慢性乙型肝炎功能性治愈治疗策略的现状和未来

doi:10.16150/j.1671-2870.2026.03.002

摘要/Abstract

摘要：

慢性乙型肝炎（chronic hepatitis B，CHB）是全球重大健康挑战，而功能性治愈是CHB的理想治疗终点。CHB发病机制复杂，涉及乙型肝炎病毒（hepatitis B virus，HBV）DNA整合、共价闭合环状DNA的持续存在，以及针对HBV的免疫功能受损，给CHB功能性治愈带来了巨大挑战。现有药物在实现功能性治愈方面成效有限，核苷（酸）类似物[nucleos（t）ide analogs，NAs]单药治疗10年，功能性治愈率不足5%；聚乙二醇干扰素（pegylated interferon，Peg-IFN）单药治疗48周，功能性治愈率不足15%。NAs治疗实现HBV e抗原（HBV e antigen， HbeAg）阴性且基线HBV表面抗原（HBV surface antigen，HBsAg）<1 500 IU/mL的优势人群，序贯Peg-IFN治疗后，功能性治愈率可达20％以上，其中基线HBsAg为500~1 500 IU/mL的患者功能性治愈率可达30%以上；基线HBsAg<100 IU/mL的患者功能性治愈率可达60%以上。满足指南推荐的停药标准的非肝硬化患者，停用NAs可能会加速HBsAg清除，助力实现功能性治愈。然而，需要严密监测这些患者发生肝炎暴发和肝细胞癌的风险。为解决现有药物对CHB功能性治愈率低的问题，研究人员正在研发新药，包括靶向HBV生命周期不同阶段的直接抗病毒药物和恢复针对HBV的免疫功能的免疫调节药物。基于目前研究结果，尚无新药能够通过单药治疗实现30%以上的CHB功能性治愈率，基于新药的联合治疗策略是当前的研究热点。

关键词: 慢性乙型肝炎, 乙型肝炎病毒, 功能性治愈, 临床治愈, 乙型肝炎表面抗原

Abstract:

Chronic hepatitis B (CHB) remains a major global health challenge. Functional cure represents the ideal therapeutic endpoint for CHB. The pathogenesis of CHB is complex, including hepatitis B virus (HBV) DNA integration, persistent covalently closed circular DNA, and impaired specific immune response against HBV, which poses significant challenges to achieving functional cure in CHB. Current therapeutic drugs have limited efficacy in achieving functional cure. After 10 years of nucleos(t)ide analogs (NAs) monotherapy, less than 5% of patients achieve functional cure, while less than 15% of patients achieve functional cure after 48 weeks of pegylated interferon (Peg-IFN) monotherapy. For the favorable population that achieves HBV e antigen (HBeAg) negativity with NAs treatment and has baseline HBV surface antigen (HBsAg) <1 500 IU/mL, the functional cure rate with sequential Peg-IFN therapy is over 20%, with a functional cure rate of over 30% for patients with baseline HBsAg between 500 and 1 500 IU/mL and over 60% for those with baseline HBsAg <100 IU/mL. For non-cirrhotic patients who meet the recommended drug discontinuation criteria in the guidelines, NAs cessation may accelerate HBsAg clearance and facilitate functional cure. However, close monitoring of hepatitis flares and hepatocellular carcinoma is required. To overcome the low functional cure rate of current drugs for CHB, researchers are exploring novel drugs, including direct-acting antivirals targeting different stages of HBV life cycle, and immunomodulatory drugs aimed at restoring immune function against HBV. Based on current research results, no new drug has achieved a functional cure rate of CHB above 30% through monotherapy. Therefore, combination therapy strategies based on new drugs are currently a research focus.

Key words: Chronic hepatitis B, Hepatitis B virus, Functional cure, Clinical cure, Hepatitis B surface antigen

中图分类号:

R512.62

李强, 陈良. 慢性乙型肝炎功能性治愈治疗策略的现状和未来[J]. 诊断学理论与实践, 2026, 25(03): 260-267.

LI Qiang, CHEN Liang. Current status and future prospects of drug treatment strategies for functional cure of chronic hepatitis B[J]. Journal of Diagnostics Concepts & Practice, 2026, 25(03): 260-267.

