修回日期: 2025-05-30
接受日期: 2025-09-12
在线出版日期: 2025-09-28
慢性乙型肝炎(chronic hepatitis B, CHB)临床治愈旨在实现持续病毒学抑制与乙肝表面抗原清除, 是当下抗病毒治疗的理想目标. 尽管核苷(酸)类似物和聚乙二醇化干扰素能有效抑制病毒复制, 但共价闭合环状DNA的持续存在、乙型肝炎病毒脱氧核糖核酸整合以及免疫耐受等问题, 仍是实现治愈的主要障碍. 新型抗病毒药物(如衣壳抑制剂、小干扰RNA与免疫调节治疗(如检查点抑制剂、治疗性疫苗)的研发, 为功能性治愈带来了新的希望. 本文全面剖析当前治疗策略的局限、疗效优化途径及未来研究方向, 为提高CHB临床治愈率提供理论支撑.
核心提示: 慢性乙型肝炎(chronic hepatitis B, CHB)临床治愈又称功能性治愈, 是指停止治疗后血清乙肝表面抗原和乙型肝炎病毒(hepatitis B virus, HBV) DNA持续检测不到、乙型肝炎E抗原阴转、伴或不伴抗-HBs出现, 肝脏生物化学指标正常, 肝脏炎症缓解和组织病理学改善等, 但HBV的复制源头共价闭合环状DNA, 可能仍然存在肝细胞核内, 另外宿主因素的免疫耐受以及免疫应答不足, 导致免疫系统无法彻底清除病毒, 即使进行抗病毒治疗也难以实现表面抗原转阴, 导致CHB难以彻底治愈. 那么发现评价疗效或预测反应的新型生物标志物以及开发具有治愈乙型肝炎潜力的新兴抗病毒药物和免疫调节剂以及药物的联合应用将是实现HBV临床治愈有效手段.
引文著录: 刘旭凌, 姜宇朗, 孙明瑜. 慢性乙型肝炎临床治愈的挑战和进展. 世界华人消化杂志 2025; 33(9): 693-700
Revised: May 30, 2025
Accepted: September 12, 2025
Published online: September 28, 2025
Chronic hepatitis B (CHB) clinical cure aims to achieve sustained virological suppression and hepatitis B surface antigen clearance, representing the ideal goal of current antiviral therapy. Although nucleos(t)ide analogues and pegylated interferon can effectively inhibit viral replication, the persistence of covalently closed circular DNA, hepatitis B virus DNA integration, and immune tolerance are still the main obstacles to cure. The development of new antiviral drugs (such as capsid inhibitors and siRNA) and immunomodulatory therapy (such as checkpoint inhibitors and therapeutic vaccines) has brought new hope for functional cure. This article comprehensively analyzes the limitations of current treatment strategies, ways to optimize efficacy, and future research directions, and provides theoretical support for improving the clinical cure rate of CHB.
- Citation: Liu XL, Jiang YL, Sun MY. Challenges and advances in clinical cure of chronic hepatitis B. Shijie Huaren Xiaohua Zazhi 2025; 33(9): 693-700
- URL: https://www.wjgnet.com/1009-3079/full/v33/i9/693.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v33.i9.693
全球在消除乙型肝炎病毒(hepatitis B virus, HBV)目标方面取得了重大进展, 全球慢性HBV感染的流行率随着时间的推移而下降[1], 特别是在5岁以下儿童中. 然而, 慢性乙型肝炎(chronic hepatitis B, CHB)及其并发症、肝硬化和肝细胞癌(hepatocellular carcinoma, HCC)仍然是全球一个重大的公共卫生威胁, 2019年全球估计有2.96亿人慢性感染和82万与HBV相关的死亡[2]. 尽管疫苗接种与抗病毒治疗显著降低了疾病进展风险, 但现有疗法对病毒共价闭合环状 DNA(covalently closed circular DNA, cccDNA)的清除作用有限, 停药后复发率居高不下. 临床治愈定义为乙肝表面抗原(hepatitis B surface antigen, HBsAg)持续清除且HBV DNA测不出, 其实现需突破病毒持续感染机制与宿主免疫修复的双重挑战[3,4]. 本文聚焦现有疗法瓶颈、潜在靶点及个体化治疗策略, 探讨临床治愈的潜力与挑战.
