乙型病毒性肝炎的诊断技术与药物治疗研究进展
Advances in Diagnostic Technique and Pharmacological Therapy of Hepatitis B
DOI: 10.12677/acm.2024.1461821, PDF,   
作者: 何 菁:首都医科大学第六临床医学院,北京;薛同贺:天津医科大学第一临床医学院,天津;赵佳晖*:首都医科大学附属北京安贞医院泌尿外科,北京
关键词: 乙型肝炎病毒诊断技术乙型病毒性肝炎药物治疗HBV Diagnostic Technology HB Pharmacological Therapy
摘要: 乙型病毒性肝炎(HB)是临床上常见的疾病,由乙型肝炎病毒(HBV)感染而引起,在我国发病率较高。HB会造成不同程度的肝功能损害,严重者将造成肝功能衰竭、肝硬化甚至肝细胞癌,威胁患者的生命。因此,HB患者的早期诊断和治疗,在避免肝功能损害、提高生存期和改善预后方面具有重要的意义。目前HB的治疗以聚乙二醇干扰素(Peg-INF)和核苷酸类似物(NUC)为代表的抗病毒药物为主。虽然这些传统药物可以抑制HBV复制,延缓肝功能受损,但无法彻底清除病毒。随着医疗技术的发展,越来越多的检测技术和新型药物应用于HB患者的诊断与治疗,并取得了良好的临床效果。本文就近年来HB诊断技术与药物治疗的进展进行综述,旨在为HB的临床诊治及未来研究提供参考。
Abstract: Hepatitis B (HB) is a prevalent disease in clinical practice with highly incidence in China, which is caused by hepatitis B virus (HBV) infection. HB could leads to liver damage progressing as liver cirrhosis, liver failure or even hepatocellular carcinoma (HCC) and threats to life in HB patients. Thus, early detection, diagnosis and treatment play a vital part in improving the prognosis and enhancing the survival of HB patients. In recent years, treatment of HB is dominated by two groups of agents: Pegylated interferons (IFN) and nucleostide analogs (NUC). Though these traditional medicines could improve liver function and inhibit HBV replication, they fail to establish a functional cure. Due to the development of medical technology, more and more advanced techniques and drugs has been developing, some of which were launched for clinical use and sachieved brilliant results. Therefore, this review focus on the recent progress in our understanding of diagnostic techniques and therapeutic agents for HB, which intends to provide references for clinical management and further scientific research.
文章引用:何菁, 薛同贺, 赵佳晖. 乙型病毒性肝炎的诊断技术与药物治疗研究进展[J]. 临床医学进展, 2024, 14(6): 643-652. https://doi.org/10.12677/acm.2024.1461821

参考文献

[1] Razavi-Shearer, D., Gamkrelidze, I., Nguyen, M.H., Chen, D., Van Damme, P., Abbas, Z., et al. (2018) Global Prevalence, Treatment, and Prevention of Hepatitis B Virus Infection in 2016: A Modelling Study. The Lancet Gastroenterology & Hepatology, 3, 383-403. [Google Scholar] [CrossRef] [PubMed]
[2] Su, S., Wong, W.C., Zou, Z., Cheng, D.D., Ong, J.J., Chan, P., et al. (2022) Cost-Effectiveness of Universal Screening for Chronic Hepatitis B Virus Infection in China: An Economic Evaluation. The Lancet Global Health, 10, e278-e287. [Google Scholar] [CrossRef] [PubMed]
[3] Bertoletti, A. and Le Bert, N. (2018) Immunotherapy for Chronic Hepatitis B Virus Infection. Gut and Liver, 12, 497-507.
[4] Coffin, C.S., Zhou, K. and Terrault, N.A. (2019) New and Old Biomarkers for Diagnosis and Management of Chronic Hepatitis B Virus Infection. Gastroenterology, 156, 355-368.e3.
[5] Wang, Y., Yang, S., Su, C., Wang, Y., Lee, K., Huo, T., et al. (2016) Predictors of Response to Pegylated Interferon in Chronic Hepatitis B: A Real-World Hospital-Based Analysis. Scientific Reports, 6, Article No. 29605. [Google Scholar] [CrossRef] [PubMed]
[6] Yeh, M.L., Huang, J.F., Dai, C.Y., et al. (2019) Pharmacokinetics and Pharmacodynamics of Pegylated Interferon for the Treatment of Hepatitis B. Expert Opinion on Drug Metabolism & Toxicology, 15, 779-785.
