Progress in the treatment of chronic viral hepatitis B_West China Medical Journal

Authors：

ZHANG Yunzhe ,  LEI Xuezhong

Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LEI Xuezhong, Email: 18980601317@163.com

Keywords：

Chronic viral hepatitis B; clinical cure; antiviral; host immunotherapy

DOI：

10.7507/1002-0179.202303141

Video：

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At present, the most commonly used nucleoside (acid) anaog (NAs) treatment regimen in clinical practice cannot completely cure chronic viral hepatitis B (CHB). However, although the polyethylene glycol interferon treatment regimen is superior to the NAs regimen in terms of immune mechanism, it has the disadvantage of low hepatitis B virus DNA response rate. In recent years, the cure of CHB is being studied all over the world. Various mechanisms and drug targets are being explored, and diversified therapeutic strategies are also being used. Clinical cure of hepatitis B is possible, but it is still in the early stage, and many potential drugs and better therapeutic strategies are still being tested. This article mainly reviews the latest progress in the treatment of CHB based on the recent research achievements in direct antiviral drugs and host immunotherapy as well as the research progress in combination therapy.

Citation： ZHANG Yunzhe, LEI Xuezhong. Progress in the treatment of chronic viral hepatitis B. West China Medical Journal, 2023, 38(8): 1247-1251. doi: 10.7507/1002-0179.202303141 Copy

1.	Martinez MG, Boyd A, Combe E, et al. Covalently closed circular DNA: the ultimate therapeutic target for curing HBV infections. J Hepatol, 2021, 75(3): 706-717.
2.	中国疾病预防控制中心传染病预防控制处. 2022 年 3 月中国甲乙丙类传染病疫情概要. 疾病监测, 2022, 37(4): 421.
3.	Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol, 2016, 18: 109-116.
4.	Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: from discovery to regulatory approval. J Hepatol, 2017, 67(4): 847-861.
5.	Phillips S, Jagatia R, Chokshi S. Novel therapeutic strategies for chronic hepatitis B. Virulence, 2022, 13(1): 1111-1132.
6.	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(1): 215-225 e6.
7.	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(10): 1684-1693.
8.	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(5): 1444-1453.
9.	Hui RW, Mak LY, Seto WK, et al. Chronic hepatitis B: a scoping review on the guidelines for stopping nucleos(t)ide analogue therapy. Expert Rev Gastroenterol Hepatol, 2023, 17(5): 443-450.
10.	Hu Y, Ye YZ, Ye LJ, et al. Efficacy and safety of interferon alpha-2b versus pegylated interferon alpha-2a monotherapy in children with chronic hepatitis B: a real-life cohort study from Shanghai, China. World J Pediatr, 2019, 15(6): 595-600.
11.	Xie Y, Zhu H, Guo Y, et al. Reduction of hepatitis B surface antigen may be more significant in PEGylated interferon-alpha therapy combined with nucleotide analogues than combined with nucleoside analogues in chronic hepatitis B patients: a propensity score matching study. Can J Gastroenterol Hepatol, 2022: 4325352.
12.	Burm R, Van Houtte F, Verhoye L, et al. A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection. JHEP Rep, 2023, 5(3): 100646.
13.	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(3): 490-498.
