慢性乙型肝炎免疫耐受期的抗病毒治疗: 系统综述

李彦霖; 王妍; 周颖琼; 杨雪亮; 陈娜; 陈方尧; 刘小静

doi:10.3969/j.issn.1001-5256.2021.06.013

慢性乙型肝炎免疫耐受期的抗病毒治疗: 系统综述

DOI: 10.3969/j.issn.1001-5256.2021.06.013

李彦霖^1a,
王妍^2a,
周颖琼^2a,
杨雪亮^1b,
陈娜^1c,
陈方尧^2b, ,,
刘小静^1d, ,

1a.
西安交通大学第一附属医院肿瘤内科，西安 710061
1b.
西安交通大学第一附属医院营养科，西安 710061
1c.
西安交通大学第一附属医院康复科，西安 710061
1d.
西安交通大学第一附属医院感染科，西安 710061
2a.
西安交通大学医学部第一临床医学院，西安 710061
2b.
西安交通大学医学部公共卫生学院卫生统计教研室，西安 710061

基金项目:

国家艾滋病和病毒性肝炎等重大传染病防治科技专项课题 (2017ZX10203201);

国家自然科学基金青年项目 (81700559)

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：李彦霖负责课题设计，论文撰写和修改; 王妍、周颖琼负责文献筛选，数据提取，质量评价及论文撰写; 杨雪亮、陈娜负责指导撰写文章; 陈方尧负责拟定写作思路，指导撰写文章并最后定稿; 刘小静负责课题设计，指导撰写文章并最后定稿。

详细信息

作者简介:
李彦霖(1998—)，男，主要从事慢性肝病的诊断与治疗研究

通信作者:
陈方尧，chenfy@mail.xjtu.edu.cn

刘小静，xiaojing406@163.com

中图分类号: R512.62
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- 被引次数: 0
出版历程
- 收稿日期: 2020-10-31
- 录用日期: 2021-01-05
- 出版日期: 2021-06-20

Antiviral therapy for patients with chronic hepatitis B in the immune-tolerant phase: A systematic review

Yanlin LI^1a,
Yan WANG^2a,
Yingqiong ZHOU^2a,
Xueliang YANG^1b,
Na CHEN^1c,
Fangyao CHEN^{2b
, ,},
Xiaojing LIU^{1d
, ,}

1a.
Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
1b.
Department of Nutrition, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
1c.
Department of Rehabilitation Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
1d.
Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
2a.
The First Clinical Medical College, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
2b.
Division of Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China

