Future Drugs in the Treatment of HBV

  • Aslıhan Demirel
  • Resat Ozaras


Chronic hepatitis B (CHB) virus infection, a major cause of cirrhosis and hepatocellular carcinoma (HCC), is a global public health problem. The treatment of CHB progressed during the last decades. Beginning with IFN and Peg-IFN, hepatitis B virus (HBV) treatment improved with the use of potent and safe antivirals. The newer antiviral agents, entecavir and tenofovir, are more potent and, with higher resistance barrier, have provided lifelong suppression of HBV replication. However, long-term use of HBV antivirals does not provide eradication.

The new strategy to completely cure CHB is described as the physical elimination of cccDNA, in addition to functional cure (HBsAg loss with or without anti-HB seroconversion, with undetectable serum DNA). This strategy may facilitate the implementation of antiviral treatments for a finite period of time, may reduce their cost, may increase drug accessibility to populations in highly endemic areas, and may have an impact on development of cirrhosis and HCC.

To provide a complete cure, the prominent promising agents are HBsAg release inhibitors, HBV entry inhibitors, antiviral effector cells that are stimulated, therapeutic vaccines, DNA vaccines, anti-cccDNA agents, and new antivirals, including tenofovir alafenamide, and besifovir. These drugs are in either preclinical or clinical levels of development.

Combinations of viral- and host-mediated drugs are promising to sustain the goal of complete cure in the near future.


Chronic hepatitis B Complete cure HBsAg release inhibitors HBV entry inhibitors Therapeutic vaccines Anti-cccDNA agents Tenofovir alafenamide Besifovir 


