慢性乙型肝炎抗病毒治疗研究现状
Research Status of Antiviral Therapy for Chronic Hepatitis B
摘要: 本文旨在全面阐述慢性乙型肝炎(CHB)抗病毒治疗的研究现状。基于核苷(酸)类似物(NAs)、干扰素(IFN)等经典抗病毒药物的作用机制、临床疗效、安全性及耐药性特征,结合最新循证医学证据,探讨现有治疗方案的优化选择策略及其临床应用价值。同时,介绍新型抗病毒药物的研发进展以及联合治疗方案的优化策略,为慢性乙型肝炎的抗病毒治疗提供综合参考。
Abstract: The purpose of this article is to comprehensively describe the research status of antiviral therapy for chronic hepatitis B. By analyzing the mechanism of action, efficacy, safety and drug resistance of common antiviral drugs such as Nucleoside analogues and interferons, the selection basis and clinical application of current treatment regimens were discussed. At the same time, the research and development progress of new antiviral drugs and the optimization strategy of combination therapy regimens are introduced, so as to provide a comprehensive reference for the antiviral treatment of chronic hepatitis B.
文章引用:赵漫, 谢华宇, 张鸿. 慢性乙型肝炎抗病毒治疗研究现状[J]. 临床医学进展, 2025, 15(4): 1194-1204. https://doi.org/10.12677/acm.2025.1541046

参考文献

[1] (2024) Global Hepatitis Report 2024: Action for Access in Low-and Middle-Income Countries. World Health Organization.
[2] Razavi-Shearer, D., Gamkrelidze, I., Pan, C., et al. (2023) Global Prevalence, Cascade of Care, and Prophylaxis Coverage of Hepatitis B in 2022: A Modelling Study. The Lancet Gastroenterology & Hepatology, 8, 879-907.
[3] 艾滋病毒、病毒性肝炎和性传播感染2022-2030年全球卫生部门战略[EB/OL].
https://www.who.int/zh/publications/i/item/9789240053779, 2025-04-02.
[4] 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版) [J]. 中华肝脏病杂志, 2022, 30(12): 1309-1331.
[5] Xie, D., Ren, Z., Zhou, J., Fan, J. and Gao, Q. (2020) 2019 Chinese Clinical Guidelines for the Management of Hepatocellular Carcinoma: Updates and Insights. Hepatobiliary Surgery and Nutrition, 9, 452-463. [Google Scholar] [CrossRef] [PubMed]
[6] Xia, Y. and Guo, H. (2020) Hepatitis B Virus cccDNA: Formation, Regulation and Therapeutic Potential. Antiviral Research, 180, Article ID: 104824. [Google Scholar] [CrossRef] [PubMed]
[7] Kramvis, A., Chang, K., Dandri, M., Farci, P., Glebe, D., Hu, J., et al. (2022) A Roadmap for Serum Biomarkers for Hepatitis B Virus: Current Status and Future Outlook. Nature Reviews Gastroenterology & Hepatology, 19, 727-745. [Google Scholar] [CrossRef] [PubMed]
[8] Yan, H., Zhong, G., Xu, G., He, W., Jing, Z., Gao, Z., et al. (2012) Sodium Taurocholate Cotransporting Polypeptide Is a Functional Receptor for Human Hepatitis B and D Virus. eLife, 1, e00049. [Google Scholar] [CrossRef] [PubMed]
[9] Trépo, C., Chan, H.L.Y. and Lok, A. (2014) Hepatitis B Virus Infection. The Lancet, 384, 2053-2063. [Google Scholar] [CrossRef] [PubMed]
[10] Gish, R., Jia, J., Locarnini, S. and Zoulim, F. (2012) Selection of Chronic Hepatitis B Therapy with High Barrier to Resistance. The Lancet Infectious Diseases, 12, 341-353. [Google Scholar] [CrossRef] [PubMed]
[11] Rivkin, A. (2005) A Review of Entecavir in the Treatment of Chronic Hepatitis B Infection. Current Medical Research and Opinion, 21, 1845-1856. [Google Scholar] [CrossRef] [PubMed]
[12] Zoulim, F. (2011) Hepatitis B Virus Resistance to Antiviral Drugs: Where Are We Going? Liver International, 31, 111-116. [Google Scholar] [CrossRef] [PubMed]
[13] Buti, M., Marcos‐Fosch, C. and Esteban, R. (2021) Nucleos(t)ide Analogue Therapy: The Role of Tenofovir Alafenamide. Liver International, 41, 9-14. [Google Scholar] [CrossRef] [PubMed]
