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.

[[[expert-person]]]

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。

参考文献

[1]SarinSK, KumarM, LauGK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update[J]. Hepatol Int, 2016, 10(1): 1-98. DOI: 10.1007/s12072-015-9675-4.

[2]TerraultNA, LokASF, McMahonBJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance[J]. Hepatology, 2018, 67(4): 1560-1599. DOI: 10.1002/hep.29800.

[3]European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67(2):370-398. DOI: 10.1016/j.jhep.2017.03.021.

[4]WongRJ, KaufmanHW, NilesJK, et al. Simplifying treatment criteria in chronic hepatitis B: reducing barriers to elimination[J]. Clin Infect Dis, 2023, 76(3):e791-e800. DOI: 10.1093/cid/ciac385.

[5]SinnDH, KimSE, KimBK, et al. The risk of hepatocellular carcinoma among chronic hepatitis B virus-infected patients outside current treatment criteria[J]. J Viral Hepat, 2019, 26(12):1465-1472. DOI: 10.1111/jvh.13185.

[6]JengWJ, LokAS. Should treatment indications for chronic hepatitis B be expanded?[J]. Clin Gastroenterol Hepatol, 2021, 19(10):2006-2014. DOI: 10.1016/j.cgh.2020.04.091.

[7]McNaughtonAL, LemoineM, van RensburgC, et al. Extending treatment eligibility for chronic hepatitis B virus infection[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(3):146-147. DOI: 10.1038/s41575-020-00398-x.

[8]FanP, LiLQ, ChenEQ. The urgency to expand the antiviral indications of general chronic hepatitis B patients[J]. Front Med (Lausanne), 2023, 10:1165891. DOI: 10.3389/fmed.2023.1165891.

[9]SuF, JacobsonIM. Chronic hepatitis B: treat all who are viremic[J]? Clin Liver Dis, 2023, 27(4):791-808. DOI: 10.1016/j.cld.2023.06.001.

[10]DieterichD, GrahamC, WangS, et al. It is time for a simplified approach to hepatitis B elimination[J]. Gastro Hep Advances, 2023, 2(2):209-218. DOI: 10.1016/j.gastha.2022.10.004.

[11]World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. Geneva, 2024.

[12]World Health Organization. Launch of new hepatitis B guidelines at APASL 2024. 2024. https://www.who.int/news-room/events/detail/2024/03/30/default-calendar/launch-of-new-hepatitis-b-guidelines-at-apasl(accessed April 6th 2024).

[13]ChenJ, LauG. HBV "viral elimination" in the Asia-Pacific region: current status and challenges[J]. Clin Liver Dis (Hoboken), 2024, 23(1): e0132. DOI: 10.1097/CLD.0000000000000132.

[14]中华医学会肝病学分会,中华医学会感染病学分会. 慢性乙型肝炎防治指南（2022年版）[J]. 中华肝脏病杂志,2022,30(12)：1309-1331.DOI:10.3760/cma.j.cn501113-20221204-00607.

[15]JindalA, SarinSK. Hepatitis B: "treat all" or "treat select"[J]. Hepatol Int, 2023, 17(1):38-41. DOI: 10.1007/s12072-022-10441-5.

[16]MusabaevE.Simplified test and treat protocols for population level screening and elimination of hepatitis B and hepatitis C in Uzbekistan[J]. J Hepatol, 2021, 75:S642-S643.

[17]ChuCM, HungSJ, LinJ, et al. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels[J]. Am J Med, 2004, 116(12):829-834. DOI: 10.1016/j.amjmed.2003.12.040.

[18]ChuCM, LiawYF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up[J]. Hepatology, 2007, 45(5):1187-1192. DOI: 10.1002/hep.21612.

[19]ChanHLY, ChanCK, HuiAJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA[J]. Gastroenterology, 2014, 146:1240-1248. DOI: 10.1053/j.gastro.2014.01.044.

[20]FordN, ScourseR, LemoineM, et al. Adherence to nucleos(t)ide analogue therapies for chronic hepatitis B infection: a systematic review and meta-analysis[J]. Hepatol Commun, 2018, 2(10):1160-1167. DOI: 10.1002/hep4.1247.

[21]LiuJ, YangHI, LeeMH, et al. Serum levels of hepatitis B surface antigen and DNA can predict inactive carriers with low risk of disease progression[J]. Hepatology, 2016, 64(2):381-389. DOI: 10.1002/hep.28552.

[22]YangHI, LuSN, LiawYF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma[J]. N Engl J Med, 2002, 347(3):168-174. DOI: 10.1056/NEJMoa013215.

[23]ChenCJ, YangHI, YouSL. Hepatitis B e antigen and the risk of hepatocellular carcinoma[J]. N Engl J Med, 2002, 347(21):1721-1722. DOI: 10.1056/NEJM200211213472119.

[24]ChuCM, HungSJ, LinJ, et al. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels[J]. Am J Med, 2004, 116(12):829-834. DOI: 10.1016/j.amjmed.2003.12.040.

[25]ChuCM, Spontaneous relapse of hepatitis in inactive HBsAg carriers[J]. Hepatol Int, 2007, 1(2):311-315. DOI: 10.1007/s12072-007-9002-9.

[26]ChoiGH, KimGA, ChoiJ, et al. High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation[J]. Aliment Pharmacol Ther, 2019, 50(2):215-226. DOI: 10.1111/apt.15311.

