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Volume 39 Issue 1
February 2024
    Citation: Jie-Li Hu, Ai-Long Huang. Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics .VIROLOGICA SINICA, 2024, 39(1) : 9-23.  http://dx.doi.org/10.1016/j.virs.2023.12.005
    shu

    Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics

    • Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China

    • Corresponding author: Jie-Li Hu, 102564@cqmu.edu.cn
      Ai-Long Huang, ahuang1964@163.com
    • Received Date: 29 January 2023
      Accepted Date: 13 December 2023
      Available online: 16 December 2023
    • The achievement of a functional cure for chronic hepatitis B (CHB) remains limited to a minority of patients treated with currently approved drugs. The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB. A critical prerequisite for the functional cure of CHB is a substantial reduction, or even eradication of covalently closed circular DNA (cccDNA). Within this context, the changes in cccDNA levels during treatment become as a pivotal concern. We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics. In this review, we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA. Building upon this foundation, we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe.
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      1. Aimo, A., Castiglione, V., Rapezzi, C., Franzini, M., Panichella, G., Vergaro, G., Gillmore, J., Fontana, M., Passino, C., Emdin, M., 2022. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat. Rev. Cardiol. 19, 655-667.

      2. Akira, S., Takeda, K., 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499-511.

      3. Al-Mahtab, M., Bazinet, M., Vaillant, A., 2016. Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naive bangladeshi patients with HBeAgþ chronic hepatitis B infection. PLoS One 11, e0156667.

      4. Alazard-Dany, N., Denolly, S., Boson, B., Cosset, F.L., 2019. Overview of hcv life cycle with a special focus on current and possible future antiviral targets. Viruses 11, 30.

      5. Allweiss, L., Volz, T., Giersch, K., Kah, J., Raffa, G., Petersen, J., Lohse, A.W., Beninati, C., Pollicino, T., Urban, S., Lutgehetmann, M., Dandri, M., 2018. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccdna in vivo. Gut 67, 542-552.

      6. Amin, O.E., Colbeck, E.J., Daffis, S., Khan, S., Ramakrishnan, D., Pattabiraman, D., Chu, R., Micolochick Steuer, H., Lehar, S., Peiser, L., Palazzo, A., Frey, C., Davies, J., Javanbakht, H., Rosenberg, W.M.C., Fletcher, S.P., Maini, M.K., Pallett, L.J., 2021. Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic hepatitis B: remodeling of antiviral and regulatory mediators. Hepatology 74, 55-71.

      7. Asabe, S., Wieland, S.F., Chattopadhyay, P.K., Roederer, M., Engle, R.E., Purcell, R.H., Chisari, F.V., 2009. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J. Virol. 83, 9652-9662.

      8. Ascentage Pharma. First-in-human Study of apg-1387, Targeting Inhibitor of Apoptosis Proteins, for the Treatment of Patients with Chronic Hepatitis B, 2022. AASLD Conference.

      9. Bassit, L., Amblard, F., Patel, D., Biteau, N., Chen, Z., Kasthuri, M., Zhou, S., Schinazi, R.F., 2023. The premise of capsid assembly modulators towards eliminating HBV persistence. Expet Opin. Drug Discov. 18, 1031-1041.

      10. Bazinet, M., Pantea, V., Placinta, G., Moscalu, I., Cebotarescu, V., Cojuhari, L., Jimbei, P., Iarovoi, L., Smesnoi, V., Musteata, T., Jucov, A., Dittmer, U., Krawczyk, A., Vaillant, A., 2020. Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naive to nucleos(t)ide therapy. Gastroenterology 158, 2180-2194.

      11. Bazinet, M., Pantea, V., Cebotarescu, V., Cojuhari, L., Jimbei, P., Anderson, M., Gersch, J., Holzmayer, V., Elsner, C., Krawczyk, A., Kuhns, M.C., Cloherty, G., Dittmer, U., Vaillant, A., 2021a. Persistent control of hepatitis B virus and hepatitis delta virus infection following rep 2139-ca and pegylated interferon therapy in chronic hepatitis B virus/hepatitis delta virus coinfection. Hepatol Commun 5, 189-202.

      12. Bazinet, M., Anderson, M., Pantea, V., Placinta, G., Moscalu, I., Cebotarescu, V., Cojuhari, L., Jimbei, P., Iarovoi, L., Smesnoi, V., Musteata, T., Jucov, A., Dittmer, U., Gersch, J., Holzmayer, V., Kuhns, M., Cloherty, G., Vaillant, A., 2021b. Analysis of HBsAg immunocomplexes and cccDNA activity during and persisting after nap-based therapy. Hepatol Commun 5, 1873-1887.

      13. Bertoletti, A., Kennedy, P.T.F., 2019. HBV antiviral immunity: not all CD8 T cells are born equal. Gut 68, 770-773.

      14. Bertoletti, A., Tan, A.T., 2020. Challenges of CAR- and TCR-T cell-based therapy for chronic infections. J. Exp. Med. 217.

      15. Blanchet, M., Sinnathamby, V., Vaillant, A., Labonte, P., 2019. Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells. Antivir. Res. 164, 97-105.

      16. Blank, A., Markert, C., Hohmann, N., Carls, A., Mikus, G., Lehr, T., Alexandrov, A., Haag, M., Schwab, M., Urban, S., Haefeli, W.E., 2016. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J. Hepatol. 65, 483-489.

      17. Block, T.M., Alter, H., Brown, N., Brownstein, A., Brosgart, C., Chang, K.M., Chen, P.J., Cohen, C., El-Serag, H., Feld, J., Gish, R., Glenn, J., Greten, T.F., Guo, J.T., Hoshida, Y., Kowdley, K.V., Li, W., Lok, A.S., McMahon, B., Mehta, A., Perrillo, R., Rice, C.M., Rinaudo, J., Schinazi, R.F., Shetty, K., 2018. Research priorities for the discovery of a cure for chronic hepatitis B: report of a workshop. Antivir. Res. 150, 93-100.

      18. Bogomolov, P., Alexandrov, A., Voronkova, N., Macievich, M., Kokina, K., Petrachenkova, M., Lehr, T., Lempp, F.A., Wedemeyer, H., Haag, M., Schwab, M., Haefeli, W.E., Blank, A., Urban, S., 2016. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase ib/iia study. J. Hepatol. 65, 490-498.

      19. Boni, C., Fisicaro, P., Valdatta, C., Amadei, B., Di Vincenzo, P., Giuberti, T., Laccabue, D., Zerbini, A., Cavalli, A., Missale, G., Bertoletti, A., Ferrari, C., 2007. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81, 4215-4225.

      20. Boni, C., Vecchi, A., Rossi, M., Laccabue, D., Giuberti, T., Alfieri, A., Lampertico, P., Grossi, G., Facchetti, F., Brunetto, M.R., Coco, B., Cavallone, D., Mangia, A., Santoro, R., Piazzolla, V., Lau, A., Gaggar, A., Subramanian, G.M., Ferrari, C., 2018.

      21. TLR7 agonist increases responses of hepatitis B virus-specific t cells and natural killer cells in patients with chronic hepatitis B treated with nucleos(t)ide analogues. Gastroenterology 154, 1764-1777 e1767.