14.	Cheng D, Han B, Zhang W, et al. Clinical effects of NTCP-inhibitor myrcludex B. J Viral Hepat, 2021, 28(6): 852-858.
15.	Miyakawa Y, Otsuka M, Sekiba K, et al. Humanized virus-suppressing factor inhibits hepatitis B virus infection by targeting viral cell entry. Heliyon, 2021, 7(7): e07586.
16.	Korolowicz KE, Suresh M, Li B, et al. Combination treatment with the vimentin-targeting antibody hzVSF and tenofovir suppresses woodchuck hepatitis virus infection in woodchucks. Cells, 2021, 10(9): 2321.
17.	Soriano V, Barreiro P, Cachay E, et al. Advances in hepatitis B therapeutics. Ther Adv Infect Dis, 2020, 7: 2049936120965027.
18.	Yuen MF, Locarnini S, Lim TH, et al. Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB. J Hepatol, 2022, 77(5): 1287-1298.
19.	Gupta SV, Fanget MC, MacLauchlin C, et al. Clinical and preclinical single-dose pharmacokinetics of VIR-2218, an RNAi therapeutic targeting HBV infection. Drugs R D, 2021, 21(4): 455-465.
20.	Yuen MF, Lim SG, Plesniak R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med, 2022, 387(21): 1957-1968.
21.	冯齐云, 高宝玉, 岳钦艳, 等. 不同阳离子聚丙烯酰胺有机脱水剂对污泥脱水性能的影响. 环境科学, 2022, 43(2): 928-935.
22.	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(1): e01686-19.
23.	Yuen MF, 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(9): 723-732.
24.	Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet, 2014, 384(9959): 2053-2063.
25.	Vaillant A. REP 2139: Antiviral mechanisms and applications in achieving functional control of HBV and HDV infection. ACS Infect Dis, 2019, 5(5): 675-687.
26.	Roehl I, Seiffert S, Brikh C, et al. Nucleic acid polymers with accelerated plasma and tissue clearance for chronic hepatitis B Therapy. Mol Ther Nucleic Acids, 2017, 8: 1-12.
27.	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 infection naïve to nucleos(t)ide therapy. Gastroenterology, 2020, 158(8): 2180-2194.
28.	Sulkowski MS, Agarwal K, Ma X, et al. Safety and efficacy of vebicorvir administered with entecavir in treatment-naive patients with chronic hepatitis B virus infection. J Hepatol, 2022, 77(5): 1265-1275.
29.	Murai K, Kodama T, Hikita H, et al. Inhibition of nonhomologous end joining-mediated DNA repair enhances anti-HBV CRISPR therapy. Hepatol Commun, 2022, 6(9): 2474-2487.
30.	Yang PL, Althage A, Chung J, et al. Immune effectors required for hepatitis B virus clearance. Proc Natl Acad Sci U S A, 2010, 107(2): 798-802.
31.	Long Q, Yan R, Hu J, et al. The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLoS Pathog, 2017, 13(12): e1006784.
32.	Kostyusheva AP, Brezgin SA, Ponomareva NI, et al. Antiviral activity of CRISPR/Cas9 ribonucleoprotein complexes on a hepatitis B virus model in vivo. Mol Biol (Mosk), 2022, 56(6): 884-891.
33.	Bloom K, Maepa M, Ely A, et al. Gene therapy for chronic HBV—can we eliminate cccDNA?. Genes, 2018, 9(4): 207.
34.	Yang YC, Yang HC. Recent progress and future prospective in HBV Cure by CRISPR/Cas. Viruses, 2021, 14(1): 4.
35.	Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut, 2012, 61(12): 1754-1764.
36.	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(7): 661-670.
37.	Chang J, Block TM, Guo JT. The innate immune response to hepatitis B virus infection: implications for pathogenesis and therapy. Antiviral Res, 2012, 96(3): 405-413.

