GSK卫星会_替诺福韦的临床应用_课件

1、替诺福韦的临床应用黄元成 教授 华中科技大学同济医学院附属同济医院缩略词表NAs 核苷（酸）类似物ADV阿德福韦酯LAM拉米夫定ETV恩替卡韦LdT替比夫定TDF富马酸替诺福韦二吡呋酯FTC恩曲他滨BMD骨密度HCC肝细胞肝癌目录慢乙肝抗病毒治疗的目标与现状替诺福韦在NAs初治慢乙肝患者中的疗效和耐受性替诺福韦在NAs经治慢乙肝患者中的疗效和耐受性123 慢乙肝治疗目标是持久抑制病毒复制和阻止疾病进展治疗首要目标是持久抑制HBV复制。短期治疗目标是达到“初步应答”，即HBeAg血清学转换和（或）HBV DNA抑制，ALT水平恢复正常，预防肝脏失代偿，达到“持久应答”，降低肝脏炎症坏死和肝纤维化

2、的发生.最终治疗目标是预防肝脏失代偿、减少或预防进展为肝硬化和（或）HCC，并延长生存期。1提高CHB患者的生活质量和延长生存期，防止疾病进展为肝硬化、失代偿期肝硬化、终末期肝病、肝癌和死亡，达到该目标需要持续抑制HBV复制2治疗CHB目标是持续抑制HBV复制和延缓疾病进展。最终目标是预防肝硬化、肝衰竭和肝癌3最大限度地长期抑制HBV, 减轻肝细胞炎症坏死及肝纤维化, 延缓和减少肝脏失代偿、肝硬化、HCC 及其并发症的发生, 从而改善生活质量和延长存活时间441 Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus sta

3、tement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6(3):531-561 ；2 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85；3 Anna S. F. Lok, Brian J. McMahon. Ch

4、ronic Hepatitis B: Update 2009.Hepatology. 2009;50(3):1-36；4 中华医学会肝病学分会，中华医学会感染病学分会。慢性乙型肝炎防治指南（2010版）。中华肝脏病杂志。2011;19(1):13-242012 欧肝指南2009 美肝指南2012 亚太共识2010 中国指南中国慢乙肝抗病毒药物发展史在过去的几十年中，慢乙肝抗病毒治疗取得了巨大的进步目前，在中国上市的慢乙肝抗病毒药物共有两大类，包括干扰素和NAsSun J, Hou JL, et al. Management of chronic hepatitis B: experience

5、from China. Journal of Viral Hepatitis, 2010,17(suppl. 1):10-17.普通干扰素 1992LAM 1999聚乙二醇干扰素-2aADV2005ETV 2006聚乙二醇干扰素-2bLdT2007TDF2013(国际2008)替诺福韦具有高抗病毒效力所引用数据来自非头对头研究*替诺福韦采用HBV DNA400拷贝/ml,其他采用HBV DNA300拷贝/mlLau DT, Bleibel W.Current status of antiviral therapy for hepatitis B. Therap Adv Gastroentero

6、l. 2008;1(1):61-75不同口服抗病毒药物治疗48或52周的病毒学应答迄今为止，尚未检测到替诺福韦相关耐药 第6年2 第7年3 第8年4 0 0 0 替诺福韦和其他核苷（酸）类似物长期治疗初治慢性乙肝患者的耐药率11 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85；2 Kitrinos KM, Corsa

7、A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2014;59(2):434-42; 3 Buti M, Tsai N, Petersen J, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hep

8、atitis B virus infection. Dig Dis Sci. 2015 May;60(5):1457-64.4 Marcellin P et al. Long Term Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Infection is Safe and Well Tolerated and Associated with Durable Virologic Response with no Detectable Resistance: 8 Year Results from Two

9、 Phase 3 Trials. Hepatology, Volume 60, Number 4 (suppl) AASLD Abstracts 229.目录慢乙肝抗病毒治疗的目标与现状替诺福韦在NAs初治慢乙肝患者中的疗效和耐受性替诺福韦在NAs经治慢乙肝患者中的疗效和耐受性123TDF 300 mg(n=250, 176)ADV 10 mg(n=125, 90)开放标签 TDF 300 mg 每日一次肝活检时间8543012研究时限（年）1 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate ver

