关于《扩大慢性乙型肝炎抗病毒治疗的专家意见》的几点思考

刘智泓; 梁携儿; 侯金林

doi:10.3969/j.issn.1001-5256.2023.01.002

关于《扩大慢性乙型肝炎抗病毒治疗的专家意见》的几点思考

DOI: 10.3969/j.issn.1001-5256.2023.01.002

刘智泓^{1, 2},
梁携儿^{1, 2},
侯金林^{1, 2, ,}

1.
南方医科大学南方医院感染内科暨肝病中心，广州 510515
2.
广东省肝脏疾病研究所，广州 510515

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：刘智泓负责查找文献，撰写文稿；梁携儿负责审阅文稿；侯金林负责审阅文稿及最后定稿。

详细信息

通信作者:
侯金林，jlhousmu@163.com (ORCID: 0000-0001-8230-8583)

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出版历程
- 收稿日期: 2022-11-10
- 出版日期: 2023-01-20

Thoughts on expert opinion on expanding antiviral therapy for chronic hepatitis B

Zhihong LIU^{1, 2},
Xieer LIANG^{1, 2},
Jinlin HOU^{1, 2
, ,}

1.
Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
2.
Institutes of Liver Diseases Research of Guangdong Province, Guangzhou 510515, China

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Corresponding author: HOU Jinlin, jlhousmu@163.com (ORCID: 0000-0001-8230-8583)

摘要

摘要: 扩大抗病毒治疗是目前慢性乙型肝炎诊疗的新趋势，相关的研究证据值得学习和讨论。其中，降低启动抗病毒治疗的ALT阈值是扩大治疗中最重要的变化之一。ALT低水平升高或正常水平高值的慢性乙型肝炎患者仍具有更高的肝癌风险，因此需要进一步干预。现有核苷(酸) 类似物(NUC)对该部分患者的病毒学抑制和纤维化改善有效，而降低ALT阈值则将对治疗后的生化学应答提出了更高的要求。另一方面，虽然经治低病毒血症(LLV)的机制和定义仍未充分明确，但进一步干预LLV是在临床实践中优化患者管理的重要策略。换用另一种强效的NUC可能会进一步提高LLV患者病毒应答率，而联合干扰素或其他新靶点药物将是未来治疗LLV的重要研究方向。
- 慢性乙型肝炎 /
- 丙氨酸转氨酶 /
- 低病毒血症
Abstract: Expanding antiviral therapy is currently the new trend for the diagnosis and treatment of chronic hepatitis B, and related research evidence should be studied and discussed. Reducing the threshold of alanine aminotransferase (ALT) for initiating antiviral therapy is one of the most important changes during the expansion of antiviral therapy. Chronic hepatitis B patients with a low-level increase in ALT or a high normal level of ALT still have a higher risk of liver cancer and thus require further intervention. At present, nucleos(t)ide analogues show a certain clinical effect in some patients in terms of virological inhibition and improvement in fibrosis, while reducing ALT threshold places higher requirements for biochemical response after treatment. In addition, although the mechanism and definition of low-level viremia (LLV) after treatment remain unclear, further intervention of LLV is an important strategy for optimizing patient management in clinical practice. Switch to another potent nucleos(t)ide analogue may improve the virologic response rate of patients with LLV, and nucleos(t)ide analogues combined with interferon or other new targeted drugs will be an important research direction for the treatment of LLV in the future.
- Hepatitis B, Chronic /
- Alanine Transaminase /
- Low Level Viremia

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图 1 一种开展临床研究、评价临床证据的思维框架

Figure 1. A thinking framework for conducting clinical research and evaluating clinical evidence

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表 1 不同地区CHB诊疗指南中对于非肝硬化患者启动抗病毒治疗的推荐意见(经原文作者同意后转载，有修订^[4])

Table 1. Recommendations for initiating antiviral therapy in patients with non-cirrhosis in the regional guidelines for the diagnosis and treatment of chronic hepatitis B(reproduced with the consent of the original author, with revision^[4])