[7] Villar, L.M., Cruz, H.M., Barbosa, J.R., Bezerra, C.S., Portilho, M.M. and Scalioni, L.d.P. (2015) Update on Hepatitis B and C Virus Diagnosis. World Journal of Virology, 4, 323-342. [Google Scholar] [CrossRef] [PubMed]
[8] World Health Organization (2017) WHO Guidelines on Hepatitis B and C Testing.
http://www.ncbi.nlm.nih.gov/books/NBK442272/
[9] European Association for the Study of the Liver (2017) Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection. Journal of Hepatology, 67, 370-398.
[10] Terrault, N.A., Lok, A.S.F., McMahon, B.J., Chang, K., Hwang, J.P., Jonas, M.M., et al. (2018) Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Hepatology, 67, 1560-1599. [Google Scholar] [CrossRef] [PubMed]
[11] Xie, Z., Zhu, S., Peng, Y., Chen, J., Wang, X., Ma, L., et al. (2015) Postoperative Hepatitis B Virus Reactivation and Surgery-Induced Immunosuppression in Patients with Hepatitis B-Related Hepatocellular Carcinoma: PHR and Immunosuppression in HCC Patients. Journal of Surgical Oncology, 112, 634-642. [Google Scholar] [CrossRef] [PubMed]
[12] Park, J.W. (2015) Differentiation of Acute and Chronic Hepatitis B in IgM Anti-HBc Positive Patients. World Journal of Gastroenterology, 21, 3953-3959. [Google Scholar] [CrossRef] [PubMed]
[13] Tabor, E., Hoofnagle, J.H., Barker, L.F., Pineda-Tamondong, G., Nath, N., Smallwood, L.A., et al. (1981) Antibody to Hepatitis B Core Antigen in Blood Donors with a History of Hepatitis. Transfusion, 21, 366-371. [Google Scholar] [CrossRef] [PubMed]
[14] Vanwolleghem, T., et al. (2021) Humoral Immunity in Hepatitis B Virus Infection: Rehabilitating the B in HBV. JHEP Reports, 4, Article ID: 100398.
https://pubmed.ncbi.nlm.nih.gov/35059620/
[15] Jeng, W., Papatheodoridis, G.V. and Lok, A.S.F. (2023) Hepatitis B. The Lancet, 401, 1039-1052. [Google Scholar] [CrossRef] [PubMed]
[16] Dini, G., Toletone, A., Barberis, I., Debarbieri, N., Massa, E., Paganino, C., et al. (2016) Persistence of Protective Anti-HBs Antibody Levels and Anamnestic Response to HBV Booster Vaccination: A Cross-Sectional Study among Healthcare Students 20 Years Following the Universal Immunization Campaign in Italy. Human Vaccines & Immunotherapeutics, 13, 440-444. [Google Scholar] [CrossRef] [PubMed]
[17] Li, Q., Ren, X., Lu, C., Li, W., Huang, Y. and Chen, L. (2017) Evaluation of APRI and FIB-4 for Noninvasive Assessment of Significant Fibrosis and Cirrhosis in HBeAg-Negative CHB Patients with ALT ≤ 2 ULN: A Retrospective Cohort Study. Medicine, 96, e6336. [Google Scholar] [CrossRef] [PubMed]
[18] Xiao, G., Yang, J. and Yan, L. (2014) Comparison of Diagnostic Accuracy of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis-4 Index for Detecting Liver Fibrosis in Adult Patients with Chronic Hepatitis B Virus Infection: A Systemic Review and Meta-Analysis. Hepatology, 61, 292-302. [Google Scholar] [CrossRef] [PubMed]
[19] Wu, S., Liu, L., Cheng, J., Liu, Y., Cheng, L., Wang, S., et al. (2018) Longitudinal Monitoring of Liver Fibrosis Status by Transient Elastography in Chronic Hepatitis B Patients during Long-Term Entecavir Treatment. Clinical and Experimental Medicine, 18, 433-443. [Google Scholar] [CrossRef] [PubMed]
[20] Bâldea, V., Bende, F., Popescu, A., Șirli, R. and Sporea, I. (2021) Comparative Study between Two 2d-Shear Waves Elastography Techniques for the Non-Invasive Assessment of Liver Fibrosis in Patients with Chronic Hepatitis C Virus (HCV) Infection. Medical Ultrasonography, 23, 257-264. [Google Scholar] [CrossRef] [PubMed]
[21] Huang, D., Lin, T., Wang, S., et al. (2019) The Liver Fibrosis Index Is Superior to the APRI and FIB-4 for Predicting Liver Fibrosis in Chronic Hepatitis B Patients in China. BMC Infectious Diseases, 19, Article No. 878.
