指南共识｜美国《慢性乙型肝炎病毒感染管理治疗流程：2021年修订》

文章选自：中华肝脏病杂志，2022,30(2):190-195.

作者：庄辉

本文简要介绍《美国慢性乙型肝炎病毒感染管理治疗流程 ：2021 年修订》提出的推荐意见。

一、修订美国《慢性乙型肝炎病毒感染管理治疗流程》的原因

美国《慢性乙型肝炎病毒感染管理治疗流程》（以下简称《流程》）最早于2004年由北美洲肝病专家制定[1]，曾于2006年、2008年和2015年进行了3次修订[2-4]，2021年6名美国和1名加拿大肝病专家对2015年版《流程》进行了修订[5]。修订该《流程》的主要原因是如下：

（1）在美国，大量符合美国肝病学会（AASLD）慢性乙型肝炎（乙肝）指导治疗标准的患者未接受治疗，诊断率仅为18%，在诊断者中仅20%治疗[6-9]；

（2）富马酸丙酚替诺福韦（TAF）已上市，其有效性与替诺福韦酯（TDF）相似，但安全性优于TDF，可作为慢性乙肝患者长期治疗的一种选择[10-12]；

（3）临床上定量乙型肝炎表面抗原（HBsAg）测定更加普遍，用以监测治疗应答 ；

（4）对乙肝病毒（HBV）感染自然史有了新的认识，新证据挑战免疫耐受期无疾病进展的老观念[13]；

（5）美国慢性乙肝患者平均年龄增大，2015年美国慢性乙肝患者≥55岁占42%，这些患者合并症多，包括代谢性肝病、慢性肾病、骨质疏松等。同时，随年龄增大用药种类增多，从而影响慢性乙肝管理[14]；

（6）世界卫生组织（WHO）要求简化慢性乙肝管理流程[15]。

二、抗病毒治疗的候选患者

专家们一致推荐：所有HBV脱氧核糖核酸（HBV DNA）≥2000 IU/ml、丙氨酸转氨酶（ALT）男性>35 U/L，女性>25 U/L[16]、乙型肝炎e抗原（HBeAg）阳性和阴性慢性乙肝患者均应接受治疗。如果HBV DNA≥2000 IU/ml、谷丙转氨酶（ALT）升高、肝脏无纤维化患者不接受治疗，则应每3~6个月监测其HBV DNA和ALT水平[6]。

关于免疫耐受期患者应否治疗，该《流程》接受欧洲肝病学会（EASL）的观点，即基于HBV和肝病指标评价，将慢性HBV感染自然史分为HBeAg阳性慢性感染（原称免疫耐受期）、HBeAg阳性乙型肝炎（原称HBeAg阳性免疫活动期或免疫清除期）、HBeAg阴性慢性感染（原称非活动携带期或低复制期）和HBeAg阴性慢性乙型肝炎（原称HBeAg阴性免疫活动期或再活动期）[17]。其特征见图 1。

基于最近报道，免疫耐受期患者与免疫活动期患者同样有HBV DNA整合至宿主染色体和克隆肝细胞扩增[13]，而且这些患者HBV高水平复制对疾病进展至肝硬化和（或）肝细胞癌（HCC）起重要作用[18]。一些专家认为，HBV DNA≥2000 IU/ml、ALT持续正常的所有成年免疫耐受期患者（包括[19-22]。

三、慢性乙肝治疗

（一）对慢性乙肝治疗的推荐意见[5]（表 1）

（二）接受TDF治疗的患者是否换用TAF

大多数专家认为TAF优于TDF，TAF发生肾和骨不良反应的风险较TDF低；治疗48周时可能有更高的ALT复常率[10-11,23-26]。关于正接受TDF治疗的慢性乙肝患者是否改用TAF，一些专家建议将TDF换用TAF，因TAF肾和骨毒性低，且ALT复常率高[27-29]；另外一些专家则建议继续用TDF治疗，因用TDF治疗慢性乙肝患者10年的研究证明其安全有效，骨密度下降多发生在治疗后第1~2年。专家组一致的意见是：对肾功能临界值[估算肾小球滤过率（eGFR）50岁患者可将TDF换用TAF[5]。

（三）联合治疗

该《流程》指出，恩替卡韦（ETV）、TDF、TAF抗病毒力强、耐药发生率低，因此，建议对几乎所有慢性乙肝患者进行ETV、TDF、TAF或聚乙二醇干扰素α-2a（PegIFNα-2a）单药治疗[5]。但有一些证据表明，与TDF或PegIFNα-2a单药治疗比较，TDF与PegIFNα-2a联合治疗有可能提高HBsAg清除率[30]。这与2017年EASL和2018年AASLD慢性乙肝指南或指导不推荐PegIFNα-2a和核苷（酸）类似物（NAs）联合治疗[16-17]的意见不同。

（四）治疗期限

该《流程》指出，虽然PegIFNα-2a治疗48周患者的HBeAg血清学转换率高于治疗24周[31]，但PegIFNα-2a治疗的最优期限尚不清楚[5]。小样本研究证明，延长PegIFNα-2a治疗至96周可提高HBeAg和HBsAg持续血清学转换率[32]。对HBeAg阴性、HBV D基因型患者，延长PegIFNα-2a治疗至96周，可提高HBV抑制率和ALT复常率[33]。对个体患者延长基于干扰素治疗是否有利，应平衡患者的耐受性问题。HBeAg阳性患者接受干扰素治疗12周时，HBsAg无下降或>20000 IU/ml，应停止治疗[34-35]。同样，HBeAg阴性患者接受干扰素治疗12周时，HBsAg无下降或HBV DNA下降[36-37]。