[14] Kim, J.H. (2014) Molecular Diagnosis and Treatment of Drug-Resistant Hepatitis B Virus. World Journal of Gastroenterology, 20, 5708-5720. [Google Scholar] [CrossRef] [PubMed]
[15] Kwon, H. and Lok, A.S. (2011) Hepatitis B Therapy. Nature Reviews Gastroenterology & Hepatology, 8, 275-284. [Google Scholar] [CrossRef] [PubMed]
[16] Chon, H.Y., Ahn, S.H., Kim, Y.J., Yoon, J., Lee, J., Sinn, D.H., et al. (2021) Efficacy of Entecavir, Tenofovir Disoproxil Fumarate, and Tenofovir Alafenamide in Treatment-Naive Hepatitis B Patients. Hepatology International, 15, 1328-1336. [Google Scholar] [CrossRef] [PubMed]
[17] Choi, J., Choi, W. and Lim, Y. (2023) Are the New Nucleos(t)ide Analogs Better than the Old Nucleos(t)ide Analogs? Clinics in Liver Disease, 27, 809-818. [Google Scholar] [CrossRef] [PubMed]
[18] Park, C.H., Jung, S.W., Shin, J.W., Bae, M.A., Lee, Y.I., Park, Y.T., et al. (2016) Comparison of Tenofovir Plus Lamivudine versus Tenofovir Monotherapy in Patients with Lamivudine-Resistant Chronic Hepatitis B. Clinical and Molecular Hepatology, 22, 152-159. [Google Scholar] [CrossRef] [PubMed]
[19] Woo, H.Y., Park, J.Y., Bae, S.H., Kim, C.W., Jang, J.Y., Tak, W.Y., et al. (2020) Entecavir + Tenofovir vs. Lamivudine/Telbivudine + Adefovir in Chronic Hepatitis B Patients with Prior Suboptimal Response. Clinical and Molecular Hepatology, 26, 352-363. [Google Scholar] [CrossRef] [PubMed]
[20] Yip, T.C., Lai, J.C., Yam, T., Tse, Y., Hui, V.W., Lai, M.S., et al. (2024) Long-Term Use of Tenofovir Disoproxil Fumarate Increases Fracture Risk in Elderly Patients with Chronic Hepatitis B. Journal of Hepatology, 80, 553-563. [Google Scholar] [CrossRef] [PubMed]
[21] Lai, C.L., et al. (2007) Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B. The New England Journal of Medicine, 357, 2576-2588.
[22] Buti, M. and Esteban, R. (2003) Adefovir Dipivoxil. Drugs Today (Barc), 39, 127-135.
[23] Choi, J. (2023) Are the New Nucleos(t)ide Analogs Better than the Old Nucleos(t)ide Analogs? Clinical Liver Disease, 27, 809-818.
[24] Rehermann, B. and Nascimbeni, M. (2005) Immunology of Hepatitis B Virus and Hepatitis C Virus Infection. Nature Reviews Immunology, 5, 215-229. [Google Scholar] [CrossRef] [PubMed]
[25] Lau, G.K.K., Piratvisuth, T., Luo, K.X., Marcellin, P., Thongsawat, S., Cooksley, G., et al. (2005) Peginterferon Alfa-2a, Lamivudine, and the Combination for HBeAg-Positive Chronic Hepatitis B. New England Journal of Medicine, 352, 2682-2695. [Google Scholar] [CrossRef] [PubMed]
[26] Terrault, N.A., Bzowej, N.H., Chang, K., Hwang, J.P., Jonas, M.M. and Murad, M.H. (2015) AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology, 63, 261-283. [Google Scholar] [CrossRef] [PubMed]
[27] Jonas, M.M., Chang, M., Sokal, E., Schwarz, K.B., Kelly, D., Kim, K.M., et al. (2015) Randomized, Controlled Trial of Entecavir versus Placebo in Children with Hepatitis B Envelope Antigen-Positive Chronic Hepatitis B. Hepatology, 63, 377-387. [Google Scholar] [CrossRef] [PubMed]
[28] Chan, H.L.Y., Fung, S., Seto, W.K., Chuang, W., Chen, C., Kim, H.J., et al. (2016) Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate for the Treatment of HBeAg-Positive Chronic Hepatitis B Virus Infection: A Randomised, Double-Blind, Phase 3, Non-Inferiority Trial. The Lancet Gastroenterology & Hepatology, 1, 185-195. [Google Scholar] [CrossRef] [PubMed]