10、sus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455; 2 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; FTC/TDF在中国并未

11、被批准用于治疗慢乙肝患者 641例CHB患者2:1随机分组 替诺福韦治疗初治慢乙肝患者：研究设计（102/103研究）主要研究终点：48周血清HBV DNA400拷贝/ml和组织学改善的患者比例。组织学改善：Knodell坏死性炎症评分下降2分且肝纤维化未加重。72周或以后，HBV DNA400 拷贝/ml的患者可加用恩曲他滨（FTC），共57例患者符合加用FTC标准，其中39例加用。102研究亚裔患者占25%，103研究亚裔患者占36%。替诺福韦临床研究第8年，仍有高达64%的患者保留在研究中替诺福韦治疗8年患者的保留情况1 Marcellin P, Heathcote EJ, Buti M

12、, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455；3 Buti M, Tsai N, Petersen J, et al. Seven-Year Efficacy and Safety of Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection. Dig Dis Sci. DOI 10.1

13、007/s10620-014-3486-7 ; 4.Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials.H

14、epatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ, Gane E, deMan R, et al. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients With Chronic Hepatitis B (Study 103). Hepatology, 2008; 48(4):suppl:376A, abstract 158；6 Marcellin P,

15、Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) Treatment and adefovir dipivoxil (ADV) switch Data in hbeag-negative patients with chronic Hepatitis b (study 102), preliminary analysis . Hepatology, 2008; 48(4):suppl:370A, abstract 146； 7 Heathcote EJ, Marcellin P, Buti M, et

16、al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43； 8 EJ Heathcote, EJ Gane, RA de Man, et al. Long term (4 year) efficacy and safety of Tenofovir disoproxil fumarate (TDF) treatment In hbeag-positive patients (

17、HBeAg+) with Chronic hepatitis b (study 103): preliminary Analysis. Hepatology, 2010; 52(4):suppl:556A, abstract 477； 9 Marcellin P, Buti M, Krastev Z, et al. Continued efficacy and safety through 4 Years of tenofovir disoproxil fumarate (TDF) Treatment in HBeAg-negative patients with Chronic hepati

18、tis B (study 102): preliminary. AnalysisHepatology, 2010; 52(4):suppl:555A, abstract 476；10 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; 11

19、Tsai N, Buti M, Edward Gane E, et al. Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical, and Serological Responses With No Detectable Resistance. Hepatol Int.2013; 7 (Suppl 1):11.abstract

20、:188891%64%替诺福韦治疗8年，98%以上的患者达到HBV DNA400拷贝/ml (On-treatment人群) 101 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455；3 Buti M, Tsai N, Petersen J, et al. Seven-Year Efficacy and Safety of Treatme

21、nt with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection. Dig Dis Sci. DOI 10.1007/s10620-014-3486-7 ; 4.Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated wit

22、h durable virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ, Gane E, deMan R, et al. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients Wi

23、th Chronic Hepatitis B (Study 103). Hepatology, 2008; 48(4):suppl:376A, abstract 158；6 Marcellin P, Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) Treatment and adefovir dipivoxil (ADV) switch Data in hbeag-negative patients with chronic Hepatitis b (study 102), preliminary a

24、nalysis . Hepatology, 2008; 48(4):suppl:370A, abstract 146； 7 Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43； 8 EJ Heathcote, EJ Gane, RA de Man, et al. Long term (4 yea

25、r) efficacy and safety of Tenofovir disoproxil fumarate (TDF) treatment In hbeag-positive patients (HBeAg+) with Chronic hepatitis b (study 103): preliminary Analysis. Hepatology, 2010; 52(4):suppl:556A, abstract 477； 9 Marcellin P, Buti M, Krastev Z, et al. Continued efficacy and safety through 4 Y

26、ears of tenofovir disoproxil fumarate (TDF) Treatment in HBeAg-negative patients with Chronic hepatitis B (study 102): preliminary. AnalysisHepatology, 2010; 52(4):suppl:555A, abstract 476；10 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumar

27、ate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; 11 Tsai N, Buti M, Edward Gane E, et al. Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical

28、, and Serological Responses With No Detectable Resistance. Hepatol Int.2013; 7 (Suppl 1):11.abstract:1888TDF-TDF组（On-treatment分析）；TDF-TDF 和ADV-TDF两组（On-treatment分析） 8,9 7 10 315,6 4 11替诺福韦治疗慢性乙肝患者8年强效抑制病毒复制*TDF-TDF组；TDF-TDF 和ADV-TDF两组替诺福韦治疗HBeAg阳性患者8年，HBeAg消失和血清转换率分别为47%和31%4。 替诺福韦治疗慢性乙肝患者8年血清学应答 7

29、10 11 3 8*1*5 4替诺福韦治疗HBeAg阳性患者8年，HBsAg消失和血清转换率分别为13%和10%4。1 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455；3 Buti M, Tsai N, Petersen J, et al. Seven-Year Efficacy and Safety of Treatment with

30、 Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection. Dig Dis Sci. DOI 10.1007/s10620-014-3486-7 ; 4.Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durab

31、le virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ, Gane E, deMan R, et al. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients With Chro

32、nic Hepatitis B (Study 103). Hepatology, 2008; 48(4):suppl:376A, abstract 158；6 Marcellin P, Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) Treatment and adefovir dipivoxil (ADV) switch Data in hbeag-negative patients with chronic Hepatitis b (study 102), preliminary analysis

33、 . Hepatology, 2008; 48(4):suppl:370A, abstract 146； 7 Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43； 8 EJ Heathcote, EJ Gane, RA de Man, et al. Long term (4 year) effi

34、cacy and safety of Tenofovir disoproxil fumarate (TDF) treatment In hbeag-positive patients (HBeAg+) with Chronic hepatitis b (study 103): preliminary Analysis. Hepatology, 2010; 52(4):suppl:556A, abstract 477； 9 Marcellin P, Buti M, Krastev Z, et al. Continued efficacy and safety through 4 Years of

35、 tenofovir disoproxil fumarate (TDF) Treatment in HBeAg-negative patients with Chronic hepatitis B (study 102): preliminary. AnalysisHepatology, 2010; 52(4):suppl:555A, abstract 476；10 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for

36、 chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; 11 Tsai N, Buti M, Edward Gane E, et al. Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical, and S

37、erological Responses With No Detectable Resistance. Hepatol Int.2013; 7 (Suppl 1):11.abstract:1888替诺福韦治疗高病毒载量（HVL）和非高病毒载量患者病毒学应答率相似替诺福韦治疗至96周，HVL及非-HVL患者病毒学应答*率相似替诺福韦治疗5年， HVL患者病毒学应答率为98.3%13*病毒学应答：HBV DNA400拷贝/ml替诺福韦治疗初治HVL和非HVL患者5年，达到HBV DNA400拷贝/ml的患者比例上图数据排除加用FTC的患者。Gordon et al, Efficacy of Ten

38、ofovir Disoproxil Fumarate at 240 Weeks in Patients With Chronic Hepatitis B With High Baseline Viral Load. Hepatology. 2013;58:505-513HVL(高病毒载量）指基线HBV DNA9log10copies/ml。入组HVL患者共129例（20%），TDF组82例， ADV组47例。Non-HVL N= 512 500 502 487 495 485 484 463 457 453 445 434 438 435 431 433 426 426 419 414 412

39、 395 396 391 387 -NonHVL N= 129 126 126 123 122 121 121 119 113 100 90 85 82 82 82 78 74 72 66 66 66 65 60 61 59在HBeAg阳性的高病毒载量初治患者中替诺福韦病毒学应答率优于ETVHBeAg阳性高病毒载量初治患者，TDF完全病毒学应答率显著高于ETV。Gao L, Trinh HN, Li J, Nguyen MH,et al.Tenofovir is superior to entecavir for achieving complete viral suppression in