诊疗指南	定义人群	血清HBV DNA水平	血清ALT水平	肝脏疾病严重程度		推荐意见(根据原文翻译)
诊疗指南	定义人群	血清HBV DNA水平	血清ALT水平	无创纤维化诊断	肝组织活检	推荐意见(根据原文翻译)
EASL 2017^[5]	慢性肝炎(HBeAg^+/-)	> 20 000 IU/mL	> 2×ULN (80 U/mL)	无论肝纤维化程度如何		启动治疗
	慢性肝炎(HBeAg^+/-)	> 2000 IU/mL	> ULN (40 U/mL)	需要至少存在中度的炎症坏死或纤维化		启动治疗
	慢性病毒感染	> 2000 IU/mL	持续正常	可用于临床决策	至少中度纤维化	可能需要治疗
	HBeAg(+)的慢性感染(免疫耐受期)	高病毒载量	持续正常	无论组织学严重程度如何		若年龄 > 30岁或具有肝硬化/HCC家族史，可以予以治疗
AASLD 2018^[6]	免疫活动的HBeAg(+) CHB	> 20 000 IU/mL	ALT > 2×ULN (男性：35 U/L，女性：25 U/L) 或存在显著的组织学改变			治疗
	免疫活动的HBeAg(-) CHB	> 2000 IU/mL	ALT > 2×ULN (男性：35 U/L，女性：25 U/L) 或存在显著的组织学改变
	其他免疫活动人群	符合相应的界值	1~2×ULN	需要考虑肝脏疾病的严重程度
	其他免疫活动人群	低于相应的界值	1~2×ULN			若年龄 > 40岁，或具有HCC家族史，既往治疗史或肝外表现则需要治疗
	免疫耐受期	≥1 000 000 IU/mL	ALT正常		存在显著炎症坏死或纤维化	治疗
APASL 2015^[7]	HBeAg(+)	> 20 000 IU/mL	> 2×ULN	需要肝活检或无创诊断		若3个月内未发生血清学转换则启动治疗
	HBeAg(-)	> 2000 IU/mL	> 2×ULN	需要肝活检或无创诊断		若3个月内未发生血清学转换则启动治疗
	其他慢性HBV感染人群	低于定义的界限		若无创诊断结果提示显著纤维化且ALT持续升高，年龄 > 35岁或具有肝硬化/HCC家族史		若肝活检提示中至重度的坏死性炎症或显著纤维化及以上则需要启动抗病毒治疗
中国2019^[2]	慢性HBV感染	阳性	ALT持续 > ULN			建议抗病毒治疗
中国2019^[2]	慢性HBV感染	阳性	ALT正常	肝组织提示明显的炎症或纤维化；或存在肝硬化/HCC家族史且年龄 > 30岁；或HBV相关肝外表现则建议抗病毒治疗
注：EASL，欧洲肝病学会；AASLD，美国肝病学会；APASL，亚太肝病学会。

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参考文献(39)