HBV是一种独特的嗜肝DNA病毒, 通过血液到达肝脏并与肝细胞表面的受体分子结合后进入肝细胞. 进入细胞后, 病毒释放出遗传物质"松弛环状DNA(rcDNA)", 后者进入细胞核并在宿主酶的作用下形成病毒复制感染的关键结构分子"共价闭合环状DNA"[5]. cccDNA既是病毒转录复制的模板, 也作为病毒的基因储存库, 可长期存留于受感染细胞的细胞核内, 被认为是乙肝慢性化和难治愈的"元凶". 以cccDNA为模板转录出不同长度的病毒mRNA, 它们进入胞质内翻译成相应的病毒蛋白质, 装配成子代病毒颗粒, 病毒前基因组RNA逆转录成rcDNA, 通过子代病毒颗粒通过分泌途径释放至肝细胞外, 感染新的肝细胞. 目前认为只有彻底清除肝细胞内的cccDNA才能实现CHB的完全治愈.
自HBV被发现以来, 科学家们一直在努力寻找有效的治疗方法. 最早的CHB治疗目标主要集中在抑制HBV DNA的复制上. 拉米夫定(Lamivudine)作为最早的核苷(酸)类似物[nucleos(t)ide analogues, NAs]之一, 于1998年被批准用于治疗CHB. 拉米夫定能够通过竞争性抑制HBV DNA聚合酶, 有效抑制病毒复制, 从而改善患者的肝功能并减缓疾病进展[6]. 然而, 随着拉米夫定的广泛应用, 其局限性也逐渐显现, 尤其是病毒耐药性的快速出现.
单药治疗下, 患者往往需要长期服药以维持病毒抑制, 但一旦停药, 病毒复制往往会迅速反弹, 且耐药株的出现使得后续治疗变得更加复杂和困难. 为克服药物耐药、骨代谢和肾脏安全性的问题, 新型NAs应运而生. 我国先后批准使用的NAs包括拉米夫定, 阿德福韦酯, 替比夫定, 恩替卡韦, 替诺福韦酯, 富马酸丙酚替诺福韦及艾米替诺福韦等[7]. 由于cccDNA的特性, 大部分患者需要长期NAs治疗, 停药后病毒学复发率高, 目前还做不到彻底治愈[8]. CHB患者在NA停药后面临复发的高风险, 在没有密切监测和及时再治疗的情况下, 可能发展为肝失代偿甚至肝癌等危及生命的临床事件[9,10].
一项荟萃研究中提示在单药NAs应用只有2%-5%的患者能够达到临床治愈[11], 面对单药治疗的局限性, 研究者们开始探索新的治疗策略. 聚乙二醇干扰素(pegylated-interferon, Peg-IFN)通过促进宿主免疫细胞的活性和诱导干扰素刺激基因的产生来发挥双重作用, 这些基因编码直接的抗病毒效应蛋白[12]. 此外, Peg-IFN还可以通过增强HBV前基因组RNA(pregenomic RNA, pgRNA)和核心颗粒的降解, 或通过修饰cccDNA的表观遗传调控[13,14], 来抑制HBV的转录, 减少病毒抗原的产生. 那么有效和协调的先天和适应性免疫对于控制HBV感染是必不可少的[15], 因此, 免疫调节以恢复功能失调的HBV特异性免疫是一个很有前途的治疗策略靶点.
