抗病毒治疗适应证变化对提高慢性乙型肝炎治疗率的影响

王皓; 单姗; 尤红; 徐小元; 魏来; 侯金林; 庄辉; 孔媛媛; 贾继东; 中国消除乙肝临床研究平台(CR-HepB)研究组

doi:10.3969/j.issn.1001-5256.2022.06.011

抗病毒治疗适应证变化对提高慢性乙型肝炎治疗率的影响

DOI: 10.3969/j.issn.1001-5256.2022.06.011

1a.
首都医科大学附属北京友谊医院临床流行病学与循证医学研究室, 北京 100050
1b.
首都医科大学附属北京友谊医院肝病中心, 北京 100050
2.
北京大学第一医院感染疾病科, 北京 100034
3.
北京清华长庚医院肝胆胰内科, 北京 100044
4.
南方医科大学南方医院感染内科, 广州 510515
5.
北京大学医学部病原生物学系, 北京 100191

基金项目:

北京市科委项目 (Z191100007619037);

北京市医院管理局消化内科学科协同发展中心消化专项协作创新课题 (XXX0104);

北京市卫生健康委员会高层次公共卫生技术人才项目 (2022-3-018);

首都医科大学校培育基金 (PYZ21051)

伦理学声明：CR-HepB病例注册系统已经于2014年4月21日经由首都医科大学附属北京友谊医院医学伦理委员会批准，批号：BJFH2014033，并在ClinicalTrails.gov注册(注册号：NCT03108794)。

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：贾继东、尤红、孔媛媛对研究的思路或设计有关键贡献；所有作者均参与研究数据的获取、分析过程；王皓负责起草文章；贾继东、尤红、孔媛媛修改文章关键内容。

详细信息

通信作者:
孔媛媛, kongyy@ccmu.edu.cn

贾继东, jia_jd@ccmu.edu.cn

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出版历程
- 收稿日期: 2022-04-08
- 录用日期: 2022-05-12
- 出版日期: 2022-06-20

Effect of the change in antiviral therapy indication in increasing the treatment rate of chronic hepatitis B

Hao WANG^1a,
Shan SHAN^1b,
Hong YOU^1b,
Xiaoyuan XU²,
Lai WEI³,
Jinlin HOU⁴,
Hui ZHUANG⁵,
Yuanyuan KONG^{1a
, ,
,},
Jidong JIA^{1b
, ,
,},
China Registry of Hepatitis B (CR-HepB) Group

1a.
Department of Clinical Epidemiology and Evidence-based Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
1b.
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
2.
Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
3.
Department of Hepatology, Beijing Tsinghua Changgung Hospital, Beijing 100044, China
4.
Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
5.
Department of Microbiology and Parasitology, Peking University Health Science Center, Beijing 100191, China

Research funding:

Beijing Municipal Science and Technology Commission (Z191100007619037);

Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXX0104);

Beijing Municipal Health Commission (2022-3-018);

Capital Medical University (PYZ21051)

More Information

Corresponding author: KONG Yuanyuan, kongyy@ccmu.edu.cn (ORCID:0000-0002-2586-1443); JIA Jidong, jia_jd@ccmu.edu.cn (ORCID:0000-0002-4673-8890)

