HBV DNA阴性、HBsAg阳性的乙型肝炎肝硬化代偿期患者需要抗病毒治疗吗？

苏丽; 徐京杭; 刘耀敏; 张国民; 郭昱廷; 王贵强

doi:10.3969/j.issn.1001-5256.2023.01.006

HBV DNA阴性、HBsAg阳性的乙型肝炎肝硬化代偿期患者需要抗病毒治疗吗？

DOI: 10.3969/j.issn.1001-5256.2023.01.006

苏丽^{1, 2},
徐京杭¹,
刘耀敏²,
张国民²,
郭昱廷³,
王贵强^1, ,

1.
北京大学第一医院感染疾病科，北京 100034
2.
承德医学院附属医院感染疾病科，河北承德 067000
3.
临汾市第三人民医院肝病一科，山西临汾 041000

基金项目:

北京市科学技术委员会肝病创新药物早期临床试验与关键技术 (Z191100007619037)

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：苏丽负责设计相关话题研究，实施研究，起草文章；王贵强、徐京杭对论文研究提出相关建设性意见及对知识性内容批评性审阅；刘耀敏、张国民、郭昱廷对文章的知识性内容批评性审阅。

详细信息

通信作者:
王贵强，John131212@sina.com (ORCID: 0000-0002-0317-7536)

计量
- 文章访问数: 2349
- HTML全文浏览量: 1347
- PDF下载量: 220
- 被引次数: 0
出版历程
- 收稿日期: 2022-08-21
- 出版日期: 2023-01-20

Do HBV DNA-negative HBsAg-positive patients with compensated hepatitis B cirrhosis need antiviral therapy?

1.
Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
2.
Department of Infectious Diseases, The Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, China
3.
First Department of Hepatology, The Third People's Hospital of Linfen City, Linfen, Shanxi 041000, China

Research funding:

Early Clinical Trials and Key Technologies of Innovative Drugs for Liver Diseases by Beijing Municipal Science and Technology Commission (Z191100007619037)

More Information

Corresponding author: WANG Guiqiang, John131212@sina.com (ORCID: 0000-0002-0317-7536)

摘要

摘要: HBV感染为我国肝病的常见病因，随着慢性乙型肝炎(CHB)抗病毒治疗相关研究的不断进展，抗病毒适应证也在不断扩大。然而，CHB患者抗病毒治疗的适应证仍存在很多争议，尤其对于HBV阴性的患者。本文通过对HBV DNA检测的局限性、HBV阴性CHB患者病毒再激活风险、DNA阴性的乙型肝炎肝硬化代偿期人群病情进展风险、抗病毒疗效及抗病毒治疗经济效益五方面进行分析，提出对HBV阴性、HBsAg阳性的乙型肝炎肝硬化代偿期患者抗病毒治疗的必要性。
- 乙型肝炎病毒 /
- 肝硬化 /
- 治疗学
Abstract: Hepatitis B virus (HBV) infection is a common cause of liver disease in China, and with the continuous progress in the research on antiviral therapy for chronic hepatitis B, the indications for antiviral therapy are constantly expanding. However, there are still controversies over the indications for antiviral therapy in patients with chronic hepatitis B (CHB), especially those with negative HBV. By analyzing the limitations of HBV DNA detection, the risk of HBV reactivation in HBV-negative CHB patients, the risk of disease progression in the DNA-negative population with compensated hepatitis B cirrhosis, antiviral response, and the economic benefits of antiviral therapy, this article proposes the necessity of antiviral therapy for HBV-negative HBsAg-positive patients with compensated hepatitis B cirrhosis.
- Hepatitis B virus /
- Liver Cirrhosis /
- Therapeutics

HTML全文

参考文献(43)

