5,605
Views
4
CrossRef citations to date
0
Altmetric
Review

Novel therapeutic strategies for chronic hepatitis B

, &
Pages 1111-1132 | Received 15 Mar 2022, Accepted 20 Jun 2022, Published online: 06 Jul 2022

References

  • Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035.
  • Asrani SK, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world. J Hepatol. 2019;70:151–171.
  • Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology. 2013;57:399–408.
  • Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: from discovery to regulatory approval. Hepatology. 2017;66:1296–1313.
  • Lampertico P, Agarwal K, Berg T; EASL. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–398. DOI:10.1016/j.jhep.2017.03.021.
  • Gish R, Jia JD, Locarnini S, et al. Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis. 2012;12:341–353.
  • Yip TC, Wong VW, Chan HL, et al. Tenofovir is associated with lower risk of hepatocellular carcinoma than Entecavir in patients with chronic HBV infection in China. Gastroenterology. 2020;158:215–225.e216.
  • Tseng CH, Tseng CM, Wu JL, et al. Magnitude of and prediction for risk of hepatocellular carcinoma in patients with chronic hepatitis B taking entecavir or tenofovir therapy: a systematic review. J Gastroenterol Hepatol. 2020;35:1684–1693.
  • Papatheodoridis GV, Idilman R, Dalekos GN, et al. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology. 2017;66:1444–1453.
  • Phillips S, Chokshi S, Riva A, et al. CD8(+) T cell control of hepatitis B virus replication: direct comparison between cytolytic and noncytolytic functions. J Immunol. 2010;184:287–295.
  • Proto S, Taylor JA, Chokshi S, et al. APOBEC and iNOS are not the main intracellular effectors of IFN-gamma-mediated inactivation of hepatitis B virus replication. Antiviral Res. 2008;78:260–267.
  • Chokshi S, Cooksley H, Riva A, et al. Identification of serum cytokine profiles associated with HBeAg seroconversion following antiviral treatment interruption. Viral Immunol. 2014;27:235–244.
  • Cooksley H, Chokshi S, Maayan Y, et al. Hepatitis B virus e antigen loss during adefovir dipivoxil therapy is associated with enhanced virus-specific CD4+ T-cell reactivity. Antimicrob Agents Chemother. 2008;52:312–320.
  • Cooksley H, Riva A, Katzarov K, et al. Differential expression of immune inhibitory checkpoint signatures on antiviral and inflammatory T cell populations in chronic hepatitis B. J Interferon Cytokine Res. 2018;38:273–282.
  • Evans A, Riva A, Cooksley H, et al. Programmed death 1 expression during antiviral treatment of chronic hepatitis B: impact of hepatitis B e-antigen seroconversion. Hepatology. 2008;48:759–769.
  • Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143:963–973.e969.
  • Xu Y, Liu Y, Zhao M, et al. Dynamic perturbations of CD4 and CD8 T cell receptor repertoires in chronic hepatitis B patients upon oral antiviral therapy. Front Immunol. 2017;8:1142.
  • Lian YF, Xu Y, Gu YR, et al. Distinct T-cell receptor profiles associated with hepatitis B e antigen seroconversion during entecavir treatment. Liver Int. 2020;40:2672–2684.
  • Lau GK, Cooksley H, Ribeiro RM, et al. Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B. Antivir Ther. 2007;12:705–718.
  • Cao W, Li M, Zhang L, et al. The characteristics of natural killer cells in chronic hepatitis B patients who received PEGylated-Interferon versus Entecavir therapy. Biomed Res Int. 2021;2021:2178143.
  • Micco L, Peppa D, Loggi E, et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol. 2013;58:225–233.
  • Penna A, Laccabue D, Libri I, et al. Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis. J Hepatol. 2012;56:1239–1246.
  • Carotenuto P, Artsen A, Niesters HG, et al. In vitro use of autologous dendritic cells improves detection of T cell responses to hepatitis B virus (HBV) antigens. J Med Virol. 2009;81:332–339.
  • Tan G, Song H, Xu F, et al. When hepatitis B virus meets interferons. Front Microbiol. 2018;9:1611.
  • Sadler AJ, Williams BR. Interferon-Inducible antiviral effectors. Nat Rev Immunol. 2008;8:559–568.
  • Xu C, Guo H, Pan XB, et al. Interferons accelerate decay of replication-competent nucleocapsids of hepatitis B virus. J Virol. 2010;84:9332–9340.
  • Reinharz V, Ishida Y, Tsuge M, et al. Understanding hepatitis B virus dynamics and the antiviral effect of interferon alpha treatment in humanized chimeric mice. J Virol. 2021;95:e0049220.
