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Role of Nucleic Acid Polymers and Entry Inhibitors in Functional Cure Strategies for HBV

  • Hepatitis B (JK Lim, Section Editor)
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Abstract

Purpose of Review

Hepatitis B virus (HBV) infection is one of the most common viral infections worldwide with an estimated 2 billion people exposed to HBV and 240 million with active chronic infection. Despite this, less than 1% of patients with chronic HBV infection receive treatment, and less than 3% of those achieve functional cure with traditional therapies. This review summarizes recent advances in the treatment of chronic HBV utilizing nucleic acid polymers (NAP) and entry inhibitors (EI).

Recent Findings

A recent phase 2 study evaluating the use of NAP following tenofovir and pegylated interferon (PEG-IFN) demonstrated increased rates of functional cure which persisted in 35% of patients after 48 weeks of follow-up. In addition, the EI Myrcludex B has demonstrated HBsAg response in up to 40% of patients when used in combination with PEG-IFN at week 72.

Summary

Functional cure is considered the “holy grail” of treatment, and many new therapies are under investigation for the treatment of chronic HBV. As we work towards functional cure for chronic HBV, NAPs and EIs have shown efficacy in reducing HBV DNA and HBsAg levels and have emerged as potential therapeutic agents that may lead to a functional cure for HBV.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva World Heal Organ [Internet]. 2015;March. Available from: https://www.ncbi.nlm.nih.gov/books/NBK305548/. Accessed 20 May 2020.

  2. Yang JD, Kim WR, Coelho R, Mettler TA, Benson JT, Sanderson SO, et al. Cirrhosis Is Present in Most Patients With Hepatitis B and Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2011;9(1):64–70.

    PubMed  Google Scholar 

  3. Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J Med. 2004;350(11):1118–29.

    CAS  PubMed  Google Scholar 

  4. Noureddin M, Gish R. Hepatitis delta: epidemiology, diagnosis and management 36 years after discovery. Curr Gastroenterol Rep. 2014;16:365.

    PubMed  Google Scholar 

  5. Koh C, Heller T, Glenn JS. Pathogenesis of and New Therapies for Hepatitis D. Gastroenterology. 2019;156(2):461–476.e1.

    CAS  PubMed  Google Scholar 

  6. World Health Organization (WHO). Hepatitis B: key facts. WHO. 2019.

  7. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):661–2.

    PubMed  Google Scholar 

  8. Lok ASF. Prevention of hepatitis B virus-related hepatocellular carcinoma. In: Gastroenterology. 2004

  9. Halegoua-De Marzio D, Hann HW. Then and now: the progress in hepatitis B treatment over the past 20 years. World J Gastroenterol. 2014;20(2):401–13.

    PubMed  PubMed Central  Google Scholar 

  10. Dianzani F, Antonelli G, Capobianchi MR. The biological basis for clinical use of interferon. J Hepatol. 1990;11:S5–S10.

    PubMed  Google Scholar 

  11. Wong VWS, Wong GLH, Yan KKL, Chim AML, Chan HY, Tse CH, et al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;52:S399.

    Google Scholar 

  12. Konerman MA, Lok AS. Interferon treatment for hepatitis B. Clinics Liver Disease. 2016;20:645–65.

    Google Scholar 

  13. Fung J, Lai CL, Seto WK, Yuen MF. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis b. J Antimicrob Chemother. 2011;66(12):2715-2725

  14. Gish RG, Chang TT, Lai CL, De Man R, Gadano A, Poordad F, et al. Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. J Viral Hepat. 2010;17(1):16–22.

    CAS  PubMed  Google Scholar 

  15. Lok ASF, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-Term Safety of Lamivudine Treatment in Patients with Chronic Hepatitis B. Gastroenterology. 2003;125(6):1714–22.

    CAS  PubMed  Google Scholar 

  16. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–51.