参考文献 40

[1]	专家共识编写组. 中国慢性乙型肝炎功能性(临床)治愈临床实践专家共识[J]. 中华肝脏病杂志, 2025, 33(10):977-987.
	Author Group of Expert Consensus. Chinese expert consensus on clinical practice of chronic hepatitis B functional (clinical) cure[J]. Chin J Hepatol, 2025, 33(10):977-987.
[2]	NAIDU S, MARGERIDON S. Chronic hepatitis B virus persistence: Mechanisms and insights[J]. Cureus,2025:e78944.
[3]	MOHD-ISMAIL N K, LIM Z, GUNARATNE J, et al. Mapping the interactions of HBV cccDNA with host factors[J]. Int J Mol Sci, 2019, 20(17):4276. doi: 10.3390/ijms20174276 URL
[4]	LI A, YI Z, MA C, et al. Innate immune recognition in hepatitis B virus infection[J]. Virulence, 2025,16:2492371.
[5]	YE B, LIU X, LI X, et al. T-cell exhaustion in chronic hepatitis B infection: Current knowledge and clinical significance[J]. Cell Death Dis, 2015, 6(3):e1694. doi: 10.1038/cddis.2015.42 URL
[6]	OLIVIERO B, CERINO A, VARCHETTA S, et al. Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections[J]. J Hepatol, 2011, 55(1):53-60. doi: 10.1016/j.jhep.2010.10.016 pmid: 21145853
[7]	MARCELLIN P, BONINO F, YURDAYDIN C, et al. Hepatitis B surface antigen levels: Association with 5-year response to peginterferon Alfa-2a in hepatitis B e-antigen-negative patients[J]. Hepatol Int, 2013, 7(1):88-97. doi: 10.1007/s12072-012-9343-x pmid: 23518903
[8]	LEE I C, YANG S S, LEE C J, et al. Incidence and predictors of HBsAg loss after peginterferon therapy in HBeAg-negative chronic hepatitis B: A multicenter, long-term follow-up study[J]. J Infect Dis, 2018, 218(7):1075-1084. doi: 10.1093/infdis/jiy272 pmid: 29741704
[9]	缪晓辉. 核苷类药物抗乙型肝炎病毒治疗的长期性探讨[J]. 诊断学理论与实践, 2015, 14(4):297-300.
	MIAO X H. Long term therapy of HBV infection by nucleoside drugs[J]. J Diagn Concepts Pract, 2015, 14(4):297-300.
[10]	YIP T C, WONG G L, CHAN H L, et al. HBsAg seroclea-rance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues[J]. J Hepatol, 2019, 70(3):361-370. doi: 10.1016/j.jhep.2018.10.014 URL
[11]	WONG R J, NGUYEN M T, TRINH H N, et al. Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study[J]. J Viral Hepat, 2017, 24(12):1089-1097. doi: 10.1111/jvh.2017.24.issue-12 URL
[12]	HSU Y C, YEH M L, WONG G L, et al. Incidences and determinants of functional cure during entecavir or tenofovir disoproxil fumarate for chronic hepatitis B[J]. J Infect Dis, 2021, 224(11):1890-1899. doi: 10.1093/infdis/jiab241 URL
[13]	CHANG T T, LAI C L, YOON S K, et al. Entecavir treatment for up to 5 years in patients with hepatitis B E antigen-positive chronic hepatitis B[J]. Hepatology, 2010, 51(2):422-430. doi: 10.1002/hep.23327 URL
[14]	BOURLIÈRE M, RABIEGA P, GANNE-CARRIE N, et al. Effect on HBs antigen clearance of addition of pegylated interferon Alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: A randomised, controlled, open-label trial[J]. Lancet Gastroenterol Hepatol, 2017, 2(3):177-188. doi: 10.1016/S2468-1253(16)30189-3 URL
[15]	MARCELLIN P, AHN S H, MA X, et al. Combination of tenofovir disoproxil fumarate and peginterferon α-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B[J]. Gastroenterology, 2016, 150(1):134-144.e10. doi: 10.1053/j.gastro.2015.09.043 pmid: 26453773
[16]	AHN S H, MARCELLIN P, MA X, et al. Hepatitis B surface antigen loss with tenofovir disoproxil fumarate plus peginterferon Alfa-2a: Week 120 analysis[J]. Dig Dis Sci, 2018, 63(12):3487-3497. doi: 10.1007/s10620-018-5251-9
[17]	NING Q, HAN M, SUN Y, et al. Switching from entecavir to PegIFN Alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial)[J]. J Hepatol, 2014, 61(4):777-784. doi: 10.1016/j.jhep.2014.05.044 pmid: 24915612
[18]	HU P, SHANG J, ZHANG W, et al. HBsAg loss with peg-interferon Alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: New switch study[J]. J Clin Transl Hepatol, 2018, 6(1):1-10.
[19]	CHEN J, QI M, FAN X G, et al. Efficacy of peginterferon Alfa-2b in nucleoside analogue experienced patients with negative HBeAg and low HBsAg: A non-randomized clinical trial[J]. Infect Dis Ther, 2021, 10(4):2259-2270. doi: 10.1007/s40121-021-00497-5
[20]	QIU K, LIU B, LI S Y, et al. Systematic review with meta-analysis: Combination treatment of regimens based on pegylated interferon for chronic hepatitis B focusing on hepatitis B surface antigen clearance[J]. Aliment Pharmacol Ther, 2018, 47(10):1340-1348. doi: 10.1111/apt.2018.47.issue-10 URL
