延长或转换至艾米替诺福韦治疗慢性乙型肝炎患者的安全性:一项Ⅲ期、多中心、随机对照研究  

Safety profile of tenofovir amibufenamide therapy extension or switching in patients with chronic hepatitis B:a phaseⅢmulticenter,randomized controlled trial

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 夏鹏 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;Xia Peng;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 StudyGroup)

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610041 [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222042 [21]TMF临床研究协作组

出　　处：《中华肝脏病杂志》2024年第10期893-903,共11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：目的研究艾米替诺福韦(TMF)治疗144周或富马酸替诺福韦酯(TDF)经治慢性乙型肝炎(CHB)患者换用TMF治疗48周后的安全性结果。方法CHB患者按2∶1比例随机分配到TMF初治组(25 mg)或TDF转换组(300 mg),并在前96周接受TMF对比TDF的双盲双模拟治疗。在96~144周期间,所有患者均接受48周的开放标签TMF治疗,并对肾脏、骨骼、代谢、体质量等进行安全性评估。结果TMF初治组和TDF转换组分别有666例和336例患者接受了试验药物。截至第144周,TMF治疗的安全性良好;在第96~144周期间,两组总体安全性相似。在接受转换治疗后,TDF转换组的肾小球滤过率(使用非参数CKD-EPI公式计算)和肌酐清除率(使用Cockcroft Gault公式计算)较第96周分别升高(2.31±8.33)ml/min和(4.24±13.94)ml/min,显著高于TMF初治组的(0.91±8.06)ml/min和(1.30±13.94)ml/min;TDF转换组的髋部和脊柱骨密度(BMD)分别较第96周升高0.75%和1.41%,显著高于TMF初治组的-0.02%±3.57%;第144周TDF转换组累计的BMD显著降低事件发生率为20.1%,仍显著高于TMF初治组(12.7%);TDF转换组总胆固醇/高密度脂蛋白胆固醇比值较第96周升高的中位数为0.16(0.00,0.43),显著高于TMF初治组的0.01(-0.17,0.31);TDF转换组体质量指数较第96周升高(0.54±0.98)kg/m^(2),显著高于TMF初治组的(0.05±0.94)kg/m^(2)。结论CHB患者接受144周TMF治疗的总体安全性良好。在接受转换治疗后,TDF转换组的肾脏和骨骼安全性得到显著改善,但同时也存在轻度的血脂和体质量增加(NCT03903796)。ObjectiveIn chronic hepatitis B(CHB)patients with previous 96-week treatment with tenofovir amibufenamide(TMF)or tenofovir disoproxil fumarate(TDF),we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.MethodsEnrolled subjects that previously assigned(2:1)to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks.Safety profiles of kidney,bone,metabolism,body weight,and others were evaluated.Results666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144.The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144.In subjects switching from TDF to TMF,the non-indexed estimated glomerular filtration rate(by non-indexed CKD-EPI formula)and creatinine clearance(by Cockcroft-Gault formula)were both increased,which were(2.31±8.33)ml/min and(4.24±13.94)ml/min,respectively.These changes were also higher than those in subjects with extending TMF treatment[(0.91±8.06)ml/min and(1.30±13.94)ml/min].Meanwhile,switching to TMF also led to an increase of the bone mineral density(BMD)by 0.75%in hip and 1.41%in spine.On the other side,a slight change in TC/HDL ratio by 0.16(IQR:0.00,0.43)and an increase in body mass index(BMI)by(0.54±0.98)kg/m^(2)were oberved with patients switched to TMF,which were significantly higher than that in TMF group.ConclusionCHB patients receiving 144 weeks of TMF treatment showed favorable safety profile.After switching to TMF,the bone and renal safety was significantly improved in TDF group,though experienceing change in metabolic parameters and weight gain(NCT03903796).

关 键 词：慢性乙型肝炎 艾米替诺福韦 富马酸替诺福韦酯 治疗 安全性 144周 

分 类 号：R512.62[医药卫生—内科学]