延长或转换为艾米替诺福韦治疗在慢性乙型肝炎患者中的疗效评估:一项Ⅲ期随机对照研究  

Efficacy evaluation of extending or switching to tenofovir amibufenamide in patients with chronic hepatitis B:a phaseⅢrandomized controlled study

作　　者：刘智泓 金清龙[2] 张跃新[3] 龚国忠[4] 巫贵成 姚履枫 温小凤[7] 高志良[8] 黄燕[9] 杨道坤[10] 陈恩强[11] 毛青 林世德 尚佳[14] 龚环宇[15] 钟丽华[16] 尹华发[17] 王凤梅[18] 胡鹏[19] 张晓青 高群杰 金超南 李川 牛俊奇[2] 侯金林 TMF临床研究协作组 Liu Zhihong;Jin Qinglong;Zhang Yuexin;Gong Guozhong;Wu Guicheng;Yao Lvfeng;Wen Xiaofeng;Gao Zhiliang;Huang Yan;Yang Daokun;Chen Enqiang;Mao Qing;Lin Shide;Shang Jia;Gong Huanyu;Zhong Lihua;Yin Huafa;Wang Fengmei;Hu Peng;Zhang Xiaoqing;Gao Qunjie;Jin Chaonan;Li Chuan;Niu Junqi;Hou Jinlin;TMF Study Group(Key Laboratory of Infectious Diseases Research in South China,Ministry of Education,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;The First Hospital of Jilin University,Changchun 130021,China;The First Affiliated Hospital of Xinjiang Medical University,Urumqi 830054,China;The Second Xiangya Hospital of Central South University,Changsha 41001l,China;Chongqing University Three Gorges Hospital,Chongqing 404000,China;Mengchao Hepatobiliary Hospital of Fujian Medical University,Fuzhou 350025,China;Liuzhou People's Hospital,Liuzhou 545006,China;The Third Affiliated Hospital of Zhongshan University,Guangzhou 510630,China;Xiangya Hospital of Central South University,Changsha 410008,China;The First Affiliated Hospital of Xinxiang Medical University,Xinxiang 453100,China;West China Hospital of Sichuan University,Chengdu 610044,China;The Southwest Hospital of AMU,Chongqing 400038,China;Affiliated Hospital of Zunyi Medical University,Zunyi 563000,China;Henan Provincial People's Hospital,Zhengzhou 450003,China;The Third Xiangya Hospital of Central South University,Changsha 410205,China;The Fourth Affiliated Hospital of Harbin Medical University,Harbin 150001,China;The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China;Tianjin Third Central Hospital,Tianjin 300170,China;The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China;Jiangsu Hansoh Pharmaceutical Group Co.,Ltd,Lianyungang 222000,China;TMF Study Group)

机构地区：[1]华南传染病防治教育部重点实验室南方医科大学南方医院,广州510515 [2]吉林大学第一医院,长春130021 [3]新疆医科大学第一附属医院,乌鲁木齐830054 [4]中南大学湘雅二医院,长沙410011 [5]重庆大学附属三峡医院,重庆404000 [6]福建医科大学孟超肝胆医院,福州350025 [7]柳州市人民医院,柳州545006 [8]中山大学附属第三医院,广州510630 [9]中南大学湘雅医院,长沙410008 [10]新乡医学院第一附属医院,新乡453100 [11]四川大学华西医院,成都610044 [12]中国人民解放军陆军军医大学第一附属医院,重庆400038 [13]遵义医科大学附属医院,遵义563000 [14]河南省人民医院,郑州450003 [15]中南大学湘雅三院,长沙410205 [16]哈尔滨医科大学附属第四医院,哈尔滨150001 [17]安徽医科大学第一附属医院,合肥230022 [18]天津市第三中心医院,天津300170 [19]重庆医科大学附属第一医院,重庆400016 [20]江苏豪森药业集团有限公司,连云港222000 [21]TMF临床研究协作组

出　　处：《中华肝脏病杂志》2024年第10期883-892,共10页Chinese Journal of Hepatology

基　　金：国家重点研发计划(2022YFC2303600);广州市科技基础与应用基础研究专题(2023A04J2288)。

摘　　要：目的研究慢性乙型肝炎患者(CHB)分别初始接受艾米替诺福韦(TMF)或富马酸替诺福韦酯(TDF)治疗96周后,延长或转换为TMF治疗48周的疗效特点。方法CHB患者按2∶1随机分配至每日1次口服TMF 25 mg或TDF 300 mg,持续96周,然后进入48周的开放标签TMF 25 mg治疗期,评估包括病毒学、血清学、生化学应答和组织学评价方面的疗效差异。据资料不同采用McNemar检验、t检验或Log-Rank检验进行统计学分析。结果TMF初治组共593例,TDF转换组共287例受试者完成144周治疗或达到研究终点。第144周时,整体人群获得乙型肝炎病毒(HBV)DNA<20 IU/ml的比例分别为86.2%和83.3%;在基线HBV DNA≥8 log 10 IU/ml的人群中,该比例分别为78.1%和73.8%;无患者新发耐药。两组第144周HBeAg转阴率和血清学转换率较96周仍有进一步显著提升,3年合计阴转率约为35%。同时TDF组在转换治疗48周后丙氨酸转氨酶(ALT)复常率进一步提高了11.4%,肝纤维化指数(FIB-4)也获得了显著改善。结论CHB患者经过144周TMF的治疗,可维持良好的病毒学应答和生化学应答。TDF治疗96周后,转换至TMF 48周可使患者获得生化学应答的提高。ObjectiveIn chronic hepatitis B(CHB)patients with previous 96-week treatment with tenofovir amibufenamide(TMF)or tenofovir disoproxil fumarate(TDF),we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.MethodsEnrolled subjects who were previously assigned(2:1)to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks.Efficacy was evaluated based on virological,serological,biological parameters,and fibrosis staging.Statistical analysis was performed using the McNemar test,t-test,or Log-Rank test according to the data.Results593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144,with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2%and 83.3%,respectively,and 78.1%and 73.8%in patients with baseline HBV DNA levels≥8 log10 IU/ml.Resistance to tenofovir was not detected in both groups.For HBeAg loss and seroconversion rates,both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35%in each group.However,HBsAg levels were less affected during 96 to 144 weeks.For patients switched from TDF to TMF,a substantial further increase in the alanine aminotransferase(ALT)normalization rate was observed(11.4%),along with improved FIB-4 scores.ConclusionAfter 144 weeks of TMF treatment,CHB patients achieved high rates of virological,serological,and biochemical responses,as well as improved liver fibrosis outcomes.Also,switching to TMF resulted in significant benefits in ALT normalization rates(NCT03903796).

关 键 词：乙型肝炎病毒 艾米替诺福韦 慢性乙型肝炎 治疗 

分 类 号：R512.62[医药卫生—内科学]