  1. 1.
    Schweitzer A, Horn J, Mikolajczyk R, et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–55.CrossRefPubMedGoogle Scholar
  2. 2.
    GBD. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;385:117–71.CrossRefGoogle Scholar
  3. 3.
    Yuen M, Seto W, Chow D, et al. Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther. 2007;12:1295–303.PubMedGoogle Scholar
  4. 4.
    Lim YS. Management of antiviral resistance in chronic hepatitis B. Gut Liver. 2017;11(2):189–95.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Terrault N, Bzowej N, Chang K, American Association for the Study of Liver Diseases, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Lampertico P, Agarwal K, Berg T, et al. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.CrossRefGoogle Scholar
  7. 7.
    Seto W, Hui A, Wong V, et al. Treatment cessation of entecavir in Asian patients with HBeAg-negative chronic hepatitis B: a multicenter prospective study. Gut. 2015;64:667–72.CrossRefPubMedGoogle Scholar
  8. 8.
    Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut. 2015;64:1972–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Durantel D, Zoulim F. New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus. J Hepatol. 2016;64(1 Suppl):S117–31. Scholar
  10. 10.
    Gish RG, Given BD, Lai C-L, Locarnini SA, Lau JYN, Lewis DL, et al. Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antivir Res. 2015;121:47–58.CrossRefPubMedGoogle Scholar
  11. 11.
    Zoulim F, Durantel D. Antiviral therapies and prospects for a cure of chronic hepatitis B. Cold Spring Harb Perspect Med. 2015;5:a021501. Scholar
  12. 12.
    Zeisel MB, Lucifora J, Mason WS, Sureau C, Beck J, Levrero M, et al. Towards an HBV cure: state-of-the-art and unresolved questions-report of the ANRS workshop on HBV cure. Gut. 2015;64:1314–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Yu MC, Yuan JM, Ross RK, et al. Presence of antibodies to the hepatitis B surface antigen is associated with an excess risk for hepatocellular carcinoma among non-Asians in Los Angeles County, California. Hepatology. 1997;25:226–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Yuen MF, Wong DK, Fung J, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135:1192–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Hoofnagle JH. Reactivation of hepatitis B. Hepatology. 2009;49:S156–65.CrossRefPubMedGoogle Scholar
  16. 16.
    Fourati S, Pawlotsky JM. Recent advances in understanding and diagnosing hepatitis B virus infection. F1000Res. 2016;5:2243.CrossRefGoogle Scholar
  17. 17.
    Seeger C, Mason W. Molecular biology of hepatitis B virus infection. Virology. 2015;479–480:672–86.CrossRefPubMedGoogle Scholar
  18. 18.
    Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. elife. 2012;1:e00049.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology. 2014;147(1):48–64.CrossRefPubMedGoogle Scholar
  20. 20.
    Lütgehetmann M, Mancke LV, Volz T, Helbig M, Allweiss L, Bornscheuer T, Pollok JM, Lohse AW, Petersen J, Urban S, Dandri M. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology. 2012;55(3):685–94.CrossRefPubMedGoogle Scholar
  21. 21.
    Ko C, Michler T, Protzer U. Novel viral and host targets to cure hepatitis B. Curr Opin Virol. 2017;24:38–45.CrossRefPubMedGoogle Scholar
  22. 22.
    Ward H, Tang L, Poonia B, et al. Treatment of hepatitis B virus: an update. Future Microbiol. 2016;11:1581–97.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Peters MG, Locarnini S. New direct-acting antiviral agents and immunomodulators for hepatitis B virus infection. Gastroenterol Hepatol (N Y). 2017;13(6):348–56.Google Scholar
  24. 24.
    Al-Mahtab M, Bazinet M, Vaillant A. Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naïve Bangladeshi patients with HBeAg+ chronic hepatitis B infection. PLoS One. 2016;11:e0156667.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bazinet M, Placinta G, Moscalu I, et al. Update on safety and efficacy in the REP 401 protocol: REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha 2A in treatment naive Caucasian patients with chronic HBeAg negative HBV infection. Hepatol Int. 2017;11:S85.Google Scholar
  26. 26.
    Xu YB, Yang L, Wang GF, et al. Benzimidazole derivative, BM601, a novel inhibitor of hepatitis B virus and HBsAg secretion. Antivir Res. 2014;107:6–15.CrossRefPubMedGoogle Scholar
  27. 27.
    Dougherty AM, Guo H, Westby G, et al. A substituted tetrahydro-tetrazolopyrimidine is a specific and novel inhibitor of hepatitis B virus surface antigen secretion. Antimicrob Agents Chemother. 2007;51(12):4427–37.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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;65:490–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Seki E, Park E, Fujimoto J. Toll-like receptor signaling in liver regeneration, fibrosis and carcinogenesis. Hepatol Res. 2011;41(7):597–610.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, Fosdick A, Frey CR, Zheng J, Wolfgang G, Halcomb RL, Tumas DB. GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013;144(7):1508–17.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Menne S, Tumas DB, Liu KH, Thampi L, AlDeghaither D, Baldwin BH, Bellezza CA, Cote PJ, Zheng J, Halcomb R, Fosdick A, Fletcher SP, Daffis S, Li L, Yue P, Wolfgang GH, Tennant BC. Sustained efficacy and seroconversion with the toll-like receptor 7 agonist GS-9620 in the woodchuck model of chronic hepatitis B. J Hepatol. 2015;62(6):1237–45.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Korolowicz KE, Iyer RP, Czerwinski S, Suresh M, Yang J, Padmanabhan S, Sheri A, Pandey RK, Skell J, Marquis JK, Kallakury BV, Tucker RD, Menne S. Antiviral efficacy and host innate immunity associated with SB 9200 treatment in the woodchuck model of chronic hepatitis B. PLoS One. 2016;11(8):e0161313.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ebert G, Allison C, Preston S, Cooney J, Toe JG, Stutz MD, Ojaimi S, Baschuk N, Nachbur U, Torresi J, Silke J, Begley CG, Pellegrini M. Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis. Proc Natl Acad Sci U S A. 2015;112(18):5803–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pham EA, Perumpail RB, Fram BJ, Glenn JS, Ahmed A, Gish RG. Future therapy for hepatitis B virus: role of immunomodulators. Curr Hepatol Rep. 2016;15(4):237–44.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kondo Y, Ninomiya M, Kakazu E, Kimura O, Shimosegawa T. Hepatitis B surface antigen could contribute to the immunopathogenesis of hepatitis B virus infection. ISRN Gastroenterol. 2013;2013:935295.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Barnes E. Therapeutic vaccines in HBV: lessons from HCV. Med Microbiol Immunol. 2015;204(1):79–86.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gaggar A, Coeshott C, Apelian D, Rodell T, Armstrong BR, Shen G, Subramanian GM, McHutchison JG. Safety, tolerability and immunogenicity of GS-4774, a hepatitis B virus-specific therapeutic vaccine, in healthy subjects: a randomized study. Vaccine. 2014;32(39):4925–31.CrossRefPubMedGoogle Scholar