[22] Malagnino, V., Fofana, D.B., Lacombe, K. and Gozlan, J. (2018) Occult Hepatitis B Virus Infection: An Old Entity with Novel Clinical Involvements. Open Forum Infectious Diseases, 5, ofy227. [Google Scholar] [CrossRef] [PubMed]
[23] Pawlotsky, J.M., Dusheiko, G., Hatzakis, A., et al. (2008) Virologic Monitoring of Hepatitis B Virus Therapy in Clinical Trials and Practice: Recommendations for a Standardized Approach. Gastroenterology, 134, 405-415.
[24] Mangia, A., Antonucci, F., Brunetto, M., Capobianchi, M., Fagiuoli, S., Guido, M., et al. (2008) The Use of Molecular Assays in the Management of Viral Hepatitis. Digestive and Liver Disease, 40, 395-404. [Google Scholar] [CrossRef] [PubMed]
[25] Chen, R.W., Piiparinen, H., Seppänen, M., Koskela, P., Sarna, S. and Lappalainen, M. (2001) Real-Time PCR for Detection and Quantitation of Hepatitis B Virus DNA: Real-Time PCR for HBV DNA. Journal of Medical Virology, 65, 250-256. [Google Scholar] [CrossRef] [PubMed]
[26] Chen, H., Sun, L., Zheng, H., Zhang, Q. and Jin, X. (2012) Total Serum DNA and DNA Integrity: Diagnostic Value in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. Pathology, 44, 318-324. [Google Scholar] [CrossRef] [PubMed]
[27] Hadziyannis, S.J., Tassopoulos, N.C., Heathcote, E.J., Chang, T., Kitis, G., Rizzetto, M., et al. (2006) Long-Term Therapy with Adefovir Dipivoxil for HBeAg-Negative Chronic Hepatitis B for up to 5 Years. Gastroenterology, 131, 1743-1751. [Google Scholar] [CrossRef] [PubMed]
[28] Kumar, R., Pérez-Del-Pulgar, S., Testoni, B., et al. (2016) Clinical Relevance of the Study of Hepatitis B Virus Covalently Closed Circular DNA. Liver International, 36, 72-77.
[29] Werle-Lapostolle, B., Bowden, S., Locarnini, S., Wursthorn, K., Petersen, J., Lau, G., et al. (2004) Persistence of cccDNA during the Natural History of Chronic Hepatitis B and Decline during Adefovir Dipivoxil Therapy. Gastroenterology, 126, 1750-1758.
[30] Al-Sadeq, D.W., Taleb, S.A., Zaied, R.E., et al. (2019) Hepatitis B Virus Molecular Epidemiology, Host-Virus Interaction, Coinfection, and Laboratory Diagnosis in the MENA Region: An Update. Pathogens (Basel, Switzerland), 8, 63.
[31] Fletcher, G.J., Eapen, C.E. and Abraham, P. (2019) Hepatitis B Genotyping: The Utility for the Clinicians. Indian Journal of Gastroenterology, 39, 315-320. [Google Scholar] [CrossRef] [PubMed]
[32] Wang, J., Zhang, P., Zeng, J., Du, P., Zheng, X., Ye, X., et al. (2020) Occurrence of Occult Hepatitis B Virus Infection Associated with Envelope Protein Mutations According to Anti-HBs Carriage in Blood Donors. International Journal of Infectious Diseases, 92, 38-45. [Google Scholar] [CrossRef] [PubMed]
[33] Wong, G.L.H., Chan, H.L.Y., Yiu, K.K.L., et al. (2013) Meta-Analysis: The Association of Hepatitis B Virus Genotypes and Hepatocellular Carcinoma. Alimentary Pharmacology & Therapeutics, 37, 517-526. [Google Scholar] [CrossRef] [PubMed]
[34] Van Campenhout, M.J.H., Van Bömmel, F., Pfefferkorn, M., et al. (2018) Host and Viral Factors Associated with Serum Hepatitis B Virus RNA Levels among Patients in Need for Treatment. Hepatology (Baltimore, Md.), 68, 839-847.
