特别关注｜慢性HBV感染人群血清HBsAg清除的影响因素及其临床意义
作者：段金伟, 张鹏, 张婧, 曾婉嘉, 鲁凤民
慢性HBV感染严重危害人类健康。现世界上约有2.57亿慢性HBV感染者，每年约有88.7万人死于HBV感染相关疾病，肝硬化和肝细胞癌(HCC)是其主要死因[1]。已知HBsAg清除与慢性乙型肝炎(CHB)患者预后改善显著相关[2]，但不论是自然状态下或者抗病毒治疗下都仅有极少数的慢性感染者会发生HBsAg清除[3]。因此，分析HBsAg清除的影响因素，不仅有助于了解HBV感染自然转归的机制，同时对如何实现CHB的临床治愈也有一定的借鉴意义。
1慢性HBV感染人群的血清HBsAg清除率低
无论是HBsAg的自发性清除还是通过药物治疗实现HBsAg转阴，均可显著降低慢性HBV感染者的失代偿期肝硬化、肝衰竭等终末期肝病和肝癌的发病风险，改善CHB患者的远期结局[4]。并且患者在获得HBsAg清除后病毒重新激活率低，具有良好的持久性[5-6]。然而，慢性HBV感染者中很少发生HBsAg清除。近期，一项对56项有关成人慢性HBV感染者HBsAg自发清除的队列研究的系统回顾和荟萃分析[7]发现，汇总的HBsAg年自发清除率仅为1.17%(95%CI: 0.94%~1.41%，I2=97%)。而另一项纳入34项研究的荟萃分析[8]发现，使用干扰素、核苷(酸)类似物(NAs)等药物抗病毒治疗的患者，其HBsAg年清除率仅为0.65%~1.8%。但值得注意的是，该荟萃分析所显示的5、10、15年累积清除率随观察时间呈递增趋势，分别为4.03%(95%CI: 2.49~5.93)、8.16%(95%CI: 5.24~11.72)、17.99%(95%CI: 6.18~23.24)，提示长期坚持抗病毒治疗有助于HBsAg清除率的提升。
2影响慢性HBV感染患者血清HBsAg自发清除的因素
既往研究[9]指出，高加索人种相较于亚洲人群更易获得HBsAg清除; 而与HBV基因B、C型相比，感染基因A、D型的患者更易获得HBsAg清除。但HBV感染流行区和非流行区之间HBsAg自发清除率并无显著差异(1.19% vs 1.29%)[7]。除此之外，一项对87例非活动性携带者的5年随访研究[10]显示，HBsAg基线水平低、年递减幅度高是其自发清除的独立影响因素。例如，HBsAg＜100 IU/ml的非活动性携带者1、3年后的HBsAg自发清除率分别为44%和56%，而HBsAg＜10 IU/ml的非活动性携带者1年后HBsAg自发清除率可达67%。HBeAg阴转后，血清HBsAg的快速下降也能更好地预测HBsAg的自发清除[11]。值得注意的是，在HBeAg阴性携带状态的慢性感染者中，HBsAg自发清除人群中出现ALT短暂升高的比例远高于未自发清除者(12.2% vs 3.6%，P=0.025)[12]。但也有研究[13]指出，基线ALT水平正常的非活动性携带者更易获得HBsAg自发清除。这种不一致性是否是因队列构成的差异或观察方式的不同所致，仍有待探讨。
年龄与血清HBsAg自发清除率呈正相关。一项对1965例非活动性HBV携带者的研究[14]表明，＜30岁的携带者中HBsAg年清除率为0.77%，而30~39岁、40~49岁和≥50岁的携带者的年清除率分别为1.07%、1.65%和1.83%。笔者认为，这一HBsAg清除率随着年龄增长而增加的现象或许与宿主对HBV感染更为长久的免疫作用有关。另有研究[15]认为，基线或随访期间发生肝硬化与HBsAg自发清除率显著相关，但也有研究[9]显示二者之间并无相关性。对于病情已进展为肝硬化或HBsAg清除时年龄＞50岁的患者，其发生HCC的风险依然较高[16]。考虑到年龄＞50岁和男性是HBsAg转阴患者发生肝癌的2个独立危险因素，而从HBsAg清除中受益最大的年轻患者的自发清除可能性更低，应尽早开展抗病毒治疗以追求早期临床治愈; 而对于已进展为肝硬化或年龄＞50岁的CHB男性患者，即使HBsAg已经阴转，也仍需密切监测HCC发生。