[29] Papatheodoridis, G.V., Mimidis, K., Manolakopoulos, S., Gatselis, N., Goulis, J., Kapatais, A., et al. (2022) HERACLIS‐TAF: A Multi‐Centre Prospective Cohort Study on 2‐Year Safety and Efficacy of Tenofovir Alafenamide in Patients with Chronic Hepatitis B with Renal and/or Bone Disorders or Risks. Alimentary Pharmacology & Therapeutics, 56, 702-712. [Google Scholar] [CrossRef] [PubMed]
[30] Janssen, H.L.A., Lim, Y., Lampertico, P., Heo, J., Chen, C., Fournier, C., et al. (2024) Switching to Tenofovir Alafenamide in Patients with Virologically Suppressed Chronic Hepatitis B and Renal or Hepatic Impairment: Final Week 96 Results from an Open-Label, Multicentre, Phase 2 Study. The Lancet Gastroenterology & Hepatology, 9, 718-733. [Google Scholar] [CrossRef] [PubMed]
[31] Lok, A.S.F., McMahon, B.J., Brown, R.S., Wong, J.B., Ahmed, A.T., Farah, W., et al. (2015) Antiviral Therapy for Chronic Hepatitis B Viral Infection in Adults: A Systematic Review and Meta‐analysis. Hepatology, 63, 284-306. [Google Scholar] [CrossRef] [PubMed]
[32] Funk, A.L. (2021) Efficacy and Safety of Antiviral Prophylaxis during Pregnancy to Prevent Mother-to-Child Transmission of Hepatitis B Virus: A Systematic Review and Meta-Analysis. The Lancet Infectious Diseases, 21, 70-84.
[33] Pan, C.Q., Duan, Z., Dai, E., Zhang, S., Han, G., Wang, Y., et al. (2016) Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. New England Journal of Medicine, 374, 2324-2334. [Google Scholar] [CrossRef] [PubMed]
[34] Benhamou, Y. (2005) HIV-1/hepatitis B Coinfection. Expert Review of Anti-infective Therapy, 3, 229-239. [Google Scholar] [CrossRef] [PubMed]
[35] Mak, J.W.Y., Law, A.W.H., Law, K.W.T., Ho, R., Cheung, C.K.M. and Law, M.F. (2023) Prevention and Management of Hepatitis B Virus Reactivation in Patients with Hematological Malignancies in the Targeted Therapy Era. World Journal of Gastroenterology, 29, 4942-4961. [Google Scholar] [CrossRef] [PubMed]
[36] Zoulim, F., Lenz, O., Vandenbossche, J.J., Talloen, W., Verbinnen, T., Moscalu, I., et al. (2020) 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, 159, 521-533.e9. [Google Scholar] [CrossRef] [PubMed]
[37] Janssen, H.L.A., Hou, J., Asselah, T., Chan, H.L.Y., Zoulim, F., Tanaka, Y., et al. (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. [Google Scholar] [CrossRef] [PubMed]
[38] Vendeville, S., Amblard, F., Bassit, L., Beigelman, L.N., Blatt, L.M., Chen, X., et al. (2024) The Discovery and Preclinical Profile of ALG-000184, a Prodrug of the Potent Hepatitis B Virus Capsid Assembly Modulator Alg-001075. Journal of Medicinal Chemistry, 67, 21126-21142. [Google Scholar] [CrossRef] [PubMed]
[39] Yuen, M., Lim, S., Plesniak, R., Tsuji, K., Janssen, H.L.A., Pojoga, C., et al. (2022) Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. New England Journal of Medicine, 387, 1957-1968. [Google Scholar] [CrossRef] [PubMed]
[40] Yuen, M., Heo, J., Jang, J., Yoon, J., Kweon, Y., Park, S., et al. (2021) Safety, Tolerability and Antiviral Activity of the Antisense Oligonucleotide Bepirovirsen in Patients with Chronic Hepatitis B: A Phase 2 Randomized Controlled Trial. Nature Medicine, 27, 1725-1734. [Google Scholar] [CrossRef] [PubMed]
[41] Gane, E., Lim, Y., Kim, J.B., Jadhav, V., Shen, L., Bakardjiev, A.I., et al. (2023) Evaluation of RNAi Therapeutics VIR-2218 and ALN-HBV for Chronic Hepatitis B: Results from Randomized Clinical Trials. Journal of Hepatology, 79, 924-932. [Google Scholar] [CrossRef] [PubMed]
