学术争鸣｜庄辉：慢性HBV感染免疫耐受期应否治疗？
编者按
慢性HBV感染免疫耐受期患者是否应该接受治疗是目前国内外学术界争议较大、关注度很高的一个问题。美国、欧洲及亚太指南一般不推荐对免疫耐受期慢性乙型肝炎予以治疗，但有多位学者建议对HBV感染免疫耐受期患者进行抗病毒治疗。
针对这一热点难点问题，《临床肝胆病杂志》特设“学术争鸣”栏目，并邀请庄辉教授撰文与大家一起讨论，作为开始，不是定论。本刊热忱欢迎广大读者就此议题踊跃参与讨论，来稿将陆续刊发。
今后，本刊将“学术争鸣”设为长期固定栏目，以问题为导向，提倡学术公正、公平，百家争鸣，百花齐放，在秉持学术民主的思辨中探索真理，为推动本学科学术争鸣尽应有职责。
据估计，全球慢性HBV感染者约2.92亿人，其中免疫耐受期患者约1.98亿［1］。我国慢性HBV感染者约8600万例，其中免疫耐受期患者约3230万［1］。
目前美国［2］、欧洲［3］和亚太［4］肝病学会发布的慢性乙型肝炎（CHB）诊治指南（以下简称美国指南、欧洲指南和亚太指南）关于免疫耐受期CHB（IT-CHB）患者的定义及治疗的推荐意见不完全一致：美国指南［2］中ALT正常值上限（ULN）男性为30 U/L，女性为25 U/L；欧洲和亚太指南中ALT ULN男女均为40 U/L。关于IT-CHB定义，美国指南：HBV DNA＞106 IU/ml，ALT正常；欧洲指南：HBV DNA＞107 IU/ml，ALT持续正常；亚太指南：HBV DNA＞20 000 IU/ml，ALT 1~2×ULN。关于IT-CHB治疗的推荐意见，美国和亚太指南均只推荐对肝活检显示中度/重度炎症（A3）或明显纤维化（F2）的IT-CHB患者治疗；欧洲指南则推荐扩大IT-CHB治疗指征：即年龄＞30岁，或有肝细胞癌（HCC）/肝硬化家族史，或有肝外表现的IT-CHB患者，即使ALT和肝活检正常，也可以治疗。
2020年5月，Jeng等［5］在“应否扩大CHB治疗指征”一文中提出，对有活动性/进展性肝病证据的灰区（即HBV DNA＜106 IU/ml）或年龄＞40岁的IT-CHB患者进行抗病毒治疗，较美国指南扩大了治疗指征。2020年9月，中国韩国和日本10名专家联合发表关于启动CHB治疗东亚专家意见［6］，推荐ALT ULN男性为30 U/L，女性为19 U/L，对ALT≥1×ULN患者，推荐抗病毒治疗。该专家意见扩大了相当一部分IT-CHB患者的抗病毒治疗。
美国、欧洲和亚太指南不推荐对IT-CHB治疗的理由是：（1）IT-CHB是良性疾病期，不发生肝硬化和HCC或发生率很低［7-12］；（2）IT-CHB患者的肝组织学无或轻微炎症和/或纤维化［2,9,13-14］；（3）治疗效果差，很少发生HBeAg血清学转换或HBsAg消失［5,15-19］；可自发免疫控制达到HBeAg血清学转换［8,20-21］；（4）IT-CHB患者多为青年人，对长期抗病毒治疗依从性差，易发生耐药［12,22］。
2015年，Bertoletti等［23］对HBV感染免疫耐受期概念提出异议，认为这是老概念，缺乏免疫学证据。2016年，Gastroenterology杂志组织专家对“免疫耐受期概念”进行了讨论［24-28］。Bertoletti等［23-25,28］认为不应称为IT-CHB，建议改为“高复制低炎症期（HRLI）”，理由是：（1）在胎儿早期已存在效应和调节免疫应答；（2）新生儿和婴儿可产生病毒特异性T淋巴细胞应答；（3）新生儿和婴儿的免疫系统本身并无缺陷；（4）儿童在1岁内注射乙型肝炎疫苗有效；（5）不同期乙型肝炎患者（包括免疫耐受期）均有HBV特异性T淋巴细胞应答、HBV DNA整合和克隆肝细胞扩增，说明肝癌发生已经启动。但Milich［26］和Liaw等［27］认为将IT-CHB改名为HRLI的证据尚不充分。2017年欧洲指南首先将IT-CHB正式改名为“HBeAg阳性慢性HBV感染”。