摘要

摘要: 目的探讨抗HBV治疗适应证变化对治疗率和需要治疗人群特征的影响。方法研究对象来自于中国消除乙肝临床研究平台(CR-HepB)数据库中未经治慢性乙型肝炎患者，收集其人口学、病毒学、血液学及血生化信息。不符合正态分布的定量资料在两组间比较采用Mann-Whitney U检验，多组间比较采用Kruskal-Wallis H检验，定性资料组间比较采用χ²检验或Fisher确切概率检验。结果本研究共纳入3640例未经治慢性乙型肝炎患者，64.4%为男性，68.7%年龄为30~59岁，46.8%临床分期不确定。根据2015年版、2019年版慢性乙型肝炎防治指南和2022年版专家共识，分别有625例(17.2%)、1333例(36.6%)、和2890例(79.4%)符合抗病毒治疗适应证。2022年版共识新增需治疗患者1557例，其中1424例(91.5%)符合男性ALT＞30 U/L、女性ALT＞19 U/L的治疗阈值。2022年版专家共识新增需治疗患者的ALT、HBV DNA水平、APRI和FIB-4评分显著低于2019年版指南新增需治疗患者(P值均＜0.05)。结论随着慢性乙型肝炎抗病毒治疗的适应证扩展，将显著提高患者的治疗比例，有利于更多有疾病进展风险的轻症患者得到及时治疗并改善长期预后。
- 乙型肝炎, 慢性 /
- 抗病毒药 /
- 适应证
Abstract: Objective To investigate the impact of the change in anti-hepatitis B virus (HBV) therapy indication on treatment rate and the features of the population requiring treatment. Methods The treatment-naïve patients with chronic hepatitis B (CHB) in the China Registry of Hepatitis B (CR-HepB) database were selected as subjects, and related demographic, virological, hematological, and biochemical data were collected. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. Results A total of 3640 treatment-naïve CHB patients were included in this study, among whom 64.4% were male, 68.7% had an age of 30-59 years, and 46.8% had an indeterminate clinical stage. According to the 2015 and 2019 editions of Guidelines for the prevention and treatment of chronic hepatitis B and the 2022 edition of expert consensus, the number of patients who had the indication for antiviral therapy was 625(17.2%), 1333(36.6%), and 2890(79.4%), respectively. The number of patients requiring treatment was increased by 1557 according to the 2022 edition of expert consensus, among whom 1424(91.5%) met the treatment threshold of alanine aminotransferase (ALT) > 30 U/L for male patients or ALT > 19 U/L for female patients. The additional patients requiring treatment according to the 2022 edition of expert consensus had significantly higher levels of ALT and HBV DNA and significantly lower scores of APRI and FIB-4 than the additional patients requiring treatment according to the 2019 edition of Guidelines (all P < 0.05). Conclusion The expansion of antiviral therapy indications for CHB may significantly increase the proportion of CHB patients receiving antiviral treatment and help mild CHB patients at the risk of disease progression to receive timely treatment and achieve the improvement in long-term prognosis.
- Hepatitis B, Chronic /
- Antiviral Agents /
- Indication

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图 1 需抗病毒治疗患者年龄和性别分布特征

Figure 1. Distribution characteristics of CHB patients requiring antiviral treatment

下载: 全尺寸图片幻灯片

图 2 新版指南新增抗病毒治疗患者临床特征比较

Figure 2. Comparison of clinical characteristics of the additional CHB patients requiring antiviral treatment

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表 1 未经治CHB患者人口学和临床特征

Table 1. Demographic and clinical characteristics of treatment-naive CHB patients

