Investigational treatments of chronic hepatitis B virus infection
- Anna SF Lok, MD
Anna SF Lok, MD
- Professor of Medicine
- University of Michigan Medical School
The main aim of treatment for chronic hepatitis B is to suppress HBV replication before there is irreversible liver damage. This topic review will discuss experimental treatments of chronic hepatitis B. A general approach to patients with hepatitis B (including other treatment options) is presented separately. (See "Hepatitis B virus: Overview of management".)
A number of antiviral agents for the treatment of chronic hepatitis B continue to be evaluated in clinical trials.
Emtricitabine — Emtricitabine (FTC) is a nucleoside analogue that is structurally similar to lamivudine and has potent antiviral activity against HBV and HIV [1,2]. The largest published study included 248 patients with chronic HBV (both HBeAg positive and negative) who had never received prior treatment with an nucleoside/tide analogue and were randomly assigned to emtricitabine or placebo for 48 weeks . Histologic improvement (defined as a 2-point reduction in the Knodell necroinflammatory score) was observed significantly more often in the active treatment group (62 versus 25 percent). Loss of detectable HBV DNA also occurred significantly more often with emtricitabine (54 versus 2 percent). However, HBV mutants with resistance to emtricitabine were observed in 13 percent of patients while HBeAg seroconversion was not significantly different than placebo.
Although studies comparing emtricitabine with lamivudine (or other oral agents) have not been performed, these data suggest that emtricitabine (200 mg daily) does not offer a clinically meaningful advantage since rates of HBV DNA loss, HBeAg seroconversion, histologic improvement and the development of resistant mutations are similar. In addition, mutants that are resistant to emtricitabine are also resistant to lamivudine and telbivudine and less sensitive to entecavir. Thus, the role of emtricitabine monotherapy in the treatment of chronic hepatitis B is limited. Emtricitabine alone is not used in clinical practice, but emtricitabine coformulated with tenofovir as a single pill is sometimes used off label in patients with lamivudine-resistant HBV.
Drugs no longer under development — Several drugs showed initial promise but are no longer under development for a variety of reasons. These include famciclovir, val-d-cytosine (LdC), valtorcitabine, LB80380, alamifovir, and pradefovir. Clevudine was approved in Korea but subsequently withdrawn due to postmarketing reports of myopathy.
- Gish RG, Trinh H, Leung N, et al. Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study. J Hepatol 2005; 43:60.
- Lim SG, Ng TM, Kung N, et al. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med 2006; 166:49.
- Fletcher SP, Delaney WE 4th. New therapeutic targets and drugs for the treatment of chronic hepatitis B. Semin Liver Dis 2013; 33:130.
- Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012; 1:e00049.
- Volz T, Allweiss L, Ben MBarek M, et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol 2013; 58:861.
- 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; 60:723.
- Cai D, Mills C, Yu W, et al. Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation. Antimicrob Agents Chemother 2012; 56:4277.
- Cradick TJ, Keck K, Bradshaw S, et al. Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs. Mol Ther 2010; 18:947.
- Zimmerman KA, Fischer KP, Joyce MA, Tyrrell DL. Zinc finger proteins designed to specifically target duck hepatitis B virus covalently closed circular DNA inhibit viral transcription in tissue culture. J Virol 2008; 82:8013.
- McCaffrey AP, Nakai H, Pandey K, et al. Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 2003; 21:639.
- Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 2005; 23:1002.
- Klein C, Bock CT, Wedemeyer H, et al. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA. Gastroenterology 2003; 125:9.
- Deres K, Schröder CH, Paessens A, et al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science 2003; 299:893.
- Feld JJ, Colledge D, Sozzi V, et al. The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antiviral Res 2007; 76:168.
- Mahtab, MA., Bazinet, M., and Vaillant, A. REP 9AC': A second generation HBsAg release inhibitor with improved tolerability. Hepatology 2012; 56: 401A-402A.
- Block TM, Lu X, Platt FM, et al. Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin. Proc Natl Acad Sci U S A 1994; 91:2235.
- Mutchnick MG, Appelman HD, Chung HT, et al. Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Hepatology 1991; 14:409.