  • Li J, Lin S, Chen Q, et al. Inhibition of hepatitis B virus replication by MyD88 involves accelerated degradation of pregenomic RNA and nuclear retention of pre-S/S RNAs. J Virol. 2010;84:6387–6399.
  • Cheng J, Zhao Q, Zhou Y, et al. Interferon alpha induces multiple cellular proteins that coordinately suppress hepadnaviral covalently closed circular DNA transcription. J Virol. 2020;94. DOI:10.1128/JVI.00442-20.
  • Belloni L, Allweiss L, Guerrieri F, et al. IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 2012;122:529–537.
  • Wang G, Guan J, Khan NU, et al. Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus. Gut Pathog. 2021;13:22.
  • Lucifora J, Xia Y, Reisinger F, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343:1221–1228.
  • Li Y, Xia Y, Han M, et al. IFN-α-Mediated base excision repair pathway correlates with antiviral response against Hepatitis B virus infection. Sci Rep. 2017;7:12715.
  • Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol. 2016;18:109–116.
  • Sonneveld MJ, Janssen HL. Chronic hepatitis B: peginterferon or nucleos(t)ide analogues? Liver Int. 2011;31(Suppl 1):78–84.
  • Nishio A, Bolte FJ, Takeda K, et al. Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection. Sci Transl Med. 2021;13:eaba6322.
  • Tangkijvanich P, Chittmittraprap S, Poovorawan K, et al. A randomized clinical trial of peginterferon alpha-2b with or without entecavir in patients with HBeAg-negative chronic hepatitis B: role of host and viral factors associated with treatment response. J Viral Hepat. 2016;23:427–438.
  • Ahn SH, Marcellin P, Ma X, et al. Hepatitis B surface antigen loss with Tenofovir Disoproxil Fumarate plus Peginterferon Alfa-2a: week 120 analysis. Dig Dis Sci. 2018;63:3487–3497.
  • Marcellin P, Ahn SH, Ma X, et al. Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a increases loss of Hepatitis B surface antigen in patients with chronic Hepatitis B. Gastroenterology. 2016;150:134–144.e110.
  • Hagiwara S, Nishida N, Watanabe T, et al. Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B. Antivir Ther. 2018;23:513–521.
  • Brouwer WP, Xie Q, Sonneveld MJ, et al. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study). Hepatology. 2015;61:1512–1522.
  • Chi H, Hansen BE, Guo S, et al. Pegylated Interferon Alfa-2b add-on treatment in hepatitis B virus envelope antigen-positive chronic hepatitis B patients treated with nucleos(t)ide analogue: a randomized, controlled trial (PEGON). J Infect Dis. 2017;215:1085–1093.
  • Kittner JM, Sprinzl MF, Grambihler A, et al. Adding pegylated interferon to a current nucleos(t)ide therapy leads to HBsAg seroconversion in a subgroup of patients with chronic hepatitis B. J Clin Virol. 2012;54:93–95.
  • Lampertico P, Brunetto MR, Craxì A, et al. Add-On peginterferon alfa-2a to nucleos(t)ide analogue therapy for Caucasian patients with hepatitis B ‘e’ antigen-negative chronic hepatitis B genotype D. J Viral Hepat. 2019;26:118–125.
  • Han M, Jiang J, Hou J, et al. Sustained immune control in HBeAg-positive patients who switched from entecavir therapy to pegylated interferon-α2a: 1 year follow-up of the OSST study. Antivir Ther. 2016;21:337–344.
  • Hu P, Shang J, Zhang W, et al. HBsAg loss with Peg-interferon Alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: new switch study. J Clin Transl Hepatol. 2018;6:25–34.
  • Tamaki N, Kurosaki M, Kusakabe A, et al. Hepatitis B surface antigen reduction by switching from long-term nucleoside/nucleotide analogue administration to pegylated interferon. J Viral Hepat. 2017;24:672–678.
  • Chong CH, Lim SG. When can we stop nucleoside analogues in patients with chronic hepatitis B? Liver Int. 2017;37(Suppl 1):52–58.
  • Hadziyannis SJ, Sevastianos V, Rapti I, et al. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology. 2012;143:629–636.e621.
  • van Bömmel F, Berg T. Risks and benefits of discontinuation of nucleos(t)ide analogue treatment: a treatment concept for patients with HBeAg-negative chronic hepatitis B. Hepatol Commun. 2021;5:1632–1648.
  • García-López M, Lens S, Pallett LJ, et al. Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients. J Hepatol. 2021;74:1064–1074.
  • Rinker F, Zimmer CL, Höner Zu Siederdissen C, et al. Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Hepatol. 2018;69:584–593.
  • Rivino L, Le Bert N, Gill US, et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest. 2018;128:668–681.
  • Jeng WJ, Sheen IS, Chen YC, et al. Off-Therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology. 2013;58:1888–1896.