      22. Boni, C., Janssen, H.L.A., Rossi, M., Yoon, S.K., Vecchi, A., Barili, V., Yoshida, E.M., Trinh, H., Rodell, T.C., Laccabue, D., Alfieri, A., Brillo, F., Fisicaro, P., Acerbi, G., Pedrazzi, G., Andreone, P., Cursaro, C., Margotti, M., Santoro, R., Piazzolla, V., Brunetto, M.R., Coco, B., Cavallone, D., Zhao, Y., Joshi, A., Woo, J., Lau, A.H., Gaggar, A., Subramanian, G.M., Massetto, B., Fung, S., Ahn, S.H., Ma, X., Mangia, A., Ferrari, C., 2019. Combined GS-4774 and tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis. Gastroenterology 157, 227-241 e227.

      23. Boulon, R., Blanchet, M., Lemasson, M., Vaillant, A., Labonte, P., 2020. Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro. Antivir. Res. 183, 104853.

      24. Bowden, S., Locarnini, S., Chang, T.T., Chao, Y.C., Han, K.H., Gish, R.G., de Man, R.A., Yu, M., Llamoso, C., Tang, H., 2015. Covalently closed-circular hepatitis B virus DNA reduction with entecavir or lamivudine. World J. Gastroenterol. 21, 4644-4651.

      25. Boyd, A., Lacombe, K., Lavocat, F., Maylin, S., Miailhes, P., Lascoux-Combe, C., Delaugerre, C., Girard, P.M., Zoulim, F., 2016. Decay of ccc-DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients. J. Hepatol. 65, 683-691.

      26. Cai, B., Chang, S., Tian, Y., Zhen, S., 2023. CRISPR/Cas9 for hepatitis B virus infection treatment. Immun Inflamm Dis 11, e866.

      27. Cargill, T., Barnes, E., 2021. Therapeutic vaccination for treatment of chronic hepatitis B. Clin. Exp. Immunol. 205, 106-118.

      28. Chai, N., Chang, H.E., Nicolas, E., Han, Z., Jarnik, M., Taylor, J., 2008. Properties of subviral particles of hepatitis B virus. J. Virol. 82, 7812-7817.

      29. Chatterjee, A., Smith, P.F., Perelson, A.S., 2013. Hepatitis C viral kinetics: the past, present, and future. Clin. Liver Dis. 17, 13-26.

      30. Chen, Y.G., Hur, S., 2022. Cellular origins of DSRNA, their recognition and consequences. Nat. Rev. Mol. Cell Biol. 23, 286-301.

      31. Chen, Y.C., Chu, C.M., Liaw, Y.F., 2010. Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology 51, 435-444.

      32. Chen, W., Gong, Y., Long, G., Wang, X., Yang, Y., Liu, J., Li, H., Tong, X., Zhao, Q., Yang, L., Zuo, J., Hu, Y., 2023. A prodrug of the capsid assembly modulator improved druggability and lowing HBsAg and HBeAg for the treatment of chronic hepatitis B. Eur. J. Med. Chem. 257, 115485.

      33. Cheng, D., Han, B., Zhang, W., Wu, W., 2021. Clinical effects of NTCP-inhibitor myrcludex B. J. Viral Hepat. 28, 852-858.

      34. Chu, Y.J., Jeng, W.J., Pan, M.H., Hu, H.H., Luo, W.S., Su, C.Y., Chiang, C.T., Jen, C.L., Chen, C.J., Yang, H.I., 2022. Serum soluble programmed death-1 levels predict the spontaneous HBsAg seroclearance in chronic hepatitis B. J. Gastroenterol. 57, 423-432.

      35. Cole, A.G., 2016. Modulators of HBV capsid assembly as an approach to treating hepatitis B virus infection. Curr. Opin. Pharmacol. 30, 131-137.

      36. Crossley, M.P., Song, C., Bocek, M.J., Choi, J.H., Kousorous, J., Sathirachinda, A., Lin, C., Brickner, J.R., Bai, G., Lans, H., Vermeulen, W., Abu-Remaileh, M., Cimprich, K.A., 2023. R-loop-derived cytoplasmic RNA-DNA hybrids activate an immune response. Nature 613, 187-194.

      37. Das, A., Hoare, M., Davies, N., Lopes, A.R., Dunn, C., Kennedy, P.T., Alexander, G., Finney, H., Lawson, A., Plunkett, F.J., Bertoletti, A., Akbar, A.N., Maini, M.K., 2008.

      38. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111-2124.

      39. de Reuver, R., Maelfait, J., 2023. Novel insights into double-stranded RNA-mediated immunopathology. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-023-00940-3.

      40. Ding, J., Yi, Z., Zai, W., Wu, M., Chen, B., Cai, Q., Zhang, X., Yuan, Z., 2023. Illuminating the live-cell dynamics of hepatitis B virus covalently closed circular DNA using the CRISPR-Tag system. mBio 14, e0355022.

      41. Dusheiko, G., Agarwal, K., Maini, M.K., 2023. New approaches to chronic hepatitis B. N. Engl. J. Med. 388, 55-69.

      42. Ebert, G., Allison, C., Preston, S., Cooney, J., Toe, J.G., Stutz, M.D., Ojaimi, S., Baschuk, N., Nachbur, U., Torresi, J., Silke, J., Begley, C.G., Pellegrini, M., 2015.

      43. Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis. Proc. Natl. Acad. Sci. U. S. A. 112, 5803-5808.

      44. Erken, R., Andre, P., Roy, E., Kootstra, N., Barzic, N., Girma, H., Laveille, C., RadreauPierini, P., Darteil, R., Vonderscher, J., Scalfaro, P., Tangkijvanich, P., Flisiak, R., Reesink, H., 2021. Farnesoid x receptor agonist for the treatment of chronic hepatitis B: a safety study. J. Viral Hepat. 28, 1690-1698.

      45. Espiritu, C.L., Mani, N., Eley, T.V., Ardzinski, A., Stever, K., Brown, J., Varughese, T.A., Sims, K.D., Picchio, G., Lam, A.M., Sofia, M.J., Thi, E.P., 2023. Hepatitis B virus core protein variant profiles observed in chronic hepatitis B patients treated with capsid inhibitor AB-836. J. Hepatol. 78, S1171-S1172.

      46. Fanning, G.C., Zoulim, F., Hou, J., Bertoletti, A., 2019. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat. Rev. Drug Discov. 18, 827-844.

      47. Feld, J.J., Lawitz, E., Nguyen, T., Lalezari, J., Hassanein, T., Martin, P., Han, S.H., Dieterich, D., Giard, J.M., De La Rosa, G., Ahmad, A., Luo, E., Conery, A.L., Adda, N., 2022. EDP-541 in healthy subjects and nucleos(t)ide reverse transcriptase inhibitorsuppressed patients with chronic hepatitis B. Antivir. Ther. 27, 13596535221127848.

      48. Fourel, I., Cullen, J.M., Saputelli, J., Aldrich, C.E., Schaffer, P., Averett, D.R., Pugh, J., Mason, W.S., 1994. Evidence that hepatocyte turnover is required for rapid clearance of duck hepatitis B virus during antiviral therapy of chronically infected ducks. J. Virol. 68, 8321-8330.

      49. Fumagalli, V., Di Lucia, P., Venzin, V., Bono, E.B., Jordan, R., Frey, C.R., Delaney, W., Chisari, F.V., Guidotti, L.G., Iannacone, M., 2020. Serum HBsAg clearance has minimal impact on CD8þ T cell responses in mouse models of HBV infection. J. Exp. Med. 217, e20200298.

