Skip to main content

Advertisement

Log in

Drugs in Development for the Treatment of Chronic Hepatitis B

  • Hepatitis B: Therapeutics (P Martin, Section Editor)
  • Published:
Current Hepatitis Reports Aims and scope Submit manuscript

Abstract

Currently available therapies for patients with chronic hepatitis B are safe, well tolerated, and highly effective in achieving improved outcomes reflecting potent viral suppression with low rates of antiviral resistance. For the majority of patients however, long-term treatment is necessary with significant cost implications and potential for complications. Current oral antiviral therapies are directed only at a single component of the hepatitis B lifecycle, while interferon therapy is effective only in a minority of patients. Efforts are underway to develop agents directed at novel targets derived from mechanisms of cellular entry, viral replication, or viral assembly leading to preclinical and clinical trials with impressive preliminary results. Additional development of agents directed at the host immune response offers the possibility of combination therapies with independent mechanisms of action that may pave the way for regimens of finite duration with long-lasting control of chronic hepatitis B infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

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

  1. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.

    Article  PubMed  Google Scholar 

  2. European Association For The Study Of The Liver. Clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–42.

    Article  Google Scholar 

  3. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–83.

    Article  PubMed  Google Scholar 

  4. Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol. 2009;51:581–92.

    Article  PubMed  CAS  Google Scholar 

  5. Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology. 2011;53:763–73.

    Article  PubMed  CAS  Google Scholar 

  6. Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology. 2009;49:1151–7.

    Article  PubMed  CAS  Google Scholar 

  7. Thomas H, Foster G, Platis D. Mechanisms of action of interferon and nucleoside analogues. J Hepatol. 2003;39:S93–8.

    Article  PubMed  CAS  Google Scholar 

  8. Chang CM, Jeng KS, Hu CP, et al. Production of hepatitis B virus in vitro by transient expression of cloned HBV DNA in a hepatoma cell line. EMBO J. 1987;6:675–80.

    PubMed  CAS  Google Scholar 

  9. • Lütgehetmann M, Mancke LV, Volz T et al. Human chimeric uPA mouse model to study hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology. 2012;55:685–94. Description of an important animal model for the evaluation of novel compounds for the treatment of chronic hepatitis B.

  10. Zlotnick A, Lee A, Bourne CR, Johnson JM, Domanico PL, Stray SJ. In vitro screening for molecules that affect virus capsid assembly and other protein association reactions. Nat Protoc. 2007;2:490–8.

    Article  PubMed  CAS  Google Scholar 

  11. Locarnini S, Zoulim F. Molecular genetics of HBV infection. Antivir Ther. 2010;15 Suppl 3:3–14.

    Article  PubMed  CAS  Google Scholar 

  12. Doo EC, Ghany MG. Hepatitis B virology for clinicians. Clin Liver Dis. 2010;14:397–408.

    Article  PubMed  Google Scholar 

  13. Bertoletti A, Maini MK, Ferrari C. The host–pathogen interaction during HBV infection: immunological controversies. Antivir Ther. 2010;15 Suppl 3:15–24.

    Article  PubMed  CAS  Google Scholar 

  14. Lee JS, Park ET, Kang SS, et al. Clevudine demonstrates potent antiviral activity in naïve chronic hepatitis B patients. Intervirology. 2010;53:83–6.

    Article  PubMed  CAS  Google Scholar 

  15. Kim JH, Yim HJ, Jung ES, et al. Virologic and biochemical responses to clevudine in patients with chronic HBV infection-associated cirrhosis: data at week 48. J Viral Hepat. 2011;18:287–93.

    Article  PubMed  CAS  Google Scholar 

  16. Yang HW, Lee BS, Lee TH, et al. Efficacy of initial treatment with clevudine in naive patients with chronic hepatitis B. Korean J Intern Med. 2010;25:372–6.

    Article  PubMed  CAS  Google Scholar 

  17. • Jang JH, Kim JW, Jeong SH, et al. Clevudine for chronic hepatitis B: antiviral response, predictors of response, and development of myopathy. J Viral Hepat. 2011;18:84–90.

    Article  PubMed  Google Scholar 

  18. Lau GK, Leung N. Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study. Korean J Hepatol. 2010;16:315–20.

    Article  PubMed  Google Scholar 

  19. Yoon EL, Yim HJ, Lee HJ, Lee YS, Kim JH, Jung ES, Kim JH, Seo YS, Yeon JE, Lee HS, Um SH, Byun KS. Comparison of clevudine and entecavir for treatment naïve patients with chronic hepatitis B virus infection: two-year follow-up data. J Clin Gastroenterol. 2011;45:893–9.

    Article  PubMed  CAS  Google Scholar 

  20. Kwon SY, Park YK, Ahn SH, et al. Identification and characterization of clevudine-resistant mutants of hepatitis B virus isolated from chronic hepatitis B patients. J Virol. 2010;84:4494–503.