  • Guo F, Zhao Q, Sheraz M, et al. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways. PLoS Pathog. 2017;13:e1006658.
  • Lahlali T, Berke JM, Vergauwen K, et al. Novel potent capsid assembly modulators regulate multiple steps of the hepatitis B virus life cycle. Antimicrob Agents Chemother. 2018;62:62. DOI:10.1128/AAC.00835-18
  • Yang L, Liu F, Tong X, et al. Treatment of chronic hepatitis B virus infection using small molecule modulators of nucleocapsid assembly: recent advances and perspectives. ACS Infect Dis. 2019;5:713–724.
  • Nijampatnam B, Liotta DC. Recent advances in the development of HBV capsid assembly modulators. Curr Opin Chem Biol. 2019;50:73–79.
  • Yuen M-F, Zhou X, Gane E, et al. Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial. Lancet Gastroenterol Hepatol. 2021;6:723–732.
  • Cosson V, Feng S, Jaminion F, et al. How Semiphysiological population pharmacokinetic modeling incorporating active hepatic uptake supports phase II dose selection of RO7049389, a novel anti-hepatitis B Virus Drug. Clin Pharmacol Ther. 2021;109:1081–1091.
  • Feng S, Gane E, Schwabe C, et al. A five-in-one first-in-human study to assess safety, tolerability, and pharmacokinetics of RO7049389, an inhibitor of hepatitis B virus capsid assembly, after single and multiple ascending doses in healthy participants. Antimicrob Agents Chemother. 2020;64:64. DOI:10.1128/AAC.01323-20
  • Zhang H, Wang F, Zhu X, et al. Antiviral activity and pharmacokinetics of the hepatitis B virus (HBV) capsid assembly modulator GLS4 in patients with chronic HBV infection. Clinl Infect Dis. 2020;73:175–182.
  • Zhao N, Jia B, Zhao H, et al. A first-in-human trial of GLS4, a novel inhibitor of hepatitis B virus capsid assembly, following single- and multiple-ascending-oral-dose studies with or without Ritonavir in healthy adult volunteers. Antimicrob Agents Chemother. 2019;64:64. DOI:10.1128/AAC.01686-19
  • Rat V, Seigneuret F, Burlaud-Gaillard J, et al. BAY 41-4109-mediated aggregation of assembled and misassembled HBV capsids in cells revealed by electron microscopy. Antiviral Res. 2019;169:104557.
  • Stray SJ, Zlotnick A. BAY 41-4109 has multiple effects on hepatitis B virus capsid assembly. J Mol Recognit. 2006;19:542–548.
  • Brezillon N, Brunelle MN, Massinet H, et al. Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice. PLoS One. 2011;6:e25096.
  • Berke JM, Dehertogh P, Vergauwen K, et al. Capsid assembly modulators have a dual mechanism of action in primary human hepatocytes infected with hepatitis B virus. Antimicrob Agents Chemother. 2017;61:61. DOI:10.1128/AAC.00560-17
  • Berke JM, Dehertogh P, Vergauwen K, et al. Antiviral properties and mechanism of action studies of the hepatitis B virus capsid assembly modulator JNJ-56136379. Antimicrob Agents Chemother. 2020;64: e02439-02419. DOI:10.1128/AAC.02439-19.
  • Vandenbossche J, Jessner W, van den Boer M, et al. Pharmacokinetics, safety and tolerability of JNJ-56136379, a novel hepatitis B virus capsid assembly modulator, in healthy subjects. Adv Ther. 2019;36:2450–2462.
  • Klumpp K, Shimada T, Allweiss L, et al. Efficacy of NVR 3-778, alone and in combination with pegylated Interferon, vs Entecavir in uPA/SCID mice with humanized livers and HBV infection. Gastroenterology. 2018;154:652–662.e658.
  • Yuen MF, Gane EJ, Kim DJ, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3-778 in patients with chronic HBV infection. Gastroenterology. 2019;156:1392–1403.e1397.
  • Zoulim F, Lenz O, Vandenbossche JJ, et al. JNJ-56136379, an HBV capsid assembly modulator, is well-tolerated and has antiviral activity in a phase 1 study of patients with chronic infection. Gastroenterology. 2020;159:521–533.e529.
  • Edward Gane MS, Ma X, Nguyen T, et al. Viral response and safety following discontinuation of treatment with the core inhibitor vebicorvir and a nucleos (t)ide reverse transcriptase inhibitor in patients with HBeAg positive or negative chronic hepatitis B virus infection. J Hepatol. 2021;75:S736.
