不同HBeAg状态慢性乙型肝炎患者停用核苷(酸)类似物后肝炎复发致慢加急性肝衰竭的病情转归差异分析

沈佳聪; 李小鹏; 程晓宇; 车媛梅; 雷弯; 周观林; 张伦理

doi:10.3969/j.issn.1001-5256.2022.01.013

不同HBeAg状态慢性乙型肝炎患者停用核苷(酸)类似物后肝炎复发致慢加急性肝衰竭的病情转归差异分析

DOI: 10.3969/j.issn.1001-5256.2022.01.013

1.
浙江省绍兴市人民医院感染科，浙江绍兴 312000
2.
南昌大学第一附属医院感染性疾病诊疗中心，江西省肝细胞再生医学重点实验室，南昌 330006
3.
南昌大学第一附属医院科技处，南昌 330006
4.
江西省赣州市第五人民医院肝病科，江西赣州 341099

基金项目:

江西省卫健委科技计划(指导性计划)项目 (202140689);

江西省科技厅计划项目 (20212BAG70022);

南昌大学教改课题 (NCUJGLX-2020-166-162)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：沈佳聪、李小鹏、张伦理负责课题设计，资料分析，撰写论文；程晓宇、车媛梅、雷弯参与收集数据，修改论文；周观林、张伦理负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
周观林，zgl99085@126.com

张伦理，lunliz@126.com

作者说明：沈佳聪和李小鹏同为第一作者

计量
- 文章访问数: 802
- HTML全文浏览量: 95
- PDF下载量: 69
- 被引次数: 0
出版历程
- 收稿日期: 2021-09-28
- 录用日期: 2021-12-01
- 出版日期: 2022-01-20

Prognosis of acute-on-chronic liver failure caused by hepatitis recurrence after withdrawal of nucleos(t)ide analogues in chronic hepatitis B patients with different HBeAg status

1.
Department of Infectious Diseases, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, China
2.
Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Key Laboratory of Liver Regeneration of Jiangxi Province, Nanchang 330006, China
3.
Department of Science and Technology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
4.
Department of Hepatology, Ganzhou Fifth People's Hospital, Ganzhou, Jiangxi 341099, China

Research funding:

Science and Technology Plan (guiding plan) Project of Jiangxi Provincial Health Commission (202140689);

Science and Technology Plan Project of Jiangxi Provincial (20212BAG70022);

Teaching Reform Project of Nanchang University (NCUJGLX-2020-166-162)