指标	总人群 (n=3640)	免疫耐受期 (n=121)	免疫清除期 (n=562)	免疫控制期 (n=885)	再活动期 (n=369)	分期不确定 (n=1703)	χ²值	P值
年龄[例(%)]							388.800	＜0.001
＜30岁	896(24.6)	77(63.6)	269(47.9)	104(11.8)	61(16.5)	385(22.6)
30~59岁	2502(68.7)	44(36.4)	289(51.4)	686(77.5)	286(77.5)	1197(70.3)
≥60岁	242(6.6)	0	4(0.7)	95(10.7)	22(6.0)	121(7.1)
性别[例(%)]							60.713	＜0.001
男性	2345(64.4)	49(40.5)	392(69.8)	530(59.9)	274(74.3)	1100(64.6)
女性	1295(35.6)	72(59.5)	170(30.2)	355(40.1)	95(25.7)	603(35.4)
PLT(×10⁹/L)	179.0(134.0~223.0)	202.0(168.0~237.0)	191.0(157.5~234.0)	179.0(133.3~223.8)	168.0(130.0~202.5)	176.0(126.0~221.0)	40.013	＜0.001
ALT(U/L)	34.5(21.0~74.0)	24.0(17.2~31.5)	116.5(67.0~264.8)	20.9(16.0~27.0)	94.3(59.0~205.5)	33.0(21.1~55.3)	1 756.882	＜0.001
AST(U/L)	30.0(22.1~52.1)	23.0(19.9~26.5)	71.1(42.9~149.7)	23.0(19.0~27.0)	61.5(41.9~123.0)	29.7(22.3~43.3)	1 429.019	＜0.001
Alb(g/L)	45.0(41.6~47.7)	45.0(42.4~46.9)	43.5(40.3~46.6)	45.9(43.0~48.0)	43.8(40.0~46.2)	45.3(41.7~48.1)	101.599	＜0.001
TBil(μmol/L)	15.0(11.2~21.6)	12.2(9.1~15.7)	16.7(12.4~23.0)	14.2(10.7~19.1)	17.0(12.5~26.3)	15.2(11.2~22.2)	97.197	＜0.001
HBV DNA[例(%)]							2 769.582	＜0.001
＜2000 IU/mL	2105(57.8)	0	0	885(100.0)	0	1220(71.6)
2000~19 999 IU/mL	306(8.4)	0	0	0	82(22.2)	224(13.2)
≥20 000 IU/mL	1229(33.8)	121(100.0)	562(100.0)	0	287(77.8)	259(15.2)
APRI评分	0.5(0.3~1.1)	0.3(0.2~0.4)	1.1(0.6~2.6)	0.3(0.2~0.5)	1.2(0.6~2.4)	0.5(0.3~1.0)	623.757	＜0.001
FIB-4评分	1.3(0.8~2.3)	0.7(0.6~1.0)	1.2(0.8~2.4)	1.3(0.9~2.0)	1.8(1.1~3.3)	1.3(0.8~2.4)	66.331	＜0.001

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表 2 需抗病毒治疗患者临床特征

Table 2. Clinical characteristics of CHB patients requiring antiviral treatment

指标	2015年版指南需治疗患者 (n=625)	2019年版指南需治疗患者 (n=1333)	2022年版共识需治疗患者 (n=2890)	P值¹⁾	P值²⁾	P值³⁾
年龄[例(%)]				0.001	＜0.001	＜0.001
＜30岁	238(38.1)	410(30.8)	668(23.1)
30~59岁	374(59.8)	871(65.3)	2051(71.0)
≥60岁	13(2.1)	52(3.9)	171(5.9)
性别[例(%)]				0.905	＜0.001	＜0.001
男性	455(72.8)	967(72.5)	1855(64.2)
女性	170(27.2)	366(27.5)	1035(35.8)
PLT(×10⁹/L)	179.0(145.0~221.0)	180.0(139.0~222.0)	177.0(132.0~222.0)	0.856	0.182	0.160
ALT(U/L)	190.0(116.0~377.0)	86.0(52.0~194.0)	45.0(27.0~97.8)	＜0.001	＜0.001	＜0.001
AST(U/L)	108.0(65.7~209.5)	54.0(36.0~110.2)	35.2(25.0~64.0)	＜0.001	＜0.001	＜0.001
Alb(g/L)	43.0(39.0~45.9)	44.2(40.8~47.1)	44.9(41.6~47.6)	＜0.001	＜0.001	＜0.001
TBil(μmol/L)	18.3(12.9~29.5)	16.3(12.2~23.5)	15.5(11.5~22.1)	＜0.001	＜0.001	0.001
HBV DNA[例(%)]				＜0.001	＜0.001	＜0.001
＜2000 IU/mL	0	306(23.0)	1445(50.0)
2000~19 999 IU/mL	28(4.5)	100(7.5)	285(9.9)
≥20 000 IU/mL	597(95.5)	927(69.5)	1160(40.1)
APRI评分	1.7(0.9~3.7)	0.9(0.5~2.1)	0.6(0.4~1.4)	＜0.001	＜0.001	＜0.001
FIB-4评分	1.7(1.0~3.0)	1.4(0.9~2.5)	1.4(0.9~2.4)	0.002	＜0.001	0.970
注：1)2015年版指南需治疗患者与2019年版指南需治疗患者比较；2)2015年版指南需治疗患者与2022年版共识需治疗患者比较; 3)2019年版指南需治疗患者与2022年版共识需治疗患者比较。