  • Huang Q, Cai D, Yan R, et al. Preclinical profile and characterization of the hepatitis B virus core protein inhibitor ABI-H0731. Antimicrob Agents Chemother. 2020;64:64. DOI:10.1128/AAC.01463-20
  • Yuen M-F, Agarwal K, Gane EJ, et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. Lancet Gastroenterol Hepatol. 2020;5:152–166.
  • Meng Z, Lu M. RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front Immunol. 2017;8. DOI:10.3389/fimmu.2017.00331
  • Wooddell CI, Yuen MF, Chan HL, et al. Rnai-Based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017;9. DOI:10.1126/scitranslmed.aan0241.
  • Gane E, Locarnini S, Lim TH, et al. GS10 - Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen suppression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment. J Hepatol. 2020;73:S20.
  • Edward Gane SL, Lim TH, and Strasser S, et al. Short interfering RNA JNJ-3989 combination therapy in chronic hepatitis B shows potent reduction of all viral markers but no correlate was identified for HBsAg reduction and baseline factors. J Hepatol. 2021;73:S20.
  • Yuen M-F, Berliba E, Sukeepaisarnjaroen W, et al. Repeat dosing of the GalNac-siRNA AB-729 in subjects with chronic hepatitis B results in robust and sustained HBsAg suppression. J Hepatol. 2021;75:S203.
  • Thi EP, Yuen M-F, Gane E, et al. Inhibition of hepatitis B surface antigen by RNA interference therapeutic AB-729 in chronic hepatitis B patients correlates with suppression of all HBsAg isoforms and HBV RNA. J Hepatol. 2021;75:S760.
  • Bhavna Paratala J-J, Ganchua SC, Gane E, et al. Inhibition of hepatitis B surface antigen in chronic hepatitis B subjects by RNA interference therapeutic AB-729 is accompanied by upregulation of HBV-specific T cell activation markers. J Hepatol. 2021;75:S761.
  • Edward Gane HS, Yuen M-F, Anderson M, et al. A single dose of the GalNac-siRNA, AB-729, results in prolonged reductions in HBsAg, HBcrAg, HBV DNA and HBV RNA in the absence of nucleos (t)ide analogue therapy in HBeAg negative subjects with chronic hepatitis B infection. J Hepatol. 2021;75:S762.
  • Man-Fung Yuen Y-S, Cloutier D, Shen L, et al. Preliminary on-treatment data from a phase 2 study evaluating VIR-2218 in combination with pegylated interferon alfa-2a in participants with chronic hepatitis B infection. J Hepatol. 2021;75:S738.
  • Kaufmann SHE, Dorhoi A, Hotchkiss RS, et al. Host-Directed therapies for bacterial and viral infections. Nat Rev Drug Discov. 2018;17:35–56.
  • Mitra B, Thapa RJ, Guo H, et al. Host functions used by hepatitis B virus to complete its life cycle: implications for developing host-targeting agents to treat chronic hepatitis B. Antiviral Res. 2018;158:185–198.
  • Allweiss L, Volz T, Giersch K, et al. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo. Gut. 2018;67:542–552.
  • Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol. 2011;201: 205–259.
  • 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;65:490–498.
  • Loglio A, Ferenci P, Uceda Renteria SC, et al. Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: a case report of 3 patients. J Hepatol. 2019;71:834–839.
  • Blank A, Markert C, Hohmann N, et al. First-In-Human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65:483–489.
  • Wedemeyer H, Schöneweis K, Bogomolov PO, 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 c with PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection. J Hepatol. 2019;70:e81.
  • Watashi K, Sluder A, Daito T, 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;59:1726–1737.
  • 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;60:723–731.
  • Shimura S, Watashi K, Fukano K, et al. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol. 2017;66:685–692.
  • Liu Y, Ruan H, Li Y, et al. Potent and specific inhibition of NTCP-mediated HBV/HDV infection and substrate transporting by a novel, oral-available cyclosporine A analogue. J Med Chem. 2021;64:543–565.
  • Sneha V, Gupta AA, Fanget MC, et al. Preliminary pharmacokinetics and safety in healthy volunteers of VIR-3434, a monoclonal antibody for the treatment of chronic hepatitis B infection. J Hepatol. 2021;75:S733.
  • Bazinet M, Pântea V, Cebotarescu V, et al. Safety and efficacy of REP 2139 and pegylated interferon Alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2017;2:877–889.
  • 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:e0156667.
  • Vaillant A. REP 2139: antiviral mechanisms and applications in achieving functional control of HBV and HDV infection. ACS Infect Dis. 2019;5:675–687.
  • Bazinet M, Pântea V, Placinta G, 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 onfection naïve to nucleos(t)ide therapy. Gastroenterology. 2020;158:2180–2194.