      50. Fung, J., Lai, C.L., Seto, W.K., Yuen, M.F., 2011. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J. Antimicrob. Chemother. 66, 2715-2725.

      51. Galun, E., Eren, R., Safadi, R., Ashour, Y., Terrault, N., Keeffe, E.B., Matot, E., Mizrachi, S., Terkieltaub, D., Zohar, M., Lubin, I., Gopher, J., Shouval, D., Dagan, S., 2002. Clinical evaluation (phase i) of a combination of two human monoclonal antibodies to HBV:safety and antiviral properties. Hepatology 35, 673-679.

      52. Gane, E., Verdon, D.J., Brooks, A.E., Gaggar, A., Nguyen, A.H., Subramanian, G.M., Schwabe, C., Dunbar, P.R., 2019. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J. Hepatol. 71, 900-907.

      53. Gane, E.J., Kim, W., Lim, T.H., Tangkijvanich, P., Yoon, J.H., Sievert, W., Sukeepaisarnjaroen, W., Thompson, A.J., Pavlovic, V., Surujbally, B., Wat, C., Brown, B.D., Achneck, H.E., Yuen, M.F., 2023. First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection. J. Hepatol. 79, 1139-1149.

      54. Gao, W., Hu, J., 2007. Formation of hepatitis B virus covalently closed circular DNA:removal of genome-linked protein. J. Virol. 81, 6164-6174.

      55. Goncalves, A., Lemenuel-Diot, A., Cosson, V., Jin, Y., Feng, S., Bo, Q., Guedj, J., 2021. What drives the dynamics of HBV RNA during treatment? J. Viral Hepat. 28, 383-392.

      56. Grimm, D., Thimme, R., Blum, H.E., 2011. HBV life cycle and novel drug targets. Hepatol Int 5, 644-653.

      57. Grudda, T., Hwang, H.S., Taddese, M., Quinn, J., Sulkowski, M.S., Sterling, R.K., Balagopal, A., Thio, C.L., 2022. Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment. J. Clin. Invest. 132, e161818.

      58. Guo, H., Jiang, D., Zhou, T., Cuconati, A., Block, T.M., Guo, J.T., 2007. Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: an intermediate of covalently closed circular DNA formation. J. Virol. 81, 12472-12484.

      59. Gyrd-Hansen, M., Meier, P., 2010. IAPs: from caspase inhibitors to modulators of nfkappab, inflammation and cancer. Nat. Rev. Cancer 10, 561-574.

      60. Han, K., Cremer, J., Elston, R., Oliver, S., Baptiste-Brown, S., Chen, S., Gardiner, D., Davies, M., Saunders, J., Hamatake, R., Losos, J., Leivers, M., Hood, S., van der Berg, F., Paff, M., Ritter, J.M., Theodore, D., 2019. A randomized, double-blind, placebo-controlled, first-time-in-human study to assess the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of GSK3389404 in healthy subjects. Clin Pharmacol Drug Dev 8, 790-801.

      61. Han, K., Theodore, D., McMullen, G., Swayze, E., McCaleb, M., Billioud, G., Wieland, S., Hood, S., Paff, M., Bennett, C.F., Kwoh, T.J., 2022. Preclinical and phase 1 assessment of antisense oligonucleotide bepirovirsen in hepatitis B virus-transgenic mice and healthy human volunteers: support for clinical dose selection and evaluation of safety, tolerability, and pharmacokinetics of single and multiple doses. Clin Pharmacol Drug Dev 11, 1191-1202.

      62. Heinke, P., Rost, F., Rode, J., Trus, P., Simonova, I., Lazar, E., Feddema, J., Welsch, T., Alkass, K., Salehpour, M., Zimmermann, A., Seehofer, D., Possnert, G., Damm, G., Druid, H., Brusch, L., Bergmann, O., 2022. Diploid hepatocytes drive physiological liver renewal in adult humans. Cell Syst 13, 499-507 e412.

      63. Heise, T., Sommer, G., Reumann, K., Meyer, I., Will, H., Schaal, H., 2006. The hepatitis B virus pre contains a splicing regulatory element. Nucleic Acids Res. 34, 353-363.

      64. Ho, D.D., Neumann, A.U., Perelson, A.S., Chen, W., Leonard, J.M., Markowitz, M., 1995. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123-126.

      65. Hou, J., Ding, Y., Niu, J., Liang, X., Massetto, B, Le, K., Wu, M., Maderazo, M., Lin, T.I., Gane, E., 2023. ALG-000184, an Orally Administered Capsid Assembly Modulator(CAM) Reduces HBsAg in Subjects with HBeAg Positive Chronic Hepatitis B (CHB). The APASL annual meeting.

      66. Hrdinka, M., Yabal, M., 2019. Inhibitor of apoptosis proteins in human health and disease. Gene Immun. 20, 641-650.

      67. Hu, J.L., Huang, A.L., 2023. Dynamics of hepatitis B virus covalently closed circular DNA:a mini-review. Microorganisms 11, 600.

      68. Hui, R.W., Mak, L.Y., Seto, W.K., Yuen, M.F., 2022. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin. Mol. Hepatol. 28, 408-424.

      69. Iannacone, M., Guidotti, L.G., 2022. Immunobiology and pathogenesis of hepatitis B virus infection. Nat. Rev. Immunol. 22, 19-32.

      70. Imam, H., Khan, M., Gokhale, N.S., McIntyre, A.B.R., Kim, G.W., Jang, J.Y., Kim, S.J., Mason, C.E., Horner, S.M., Siddiqui, A., 2018. N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle. Proc. Natl. Acad. Sci. U. S. A. 115, 8829-8834.

      71. Janssen, H.L.A., Hou, J., Asselah, T., Chan, H.L.Y., Zoulim, F., Tanaka, Y., Janczewska, E., Nahass, R.G., Bourgeois, S., Buti, M., Lampertico, P., Lenz, O., Verbinnen, T., Vandenbossche, J., Talloen, W., Kalmeijer, R., Beumont, M., Biermer, M., Shukla, U., 2023. Randomised phase 2 study (jade) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection. Gut 72, 1385-1398.

      72. Jia, H., Mai, J., Wu, M., Chen, H., Li, X., Li, C., Liu, J., Liu, C., Hu, Y., Zhu, X., Jiang, X., Hua, B., Xia, T., Liu, G., Deng, A., Liang, B., Guo, R., Lu, H., Wang, Z., Chen, H., Zhang, Z., Zhang, H., Niu, J., Ding, Y., 2023. Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial. BMC Med. 21, 98.

      73. Kantor, A., McClements, M.E., MacLaren, R.E., 2020. CRISPR-Cas9 DNA base-editing and prime-editing. Int. J. Mol. Sci. 21, 6240.

      74. Karayiannis, P., 2017. Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread. Hepatol Int 11, 500-508.

      75. Kayesh, M.E.H., Amako, Y., Hashem, M.A., Murakami, S., Ogawa, S., Yamamoto, N., Hifumi, T., Miyoshi, N., Sugiyama, M., Tanaka, Y., Mizokami, M., Kohara, M., Tsukiyama-Kohara, K., 2020. Development of an in vivo delivery system for CRISPR/Cas9-mediated targeting of hepatitis B virus cccDNA. Virus Res. 290, 198191.