摘要

摘要: 目的系统评价抗病毒治疗在免疫耐受期慢性乙型肝炎(CHB)患者中的有效性和安全性。方法检索PubMed、EMBASE、Cochrane library、中国知网、万方数据库自数据库建立至2020年9月抗病毒药物治疗免疫耐受期CHB的临床试验，进行质量评价后提取相关效应量并进行系统评价。主要结局指标为HBV DNA阴转率。结果共纳入9项研究821例患者。8项研究报道了治疗组中HBV DNA阴转率，6项研究中治疗组HBV DNA阴转率均超过60%，明显高于未治疗患者(0~29.1%)，且联合治疗组优于单药治疗组。但在长期观察中，病毒学复发较常见。8项研究报告了HBeAg血清学转换，仅2项IFNα治疗儿童的研究中治疗组血清学转换率超过20%，高于未治疗组。HBsAg阴转出现在2项使用IFNα治疗的研究中，无研究观察到HBsAg血清学转换。1项研究报告了肝硬化和肝细胞癌(HCC)的风险，显示抗病毒治疗可降低患者肝硬化和HCC的风险。不良反应发生率在核苷(酸)类似物治疗中为4.1%~13.0%，在IFNα治疗中达到了100%，严重不良反应少见。结论免疫耐受期CHB患者给予抗病毒后绝大多数可出现满意的病毒学应答，但停药后易复发，且血清学转换率低。抗病毒治疗安全性良好。目前证据表明，对于该类患者如无明确疾病进展可动态观察。
- 乙型肝炎，慢性 /
- 免疫耐受 /
- 治疗学 /
- 系统评价
Abstract: Objective Objective To systematically evaluate the efficacy and safety of antiviral therapy in patients with chronic hepatitis B (CHB) in the immune-tolerant phase. Methods PubMed, Embase, Cochrane Library, CNKI, and Wanfang Data were searched for clinical trials of antiviral therapy for CHB patients in the immune-tolerant phase published up to September 2020. Related data were extracted after quality assessment for systematic review. HBV DNA clearance rate was the primary outcome. Results A total of 9 studies involving 821 patients were included. Eight studies reported HBV DNA clearance rate in the treatment group, among which 6 studies had an HBV DNA clearance rate of > 60%, which was significantly higher than that in the untreated patients (0%-29.1%), and the combination therapy group had a better clearance rate than the monotherapy group. However, virologic recurrence was more common in the long term. Eight studies reported HBeAg seroconversion, and only 2 studies of the treatment of children with interferon-α (IFN-α) reported a seroconversion rate of > 20% in the treatment group, which was higher than that in the untreated group. HBsAg clearance was observed in 2 studies of IFN-α treatment, while HBsAg seroconversion was not observed. One study reported the risk of liver cirrhosis and hepatocellular carcinoma (HCC) and showed that antiviral therapy could reduce the risk of liver cirrhosis and HCC in patients. The incidence rate of adverse events ranged from 4.1%-13.0% in the treatment with nucleos(t)ide analogues and reached 100% in the treatment with IFN-α, and serious adverse events were rare. Conclusion The majority of CHB patients in the immune-tolerant phase show satisfactory virologic response after antiviral therapy, but they tend to experience recurrence after drug withdrawal and have a low seroconversion rate. Antiviral therapy has good safety. Current evidence suggests that such patients can be dynamically observed if there is no clear evidence for disease progression.
- Hepatitis B, Chronic /
- Immune Tolerance /
- Therapeutics /
- Systematic Review

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图 1 文献筛选流程及结果

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表 1 纳入研究的基本特征

纳入研究	国家	例数(男/女)	抗病毒策略	年龄(岁)	HBeAg阳性(例)	ALT(U/ml)	HBV DNA(U/ml)	治疗时间(周)	随访时间(周)	结局指标	研究类型
Artan^[17](2005)	土耳其	13/4 3/3	拉米夫定未治疗	10.6 9	17 6	37.3 30.7	NR NR	140 -	164 164	①③	NRCT
Chan^[18](2014)	多国	31/33 31/31	替诺福韦替诺福韦+恩曲他滨	33 33	63 62	26.9 26.2	8.42 log₁₀ 8.40 log₁₀	192 192	192 192	①②③④	RCT
Chang^[11](2017)	韩国	46/41 195/202	核苷(酸)类似物未治疗	43.2 41.5	87 397	26.9 26.8	7.3 log₁₀ 7.4 log₁₀	NR NR	200 285	①③⑥⑦	队列研究
Feld^[13](2019)	加拿大	15/13	恩替卡韦+PEG-IFNα	37.2	28	21	8.2 log₁₀	48	96	①②③④⑤	单臂NRCT
Lau^[19](2002)	中国	12/20 15/17	泛昔洛韦未治疗	29 30	32 32	38 22	9.04 log₁₀ 9.05 log₁₀	26 -	78 78	③	NRCT
Leung^[20](2014)	中国	9/7 9/5 6/10	替比夫定替诺福韦替比夫定+替诺福韦	28.0 27.3 28.9	16 14 16	31.6 33.9 33.3	8.98 log₁₀ 8.78 log₁₀ 8.89 log₁₀	12 12 12	12 12 12	①②	RCT
Poddar^[21](2013)	印度	24/4 27/7	拉米夫定+IFNα 未治疗	5.92 7.82	28 34	46.60 50.62	NR NR	52 -	21.14 28.70	①③④	NRCT
Wu^[22](2019)	中国	26/34 24/37	替诺福韦+替比夫定替诺福韦	33 32	60 61	32.1 31.2	6.5 log₁₀ 7.1 log₁₀	48 48	48 48	①③⑤	RCT
Zhu^[23](2018)	中国	30/16 13/10	IFNα/IFN+拉米夫定未治疗	7 8	46 23	45 48	9.95×10⁷ 1.72×10⁸	72 -	96 96	①③④⑤	RCT
注：NR，未报告; RCT，随机对照研究; NRCT，非随机对照研究; 结局指标中①HBV DNA阴转率; ②HBeAg阴转率; ③HBeAg血清学转换率; ④HBsAg阴转率; ⑤HBsAg血清学转换率; ⑥HCC发生率; ⑦肝硬化发生率。

