加用干扰素治疗核苷(酸)类似物经治的HBsAg低水平的慢性乙型肝炎患者获得临床治愈的效果观察

牛卫理; 王永素; 吴清山; 张林; 张中琴; 杨小军; 朱先彬; 肖文琴; 纪明平

doi:10.3969/j.issn.1001-5256.2021.08.010

加用干扰素治疗核苷(酸)类似物经治的HBsAg低水平的慢性乙型肝炎患者获得临床治愈的效果观察

DOI: 10.3969/j.issn.1001-5256.2021.08.010

1.
鹤壁市第三人民医院感染科，河南鹤壁 458000
2.
鹤壁市人民医院感染科，河南鹤壁 458030

基金项目:

佑安肝病感染病专科医疗联盟科研专项 (LM202010);

北京医卫健康公益基金会医学科学研究基金资助项目 (YWJKJJHKYJJ-B17715)

利益冲突声明: 本研究不存在研究者、伦理委员会成员、观察对象以及与公开研究成果有关的利益冲突。

作者贡献声明: 牛卫理、王永素、张林负责课题设计，资料分析，撰写论文；吴清山、张中琴、杨小军、朱先彬、肖文琴、纪明平参与收集和分析数据。

详细信息

通信作者:
牛卫理，nwl_0082004@sina.com

中图分类号: R512.62
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出版历程
- 收稿日期: 2021-01-15
- 录用日期: 2021-02-19
- 出版日期: 2021-08-20

A clinical study of clinical cure after the addition of interferon therapy in chronic hepatitis B patients with low-level HBsAg previously treated with nucleos(t)ide analogues

1.
Department of Infectious Diseases, Hebi Third People's Hospital, Hebi, Henan 458000, China
2.
Department of Infectious Diseases, Hebi People's Hospital, Hebi, Henan 458030, China

Research funding:

Special Research Fund of YouAn Medical Alliance for the Liver and Infectious Diseases (LM202010);

Medical Science Research Fund Project of Beijing Medical and Health Foundation (YWJKJJHKYJJ-B17715)

摘要

摘要: 目的探讨核苷(酸)类似物(NAs)经治的慢性乙型肝炎患者获得临床治愈的优势人群，为临床医生追求乙型肝炎临床治愈提供更多的方法。方法选取2017年10月—2019年10月在鹤壁市第三人民医院接受NAs治疗且HBsAg低水平的慢性乙型肝炎患者42例作为研究对象，分为联合治疗组(A组, n=22)和NAs单药治疗组(B组, n=20)。A组采用NAs联合聚乙二醇干扰素(PEG-IFN)抗病毒治疗48周，部分患者24周停用PEG-IFN继续NAs单药治疗。B组仅采用NAs抗病毒治疗，两组均观察至48周，通过乙型肝炎五项定量检测评估疗效。计量资料两组间比较采用t检验；计数资料两组间比较采用Fisher精确检验。影响因素相关分析采用logistic回归法。结果 48周治疗终点A组的HBsAg清除率(45.5%)和HBsAg血清学转换率(31.8%)远高于B组(均为0)(P值均＜0.01)；HBsAg＜1000 IU/ml、＜500 IU/ml、＜100 IU/ml、＜10 IU/ml人群的HBsAg清除率分别为52.6%、61.5%、66.7%和100%；HBsAg在500~1000 IU/ml、100~500 IU/ml、10~100 IU/ml、＜10 IU/ml区间人群的HBsAg清除率分别为33.3%、50%、40%和100%。4例基线HBsAg＜10 IU/ml者(占联合治疗组18.2%)，联合治疗12周取得临床治愈，观察至48周时2例抗-HBs＞100 IU/ml，2例抗-HBs＞1000 IU/ml。HBsAg清除的多因素logsitic回归分析结果显示：开始联合治疗时的年龄对HBsAg清除存在影响(OR=0.877，95%CI：0.781~0.985，P=0.026)，HBsAg阴转患者的年龄集中在36~49(44.20±4.49)岁；基线HBsAg水平也对HBsAg清除存在影响(OR=0.996，95%CI：0.992~1.000，P=0.050)。结论加用IFN治疗核苷(酸)类似物经治的HBsAg低水平的慢性乙型肝炎患者能够显著提高临床治愈率，年龄越小、HBsAg水平越低，联合治疗时间越短，相较于NAs用药时间、种类，年龄和基线HBsAg水平更关键。
- 乙型肝炎, 慢性 /
- 干扰素类 /
- 核苷类 /
- 核苷酸类 /
- 治疗学
Abstract: Objective To investigate the population with an advantage of clinical cure previously treated with nucleos(t)ide analogues (NAs), and to provide more methods for clinicians in pursuing the clinical cure of hepatitis B. Methods A total of 42 chronic hepatitis B patients with low-level HBsAg who received NAs treatment in Hebi Third People's Hospital from October 2017 to October 2019 were enrolled as subjects and divided into combination treatment group (group A) and NA monotherapy group (group B). The 22 subjects in group A were treated with NAs combined with PEG-IFN antiviral therapy for 48 weeks, and some patients withdrew from PEG-IFN after 24 weeks and continued to receive NA monotherapy, while the 20 subjects in group B received NA antiviral therapy alone. Both groups were observed till week 48, and the five makers for hepatitis B were measured to evaluate clinical outcome. The t-test was used for comparison of continuous data between two groups, and the Fisher's exact test was used for comparison of categorical data between two groups; a multivariate logistic regression analysis was used to perform a multivariate analysis. Results Compared with group B at the 48-week treatment endpoint, group A had significantly higher HBsAg clearance rate (45.5% vs 0, P < 0.01) and HBsAg seroconversion rate (31.8% vs 0, P < 0.01). The population with HBsAg < 1000 IU/ml, < 500 IU/ml, < 100 IU/ml, and < 10 IU/ml had an HBsAg clearance rate of 52.6%, 61.5%, 66.7%, and 100%, respectively, and the population with an HBsAg level of 500-1000 IU/ml, 100-500 IU/ml, 10-100 IU/ml, and < 10 IU/ml had an HBsAg clearance rate of 33.3%, 50%, 40%, and 100%, respectively. The 4 patients with baseline HBsAg < 10 IU/ml (accounting for 18.2% in group A) achieved clinical cure at week 12 of combined treatment, and after observation to week 48, 2 patients had an anti-HBs level of > 100 IU/ml and 2 had an anti-HBs level of > 1000 IU/ml. The multivariate logistic regression analysis of HBsAg clearance showed that age at the initiation of combined treatment affected HBsAg clearance (odds ratio [OR]=0.877, 95% confidence interval [CI]: 0.781-0.985, P=0.026), and most of the patients with HBsAg clearance had an age of 36-49 (44.20±4.49) years; baseline HBsAg level also had an impact on HBsAg clearance (OR=0.996, 95% CI: 0.992-1.000, P=0.050). Conclusion The addition of interferon therapy in chronic hepatitis B patients with low-level HBsAg previously treated with NAs can significantly improve the clinical cure rate. The younger the age and the lower the HBsAg level, the shorter the duration of combined treatment. Age and baseline HBsAg level are more important than the duration and type of NA medication.
- Hepatitis B, Chronic /
- Interferons /
- Nucleosides /
- Nucleotides /
- Therapeutics