2010年后, Peg-IFN与NAs的联合应用, 开启了临床治愈的探索之路. 临床治愈又称"功能性治愈"或"免疫学治愈", 该概念于2015年《慢性乙型肝炎防治指南》首次提出[16]. 临床治愈被定义为持续病毒学应答(即HBV DNA持续低于检测下限)且HBsAg清除或伴有抗-HBs抗体阳转, 同时肝脏炎症和组织学病变显著改善. 这一概念的提出, 标志着CHB治疗从单纯的病毒抑制向病毒清除和疾病治愈的转变. 2017-2018, 我国CHB临床治愈得到国际认可; 2019-2021, 我国CHB临床治愈进入快速发展、深入发展阶段; 目前的抗病毒治疗方案包括两类药物: 目前的抗病毒治疗方案包括两类药物: NAs与聚乙二醇化干扰素(Peg-IFN)[17-19]. 2022年, 《慢性乙型肝炎防治指南(2022年版)》(以下简称《指南》)发布[20], 《指南》要求, 对于部分适合条件的患者, 应追求临床治愈; 推荐核苷(酸)类似物(NAs)经治优势患者加用聚乙二醇干扰素α(pegylated-interferon α, Peg-IFNα), 追求临床治愈. 至此, 我国CHB临床治愈开始扩大抗病毒治疗人群, 拓展临床治愈人群.
HBsAg清除的可能性随着年龄的增长而降低[21-24]. 此外, HBV基线DNA水平较低的[21,25]、乙型肝炎E抗原(hepatitis B e antigen, HBeAg)阴性[26]和丙氨酸转氨酶(alanine transaminase, ALT)升高超过正常(5×ULN)上限的患者对干扰素治疗的反应性增强[14]. 由中国肝炎预防基金会发起多中心、前瞻性的现实世界研究的"绿洲"项目(NCT04896255)表明HBsAg基线水平越低, 48 wk时HBsAg清除的概率越高, (OR = 0.371, 95%CI: 0.307-0.448, P<0.001). 肝硬化的存在也影响了接受干扰素治疗的患者在48 wk时HBsAg清除的可能性. 患者在48 wk时发生HBsAg清除的概率显著降低.
一项涉及518例HBeAg阴性CHB患者的大型队列研究表明, 女性患者在干扰素治疗后24 wk获得病毒学应答的几率比男性患者高1.93倍[27]. 然而, 年龄、基线HBV DNA水平、基线HBeAg和ALT水平与HBsAg清除没有显著相关性. 这可能是由于研究人群的特征、随访时间的差异、样本量的限制和研究终点的差异所致[28]. 此外, 基线HBsAg水平<100 IU/mL被认为是临床治愈[29]的独立预测指标. 在长期NAs治疗中, Peg-IFNα−2b在HBeAg阴性CHB中与HBsAg≤1500 IU/mL联合治疗策略与单药治疗相比产生更高的HBsAg清除率.
病毒学预测因子包括定量HBsAg(quantitative HBsAg, qHBsAg)、HBV RNA和乙型肝炎核心相关抗原(hepatitis B core-related antigen, HBcrAg). 特别是qHBsAg及其动力学已被多项研究证实为预测功能性治愈[30-32], 一例来自香港大学的研究表明[33], 在194名患者停用恩替卡韦治疗后进行随访, 进行48 wk随访发现ALT/qHBsAg比率可独立预测HBsAg血清清除率(HR范围为1.003-1.028, 所有P<0.01), 具有出色的诊断性能(接收器操作特征下面积0.799-0.933, 不同时间点的阴性预测值>90%), 即使在恢复治疗的患者中也是如此, 恩替卡韦停药后ALT/qHBsAg比值可预测HBsAg血清清除. HBsAg完全消失可能意味着HBV基因组(包括cccDNA和整合的HBVDNA)的消除或持续失活. HBsAg消失促进异常免疫功能的恢复, 进而可能进一步促进残留病毒的清除, 高灵敏度定量HBsAg的持续血清学清除可能代表CHB的完全治愈. 对于除HBV本身之外的许多其他危险因素, HBsAg消失的患者仍需要定期监测[34].
在CHB的治疗过程中, 生物标志物的监测对于评估治疗效果和制定停药决策具有重要意义. 近年来, HBV RNA和核心抗原(HBcrAg)作为反映cccDNA活性的间接指标, 逐渐受到研究者的关注. HBcrAg低与乙型肝炎表面抗原水平高的CHB患者中乙型肝炎表面抗原的自发血清清除率增加相关[35]. 该研究选取台湾1539例HBsAg水平>1000 IU/mL的患者, HBcrAg<10000 U/mL可作为HBsAg血清学清除的独立病毒预测因子发现基线时较低的HBcrAg水平与HBsAg血清学清除的可能性增加相关. 研究表明[36], 在抗病毒治疗过程中, HBcrAg水平的下降往往与HBsAg的清除呈正相关. 因此, HBcrAg可能成为潜在评估治疗效果和预测停药时机的重要生物标志物.