  • Leeor Hershkovich LS, Bazinet M, Pântea V, et al. HBsAg, anti-HBs and ALT kinetic characterization during NAP based combination therapy of HBeAg negative chronic hepatitis B infection. J Hepatol. 2021;75:S750.
  • Blanchet M, Sinnathamby V, Vaillant A, et al. Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells. Antiviral Res. 2019;164:97–105.
  • Guillot C, Martel N, Berby F, et al. Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes. PLoS One. 2017;12:e0179697.
  • Real CI, Werner M, Paul A, et al. Nucleic acid-based polymers effective against hepatitis B virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells. Sci Rep. 2017;7:43838.
  • Mouzannar K, Fusil F, Lacombe B, et al. Farnesoid X receptor-α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. FASEB J. 2019;33:2472–2483.
  • Radreau P, Porcherot M, Ramière C, et al. Reciprocal regulation of farnesoid X receptor α activity and hepatitis B virus replication in differentiated HepaRG cells and primary human hepatocytes. FASEB J. 2016;30:3146–3154.
  • Scalfaro P, Heo J, Liu C-J, et al. A phase 2 study testing FXR agonist Vonafexor in treatment naive patients with chronic hepatitis B (CHB): preliminary week 16 results. J Hepatol. 2021;75:S761.
  • Wang P, Heitman J. The cyclophilins. Genome Biol. 2005;6:226.
  • Galat A. Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Curr Top Med Chem. 2003;3:1315–1347.
  • Bosco DA, Kern D. Catalysis and binding of cyclophilin a with different HIV-1 capsid constructs. Biochemistry. 2004;43:6110–6119.
  • Luban J. Absconding with the chaperone: essential cyclophilin-Gag interaction in HIV-1 virions. Cell. 1996;87:1157–1159.
  • Braaten D, Aberham C, Franke EK, et al. Cyclosporine A-resistant human immunodeficiency virus type 1 mutants demonstrate that Gag encodes the functional target of cyclophilin a. J Virol. 1996;70:5170–5176.
  • Braaten D, Franke EK, Luban J. Cyclophilin a is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription. J Virol. 1996;70:3551–3560.
  • Braaten D, Luban J. Cyclophilin a regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells. Embo J. 2001;20:1300–1309.
  • Selyutina A, Persaud M, Simons LM, et al. Cyclophilin a prevents HIV-1 restriction in lymphocytes by blocking human TRIM5α binding to the viral core. Cell Rep. 2020;30:3766–3777.e3766.
  • Chen J, Chen S, Wang J, et al. Cyclophilin J is a novel peptidyl-prolyl isomerase and target for repressing the growth of hepatocellular carcinoma. PLoS One. 2015;10:e0127668.
  • Cheng S, Luo M, Ding C, et al. Downregulation of Peptidylprolyl isomerase a promotes cell death and enhances doxorubicin-induced apoptosis in hepatocellular carcinoma. Gene. 2016;591:236–244.
  • Lee J, Kim SS. An overview of cyclophilins in human cancers. J Int Med Res. 2010;38:1561–1574.
  • Theuerkorn M, Fischer G, Schiene-Fischer C. Prolyl cis/trans isomerase signalling pathways in cancer. Curr Opin Pharmacol. 2011;11:281–287.
  • Goto K, Watashi K, Murata T, et al. Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun. 2006;343:879–884.
  • Watashi K, Ishii N, Hijikata M, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell. 2005;19:111–122.
  • Gaither LA, Borawski J, Anderson LJ, et al. Multiple cyclophilins involved in different cellular pathways mediate HCV replication. Virology. 2010;397:43–55.
  • Stanciu C, Trifan A, Muzica C, et al. Efficacy and safety of alisporivir for the treatment of hepatitis C infection. Expert Opin Pharmacother. 2019;20:379–384.
  • Flisiak R, Feinman SV, Jablkowski M, et al. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naïve hepatitis C patients. Hepatology. 2009;49:1460–1468.
  • Hopkins S, DiMassimo B, Rusnak P, et al. The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection. J Hepatol. 2012;57:47–54.
  • Phillips S, Chokshi S, Chatterji U, et al. Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production. Gastroenterology. 2015;148:403–414.
  • Nilsson J, Moss S, Coates N, et al. P1044 NVP018, a cyclophilin inhibitor for treatment of chronic HBV infection. J Hepatol. 2014;60:S423.
  • Gallay P, Ure D, Bobardt M, et al. The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. PLoS One. 2019;14:e0217433.
  • Lavanchy D, Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat. 1999;6:35–47.
  • Kuo J, Bobardt M, Chatterji U, et al. A Pan-Cyclophilin inhibitor, CRV431, decreases fibrosis and tumor development in chronic liver disease models. J Pharmacol Exp Ther. 2019;371:231–241.