[35] Giersch, K., Allweiss, L., Volz, T., Dandri, M. and Lütgehetmann, M. (2017) Serum HBV pgRNA as a Clinical Marker for Cccdna Activity. Journal of Hepatology, 66, 460-462. [Google Scholar] [CrossRef] [PubMed]
[36] Xu, L., Li, X., Lu, L., Liu, X., Song, X., Li, Y., et al. (2022) HBV pgRNA Profiles in Chinese HIV/HBV Coinfected Patients under Pre-and Post-Treatment: A Multicentre Observational Cohort Study. Journal of Viral Hepatitis, 29, 616-626. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, J., Shen, T., Huang, X., Kumar, G.R., Chen, X., Zeng, Z., et al. (2016) Serum Hepatitis B Virus RNA Is Encapsidated Pregenome RNA That May Be Associated with Persistence of Viral Infection and Rebound. Journal of Hepatology, 65, 700-710. [Google Scholar] [CrossRef] [PubMed]
[38] Ji, X., Xia, M., Zhou, B., Liu, S., Liao, G., Cai, S., et al. (2020) Serum Hepatitis B Virus RNA Levels Predict HBeAg Seroconversion and Virological Response in Chronic Hepatitis B Patients with High Viral Load Treated with Nucleos(t)ide Analog. Infection and Drug Resistance, 13, 1881-1888. [Google Scholar] [CrossRef] [PubMed]
[39] Ye, J. and Chen, J. (2021) Interferon and Hepatitis B: Current and Future Perspectives. Frontiers in Immunology, 12, Article ID: 733364.
[40] Marcellin, P., Xie, Q., Woon Paik, S., et al. (2020) Final Analysis of the International Observational S-Collate Study of Peginterferon Alfa-2a in Patients with Chronic Hepatitis B. PLOS ONE, 15, e0230893.
[41] Tan, G., Song, H., Xu, F., et al. (2018) When Hepatitis B Virus Meets Interferons. Frontiers in Microbiology, 9, Article No. 1611.
[42] Lebossé, F., Testoni, B., Fresquet, J., et al. (2017) Intrahepatic Innate Immune Response Pathways Are Downregulated in Untreated Chronic Hepatitis B. Journal of Hepatology, 66, 897-909.
[43] Li, G.J., Yu, Y.Q., Chen, S.L., et al. (2015) Sequential Combination Therapy with Pegylated Interferon Leads to Loss of Hepatitis B Surface Antigen and Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Chronic Hepatitis B Patients Receiving Long-Term Entecavir Treatment. Antimicrobial Agents and Chemotherapy, 59, 4121-4128.
[44] Brideau-Andersen, A.D., Huang, X., Sun, S.C., Chen, T.T., Stark, D., Sas, I.J., et al. (2007) Directed Evolution of Gene-Shuffled IFN-α Molecules with Activity Profiles Tailored for Treatment of Chronic Viral Diseases. Proceedings of the National Academy of Sciences, 104, 8269-8274. [Google Scholar] [CrossRef] [PubMed]
[45] Bahardoust, M., Mokhtare, M., Barati, M., Bagheri-Hosseinabadi, Z., Karimi Behnagh, A., Keyvani, H., et al. (2020) A Randomized Controlled Trial of Pegylated Interferon-Alpha with Tenofovir Disoproxil Fumarate for Hepatitis B E Antigen-Negative Chronic Hepatitis B: A 48-Week Follow-Up Study. Journal of Infection and Chemotherapy, 26, 1265-1271. [Google Scholar] [CrossRef] [PubMed]
[46] Ning, Q., Han, M., Sun, Y., Jiang, J., Tan, D., Hou, J., et al. (2014) Switching from Entecavir to PegIFN Alfa-2a in Patients with Hbeag-Positive Chronic Hepatitis B: A Randomised Open-Label Trial (OSST Trial). Journal of Hepatology, 61, 777-784. [Google Scholar] [CrossRef] [PubMed]
[47] Lok, A.S.F., Mcmahon, B.J., Brown, R.S., et al. (2016) Antiviral Therapy for Chronic Hepatitis B Viral Infection in Adults: A Systematic Review and Meta-Analysis. Hepatology (Baltimore, Md.), 63, 284-306.
