【摘要】 目的  评估长期服用国产恩替卡韦（entecavir，ETV）治疗产生完全病毒学应答的慢性乙型病毒性肝炎（chronic hepatitis B,CHB）患者换药为集采恩替卡韦治疗的有效性与安全性。方法  纳入2019年1月1日至2021年5月18日在郑州大学第一附属医院河医院区感染肝病五门诊就诊的服用国产恩替卡韦治疗超过1年已产生完全病毒学应答的CHB患者260例，回顾性分析未换药一直服用国产恩替卡韦治疗组（未换药组）和换药服用集采恩替卡韦组（换药组）患者年龄、性别、基线，治疗24周及48周时乙肝病毒脱氧核糖核酸（hepatitis B virus deoxyribonucleic acid,HBVDNA）、丙氨酸氨基转移酶（alanine aminotransferase,ALT）、乙型肝炎病毒e抗原（HBeAg）、乙型肝炎病毒e抗体（HBeAb/抗-HBe）水平。结果  共纳入260名患者，未换药组104例（40.0%），换药组156例（60.0%）。治疗24周时，未换药组完全病毒学应答率为97.12%（101/104），换药组为96.79%（151/156），组间比较无统计学差异（P=1.000）；治疗48周时两组患者HBVDNA均低于检测下线，完全病毒学应答率均为100%，无统计学差异。未换药组与换药组治疗24周和治疗48周，ALT复常率组间比较均无统计学差异（²=0.157 P=0.692，²=2.316 P=0.128）。未换药组基线HBeAg(+)患者44例(42.3%),换药组基线HBeAg(+)患者69例(44.2%),组间比较无统计学差异(²=0.094 P=0.759)；治疗24周时，两组分别有2例vs3例HBeAg转阴，2例vs0例产生抗-HBe，组间比较均无统计学差异；治疗48周时，两组分别有4例vs9例HBeAg转阴，1例vs3例产生抗-HBe，组间比较均无统计学差异，即两组患者治疗24周和48周时，HBeAg转阴率、HBeAg/抗-HBe血清学转换率均无统计学差异（均P＞0.05）。两组均无不良反应发生。结论  集采恩替卡韦与国产恩替卡韦相比，疗效与安全性无统计学差异。
【关键词】慢性乙型病毒性肝炎；抗病毒药物；恩替卡韦
中图分类号：R453.9

Evaluating the efficacy and safety of centrally collected entecavir in patients with chronic hepatitis B
HUANG Yanqing,ZHANG Hongyu,LI Shasha,LI Miaoqing,JIA Qiaodi
Department of Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450199, China
【 Abstract 】 Objective  To evaluate the efficacy and safety of intensive entecavir (ETV) for chronic hepatitis B (CHB) patients with complete virology response after long-term treatment. Methods  CHB patients who received domestic entecavir treatment for more than 1 year and had a complete virology response were enrolled in the 5th Outpatient Department of Infected Liver Disease at the First Affiliated Hospital of Zhengzhou University on January 1, 2019 and May 18, 2021. The age, sex, baseline, and levels of HBVDNA, ALT, HBeAg, and anti-HBe at 24 and 48 weeks of treatment were retrospectively analyzed. The changes of HBVDNA, ALT, HBeAg and anti-HBe were compared before treatment, 24 weeks and 48 weeks after treatment in the unchanged group and the group receiving centrally collected treatment with enticavir. Results  A total of 260 patients were included, including 104 patients (40.0%) in the unchanging group and 156 patients (60.0%) in the changing group.At 24 weeks of treatment, the complete virological response rate was 97.12% (101/104) in the unchanging group and 96.79% (151/156) in the changing group, and there was no statistical difference between the two groups (P=1.000).At 48 weeks of treatment, HBVDNA in both groups was lower than the detection line, and the complete virological response rate was 100%, showing no statistical difference. There was no statistical difference in ALT normalization rate between the two groups after 24 and 48 weeks of treatment (²=0.157 P=0.692, ²=2.316 P=0.128).There were 44 (42.3%) baseline HBeAg (+) patients in the unchanging group and 69 (44.2%) baseline HBeAg(+) patients in the changing group, and there was no statistical difference between groups (²=0.094 P=0.759).After 24 weeks of treatment, 2 cases of VS 3 cases of HBeAg turned negative, and 2 cases of VS 0 cases produced anti-HBe, respectively, and there was no statistical difference between the two groups. After 48 weeks of treatment, 4 patients VS 9 patients HBeAg turned negative and 1 patient VS 3 patients developed anti-HBe in the two groups, respectively. There were no statistical differences in HBeAg conversion rate and HBeAg/anti-HBe serological conversion rate between the two groups at 24 and 48 weeks of treatment (all P > 0.05). No adverse reactions occurred in both groups. Conclusion  There is no significant difference in efficacy and safety between centrally collected entecavir and domestic entecavir.