    CAS  PubMed  Google Scholar 

  17. Marcellin P, Heathcote EJ, Buti M, Gane E, De Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359(23):2442–55.

    CAS  PubMed  Google Scholar 

  18. Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018;68(4):672–81.

    CAS  PubMed  Google Scholar 

  19. Marcellin P, Asselah T, Boyer N. Treatment of chronic hepatitis B. J Viral Hepat. 2005;12(4):333–45.

    CAS  PubMed  Google Scholar 

  20. Prescott NA, Bram Y, Schwartz RE, David Y. Targeting hepatitis B virus covalently closed circular DNA and hepatitis B virus X protein: recent advances and new approaches. ACS Infect Dis. 2019;5:1657–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lucifora J, Protzer U. Attacking hepatitis B virus cccDNA – The holy grail to hepatitis B cure. J Hepatol. 2016;64(1 Supplement):S41–8.

    CAS  PubMed  Google Scholar 

  22. Block TM, Rawat S, Brosgart CL. Chronic hepatitis B: a wave of new therapies on the horizon. Antivir Res. 2015;121:69–81.

    CAS  PubMed  Google Scholar 

  23. Eckstein F Phosphorothioates, essential components of therapeutic oligonucleotides. Vol. 24, Nucleic Acid Therapeutics. Mary Ann Liebert Inc.; 2014. p. 374–87.

  24. Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers inhibit duck hepatitis B virus infection in vitro. Antimicrob Agents Chemother. 2013;57(11):5291–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Guzman EM, Cheshenko N, Shende V, Keller MJ, Goyette N, Juteau J-M, et al. Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression. Antivir Ther. 2007;12(8):1147–56.

    CAS  PubMed  Google Scholar 

  26. Matsumura T, Hu Z, Kato T, Dreux M, Zhang Y-Y, Imamura M, et al. Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry. YGAST. 2009;137:673–81.

    CAS  Google Scholar 

  27. Vaillant A, Juteau J-M, Lu H, Liu S, Lackman-Smith C, Ptak R, et al. Phosphorothioate oligonucleotides inhibit human immunodeficiency virus type 1 fusion by blocking gp41 Core formation downloaded from. Antimicrob Agents Chemother. 2006;50(4):1393–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kocisko DA, Vaillant A, Lee KS, Arnold KM, Bertholet N, Race RE, et al. Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides. Antimicrob Agents Chemother. 2006;50(3):1034–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Schultz U, Grgacic E, Nassal M. Duck hepatitis B virus: an invaluable model system for HBV infection. Adv Virus Res. 2004;63:1–70.

    CAS  PubMed  Google Scholar 

  30. Guillot C, Martel N, Berby F, Bordes I, Hantz O, Blanchet M, et al. Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes. PLoS One. 2017;12(6):1–15.

    Google Scholar 

  31. Koller E, Vincent TM, Chappell A, De S, Manoharan M, Bennett CF. Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes. Nucleic Acids Res. 2011;39(11):4795–807.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang B, Ming X, Cao C, Laing B, Yuan A, Porter MA, et al. High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides. Nucleic Acids Res. 2015;43(4):1987–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. •• Blanchet M, Sinnathamby V, Vaillant A, Labonté P. Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells. Antivir Res. 2019;164:97–105 First proposed NAP mechanism of action during SVP assembly.

    CAS  PubMed  Google Scholar 

  34. 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):5299–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Krieg AM. Immune effects and mechanisms of action of CpG motifs. Vol. 19, Vaccine. Elsevier BV; 2000. p. 618–22.

  36. Noordeen F, Scougall CA, Grosse A, Qiao Q, Ajilian BB, Reaiche-Miller G, 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.

    PubMed  PubMed Central  Google Scholar 

  37. Roehl I, Seiffert S, Brikh C, Quinet J, Jamard C, Dorfler N, et al. Nucleic acid polymers with accelerated plasma and tissue clearance for chronic hepatitis B therapy. Mol Ther - Nucleic Acids. 2017;8:1–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. • 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(6):e0156667 First NAP clinical trial showing successful antiviral activity in humans.

