1、替诺福韦的临床应用黄元黄元成成 教授教授 华中科技大学同济医学院附属同济医院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，
2、达到“持久应答”，降低肝脏炎症坏死和肝纤维化的发生.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-Pacifi
3、c consensus statement 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.
4、Chronic 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l 在过去的几十年中，慢乙肝抗病毒治疗取得了巨大的进步l 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 Gastroenterol.200
6、8;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39216760767251908893020406080100拉米夫定阿德福韦酯恩替卡韦替比夫定替诺福韦HBV DNA检测不到患者比例（%）HBeAg阳性患者HBeAg阴性患者2400.2403830.51749111.267181.270291.2020406080100拉米夫定阿德福韦酯恩替卡韦替比夫定替诺福韦耐药性（%）第1年第2年第3年第4年第5年迄今为止，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 As
7、sociation 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 A,Liu Y,et al.No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis
8、 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 hepatitis 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 Ch
9、ronic 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.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
10、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 versus 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 wit
11、h 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）l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。l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。l72周或以后，HBV DNA400 拷贝/ml的患者可加用恩曲他滨
12、（FTC），共57例患者符合加用FTC标准，其中39例加用。l102研究亚裔患者占25%，103研究亚裔患者占36%。0102030405060708090100第1年第2年第3年第4年第5年第6年第7年第8年仍参加研究的随机化 患者(%)研究102研究103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,et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl
13、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 10.1007/s10620-014-3486-7;4.Marcellin P,Gane EJ,Flisiak R,et al.Long term treatment with tenofovir disoproxi
14、l 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.Hepatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ,Gane E,deMan R,et al.Two Year Tenofovir Disoproxil Fumarate(T
15、DF)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,Buti M,Krastev Z,et al.Two year tenofovir disoproxil fumarate(TDF)Treatment and adefovir dipivoxil(ADV)switch Data in hbeag-n
16、egative 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 al.Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.Gastroenterology.2011;140(1):132-43；8 EJ H
17、eathcote,EJ Gane,RA de Man,et al.Long term(4 year)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
18、 efficacy and safety through 4 Years 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 tenofo
19、vir disoproxil fumarate 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,
20、Biochemical,and Serological Responses With No Detectable Resistance.Hepatol Int.2013;7(Suppl 1):11.abstract:188891%64%83899396979999.498979899999999.699.399.6020406080100第1年第2年第3年第4年第5年第6年第7年第8年HBV DNA400拷贝/ml患者比例（%）治疗时间（年）HBeAg阳性患者HBeAg阴性患者替诺福韦治疗8年，98%以上的患者达到HBV DNA400拷贝/ml(On-treatment人群)101 Marce
21、llin 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 Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection.Dig
22、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 durable virologic response with no detectable resistance:8 year results from two phase 3
23、 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 Chronic Hepatitis B(Study 103).Hepatology,2008;48(4):suppl:376A,abstract 158；6 Marcellin P,Buti
24、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 al.Three-year efficacy
25、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(HBeAg+)with Chronic hepatitis b(stud
26、y 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 hepatitis B(study 102):preliminary.AnalysisHepatology,20
27、10;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 Tsai N,Buti M,Edward Gane E,et al.Six Years of Treatment With Te
28、nofovir 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:1888TDF-TDF组（On-treatment分析）；TDF-TDF 和ADV-TDF两组（On-treatment分析）8,9 7 10
29、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l 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21272631403739.63101020304050第1年第2年第3年第4年第5年第6年第7年第8年HBeAg血清转换率（%）治疗时间（年）7 10 11 3 8*1*5 4l 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.T
30、enofovir 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 10.1007/s10620-014-348
31、6-7;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.Hepatology.2014;60(S1):313
32、A,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,Buti M,Krastev Z,et al.Two year tenofov
33、ir 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 al.Three-year efficacy and safety of tenofovir disoproxil
34、 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(HBeAg+)with Chronic hepatitis b(study 103):preliminary Analysis.Hepato
35、logy,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 hepatitis B(study 102):preliminary.AnalysisHepatology,2010;52(4):suppl:555A,abstract 476；1
36、0 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 Tsai N,Buti M,Edward Gane E,et al.Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B
37、 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:18880102030405060708090100048 12 16 20 24 28 32 36 40 44 4856647280889610812013214415616818019220421622824
38、0HBV DNA400拷贝/mL的患者比例（%）研究周数Non-High Viral Load(Non-HVL)High Viral(HVL)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l 替诺福韦治疗至96周，HVL及非-HVL患者病毒学应答*率相似l 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 Tenofovir Disoproxil Fumarat
39、e 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=512 500 502 487 495 485 484 463 457 453 445 434 438 435 431 433 426 426 419 414 412 395 396 391 387-NonHVL N=129
40、 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ETVl HBeAg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 HBeAg-positive chronic hepatitis
41、 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%)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
42、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.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B:a 5-year open-label follow-up study.Lancet.2013 9;381(9865):468-75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l Is
43、hak 评分 2的患者:基线为39%，5年时上升至63%l Ishak 评分 4的患者:基线为38%，5年时下降至12%l 肝硬化患者(Ishak评分 5):基线为28%，5年时降至8%0102030405060708090100基线1年5年患者百分比（%）6543210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.Regression of cirrhosis during treatment with tenofov
44、ir disoproxil fumarate for chronic 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l 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。l 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.Regression of
45、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.*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-6-5-4-3-2-10123456Ishak纤维化评分变化基线肝硬化患者240周Ishak纤维化评分的变化 N=96N=24N=14N=41N=15N=1N=1替
46、诺福韦长期治疗的耐受性l 替诺福韦治疗8年耐受性良好：各项肾脏不良事件*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
47、 tolerated and associated with durable virologic response with no detectable resistance:8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A,Abs.229n=169.7%n=4225.5%n=3923.6%n=6841.2%,0.0%治疗8年期间未检测到替诺福韦相关耐药l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。l65%（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）
48、的患者在pol/RT区出现保守位点变化。l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,John 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,Is
49、tanbul,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,e
50、t al.Asian-Pacific consensus statement on the management 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,