[1]	Chinese Society of Hepatology, Chinese Medical Association. Expert opinion on expanding anti-HBV treatment for chronic hepatitis B[J]. Chin J Hepatol, 2022, 30(2): 131-136. DOI: 10.3760/cma.j.cn501113-20220209-00060. 中华医学会肝病学分会. 扩大慢性乙型肝炎抗病毒治疗的专家意见[J]. 中华肝脏病杂志, 2022, 30(2): 131-136. DOI: 10.3760/cma.j.cn501113-20220209-00060.
[2]	Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[3]	KWO PY, COHEN SM, LIM JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries[J]. Am J Gastroenterol, 2017, 112(1): 18-35. DOI: 10.1038/ajg.2016.517.
[4]	LIU LZ, SUN J, HOU J, et al. Improvements in the management of chronic hepatitis B virus infection[J]. Expert Rev Gastroenterol Hepatol, 2018, 12(11): 1153-1166. DOI: 10.1080/17474124.2018.1530986.
[5]	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.
[6]	TERRAULT NA, LOK A, MCMAHON BJ, 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.
[7]	SARIN SK, KUMAR M, LAU GK, 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.
[8]	TERRAULT NA, BZOWEJ NH, CHANG KM, et al. AASLD guidelines for treatment of chronic hepatitis B[J]. Hepatology, 2016, 63(1): 261-283. DOI: 10.1002/hep.28156.
[9]	ZHUANG H. Should the threshold of alanine aminotransferase level for initiation of treatment for chronic hepatitis B be modified?[J]. Chin J Hepatol, 2021, 29(9): 878-881. DOI: 10.3760/cma.j.cn501113-20210823-00419. 庄辉. 慢性乙型肝炎启动治疗的ALT阈值应否修订?[J]. 中华肝脏病杂志, 2021, 29(9): 878-881. DOI: 10.3760/cma.j.cn501113-20210823-00419.
[10]	LIAW YF, SUNG JJ, CHOW WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease[J]. N Engl J Med, 2004, 351(15): 1521-1531. DOI: 10.1056/NEJMoa033364.
[11]	MARCELLIN P, CHANG TT, LIM SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[J]. N Engl J Med, 2003, 348(9): 808-816. DOI: 10.1056/NEJMoa020681.
[12]	HADZIYANNIS SJ, TASSOPOULOS NC, HEATHCOTE EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B[J]. N Engl J Med, 2003, 348(9): 800-807. DOI: 10.1056/NEJMoa021812.
[13]	CHANG TT, GISH RG, DE MAN R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B[J]. N Engl J Med, 2006, 354(10): 1001-1010. DOI: 10.1056/NEJMoa051285.
[14]	MARCELLIN P, HEATHCOTE EJ, BUTI M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[J]. N Engl J Med, 2008, 359(23): 2442-2455. DOI: 10.1056/NEJMoa0802878.
[15]	HOU JL, GAO ZL, XIE Q, et al. Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial[J]. J Viral Hepat, 2015, 22(2): 85-93. DOI: 10.1111/jvh.12313.
[16]	BUTI M, GANE E, SETO WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial[J]. Lancet Gastroenterol Hepatol, 2016, 1(3): 196-206. DOI: 10.1016/S2468-1253(16)30107-8.
[17]	CHAN HL, FUNG S, SETO WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial[J]. Lancet Gastroenterol Hepatol, 2016, 1(3): 185-195. DOI: 10.1016/S2468-1253(16)30024-3.
[18]	CHAN HL, CHAN CK, HUI AJ, 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(5): 1240-1248. DOI: 10.1053/j.gastro.2014.01.044.
[19]	HSU YC, CHEN CY, CHANG IW, et al. Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial[J]. Lancet Infect Dis, 2021, 21(6): 823-833. DOI: 10.1016/S1473-3099(20)30692-7.
[20]	CHAN HL. Debate settled for elevated alanine aminotransferase in hepatitis B?[J]. Lancet Infect Dis, 2021, 21(6): 750-751. DOI: 10.1016/S1473-3099(20)30682-4.
[21]	LIU Z, JIN Q, ZHANG Y, et al. Randomised clinical trial: 48 weeks of treatment with tenofovir amibufenamide versus tenofovir disoproxil fumarate for patients with chronic hepatitis B[J]. Aliment Pharmacol Ther, 2021, 54(9): 1134-1149. DOI: 10.1111/apt.16611.
[22]	AGARWAL K, BRUNETTO M, SETO WK, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection[J]. J Hepatol, 2018, 68(4): 672-681. DOI: 10.1016/j.jhep.2017.11.039.