    PubMed  PubMed Central  Google Scholar 

  39. •• Bazinet M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, et al. Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naïve to nucleos(t)ide therapy. Gastroenterology. 2020;158(8):2180–94 Largest clinical trial to date investigating NAP in combination therapy with traditional HBV therapies.

    CAS  PubMed  Google Scholar 

  40. Shekhtman L, Borochov N, Cotler S, Hershkovich L, Uprichard S, Al-Mahtab M, et al. Modeling serum HBsAg, HBV DNA and transaminase kinetics during REP 2139 monotherapy in chronic HBeAg+ HBV infection. J Hepatol. 2018;68:S508.

    Google Scholar 

  41. Lobritz MA, Ratcliff AN, Arts EJ. HIV-1 entry, inhibitors, and resistance. Viruses. 2010;2:1069–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Fernholz D, Galle PR, Stemler M, Brunetto M, Bonino F, Will H. Infectious hepatitis b virus variant defective in pre-s2 protein expression in a chronic carrier. Virology. 1993;194:137–48.

    CAS  PubMed  Google Scholar 

  43. •• Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012;1:e00049 Key study that identified NTCP as the receptor for HBV, opening the possibility of a new therapeutic target.

    PubMed  PubMed Central  Google Scholar 

  44. Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014;146(4):1070–83.

    CAS  PubMed  Google Scholar 

  45. Yan H, Liu Y, Sui J, Li W. NTCP opens the door for hepatitis B virus infection. Antivir Res. 2015;121:24–30.

    CAS  PubMed  Google Scholar 

  46. Huang H-C, Chen C-C, Chang W-C, Tao M-H, Huang C. Entry of hepatitis B virus into immortalized human primary hepatocytes by clathrin-dependent endocytosis. J Virol. 2012;86:9443–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao K, Liu S, Chen Y, Yao Y, Zhou M, Yuan Y, et al. Upregulation of HBV transcription by sodium taurocholate cotransporting polypeptide at the postentry step is inhibited by the entry inhibitor Myrcludex B. Emerg Microbes Infect. 2018;7(1):186.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. • König A, Döring B, Mohr C, Geipel A, Geyer J, Glebe D. Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes. J Hepatol. 2014;61(4):867–75 Study demonstrating that NTCP can be used as a target for entry inhibitors.

    PubMed  Google Scholar 

  49. Fu LL, Liu J, Chen Y, Wang FT, Wen X, Liu HQ, et al. In silico analysis and experimental validation of azelastine hydrochloride (N4) targeting sodium taurocholate co-transporting polypeptide (NTCP) in HBV therapy. Cell Prolif. 2014;47:326–35.

    CAS  PubMed  Google Scholar 

  50. Serrao E, Xu ZL, Debnath B, Christ F, Debyser Z, Long YQ, et al. Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction. Bioorg Med Chem. 2013;21:5963–72.

    CAS  PubMed  Google Scholar 

  51. Saso W, Tsukuda S, Ohashi H, Fukano K, Morishita R, Matsunaga S, et al. A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction. Biochem Biophys Res Commun. 2018;501(2):374–9.

    CAS  PubMed  Google Scholar 

  52. Osada H. Introduction of new tools for chemical biology research on microbial metabolites. Bioscience, Biotechnology and Biochemistry. 2010;74(6):1135-1140

  53. Kaneko M, Futamura Y, Tsukuda S, Kondoh Y, Sekine T, Hirano H, et al. Chemical array system, a platform to identify novel hepatitis b virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide. Sci Rep. 2018;8:2769.

    PubMed  PubMed Central  Google Scholar 

  54. Passioura T, Suga H. A RaPID way to discover nonstandard macrocyclic peptide modulators of drug targets. Chem Commun. 2017;53(12):1931–40.

    CAS  Google Scholar 

  55. Passioura T, Watashi K, Fukano K, Shimura S, Saso W, Morishita R, et al. De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry. Cell Chem Biol. 2018;25(7):906–915.e5.

