韋瑞德應(yīng)答不佳篇

1、,CNRX/TDF/0070/14,,“半年前發(fā)現(xiàn)慢性乙肝，即開始服用拉米夫定。最近覺得特別累，沒有精力去陪伴家人和孩子，檢查發(fā)現(xiàn)病毒水平仍未降下來。” “我是服用了半年的替比夫定，病毒水平始終不理想??” “我吃了1年恩替卡韋，現(xiàn)在情況跟你們一樣??”,小云，38歲工程項(xiàng)目經(jīng)理……,小云們的擔(dān)心,這種情況是不是無藥可治了？之前服用過抗病毒藥物，會不會對新的藥物療效有影響？會不會還像之前一樣，病毒總是控制不

2、好？長期吃藥有什么副作用？,,對小云們這樣出現(xiàn)應(yīng)答不佳的患者，繼續(xù)當(dāng)前方案治療，后續(xù)療效和耐藥率是否會受到影響呢？,LAM和LdT治療的患者，24周時的病毒載量是預(yù)測1年時療效及耐藥率的最顯著因素,Lai CL, Gane E, Liaw YF, et al. Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B. New England Journa

3、l Medicine, 2007, 357:2576-2588.,*HBV DNA不可測：HBV DNA<300拷貝/ml,,LAM及LdT治療1年，HBV DNA不可測*的患者比例,LAM：拉米夫定；LdT：替比夫定,一項(xiàng)雙盲、III期臨床研究，納入1370例慢性乙肝患者，1:1隨機(jī)給予LdT600mg/d或LAM100mg/d，治療52周后，分析其療效及耐藥情況治療24周時各病毒載量的患者來自LAM及LdT兩組患者總和,E

4、TV治療12個月HBV DNA可測的患者，繼續(xù)治療至3年病毒學(xué)應(yīng)答率為57.5%,一項(xiàng)回顧性隊(duì)列研究，納入440例核苷（酸）類似物初治患者（HBeAg陽性，n=160），接受ETV 0.5mg/d治療，平均隨訪34±9個月。研究的主要終點(diǎn)為累積病毒學(xué)應(yīng)答率。治療12個月， 2 例患者原發(fā)無應(yīng)答，114例（25.9%）患者出現(xiàn)部分病毒學(xué)應(yīng)答,Wong GL, Wong VW, Chan HY, et al. Undetecta

5、ble HBV DNA at month 12 of entecavir treatment predicts maintained viral suppression and HBeAg-seroconversion in chronic hepatitis B patients at 3 years. Alimentary Pharmacology & Therapeutics, 2012, 35(11):1326-1335

6、.,*病毒學(xué)應(yīng)答：HBV DNA300拷貝/ml,,ETV治療至3年的病毒學(xué)應(yīng)答率*,ETV：恩替卡韋,p<0.001,p=0.003,#,EASL指南對應(yīng)答不佳患者的治療推薦,1 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus in

7、fection. J Hepatol, 2012,57(1):167-85.,LAM經(jīng)治后，換用ETV的挽救治療措施是否得當(dāng)？核苷類似物治療發(fā)生應(yīng)答不佳后，換用韋瑞德 ®是否能獲得滿意療效呢？,韋瑞德®：富馬酸替諾福韋二吡呋酯片(TDF),ETV治療LAM難治性（Lamivudine-refractory）*慢性乙肝患者耐藥率逐年上升，5年時高達(dá)51%,*拉米夫定難治性患者是指經(jīng)拉米夫定治療后HBV DNA>

8、;300拷貝/ml或出現(xiàn)拉米夫定耐藥患者本研究中拉米夫定難治性患者共187例，其中84.5%的患者檢出拉米夫定基因型耐藥#病毒學(xué)突破是指患者HBV DNA較治療中的最低點(diǎn)升高>1 log10拷貝/ml,Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nuc