自2018年以来，特别是2020年，多位学者［29-33］提出，应对HBV免疫耐受期患者治疗，以降低其发生肝硬化和HCC的风险，理由如下。
1IT-CHB不是良性疾病期，如不治疗，可进展为肝硬化和HCC
Mason等［24］检测26例慢性HBV感染者，其中9例IT-CHB患者、10例HBeAg阳性CHB患者、7例HBeAg阴性CHB患者，发现IT-CHB患者与HBeAg阳性和阴性CHB患者一样，也可检测到HBV DNA整合、肝细胞突变、克隆肝细胞扩增、HBV特异性T淋巴细胞应答以及肝脏损伤。Chu等［8］随访240例IT-CHB患者17年，肝硬化累积发生率为12.6%。Chen等［34］随访251例IT-CHB患者13年，HCC累积发生率为5.1%。Beasley等［35］前瞻性随访22 707例40~59岁中国台湾男性，其中15.2%为HBsAg携带者，平均随访3.3年，HBsAg携带者的HCC发病率（1158/10万人年）显著高于非携带者（5/10万人年）。Sun等［36］分析我国161个疾病监测点1990年—2014年的HCC死亡率资料发现，无论是城市还是农村，男性和女性HCC死亡率均随年龄增长而明显升高，特别是在30岁以后（图1）。HCC的发生是一个长期发展致病过程，说明早在30岁以前HCC发生已经启动［35］。
图1 我国1990年—2014年161个疾病监测点城乡男女HCC年龄死亡专率［36］
Kim等［37］分析韩国一所三甲医院2000年—2013年病例队列，其中未治疗的IT-CHB患者413例、核苷(酸)类似物（NAs）治疗的免疫活动期CHB患者1497例，结果显示，未治疗的IT-CHB患者10年累积HCC发病率和死亡/肝移植发生率（分别为12.7%和9.7%）显著高于治疗的免疫活动期CHB患者（分别为6.1%和3.4%）（P值分别为0.001、0.001）。
2相当一部分IT-CHB患者有明显的肝细胞炎症坏死和肝纤维化病理学改变
既往虽有报道［2,9,13-14］，IT-CHB患者的肝组织学无或轻微炎症和/或纤维化，但近年来有多篇报道［9,38-44］表明，28%~49%的IT-CHB患者有明显的肝细胞炎症坏死和肝纤维化（≥G2/S2）病理学改变（表1）。
3NAs治疗IT-CHB患者可显著降低血清HBV DNA
既往曾报道［5,15-19］，IT-CHB患者接受抗病毒治疗效果较差，很少发生HBeAg血清学转换或HBsAg消失。但近年来有多项研究［45-47］显示，应用NAs治疗IT-CHB患者，虽然HBeAg血清学转换或HBsAg消失率低，但降低血清HBV DNA水平效果显著。Chan等［45］用替诺福韦酯（TDF）或TDF/恩曲他滨（FTC）分别治疗64例和62例IT-CHB患者，平均年龄为33岁，89%为亚洲人，B和C基因型占93%，99%为HBeAg阳性，HBV DNA水平为8.41 log10 IU/ml,治疗至192周时，TDF组55%(35/64)、TDF/FTC组76%(47/62) 患者的HBV DNA水平降至＜69 IU/ml，与基线比较有显著差异（P=0.016）。Pan等［46］和Jourdain等［47］先后在IT-CHB孕妇中，开展TDF预防HBV母婴传播的随机对照研究，将IT-CHB孕妇随机分为治疗组和对照组，Pan等［46］于孕30~32周至产后4周，Jourdain等［47］于孕28周至产后2周，分别给予各组孕妇TDF或安慰剂，分娩时（即治疗8~12周）检测所有孕妇HBV DNA，结果显示TDF组HBV DNA水平分别下降4.7 log IU/ml和4.0 log IU/ml，而安慰剂组HBV DNA水平无下降，仍维持在基线水平。韩国Chang等［48］开展了一项全国性多中心回顾性研究，分析2006年1月—2016年3月韩国8所大型医院共计484例IT-CHB患者（HBeAg阳性、HBV DNA水平＞20 000 IU/ml，ALT水平＜40 U/L、无肝硬化），其中87例接受抗病毒治疗，397例未接受抗病毒治疗作为对照，经倾向记分配对分析，10年间治疗组累积HCC及肝硬化发生率显著低于对照组（P值分别为0.046、0.015）（图2）。