    CAS  PubMed  Google Scholar 

  56. Miyakawa K, Matsunaga S, Yamaoka Y, Dairaku M, Fukano K, Kimura H, et al. Development of a cell-based assay to identify hepatitis B virus entry inhibitors targeting the sodium taurocholate cotransporting polypeptide. Oncotarget. 2018;9(34):23681–94.

    PubMed  PubMed Central  Google Scholar 

  57. Goh B, Choi J, Kang JA, Park SG, Seo J, Kim TY. Development of a mass spectrometric screening assay for hepatitis B virus entry inhibitors. J Pharm Biomed Anal. 2020;178:112959.

    CAS  PubMed  Google Scholar 

  58. Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, et al. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol. 2017;66:685–92.

    CAS  PubMed  Google Scholar 

  59. Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, et al. Cyclosporin a and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology. 2014;59:1726–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Nkongolo S, Ni Y, Lempp FA, Kaufman C, Lindner T, Esser-Nobis K, et al. Cyclosporin a inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol. 2014;60:723–31.

    CAS  PubMed  Google Scholar 

  61. Donkers JM, Zehnder B, Van Westen GJP, Kwakkenbos MJ, Ijzerman AP, Oude Elferink RPJ, et al. Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep. 2017;7(1):15307.

    PubMed  PubMed Central  Google Scholar 

  62. Iwamoto M, Watashi K, Tsukuda S, Aly HH, Fukasawa M, Fujimoto A, et al. Evaluation and identification of hepatitis B virus entry inhibitors using HepG2 cells overexpressing a membrane transporter NTCP. Biochem Biophys Res Commun. 2014;443:808–13.

    CAS  PubMed  Google Scholar 

  63. Lucifora J, Esser K, Protzer U. Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antivir Res. 2013;97(2):195–7.

    CAS  PubMed  Google Scholar 

  64. Abbas Z, Saad M, Asim M, Abbas M, Samejo SA. The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D. Turk J Gastroenterol. 2020;31:136–41.

    PubMed  PubMed Central  Google Scholar 

  65. Fukano K, Tsukuda S, Oshima M, Suzuki R, Aizaki H, Ohki M, et al. Troglitazone impedes the oligomerization of sodium taurocholate cotransporting polypeptide and entry of hepatitis B virus into hepatocytes. Front Microbiol. 2019;9:3257.

    PubMed  PubMed Central  Google Scholar 

  66. Nio Y, Akahori Y, Okamura H, Watashi K, Wakita T, Hijikata M. Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide. Biochem Biophys Res Commun. 2018;501:820–5.

    CAS  PubMed  Google Scholar 

  67. Blanchet M, Sureau C, Labonté P. Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle. Antivir Res. 2014;106:111–5.

    CAS  PubMed  Google Scholar 

  68. Ko C, Park WJ, Park S, Kim S, Windisch MP, Ryu WS. The FDA-approved drug irbesartan inhibits HBV-infection in HepG2 cells stably expressing sodium taurocholate co-transporting polypeptide. Antivir Ther. 2015;20:835–42.

    CAS  PubMed  Google Scholar 

  69. Jun WX, Hu W, Yu ZT, Ying MY, Nan LN, Qi WS. Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na+−dependent taurocholate cotransporting polypeptide activity. Antivir Res. 2015;120:140–6.

    Google Scholar 

  70. Pereira IVA, Buchmann B, Sandmann L, Sprinzl K, Schlaphoff V, Döhner K, et al. Primary biliary acids inhibit hepatitis D virus (HDV) entry into human hepatoma cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP). PLoS One. 2015;10(2):e0117152.

    Google Scholar 

  71. Umetsu T, Inoue J, Kogure T, Kakazu E, Ninomiya M, Iwata T, et al. Inhibitory effect of silibinin on hepatitis B virus entry. Biochem Biophys Reports. 2018;14:20–5.