  • Allweiss L, Dandri M. The role of cccDNA in HBV maintenance. Viruses. 2017;9(6):156.
  • Slagle BL, Bouchard MJ. Role of HBx in hepatitis B virus persistence and its therapeutic implications. Curr Opin Virol. 2018;30:32–38.
  • Decorsière A, Mueller H, van Breugel PC, et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature. 2016;531(7594):386–389. DOI:10.1038/nature17170
  • Sekiba K, Otsuka M, Ohno M, et al. Inhibition of HBV transcription from cccDNA with Nitazoxanide by targeting the HBx-DDB1 interaction. Cell Mol Gastroenterol Hepatol. 2019;7:297–312.
  • Rossignol J-F, Bréchot C. A pilot clinical trial of Nitazoxanide in the treatment of chronic hepatitis B. Hepatol Commun. 2019;3:744–747.
  • Belloni L, Pollicino T, De Nicola F, et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci U S a. 2009;106:19975–19979.
  • Guo YH, Li YN, Zhao JR, et al. Hbc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state. Epigenetics. 2011;6:720–726.
  • Chong CK, Cheng CYS, Tsoi SYJ, et al. Role of hepatitis B core protein in HBV transcription and recruitment of histone acetyltransferases to cccDNA minichromosome. Antiviral Res. 2017;144:1–7.
  • Hu C, Liu X, Zeng Y, et al. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenetics. 2021;13:166.
  • Mayr C, Kiesslich T, and Erber S, et al. HDAC screening identifies the HDAC Class I inhibitor Romidepsin as a promising epigenetic drug for biliary tract cancer. Cancers (Basel). 2021;13(15):3862. DOI:10.3390/cancers13153862
  • Yu H, Jiang H, Cheng S-T, et al. AGK2, a SIRT2 inhibitor, inhibits hepatitis B virus replication in vitro and in vivo. Int J Med Sci. 2018;15:1356–1364.
  • Ma W, Zhao X, Wang K, et al. Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer. Cancer Biol Ther. 2018;19:835–846.
  • Gilmore S, Tam D, Dick R, et al. SAT-160 - antiviral activity of GS-5801, a liver-targeted prodrug of a lysine demethylase 5 inhibitor, in a hepatitis B virus primary human hepatocyte infection model. J Hepatol. 2017;66:S690–S691.
  • Harris RS, Dudley JP. Apobecs and virus restriction. Virology. 2015;479-480:131–145.
  • Harris RS, Bishop KN, Sheehy AM, et al. DNA deamination mediates innate immunity to retroviral infection. Cell. 2003;113:803–809.
  • Olson ME, Harris RS, Harki DA. APOBEC enzymes as targets for virus and cancer therapy. Cell Chem Biol. 2018;25:36–49.
  • Bockmann JH, Stadler D, Xia Y, et al. Comparative analysis of the antiviral effects mediated by Type I and III interferons in hepatitis B virus-infected hepatocytes. J Infect Dis. 2019;220:567–577.
  • Xia Y, Stadler D, Lucifora J, et al. Interferon-γ and tumor necrosis factor-α produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis. Gastroenterology. 2016;150:194–205.
  • Wang J, Xu Z-W, Liu S, et al. Dual gRnas guided CRISPR/Cas9 system inhibits hepatitis B virus replication. World J Gastroenterol. 2015;21:9554–9565.
  • Kostyushev D, Kostyusheva A, Brezgin S, et al. Suppressing the NHEJ pathway by DNA-PKcs inhibitor NU7026 prevents degradation of HBV cccDNA cleaved by CRISPR/Cas9. Sci Rep. 2019;9:1847.
  • Ramanan V, Shlomai A, Cox DB, et al. Crispr/cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus. Sci Rep. 2015;5:10833.
  • Dong C, Qu L, Wang H, et al. Targeting hepatitis B virus cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication. Antiviral Res. 2015;118:110–117.
  • Schiwon M, Ehrke-Schulz E, Oswald A, et al. One-Vector system for multiplexed CRISPR/Cas9 against hepatitis B virus cccDNA utilizing high-capacity adenoviral vectors. Mol Ther Nucleic Acids. 2018;12:242–253.
  • Liu X, Hao R, Chen S, et al. Inhibition of hepatitis B virus by the CRISPR/Cas9 system via targeting the conserved regions of the viral genome. J Gen Virol. 2015;96:2252–2261.
  • Kostyushev D, Brezgin S, Kostyusheva A, et al. Orthologous CRISPR/Cas9 systems for specific and efficient degradation of covalently closed circular DNA of hepatitis B virus. Cell Mol Life Sci. 2019;76:1779–1794.
  • Seeger C, Sohn JA. Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA. Mol Ther. 2016;24:1258–1266.