1. Martinez MG, Boyd A, Combe E, et al. Covalently closed circular DNA: the ultimate therapeutic target for curing HBV infections. J Hepatol, 2021, 75(3): 706-717.
2. 中国疾病预防控制中心传染病预防控制处. 2022 年 3 月中国甲乙丙类传染病疫情概要. 疾病监测, 2022, 37(4): 421.
3. Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol, 2016, 18: 109-116.
4. Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: from discovery to regulatory approval. J Hepatol, 2017, 67(4): 847-861.
5. Phillips S, Jagatia R, Chokshi S. Novel therapeutic strategies for chronic hepatitis B. Virulence, 2022, 13(1): 1111-1132.
6. 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(1): 215-225 e6.
7. 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(10): 1684-1693.
8. 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(5): 1444-1453.
9. Hui RW, Mak LY, Seto WK, et al. Chronic hepatitis B: a scoping review on the guidelines for stopping nucleos(t)ide analogue therapy. Expert Rev Gastroenterol Hepatol, 2023, 17(5): 443-450.
10. Hu Y, Ye YZ, Ye LJ, et al. Efficacy and safety of interferon alpha-2b versus pegylated interferon alpha-2a monotherapy in children with chronic hepatitis B: a real-life cohort study from Shanghai, China. World J Pediatr, 2019, 15(6): 595-600.
11. Xie Y, Zhu H, Guo Y, et al. Reduction of hepatitis B surface antigen may be more significant in PEGylated interferon-alpha therapy combined with nucleotide analogues than combined with nucleoside analogues in chronic hepatitis B patients: a propensity score matching study. Can J Gastroenterol Hepatol, 2022: 4325352.
12. Burm R, Van Houtte F, Verhoye L, et al. A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection. JHEP Rep, 2023, 5(3): 100646.
13. 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(3): 490-498.
14. Cheng D, Han B, Zhang W, et al. Clinical effects of NTCP-inhibitor myrcludex B. J Viral Hepat, 2021, 28(6): 852-858.
15. Miyakawa Y, Otsuka M, Sekiba K, et al. Humanized virus-suppressing factor inhibits hepatitis B virus infection by targeting viral cell entry. Heliyon, 2021, 7(7): e07586.
16. Korolowicz KE, Suresh M, Li B, et al. Combination treatment with the vimentin-targeting antibody hzVSF and tenofovir suppresses woodchuck hepatitis virus infection in woodchucks. Cells, 2021, 10(9): 2321.
17. Soriano V, Barreiro P, Cachay E, et al. Advances in hepatitis B therapeutics. Ther Adv Infect Dis, 2020, 7: 2049936120965027.
18. Yuen MF, Locarnini S, Lim TH, et al. Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB. J Hepatol, 2022, 77(5): 1287-1298.
19. Gupta SV, Fanget MC, MacLauchlin C, et al. Clinical and preclinical single-dose pharmacokinetics of VIR-2218, an RNAi therapeutic targeting HBV infection. Drugs R D, 2021, 21(4): 455-465.
20. Yuen MF, Lim SG, Plesniak R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med, 2022, 387(21): 1957-1968.
21. 冯齐云, 高宝玉, 岳钦艳, 等. 不同阳离子聚丙烯酰胺有机脱水剂对污泥脱水性能的影响. 环境科学, 2022, 43(2): 928-935.
22. 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(1): e01686-19.
23. Yuen MF, 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(9): 723-732.
24. Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet, 2014, 384(9959): 2053-2063.
25. Vaillant A. REP 2139: Antiviral mechanisms and applications in achieving functional control of HBV and HDV infection. ACS Infect Dis, 2019, 5(5): 675-687.
26. Roehl I, Seiffert S, Brikh C, et al. Nucleic acid polymers with accelerated plasma and tissue clearance for chronic hepatitis B Therapy. Mol Ther Nucleic Acids, 2017, 8: 1-12.
27. 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 infection naïve to nucleos(t)ide therapy. Gastroenterology, 2020, 158(8): 2180-2194.
28. Sulkowski MS, Agarwal K, Ma X, et al. Safety and efficacy of vebicorvir administered with entecavir in treatment-naive patients with chronic hepatitis B virus infection. J Hepatol, 2022, 77(5): 1265-1275.
29. Murai K, Kodama T, Hikita H, et al. Inhibition of nonhomologous end joining-mediated DNA repair enhances anti-HBV CRISPR therapy. Hepatol Commun, 2022, 6(9): 2474-2487.
30. Yang PL, Althage A, Chung J, et al. Immune effectors required for hepatitis B virus clearance. Proc Natl Acad Sci U S A, 2010, 107(2): 798-802.
31. Long Q, Yan R, Hu J, et al. The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLoS Pathog, 2017, 13(12): e1006784.
32. Kostyusheva AP, Brezgin SA, Ponomareva NI, et al. Antiviral activity of CRISPR/Cas9 ribonucleoprotein complexes on a hepatitis B virus model in vivo. Mol Biol (Mosk), 2022, 56(6): 884-891.
33. Bloom K, Maepa M, Ely A, et al. Gene therapy for chronic HBV—can we eliminate cccDNA?. Genes, 2018, 9(4): 207.
34. Yang YC, Yang HC. Recent progress and future prospective in HBV Cure by CRISPR/Cas. Viruses, 2021, 14(1): 4.
35. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut, 2012, 61(12): 1754-1764.
36. 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(7): 661-670.
37. Chang J, Block TM, Guo JT. The innate immune response to hepatitis B virus infection: implications for pathogenesis and therapy. Antiviral Res, 2012, 96(3): 405-413.

West China Medical Journal

Progress in the treatment of chronic viral hepatitis B

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