    Article  PubMed  CAS  Google Scholar 

  21. • Seok JI, Lee DK, Lee CH, et al. Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA. Hepatology. 2009;49:2080–6. Initial report of mitochondrial myopathy in patients receiving clevudine. A cautionary tale of potential toxicity with nucleoside analogue agents.

    Article  PubMed  CAS  Google Scholar 

  22. Tak WY, Park SY, Jung MK, et al. Mitochondrial myopathy caused by clevudine therapy in chronic hepatitis B patients. Hepatol Res. 2009;39:944–7.

    Article  PubMed  CAS  Google Scholar 

  23. Kim BK, Oh J, Kwon SY, Choe WH, Ko SY, Rhee KH, et al. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol. 2009;51:829–34.

    Article  PubMed  Google Scholar 

  24. Kim HJ, Park DI, Park JH, et al. Comparison between clevudine and entecavir treatment for antiviral-naïve patients with chronic hepatitis B. Liver Int. 2010;30:834–40.

    Article  PubMed  CAS  Google Scholar 

  25. • Tak WY, Park SY, Cho CM, et al. Clinical, biochemical, and pathological characteristics of clevudine-associated myopathy. J Hepatol. 2010;53:261–6. A detailed assessment of patients with mitochondrial myopathy secondary to clevudine..

    Article  PubMed  CAS  Google Scholar 

  26. • Berg T, Marcellin P, Zoulim F, et al. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection. Gastroenterology. 2010;139(4):1207–17. Important paper demonstrating that combination therapy may not offer advantages over monotherapy with a well-tolerated potent agent with a high barrier to resistance even in patients with prior antiviral drug resistance.

    Article  PubMed  CAS  Google Scholar 

  27. Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247–54.

    Article  PubMed  CAS  Google Scholar 

  28. Si-Ahmed SN, Pradat P, Zoutendijk R, et al. Efficacy and tolerance of a combination of tenofovir disoproxil fumarate plus emtricitabine in patients with chronic hepatitis B: a European multicenter study. Antiviral Res. 2011;92:90–5.

    Article  PubMed  CAS  Google Scholar 

  29. Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62–72.

    Article  PubMed  CAS  Google Scholar 

  30. Fung J, Lai CL, Yuen MF. LB80380: a promising new drug for the treatment of chronic hepatitis B. Expert Opin Investig Drugs. 2008;17:1581–8.

    Article  PubMed  CAS  Google Scholar 

  31. Min CH, Kim CR, Steffy K, Averett D, Locarnini S, Shaw T. The active metabolite of LB80380/ANA380, a novel nucleotide analog, exhibits activity in vitro against multiple clinically relevant hepatitis B virus mutants. J Hepatol. 2007;46 Suppl 1:S159.

    Article  Google Scholar 

  32. Yuen MF, Kim J, Kim CR, et al. A randomized placebo-controlled, dose-finding study of oral LB80380 in HBeAg-positive patients with chronic hepatitis B. Antivir Ther. 2006;11:977–83.

    PubMed  CAS  Google Scholar 

  33. • Yuen MF, Han KH, Um SH, et al. Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive chronic hepatitis B patients with lamivudine-resistant disease. Hepatology. 2010;51:767–76. Demonstration that in patients with lamivudine-resistant chronic hepatitis B, 12 weeks of therapy with LB80380 resulted in profound viral suppression, and was safe and well tolerated. Publications of long-term outcomes in treatment naïve and patients with antiviral resistance are awaited.

    Article  PubMed  CAS  Google Scholar 

  34. Lai CL, Ahn SH, Lee KS, et al. Week 48 analysis of a phase IIb study of the efficacy and safety of LB80380 vs. entecavir in treatment-naïve patients with chronic hepatitis B. Hepatology. 2011;54 (Suppl S1):1442A.

    Google Scholar 

  35. Reddy KR, Matelich MC, Ugarkar BG, et al. Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B. J Med Chem. 2008;51:666–76.

    Article  PubMed  CAS  Google Scholar 

  36. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49:1898–906.

    Article  PubMed  CAS  Google Scholar 

  37. Jacquard AC, Brunelle MN, Pichoud C, et al. In vitro characterization of the anti-hepatitis B virus activity and cross-resistance profile of 2′,3′-dideoxy-3′-fluoroguanosine. Antimicrob Agents Chemother. 2006;50:955–61.

    Article  PubMed  CAS  Google Scholar 

  38. Michalak TI, Zhang H, Churchill ND, Larsson T, Johansson NG, Öberg B. Profound antiviral effect of oral administration of MIV-210 on chronic hepadnaviral infection in a woodchuck model of hepatitis B. Antimicrob Agents Chemother. 2009;53:3803–14.