HBV RNA的临床应用: HBV RNA主要来源于cccDNA的转录产物, 包括pgRNA和亚基因组RNA. 这些RNA分子在病毒复制和蛋白质合成过程中发挥关键作用. 因此, HBV RNA水平可以间接反映cccDNA的转录活性. 研究表明, 病毒学反弹组参与者的HBV RNA半衰期中位数明显(P = 0.01)高于临床治愈组(分别为5.7 wk和2.7 wk). 实现部分/功能性治愈与较短的HBV RNA半衰期有关, 这可能反映cccDNA转录活性的更快失活[37]. 在接受抗病毒治疗的患者中, HBV RNA水平的下降往往先于HBsAg的清除, 提示HBV RNA可能作为预测HBsAg清除的早期生物标志物. 此外, HBV RNA水平的持续监测还有助于评估治疗过程中的病毒学应答和耐药情况[38].
病毒的基因型可能也是影响患者临床治愈与干扰素应答的一个重要因素. HBV至少有9种(A型至Ⅰ型)基因型和1种未定基因型(J型). 我国以B基因型和C基因型为主. 病毒学预测因子中, 病毒的基因型可能也是影响患者临床治愈与干扰素应答的一个重要因素, 多项研究发现如基因型C的乙肝患者, 相较基因型B, 更易发生原发性肝癌, 基因型B感染患者比基因型C感染患者更早经历HBeAg血清转化,且B型干扰素治疗优先,但基因型B的急性乙肝患者肝细胞损伤更严重[39,40].
生物标志物的联合应用: 单一生物标志物的监测往往存在一定的局限性. 因此, 将HBV RNA和HBcrAg等生物标志物联合应用, 可以提高对治疗效果和病毒学应答的评估准确性, 为个体化治疗方案的制定提供更加可靠的依据[41].
此外, 研究发现CHB和临床治愈患者的肝内环境表现出特异性细胞特性和分子特征不同[42]. 临床治愈患者与以CD+T淋巴细胞及自然杀伤细胞、特定库普弗细胞和中性粒细胞为标志的适应性免疫反应的改变有关. 临床治愈患者的特征还在于存在表达MHC Ⅱ类的肝细胞以及持续低水平的cccDNA和pgRNA, 这可能在HBV患者实现临床治愈中发挥重要作用, 为临床检测管理、生物标志物发现和治疗干预开辟了新途径.
CHB患者的异质性使得单一治疗方案难以满足所有患者的需求. 因此, 个体化治疗路径的探索成为了CHB治疗领域的重要方向[43]. 基于HBsAg动态监测的应答指导治疗(response guided therapy, RGT)策略, 通过精准筛选优势人群和优化治疗方案, 为CHB患者提供了更加个性化的治疗选择.
RGT策略的原理: RGT策略的核心在于根据患者的HBsAg水平动态调整治疗方案. 具体而言, 该策略通过定期监测患者血清中的HBsAg水平, 根据HBsAg的动态变化来评估治疗效果并调整治疗策略. 对于治疗初期HBsAg水平较低的患者, 这往往意味着患者体内病毒复制活跃程度较低, 免疫系统对病毒的清除能力较强[44]. 因此, 这类患者可以优先考虑使用具有免疫调节作用的抗病毒药物, 如PegIFN或治疗性疫苗等, 以期通过增强机体免疫应答来实现病毒的持久控制. 而对于治疗初期HBsAg水平较高的患者, 则表明患者体内病毒复制活跃, 需要首先通过核苷(酸)类似物等药物迅速抑制病毒复制, 降低病毒载量, 待HBsAg水平有所下降后, 再考虑联合或序贯使用PegIFN等免疫调节药物, 以进一步提高治疗效果并追求HBsAg的清除.