摘要

摘要: 目的探讨HBeAg阳性与HBeAg阴性慢性乙型肝炎(CHB)患者停用核苷(酸)类似物(NUC)抗病毒治疗后肝炎复发致HBV相关慢加急性肝衰竭(HBV-ACLF)的临床病情转归的差异及可能的原因。方法选取2017年1月—2018年12月于南昌大学第一附属医院收治的108例停用NUC后致HBV-ACLF的CHB患者。根据HBeAg状态分为HBeAg阳性组(n=57)和HBeAg阴性组(n=51)，分析比较两组患者性别、年龄、临床表现、体征和入院时TBil、DBil、ALT、AST、PT、活化部分PT(APTT)、PT/INR、HBV DNA定量检测结果，以及并发症(肝性脑病、肝肾综合征、自发性腹膜炎等)情况、HBV-ACLF病情转归差异。同时，选取48例持续NUC抗病毒治疗＞2年且HBV DNA＜20 IU/mL的CHB患者，收集并检测其血清HBV pgRNA水平，探讨影响停药时不同HBeAg状态患者HBV-ACLF预后差异的可能原因。符合正态分布的计量资料两组间比较采用两独立样本t检验；不符合正态分布的计量资料两组间比较采用Kruskal-Wallis H检验。计数资料两组间比较采用χ²检验。结果在108例停药复发HBV-ACLF患者中，HBeAg阳性组好转率49.1%，HBeAg阴性组好转率74.5%。HBeAg阴性组的好转率高于HBeAg阳性组，差异有统计学意义(χ²=2.811，P=0.006)。HBeAg阳性组入院时HBV DNA水平明显高于HBeAg阴性组，差异有统计学意义(t=-3.138，P=0.002)。在48例长期NUC抗病毒治疗达到病毒学应答的CHB患者中，HBeAg阳性组HBV pgRNA载量明显高于HBeAg阴性组(H=2.814，P=0.049)。结论 HBeAg阴性CHB患者停用NUC抗病毒治疗后肝炎复发致HBV-ACLF的病情好转率高于HBeAg阳性患者。基线HBV pgRNA水平差异可能与不同HBeAg状态HBV-ACLF的病情转归存在差异有关。
- 肝炎，乙型，慢性 /
- 肝炎e抗原，乙型 /
- 慢加急性肝衰竭 /
- 核苷类 /
- 核苷酸类
Abstract: Objective To investigate the difference in the prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) caused by hepatitis recurrence after withdrawal of nucleos(t)ide analogues (NUC) and possible causes in HBeAg-positive versus HBeAg-negative chronic hepatitis B (CHB) patients. Methods A total of 108 CHB patients with HBV-ACLF caused by withdrawal of NUC who were admitted to The First Affiliated Hospital of Nanchang University from January 2017 to December 2018 were enrolled, and according to HBeAg status, these patients were divided into HBeAg-positive group with 57 patients and HBeAg-negative group with 51 patients. The two groups were compared in terms of sex, age, clinical manifestation, signs, levels of total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, prothrombin time, activated partial thromboplastin time, prothrombin time/international normalized ratio, and HBV DNA quantification on admission, complications (including hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis), and prognosis of HBV-ACLF. In addition, 48 CHB patients with continuous NUC antiviral therapy for > 2 years and HBV DNA < 20 IU/mL were enrolled, and the serum level of HBV pgRNA was measured to investigate the possible causes of the difference in the prognosis of HBV-ACLF between the patients with different HBeAg statuses. The two-independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data. Results For the 108 patients with HBV-ACLF caused by drug withdrawal and recurrence, the HBeAg-positive group had an improvement rate of 49.1% and the HBeAg-negative group had an improvement rate of 74.5%. The HBeAg-negative group had a significantly higher improvement rate than the HBeAg-positive group (χ²=2.811, P=0.006). The HBeAg-positive group had a significantly higher level of HBV DNA than the HBeAg-negative group on admission (t=-3.138, P=0.002). For the 48 CHB patients who achieved virologic response after long-term antiviral therapy, the HBeAg-positive group had a significantly higher HBV pgRNA load than the HBeAg-negative group (H=2.814, P=0.049). Conclusion Compared with the HBeAg-positive CHB patients, HBeAg-negative CHB patients have a significantly better improvement rate of HBV-ACLF caused by hepatitis recurrence after withdrawal of NUC antiviral therapy. The difference in baseline HBV pgRNA level may be associated with the difference in the prognosis of HBV-ACLF in patients with different HBeAg statuses.
- Hepatitis B, Chronic /
- Hepatitis B e Antigens /
- Acute-On-Chronic Liver Failure /
- Nucleosides /
- Nucleotides

HTML全文

表 1 两组患者一般资料比较

项目	HBeAg阳性组(n=57)	HBeAg阴性组(n=51)	统计值	P值
年龄(岁)	44.28±11.27	44.28±9.01	t=0.348	0.728
性别[例(%)]			χ²=0.260	0.610
男	51(89.5)	44(86.3)
女	6(10.5)	7(13.7)
合并肝硬化病史[例(%)]			χ²=2.149	0.143
是	20(35.1)	25(49.0)
否	37(64.9)	26(51.0)