40、HBeAg-positive chronic hepatitis B patients with high HBV DNA. Aliment Pharmacol Ther. 2014 Mar;39(6):629-37. 完全病毒抑制：HBV DNA 6log10IU/mLHBeAg阳性HBeAg阴性一项回顾性病例队列研究，275例初治高病毒载量（ HBV DNA6 log10 IU/ml ）患者纳入分析，其中59例接受TDF治疗，216例接受ETV治疗348例在基线和5年均接受肝活检96例在基线时为肝硬化(Ishak评分5)252例在基线时无肝硬化(Ishak评分4)基线治疗5年71例 (74

41、%)无肝硬化25例肝硬化240例 (95%)改善或未加重12例肝纤维化加重9例Ishak评分升高1分3例肝硬化*逆转肝硬化（ regression of cirrhosis）定义为基线肝硬化患者治疗后Ishak评分下降1分且组织学检测已无肝硬化Marcellin, P, et al. Regressionofcirrhosisduringtreatmentwithtenofovir disoproxil fumarateforchronic hepatitis B: a 5-year open-label follow-up study. Lancet.2013 9; 381(9865):46

42、8-75替诺福韦治疗慢乙肝患者5年有机会逆转肝硬化，阻止肝纤维化进展Ishak 评分 2的患者: 基线为39% ，5年时上升至63% Ishak 评分 4的患者: 基线为38% ，5年时下降至12% 肝硬化患者(Ishak评分 5): 基线为28%，5年时降至8%替诺福韦治疗5年纤维化分期明显改善*进行了基线和5年肝穿的患者；其中344例进行了基线、1年、5年的肝穿*N=348Ishak 评分38%39%12%63%Patrick M, Edward G, Maria B, et al. Regressionofcirrhosisduringtreatmentwithtenofovir dis

43、oproxil fumarateforchronic hepatitis B: a 5-year open-label follow-up study. Lancet, 2013; 381(9865): 468-75.P0.001P0.001替诺福韦治疗5年基线肝硬化的患者74%肝硬化逆转有配对肝穿刺标本的患者中28% (96/348)基线肝组织学显示肝硬化。96例基线肝硬化患者（Ishak评分56）中，74%（71/96）肝硬化逆转；58%（56/96）的患者Ishak评分减少3分以上。Patrick M, Edward G, Maria B, et al. Regressionofcirr

44、hosisduringtreatmentwithtenofovir disoproxil fumarateforchronic hepatitis B: a 5-year open-label follow-up study. Lancet, 2013; 381(9865): 468-75.*逆转肝硬化（ regression of cirrhosis）定义为基线肝硬化患者治疗后Ishak评分下降1分且组织学检测已无肝硬化基线肝硬化患者240周Ishak纤维化评分的变化 N=96N=24N=14N=41N=15N=1N=1替诺福韦长期治疗的耐受性替诺福韦治疗8年耐受性良好： 各项肾脏不良事件*

45、发生率均2.2%。从第4年开始，每年均通过DXA#扫描对骨密度（BMD）进行评估，结果显示，平均BMD（T评分）持续保持稳定。*肾脏不良事件：血清肌酐较基线升高0.5mg/dl或肌酐清除率50ml/min或血磷2mg/dl#DXA：双能X线吸收法Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with d

46、urable virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A, Abs.229治疗8年期间未检测到替诺福韦相关耐药替诺福韦治疗8年，共90例患者在165个时间点符合基因型分析。65%（107/165）的患者相对于基线无变化或者不能进行基因分型。仅9.7%（16/165）的患者在pol/RT区出现保守位点变化。表型分析发现：保守性位点变化未导致TDF表型耐药。Amoreena Corsa,Yang Liu, Jo

47、hn Flaherty, et al. No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) in HBeAg+ and HBeAg- Patients With Chronic Hepatitis B (CHB) After Eight Years of Treatment. Presented at the 24th Conference of APASL, March 1215, 2015, Istanbul, Turkey. PP-1203基因型变化无变化无法进行基因分析多态性位点变化 保守性位点变化对慢乙肝初治