      76. Kesic, S., 2019. Rethinking the pragmatic systems biology and systems-theoretical biology divide: toward a complexity-inspired epistemology of systems biomedicine. Med.Hypotheses 131, 109316.

      77. Kim, C.W., Chang, K.M., 2013. Hepatitis C virus: virology and life cycle. Clin. Mol. Hepatol. 19, 17-25.

      78. Kim, D.H., Kang, H.S., Kim, K.H., 2016. Roles of hepatocyte nuclear factors in hepatitis B virus infection. World J. Gastroenterol. 22, 7017-7029.

      79. Kim, E., Koo, T., Park, S.W., Kim, D., Kim, K., Cho, H.Y., Song, D.W., Lee, K.J., Jung, M.H., Kim, S., Kim, J.H., Kim, J.H., Kim, J.S., 2017. In vivo genome editing with a small Cas9 orthologue derived from campylobacter jejuni. Nat. Commun. 8, 14500.

      80. Kim, H., Ko, C., Lee, J.Y., Kim, M., 2021. Current progress in the development of hepatitis B virus capsid assembly modulators: chemical structure, mode-of-action and efficacy. Molecules 26, 7420.

      81. Lai, C.L., Wong, D., Ip, P., Kopaniszen, M., Seto, W.K., Fung, J., Huang, F.Y., Lee, B., Cullaro, G., Chong, C.K., Wu, R., Cheng, C., Yuen, J., Ngai, V., Yuen, M.F., 2017.

      82. Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B. J. Hepatol. 66, 275-281.

      83. Lampertico, P., Chan, H.L., Janssen, H.L., Strasser, S.I., Schindler, R., Berg, T., 2016. Review article: long-term safety of nucleoside and nucleotide analogues in HBVmonoinfected patients. Aliment. Pharmacol. Ther. 44, 16-34.

      84. Lanford, R.E., Guerra, B., Chavez, D., Giavedoni, L., Hodara, V.L., Brasky, K.M., Fosdick, A., Frey, C.R., Zheng, J., Wolfgang, G., Halcomb, R.L., Tumas, D.B., 2013.

      85. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 144, 1508-1517, 1517 e1501-1510.

      86. Lee, H.W., Lee, J.S., Ahn, S.H., 2020a. Hepatitis B virus cure: targets and future therapies. Int. J. Mol. Sci. 22.

      87. Lee, H.W., Park, J.Y., Hong, T., Park, M.S., Ahn, S.H., 2020b. Efficacy of lenvervimab, a recombinant human immunoglobulin, in treatment of chronic hepatitis B virus infection. Clin. Gastroenterol. Hepatol. 18, 3043-3045 e3041.

      88. Li, M., Sun, F., Bi, X., Lin, Y., Yang, L., Lu, Y., Zhang, L., Wan, G., Yi, W., Zhao, L., Xie, Y., 2022. Consolidation treatment needed for sustained HBsAg-negative response induced by interferon-alpha in HBsAg positive chronic hepatitis B patients. Virol. Sin. 37, 390-397.

      89. Li, F., Song, B., Zhou, W.F., Chu, L.J., 2023. Toll-like receptors 7/8: a paradigm for the manipulation of immunologic reactions for immunotherapy. Viral Immunol. 36, 564-578.

      90. Liang, X.H., Sun, H., Nichols, J.G., Crooke, S.T., 2017. RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus. Mol. Ther. 25, 2075-2092.

      91. Ligat, G., Verrier, E.R., Nassal, M., Baumert, T.F., 2021. Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol 49, 41-51.

      92. Lim, S.G., Baumert, T.F., Boni, C., Gane, E., Levrero, M., Lok, A.S., Maini, M.K., Terrault, N.A., Zoulim, F., 2023. The scientific basis of combination therapy for chronic hepatitis B functional cure. Nat. Rev. Gastroenterol. Hepatol. 20, 238-253.

      93. Liu, F., Campagna, M., Qi, Y., Zhao, X., Guo, F., Xu, C., Li, S., Li, W., Block, T.M., Chang, J., Guo, J.T., 2013. Alpha-interferon suppresses hepadnavirus transcription by altering epigenetic modification of cccdna minichromosomes. PLoS Pathog. 9, e1003613.

      94. Liu, H., Hou, J., Zhang, X., 2018. Targeting ciaps, a new option for functional cure of chronic hepatitis B infection? Virol. Sin. 33, 459-461.

      95. Liu, F., Lee, A.C.H., Guo, F., Kondratowicz, A.S., Micolochick Steuer, H.M., Miller, A., Bailey, L.D., Wang, X., Chen, S., Kultgen, S.G., Cuconati, A., Cole, A.G., Gotchev, D., Dorsey, B.D., Rijnbrand, R., Lam, A.M., Sofia, M.J., Gao, M., 2021. Host poly(a) polymerases PAPD5 and PAPD7 provide two layers of protection that ensure the integrity and stability of hepatitis B RNA. J. Virol. 95, e0057421.

      96. Liu, Y., Maya, S., Ploss, A., 2021. Animal models of hepatitis B virus infection-success, challenges, and future directions. Viruses 13.

      97. Lok, A.S., Pan, C.Q., Han, S.H., Trinh, H.N., Fessel, W.J., Rodell, T., Massetto, B., Lin, L., Gaggar, A., Subramanian, G.M., McHutchison, J.G., Ferrari, C., Lee, H., Gordon, S.C., Gane, E.J., 2016a. Randomized phase ii study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J. Hepatol. 65, 509-516.

      98. Lok, A.S., McMahon, B.J., Brown Jr., R.S., Wong, J.B., Ahmed, A.T., Farah, W., Almasri, J., Alahdab, F., Benkhadra, K., Mouchli, M.A., Singh, S., Mohamed, E.A., Abu Dabrh, A.M., Prokop, L.J., Wang, Z., Murad, M.H., Mohammed, K., 2016b. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and metaanalysis. Hepatology 63, 284-306.

      99. Lok, A.S., Zoulim, F., Dusheiko, G., Ghany, M.G., 2017. Hepatitis B cure: from discovery to regulatory approval. Hepatology 66, 1296-1313.

      100. Lucifora, J., Xia, Y., Reisinger, F., Zhang, K., Stadler, D., Cheng, X., Sprinzl, M.F., Koppensteiner, H., Makowska, Z., Volz, T., Remouchamps, C., Chou, W.M., Thasler, W.E., Huser, N., Durantel, D., Liang, T.J., Munk, C., Heim, M.H., Browning, J.L., Dejardin, E., Dandri, M., Schindler, M., Heikenwalder, M., Protzer, U., 2014. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221-1228.

      101. Macdonald, R.A., 1961. "Lifespan" of liver cells. Autoradio-graphic study using tritiated thymidine in normal, cirrhotic, and partially hepatectomized rats. Arch. Intern. Med. 107, 335-343.

      102. Mackman, R.L., Mish, M., Chin, G., Perry, J.K., Appleby, T., Aktoudianakis, V., Metobo, S., Pyun, P., Niu, C., Daffis, S., Yu, H., Zheng, J., Villasenor, A.G., Zablocki, J., Chamberlain, J., Jin, H., Lee, G., Suekawa-Pirrone, K., Santos, R., Delaney, WEt, Fletcher, S.P., 2020. 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. 63, 10188-10203.