[23]	HOU J, NING Q, DUAN Z, et al. 3-year treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for chronic HBV infection in China[J]. J Clin Transl Hepatol, 2021, 9(3): 324-334. DOI: 10.14218/JCTH.2020.00145.
[24]	LIU Z, JIN Q, ZHANG Y, et al. 96-week treatment of tenofovir amibufenamide and tenofovir disoproxil fumarate in chronic hepatitis B patients[J]. J Clin Transl Hepatol, 2022. DOI: 10.14218/jcth.2022.00058.[Online anead of print]
[25]	KIM JH, SINN DH, KANG W, et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment[J]. Hepatology, 2017, 66(2): 335-343. DOI: 10.1002/hep.28916.
[26]	LU FM, FENG B, ZHENG SJ, et al. Current status of the research on low-level viremia in chronic hepatitis B patients receiving nucleos(t)ide analogues[J]. J Clin Hepatol, 2021, 37(6): 1268-1274. DOI: 10.3969/j.issn.1001-5256.2021.06.007. 鲁凤民, 封波, 郑素军, 等. 核苷(酸)类似物经治的慢性乙型肝炎患者低病毒血症的研究现状[J]. 临床肝胆病杂志, 2021, 37(6): 1268-1274. DOI: 10.3969/j.issn.1001-5256.2021.06.007.
[27]	HOU JL, ZHAO W, LEE C, et al. Outcomes of long-term treatment of chronic HBV infection with entecavir or other agents from a randomized trial in 24 countries[J]. Clin Gastroenterol Hepatol, 2020, 18(2): 457-467. e21. DOI: 10.1016/j.cgh.2019.07.010.
[28]	ZIMMERMAN T. 3-year efficacy and safety of tenofovir alafenamide compared with tenofovir disoproxil fumarate in HBeAg-negative and -positive patients with chronic hepatitis B[G]. 2018: 1-3. E-poster on AASLD The liver meeting 2018.
[29]	ZHANG Q, PENG H, LIU X, et al. Chronic hepatitis B infection with low level viremia correlates with the progression of the liver disease[J]. J Clin Transl Hepatol, 2021, 9(6): 850-859. DOI: 10.14218/JCTH.2021.00046.
[30]	LEE SB, JEONG J, PARK JH, et al. Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir[J]. Clin Mol Hepatol, 2020, 26(3): 364-375. DOI: 10.3350/cmh.2020.0012.
[31]	LI ZB, LI L, NIU XX, et al. Switching from entecavir to tenofovir alafenamide for chronic hepatitis B patients with low-level viraemia[J]. Liver Int, 2021, 41(6): 1254-1264. DOI: 10.1111/liv.14786.
[32]	SUN Y, WU X, ZHOU J, et al. Persistent low level of hepatitis B virus promotes fibrosis progression during therapy[J]. Clin Gastroenterol Hepatol, 2020, 18(11): 2582-2591. e6. DOI: 10.1016/j.cgh.2020.03.001.
[33]	LU J, ZHANG C, HE P, et al. Risk factors for very low-level viremia in patients with chronic hepatitis B virus infection: A single-center retrospective study[J]. Liver Res, 2022, 6(1): 39-44. DOI: 10.1016/j.livres.2022.02.001.
[34]	CHEN H, FU JJ, LI L, et al. Influencing factors for low-level viremia in chronic hepatitis B patients treated with long-term entecavir antiviral therapy[J]. J Clin Hepatol, 2021, 37(3): 556-559. DOI: 10.3969/j.issn.1001-5256.2021.03.011. 陈贺, 傅涓涓, 李丽, 等. 长期恩替卡韦经治慢性乙型肝炎患者低病毒血症的相关影响因素[J]. 临床肝胆病杂志, 2021, 37(3): 556-559. DOI: 10.3969/j.issn.1001-5256.2021.03.011.
[35]	PALLIER C, RODRIGUEZ C, BRILLET R, et al. Complex dynamics of hepatitis B virus resistance to adefovir[J]. Hepatology, 2009, 49(1): 50-59. DOI: 10.1002/hep.22634.
[36]	ZHANG H, HU Y, WU M, et al. Randomised clinical trial: safety, efficacy and pharmacokinetics of HS-10234 versus tenofovir for the treatment of chronic hepatitis B infection[J]. Aliment Pharmacol Ther, 2021, 53(2): 243-252. DOI: 10.1111/apt.16196.
[37]	CHEN XY, REN S, LU J, et al. Combination therapy in HBeAg-negative chronic hepatitis B patients with low-level viremia to nucleos (tide) analogues[J]. J Hepatol, 2022, 77: S844. DOI: 10.1016/S0168-8278(22)01984-5.
[38]	SULKOWSKI MS, AGARWAL K, MA X, et al. Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection[J]. J Hepatol, 2022, 77(5): 1265-1275. DOI: 10.1016/j.jhep.2022.05.027.
[39]	YUEN MF, AGARWAL K, MA X, et al. Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection[J]. J Hepatol, 2022, 77(3): 642-652. DOI: 10.1016/j.jhep.2022.04.005.