  38. 38.
    Lok AS, Pan CQ, Han SH, Trinh HN, Fessel WJ, Rodell T, Massetto B, Lin L, Gaggar A, Subramanian GM, McHutchison JG, Ferrari C, Lee H, Gordon SC, Gane EJ. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J Hepatol. 2016;65(3):509–16.CrossRefPubMedGoogle Scholar
  39. 39.
    Mancini M, Hadchouel M, Davis HL, Whalen RG, Tiollais P, Michel ML. DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state. Proc Natl Acad Sci U S A. 1996;93:12496–501.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Prince AM, Whalen R, Brotman B. Successful nucleic acid based immunization of newborn chimpanzees against hepatitis B virus. Vaccine. 1997;15:916–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Donnelly JJ, Wahren B, Liu MA. DNA vaccines: progress and challenges. J Immunol. 2005;175:633–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Loirat D, Lemonnier FA, Michel ML. Multiepitopic HLA-A/0201-restricted immune response against hepatitis B surface antigen after DNA-based immunization. J Immunol. 2000;165:4748–55.CrossRefPubMedGoogle Scholar
  43. 43.
    Mancini-Bourgine M, Fontaine H, Scott-Algara D, Pol S, Brechot C, Michel ML. Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology. 2004;40:874–82.CrossRefPubMedGoogle Scholar
  44. 44.
    Yang FQ, Yu YY, Wang GQ, Chen J, Li JH, Li YQ, Rao GR, Mo GY, Luo XR, Chen GM. A pilot randomized controlled trial of dual-plasmid HBV DNA vaccine mediated by in vivo electroporation in chronic hepatitis B patients under lamivudine chemotherapy. J Viral Hepat. 2012;19(8):581–93.CrossRefPubMedGoogle Scholar
  45. 45.
    Yang FQ, Rao GR, Wang GQ, Li YQ, Xie Y, Zhang ZQ, Deng CL, Mao Q, Li J, Zhao W, Wang MR, Han T, Chen SJ, Pan C, Tan DM, Shang J, Zhang MX, Zhang YX, Yang JM, Chen GM. Phase IIb trial of in vivo electroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy. World J Gastroenterol. 2017;23(2):306–17.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Fung J, Lai C, Seto W, et al. Emerging drugs for the treatment of hepatitis B. Expert Opin Emerg Drugs. 2016;21:183–93.CrossRefPubMedGoogle Scholar
  47. 47.
    Lucifora J, Xia Y, Reisinger F, et al. Specific and non-hepatotoxic degradation of nuclear HBV cccDNA. Science. 2014;343:1221–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Revill P, Locarnini S. Antiviral strategies to eliminate hepatitis B virus covalently closed circular DNA (cccDNA). Curr Opin Pharmacol. 2016;30:144–50.CrossRefPubMedGoogle Scholar
  49. 49.
    Moyo B, Bloom K, Scott T, et al. Advances with using CRISPR/CASmediated gene editing to treat infections with hepatitis B virus and hepatitis C virus. Virus Res. 2018;244:311–20.CrossRefPubMedGoogle Scholar
  50. 50.
    Dong C, Qu L, Wang H, et al. Targeting HBV cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication. Antivir Res. 2015;118:110–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Ramanan V, Shlomai A, Cox DB, Schwartz RE, Michailidis E, Bhatta A, Scott DA, Zhang F, Rice CM, Bhatia SN. CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus. Sci Rep. 2015;5:10833.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lin G, Zhang K, Li J. Application of CRISPR/Cas9 technology to HBV. Int J Mol Sci. 2015;16(11):26077–86.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, Joung JK, Sander JD. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol. 2013;31(9):822–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, Hui AJ, Janssen HL, Chowdhury A, Tsang TY, Mehta R, Gane E, Flaherty JF, Massetto B, Gaggar A, Kitrinos KM, Lin L, Subramanian GM, McHutchison JG, Lim YS, Acharya SK, Agarwal K, GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):185–95.CrossRefPubMedGoogle Scholar
  55. 55.
    Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, Hui AJ, Lim YS, Mehta R, Janssen HL, Acharya SK, Flaherty JF, Massetto B, Cathcart AL, Kim K, Gaggar A, Subramanian GM, McHutchison JG, Pan CQ, Brunetto M, Izumi N, Marcellin P, GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):196–206.CrossRefPubMedGoogle Scholar
  56. 56.
    Mak LY, Seto WK, Lai CL, Yuen MF. Pharmacokinetic evaluation of besifovir for the treatment of HBV infection. Expert Opin Drug Metab Toxicol. 2018;14(1):101–6.CrossRefPubMedGoogle Scholar
  57. 57.
    Lai CL, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, Lee JW, Park NH, Kweon YO, Sohn JH, Lee J, Kim JA, Han KH, Yuen MF. Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B. Gut. 2014;63(6):996–1004.CrossRefPubMedGoogle Scholar
  58. 58.
    Yuen MF, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, Lee JW, Park NH, Kweon YO, Sohn JH, Lee J, Kim JA, Lai CL, Han KH. Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: results from a multicentre study. J Hepatol. 2015;62(3):526–32.CrossRefPubMedGoogle Scholar
  59. 59.
    Yuen MF, Han KH, Um SH, Yoon SK, Kim HR, Kim J, Kim CR, Lai CL. Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive chronic hepatitis B patients with lamivudine-resistant disease. Hepatology. 2010;51(3):767–76. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Aslıhan Demirel
    • 1
  • Resat Ozaras
    • 2
  1. 1.Department of Infectious Diseases and Clinical MicrobiologyFlorence Nightingale Hospital, Bilim UniversityIstanbulTurkey
  2. 2.Department of Infectious Diseases and Clinical MicrobiologyCerrahpasa Medical School, Istanbul UniversityIstanbulTurkey

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