      103. Magami, Y., Azuma, T., Inokuchi, H., Kokuno, S., Moriyasu, F., Kawai, K., Hattori, T., 2002. Cell proliferation and renewal of normal hepatocytes and bile duct cells in adult mouse liver. Liver 22, 419-425.

      104. Mak, L.Y., Seto, W.K., Yuen, M.F., 2021. Novel antivirals in clinical development for chronic hepatitis B infection. Viruses 13, 1169.

      105. Mak, L.Y., Cheung, K.S., Fung, J., Seto, W.K., Yuen, M.F., 2022. New strategies for the treatment of chronic hepatitis B. Trends Mol. Med. 28, 742-757.

      106. Man-Fung, Yuen ea, 2021. Low HBsAg Levels Maintained Following Cessation of the GalNAc-siRNA, AB-729, in Chronic Hepatitis B Subjects on Nucleos(t)ide Analogue Therapy. AASLD-The Liver Meeting.

      107. Martinez, M.G., Boyd, A., Combe, E., Testoni, B., Zoulim, F., 2021. Covalently closed circular DNA: the ultimate therapeutic target for curing HBV infections. J. Hepatol. 75, 706-717.

      108. Martinez, M.G., Combe, E., Inchauspe, A., Mangeot, P.E., Delberghe, E., Chapus, F., Neveu, G., Alam, A., Carter, K., Testoni, B., Zoulim, F., 2022. CRISPR-Cas9 targeting of hepatitis B virus covalently closed circular DNA generates transcriptionally active episomal variants. mBio 13, e0288821.

      109. Martinez-Ruiz, G., Maldonado, V., Ceballos-Cancino, G., Grajeda, J.P., MelendezZajgla, J., 2008. Role of Smac/DIABLO in cancer progression. J. Exp. Clin. Cancer Res. 27, 48.

      110. Mason, W.S., Xu, C., Low, H.C., Saputelli, J., Aldrich, C.E., Scougall, C., Grosse, A., Colonno, R., Litwin, S., Jilbert, A.R., 2009. The amount of hepatocyte turnover that occurred during resolution of transient hepadnavirus infections was lower when virus replication was inhibited with entecavir. J. Virol. 83, 1778-1789.

      111. Mata, M., Neben, S., Majzoub, K., Carette, J., Ramanathan, M., Khavari, P.A., Sarnow, P., 2019. Impact of a patient-derived hepatitis C viral RNA genome with a mutated microrna binding site. PLoS Pathog. 15, e1007467.

      112. Meng, F., Zhao, J., Tan, A.T., Hu, W., Wang, S.Y., Jin, J., Wu, J., Li, Y., Shi, L., Fu, J.L., Yu, S., Shen, Y., Liu, L., Luan, J., Shi, M., Xie, Y., Zhou, C.B., Wong, R.W., Lu-En, W., Koh, S., Bertoletti, A., Wang, T., Zhang, J.Y., Wang, F.S., 2021. Immunotherapy of HBV-related advanced hepatocellular carcinoma with short-term HBV-specific TCR expressed T cells: results of dose escalation, phase I trial. Hepatol Int 15, 1402-1412.

      113. Michalak, T.I., Pasquinelli, C., Guilhot, S., Chisari, F.V., 1994. Hepatitis B virus persistence after recovery from acute viral hepatitis. J. Clin. Invest. 93, 230-239.

      114. Milich, D.R., McLachlan, A., 1986. The nucleocapsid of hepatitis B virus is both a T-cellindependent and a T-cell-dependent antigen. Science 234, 1398-1401.

      115. Miller, C.M., Tanowitz, M., Donner, A.J., Prakash, T.P., Swayze, E.E., Harris, E.N., Seth, P.P., 2018. Receptor-mediated uptake of phosphorothioate antisense oligonucleotides in different cell types of the liver. Nucleic Acid Therapeut. 28, 119-127.

      116. Mohebbi, A., Lorestani, N., Tahamtan, A., Kargar, N.L., Tabarraei, A., 2018. An overview of hepatitis B virus surface antigen secretion inhibitors. Front. Microbiol. 9, 662.

      117. Moini, M., Fung, S., 2022. HBsAg Loss as a Treatment Endpoint for Chronic HBV Infection: HBV Cure. Viruses 14, 657.

      118. Momsen, J., Speth, E.B., Wyse, S., Long, T., 2022. Using systems and systems thinking to unify biology education. CBE-Life Sci. Educ. 21, es3.

      119. Mouzannar, K., Fusil, F., Lacombe, B., Ollivier, A., Menard, C., Lotteau, V., Cosset, F.L., Ramiere, C., Andre, P., 2019. Farnesoid x receptor-alpha is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. Faseb. J. 33, 2472-2483.

      120. Naggie, S., Lok, A.S., 2021. New therapeutics for hepatitis B: the road to cure. Annu. Rev. Med. 72, 93-105.

      121. Nguyen, T.H.T., Guedj, J., Uprichard, S.L., Kohli, A., Kottilil, S., Perelson, A.S., 2017. The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics? Sci. Rep. 7, 10233.

      122. Nijampatnam, B., Liotta, D.C., 2019. Recent advances in the development of HBV capsid assembly modulators. Curr. Opin. Chem. Biol. 50, 73-79.

      123. Ning, Q., Wu, D., Wang, G.Q., Ren, H., Gao, Z.L., Hu, P., Han, M.F., Wang, Y., Zhang, W.H., Lu, F.M., Wang, F.S., 2019. Roadmap to functional cure of chronic hepatitis B: an expert consensus. J. Viral Hepat. 26, 1146-1155.

      124. Noordeen, F., Vaillant, A., Jilbert, A.R., 2013. Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo. Antimicrob. Agents Chemother. 57, 5299-5306.

      125. Nowak, M.A., Bonhoeffer, S., Hill, A.M., Boehme, R., Thomas, H.C., McDade, H., 1996. Viral dynamics in hepatitis B virus infection. Proc. Natl. Acad. Sci. U. S. A. 93, 4398-4402.

      126. Pan, Y., Xia, H., He, Y., Zeng, S., Shen, Z., Huang, W., 2023. The progress of molecules and strategies for the treatment of HBV infection. Front. Cell. Infect. Microbiol. 13, 1128807.

      127. Park, J.J., Wong, D.K., Wahed, A.S., Lee, W.M., Feld, J.J., Terrault, N., Khalili, M., Sterling, R.K., Kowdley, K.V., Bzowej, N., Lau, D.T., Kim, W.R., Smith, C., Carithers, R.L., Torrey, K.W., Keith, J.W., Levine, D.L., Traum, D., Ho, S., Valiga, M.E., Johnson, G.S., Doo, E., Lok, A.S., Chang, K.M., Hepatitis, B.R.N., 2016. Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology 150, 684-695 e685.

      128. Perelson, A.S., Neumann, A.U., Markowitz, M., Leonard, J.M., Ho, D.D., 1996. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582-1586.

      129. Ploss, A., Strick-Marchand, H., Li, W., 2021. Animal models for hepatitis B: does the supply meet the demand? Gastroenterology 160, 1437-1442.

      130. Polaris Observatory, C., 2018. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol 3, 383-403.

      131. Pollicino, T., Caminiti, G., 2021. HBV-integration studies in the clinic: role in the natural history of infection. Viruses 13, 368.