    Article  PubMed  CAS  Google Scholar 

  39. Zeuzem S, Arora S, Bacon B, et al. Pegylated interferon-lambda (pegIFN-λ) shows superior viral response with improved safety and tolerability versus pegIFN-α2a in HCV patients (G1/2/3/4): EMERGE phase IIb through week 12. J Hepatol. 2011;54 Suppl 1:S538–9.

    Article  Google Scholar 

  40. Pagliaccetti NE, Chu EN, Bolen CR, Kleinstein SH, Robek MD. Lambda and alpha interferons inhibit hepatitis B virus replication through a common molecular mechanism but with different in vivo activities. Virology. 2010;401:197–206.

    Article  PubMed  CAS  Google Scholar 

  41. Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–4.

    Article  PubMed  CAS  Google Scholar 

  42. • 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;26:335–41. Key paper describing the profound effects of Myrcludex-B, the leading HBV entry inhibitor in clinical development.

    Article  PubMed  CAS  Google Scholar 

  43. Ben M’ Barek M, Volz T, Lutgehetmannet M, et al. Administration of the entry inhibitor Myrcludex-B after establishment of hepatitis B virus infection prevents viral spreading among human hepatocytes in uPa mice. J Hepatol. 2011;54 Suppl 1:S33.

    Article  Google Scholar 

  44. Deres K, Schröder CH, Paessens A, et al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science. 2003;299:893–6.

    Article  PubMed  CAS  Google Scholar 

  45. Stray SJ, Bourne CR, Punna S, et al. A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly. Proc Natl Acad Sci USA. 2005;102:8138–43.

    Article  PubMed  CAS  Google Scholar 

  46. Stray SJ, Zlotnick A. BAY 41–4109 has multiple effects on Hepatitis B virus capsid assembly. J Mol Recognit. 2006;19:542–8.

    Article  PubMed  CAS  Google Scholar 

  47. Brezillon N, Brunelle M-N, Massinet H et al. Antiviral activity of Bay 41–4109 on hepatitis B virus in humanized Alb-uPA/SCID mice. PLoS One. 2011; Epub ahead of print.

  48. Bernstein DI, Goyette N, Cardin R, et al. Amphipathic DNA polymers exhibit antiherpetic activity in vitro and in vivo. Antimicrob Agents Chemother. 2008;52:2727–33.

    Article  PubMed  CAS  Google Scholar 

  49. Cardin RD, Bravo FJ, Sewell AP, et al. Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection. Virol J. 2009;6:214.

    Article  PubMed  Google Scholar 

  50. Vaillant A, Juteau JM, Lu H, et al. Phosphorothioate oligonucleotides inhibit human immunodeficiency virus type 1 fusion by blocking gp41 core formation. Antimicrob Agents Chemother. 2006;50:1393–401.

    Article  PubMed  CAS  Google Scholar 

  51. Matsumura T, Hu Z, Kato T, et al. Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry. Gastroenterology. 2009;137:673–81.

    Article  PubMed  CAS  Google Scholar 

  52. Mahtab MA, Bazinet M, Vaillant A. REP 9 AC: a potent HBsAg release inhibitor that elicits durable immunological control of chronic HBV infection. Hepatology. 2011;54(Suppl S1):478A.

    Google Scholar 

  53. Mahtab MA, Bazinet M, Patient R, Roingeard P, Vaillant A. Nucleic acid polymers REP 9 AC/REP 9 AC’ elicit sustained immunologic control of chronic HBV infection. Glob Antiviral J. 2011;7 Suppl 1:64A.

    Google Scholar 

  54. Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-Like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79:7269–72.

    Article  PubMed  CAS  Google Scholar 

  55. Lanford RE, Guerra B, Chavez DC, et al. Therapeutic efficacy of the TLR7 agonist GS-9620 for HBV chronic infection in chimpanzees. J Hepatol. 2011;54 Suppl 1:S45.

    Article  Google Scholar 

  56. Lopatin U, Wolfgang G, Kimberlin R, et al. A phase-I, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single escalating oral doses of GS-9620 in healthy subjects. J Hepatol. 2011;54 Suppl 1:S296.

    Article  Google Scholar 

  57. Keeffe EB, Rossignol JF. Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides. World J Gastroenterol. 2009;15(15):1805–8.

    Article  PubMed  CAS  Google Scholar 

  58. Rossignol JF, Keeffe EB. Thiazolides: a new class of drugs for the treatment of chronic hepatitis B and C. Future Microbiol. 2008;3:539–45.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Dr Strasser serves on advisory boards for Gilead Sciences, Bristol Myers Squibb and Roche.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Simone I. Strasser.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strasser, S.I. Drugs in Development for the Treatment of Chronic Hepatitis B. Curr Hepatitis Rep 11, 111–118 (2012). https://doi.org/10.1007/s11901-012-0131-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-012-0131-9

Keywords

Navigation