[1]	Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study[J]. Lancet Gastroenterol Hepatol, 2018, 3(6): 383-403. DOI: 10.1016/S2468-1253(18)30056-6.
[2]	LIU J, LIANG W, JING W, et al. Countdown to 2030: eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97(3): 230-238. DOI: 10.2471/BLT.18.219469.
[3]	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.
[4]	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.
[5]	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.
[6]	ILOEJE UH, YANG HI, SU J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J]. Gastroenterology, 2006, 130(3): 678-686. DOI: 10.1053/j.gastro.2005.11.016.
[7]	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.
[8]	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.
[9]	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.
[10]	World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection[R]. Geneva: WHO, 2015.
[11]	ZHANG XM, HE CT, ZHANG CY, et al. The clinical significance of high-sensitive HBV DNA and HBsAg quantitative detection for chronic hepatitis B patients with low viral load[J]. Chin Hepatol, 2020, 25(11): 1153-1157. DOI: 10.14000/j.cnki.issn.1008-1704.2020.11.008. 张小曼, 何彩婷, 张纯瑜, 等. HBV DNA及HBsAg定量对低病毒载量慢性乙型肝炎的临床价值[J]. 肝脏, 2020, 25(11): 1153-1157. DOI: 10.14000/j.cnki.issn.1008-1704.2020.11.008.
[12]	LU JH, YANG L, ZHAO ZX, et al. Comparative study of high-sensitivity and conventional fluorescence quantitative PCR in the monitoring of antiviral efficacy in patients with chronic hepatitis B[J]. J Mol Diagn Ther, 2019, 11(5): 361-364. DOI: 10.3969/j.issn.1674-6929.2019.05.005. 卢建华, 杨莉, 赵召霞, 等. 高敏与普通荧光定量PCR技术在慢乙肝患者抗病毒疗效监测中的对比研究[J]. 分子诊断与治疗杂志, 2019, 11(5): 361-364. DOI: 10.3969/j.issn.1674-6929.2019.05.005.
[13]	The Hepatitis Group, Chinese Society of Hepatology, Chinese Medical Association; Chinese Journal of Hepatology. An expert consensus for the adjustment of treatment strategies in patients with chronic hepatitis B treated with non-first-line nucleos(t)ide analogues[J]. J Clin Hepatol, 2019, 35(6): 1212-1214. DOI: 10.3969/j.issn.1001-5256.2019.06.008. 中华医学会肝病学分会肝炎学组, 中华肝脏病杂志. 非一线核苷(酸)类似物经治慢性乙型肝炎患者治疗策略调整专家共识[J]. 临床肝胆病杂志, 2019, 35(6): 1212-1214. DOI: 10.3969/j.issn.1001-5256.2019.06.008.
[14]	LI J, SUN X, FANG J, et al. Analysis of intrahepatic total HBV DNA, cccDNA and serum HBsAg level in chronic hepatitis B patients with undetectable serum HBV DNA during oral antiviral therapy[J]. Clin Res Hepatol Gastroenterol, 2017, 41(6): 635-643. DOI: 10.1016/j.clinre.2017.03.004.
[15]	ZOULIM F. New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA[J]. J Hepatol, 2005, 42(3): 302-308. DOI: 10.1016/j.jhep.2004.12.015.
[16]	LARAS A, KOSKINAS J, DIMOU E, et al. Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients[J]. Hepatology, 2006, 44(3): 694-702. DOI: 10.1002/hep.21299.
[17]	NASSAL M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B[J]. Gut, 2015, 64(12): 1972-1984. DOI: 10.1136/gutjnl-2015-309809.