[48] Manzoor, S., Saalim, M., Imran, M., et al. (2015) Hepatitis B Virus Therapy: What’s the Future Holding for Us? World Journal of Gastroenterology, 21, 12558-12575.
[49] Thompson, A.J.V., Ayres, A., Yuen, L., Bartholomeusz, A., Bowden, D.S., Iser, D.M., et al. (2006) Lamivudine Resistance in Patients with Chronic Hepatitis B: Role of Clinical and Virological Factors. Journal of Gastroenterology and Hepatology, 22, 1078-1085. [Google Scholar] [CrossRef] [PubMed]
[50] Ho, E.Y., Yau, T., Rousseau, F., Heathcote, E.J. and Lau, G.K.K. (2015) Preemptive Adefovir versus Lamivudine for Prevention of Hepatitis B Reactivation in Chronic Hepatitis B Patients Undergoing Chemotherapy. Hepatology International, 9, 224-230. [Google Scholar] [CrossRef] [PubMed]
[51] Agarwal, K., Fung, S.K., Nguyen, T.T., Cheng, W., Sicard, E., Ryder, S.D., et al. (2015) Twenty-Eight Day Safety, Antiviral Activity, and Pharmacokinetics of Tenofovir Alafenamide for Treatment of Chronic Hepatitis B Infection. Journal of Hepatology, 62, 533-540. [Google Scholar] [CrossRef] [PubMed]
[52] Su, T., Hu, T., Chen, C., Huang, Y., Chuang, W., Lin, C., et al. (2016) Four-Year Entecavir Therapy Reduces Hepatocellular Carcinoma, Cirrhotic Events and Mortality in Chronic Hepatitis B Patients. Liver International, 36, 1755-1764. [Google Scholar] [CrossRef] [PubMed]
[53] Wooddell, C.I., Gehring, A.J., Yuen, M.F., et al. (2021) RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies. Viruses, 13, 581.
[54] Yuen, M.F., Schiefke, I., Yoon, J.H., et al. (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.
[55] Yuen, M.F., Gane, E.J., Kim, D.J., et al. (2019) Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection. Gastroenterology, 156, 1392-1403.e7.
[56] 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]
[57] Hu, J. and Liu, K. (2017) Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application. Viruses, 9, 56.
[58] Bazinet, M., Pântea, V., Placinta, G., Moscalu, I., Cebotarescu, V., Cojuhari, L., et al. (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 Naïve to Nucleos(t)ide Therapy. Gastroenterology, 158, 2180-2194. [Google Scholar] [CrossRef] [PubMed]
[59] Bazinet, M., Pântea, V., Cebotarescu, V., Cojuhari, L., Jimbei, P., Albrecht, J., et al. (2017) 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. The Lancet Gastroenterology & Hepatology, 2, 877-889. [Google Scholar] [CrossRef] [PubMed]
[60] Ruiz de Galarreta, M. and Lujambio, A. (2017) Therapeutic Editing of Hepatocyte Genome in Vivo. Journal of Hepatology, 67, 818-828. [Google Scholar] [CrossRef] [PubMed]
[61] Liu, X., Hao, R., Chen, S., Guo, D. and Chen, Y. (2015) Inhibition of Hepatitis B Virus by the Crispr/cas9 System via Targeting the Conserved Regions of the Viral Genome. Journal of General Virology, 96, 2252-2261. [Google Scholar] [CrossRef] [PubMed]
[62] Hong, X., Kim, E.S. and Guo, H. (2017) Epigenetic Regulation of Hepatitis B Virus Covalently Closed Circular DNA: Implications for Epigenetic Therapy against Chronic Hepatitis B. Hepatology (Baltimore, Md.), 66, 2066-2077.
[63] Krebs, K., Böttinger, N., Huang, L.R., et al. (2013) T Cells Expressing a Chimeric Antigen Receptor That Binds Hepatitis B Virus Envelope Proteins Control Virus Replication in Mice. Gastroenterology, 145, 456-465.
[64] Gehring, A.J., Xue, S.A., Ho, Z.Z., et al. (2011) Engineering Virus-Specific T Cells That Target HBV Infected Hepatocytes and Hepatocellular Carcinoma Cell Lines. Journal of Hepatology, 55, 103-110.
[65] Janssen, H.L.A., Brunetto, M.R., Kim, Y.J., 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.