[21]	LIM S G, YANG W L, NGU J H, et al. Switching to or add-on peginterferon in patients on nucleos(t)ide analogues for chronic hepatitis B: The SWAP RCT[J]. Clin Gastroenterol Hepatol, 2022, 20(2):e228-e250. doi: 10.1016/j.cgh.2021.04.031 URL
[22]	CHEN X, CHEN X, CHEN W, et al. Extended peginterferon Alfa-2a (Pegasys) therapy in Chinese patients with HBeAg-negative chronic hepatitis B: Extended pegasys for HBeAg-negative chronic hepatitis B[J]. J Med Virol, 2014, 86(10):1705-1713. doi: 10.1002/jmv.24013 pmid: 24980710
[23]	HADZIYANNIS S J, SEVASTIANOS V, RAPTI I, et al. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir[J]. Gastroenterology, 2012, 143(3):629-636.e1. doi: S0016-5085(12)00805-0 pmid: 22659218
[24]	BERG T, SIMON K G, MAUSS S, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients-FINITE study[J]. J Hepatol, 2017, 67(5):918-924. doi: 10.1016/j.jhep.2017.07.012 URL
[25]	JENG W J, CHEN Y C, CHIEN R N, et al. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B[J]. Hepato-logy, 2018, 68(2):425-434.
[26]	HIRODE G, CHOI H S J, CHEN C H, et al. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: An international, multicenter, multiethnic cohort (RETRACT-B study)[J]. Gastroenterology, 2022, 162(3):757-771.e4. doi: 10.1053/j.gastro.2021.11.002 URL
[27]	SONNEVELD M J, PARK J Y, KAEWDECH A, et al. Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels: A multicenter study (CREATE)[J]. Clin Gastroenterol Hepatol, 2022, 20(4):e784-e793. doi: 10.1016/j.cgh.2020.12.005 URL
[28]	BUTI M, WONG D K, GANE E, et al. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: A prespecified follow-up analysis of two randomised trials[J]. Lancet Gastroenterol Hepatol, 2019, 4(4):296-304. doi: 10.1016/S2468-1253(19)30015-9 URL
[29]	TSAI Y N, WU J L, TSENG C H, et al. Association between elevation of serum alanine aminotransferase and HBsAg seroclearance after nucleos(t)ide analog withdrawal[J]. Aliment Pharmacol Ther, 2025, 61(7):1208-1217. doi: 10.1111/apt.v61.7 URL
[30]	CORNBERG M, SANDMANN L, JAROSZEWICZ J, et al. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2025, 83(2):502-583. doi: 10.1016/j.jhep.2025.03.018 pmid: 40348683
[31]	JENG W J, CHEN Y C, SHEEN I S, et al. Clinical relapse after cessation of tenofovir therapy in hepatitis B e antigen-negative patients[J]. Clin Gastroenterol Hepatol, 2016, 14(12):1813-1820.e1. doi: 10.1016/j.cgh.2016.07.002 URL
[32]	孙烨, 蔡伟. 预测慢性乙型肝炎抗病毒治疗终点标志物的研究进展[J]. 诊断学理论与实践, 2018, 17(1):115-118.
	SUN Y, CAI W. Advances in study on markers of predic-ting endpoint of antiViral therapy of hepatitis B[J]. J Diagn Concepts Pract, 2018, 17(1):115-118.
[33]	YUEN M F, LIM S G, PLESNIAK R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection[J]. N Engl J Med, 2022, 387(21):1957-1968. doi: 10.1056/NEJMoa2210027 URL
[34]	HUI R W, FUNG J, SETO W K, et al. Emerging therapies for HBsAg seroclearance: Spotlight on novel combination strategies[J]. Hepatol Int, 2025, 19(4):704-719. doi: 10.1007/s12072-025-10828-0
[35]	HOU J, ZHANG W, XIE Q, et al. Xalnesiran with or without an immunomodulator in chronic hepatitis B[J]. N Engl J Med, 2024, 391(22):2098-2109. doi: 10.1056/NEJMoa2405485 URL
[36]	WONG G L, YUEN M F, LIN B, et al. Elebsiran and PEG-IFNα for chronic hepatitis B infection: A partially randomized, open-label, phase 2 trial[J]. Nat Med, 2026, 32(1):151-159. doi: 10.1038/s41591-025-04049-z
[37]	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[J]. Gastroenterology,2020, 158(8):2180-2194. doi: 10.1053/j.gastro.2020.02.058 URL
[38]	YUEN M F, LIM Y S, YOON K T, et al. VIR-2218 (elebsiran) plus pegylated interferon-Alfa-2a in participants with chronic hepatitis B virus infection: A phase 2 study[J]. Lancet Gastroenterol Hepatol,2024, 9(12):1121-1132. doi: 10.1016/S2468-1253(24)00237-1 URL
[39]	GANE E, VERDON D J, BROOKS A E, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study[J]. J Hepatol, 2019, 71(5):900-907. doi: S0168-8278(19)30400-3 pmid: 31306680
[40]	YUEN M, LOCARNINI S, LIM T H, et al. Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB[J]. J Hepatol, 2022, 77(5):1287-1298. doi: 10.1016/j.jhep.2022.07.010 URL