下载: 导出CSV

表 2 两组患者病毒学、生化学指标比较

项目	HBeAg阳性组(n=57)	HBeAg阴性组(n=51)	统计值	P值
HBV DNA (log₁₀拷贝/mL)	5.3±1.8	4.2±1.9	t=-3.138	0.002
ALT (U/L)	327.7(80.5~1 500.6)	427.8(50.3~1 608.7)	H=0.001	0.999
AST (U/L)	361.9(160.8~405.8)	251.1(180.5~1 398.5)	H=-0.119	0.905
TBil (μmol/L)	292.3±109.6	285.2±117.7	t=-0.321	0.749
DBil (μmol/L)	198.5±79.2	190.0±68.6	t=-0.599	0.550
PT (s)	25.8±4.7	22.6±6.3	H=-1.335	0.185
APTT (s)	52.9±15.3	52.7±18.1	t=-0.061	0.951
INR	2.2±1.2	2.0±0.8	H=-1.262	0.210

下载: 导出CSV

表 3 不同临床转归患者入院时血清学指标比较

项目	生存/好转组(n=66)	死亡/恶化组(n=42)	统计值	P值
HBeAg(例)			χ²=2.811	0.006
阳性	28	29
阴性	38	13
HBeAg水平(PEI U/mL)	40.4±13.1	59.7±22.6	t=1.075	0.285
抗-HBe水平(PEI U/mL)	5.7±2.6	8.9±3.7	t=1.259	0.211
抗-HBc水平(U/mL)	9.2±2.2	8.8±2.1	t=-1.030	0.306

下载: 导出CSV

表 4 长期NUC治疗后不同HBeAg状态患者HBV pgRNA水平比较

项目	HBeAg阳性组(n=27)	HBeAg阴性组(n=21)	统计值	P值
男/女(例)	19/8	17/4	χ²=1.693	0.185
年龄(岁)	38.2±8.3	40.4±10.9	t=0.716	0.479
HBsAg (IU/mL)	3 247.7±501.9	3 324.7±817.9	t=0.746	0.885
HBV pgRNA(例)			χ²=3.137	0.077
阳性	26	16
阴性	1	5
HBV pgRNA载量(拷贝/mL)	2 995.0(827.8~5 970.0)	114.4(19.6~1 647.4)	H=2.814	0.049

下载: 导出CSV

参考文献(15)