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表 1 基线时两组患者的临床资料对比

组别	例数	年龄 (岁)	男性 [例(%)]	BMI (kg/m²)	NAs治疗时间 (年)	HBsAg (log₁₀ IU/ml)
总体	42	47.43±7.10	35(83.33)	25.20±3.01	5.91±3.17	2.12±0.93
A组	22	44.82±6.20	19(86.36)	24.69±3.33	5.72±4.00	2.02±1.06
B组	20	47.70±5.11	16(80.00)	25.39±2.66	6.10±1.97	2.23±0.78
统计值		t=-1.634		t=-0.746	t=-0.388	t=-0.744
P值		0.110	0.691	0.460	0.701	0.462

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表 2 两组不同时间节点临床治愈结果比较

组别	例数	24周		48周
组别	例数	HBsAg清除[例(%)]	抗-HBs阳性[例(%)]	HBsAg清除[例(%)]	抗-HBs阳性[例(%)]
A组	22	6(27.3)	5(22.7)	10(45.5)	7(31.8)
B组	20	0	0	0	0
P值		0.022	0.049	0.001	0.009

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表 3 联合治疗基线值不同HBsAg定量节点的患者在12、24和48周获得临床治愈率比较

HBsAg节点	例数	12周治愈率	24周治愈率	48周治愈率
＜1000 IU/ml	19	26.3%(5/19)	31.6%(6/19)	52.6%(10/19)
＜500 IU/ml	13	38.5%(5/13)	46.2%(6/13)	61.5%(8/13)
＜100 IU/ml	9	55.6%(5/9)	55.6%(5/9)	66.7%(6/9)
＜10 IU/ml	4	100%(4/4)	100%(4/4)	100%(4/4)

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表 4 联合治疗基线值不同HBsAg定量区间的患者在12、24和48周获得临床治愈率比较

HBsAg区间	例数	12周治愈率	24周治愈率	48周治愈率
500~1000 IU/ml	6	0(0/6)	0(0/6)	33.3%(2/6)
100~500 IU/ml	4	0(0/4)	25.0%(1/4)	50.0%(2/4)
10~100 IU/ml	5	20.0%(1/5)	20.0%(1/5)	40.0%(2/5)
＜10 IU/ml	4	100%(4/4)	100%(4/4)	100%(4/4)