  • Lin SR, Yang HC, Kuo YT, et al. The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo. Mol Ther Nucleic Acids. 2014;3:e186.
  • Charlesworth CT, Deshpande PS, Dever DP, et al. Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat Med. 2019;25:249–254.
  • Li A, Tanner MR, Lee CM, et al. AAV-CRISPR gene editing is negated by pre-existing immunity to Cas9. Mol Ther. 2020;28:1432–1441.
  • Ates I, Rathbone T, Stuart C, et al. Delivery approaches for therapeutic genome editing and challenges. Genes (Basel). 2020;11:1113.
  • Moyo B, Bloom K, Scott T, et al. Advances with using CRISPR/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus. Virus Res. 2018;244:311–320.
  • Tong S, Moyo B, Lee CM, et al. Engineered materials for in vivo delivery of genome-editing machinery. Nature Rev Mater. 2019;4:726–737.
  • Yang YC, Chen YH, Kao JH, et al. Permanent inactivation of HBV genomes by CRISPR/Cas9-mediated non-cleavage base editing. Mol Ther Nucleic Acids. 2020;20:480–490.
  • Lang J, Neumann-Haefelin C, Thimme R. Immunological cure of HBV infection. Hepatol Int. 2019;13:113–124.
  • Marinos G, Naoumov NV, Rossol S, et al. Tumor necrosis factor receptors in patients with chronic hepatitis B virus infection. Gastroenterology. 1995;108:1453–1463.
  • Marinos G, Naoumov NV, Williams R. Impact of complete inhibition of viral replication on the cellular immune response in chronic hepatitis B virus infection. Hepatology. 1996;24:991–995.
  • Marinos G, Torre F, Chokshi S, et al. Induction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus. Hepatology. 1995;22:1040–1049.
  • Neumann AU, Phillips S, Levine I, et al. Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells. Hepatology. 2010;52:875–885.
  • Du K, Liu J, Broering R, et al. Recent advances in the discovery and development of TLR ligands as novel therapeutics for chronic HBV and HIV infections. Expert Opin Drug Discov. 2018;13:661–670.
  • Chang J, Block TM, Guo JT. The innate immune response to hepatitis B virus infection: implications for pathogenesis and therapy. Antiviral Res. 2012;96:405–413.
  • Chan YK, Gack MU. Viral evasion of intracellular DNA and RNA sensing. Nature Rev Microbiol. 2016;14:360–373.
  • Mozer-Lisewska I, Sikora J, Kowala-Piaskowska A, et al. The incidence and significance of pattern-recognition receptors in chronic viral hepatitis types B and C in man. Arch Immunol Ther Exp (Warsz). 2010;58:295–302.
  • Suslov A, Wieland S, Menne S. Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B. Curr Opin Virol. 2018;30:9–17.
  • Bourquin C, Schmidt L, Lanz A-L, et al. Immunostimulatory RNA oligonucleotides induce an effective antitumoral NK cell response through the TLR7. J Immunol. 2009;183:6078.
  • Hackstein H, Hagel N, Knoche A, et al. Skin TLR7 triggering promotes accumulation of respiratory dendritic cells and natural killer cells. PLoS One. 2012;7:e43320.
  • Budimir N, de Haan A, Meijerhof T, et al. Critical role of TLR7 signaling in the priming of cross-protective cytotoxic T lymphocyte responses by a whole inactivated influenza virus vaccine. PLoS One. 2013;8:e63163.
  • Kader M, Smith AP, Guiducci C, et al. Blocking TLR7- and TLR9-mediated IFN-α production by plasmacytoid dendritic cells does not diminish immune activation in early SIV infection. PLoS Pathog. 2013;9:e1003530.
  • Gantier MP, Tong S, Behlke MA, et al. TLR7 is involved in sequence-specific sensing of single-stranded RNAs in human macrophages. J Immunol. 2008;180:2117.
  • Luk A, Jiang Q, Glavini K, et al. A single and multiple ascending dose study of toll-like receptor 7 Agonist (RO7020531) in Chinese healthy volunteers. Clin Transl Sci. 2020;13:985–993.
  • Lanford RE, Guerra B, and 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;144:1508–1517. e1501-1510. doi: 10.1053/j.gas-tro.2013.02.003
  • 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;62:1237–1245.
  • Agarwal K, Ahn SH, Elkhashab M, et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. J Viral Hepat. 2018;25:1331–1340.
  • Janssen HLA, Brunetto MR, Kim YJ, et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J Hepatol. 2018;68:431–440.
  • Herschke F, Li C, Creus AD, et al. PS-076-Antiviral activity of JNJ-4964 (AL-034/TQ-A3334), a selective toll-like receptor 7 agonist, in AAV/HBV mice after oral administration for 12 weeks. J Hepatol. 2019;70:e49–e50.