近年来, 针对HBV感染的药物研发取得了实质性进展. 其中进入抑制剂[45]、衣壳组装调节剂、亚病毒颗粒释放抑制剂、cccDNA沉默剂和RNA干扰分子[46]等直接作用抗病毒药物已进入临床试验. 此外, 包括治疗性疫苗[47-49]、Toll样受体激动剂[50]、检查点抑制剂[48]和单克隆抗体在内的多种免疫调节剂也正在走向临床应用.
免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)可以恢复耗竭的T细胞的免疫功能, 不仅可以用于癌症治疗, 还可以用于治疗CHB. 一例回顾性研究分析了[51], 2020-2022的HBsAg呈阳性的HCC患者(n = 44), 另外一个没有ICI的HBV-HCC队列(n = 85)作为对照组, 分析了与HBsAg消失或HBsAg下降>1 log相关的因素. 结果提示ICIs可能会加速基线HBsAg<100 IU/mL的癌症患者的HBsAg血清清除. 这一发现为未来ICI试验的设计提供了重要信息, 以实现CHB患者的功能性治愈.
Toll样受体8激动剂Selgantolimod已在CHB的临床前模型和临床试验研究, 转录组学特征揭示了Selgantolimod可能通过肝巨噬细胞重塑肝内免疫微环境, 并通过白细胞介素-6依赖性机制损害HBV进入肝细胞[52]. 在Ⅰ期临床试验中显示出体外抗病毒活性和安全性, 在Ⅱ期研究中[53], Selgantolimod治疗与参与者血清细胞因子短暂增加、循环免疫细胞亚群快速重新分布、HBsAg和HBeAg水平适度降低以及HBsAg(5%)和HBeAg(16%)偶尔消失相关. 同时, 治疗性疫苗[54]可以诱导CD8+ T细胞并降低CHB患者的HBsAg, 无论是单独使用还是与检查点抑制剂联合使用时更加有效.
实现功能性治愈的目标需要满足: 完全抑制HBV DNA复制、抑制cccDNA和整合HBV DNA产生的HBsAg、恢复宿主固有免疫和整合HBV DNA特异性免疫. 目前抑制复制联合刺激免疫再临床上已广泛应用, 但尚未完全满足临床患者对功能性治愈的需求, 再降低抗原方面, 小核酸类药物(包括siRNA和反义寡核苷酸)发挥RNA干扰作用, 靶向mRNA和pgRNA, 减少HBV抗原生产和病毒复制, 是未来联合治疗策略的关键性药物[55-57].
目前, 许多新化合物正在开发中, 包括GSK836-贝匹罗韦森(Bepirovirsen), 一种反义寡核苷酸. Bepirovirsen是一种20聚体ASO, 已进入Ⅲ期临床评估, 从长远来看, 其有可能促进消除病毒性肝炎[58,59]. AHB-137是联合RNA干扰疗法及PD-L1抑制剂(双机制协同)药物, 欧洲肝病学会年会(EASL™)公布AHB-137在中国大陆开展的临床Ⅱb期治疗期结束数据: 在该研究中, 达到主要终点的受试者中, 超过80%的受试者在治疗12 wk内实现了HBsAg的清除, 并且在治疗结束时, 24 wk和16 wk组分别有54%和33%的受试者出现了乙肝表面抗体的血清转换. AHB-137在两个治疗组中均表现出良好的耐受性和有效的安全性. GSK5637608, 原名JNJ-3989(ARO-HBV)[60]为皮下注射RNA干扰疗法, 通过N-乙酰半乳糖胺修饰, 以提高其在肝脏中的靶向性. 其靶向所有HBV RNA(包括cccDNA转录产物), 目前多项Ⅱ期研究正在进行, GSK5637608的临床研究正在推进中, 其与Bepirovirsen的序贯治疗方案有望为CHB患者提供新的治疗选择. Xalnesiran(RG6346)也是一款靶向HBV的siRNA药物. 它靶向HBV基因组的S保守区域, 抑制病毒转录和抗原表达[61], 从而降低病毒载量. 一项Ⅱ期研究结果显示, HBsAg清除率: 在治疗结束时和主要终点, Xalnesiran联合Peg-IFN-α和NA的治疗方案的HBsAg清除率最高. GST-HG141奈瑞可韦是新型乙肝核心蛋白或核衣壳调节剂, 属于全新机制的在研抗乙肝病毒一类新药[62,63]. 