学术速递 | 庄辉院士：慢性乙型肝炎：从"只治"到"全治

2024-06-21 11:39:37来源：中华肝脏病杂志阅读：135次

引用本文

庄辉. 慢性乙型肝炎：从"只治"到"全治" [J] . 中华肝脏病杂志, 2024, 32(5) : 389-393. DOI: 10.3760/cma.j.cn501113-20240411-00194.

摘要

以往慢性乙型肝炎的治疗标准是基于发生合并症的风险，国际指南建议只治疗发生合并症风险高的患者，称之为"只治"("treat only if…")策略。后来发现，在发生肝细胞癌的病例中，33.5%～64.0%不符合国际指南的治疗标准，提示需要扩大慢性乙型肝炎的治疗标准。尔后，"只治"("treat only if…")策略被"全治但除外"("treat all except…")策略所替代。后者是慢性乙型肝炎全治，但除外发生合并症风险低的患者。

在慢性乙型肝炎患者中，符合该策略治疗标准的比例由10.3%提高至26.5%～33.9%，但距世界卫生组织提出的80%治疗目标仍较远。因此，为及早达到2030年消除乙型肝炎的目标，提出了"全治"("treat all")策略，即对所有HBV DNA阳性的慢性乙型肝炎患者均治疗。

既往，国际上治疗慢性乙型肝炎的策略是：只对发生肝硬化、肝失代偿和肝细胞癌（hepatocellular carcinoma, HCC）等并发症风险高的慢性乙型肝炎肝炎患者治疗，称之为"只治…"("treat only if…")策略。所谓发生并发症风险高的慢性乙型肝炎肝炎患者是指：HBV DNA水平高、丙氨酸转氨酶( ALT)水平高和肝组织病理学有显著炎症坏死和/或纤维化。

如亚太肝病学会(Asian-Pacific Association for the Study of the Liver, APASL) 2015年版乙型肝炎管理指南^[1]和美国肝病学会(American Association for the Study of the Liver, AASLD) 2018年版乙型肝炎指导^[2]均建议，对HBeAg阳性慢性乙型肝炎，HBV DNA水平>20 000 IU/ml、ALT>2×正常值上限(upper limit of normal, ULN)，或有显著肝组织学病变者治疗。

欧洲肝病学会(European Association for the Study of the Liver, EASL) 2017年版指南^[3]的治疗标准是：HBV DNA>2 000 IU/ml和ALT>ULN，或有显著肝组织学病变者。对HBeAg阴性慢性乙型肝炎，APASL^[1]和AASLD^[2]指南的治疗标准是：HBV DNA>2 000 IU/ml和ALT>2×ULN，或有显著肝组织学病变者。EASL指南^[3]的治疗标准是：HBV DNA>2 000 IU/ml和ALT>ULN，或有显著肝组织学病变者(表1)。

但美国对实验室数据库中有2次HBV检测结果的54 942例慢性乙型肝炎患者进行分析，结果显示符合APASL、AASLD、EASL指南治疗标准的比例分别为5.8%、6.7%和6.2%，即约93%~94%的患者不符合这3个指南的治疗标准^[4]。但这些不符合指南治疗标准的慢性乙型肝炎患者经长期随访，仍可发生HCC。

韩国的一项多中心队列研究，对3 624例未治疗的慢性乙型肝炎患者中位随访时间4.6年，在HCC死亡者中，不符合该3个指南治疗标准者分别占33.5%、46.0%和64.0%，提示需要扩大治疗^[5,6,7,8]，并建议将启动治疗的HBV DNA水平由20 000 IU/ml降至2 000 IU/ml；ALT ULN由40 U/L降至男30 U/L、女19 U/L。

Su等^[9]和Dieterich等^[10]提出了"全治但除外"(treat all except…)策略，即全治，但除外发生并发症风险低的患者(图1)。按"全治但除外"(Treat all except…)策略，符合治疗标准的慢性乙型肝炎比例由10.3%上升至26.5%~ 33.9%^[4]。

最近发布的WHO 2024年版指南建议，慢性乙型肝炎全治但除外ALT正常和HBV DNA<2 000 IU/ml患者^[11,12]。亚太消除病毒性肝炎工作组^[13]建议，慢性乙型肝炎全治但除外检测不到HBV DNA、ALT< ULN (男30 U/L,女19 U/L)、无显著肝硬化和进展性纤维化、无计划接受免疫抑制剂治疗，以及无肝外表现的患者。该工作组建议的慢性乙型肝炎治疗标准较WHO 2024版指南更扩大了。

2022年我国发布了"慢性乙型肝炎防治指南(2022年版)"^[14]，进一步降低了慢性乙型肝炎的治疗标准，约94%患者符合该指南的治疗标准，是目前"全治但除外"(treat all except…)策略中治疗标准最低的指南(图2)，已接近"全治"(treat all)策略。