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表 2 纳入研究中对免疫耐受期人群的描述

纳入研究	免疫耐受期人群描述
Artan^[17](2005)	HBsAg(+)＞6月，HBeAg(+)，抗-HBs(-)，抗-HBe(-)，HBV DNA＞10⁵拷贝/ml，ALT＜45 U/L
Chan^[18](2014)	HBsAg(+)，HBV DNA＞1.7×10⁷ IU/ml，ALT＜43 U/L(男)/34 U/L(女)
Chang^[11](2017)	HBeAg(+)，HBV DNA＞2000 IU/ml，ALT＜40 U/L
Feld^[13](2019)	HBsAg(+)，HBeAg(+)＞12周，HBV DNA＞10⁷ IU/ml＞12周，ALT＜45 U/L(男)/30 U/L(女)
Lau^[19](2002)	HBsAg(+)＞6月，HBV DNA＞4000 Meq/ml，ALT＜1.5倍正常值上限
Leung^[20](2014)	HBsAg(+)＞6月，HBeAg(+)＞3月，HBV DNA＞10⁷ log₁₀拷贝/ml，ALT＜正常值上限，抗-HBc(-)
Poddar^[21](2013)	HBsAg(+)＞6月，HBeAg(+)，HBV DNA＞10⁷拷贝/ml，ALT＜2倍正常值上限
Wu^[22](2019)	HBsAg(+)＞6月，HBeAg(+)，抗-HBe(-)，HBV DNA＞10⁷ IU/ml，ALT＜40 U/L(男)/30 U/L(女)
Zhu^[23](2018)	HBsAg(+)＞6月，HBeAg(+)，抗-HBe(-)，HBV DNA＞10⁷ IU/ml，ALT＜60 U/L

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表 3 纳入研究的偏倚风险评价结果

纳入研究	序列产生	分配隐藏	盲法	结局数据完整性	选择性结局报告	其他偏倚来源
Artan^[17](2005)	-	-	不清楚	是	不清楚	无
Chan^[18](2014)	不清楚	不清楚	是	是	不清楚	无
Feld^[13](2019)	-	-	否	是	无	无
Lau^[19](2002)	-	-	不清楚	是	无	无
Leung^[20](2014)	不清楚	不清楚	不清楚	是	无	无
Poddar^[21](2013)	-	-	不清楚	是	不清楚	无
Wu^[22](2019)	不清楚	-	否	是	无	无
Zhu^[23](2018)	随机数字表法	-	否	是	无	无
注：-，未予评估。文献11为回顾性队列研究，未列入表中，偏倚风险评价结果如下，非暴露队列选择(★)，暴露资料的确定(★)，证实初始无观察结局(★)，考虑可比性(★ ★)，结局评价(★)，随访时限不得分，随访充足性(★)，总计7★。