[18]	KUMAR R, PÉREZ-DEL-PULGAR S, TESTONI B, et al. Clinical relevance of the study of hepatitis B virus covalently closed circular DNA[J]. Liver Int, 2016, 36(Suppl 1): 72-77. DOI: 10.1111/liv.13001.
[19]	LOOMBA R, LIANG TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions[J]. Gastroenterology, 2017, 152(6): 1297-1309. DOI: 10.1053/j.gastro.2017.02.009.
[20]	PERRILLO RP, GISH R, FALCK-YTTER YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy[J]. Gastroenterology, 2015, 148(1): 221-244. e3. DOI: 10.1053/j.gastro.2014.10.038.
[21]	MOZESSOHN L, CHAN KK, FELD JJ, et al. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis[J]. J Viral Hepat, 2015, 22(10): 842-849. DOI: 10.1111/jvh.12402.
[22]	ANDERSON RT, CHOI H, LENZ O, et al. Association between seroclearance of hepatitis B surface antigen and long-term clinical outcomes of patients with chronic hepatitis B virus infection: systematic review and meta-analysis[J]. Clin Gastroenterol Hepatol, 2021, 19(3): 463-472. DOI: 10.1016/j.cgh.2020.05.041.
[23]	CHEN CJ, YANG HI, SU J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level[J]. JAMA, 2006, 295(1): 65-73. DOI: 10.1001/jama.295.1.65.
[24]	ILOEJE UH, YANG HI, JEN CL, et al. Risk and predictors of mortality associated with chronic hepatitis B infection[J]. Clin Gastroenterol Hepatol, 2007, 5(8): 921-931. DOI: 10.1016/j.cgh.2007.06.015.
[25]	CHEN JD, YANG HI, ILOEJE UH, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death[J]. Gastroenterology, 2010, 138(5): 1747-1754. DOI: 10.1053/j.gastro.2010.01.042.
[26]	TSENG TC, LIU CJ, YANG HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load[J]. Gastroenterology, 2012, 142(5): 1140-1149. e3; quiz e13-14. DOI: 10.1053/j.gastro.2012.02.007.
[27]	HUANG X, YAO L, DENG ZR, et al. Analysis of clinical characteristics of 481 patients with HBV-related cirrhosis with low viral load[J]. Chin J Hepatol, 2021, 29(3): 227-233. DOI: 10.3760/cma.j.cn501113-20200302-00081. 皇旭, 姚磊, 邓泽润, 等. 481例低病毒载量HBV相关肝硬化患者临床特征分析[J]. 中华肝脏病杂志, 2021, 29(3): 227-233. DOI: 10.3760/cma.j.cn501113-20200302-00081.
[28]	CHEN CH, LU SN, HUNG CH, et al. The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment[J]. J Hepatol, 2014, 61(3): 515-522. DOI: 10.1016/j.jhep.2014.04.029.
[29]	SETO WK, LIU K, WONG DK, et al. Patterns of hepatitis B surface antigen decline and HBV DNA suppression in Asian treatment-experienced chronic hepatitis B patients after three years of tenofovir treatment[J]. J Hepatol, 2013, 59(4): 709-716. DOI: 10.1016/j.jhep.2013.06.007.
[30]	CHEN JL, YUAN ZH. Influence of interferon and nucleos (t) ide analogues on HBV cccDNA and functional cure of chronic hepatitis B[J]. J Clin Hepatol, 2019, 35(6): 1181-1187. DOI: 10.3969/j.issn.1001-5256.2019.06.002. 陈捷亮, 袁正宏. 干扰素和核苷(酸)类似物治疗对HBV cccDNA的影响与慢性乙型肝炎的功能性治愈[J]. 临床肝胆病杂志, 2019, 35(6): 1181-1187. DOI: 10.3969/j.issn.1001-5256.2019.06.002.
[31]	WU FP, LI MX, WANG YK, et al. Dynamic changes of HBsAg and hepatitis B virus DNA in chronic hepatitis B patients with entecavir monotherapy for 5 years[J]. J Clin Hepatol, 2021, 37(5): 1047-1052. DOI: 10.3969/j.issn.1001-5256.2021.05.015. 吴凤萍, 李妙羡, 王怡恺, 等. 恩替卡韦单药治疗慢性乙型肝炎患者5年HBsAg与HBV DNA的动态变化[J]. 临床肝胆病杂志, 2021, 37(5): 1047-1052. DOI: 10.3969/j.issn.1001-5256.2021.05.015.
