乙型肝炎病毒表面抗原&lt;100 IU/mL的核苷（酸）类似物经治慢性乙型肝炎患者的临床治愈策略

鲁俊锋; 任姗; 郑素军; 陈新月

doi:10.12449/JCH260407

乙型肝炎病毒表面抗原<100 IU/mL的核苷（酸）类似物经治慢性乙型肝炎患者的临床治愈策略

DOI: 10.12449/JCH260407

首都医科大学附属北京佑安医院肝病中心一科，北京 100069

基金项目:

科技部国家重点研发计划 (2023YFC2308100)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：鲁俊锋负责设计框架和撰写文章；任姗负责修改论文；郑素军负责指导撰写文章；陈新月负责拟定写作思路并最后定稿。

详细信息

通信作者:
陈新月， chenxydoc@163.com （ORCID： 0000-0001-9569-4540）

计量
- 文章访问数: 14
- HTML全文浏览量: 3
- PDF下载量: 4
- 被引次数: 0
出版历程
- 收稿日期: 2026-01-06
- 录用日期: 2026-02-25
- 出版日期: 2026-04-25

Clinical cure strategies for chronic hepatitis B patients with hepatitis B virus surface antigen <100 IU/mL after treatment with nucleos（t）ide analogues

First Department of Liver Disease Center，Beijing YouAn Hospital，Capital Medical University，Beijing 100069，China

Research funding:

National Key Research and Development Program of Ministry of Science and Technology (2023YFC2308100)

More Information

Corresponding author: CHEN Xinyue， chenxydoc@163.com （ORCID： 0000-0001-9569-4540）

摘要

摘要: 在长期接受核苷（酸）类似物（NAs）治疗的慢性乙型肝炎（CHB）患者中，10%～20%可达到乙型肝炎病毒表面抗原（HBsAg）<100 IU/mL的低水平状态。该人群是实现临床治愈（HBsAg清除）的优势人群，也是当前停药及联合治疗策略重点关注的对象。在临床管理策略选择方面，基于“免疫再激活”理论的NAs停药策略虽能促使部分患者（尤其是高加索人群）实现HBsAg清除，但其停药后复发风险不容忽视。以聚乙二醇干扰素α为基础的治疗策略显示出更高的主动清除潜力，部分新型免疫调节剂亦显示出初步疗效。总体而言，对于HBsAg<100 IU/mL的NAs经治CHB患者，应基于个体风险与获益，审慎评估停药或主动联合治疗路径。未来需结合更精细的生物标志物进行精准分层，并探索有限疗程、安全高效的新型联合方案，以推动更多患者实现临床治愈，并降低远期肝病风险。
- 慢性乙型肝炎 /
- 乙型肝炎病毒表面抗原 /
- 核苷（酸）类似物 /
- 乙型肝炎临床治愈
Abstract: Among chronic hepatitis B patients undergoing long-term treatment with nucleos（t）ide analogues （NAs）， approximately 10%—20% can achieve a low level of <100 IU/mL for hepatitis B surface antigen （HBsAg）. These patients have the advantage to achieve clinical cure （HBsAg clearance） and are currently a key focus for treatment discontinuation and combination treatment strategies. As for the selection of clinical management strategies， the NAs discontinuation strategy， based on the “immune reactivation” hypothesis， may lead to HBsAg clearance in some patients， especially among Caucasians， but the risk of recurrence after discontinuation cannot be neglected. The treatment strategies based on pegylated interferon-α exhibit a higher potential for active HBsAg clearance， and some novel immunomodulators have also shown preliminary efficacy. Overall， for patients with HBsAg <100 IU/mL previously treated with NAs， treatment discontinuation or active combination treatment should be carefully assessed based on individual risk-benefit profiles. In the future， it is essential to incorporate more refined biomarkers for precise stratification and explore novel combination regimens with finite treatment courses that are safe and highly effective， in order to help more patients achieve clinical cure and reduce long-term risks of liver disease.
- Hepatitis B， Chronic /
- HBV Surface Antigen /
- Nucleos（t）ide Analogues /
- Hepatitis B Clinical Cure

HTML全文

参考文献(28)

[1]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B[J]. Infect Dis Info, 2023, 36( 1): 1- 17. DOI: 10.3969/j.issn.1007-8134.2023.01.01. 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]. 传染病信息, 2023, 36( 1): 1- 17. DOI: 10.3969/j.issn.1007-8134.2023.01.01.
[2]	European Association for the Study of the Liver. 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.
[3]	GHANY MG, PAN CQ, LOK AS, et al. AASLD IDSA practice guideline on treatment of chronic hepatitis B[J]. Hepatology, 2026, 83( 4): 974- 997. DOI: 10.1097/HEP.0000000000001549.
[4]	Chinese Society of Infectious Disease, Chinese Society of Hepatology, Chinese Medical Association. The expert consensus on clinical cure(functional cure) of chronic hepatitis B[J]. J Chin Hepatol, 2019, 35( 8): 1693- 1701. DOI: 10.3969/j.issn.1001-5256.2019.08.008. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎临床治愈(功能性治愈)专家共识[J]. 临床肝胆病杂志, 2019, 35( 8): 1693- 1701. DOI: 10.3969/j.issn.1001-5256.2019.08.008.
[5]	WANG J, FAN T, ZHANG ZY, et al. Incidence and determinants of achieving HBsAg<100 IU/mL in HBeAg-negative CHB patients with nucleos(t)ide analogue treatment[J]. Emerg Microbes Infect, 2025, 14( 1): 2552718. DOI: 10.1080/22221751.2025.2552718.
[6]	HUI RW, WU TK, HO KC, et al. Large-scale profile study on hepatitis B surface antigen levels in chronic hepatitis B: Implications for drug development targeting functional cure[J]. Gut, 2026, 75( 1): 119- 130. DOI: 10.1136/gutjnl-2025-335219.
[7]	FAN R, ZHAO SR, NIU JQ, et al. High accuracy model for HBsAg loss based on longitudinal trajectories of serum qHBsAg throughout long-term antiviral therapy[J]. Gut, 2024, 73( 10): 1725- 1736. DOI: 10.1136/gutjnl-2024-332182.
[8]	MAUNG ST, DECHARATANACHART P, CHAITEERAKIJ R. Hepatitis B surface antigen seroclearance rate after stopping nucleos(t)ide analogues in chronic hepatitis B: A systematic review and meta-analysis[J]. J Gastroenterol Hepatol, 2025, 40( 5): 1079- 1104. DOI: 10.1111/jgh.16920.
[9]	LIM SG, DER TEO AE, CHAN ES, et al. Stopping nucleos(t)ide analogues in chronic hepatitis B using HBsAg thresholds: A meta-analysis and meta-regression[J]. Clin Gastroenterol Hepatol, 2024, 22( 12): 2403- 2412. DOI: 10.1016/j.cgh.2024.05.040.
[10]	HIRODE G, CHOI HSJ, CHEN CH, 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.
[11]	van BÖMMEL F, STEIN K, HEYNE R, et al. A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B[J]. J Hepatol, 2023, 78( 5): 926- 936. DOI: 10.1016/j.jhep.2022.12.018.
[12]	LI YY, WEN CH, GU SQ, et al. Differential response of HBV envelope-specific CD4⁺ T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy[J]. Hepatology, 2023, 78( 2): 592- 606. DOI: 10.1097/HEP.0000000000000334.
[13]	Infectious Disease Prevention and Control Branch of Chinese Preventive Medicine Association. Chinese expert consensus on clinical practice of chronic hepatitis B functional(clinical)cure[J]. Chin J Viral Dis, 2026, 16( 1): 16- 27. DOI: 10.16505/j.2095-0136.2025.0080. 中华预防医学会感染性疾病防控分会. 中国慢性乙型肝炎功能性(临床)治愈临床实践专家共识[J]. 中国病毒病杂志, 2026, 16( 1): 16- 27. DOI: 10.16505/j.2095-0136.2025.0080.
[14]	LI FH, QU LH, LIU YH, et al. PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial[J]. J Hepatol, 2025, 82( 2): 211- 221. DOI: 10.1016/j.jhep.2024.07.019.
[15]	XIE C, XIE DY, FU L, et al. SAT369 Functional cure based on pegylated interferon alpha therapy in nucleoside analog-suppressed HBeAg negative chronic hepatitis B: A multicenter real-world study(Everest Project in China)-3.5 years data update[J]. J Hepatol, 2022, 77: S838. DOI: 10.1016/S0168-8278(22)01971-7.
[16]	WEN CJ, WANG YX, TIAN HY, et al. Clinical cure induced by pegylated interferon α-2b in the advantaged population of chronic hepatitis B virus infection: A retrospective cohort study[J]. Front Cell Infect Microbiol, 2024, 13: 1332232. DOI: 10.3389/fcimb.2023.1332232.
[17]	ZHANG WC, XING MY, SUN WJ, et al. Early clinical efficacy of pegylated interferon treatment in patients with different phases of chronic HBV infection: A real-world analysis[J]. J Viral Hepat, 2023, 30( 5): 427- 436. DOI: 10.1111/jvh.13792.
[18]	PENG Y, MA MZ, LIU T, et al. Predictors of HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients treated with nucleotide analogs plus polyethylene glycol interferon[J]. Front Med, 2025, 11: 1510230. DOI: 10.3389/fmed.2024.1510230.
[19]	WANG GQ, HOU FQ, XIE Q, et al. Peginterferon alpha-2b combined with TDF promotes durable HBsAg loss in patients with chronic hepatitis B: A multicenter, randomized controlled, phase 3 clinical trial[J]. AASLD, 2024, Abstract(276).
[20]	WU JJ, WANG GQ, HU GX, et al. Efficacy and safety of PD-L1 antibody ASC22(Envafolimab) in patients with low baseline HBsAg levels: a randomized phase IIb expansion cohort[J]. AASLD, 2024, Abstract(292).
[21]	GAO ZL, YAN LB, LI JP, et al. LBP-021 BRII-179 induced functional immune response, demonstrating potential to improve chronic hepatitis B functional cure[J]. J Hepatol, 2024, 80: S87. DOI: 10.1016/s0168-8278(24)00588-9.
[22]	GAO ZL, YAN LB, LI JP, et al. Phase 2 interim results: BRII-179(VBI-2601), a protein-based HBV therapeutic vaccine, induced robust HBsAb responses that are strongly associated with increased HBsAg loss in subjects receiving PEG-IFNα treatment[J]. AASLD, 2023, Abstract(5031-C).
[23]	GAO ZL, YAN LB, LI JP, et al. Functional HBsAb responses induced by BRl-179 are strongly associated with improved HBsAg loss[J]. APASL, 2024, Abstract(O-0135).
[24]	Author Group of Expert Opinions. Expert opinions on the technical guiding principles for clinical trials of drugs in the treatment of chronic hepatitis B virus infection[J]. Chin J Hepatol, 2025, 33( 6): 534- 544. DOI: 10.3760/cma.j.cn501113-20250524-00198. 专家意见编写组. 慢性乙型肝炎病毒感染治疗药物临床试验技术指导原则专家意见[J]. 中华肝脏病杂志, 2025, 33( 6): 534- 544. DOI: 10.3760/cma.j.cn501113-20250524-00198.
[25]	TSENG TN, HU TH, WANG JH, et al. Incidence and factors associated with HBV relapse after cessation of entecavir or tenofovir in patients with HBsAg below 100 IU/mL[J]. Clin Gastroenterol Hepatol, 2020, 18( 12): 2803- 2812.e2. DOI: 10.1016/j.cgh.2020.04.037.
[26]	KUO YH, WANG JH, HUNG CH, et al. Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation[J]. Hepatol Int, 2021, 15( 2): 301- 309. DOI: 10.1007/s12072-021-10159-w.
[27]	SONNEVELD MJ, CHIU SM, PARK JY, et al. HBV DNA and HBsAg levels at 24 weeks off-treatment predict clinical relapse and HBsAg loss in HBeAg-negative patients who discontinued antiviral therapy[J]. Gastroenterology, 2024, 166( 1): 168- 177.e8. DOI: 10.1053/j.gastro.2023.09.033.
[28]	FAN R, DENG R, XIE Q, et al. Novel HBV biomarkers-guided NAs withdrawal strategy promotes HBsAg clearance in Asian CHB patients: A randomized controlled trial[J]. Clin Gastroenterol Hepatol, 2025. DOI: 10.1016/j.cgh.2025.09.009.[ Online ahead of print]