      132. Porto, E.M., Komor, A.C., Slaymaker, I.M., Yeo, G.W., 2020. Base editing: advances and therapeutic opportunities. Nat. Rev. Drug Discov. 19, 839-859.

      133. Radreau, P., Porcherot, M., Ramiere, C., Mouzannar, K., Lotteau, V., Andre, P., 2016. Reciprocal regulation of farnesoid x receptor alpha activity and hepatitis B virus replication in differentiated heparg cells and primary human hepatocytes. Faseb. J. 30, 3146-3154.

      134. Ran, F.A., Cong, L., Yan, W.X., Scott, D.A., Gootenberg, J.S., Kriz, A.J., Zetsche, B., Shalem, O., Wu, X., Makarova, K.S., Koonin, E.V., Sharp, P.A., Zhang, F., 2015. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186-191.

      135. Rehermann, B., Ferrari, C., Pasquinelli, C., Chisari, F.V., 1996. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat. Med. 2, 1104-1108.

      136. Roca Suarez, A.A., Testoni, B., Zoulim, F., 2021. HBV 2021: new therapeutic strategies against an old foe. Liver Int. 41 (Suppl 1), 15-23.

      137. Rossi, M., Vecchi, A., Tiezzi, C., Barili, V., Fisicaro, P., Penna, A., Montali, I., Daffis, S., Fletcher, S.P., Gaggar, A., Medley, J., Graupe, M., Lad, L., Loglio, A., Soffredini, R., Borghi, M., Pollicino, T., Musolino, C., Alfieri, A., Brillo, F., Laccabue, D., Massari, M., Boarini, C., Abbati, G., Pedrazzi, G., Missale, G., Lampertico, P., Ferrari, C., Boni, C., 2023. Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro. Gut 72, 2123-2137.

      138. Schoneweis, K., Motter, N., Roppert, P.L., Lu, M., Wang, B., Roehl, I., Glebe, D., Yang, D., Morrey, J.D., Roggendorf, M., Vaillant, A., 2018. Activity of nucleic acid polymers in rodent models of HBV infection. Antivir. Res. 149, 26-33.

      139. Schurich, A., Khanna, P., Lopes, A.R., Han, K.J., Peppa, D., Micco, L., Nebbia, G., Kennedy, P.T., Geretti, A.M., Dusheiko, G., Maini, M.K., 2011. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection. Hepatology 53, 1494-1503.

      140. Sedano, C.D., Sarnow, P., 2014. Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell Host Microbe 16, 257-264.

      141. Selzer, L., Zlotnick, A., 2015. Assembly and release of hepatitis B virus. Cold Spring Harb. Perspect. Med. 5, a021394.

      142. Shin, E.C., Sung, P.S., Park, S.H., 2016. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat. Rev. Immunol. 16, 509-523.

      143. Silke, J., Meier, P., 2013. Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harbor Perspect. Biol. 5, a008730.

      144. Sobao, Y., Tomiyama, H., Sugi, K., Tokunaga, M., Ueno, T., Saito, S., Fujiyama, S., Morimoto, M., Tanaka, K., Takiguchi, M., 2002. The role of hepatitis B virus-specific memory CD8 T cells in the control of viral replication. J. Hepatol. 36, 105-115.

      145. Stone, D., Long, K.R., Loprieno, M.A., De Silva Feelixge, H.S., Kenkel, E.J., Liley, R.M., Rapp, S., Roychoudhury, P., Nguyen, T., Stensland, L., ColonThillet, R., Klouser, L.M., Weber, N.D., Le, C., Wagoner, J., Goecker, E.A., Li, A.Z., Eichholz, K., Corey, L., Tyrrell, D.L., Greninger, A.L., Huang, M.L., Polyak, S.J., Aubert, M., Sagartz, J.E., Jerome, K.R., 2021. CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice. Mol. Ther. Methods Clin. Dev. 20, 258-275.

      146. Takkenberg, B., Terpstra, V., Zaaijer, H., Weegink, C., Dijkgraaf, M., Jansen, P., Beld, M., Reesink, H., 2011. Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha-2a and adefovir. J. Gastroenterol. Hepatol. 26, 1527-1535.

      147. Tan, A.T., Schreiber, S., 2020. Adoptive T-cell therapy for HBV-associated HCC and HBV infection. Antivir. Res. 176, 104748.

      148. Taverniti, V., Ligat, G., Debing, Y., Kum, D.B., Baumert, T.F., Verrier, E.R., 2022. Capsid assembly modulators as antiviral agents against HBV: molecular mechanisms and clinical perspectives. J. Clin. Med. 11, 1349.

      149. Thimme, R., Wieland, S., Steiger, C., Ghrayeb, J., Reimann, K.A., Purcell, R.H., Chisari, F.V., 2003. CD8(þ) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77, 68-76.

      150. Tsiang, M., Rooney, J.F., Toole, J.J., Gibbs, C.S., 1999. Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy. Hepatology 29, 1863-1869.

      151. Tsounis, E.P., Tourkochristou, E., Mouzaki, A., Triantos, C., 2021. Toward a new era of hepatitis B virus therapeutics: the pursuit of a functional cure. World J. Gastroenterol. 27, 2727-2757.

      152. Tsukuda, S., Watashi, K., 2020. Hepatitis B virus biology and life cycle. Antivir. Res. 182, 104925.

      153. Tu, T., Zehnder, B., Wettengel, J.M., Zhang, H., Coulter, S., Ho, V., Douglas, M.W., Protzer, U., George, J., Urban, S., 2022. Mitosis of hepatitis B virus-infected cells in vitro results in uninfected daughter cells. JHEP Rep. 4, 100514.

      154. Turton, K.L., Meier-Stephenson, V., Badmalia, M.D., Coffin, C.S., Patel, T.R., 2020. Host transcription factors in hepatitis B virus RNA synthesis. Viruses 12, 160.

      155. Vaillant, A., 2022. Oligonucleotide-based therapies for chronic HBV infection: a primer on biochemistry, mechanisms and antiviral effects. Viruses 14, 2052.

      156. van Nunen, A.B., Baumann, M., Manns, M.P., Reichen, J., Spengler, U., Marschner, J.P., de Man, R.A., International Study, G., 2001. Efficacy and safety of an intravenous monoclonal anti-HBs in chronic hepatitis B patients. Liver 21, 207-212.

      157. Volz, T., Lutgehetmann, M., Wachtler, P., Jacob, A., Quaas, A., Murray, J.M., Dandri, M., Petersen, J., 2007. Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients. Gastroenterology 133, 843-852.

      158. Volz, T., Allweiss, L., Ben, M.M., Warlich, M., Lohse, A.W., Pollok, J.M., Alexandrov, A., Urban, S., Petersen, J., Lutgehetmann, M., Dandri, M., 2013. The entry inhibitor myrcludex-b efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J. Hepatol. 58, 861-867.

      159. Wang, G., Cui, Y., Xie, Y., Mao, Q., Xie, Q., Gu, Y., Chen, X., Hu, G., Yang, Y., Lu, J., Zou, G., Zhang, Q., Fu, L., Chen, Y., Guo, X., Hou, J., Yan, Y., He, H., Wu, J., 2022.

      160. ALT flares were linked to HBsAg reduction, seroclearance and seroconversion:interim results from a phase IIb study in chronic hepatitis B patients with 24-week treatment of subcutaneous PD-L1 Ab ASC22 (Envafolimab) plus nucleos (t)ide analogs. J. Hepatol. 77, S70.