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表 3 指南新增需抗病毒治疗患者的人口学和病毒学特征

Table 3. Demographic and virological characteristics of additional CHB patients requiring antiviral treatment

指标	2019版指南新增需抗病毒治疗(与2015版指南相比) (n=708，19.5%)			2022版共识新增需抗病毒治疗(与2019版指南相比) (n=1557，42.8%)
指标	HBV DNA阳性	ALT＞40 U/L	有家族史且年龄＞30岁	ALT＞19 U/L/ALT＞30 U/L	有家族史	年龄＞30岁
患者例数(%)	611(86.3)	599(84.6)	165(23.3)	1424(91.5)	20(1.3)	1299(83.4)
年龄[例(%)]
＜30岁	172(28.2)	172(28.7)	0	125(8.8)	20(100.0)	0
30~59岁	413(67.6)	398(66.4)	149(90.3)	1180(82.9)	0	1180(90.8)
≥60岁	26(4.3)	29(4.8)	16(9.7)	119(8.4)	0	119(9.2)
性别[例(%)]
男性	454(74.3)	449(75.0)	106(64.2)	760(53.4)	10(50.0)	760(58.5)
女性	157(25.7)	150(25.0)	59(35.8)	664(46.6)	10(50.0)	539(41.5)
PLT(×10⁹/L)	178.0(130.0~223.0)	176.0(129.5~222.0)	191.0(143.5~224.5)	172.0(123.0~222.0)	222.0(210.3~259.8)	166.0(120.5~217.0)
ALT(U/L)	56.7(46.0~70.0)	57.6(48.0~72.0)	28.0(18.0~50.7)	29.0(21.0~39.0)	50.0(26.8~284.5)	29.5(21.0~39.0)
AST(U/L)	39.0(32.0~50.0)	39.4(33.0~51.0)	26.4(21.0~38.0)	27.0(21.1~36.0)	31.0(23.3~153.8)	27.1(22.1~36.3)
Alb(g/L)	45.3(42.0~48.0)	45.3(42.0~48.0)	44.5(41.0~46.1)	45.3(42.1~48.0)	45.0(40.2~47.7)	45.4(42.1~48.0)
TBil(μmol/L)	15.4(11.6~20.5)	15.5(11.6~20.6)	15.1(11.4~19.5)	14.7(11.0~21.0)	14.8(12.5~18.0)	14.9(11.2~21.5)
HBV DNA[例(%)]
＜2000 IU/mL	209(34.2)	213(35.6)	129(78.2)	1040(73.0)	16(80.0)	978(75.3)
2000~19 999 IU/mL	72(11.8)	65(10.9)	12(7.3)	171(12.0)	1(5.0)	164(12.6)
≥20 000 IU/mL	330(54.0)	321(53.6)	24(14.5)	213(15.0)	3(15.0)	157(12.1)
APRI评分	0.6(0.3~0.8)	0.6(0.4~1.0)	0.3(0.2~0.5)	0.4(0.3~0.8)	0.4(0.3~1.9)	0.4(0.3~0.8)
FIB-4评分	1.4(0.9~2.4)	1.2(0.7~2.1)	1.3(1.0~2.1)	1.5(0.9~2.5)	0.7(0.5~0.8)	1.6(1.0~2.6)

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