9、leoside-naïve patients is rare through 5 years of therapy. Hepatology,2009,49(5):1503-1514.,,ETV治療LAM難治性慢性乙肝患者的累積耐藥率,LAM治療失敗#患者換用韋瑞德®治療,一項(xiàng)回顧性隊(duì)列研究納入197例 慢性乙肝患者，接受TDF單藥或聯(lián)合LAM中位治療29個月主要研究終點(diǎn)為達(dá)到完全病毒學(xué)應(yīng)答*的患者比例,Baran

10、B, Soyer OM, Ormeci AC, et al. Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naïve patients with chronic hepatitis B. Antimicrob Agents Chemot

11、her, 2013, 57(4):1790-1796.,#拉米夫定治療失敗定義為經(jīng)拉米夫定治療6個月后產(chǎn)生耐藥或部分病毒學(xué)應(yīng)答者（HBV DNA >50 IU/ml）*完全病毒學(xué)應(yīng)答：HBV DNA<20 IU/ml,LAM治療失敗患者，換用韋瑞德®治療24個月，病毒學(xué)應(yīng)答率達(dá)89%,Baran B, Soyer OM, Ormeci AC, et al. Efficacy of tenofovir in pa

12、tients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naïve patients with chronic hepatitis B. Antimicrob Agents Chemother, 2013, 57(4):1790-1796.,p=0.23,,韋瑞德®或韋瑞德®聯(lián)合L

13、AM治療 LAM治療失敗患者24個月累積完全病毒學(xué)應(yīng)答率,LAM耐藥患者的挽救治療,一項(xiàng)前瞻性、隨機(jī)、雙盲、多中心、240周研究（Gilead 121 研究，ClinicalTrials.gov No. NCT00737568） ，入選280例LAM耐藥慢性乙肝患者（HBV DNA ≥3log 10 IU/ml)，隨機(jī)分為TDF組（n=141）和FTC/TDF組（n=139）主要研究終點(diǎn)為治療96周達(dá)到HBV DNA<69 I

14、U/ml的患者比例,Fung 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. Gastroenterol

15、ogy,2014,146(4):980-988.,FTC：恩曲他濱,FTC 在中國未被批準(zhǔn)用于治療HBV感染,入組患者基線特征,Fung S, Kwan P, Fabri M, et al. Randomized Comparison of Tenofovir Disoproxil Fumarate vs Emtricitabine and Tenofovir Disoproxil Fumarate in Patients with L

16、amivudine-Resistant Chronic Hepatitis B. Gastroenterology,2014,146(4):980-988..,LAM耐藥患者，換用韋瑞德®治療96周病毒學(xué)應(yīng)答率達(dá)89.4%,Fung S, Kwan P, Fabri M, et al. Randomized Comparison of Tenofovir Disoproxil Fumarate vs Emtricitabi

17、ne and Tenofovir Disoproxil Fumarate in Patients with Lamivudine-Resistant Chronic Hepatitis B. Gastroenterology,2014,146(4):980-988.,,韋瑞德®或FTC/TDF治療LAM耐藥患者96周病毒學(xué)應(yīng)答率*,數(shù)據(jù)來自ITT人群,*病毒學(xué)應(yīng)答：HBV DNA<69 IU/mlFTC/TDF在中國未

18、被批準(zhǔn)用于治療HBV感染,韋瑞德®單藥 與FTC/TDF治療兩組療效相當(dāng),ETV應(yīng)答不佳患者的挽救治療方案,一項(xiàng)回顧性研究中，42例亞洲患者經(jīng)ETV治療后出現(xiàn)部分病毒學(xué)應(yīng)答（治療12個月HBV DNA>60 IU/ml）的患者，分三組進(jìn)行挽救治療ETV+ADV（n=5）TDF（n=6）ETV+TDF（n=31）,Yip B, Chaung K, Wong CR, et al. Tenofovir monothera

