbiol Immunol 2006; 307: 67-89
• 9 Huang WH, Chen CW, Wu HL, Chen PJ. Post-translational modification of delta antigen of hepatitis D virus. Curr Top Microbiol Immunol 2006; 307: 91-112
• 10 Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science 1992; 256 (5061): 1331-1333
• 11 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 (04) 322-331
• 12 Heidrich B, Yurdaydın C, Kabaçam G. , et al; HIDIT-1 Study Group. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 2014; 60 (01) 87-97
• 13 Ponzetto A, Hoyer BH, Popper H, Engle R, Purcell RH, Gerin JL. Titration of the infectivity of hepatitis D virus in chimpanzees. J Infect Dis 1987; 155 (01) 72-78
• 14 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 (04) 1070-1083
• 15 Blanchet M, Sureau C, Labonté P. Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle. Antiviral Res 2014; 106: 111-115
• 16 Nkongolo S, Ni Y, Lempp FA. , et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol 2014; 60 (04) 723-731
• 17 Shimura S, Watashi K, Fukano K. , et al. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol 2017; 66 (04) 685-692
• 18 Tsukuda S, Watashi K, Hojima T. , et al. A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins. Hepatology 2017; 65 (04) 1104-1116
• 19 Li D, He W, Liu X. , et al. A potent human neutralizing antibody Fc-dependently reduces established HBV infections. eLife 2017; 6: e26738
• 20 Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 2016; 13 (10) 580-589
• 21 Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 2005; 79 (03) 1613-1622
• 22 Schulze A, Schieck A, Ni Y, Mier W, Urban S. Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J Virol 2010; 84 (04) 1989-2000
• 23 Lempp FA, Urban S. Hepatitis delta virus: replication strategy and upcoming therapeutic options for a neglected human pathogen. Viruses 2017; 9 (07) 172
• 24 Blank A, Markert C, Hohmann N. , et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 2016; 65 (03) 483-489
• 25 Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer 2011; 11 (11) 775-791
• 26 Glenn JS. Prenylation of HDAg and antiviral drug development. Curr Top Microbiol Immunol 2006; 307: 133-149
• 27 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
• 28 Bordier BB, Ohkanda J, Liu P. , et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003; 112 (03) 407-414
• 29 Vaillant A. Nucleic acid polymers: broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection. Antiviral Res 2016; 133: 32-40
• 30 Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo. Antimicrob Agents Chemother 2013; 57 (11) 5299-5306
• 31 Noordeen F, Scougall CA, Grosse A. , et al. Therapeutic antiviral effect of the nucleic acid polymer rep 2055 against persistent duck hepatitis B virus infection. PLoS One 2015; 10 (11) e0140909
• 32 Al-Mahtab M, Bazinet M, Vaillant A. Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naive Bangladeshi patients with HBeAg+ chronic hepatitis B infection. PLoS One 2016; 11 (06) e0156667
• 33 Bogomolov P, Alexandrov A, Voronkova N. , et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol 2016; 65 (03) 490-498
• 34 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 (10) 1167-1174
• 35 Ghosal A, Chowdhury SK, Tong W. , et al. Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos 2006; 34 (04) 628-635
• 36 Yurdaydin C, Idilman R, Kalkan C. , et al. Exploring optimal dosing of Lonafarnib with Ritonavir for the treatment of chronic Delta hepatitis-Interim results from the lowr HDV-2 study. Hepatology 2016; 64, abstract 1845 : 910A
• 37 Wedemeyer H, Port K, Deterding K. , et al. A phase 2 study of titrating dose Lonafarnib plus Ritonavir in patients with chronic hepatitis D: interim results from the Lonafarnib with Ritonavir in HDV-4 study. AASLD. Hepatology 2016; 64 abstract 230,121A
• 38 Bazinet M, Pântea V, Cebotarescu V. , et al. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol 2017; 2 (12) 877-889
• 39 European Association for the Study of the Liver. Electronic address: [e-mail]; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67 (02) 370-398
• 40 Triantos C, Kalafateli M, Nikolopoulou V, Burroughs A. Meta-analysis: antiviral treatment for hepatitis D. Aliment Pharmacol Ther 2012; 35 (06) 663-673
• 41 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 (06) 1258-1259
• 42 Niro GA, Smedile A, Fontana R. , et al. HBsAg kinetics in chronic hepatitis D during interferon therapy: on-treatment prediction of response. Aliment Pharmacol Ther 2016; 44 (06) 620-628
• 43 Erhardt A, Gerlich W, Starke C. , et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int 2006; 26 (07) 805-810
• 44 Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL. Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 2010; 52 (04) 1251-1257
• 45 Martinot-Peignoux M, Asselah T, Marcellin P. HBsAg quantification to optimize treatment monitoring in chronic hepatitis B patients. Liver Int 2015; 35 (Suppl. 01) 82-90
• 46 Wranke A, Pinheiro Borzacov LM, Parana R. , et al; Hepatitis Delta International Network. Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN). Liver Int 2017; •••
• 47 Quinet J, Jamard C, Vaillant A, Cova L. Achievement of surface antigen clearance in the liver by combination therapy with REP 2139-Ca and nucleoside analogues against chronic hepatitis B. International Liver Congress; Barcelona, Spain; April 12–17, 2016. THU-177
• 48 Roehl I, Seiffert S, Brikh C. , et al. Nucleic acid polymers with accelerated plasma and tissue clearance for chronic hepatitis B therapy. Mol Ther Nucleic Acids 2017; 8: 1-12
• 49 Guillot C, Martel N, Berby F. , et al. Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes. PLoS One 2017; 12 (06) e0179697
• 50 Blanchet M, Vaillant A, Labonté P. Post-entry antiviral effects of nucleic acid polymers against hepatitis B infection in vitro. International Liver Congress; Amsterdam, Netherlands April 19–23, 2017. THU 46
• 51 Suhail M, Abdel-Hafiz H, Ali A. , et al. Potential mechanisms of hepatitis B virus induced liver injury. World J Gastroenterol 2014; 20 (35) 12462-12472
• 52 Eslam M, George J. Targeting IFN-λ: therapeutic implications. Expert Opin Ther Targets 2016; 20 (12) 1425-1432