      161. Wang, Y., Liu, Y., Liao, H., Deng, Z., Bian, D., Ren, Y., Yu, G., Jiang, Y., Bai, L., Liu, S., Liu, M., Zhou, L., Chen, Y., Chen, X., Duan, Z., Lu, F., Zheng, S., 2022. Serum HBV DNA plus RNA reflecting cccDNA level before and during NAs treatment in HBeAg positive CHB patients. Int. J. Med. Sci. 19, 858-866.

      162. Wang, L., Zhu, Q., Zhang, J.D., Zhang, Y., Ni, X., Xiang, K., Jiang, J., Li, B., Yu, Y., Hu, H., Zhang, M., Wu, W., Zeng, J., Yan, Z., Dai, J., Sun, K., Zhang, X., Chen, D., Feng, S., Sach-Peltason, L., Young, J.A.T., Gao, L., 2023. Discovery of a first-in-class orally available HBV cccDNA inhibitor. J. Hepatol. 78, 742-753.

      163. Webster, G.J., Reignat, S., Maini, M.K., Whalley, S.A., Ogg, G.S., King, A., Brown, D., Amlot, P.L., Williams, R., Vergani, D., Dusheiko, G.M., Bertoletti, A., 2000. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 32, 1117-1124.

      164. Wedemeyer, H., Schoneweis, K., Bogomolov, P., Blank, A., Voronkova, N., Stepanova, T., Sagalova, O., Chulanov, V., Osipenko, M., Morozov, V., Geyvandova, N., Sleptsova, S., Bakulin, I.G., Khaertynova, I., Rusanova, M., Pathil, A., Merle, U., Bremer, B., Allweiss, L., Lempp, F.A., Port, K., Haag, M., Schwab, M., Zur Wiesch, J.S., Cornberg, M., Haefeli, W.E., Dandri, M., Alexandrov, A., Urban, S., 2023. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect. Dis. 23, 117-129.

      165. Wei, L., Zhao, T., Zhang, J., Mao, Q., Gong, G., Sun, Y., Chen, Y., Wang, M., Tan, D., Gong, Z., Li, B., Niu, J., Li, S., Gong, H., Zou, L., Zhou, W., Jia, Z., Tang, Y., Fei, L., Hu, Y., Shang, X., Han, J., Zhang, B., Wu, Y., 2022. Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: a randomized clinical trial. Hepatology 75, 182-195.

      166. Werle-Lapostolle, B., Bowden, S., Locarnini, S., Wursthorn, K., Petersen, J., Lau, G., Trepo, C., Marcellin, P., Goodman, Z., Delaney, Wet, Xiong, S., Brosgart, C.L., Chen, S.S., Gibbs, C.S., Zoulim, F., 2004. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126, 1750-1758.

      167. Wisskirchen, K., Kah, J., Malo, A., Asen, T., Volz, T., Allweiss, L., Wettengel, J.M., Lutgehetmann, M., Urban, S., Bauer, T., Dandri, M., Protzer, U., 2019. T cell receptor grafting allows virological control of hepatitis B virus infection. J. Clin. Invest. 129, 2932-2945.

      168. Wolters, L.M., Hansen, B.E., Niesters, H.G., DeHertogh, D., de Man, R.A., 2002a. Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B. J. Hepatol. 37, 137-144.

      169. Wolters, L.M., Hansen, B.E., Niesters, H.G., Zeuzem, S., Schalm, S.W., de Man, R.A., 2002b. Viral dynamics in chronic hepatitis B patients during lamivudine therapy. Liver 22, 121-126.

      170. Wong, D.K., Yuen, M.F., Ngai, V.W., Fung, J., Lai, C.L., 2006. One-year entecavir or lamivudine therapy results in reduction of hepatitis B virus intrahepatic covalently closed circular DNA levels. Antivir. Ther. 11, 909-916.

      171. Wooddell, C.I., Rozema, D.B., Hossbach, M., John, M., Hamilton, H.L., Chu, Q., Hegge, J.O., Klein, J.J., Wakefield, D.H., Oropeza, C.E., Deckert, J., Roehl, I., JahnHofmann, K., Hadwiger, P., Vornlocher, H.P., McLachlan, A., Lewis, D.L., 2013.

      172. Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol. Ther. 21, 973-985.

      173. Wooddell, C.I., Yuen, M.F., Chan, H.L., Gish, R.G., Locarnini, S.A., Chavez, D., Ferrari, C., Given, B.D., Hamilton, J., Kanner, S.B., Lai, C.L., Lau, J.Y.N., Schluep, T., Xu, Z., Lanford, R.E., Lewis, D.L., 2017. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg.SCI. Transl. Med. 9, eaan0241.

      174. Xia, Y., Guo, H., 2020. Hepatitis B virus cccDNA: formation, regulation and therapeutic potential. Antivir. Res. 180, 104824.

      175. Yan, H., Zhong, G., Xu, G., He, W., Jing, Z., Gao, Z., Huang, Y., Qi, Y., Peng, B., Wang, H., Fu, L., Song, M., Chen, P., Gao, W., Ren, B., Sun, Y., Cai, T., Feng, X., Sui, J., Li, W., 2012. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1, e00049.

      176. Yang, Y.C., Yang, H.C., 2021. Recent progress and future prospective in HBV Cure by CRISPR/Cas. Viruses 14, 4.

      177. Yeo, Y.H., Ho, H.J., Yang, H.I., Tseng, T.C., Hosaka, T., Trinh, H.N., Kwak, M.S., Park, Y.M., Fung, J.Y.Y., Buti, M., Rodriguez, M., Treeprasertsuk, S., Preda, C.M., Ungtrakul, T., Charatcharoenwitthaya, P., Li, X., Li, J., Zhang, J., Le, M.H., Wei, B., Zou, B., Le, A., Jeong, D., Chien, N., Kam, L., Lee, C.C., Riveiro-Barciela, M., Istratescu, D., Sriprayoon, T., Chong, Y., Tanwandee, T., Kobayashi, M., Suzuki, F., Yuen, M.F., Lee, H.S., Kao, J.H., Lok, A.S., Wu, C.Y., Nguyen, M.H., 2019. Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection:A Systematic Review and Meta-analysis. Gastroenterology 156, 635-646 e639.

      178. Yi, J., Lei, X., Guo, F., Chen, Q., Chen, X., Zhao, K., Zhu, C., Cheng, X., Lin, J., Yin, H., Xia, Y., 2023. Co-delivery of Cas9 mRNA and guide RNAs edits hepatitis B virus episomal and integration DNA in mouse and tree shrew models. Antivir. Res. 215, 105618.

      179. Yuen, M.F., Yuan, H.J., Wong, D.K., Yuen, J.C., Wong, W.M., Chan, A.O., Wong, B.C., Lai, K.C., Lai, C.L., 2005. Prognostic determinants for chronic hepatitis B in Asians:therapeutic implications. Gut 54, 1610-1614.

      180. Yuen, M.F., Chen, D.S., Dusheiko, G.M., Janssen, H.L.A., Lau, D.T.Y., Locarnini, S.A., Peters, M.G., Lai, C.L., 2018. Hepatitis B virus infection. Nat. Rev. Dis. Prim. 4, 18035.