[1]	ZHAO RH, SHI Y, ZHAO H, et al. Acute-on-chronic liver failure in chronic hepatitis B: An update[J]. Expert Rev Gastroenterol Hepatol, 2018, 12(4): 341-350. DOI: 10.1080/17474124.2018.1426459.
[2]	Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure(2018)[J]. J Clin Hepatol, 2019, 35(1): 38-44. DOI: 10.3969/j.issn.1001-5256.2019.01.007. 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 临床肝胆病杂志, 2019, 35(1): 38-44. DOI: 10.3969/j.issn.1001-5256.2019.01.007.
[3]	PETERSEN J, BUTI M. Considerations for the long-term treatment of chronic hepatitis B with nucleos(t)ide analogs[J]. Expert Rev Gastroenterol Hepatol, 2012, 6(6): 683-693; quiz 694. DOI: 10.1586/egh.12.52.
[4]	SHOUVAL D, LAI CL, CHANG TT, et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: The case for continuous antiviral therapy[J]. J Hepatol, 2009, 50(2): 289-295. DOI: 10.1016/j.jhep.2008.10.017.
[5]	HU GF, LI XP, WU ZP, et al. Clinical features of acute-on-chronic liver failure induced by withdrawal of nucleos (t) ide analogues[J]. J Clin Hepatol, 2017, 33(7): 1320-1323. DOI: 10.3969/j.issn.1001-5256.2017.07.023. 胡高飞, 李小鹏, 吴振平, 等. 停用核苷和核苷酸类药物抗HBV后诱发慢加急性肝衰竭的临床特征[J]. 临床肝胆病杂志, 2017, 33(7): 1320-1323. DOI: 10.3969/j.issn.1001-5256.2017.07.023.
[6]	TAN M, BHADORIA AS, CUI F, et al. Estimating the proportion of people with chronic hepatitis B virus infection eligible for hepatitis B antiviral treatment worldwide: A systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol, 2021, 6(2): 106-119. DOI: 10.1016/S2468-1253(20)30307-1.
[7]	SU TH, KAO JH. Improving clinical outcomes of chronic hepatitis B virus infection[J]. Expert Rev Gastroenterol Hepatol, 2015, 9(2): 141-154. DOI: 10.1586/17474124.2015.960398.
[8]	GUO W, LI WN, NING Q. Definition and natural history of severe hepatitis B[J]. J Pract Hepatol, 2016, 19(3): 264-265. DOI: 10.3969/j.issn.1672-5069.2016.03.003. 郭威, 李维纳, 宁琴. 乙型肝炎重症化的概念及自然史[J]. 实用肝脏病杂志, 2016, 19(3): 264-265. DOI: 10.3969/j.issn.1672-5069.2016.03.003.
[9]	YU Y, WANG J, LI G, et al. Nucleos(t)ide analogue interruption: Alternative approach to intrahepatic set point for spontaneous control of HBV replication?[J]. J Hepatol, 2018, 68(3): 609-610. DOI: 10.1016/j.jhep.2017.09.026.
[10]	LIU JY, DANG DJ, LU ZN, et al. Clinical observation on Tenofovir Disoproxil treating the poor effect of Lamivudine resistance combined with Adefovir Dipivoxil[J. China Med Herald, 2020, 17(15): 127-130. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202015034.htm 刘军英, 党殿杰, 路振宇, 等. 替诺福韦酯治疗拉米夫定耐药联合阿德福韦酯效果不佳的临床观察[J]. 中国医药导报, 2020, 17(15): 127-130. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202015034.htm
[11]	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.
[12]	MAK LY, SETO WK, FUNG J, et al. Novel developments of hepatitis B: Treatment goals, agents and monitoring tools[J]. Expert Rev Clin Pharmacol, 2019, 12(2): 109-120. DOI: 10.1080/17512433.2019.1567327.
[13]	CAI Y, PAN L, LIN B, et al. Relationship between Treg/Th17 balance and changes in HBeAg among HBeAg-positive chronic hepatitis B patients receiving entecavir therapy[J]. Int J Virol, 2020, 27(5): 407-411. DOI: 10.3760/cma.j.issn.1673-4092.2020.05.013. 蔡云, 潘良, 林斌, 等. 恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者外周血Treg/Th17平衡与HBeAg的变化[J]. 国际病毒学杂志, 2020, 27(5): 407-411. DOI: 10.3760/cma.j.issn.1673-4092.2020.05.013.
[14]	BIAN DD, ZHENG SJ. Role of serum hepatitis B virus RNA quantification in guiding antiviral therapy for chronic hepatitis B[J]. J Clin Hepatol, 2020, 36(8): 1838-1841. DOI: 10.3969/j.issn.1001-5256.2020.08.035. 卞丹丹, 郑素军. 血清HBV RNA定量在指导慢性乙型肝炎抗病毒治疗过程中的作用[J]. 临床肝胆病杂志, 2020, 36(8): 1838-1841. DOI: 10.3969/j.issn.1001-5256.2020.08.035.
[15]	LIU BX, ZHANG LL, ZHANG WF. Changes of hepatitis B core antigen-specific cytotoxic T lymphocytes in chronic hepatitis B patients during antiviral treatment and relapse after withdrawal of treatment[J]. Chin J Infect Dis, 2016, 34(8): 480-484. DOI: 10.3760/cma.j.issn.1000-6680.2016.08.006. 刘碧霞, 张伦理, 张文峰. 慢性乙型肝炎患者抗病毒治疗与停药复发后体内乙型肝炎核心抗原特异性T淋巴细胞变化[J]. 中华传染病杂志, 2016, 34(8): 480-484. DOI: 10.3760/cma.j.issn.1000-6680.2016.08.006.