    Google Scholar 

  72. Bruss V, Hagelstein J, Gerhardt E, Galle PR. Myristylation of the large surface protein is required for hepatitis B virus in vitro infectivity. Virology. 1996;218(2):396–9.

    CAS  PubMed  Google Scholar 

  73. Gripon P, Seyec JLE, Rumin S, Guguen-Guillouzo C. Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity. Virology. 1995;213:292–9.

    CAS  PubMed  Google Scholar 

  74. •• 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(3):1613–22 Important study that led to Myrcludex B.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 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;84:1989–2000.

    CAS  PubMed  Google Scholar 

  76. Glebe D, Urban S, Knoop EV, Çaǧ N, Krass P, Grün S, et al. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology. 2005;129:234–45.

    CAS  PubMed  Google Scholar 

  77. Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, Von Weizsäcker F, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol. 2008;26(3):335–41.

    CAS  PubMed  Google Scholar 

  78. Volz T, Allweiss L, ḾBarek MB, Warlich M, Lohse AW, Pollok JM, et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol. 2013;58(5):861–7.

    CAS  PubMed  Google Scholar 

  79. Lütgehetmann M, Mancke LV, Volz T, Helbig M, Allweiss L, Bornscheuer T, et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology. 2012;55:685–94.

    PubMed  Google Scholar 

  80. Schieck A, Schulze A, Gähler C, Müller T, Haberkorn U, Alexandrov A, et al. Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts. Hepatology. 2013;58(1):43–53.

    CAS  PubMed  Google Scholar 

  81. Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T, et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65:483–9.

    CAS  PubMed  Google Scholar 

  82. •• Bogomolov P. A phase 1b/2a randomized, open-label clinical trial of daily Myrcludex B versus entecavir in patients with HBeAg negative chronic hepatitis B [internet]. Available from: https://clinicaltrials.gov/ct2/show/results/NCT02881008. Accessed 28 Sept 2020. First human trial showing efficacy in HBV DNA suppression.

  83. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65:490–8.

    CAS  PubMed  Google Scholar 

  84. • Wedemeyer H, Bogomolov P, Blank A, Allweiss L, Dandri-Petersen M, Bremer B, et al. Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection. J Hepatol. 2018;68(1):S3 Phase II study demonstrating HBsAg decline and negativation.

    Google Scholar 

  85. Wedemeyer H A Multicenter, open-label, randomized clinical study to assess efficacy and safety of 3 doses of Myrcludex B for 24 weeks in combination with tenofovir compared to tenofovir alone to suppress HBV replication in patients with chronic hepatitis D [Internet]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT03546621. Accessed 28 Sept 2020.

  86. Wedemeyer H, Schöneweis K, Bogomolov PO, Voronkova N, Chulanov V, Stepanova T, et al. GS-13-Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in cwith PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection. J Hepatol. 2019;70(1):e81 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0618827819301410. Accessed 28 Sept 2020.

  87. Wedemeyer H, Schöneweis, Bogomolov PO, Chulanov V, Stepanova T, Viacheslav M, et al. 48 weeks of high dose (10mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection. J Hepatol. 2020;73:S52–3 Available from: https://ilc-congress.eu/wp-content/uploads/2020/08/digital-ilc-2020-abstract-book-20-august.pdf. Accessed 28 Sept 2020.

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  1. Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD, 21201, USA

    Sasan Sakiani, Bilal Asif & Alexander Yang

  2. Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, 10 Center Drive, CRC 5-2740, Bethesda, MD, 20892, USA

    Bilal Asif & Alexander Yang

  3. Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, 10 Center Drive, CRC 5-2740, Bethesda, MD, 20892, USA

    Christopher Koh

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Sakiani, S., Asif, B., Yang, A. et al. Role of Nucleic Acid Polymers and Entry Inhibitors in Functional Cure Strategies for HBV. Curr Hepatology Rep 19, 370–381 (2020). https://doi.org/10.1007/s11901-020-00550-w

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