      181. Yuen, M.F., Schiefke, I., Yoon, J.H., Ahn, S.H., Heo, J., Kim, J.H., Lik Yuen Chan, H., Yoon, K.T., Klinker, H., Manns, M., Petersen, J., Schluep, T., Hamilton, J., Given, B.D., Ferrari, C., Lai, C.L., Locarnini, S.A., Gish, R.G., 2020. RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection. Hepatology 72, 19-31.

      182. Yuen, M.F., Heo, J., Jang, J.W., Yoon, J.H., Kweon, Y.O., Park, S.J., Tami, Y., You, S., Yates, P., Tao, Y., Cremer, J., Campbell, F., Elston, R., Theodore, D., Paff, M., Bennett, C.F., Kwoh, T.J., 2021. Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nat. Med. 27, 1725-1734.

      183. Yuen, M.F., Wong, D.K., Schluep, T., Lai, C.L., Ferrari, C., Locarnini, S., Lo, R.C., Gish, R.G., Hamilton, J., Wooddell, C.I., Mak, L.Y., Given, B.D., 2022a. Longterm serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment. Gut 71, 789-797.

      184. Yuen, M.F., Locarnini, S., Lim, T.H., Strasser, S.I., Sievert, W., Cheng, W., Thompson, A.J., Given, B.D., Schluep, T., Hamilton, J., Biermer, M., Kalmeijer, R., Beumont, M., Lenz, O., De Ridder, F., Cloherty, G., Ka-Ho Wong, D., Schwabe, C., Jackson, K., Lai, C.L., Gish, R.G., Gane, E., 2022b. Combination treatments including the smallinterfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB. J. Hepatol. 77, 1287-1298.

      185. Yuen, M.F., Heo, J., Kumada, H., Suzuki, F., Suzuki, Y., Xie, Q., Jia, J., Karino, Y., Hou, J., Chayama, K., Imamura, M., Lao-Tan, J.Y., Lim, S.G., Tanaka, Y., Xie, W., Yoon, J.H., Duan, Z., Kurosaki, M., Park, S.J., Labio, M.E., Kumar, R., Kweon, Y.O., Yim, H.J., Tao, Y., Cremer, J., Elston, R., Davies, M., Baptiste-Brown, S., Han, K., Campbell, F.M., Paff, M., Theodore, D., 2022c. Phase iia, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy. J. Hepatol. 77, 967-977.

      186. Yuen, M.F., Lim, S.G., Plesniak, R., Tsuji, K., Janssen, H.L.A., Pojoga, C., Gadano, A., Popescu, C.P., Stepanova, T., Asselah, T., Diaconescu, G., Yim, H.J., Heo, J., Janczewska, E., Wong, A., Idriz, N., Imamura, M., Rizzardini, G., Takaguchi, K., Andreone, P., Arbune, M., Hou, J., Park, S.J., Vata, A., Cremer, J., Elston, R., Lukic, T., Quinn, G., Maynard, L., Kendrick, S., Plein, H., Campbell, F., Paff, M., Theodore, D., Group, B.C.S., 2022d. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N. Engl. J. Med. 387, 1957-1968.

      187. Yuen, M.F., Balabanska, R., Cottreel, E., Chen, E., Duan, D., Jiang, Q., Patil, A., Triyatni, M., Upmanyu, R., Zhu, Y., Canducci, F., Gane, E.J., 2023a. TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial. Lancet Infect. Dis. 23, 496-507.

      188. Yuen, M.F., Asselah, T., Jacobson, I.M., Brunetto, M.R., Janssen, H.L.A., Takehara, T., Hou, J.L., Kakuda, T.N., Lambrecht, T., Beumont, M., Kalmeijer, R., GuinardAzadian, C., Mayer, C., Jezorwski, J., Verbinnen, T., Lenz, O., Shukla, U., Biermer, M., Group, R.-S., 2023b. Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, doubleblind, active-controlled, randomised, phase 2b trial. Lancet Gastroenterol Hepatol 8, 790-802.

      189. Zhang, Q., Vendeville, S., Serebryany, V., Welch, M., Liu, J., Williams, C., Debing, Y., Jekle, A., Stevens, S., Deval, J., Lin, T.I., Misner, D., Chanda, S., Schinazi, R.F., Raboisson, P., Symons, J., Blatt, L., Beigelman, L., Smith, D., 2020. ALG-000184, a prodrug of capsid assembly modulator ALG-001075 demonstrates best-in-class preclinical characteristics for the treatment of chronic hepatitis B. J. Hepatol. 73, S880-S881.

      190. Zhang, H., Wang, F., Zhu, X., Chen, Y., Chen, H., Li, X., Wu, M., Li, C., Liu, J., Zhang, Y., Ding, Y., Niu, J., 2021. Antiviral Activity and Pharmacokinetics of the Hepatitis B Virus (HBV) Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection. Clin. Infect. Dis. 73, 175-182.

      191. Zheng, Q., Zhu, Y.Y., Chen, J., Liu, Y.R., You, J., Dong, J., Zeng, D.W., Gao, L.Y., Chen, L.H., Jiang, J.J., 2014. Decline in intrahepatic cccdna and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss. J. Viral Hepat. 21, 909-916.

      192. Zhou, K., Contag, C., Whitaker, E., Terrault, N., 2019. Spontaneous loss of surface antigen among adults living with chronic hepatitis B virus infection: a systematic review and pooled meta-analyses. Lancet Gastroenterol Hepatol 4, 227-238.

      193. Zhu, Y., Yamamoto, T., Cullen, J., Saputelli, J., Aldrich, C.E., Miller, D.S., Litwin, S., Furman, P.A., Jilbert, A.R., Mason, W.S., 2001. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J. Virol. 75, 311-322.

      194. Zoulim, F., Fournier, C., Habersetzer, F., Sprinzl, M., Pol, S., Coffin, C.S., Leroy, V., Ma, M., Wedemeyer, H., Lohse, A.W., Thimme, R., Lugardon, K., Martin, P., Bastien, B., Sansas, B., Adda, N., Halluard, C., Bendjama, K., Brandely, M., Inchauspe, G., 2020. Safety and immunogenicity of the therapeutic vaccine tg1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial. Hum. Vaccines Immunother. 16, 388-399.

      195. Zoulim, F., Zlotnick, A., Buchholz, S., Donaldson, E., Fry, J., Gaggar, A., Hu, J., Kann, M., Lenz, O., Lin, K., Mani, N., Nassal, M., Delaney, W., Wang, S., Westman, G., Miller, V., Janssen, H.L.A., 2022. Nomenclature of HBV core protein-targeting antivirals. Nat. Rev. Gastroenterol. Hepatol. 19, 748-750.

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      Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics

        Corresponding author: Jie-Li Hu, 102564@cqmu.edu.cn
        Corresponding author: Ai-Long Huang, ahuang1964@163.com
      • Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
      • Received Date: 29 January 2023
      • Accepted Date: 13 December 2023

      Abstract: The achievement of a functional cure for chronic hepatitis B (CHB) remains limited to a minority of patients treated with currently approved drugs. The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB. A critical prerequisite for the functional cure of CHB is a substantial reduction, or even eradication of covalently closed circular DNA (cccDNA). Within this context, the changes in cccDNA levels during treatment become as a pivotal concern. We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics. In this review, we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA. Building upon this foundation, we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe.

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