图2 韩国多中心IT-CHB患者抗病毒治疗回顾性分析HCC及肝硬化累积发生率［48］
HBV DNA水平是HCC发生的独立危险因素，降低血清HBV DNA水平可显著减少HCC发生风险。Chen等［49］对基于社区1991年—1992年入组的3653例（30~65岁）HBsAg阳性者前瞻性队列，平均随访11.4年，发现其累积HCC发生率与入组时HBV DNA水平有关，入组时HBV DNA水平＜300、300~9999、10 000~99 999、100 000~999 999和≥1 000 000 拷贝/ml患者HCC累积发生率分别为1.30%、1.37%、3.57%、12.17%和14.89%，随HBV DNA水平上升而显著升高。
各国指南［2-4,50］指出，治疗CHB的目的是：最大限度地长期抑制HBV复制，减轻肝细胞炎症坏死及肝脏纤维组织增生，延缓和减少肝功能衰竭、肝硬化失代偿、HCC和其他并发症的发生，改善患者生活质量，延长其生存时间，而不仅仅是为了个别HBV标志物的转换或消失。因此，从降低肝硬化和HCC风险来看，NAs治疗IT-CHB患者的效果是显著的。
4扩大对IT-CHB患者治疗的其他理由
（1）现有乙型肝炎口服抗病毒药物恩替卡韦（ETV）、TDF、富马酸丙酚替诺福韦（TAF）长期治疗安全性好、耐药发生率低［51-59］：ETV 5年累积耐药发生率仅为1.2%［53］；TDF 8年未发现耐药［55］；TAF 3年无耐药［58-59］。
（2）长期治疗依从性差，不能作为不治疗的理由，因CHB患者和其他慢性疾病患者也需长期治疗，治疗的依从性可通过健康教育等措施提高［31,60-61］。
（3）治疗性价比高。目前乙型肝炎抗病毒药物的治疗费用低于监测费用，且IT-CHB患者对监测依从性差。据报道［19，62］，约61%的HCC患者为首次就诊，说明这些患者既往未接受监测。
（4）对IT-CHB患者抗病毒治疗可降低HBV水平传播和母婴传播，并可减少乙型肝炎歧视［46-47,63-64］。
（5）对IT-CHB患者治疗可提高乙型肝炎诊断率和治疗率［30，32，65］，实现世界卫生组织提出的到2030年消除乙型肝炎公共卫生威胁的目标［66］。
5小结
鉴于（1） IT-CHB不是良性疾病期；（2）对IT-CHB患者治疗可降低肝硬化和HCC的发生；（3）一线药物抗病毒能力强，耐药发生率低，长期治疗安全有效；（4）治疗费用低于监测费用，性价比高；（5）可降低HBV水平传播和母婴传播，减少乙型肝炎歧视；（6）可提高乙型肝炎诊断率和治疗率，实现世界卫生组织提出的到2030年消除乙型肝炎公共威胁的目标。因此，应扩大对IT-CHB患者的治疗。同时，应开展对IT-CHB患者治疗的研究，提供更多的循证医学证据，如（1）回顾性前瞻性队列研究：比较IT-CHB治疗组、未治疗组和HBeAg阳性免疫活动性乙型肝炎治疗组累积肝硬化发生率、HCC发病率、肝移植率及死亡率；（2）前瞻性队列研究：比较3组累积肝硬化发生率、HCC发病率、肝移植率及死亡率；（3）随机对照研究：比较2组累积肝硬化发生率、HCC发病率、肝移植率及死亡率等。
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庄辉. 慢性HBV感染免疫耐受期应否治疗？[J]. 临床肝胆病杂志, 2021, 37(2): 272-277.
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