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参考文献(17)

[1]	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.
[2]	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.
[3]	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.
[4]	GAO ZL. Hot and difficult points of functional cure (clinical cure) of chronic hepatitis B[J]. Mod Digest Interv, 2019, 24(9): 949-951. DOI: 10.3969/j.issn.1672-2159.2019.09.001. 高志良. 慢性乙型肝炎功能性治愈(临床治愈)的热点和难点[J]. 现代消化及介入诊疗, 2019, 24(9): 949-951. DOI: 10.3969/j.issn.1672-2159.2019.09.001.
[5]	Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B: A 2015 update[J]. J Clin Hepatol, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002. 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(2015年更新版)[J]. 临床肝胆病杂志, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002.
[6]	WU Y, LIU Y, LU J, et al. Durability of interferon-induced hepatitis B surface antigen seroclearance[J]. Clin Gastroenterol Hepatol, 2020, 18(2): 514-516.e2. DOI: 10.1016/j.cgh.2019.04.020.
[7]	MARCELIN P, FLISIAK R, TRINH H, et al. Long term treatment with tenofbvir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials[J]. Hepatol, 2014, 60: 313a-314a. DOI: 10.1002/hep.27059.
[8]	LAMPERTICO P, VIGANÒ M, DI COSTANZO GG, et al. Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B[J]. Gut, 2013, 62(2): 290-298. DOI: 10.1136/gutjnl-2011-301430.
[9]	CHELBI-ALIX MK, WIETZERBIN J. Interferon, a growing cytokine family: 50 years of interferon research[J]. Biochimie, 2007, 89(6-7): 713-718. DOI: 10.1016/j.biochi.2007.05.001.
[10]	ZHANG S, SUN J, XING HC. Progress on clinical cure of chronic hepatitis B[J/CD]. Chin J Liver Dis (Electronic Version), 2018, 10(4): 54-58. DOI: 10.3969/j.issn.1674-7380.2018.04.009. 张珊, 孙静, 邢卉春. 慢性乙型肝炎临床治愈研究进展[J/CD]. 中国肝脏病杂志(电子版), 2018, 10(4): 54-58. DOI: 10.3969/j.issn.1674-7380.2018.04.009.
[11]	HAGIWARA S, NISHIDA N, KUDO M. Antiviral therapy for chronic hepatitis B: Combination of nucleoside analogs and interferon[J]. World J Hepatol, 2015, 7(23): 2427-2431. DOI: 10.4254/wjh.v7.i23.2427.
[12]	TAN AT, HOANG LT, CHIN D, et al. Reduction of HBV replication prolongs the early immunological response to IFNα therapy[J]. J Hepatol, 2014, 60(1): 54-61. DOI: 10.1016/j.jhep.2013.08.020.
[13]	NING Q, HAN M, SUN Y, et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial)[J]. J Hepatol, 2014, 61(4): 777-784. DOI: 10.1016/j.jhep.2014.05.044.
[14]	HU P, SHANG J, ZHANG WH, et al. HBsAg loss with Pegylated-interferon alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: New Switch study[J]. Chin J Hepatol, 2018, 26(10): 756-764. DOI: 10.3760/cma.j.issn.1007-3418.2018.10.005. 胡鹏, 尚佳, 张文宏, 等. 核苷(酸)类似物治疗部分应答的乙型肝炎患者通过聚乙二醇干扰素α-2a治疗获得HBsAg消失: New Switch研究[J]. 中华肝脏病杂志, 2018, 26(10): 756-764. DOI: 10.3760/cma.j.issn.1007-3418.2018.10.005.
[15]	LIN B, HA NB, LIU A, et al. Low incidence of hepatitis B e antigen seroconversion in patients treated with oral nucleos(t)ides in routine practice[J]. J Gastroenterol Hepatol, 2013, 28(5): 855-860. DOI: 10.1111/jgh.12108.
[16]	ZOUTENDIJK R, HANSEN BE, van VUUREN AJ, et al. Serum HBsAg decline during long-term potent nucleos(t)ide analogue therapy for chronic hepatitis B and prediction of HBsAg loss[J]. J Infect Dis, 2011, 204(3): 415-418. DOI: 10.1093/infdis/jir282.
[17]	CHEN XY, LIU YL. How patients with hepatitis B get really recovered[J]. J Prac Hepatol, 2016, 19(3): 257-260. DOI: 10.3969/j.issn.1672-5069.2016.03.001. 陈新月, 刘雅立. 慢性乙型肝炎患者如何获得临床治愈[J]. 实用肝脏病杂志, 2016, 19(3): 257-260. DOI: 10.3969/j.issn.1672-5069.2016.03.001.