  • Gane E, Pastagia M, Creus AD, et al. FRI-198-A phase, double-blind, randomized, placebo-controlled, first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of oral JNJ-64794964, a toll-like receptor-7 agonist, in healthy adults. J Hepatol. 2019;70:e478.
  • Mackman RL, Mish M, Chin G, et al. Discovery of GS-9688 (Selgantolimod) as a potent and selective oral toll-like receptor 8 agonist for the treatment of chronic hepatitis B. J Med Chem. 2020;63:10188–10203.
  • Harry LA, Janssen Y-S, Kim HJ, et al. Safety and efficacy of oral TLR8 agonist, selgantolimod, in viremic adult patients with chronic hepatitis B. J Hepatol. 2021;75:S757.
  • Amin OE, Colbeck EJ, Daffis S, et al. Therapeutic potential of TLR8 Agonist GS-9688 (Selgantolimod) in chronic hepatitis B: remodeling of antiviral and regulatory mediators. Hepatology. 2021;74:55–71.
  • Sato S, Li K, Kameyama T, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity. 2015;42:123–132.
  • Phillips S, Mistry S, Riva A, et al. Peg-Interferon lambda treatment induces robust innate and adaptive immunity in chronic hepatitis B patients. Front Immunol. 2017;8:621.
  • Chan HLY, Ahn SH, Chang TT, et al. Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: a randomized phase 2b study (LIRA-B). J Hepatol. 2016;64:1011–1019.
  • Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–3854.
  • Young-Suk Lim AJH, Jang J-W, Tak W-Y, et al. Safety, efficacy, and pharmacodynamic (PD) activity of 12 weeks treatment with oral RIG-I agonist, inarigivir (IRIG), plus 48 weeks of tenofovir alafenamide in adult patients with chronic hepatitis B: a phase 2 collaboration study. J Hepatol. 2021;75:S294–S803.
  • Visvanathan K, Skinner NA, Thompson AJ, et al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology. 2007;45:102–110.
  • Vincent IE, Zannetti C, Lucifora J, et al. Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One. 2011;6:e26315.
  • Deng G, Ge J, Liu C, et al. Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-α-2a antiviral therapy. Clin Res Hepatol Gastroenterol. 2017;41:386–398.
  • Riva A, Chokshi S. Immune checkpoint receptors: homeostatic regulators of immunity. Hepatol Int. 2018;12:223–236.
  • Gane E, Verdon DJ, Brooks AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J Hepatol. 2019;71:900–907.
  • De Martin E, Michot JM, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–1190.
  • Lyon AR, Yousaf N, Battisti NML, et al. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 2018;19:e447–e458.
  • Ye L, Schnepf D, Staeheli P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat Rev Immunol. 2019;19:614–625.
  • Koh C, Hercun J, Rahman F, et al. LBP13 - a phase 2 study of Peginterferon Lambda, Lonafarnib and Ritonavir for 24 weeks: end-of-treatment results from the LIFT HDV study. J Hepatol. 2020;73:S130.
  • Etzion O, Hamid SS, Lurie Y, et al. PS-052-End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection. J Hepatol. 2019;70:e32.
  • Buchmann P, Dembek C, Kuklick L, et al. A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice. Vaccine. 2013;31:1197–1203.
  • Bian Y, Zhang Z, Sun Z, et al. Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice. Hepatology. 2017;66:1067–1082.
  • Chuai X, Xie B, Chen H, et al. The immune response of rhesus macaques to novel vaccines comprising hepatitis B virus S, PreS1, and core antigens. Vaccine. 2018;36:3740–3746.
  • Zoulim F, Fournier C, Habersetzer F, et al. Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial. Human Vaccines Immun-other. 2020;16:388–399.
  • Lok AS, Pan CQ, Han S-H, et al. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J Hepatol. 2016;65:509–516.
  • Boni C, Janssen HLA, Rossi M, et al. Combined GS-4774 and Tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis. Gastroenterology. 2019;157:227–241.e227.
  • Fontaine H, Kahi S, Chazallon C, et al. Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial—anrs HB02 VAC-ADN. Gut. 2015;64:139.
  • Al Mahtab M, Akbar SMF, Aguilar JC, et al. Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS One. 2018;13:e0201236.
  • Ma H, Lim TH, Leerapun A, et al. Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study. JHEP Rep. 2021;3:100361.
  • Yuen MFL, Locarnini S, Given B, et al. First clinical experience with RNA interference [RNAi]-based triple combination therapy in chronic hepatitis B (CHB): JNJ-73763989 (JNJ-3989), JNJ-56136379 (JNJ-6379) and a nucleos(t)ide analogue (NA). Hepatology. 2019;2019:1489A.