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表 4 抗病毒治疗的有效性分析

纳入研究	纳入人群	抗病毒方案	治疗持续时间(周)	HBV DNA阴转率(%)	HBeAg阴转率(%)	HBeAg血清学转换率(%)	HBsAg阴转率(%)	HBsAg血清学转换率(%)	HCC发生风险(HR)	肝硬化发生风险(HR)
Artan^[17](2005)	儿童	拉米夫定vs非治疗	150	5.9 vs 0(P=1.000)	NR	0 vs 0	NR	NR	NR	NR
Chan^[18](2014)	成人	替诺福韦+恩曲他滨vs替诺福韦	192	75.8 vs 54.7(P=0.016)	1.6 vs 6.3(P=0.365)	0 vs 4.8(P=0.244)	0 vs 0	NR	NR	NR
Chang^[11](2017)	成人	核苷(酸)类似物vs非治疗	NR	70.4 vs 29.1(P＜0.001)¹⁾	NR	18.3 vs 14.4(P=0.106)	NR	NR	0.189(P=0.004)	0.347(P=0.036)
Feld^[13](2019)	成人	恩替卡韦+ PEG-IFNα	48	93	3.57	3.57	0	0	NR	NR
Lau^[19](2002)	成人	泛昔洛韦vs非治疗	78	NR²⁾	NR	0 vs 0	NR	NR	NR	NR
Leung^[20](2014)	成人	替诺福韦+替比夫定vs替诺福韦vs替比夫定	12	6.25 vs 0 vs 0(P=1.000)³⁾(P=1.000)⁴⁾	6.25 vs 0 vs 0(P=1.000)³⁾(P=1.000)⁴⁾	NR	NR	NR	NR	NR
Poddar^[21](2013)	儿童	IFNα+拉米夫定vs非治疗	52	60.7⁵⁾	NR	39.3 vs 0(P＜0.001)	17.9 vs 0(P=0.036)	NR	NR	NR
Wu^[22](2019)	成人	替诺福韦+替比夫定vs替诺福韦	48	96.6 vs 85.2(P=0.028)	NR	8.3 vs 3.3(P=0.233)	NR	0 vs 0	NR	NR
Zhu^[23](2018)	儿童	IFNα/ IFNα+拉米夫定vs非治疗	72	67.39 vs 4.53(P＜0.001)	NR	21.74 vs 4.53(P=0.131)	19.75 vs 0(P=0.058)	0 vs 0	NR	NR
注：NR，未报告。1)在第48周时的HBV DNA阴转率; 2)文章提供了治疗过程中的HBV DNA水平变化图; 3)替诺福韦+替比夫定vs替诺福韦; 4)替诺福韦+替比夫定vs替比夫定; 5)治疗组中的HBV DNA阴转率。

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表 5 抗病毒治疗的长期有效性分析

纳入研究	研究人群	抗病毒方案	随访时间(周)	治疗时间(周)	治疗结束后随访	治疗中病毒学复发	治疗结束后HBV DNA水平变化	治疗结束后HBeAg转换率变化(%)
Artan^[17](2005)	儿童	拉米夫定	150	150	否	是	NR	NR
Chan^[18](2014)	成人	替诺福韦+恩曲他滨vs替诺福韦	192	192	否	否	NR	NR
Chang^[11](2017)	成人	核苷(酸)类似物	285	NR	否	否	NR	NR
Feld^[13](2019)	成人	恩替卡韦+ PEG-IFNα	96	48	是	否	上升	稳定
Lau^[19](2002)	成人	泛昔洛韦	78	26	是	否	上升	稳定
Zhu^[23](2018)	儿童	IFNα/ IFNα+拉米夫定	96	72	是	否	下降	上升
注：NR，未报告。

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表 6 抗病毒治疗的安全性评价

纳入研究	抗病毒策略	药物相关不良反应发生率	药物相关严重不良反应发生率(%)
Chan^[18](2014)	替诺福韦+恩曲他滨vs替诺福韦	8.1% vs 6.3%(P=0.742)	0
Feld^[13](2019)	恩替卡韦+PEG-IFNα	33%	4.8
Leung^[20](2014)	替诺福韦+替比夫定vs替诺福韦vs替比夫定	25% vs 14.3% vs 0(P=0.657¹⁾; P=0.101²⁾)	0
Poddar^[21](2013)	IFNα+拉米夫定vs非治疗	100%	0
Wu^[22](2019)	替诺福韦+比夫定vs替诺福韦	5.0% vs 3.3% (P=0.66)	0
Zhu^[23](2018)	IFNα/IFNα+拉米夫定vs非治疗	NR	0
注：1)替诺福韦+替比夫定vs替诺福韦组; 2)替诺福韦+替比夫定vs替比夫定组。NR，未报告。

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