- Andreone P, Cursaro C, Gramenzi A, et al. A randomized controlled trial of thymosin-alpha1 versus interferon alfa treatment in patients with hepatitis B e antigen antibody--and hepatitis B virus DNA--positive chronic hepatitis B. Hepatology 1996; 24:774.
- Chien RN, Liaw YF, Chen TC, et al. Efficacy of thymosin alpha1 in patients with chronic hepatitis B: a randomized, controlled trial. Hepatology 1998; 27:1383.
- Mutchnick MG, Lindsay KL, Schiff ER, et al. Thymosin alpha1 treatment of chronic hepatitis B: results of a phase III multicentre, randomized, double-blind and placebo-controlled study. J Viral Hepat 1999; 6:397.
- Fattovich G, Giustina G, Alberti A, et al. A randomized controlled trial of thymopentin therapy in patients with chronic hepatitis B. J Hepatol 1994; 21:361.
- Chan HL, Tang JL, Tam W, Sung JJ. The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis. Aliment Pharmacol Ther 2001; 15:1899.
- Lau GK, Nanji A, Hou J, et al. Thymosin-alpha1 and famciclovir combination therapy activates T-cell response in patients with chronic hepatitis B virus infection in immune-tolerant phase. J Viral Hepat 2002; 9:280.
- Saruc M, Yuceyar H, Kucukmetin N, et al. Combination thymosin-alpha 1 and interferon-alpha 2b in the treatment of anti-HBe-positive chronic hepatitis B in Turkey. Hepatogastroenterology 2002; 49:798.
- Publicover J, Goodsell A, Nishimura S, et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest 2011; 121:1154.
- Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis 2007; 7:804.
- Shouval D, Roggendorf H, Roggendorf M. Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S vaccine. Med Microbiol Immunol 2015; 204:57.
- Couillin I, Pol S, Mancini M, et al. Specific vaccine therapy in chronic hepatitis B: induction of T cell proliferative responses specific for envelope antigens. J Infect Dis 1999; 180:15.
- Whalen RG, Leclerc C, Dériaud E, et al. DNA-mediated immunization to the hepatitis B surface antigen. Activation and entrainment of the immune response. Ann N Y Acad Sci 1995; 772:64.
- Mancini M, Hadchouel M, Davis HL, et al. 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.
- Rehermann B, Fowler P, Sidney J, et al. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med 1995; 181:1047.
- Heathcote J, McHutchison J, Lee S, et al. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group. Hepatology 1999; 30:531.
- King TH, Kemmler CB, Guo Z, et al. A whole recombinant yeast-based therapeutic vaccine elicits HBV X, S and Core specific T cells in mice and activates human T cells recognizing epitopes linked to viral clearance. PLoS One 2014; 9:e101904.
- Roethle PA, McFadden RM, Yang H, et al. Identification and optimization of pteridinone Toll-like receptor 7 (TLR7) agonists for the oral treatment of viral hepatitis. J Med Chem 2013; 56:7324.
- Menne S, Tumas DB, Liu KH, et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol 2015; 62:1237.
- Lanford RE, Guerra B, Chavez D, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013; 144:1508.
- Lau GK, Lok AS, Liang RH, et al. Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer. Hepatology 1997; 25:1497.
- Lau GK, Suri D, Liang R, et al. Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen. Gastroenterology 2002; 122:614.
- Weng HL, Wang BE, Jia JD, et al. Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clin Gastroenterol Hepatol 2005; 3:819.
- Pockros PJ, Jeffers L, Afdhal N, et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 2007; 45:569.
- ANTIVIRAL AGENTS
- Drugs no longer under development
- NOVEL ANTIVIRAL APPROACHES
- Viral entry inhibitors
- ccc DNA inhibitors
- Agents that decrease transcription and/or stability of HBV RNA
- Inhibitors of nucelocapsid assembly
- Inhibitors of HBsAg or HBV virion secretion
- Immunomodulatory agents
- - Thymosin
- - Cytokines
- - Blocking suppressive cytokines and regulatory T-cells
- HBV vaccines
- - S and pre-S vaccines +/- antiviral therapy
- - DNA vaccination
- - T cell vaccines
- - Other strategies
- Toll-like receptor (tlr) agonists
- Adoptive immunity transfer
- THERAPY AIMED AT IMPROVING FIBROSIS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS