乙型肝炎功能性治愈新药： 聚焦反义寡核苷酸和小干扰RNA

梁携儿; 刘智泓; 侯金林

doi:10.12449/JCH250102

乙型肝炎功能性治愈新药：聚焦反义寡核苷酸和小干扰RNA

DOI: 10.12449/JCH250102

梁携儿^1, , ,,
刘智泓¹,
侯金林^{1, 2}

1.
南方医科大学南方医院感染内科，广州 510515
2.
广东省肝脏疾病研究所，广州 510515

基金项目:

国家重点研发计划 (2022YFC2304800);

国家重点研发计划 (2022YFC2303600)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：南方医科大学南方医院感染内科为本研究第一完成单位。梁携儿负责研究设计，文章撰写；梁携儿、刘智泓参与研究数据/信息的收集与解读分析；侯金林、梁携儿负责文章提纲与全文审核。

详细信息

通信作者:
梁携儿， liangxieer@163.com （ORCID： 0000-0002-0862-3291）

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出版历程
- 收稿日期: 2024-11-26
- 录用日期: 2024-12-17
- 出版日期: 2025-01-25

New drugs for the functional cure of hepatitis B: Focusing on antisense oligonucleotides and small interfering RNAs

Xieer LIANG^{1
, ,
,},
Zhihong LIU¹,
Jinlin HOU^{1, 2}

1.
Department of Infectious Diseases，Nanfang Hospital，Southern Medical University，Guangzhou 510515，China
2.
Guangdong Provincial Institute of Liver Diseases，Guangzhou 510515，China

Research funding:

National Key R & D Program of China (2022YFC2304800);

National Key R & D Program of China (2022YFC2303600)

More Information

Corresponding author: LIANG Xieer， liangxieer@163.com （ORCID： 0000-0002-0862-3291）

摘要

摘要: 在乙型肝炎治疗领域，现有的核苷（酸）类似物以及聚乙二醇干扰素在功能性治愈方面的疗效较为有限。最近，反义寡核苷酸与小干扰RNA等小核酸药物以全新的作用机制和令人瞩目的早期临床研究疗效，为乙型肝炎的功能性治愈带来了前所未有的突破性进展。反义寡核苷酸和小干扰RNA等小核酸药物可降低HBsAg水平甚至HBsAg转阴。随着HBsAg的减少，可能部分恢复机体的乙型肝炎特异性免疫功能，并可能将单纯的HBsAg清除进一步转化为减少乙型肝炎相关肝脏事件等具有临床价值的硬终点。紧密结合新药背景下HBsAg的动态变化轨迹，进一步优化联合治疗的策略与方案，有望将乙型肝炎功能性治愈转化为提升患者生存率及显著改善其生活质量的最终目标。
- 乙型肝炎 /
- 寡核苷酸类，反义 /
- RNA，小分子干扰 /
- 乙型肝炎表面抗原 /
- 功能性治愈
Abstract: Existing nucleos（t）ide analogues and pegylated interferon exhibit limited efficacy in the functional cure of hepatitis B. Recently， small nucleic acid drugs， such as antisense oligonucleotides and small interfering RNAs， have brought unprecedented breakthroughs in the functional cure of hepatitis B with their brand-new mechanisms of action and remarkable efficacy in early clinical studies. Small nucleic acid drugs， such as antisense oligonucleotides and small interfering RNAs， can reduce the level of HBsAg and strive to achieve HBsAg seroclearance. The reduction in HBsAg may restore the hepatitis B-specific immune function of the body to some extent and may further transform the simple clearance of HBsAg into hard endpoints with clinical value， such as reducing hepatitis B-related liver events. By meticulously analyzing the dynamic trajectory of HBsAg alterations within the context of new drug applications and further optimizing combined treatment strategies and regimens， it is expected to transform the functional cure of hepatitis B into the ultimate goal of improving survival rates and quality of life.
- Hepatitis B /
- Oligonucleotides， Antisense /
- RNA， Small Interfering /
- Hepatitis B Surface Antigens /
- Functional Cure

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表 1 NAs与siRNA、ASO药物的比较

Table 1. Comparison of nucleoside/nucleotide analogues with siRNA and ASO

项目	NAs	siRNA	ASO
分子量	<500 Da	>7 kDa	>7 kDa
分子靶点	HBV聚合酶/逆转录酶	HBV RNA	HBV RNA
作用部位	肝细胞核内	肝细胞内	肝细胞内、间质细胞？
作用机制	竞争性抑制HBV聚合酶，终止病毒DNA链的延长，从而抑制病毒复制	通过募集RNase H来调节mRNA切割，从而阻止病毒蛋白翻译	加载到RISC中与靶标mRNA结合导致mRNA切割，从而阻止蛋白翻译
用法	口服，每日1次	皮下注射，每4周1次或间隔更长	皮下注射，每周1次
挑战	耐药性与肾毒性，可改良	内体逃逸仅少量能进入肝细胞	潜在肝肾损伤，在修饰后可改良

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表 2 部分已发布的ASO与siRNA的疗效数据

Table 2. Some of the published efficacy data of ASO and siRNA

研究对象			用药方案			治疗结束时		治疗结束后
纳入人群	筛选时HBsAg	基线HBsAg	新药	NAs联合用药	新药疗程	HBsAg<0.05 IU/mL	HBsAg<100 IU/mL	停药随访时长	HBsAg<0.05 IU/mL	HBsAg<100 IU/mL
初治	>100 IU/mL	（3.72±0.77）log₁₀ IU/mL	Bepirovirsen 300 mg^［18］	无	24周	20/70（29%）	59%	24周	10/70（14%）	29%
NAs经治	>100 IU/mL	（3.29±0.62）log₁₀ IU/mL	Bepirovirsen 300 mg^［18］	NAs	24周	18/68（26%）	63%	24周^#	8/68（12%）	39%
NAs经治	>100 IU/mL	（5 231.4± 8 939.8）IU/mL	Bepirovirsen 300 mg^［19］	序贯PEG-IFN-α 24周	24周	BPV：20/55（36%） IFN：13/55（24%）	BPV：65% IFN：29%	24周^#	5/55（9%）	36%
NAs经治	>100 IU/mL	（5 218.5± 8 437.4）IU/mL	Bepirovirsen 300 mg^［19］	序贯PEG-IFN-α 24周	12周	BPV：12/53（23%） IFN：9/53（17%）	BPV：59% IFN：28%	24周^#	8/53（15%）	23%
NAs经治	>0.05 IU/mL	（2.8±1.0）log₁₀ IU/mL	Xalnesiran 200 mg^［16］	NAs	48周	1/30（3%）	93.3%	24周	1/30（3%）	76.6%
NAs经治	>0.05 IU/mL	（2.9±1.0）log₁₀ IU/mL	Xalnesiran 200 mg^［16］	联合Ruzotolimod 24周	48周	6/34（18%）	85.2%	24周	4/34（12%）	50%
NAs经治	>0.05 IU/mL	（2.9±0.8）log₁₀ IU/mL	Xalnesiran 200 mg^［16］	联合PEG-IFN-α 48周	48周	9/30（30%）	63.3%	24周	7/30（23%）	46.4%
NAs经治	>0.05 IU/mL	0.05～1 000 IU/mL	Xalnesiran 200 mg^［16］	联合PEG-IFN-α 48周	48周	9/15（60%）	未报告	24周	7/15（47%）	未报告
NAs经治	>50 IU/mL	3.37（2.83～3.91）log₁₀ IU/mL	VIR-2218 200 mg^［22］	联合PEG-IFN-α 24周	24周	1/18（6%）	88%	24周^#	0/18（0）	44%
NAs经治	>50 IU/mL	2.92（2.12～3.62）log₁₀ IU/mL	VIR-2218 200 mg^［22］	联合PEG-IFN-α 48周	24周	4/18（22%）	61%	24周^#	3/18（17%）	44%
NAs经治	>50 IU/mL	3.69（2.92～3.72）log₁₀ IU/mL	VIR-2218 200 mg^［22］	联合PEG-IFN-α 48周	48周	4/13（31%）	92%	24周^#	2/13（15%）	69%
初治与经治	>0.05 IU/mL	3.8（3.2～4.3）log₁₀ IU/mL	JNJ-3989 100 mg^［28］	NAs	48周	1/88（1%）	69.3%	24周	0	37.8%
初治与经治	>0.05 IU/mL	3.9（3.3～4.3）log₁₀ IU/mL	JNJ-3989 200 mg^［28］	NAs	48周	3/91（3%）	74.7%	24周	0	47.0%
NAs经治	>100 IU/mL	（3.43±0.53）log₁₀ IU/mL	JNJ-3989 200 mg^［31］	JNJ-6379 250 mg 48周	48周	0/76（0）	71%	24周	0	67%
NAs经治	200～5 000 IU/mL	（3.21±0.40）log₁₀ IU/mL	HT-101 200 mg^［29］	NAs	4周	W12<10 IU/mL： 3/6	W12： 83%	W24^#	未报告	33.3%
NAs经治	200～5 000 IU/mL	（3.02±0.42）log₁₀ IU/mL	HT-101 400 mg^［29］	NAs	4周	W16<10 IU/mL： 6/6	W16： 100%	W24^#	未报告	100%
NAs经治	100～3 000 IU/mL	2.87（2.07～3.54）log₁₀ IU/mL	AHB-137 300 mg^［30］	NAs	24周	W12：20/32（62%）	未报告	未报告	未报告	未报告
注：#未涉及NAs停药；JNJ-3989：JNJ-73763989；JNJ-6379：JNJ-56136379；BPV指Bepirovisen；IFN指PEG-IFN-α；W12、W16、W24分别指基线后第12周时、第16周时、第24周时。

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