48、患者，权威指南推荐首选强效、高耐药基因屏障药物推荐高耐药屏障药物（替诺福韦或恩替卡韦）1首选恩替卡韦或替诺福韦2长期治疗： 高耐药屏障的强效NAs（恩替卡韦或替诺福韦）3首选聚乙二醇干扰素a、替诺福韦或恩替卡韦41. Guidelines for the prevention, care and treatment of persons with chronic hepatitis b infection. WHO.20152. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the man

49、agement of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6(3):531-5613. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85 4.Anna S. F. Lok, Brian J. McMahon. Chronic Hepatitis B:

50、 Update 2009.Hepatology. 2009;50(3):1-362015 WHO2012 亚太共识2012 欧肝指南2009 美肝指南目录慢乙肝抗病毒治疗的目标与现状替诺福韦在NAs初治慢乙肝患者中的疗效和耐受性替诺福韦在NAs经治慢乙肝患者中的疗效和耐受性1232012年7月启动的中国乙肝随访与临床科研平台回顾性分析了自2000年始的13,493例慢乙肝患者，发现高耐药的LAM/ADV使用比例高，而低耐药的ETV和TDF使用比例低1我国慢乙肝治疗挑战：高耐药NA使用比例高，耐药类型多样302医院分析了1,803例接受NAs经治慢乙肝患者，共检测到560例患者发生突变，其中LA

51、M耐药类型最常见，为431/5602Jia J, Hou J, Han T, et al. CR-HepB: A new registry system for documenting and analyzing the demography, virology and medicine treatments of hepatitis B in China. Hepatology. 58(S1): 607A-26A, abstract 867.Liu Y, Wang C, Zhong Y, et al. Genotypic resistance profile of hepatitis B v

52、irus (HBV) in a large cohort of nucleos(t)ide analogue-experienced Chinese patients with chronic HBV infection J Viral Hepat. 2011;18:e29-39.NAs耐药类型及构成比（n=560）各Nas使用比例 拉米夫定耐药后换用ETV或LAM+ADV 疗效不佳，且耐药率高2年后的基因型耐药率2年后的病毒学应答率（PP分析）P = 0.025 LAM耐药后换用ETV治疗2年，病毒学应答率仅为40.0% （PP分析）；累积耐药率为24.6%。Yim HJ, Seo YS,

53、Yoon EL, et al. Adding adefovir vs. switching to entecavir for lamivudine-resistant chronic hepatitis B (ACE study): a 2-year follow-up randomized controlled trial Liver Int. 2013: 33: 24454P = 0.005 *HBV DNA44mol/l)或肌酐清除率50ml/min或PO42mg/dl (0.65mmol/l)121研究：替诺福韦治疗LAM耐药患者能获得较高的病毒学应答率双盲1年5年3年4年2年Fung

54、 S, Kwan P, Fabri M, et al. Randomized Comparison of Tenofovir Disoproxil Fumarate vs Emtricitabine and Tenofovir Disoproxil Fumarate in Patients with Lamivudine-resistant Chronic Hepatitis B. Gastroenterology. 2014; 146(4):980-988两组96周均未检测出TDF相关耐药耐受性好，肾脏不良事件*轻微且发生率60 IU/mL患者多中心、随机、开放性研究TDF组： 71.1%(

55、32/45)ETV+TDF组： 73,3%（33/45）和基线相比，没有患者在多聚酶区/逆转录区均出现新发突变位点 治疗48周无患者出现血肌酐较基线升高0.5 mg/dL;平均eGRF和平均血磷的改变也是轻微的。ETV耐药患者 TDF单药与TDF+ETV联合治疗疗效相当P0.99CharacteristicValueAge, yr49.5 (23-65)Sex (male)39 (75.0)HBeAg positivity48 (92.3)Serum HBV DNA, log IU/mL5.41.76Serum HBsAg titer, log IU/mLa3.70.64aALT, U/L45.5 (17-951)Prior exposed NAsLAM, ADV12 (23.1)LAM, ADV, ETV39 (75.0)ETV, ADV1 (1.9)Treatment regimenTDF17 (32.7)TDF+LAM15 (28.9)TDF+ETV20 (38.5)TDF treatment duration, mon34.5 (6-55)Table 1. baseline characteristic