[27]AndreaniT, SerfatyL, MohandD, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome[J]. Clin Gastroenterol Hepatol, 2007 ,5(5): 636-641. DOI: 10.1016/j.cgh.2007.01.005.

[28]SetoWK,LaiC, IpPPC, et al. A large population histology study showing the lack of association between ALT elevation and significant fibrosis in chronic hepatitis B[J]. PLoS One, 2012, 7(2):e32622. DOI: 10.1371/journal.pone.0032622.

[29]KennedyPT, SandalovaE, JoJ, et al. Preserved Tcell function in children and young adults with immune-tolerant chronic hepatitis B[J]. Gastroenterology, 2012, 143(3):637-645. DOI: 10.1053/j.gastro.2012.06.009.

[30]MasonWS, GillUS, LitwinS, et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant[J]. Gastroenterology, 2016, 151(5):986-998.e4. DOI: 10.1053/j.gastro.2016.07.012.

[31]LimUS. Gray zone of hepatitis B virus infection[J]. Saudi J Gastroenterol, 2024, 30(2):76-78. DOI: 10.4103/sjg.sjg_279_23.

[32]CaoZ, LiuYL, MaLN, et al. A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha[J]. Hepatol (Baltimore Md), 2017, 66(4):1058-1066. DOI: 10.1002/hep.29213.

[33]ShiL, ZhouG, SunD. Prediction of response in patients with low serum HBsAg level chronic hepatitis B receiving peginterferon-a-2a after nucleos(t)ide analogues treatment[J]. J Pract Hepatol, 2018, 21(4):565-568. DOI: 10.3969/j.issn.1672-5069.2018.04.020.

[34]Lim SGLG, Dan YY, Lee YM, et al. HBsAg loss in inactive chronic hepatitis B carriers is dependent on level of HBsAg and interferon response: a randomized control trial. AASLD 2019, Abstracts (oral196).

[35]ZengQL, YuZJ, ShangJ, et al. Short-term peginterferon-induced high functional cure rate in inactive chronic hepatitis B virus carriers with low surface antigen levels[J]. Open Forum Infect Dis, 2020, 7(6):ofaa208. DOI: 10.1093/ofid/ofaa208.

[36]ZhaoH, ChenL, LinQ, et al. The efficacy of short-term treatment with peg-interferon-a for inactive hepatitis B surface antigen carriers with extremely low HBsAg levels[J]. Chin Hepatol, 2020, 25(9):3. DOI: 10.3969/j.issn.1008-1704.2020.09.013.

[37]ChenX, ZhaoW, SunY, et al. Value of baseline HBsAg quantification in predicting the clinical effect of pegylated interferona-2b in treatment of chronic hepatitis B[J]. J Clin Hepatol ,2020, 36(8):1723-1726. DOI: 10.3969/j.issn.1001-5256.2020.08.009.

[38]ChenXB, LiuFF, ShuFL, et al. Peginterferon alfa-2b combined with tenofovir disoproxil fumarate induced high clinical cure rate in inactive chronic hepatitis B virus carriers[J]. Clin Res Hepatol Gastroenterol, 2021, 45(5):101723. DOI: 10.1016/j.clinre.2021.101723.

[39]WuF, LuR, LiuY, et al. Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers[J]. Liver Int, 2021, 41(9):2032-2045. DOI: 10.1111/liv.14897.

[40]HuangY, QiM, LiaoC, et al. Analysis of the efficacy and safety of pegylated interferon- 2b treatment in inactive hepatitis B surface antigen carriers[J]. Infect Dis Ther, 2021, 10(4):2323-2331. DOI: 10.1007/s40121-021-00511-w.

[41]SongAX, LinX, LuJF, et al. Pegylated interferon treatment for the effective clearance of hepatitis B surface antigen in inactive HBsAg carriers: a meta-analysis[J]. Front Immunol, 2021, 12:779347. DOI: 10.3389/fimmu.2021.779347.

[42]HsuYC, SuriV, NguyenMH, et al. Inhibition of viral replication reduces transcriptionally active distinct hepatitis B virus integrations with implications on host gene dysregulation[J]. Gastroenterology, 2022, 162(4):1160-1170.e1. DOI: 10.1053/j.gastro.2021.12.286.

[43]SpradlingPR, XingJ, RuppLB, et al. Infrequent clinical assessment of chronic hepatitis B patients in United States general healthcare settings[J]. Clin Infect Dis, 2016, 63(9):1205-1208. DOI: 10.1093/cid/ciw516.

[44]PremkumarM, ChawlaYK. Should we treat immune tolerant chronic hepatitis B? Lessons from Asia[J]. J Clin Exp Hepatol, 2022, 12(1):144-154. DOI: 10.1016/j.jceh.2021.08.023.

[45]EnriquezAD,CampbellMS,ReddyKR. Cost-effectiveness of suppressing hepatitis B virus DNA in immune tolerant patients to prevent hepatocellular carcinoma and cirrhosis[J].Aliment Pharmacol Ther, 2007, 26(3):383-391. DOI: 10.1111/j.1365-2036.2007.03382.x.

[46]KimHL, KimGA, ParkJA, et al. Cost-effectiveness of antiviral treatment in adult patients with immune-tolerant phase chronic hepatitis B[J]. Gut, 2021, 70(11):2172-2182. DOI: 10.1136/gutjnl-2020-321309.

[47]Perez-MolinaJA, Cancio-SuárezMR, MorenoSantiago. Is it time for treatment as prevention of chronic hepatitis B? [J]. Pathogens, 2023, 12(9):1137. DOI: 10.3390/pathogens12091137.