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.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.
European Association For The Study Of The Liver. Clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–42.
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.
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.
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.
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.
Thomas H, Foster G, Platis D. Mechanisms of action of interferon and nucleoside analogues. J Hepatol. 2003;39:S93–8.
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.
• 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.
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.
Locarnini S, Zoulim F. Molecular genetics of HBV infection. Antivir Ther. 2010;15 Suppl 3:3–14.
Doo EC, Ghany MG. Hepatitis B virology for clinicians. Clin Liver Dis. 2010;14:397–408.
Bertoletti A, Maini MK, Ferrari C. The host–pathogen interaction during HBV infection: immunological controversies. Antivir Ther. 2010;15 Suppl 3:15–24.
Lee JS, Park ET, Kang SS, et al. Clevudine demonstrates potent antiviral activity in naïve chronic hepatitis B patients. Intervirology. 2010;53:83–6.
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.
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.
• 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.
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.
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.
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.
• 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.
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.
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.
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.
• 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..
• 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.
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.
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.
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.
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.
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.
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.
• 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.
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.
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.
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.
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.
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.
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.
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.
Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–4.
• 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.
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.
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.
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.
Stray SJ, Zlotnick A. BAY 41–4109 has multiple effects on Hepatitis B virus capsid assembly. J Mol Recognit. 2006;19:542–8.
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.
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.
Cardin RD, Bravo FJ, Sewell AP, et al. Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection. Virol J. 2009;6:214.
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.
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.
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.
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.
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.
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.
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.
Keeffe EB, Rossignol JF. Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides. World J Gastroenterol. 2009;15(15):1805–8.
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.
Disclosure
Dr Strasser serves on advisory boards for Gilead Sciences, Bristol Myers Squibb and Roche.
Author information
Authors and Affiliations
Corresponding author
Rights 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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11901-012-0131-9