【 Key words 】 Chronic viral hepatitis B; Antiviral drugs; Entecavir
乙型肝炎病毒（HBV）感染呈世界性流行,据WHO报道，全球约有2.57亿慢性HBV感染[1]。据估计，目前我国一般人群HBsAg流行率为5%～6%，慢性HBV感染者约7000万例，其中CHB患者约2000万～3000万例[2]。乙型病毒性肝炎是慢性肝病进展为肝硬化、肝癌等终末期肝病最常见的病因[3]。抗病毒治疗是治疗 CHB 患者的关键措施。恩替卡韦可强效抑制病毒复制，改善肝脏炎症，长期治疗可改善乙型肝炎肝硬化患者的组织学病变，显著降低肝硬化并发症和HCC的发生率[4]。多项权威指南/共识推荐：抗病毒治疗，HBVDNA应控制在20IU/ml以下以产生完全病毒学应答[1][5][6][7]。若HBVDNA持续/间歇处于20IU/ml—2000IU/ml即为低病毒血症可显著增加患者肝纤维化进展风险，进而增加肝硬化、肝癌等终末期肝病发生风险[5][8]。大量研究显示国产恩替卡韦分散片活性成分与进口恩替卡韦片相同，长期规律口服国产恩替卡韦分散片可有效将HBVDNA控制在20IU/ml以下（即产生完全病毒学应答），显著降低HCC风险和肝脏相关死亡风险，且价格较低廉，成为很多患者的第一选择[9][10]。为响应国家医保局、国家卫健委、国家药监局等部门组织的以公立医疗机构为集中采购主体采购药品，进而解决药品价格虚高问题号召，我院于2019年12月28日集采恩替卡韦片（北京百奥）。集采恩替卡韦片服用28天仅需5.5元，价格是一般国产恩替卡韦分散片的1/37，但因上市时间短，其疗效与安全性仍存在很多疑问。尤其对于已长期规律口服国产抗病毒药物慢乙肝患者而言，换药长期口服集采恩替卡韦片对维持患者完全病毒学应答等疗效及安全性不确切。本研究欲探究长期规律口服国产恩替卡韦分散片的慢乙肝患者换药口服集采恩替卡韦片的长期疗效及安全性评估。

1资料与方法
1.1 一般资料  回顾性分析2019年1月1日至2021年5月18日在郑州大学第一附属医院河医院区感染肝病五门诊就诊的CHB患者。入选标准：①诊断符合2019年《慢性乙型肝炎防治指南（2019）版》；②接受国产恩替卡韦分散片治疗至少一年已产生完全病毒学应答的CHB患者；③年龄≥18周岁。剔除标准：①合并丙型肝炎病毒(HCV)、 丁型肝炎病毒(HDV)、人类免疫缺陷病毒(HIV)感染者；②曾用免疫抑制剂、干扰素患者；③肝移植患者；④依从性差，不能规律口服抗病毒药物，不能定期至我院复查。按照纳入排除标准，纳入已长期口服国产抗病毒药物治疗超过一年，并产生完全病毒学应答CHB患者，共计260例。将一直服用国产恩替卡韦分散片时间≥2年的104名患者分为未换药组；将口服国产恩替卡韦分散片≥1年且换药口服集采恩替卡韦时间≥1年的156名患者分为换药组。两组剂量均为0.5mg／d，疗程均超过48周，患者依从性好，能按要求定期回我院复查，复诊同时了解依从性及药物不良反应。观察终点为：纳入研究期间，在治疗24周及48周时，是否为持续性完全病毒学应答。