关于NAs，专家组建议对于大多数开始治疗时有明显肝纤维化（F3）和代偿期肝硬化（F4）患者，应进行长期治疗。开始治疗时为代偿期肝病患者，如HBsAg清除6~12个月或HBsAg血清学转换，则可以停药。但患者即使已无肝硬化，也必须终生进行HCC监测[5]。

证明为轻度肝纤维化（[38-39]。虽然不建议停药，但患者希望停药，则在停药前，应对患者进行肝活组织学检查或肝脏硬度值测定，确保只有轻微肝纤维化（F0~F1），方可停药。对停药患者，应监测其HBV DNA和ALT水平；复发患者可再治疗。

对未达到HBsAg血清学转换的HBeAg阴性患者，该《流程》不建议停药。但如果患者希望停药，如经肝活组织学检查或肝脏硬度无创诊断为轻微肝纤维化（F0~F1）和轻微炎症患者，医生可与其对话，告知停药5年后的利弊。接受NAs治疗的HBeAg阴性患者停药后，几乎均发生病毒学复发，至少出现低病毒水平[40]。因此，对停药的患者，应监测其HBV DNA和ALT水平；复发患者可用同一种药物再治疗。

（五）监测肾毒性

由于一些NAs（ADV、TDF）与肾功能下降有关[41]，因此，该《流程》推荐：在应用NAs治疗前，应评价血清肌酐水平和肌酐清除率；对高危患者，在治疗前或在治疗过程中，根据肾功能评价结果调整药物剂量；有进展性肾损伤的慢性乙肝患者，应调整NAs剂量，但TAF除外。如GFR[42]；发生肾脏不良事件的危险因素包括失代偿期肝硬化、治疗前肌酐清除

40岁以上人群的生理性肾功能（eGFR）每10年预期下降约8 ml/min/1.73 m²[43]。2015年，美国42%慢性乙肝患者的年龄已达55岁；日本2016年60%慢性乙肝患者的年龄在65岁或更大，因此，应关注老年患者[44-48]。对有肾毒性风险和服用TDF的患者，在治疗第1年，应每3个月监测eGFR和血磷；如肾功能无改变，可每6个月监测1次[49]。对于高危患者于治疗前或治疗过程中，根据肾功能评价结果，调整药物剂量。

（六）骨密度检查

慢性肝病包括慢性乙肝患者发生骨质疏松的风险较高，并常被漏诊[44,50]。此外，由于慢性乙肝患者大部分为男性，曾报道男性病理性骨折与治疗第1年病死率高有关，骨健康与慢性乙肝管理明显相关[51-52]。2项有关TDF与TAF的关键性临床研究表明，48周时，TDF组和TAF组髋骨和脊髓骨密度下降分别为33%~39%和10%~22%[10-11]。因此，一些专家建议，在启动NAs治疗前，应进行骨密度扫描，特别是有骨质疏松风险的患者；另一些专家建议口服营养补充剂[5]。

（七）治疗过程中监测

启动治疗12周时，应监测血清HBV DNA水平，以评价其治疗应答；24周时监测血清HBV DNA水平，以确证是否获得病毒学应答。治疗第1年，应每3~6个月监测HBV DNA水平，以确认是良好的病毒学抑制或病毒学突破。

1. 原发性治疗失败

对于原发性治疗失败，AASLD 2018年慢性乙肝指南的定义是：治疗6个月HBV DNA下降[16]；EASL 2017年慢性乙肝指南的定义是：治疗3个月HBV DNA下降[17]。

该《流程》指出：ETV、TDF和TAF治疗慢性乙肝患者发生原发性无应答少见，对治疗12~24周无应答患者，应评价其依从性；对依从性好的患者，治疗24周时应检测耐药，以确定针对耐药变异株的最佳救治策略。

2. 部分病毒学应答或应答不佳

部分病毒学应答的定义指治疗至24周HBV DNA≥2000 IU/ml或治疗至48周HBV DNA仍可检测到。该《流程》指出，对部分应答或应答欠佳的患者，应评价其依从性。用ETV、TDF或TAF治疗慢性乙肝48周时还可检测到HBV DNA的患者的最佳管理策略尚不清楚。对于血清HBV DNA呈下降的患者，可继续用ETV或TDF治疗，病毒学应答率可随治疗时间延长而升高，发生耐药的风险很低[53-54]。用ETV治疗1年后HBV DNA[55]。另一治疗策略是：对ETV治疗1年部分应答的患者，换用TDF或TAF单药治疗，或与TDF或TAF加ETV联合治疗[56]。有研究报道，用0.5 mg/d ETV治疗部分应答的慢性乙肝患者，增加ETV剂量至1 mg/d不能达到完全病毒学抑制[57]。

3. 病毒学耐药监测

病毒学耐药在临床上为病毒学突破，其定义是：患者有病毒学应答且依从性好，但血清HBV DNA检测2次，间隔1个月， 较原应答的HBV DNA下限上升1 log₁₀ IU/ml[58]。该《流程》指出，ETV治疗5年耐药发生率为1.2%，TDF和TAF未报告耐药。临床上大量耐药是依从性差所致，真正耐药发生率低[59-60]（表 2）。

耐药管理的推荐意见不一[61-63]，但一般是加用或换用不同种类的药。在临床上，对怀疑ETV耐药的患者，推荐用TDF或TAF单药治疗。对合并人类免疫缺陷病毒感染患者，选择TAF 25 mg/d和恩曲他滨200 mg/d治疗。

四、结论

制订该《流程》的专家组预计，虽然有多种药物正在临床研发中，但在未来几年内，现已获批的药物仍将是治疗慢性乙肝的唯一选择。同时专家组认为，接下来的重要目标是努力识别HBV感染患者和继续重新评估每例患者是否需要抗病毒治疗。

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