[42] Zhaori, G. (2018) Potential Clinical Application of RNAi‐Based Therapeutic Strategies for Treatment of Chronic Hepatitis B. Pediatric Investigation, 2, 4-7. [Google Scholar] [CrossRef] [PubMed]
[43] Zhao, H., Shao, X., Yu, Y., Huang, L., Amor, N.P., Guo, K., et al. (2024) A Therapeutic Hepatitis B mRNA Vaccine with Strong Immunogenicity and Persistent Virological Suppression. npj Vaccines, 9, Article No. 22. [Google Scholar] [CrossRef] [PubMed]
[44] Nguyen, M.H., Wong, G., Gane, E., Kao, J. and Dusheiko, G. (2020) Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy. Clinical Microbiology Reviews, 33, e00046-19. [Google Scholar] [CrossRef] [PubMed]
[45] Du, Y., Wu, J., Liu, J., Zheng, X., Yang, D. and Lu, M. (2022) Toll-Like Receptor-Mediated Innate Immunity Orchestrates Adaptive Immune Responses in HBV Infection. Frontiers in Immunology, 13, Article 965018. [Google Scholar] [CrossRef] [PubMed]
[46] Janssen, H.L.A., Brunetto, M.R., Kim, Y.J., Ferrari, C., Massetto, B., Nguyen, A., et al. (2018) Safety, Efficacy and Pharmacodynamics of Vesatolimod (GS-9620) in Virally Suppressed Patients with Chronic Hepatitis B. Journal of Hepatology, 68, 431-440. [Google Scholar] [CrossRef] [PubMed]
[47] Fung, S., Choi, H.S.J., Gehring, A. and Janssen, H.L.A. (2022) Getting to HBV Cure: The Promising Paths Forward. Hepatology, 76, 233-250. [Google Scholar] [CrossRef] [PubMed]
[48] Lee, H.W., Park, J.Y., Hong, T., Park, M.S. and Ahn, S.H. (2020) Efficacy of Lenvervimab, a Recombinant Human Immunoglobulin, in Treatment of Chronic Hepatitis B Virus Infection. Clinical Gastroenterology and Hepatology, 18, 3043-3045.e1. [Google Scholar] [CrossRef] [PubMed]
[49] Lempp, F.A., Volz, T., Cameroni, E., Benigni, F., Zhou, J., Rosen, L.E., et al. (2023) Potent Broadly Neutralizing Antibody VIR-3434 Controls Hepatitis B and D Virus Infection and Reduces HBsAg in Humanized Mice. Journal of Hepatology, 79, 1129-1138. [Google Scholar] [CrossRef] [PubMed]
[50] Li, S., Li, N., Yang, S., Deng, H., Li, Y., Wang, Y., et al. (2022) The Study of Immune Checkpoint Inhibitors in Chronic Hepatitis B Virus Infection. International Immunopharmacology, 109, Article ID: 108842. [Google Scholar] [CrossRef] [PubMed]
[51] Urbanek-Quaing, M., Chou, Y., Gupta, M.K., Steppich, K., Bremer, B., Schmaus, H., et al. (2024) Enhancing HBV-Specific T Cell Responses through a Combination of Epigenetic Modulation and Immune Checkpoint Inhibition. Hepatology. [Google Scholar] [CrossRef] [PubMed]
[52] Xie, Y., Zhu, H., Guo, Y., Ma, Z., Qi, X., Yang, F., et al. (2022) 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. Canadian Journal of Gastroenterology and Hepatology, 2022, Article ID: 4325352. [Google Scholar] [CrossRef] [PubMed]
[53] Ma, H., Lim, T.H., Leerapun, A., Weltman, M., Jia, J., Lim, Y., et al. (2021) Therapeutic Vaccine BRII-179 Restores HBV-Specific Immune Responses in Patients with Chronic HBV in a Phase IB/IIA Study. JHEP Reports, 3, Article ID: 100361. [Google Scholar] [CrossRef] [PubMed]
[54] Yuen, M., Lim, Y., Yoon, K.T., Lim, T., Heo, J., Tangkijvanich, P., et al. (2024) VIR-2218 (Elebsiran) Plus Pegylated Interferon-Alfa-2a in Participants with Chronic Hepatitis B Virus Infection: A Phase 2 Study. The Lancet Gastroenterology & Hepatology, 9, 1121-1132. [Google Scholar] [CrossRef] [PubMed]