它通过独特的机制, 有效调节乙肝病毒核心蛋白的构象, 进而影响病毒的复制过程, 为乙肝的临床治愈提供了新的解决方案. 2024-11, GST-HG141奈瑞可韦的临床研究成果被国际权威专业机构-美国肝病研究协会(American Association for the Study of Liver Diseases, AASLD)作为最新突破摘要(Late-breaking Abstract)形式在AASLD年会上进行展示; 2024-12, GST-HG141奈瑞可韦被国家药品监督管理局药品审评中心纳入突破性治疗品种名单, 未来有望成为全球乙肝抗病毒治疗里程碑式的创新药, 目前已经完成了从临床前研究到Ⅱ期临床试验的全部工作, 且Ⅱ期临床试验的研究总结报告显示GST-HG141奈瑞可韦对于CHB低病毒血症患者具有良好的安全性和显著药效. BRII-179是VBI Vaccines公司和腾盛博药开发的一种多抗原治疗性乙肝疫苗, 该疫苗包含preS1蛋白、preS2蛋白和HBsAg. 该药的Ⅰb/Ⅱa期研究结果显示, 与IFN-α联合治疗具有良好的耐受性. 虽然多抗原疫苗具有诱导机体免疫反应的能力, 但仍需要与Peg-IFN-α联用才可在HBsAg较低的患者中显示出一定的抗病毒的效果[64,65].
此外, 一类创新药GST-HG131联合GST-HG141用于CHB经治患者的Ⅱ期临床试验. 临床前研究显示[66,67], GST-HG131可显著抑制HBsAg, 而GST-HG141作为衣壳组装调节剂, 能高效抑制HBV DNA并降低pgRNA, 间接提示其对乙肝病毒cccDNA的潜在耗竭作用. 两者联用有望通过协同机制实现"功能性治愈"-即HBsAg转阴的临床目标.
祖国医学对于慢乙肝的认识和临床诊疗积累了丰富的经验, 在肝病治疗的临床上具有重要的地位. 目前广泛应用于临床的一系列的保肝、降酶、抗炎、抗纤维化甚至是抗病毒和抗肿瘤的药物, 都是从祖国医学发展而来[68,69]. 中医药治疗强调个性化治疗方案, 在调节免疫功能、促进肝细胞修复与再生、改善临床症状、延缓肝纤维化进程, 甚至逆转早期肝硬化以及协同增效等方面发挥重要作用[70].
中医药防治乙肝除内服药物以外还有其他特色疗法包括中药穴位贴敷、针灸治疗、耳穴压豆等, 对于常伴有胁痛、腹胀、乏力、纳差、睡眠差等症状的患者, 进行辨证施护, 在缓解临床症状方面具有一定作用, 值得进一步临床研究[71].
综上所述, 基于HBsAg动态监测的RGT策略为CHB患者提供了更加个性化的治疗选择. 通过精准筛选优势人群和优化治疗方案, RGT策略有望提高CHB患者的治疗效果和临床治愈率. 未来, 随着技术的不断进步和临床经验的积累, RGT策略有望在CHB治疗中发挥更加重要的作用.
CHB的临床治愈是一个复杂而艰巨的任务, 需要多学科协同创新, 整合病毒学、免疫学、药物学等多领域的研究成果. 短期内, 优化现有的联合治疗方案是提升HBsAg清除率的关键路径. 目前, NAs与Peg-IFN的序贯或联合应用已显示出一定的临床疗效, 特别是在优势人群中, 如低HBsAg水平、HBeAg阴性的患者. 然而, 这种联合方案的具体用药时机、序贯或联合方式、治疗疗程等细节尚需进一步大样本研究来统一标准, 以实现治疗方案的最优化, 从而让更多患者受益.
未来的研究方向应着重于深入探究CHB的发病机制, 为开发更有效的治疗策略提供理论依据. 此外, 还需要加强对不同治疗方案的联合应用的研究, 以提高临床治愈率. 同时, 个体化治疗将成为未来的发展趋势, 根据患者的具体情况制定精准的治疗方案.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑: 刘继红 制作编辑:张砚梁
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