19、py and tenofovir plus entecavir combination as rescue therapy for entecavir partial responders. Dig Dis Sci,2012,57(11): 3011-3016.,ADV：阿德福韋酯,ETV應(yīng)答不佳患者，換用韋瑞德®單藥療效優(yōu)于ETV+ADV，且與韋瑞德® +ETV療效相當(dāng),Yip B, Chaung K, Wong

20、 CR, et al. Tenofovir monotherapy and tenofovir plus entecavir combination as rescue therapy for entecavir partial responders. Dig Dis Sci,2012,57(11): 3011-3016.,*完全病毒學(xué)應(yīng)答指HBV DNA<60 IU/ml,6個月時，三組比較，p=0.00112個月時，三組比較

21、，p=0.01,ETV應(yīng)答不佳后分別聯(lián)合ADV，韋瑞德®或換用韋瑞德®單藥的累積完全病毒學(xué)應(yīng)答率*,出現(xiàn)應(yīng)答不佳的患者，更換治療方案時應(yīng)考慮耐藥率的問題,韋瑞德®具有高耐藥基因屏障,Corrigendum to: “EASL clinical practice guidelines: Management of chronic hepatitis B virus infection” [J Hepatol

22、 2012;57:167–185]. J Hepatol, 2013, 58:201.,S：敏感；I：中度敏感/敏感性降低；R：耐藥*在臨床實(shí)踐中，單一M204V突變通常檢測不到，其交叉耐藥特征主要在體外試驗(yàn)中研究,最常見的HBV變異株交叉耐藥位點(diǎn),迄今為止，眾多循證醫(yī)學(xué)證據(jù)顯示韋瑞德®在各類慢性乙肝患者長期治療耐藥率為0,1.Patrick Marcellin, Edward J. Gane, Naoky Tsai,e

23、t al.Seven 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 Resis

24、tance. Hepatology, 2013, 58(4 suppl):649A.2.JL Hou, ZL Gao, Q Xie, et al. Continued Use of Tenofovir Disoproxil Fumarate Monotherapy or Switching from Adefovir Dipivoxil Results in Potent Viral Suppression and a Favora

25、ble Safety Profile in Chinese Patients with Chronic Hepatitis B. Hepatol Int (2014) 8：S147.3.Fung S, Kwan P, Fabri M, et al. Randomized Comparison of Tenofovir Disoproxil Fumarate vs Emtricitabine and Tenofovir Disopro

26、xil Fumarate in Patients with Lamivudine-Resistant Chronic Hepatitis B. Gastroenterology,2014,146(4):980-988.4.Berg T, Zoulim F, Moeller B, et al. Long-term efficacy and safety of emtricitabine plus tenofovir DF vs ten

27、ofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol,2014,60(4):715-22.,韋瑞德 ®長期治療的耐受性如何？,韋瑞德®長期治療慢性乙肝患者耐受性良好,*腎臟不良事件：肌酐清除率<50ml/min或血磷<2mg/dl或血清肌酐較基線升高≥0.5mg/dl # DXA：雙能X

28、線吸收法,Fung 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,2

29、014,146(4):980-988.Berg T, Zoulim F, Moeller B, et al. Long-term efficacy and safety of emtricitabine plus tenofovir DF vs tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol,2014,60

30、(4):715-22.Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. New England Journal Medicine, 2008, 359:2442-2455.Patrick Marcellin, Edward J. Gane,

31、 Naoky Tsai,et al.Seven 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 Det

32、ectable Resistance. Hepatology, 2013, 58(4 suppl):649A.,小結(jié),被批準(zhǔn)上市的口服抗乙肝病毒藥物中：韋瑞德®是唯一與LAM、LdT、ETV無交叉耐藥且強(qiáng)效的藥物,,權(quán)威指南推薦替諾福韋治療長期治療耐藥率為0耐受性良好,,富馬酸替諾福韋二吡呋酯片,警告：乳酸酸中毒/伴有脂肪變性的重度肝腫大和中斷治療后肝炎惡化 核苷類似物（包括富馬酸替諾福韋二吡呋酯片）與其它