[32]	GONG WF, ZHONG JH, LU SD, et al. Effects of antiviral therapy on post-hepatectomy HBV reactivation and liver function in HBV DNA-negative patients with HBV-related hepatocellular carcinoma[J]. Oncotarget, 2017, 8(9): 15047-15056. DOI: 10.18632/oncotarget.14789.
[33]	ZHAO HD, CHEN LF, LIN QX, et al. The efficacy of short-term treatment with Peg-interferon α for inactive hepatitis B surface antigen carriers with extremely low HBsAg levels[J]. Chin Hepatol, 2020, 25(9): 937-939. DOI: 10.3969/j.issn.1008-1704.2020.09.013. 赵海东, 陈灵峰, 林巧欣, 等. 聚乙二醇干扰素α短期治疗HBsAg水平极低的非活动性HBsAg携带者的疗效观察[J]. 肝脏, 2020, 25(9): 937-939. DOI: 10.3969/j.issn.1008-1704.2020.09.013.
[34]	ZENG QL, YU ZJ, SHANG J, 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.
[35]	GAO XH, CHENG N, CAO JJ. Clinical cure in patients with hepatitis B cirrhosis treated with pegylated interferon α-2b: A case report[J]. J Clin Hepatol, 2020, 36(6): 1347-1348. DOI: 10.3969/j.issn.1001-5256.2020.06.031. 高晓红, 成妮, 曹姣姣. 聚乙二醇干扰素α-2b治疗乙型肝炎肝硬化实现临床治愈1例报告[J]. 临床肝胆病杂志, 2020, 36(6): 1347-1348. DOI: 10.3969/j.issn.1001-5256.2020.06.031.
[36]	World Health Organization. Global Hepatitis Report, 2017[R]. Geneva: WHO, 2017.
[37]	FATTOVICH G, BORTOLOTTI F, DONATO F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors[J]. J Hepatol, 2008, 48(2): 335-352. DOI: 10.1016/j.jhep.2007.11.011.
[38]	World Health Organization. Combating hepatitis B and C to reach elimination by 2030: Advocacy brief[R]. Geneva: WHO, 2016.
[39]	World Health Organization. Global health sector strategy on viral hepatitis, 2016-2021: Towards ending viral hepatitis[R]. Geneva: WHO, 2018.
[40]	FU SM, KANG GJ, TIAN X, et al. Analysis of the economic burden of hepatitis B related diseases and its influencing factors in Changchun City[J]. Chin Public Health Manage, 2021, 37(2): 172-175. DOI: 10.19568/j.cnki.23-1318.2021.02.0009. 付思美, 康国俊, 田鑫, 等. 长春市乙型肝炎相关疾病经济负担及其影响因素分析[J]. 中国公共卫生管理, 2021, 37(2): 172-175. DOI: 10.19568/j.cnki.23-1318.2021.02.0009.
[41]	LIANG S, ZHANG SX, MA QS, et al. Financial burden of hepatitis B-related diseases and factors influencing the costs in Shenzhen, China[J]. Chin J Epidemiol, 2010, 31(12): 1340-1345. DOI: 10.3760/cma.j.issn.0254-6450.2010.12.004. 梁森, 张顺祥, 马起山, 等. 深圳市乙型肝炎相关疾病经济负担及其影响因素分析[J]. 中华流行病学杂志, 2010, 31(12): 1340-1345. DOI: 10.3760/cma.j.issn.0254-6450.2010.12.004.
[42]	ZHOU Y, HE HQ, DENG X, et al. The economic burden of hepatitis B-related diseases in Zhejiang province[J]. Chin J Vacc Immun, 2019, 25(6): 669-674, 687. DOI: 1006-916X(2019)06-0669-07. 周洋, 何寒青, 邓璇, 等. 浙江省乙型病毒性肝炎相关疾病的经济负担[J]. 中国疫苗和免疫, 2019, 25(6): 669-674, 687. DOI: 1006-916X(2019)06-0669-07.
[43]	SHU Q, YAO ZR, WANG YH, et al. Stakeholder analysis of drug consumption policy[J]. Health Econom Res, 2019, 36(8): 8-9, 12. DOI: 10.14055/j.cnki.33-1056/f.2019.08.002. 舒茜, 姚峥嵘, 王艳翚, 等. 药品带量采购政策的利益相关者分析[J]. 卫生经济研究, 2019, 36(8): 8-9, 12. DOI: 10.14055/j.cnki.33-1056/f.2019.08.002.