印度于2018年开始实施国家病毒性肝炎控制计划，实施对慢性乙型肝炎全部免费治疗^[15]。2022年11月美国乙型肝炎基金会Gish建议对HBV DNA阳性慢性乙型肝炎全治。2017年乌兹别克斯坦批准预防传染病计划，以提高乙型肝炎和丙型肝炎诊断率，并于2019年12月至2020年12月开展项目试点，对全人群检测HBsAg和抗-HCV，HBsAg阳性患者检测人类免疫缺陷病毒和肌酸酐，HBsAg阳性、人类免疫缺陷病毒阴性、肾功能正常患者，应用替诺夫韦酯(tenofovir disoproxil fumarate, TDF)治疗12个月并免费随访；对所有人类免疫缺陷病毒阳性患者转诊至专科医院治疗^[16]。

因此，全治策略可分为：

（1） HBV DNA阳性者全治；

（2） HBsAg阳性者全治；

（3）检测并治疗所有HBsAg阳性患者。

关于慢性乙型肝炎治疗，目前主要的争议是：真正HBeAg阳性慢性HBV感染(既往称免疫耐受期)和真正HBeAg阴性HBV感染(既往称免疫控制期或非活动期)是否需要治疗。

对这些慢性HBV感染者主张不治疗的理由是：

（1）发生HCC风险低^[17,18]；

（2）抗病毒疗效差^[19]；

（3）对治疗依从性差^[20]；

（4）可随访监测，当符合治疗标准时再治疗^[21]。

对这些慢性HBV感染者主张治疗的理由是：

（1）发生HCC风险低是由于随访时间短、样本量小。如果扩大样本并延长随访时间，这些患者发生HCC的风险较高。Yang等^[22]和Chen等^[23]对中国台湾7个城镇11 893例男性随访10年，HBsAg和HBeAg双阳性者的累计HCC发病率较HBsAg和HBeAg均阴性者高109倍。

Chu等^[24,25]随访240例免疫控制期期患者17年，累计肝炎再活动的发生率为15%，每年再活动发生率为2.2%；累计肝硬化发生率为12.6%，每年肝硬化发生率为0.5%。Choi等^[26]的一项历史队列研究表明，未治疗的免疫控制期患者的HCC累计发生率显著高于治疗的免疫活动期患者。

既往认为免疫耐受期患者仅有轻度肝组织病理学改变^[27]，无免疫介导的肝损伤，不建议抗病毒治疗。但最近的证据表明，免疫耐受期患者有明显的肝组织病理学改变^[28]；有HBV特异性T淋巴细胞应答^[29]；有HBV DNA整合和克隆肝细胞扩增^[30]。

（2）对真正免疫耐受期和免疫控制期患者治疗是有效的。Lim等^[31]报告，抗病毒治疗可降低免疫耐受期患者的HCC发病率。多项研究^{[32,33,34,35,36,37,38,39,40,41]}表明，用聚乙二醇干扰素(pegylated interferon, PEG-IFN )治疗免疫控制期患者，48周时治疗组HBsAg清除率显著高于未治疗组(表2)。

Hsu等^[42]对HBV DNA >2 000 IU/ml、轻度肝酶升高的慢性乙型肝炎患者随机分为2组，一组用TDF治疗，另一组用安慰剂，干预3年，前后有肝活检患者共计119例，TDF组64例，安慰剂组55例，与基线HBV DNA整合数比较，TDF组减少3.28倍，安慰剂组减少1.81倍，两组差异有统计学意义(P = 0.037)，提示抗病毒治疗可减少HBV DNA整合，可降低致HCC风险。

（3）慢性HBV感染者对随访监测的依从性差。Spradling等^[43]对美国2 338例慢性乙型肝炎患者随访7年，每年ALT至少检测1次者占78%，每年检测HBV DNA 1次和未检测者占62.5%，提示随访监测的依从性差，有可能错过治疗良机^[44]。同时，监测费用显著高于治疗费用，不符合成本效益比。

（4）对免疫耐受期患者治疗符合成本效益比^[45,46]。

（5）治疗即预防，可减少HBV传播和社会歧视^[15,47]。

基于WHO提出到"2030年消除病毒性肝炎公共卫生危害"的目标，即新发感染率下降90%，死亡率下降65%，诊断率达到90%，治疗率达到80%；现行口服抗病毒药物价格便宜，可及性高，安全性良好，长期治疗未发现耐药(如替诺福韦酯)或耐药发生率很低(如恩替卡韦)；人类免疫缺陷病毒和丙型肝炎病毒感染全治策略的成功经验，为慢性乙型肝炎"全治"("treat all")策略提供了充分依据。

对慢性乙型肝炎患者全治，可以减少多次到医院随访监测，降低远高于治疗的监测费用，同时还可避免因随访监测依从性差而错失治疗良机；及早抗病毒治疗可显著抑制HBV DNA水平，从而减少肝硬化、肝失代偿和HCC等的发生率和死亡率；病毒水平下降还可预防HBV传播(包括母婴传播)和减少社会歧视，有利于患者的身心健康。同时，"全治"("treat all")策略符合成本效益比，有助于早日实现WHO提出的"到2030年消除病毒性肝炎公共卫生危害"的宏伟目标。

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