3抗病毒治疗下影响CHB患者血清HBsAg清除的因素
Yeo等[8]通过系统回顾和荟萃分析发现，基线时HBeAg阴性和阳性患者间的HBsAg清除率有显著差异(1.33% vs 0.40%，P＜0.01)，且基线时HBV DNA和HBsAg的水平低也有利于HBsAg清除(P＜0.01)。治疗后HBsAg快速下降是HBsAg清除的预测因素[17]。一项总结了亚洲CHB患者HBsAg定量检测在NAs停药中的作用的系统综述[18]发现，停药时HBsAg＜100 IU/ml的患者HBsAg清除率为21.1%~58.8%，而HBsAg＞100 IU/ml的患者清除率仅为3.3%~7.4%。此外，宿主免疫可通过溶细胞和非溶细胞2种机制发挥抗病毒作用，前者多伴有肝脏炎症发生。研究[19]表明，治疗前较高的肝坏死性炎症评分更利于HBsAg清除。而来自笔者实验室的近期研究[20]也显示，较高的炎症活动度与更好的病毒学应答相关。值得关注的是，尽管有研究认为抗病毒治疗后HBsAg清除与基线ALT水平无关，但抗病毒治疗期间和停药后血清ALT升高可以预测后续HBsAg清除。一项聚乙二醇干扰素(PEG-IFN)治疗慢性非活动性HBsAg携带者的临床研究[21]表明，患者治疗第12周时ALT水平升高是96周时HBsAg清除的预测指标。同样有研究[22]显示，阿德福韦和替诺福韦(TDF)治疗时ALT短暂升高与HBsAg下降或清除相关，并且HBsAg清除和ALT升高之间有明显的时间延迟，即ALT升高先于HBsAg下降。此外，对HBeAg阴性的非肝硬化CHB患者的停药观察研究[23]提示，TDF治疗结束后出现ALT水平升高与停药后HBsAg下降相关。总之，接受抗病毒治疗的患者若HBeAg阴性、基线HBV DNA和HBsAg水平低、反应肝脏炎症损伤的ALT活性升高均与患者能否获得HBsAg清除有关。此外，有停药观察研究[24]发现，CHB患者达到亚太停药标准后停止治疗，肝炎复发但未再治疗患者的HBsAg阴转率显著高于再治疗者，这也提示了宿主免疫在HBsAg清除中的作用。考虑到停药后肝炎复发以及发展为肝功能失代偿甚至死亡的风险较高，停药后定期随访和肝炎复发后治疗时机的选择至关重要。
4慢性HBV感染患者HBsAg清除与宿主免疫应答间的关联
对HBsAg阴转患者的单核细胞研究[25]发现，树突状细胞可能在HBsAg清除中起着关键作用。同时，HBV特异性CD8+T淋巴细胞应答在病毒清除中也起着重要作用。一项基于全基因组表达谱分析[26]发现，与自发清除感染患者中功能正常的CD8+T淋巴细胞相比，CHB患者中耗竭表型的HBV特异性CD8+T淋巴细胞中各类基因的表达均显著下调; 与HBsAg阳性的CHB患者相比，NAs停药后HBsAg转阴患者的耗竭表型T淋巴细胞减少，活化表型比例增加且T淋巴细胞表面抑制性受体程序性死亡受体1和杀伤细胞凝集素样受体G亚家族成员1的表达水平也相对较低。特异性CD4+T淋巴细胞在CD8+T淋巴细胞应答和功能性B淋巴细胞抗体产生中都起着关键的调节作用。研究[27]表明，能产生HBV特异性IFNγ的CD4+T淋巴细胞有利于病毒清除，其频率与HBsAg下降呈正相关; 分泌IL-4的CD4+T淋巴细胞的数量与HBsAg水平呈显著负相关。在HBV携带者中甚至在“治愈”的患者中使用B淋巴细胞耗竭药物(利妥昔单抗)可以诱导HBV重新激活[28]，表明B淋巴细胞通过分泌HBsAg中和性抗体在HBV感染清除中起着至关重要的作用。但从CHB患者中分离的B淋巴细胞增殖能力减弱，且抗原刺激后无法产生抗HBsAg抗体[29]。此外，研究报道自然杀伤(NK)细胞功能增强也与NAs巩固治疗停药后HBsAg血清清除有关[30]，而NK细胞可通过TNF相关的诱导配体的死亡受体2途径介导病毒特异性CD8+T淋巴细胞的耗竭[31]，反过来，HBV可诱导产生抑制性单核细胞，启动调节性NK细胞分化，导致T淋巴细胞抑制[32]。近期一项研究[33]结果显示，降低小鼠肝内HBsAg水平能够显著增强HBV治疗性疫苗的疗效，促进HBsAg转阴和病毒清除，提示肝脏原位病毒抗原清除可能才是HBV特异性免疫应答恢复的关键。
5抗病毒药物与CHB患者血清HBsAg清除
整合的病毒DNA含有完整的HBsAg开放阅读框及其调控元件，可持续产生HBsAg。由于其并非来自病毒cccDNA，靶向病毒复制过程的NAs药物及核衣壳抑制剂等对此往往无效，而干扰素治疗则有助于宿主免疫清除具有功能性整合病毒DNA的感染肝细胞。因此，对于NAs经治的某些特定优势应答人群，NAs联合或序贯具有免疫调节作用的PEG-IFN进行治疗可显著提高患者的HBsAg阴转率[34]。一项荟萃分析[35]表明，与NAs单药治疗相比，联合IFN(RR=15.59, 95%CI: 3.22~75.49)或换用IFN(RR=12.15, 95%CI: 3.99~37.01)治疗可以显著提高HBsAg清除率。尽管目前现有一线药物的转换、联合及序贯治疗在一定程度上提高了血清HBsAg清除，但与临床治愈的需求仍有很大差距。
核酸聚合物是一类新型的广谱抗病毒化合物，通过抑制感染的肝细胞释放HBsAg，或可有助于使慢性HBV感染者获得HBsAg清除[36]。近期新药临床研究[37]显示，在TDF联合PEG-IFN中加入核酸聚合物，HBsAg清除率在治疗期间和治疗后均显著增加。反义寡核苷酸新药(ISIS505358/GSK3228836和RO7062931)可显著降低HBsAg水平，并且与NAs联合治疗时HBsAg平均下降幅度更大[38]。接受NAs联合新型RNA干扰药物(JNJ-3989[39]、VIR-2218[40])的CHB患者，其HBsAg水平较基线均下降了1.0 log10 IU/ml。在免疫调节药物的研发方面，口服Toll样受体8激动剂(selgantolimod)48周时可使5%的患者达到HBsAg清除[41]。此外，有报道[42]显示，一种高亲和力结合T淋巴细胞抗原受体和CD3(ScFv)激活T淋巴细胞的双特异性分子(ImmTAV)能够有效、快速和特异性地清除感染HBV的肝细胞。需要指出的是，尽管新型HBV药物在清除HBsAg方面具有强大潜力，但其有效性和安全性仍需要更多的研究。
6HBsAg清除后的持久性
值得庆幸的是，当CHB患者HBsAg清除后，其持久性可维持在较高水平且复发率较低，HBV感染相关的终末期肝病及肝癌的发生风险也大幅下降。一项基于PEG-IFN联合NAs治疗的临床随访研究[43]显示，CHB患者发生HBsAg清除后的第26、52、78、104及597周的累计HBsAg复阳率分别为0.84%、6.29%、6.88%、8.18%和9.66%，表明CHB患者HBsAg清除后的持久性较好且复发率较低。有报道[43-44]认为，基于IFNα治疗获得HBsAg清除的患者再巩固治疗12周以上可提高HBsAg清除的持久性，且伴随着抗-HBs的血清学转换，抗体水平越高，复发反弹的风险越低。除了抗-HBs外，停药时患者血清抗-HBc水平也是预测复发的独立相关因素[45]。而且，笔者团队实验室的一项研究[46]也提示，当患者HBsAg阴转时血清HBV RNA阳性也是临床治愈患者停药后发生HBsAg复阳的风险因素。
7总结与展望
由于HBV复杂的生命周期以及病毒抗原对宿主免疫的抑制作用，慢性HBV感染者的HBsAg自发清除率较低，而现有抗病毒药物清除HBsAg的作用也非常有限。通过研究这些可影响HBsAg清除的病毒和宿主因素，有助于探究能够有效清除HBsAg的新药物、新举措。在期待新药研发取得进展的同时，如何基于现有药物优化治疗方案以提高患者HBsAg清除率及降低HBsAg清除后的反弹和复发，也应成为今后一段时间内重要的研究方向。
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