韦瑞德应答不佳篇

,CNRX/TDF/0070/14,“半年前发现慢性乙肝，即开始服用拉米夫定。最近觉得特别累，没有精力去陪伴家人和孩子，检查发现病毒水平仍未降下来。” “我是服用了半年的替比夫定，病毒水平始终不理想” “我吃了1年恩替卡韦，现在情况跟你们一样”,小云，38岁工程项目经理,小云们的担心,这种情况是不是无药可治了？之前服用过抗病毒药物，会不会对新的药物疗效有影响？会不会还像之前一样，病毒总是控制不好？长期吃药有什么副作用？,对小云们这样出现应答不佳的患者，继续当前方案治疗，后续疗效和耐药率是否会受到影响呢？,LAM和LdT治疗的患者，24周时的病毒载量是预测1年时疗效及耐药率的最显著因素,Lai CL, Gane E, Liaw YF, et al. Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B. New England Journal Medicine, 2007, 357:2576-2588.,*HBV DNA不可测：HBV DNA300拷贝/ml,LAM及LdT治疗1年，HBV DNA不可测*的患者比例,LAM：拉米夫定；LdT：替比夫定,一项双盲、III期临床研究，纳入1370例慢性乙肝患者，1:1随机给予LdT600mg/d或LAM100mg/d，治疗52周后，分析其疗效及耐药情况治疗24周时各病毒载量的患者来自LAM及LdT两组患者总和,ETV治疗12个月HBV DNA可测的患者，继续治疗至3年病毒学应答率为57.5%,一项回顾性队列研究，纳入440例核苷（酸）类似物初治患者（HBeAg阳性，n=160），接受ETV 0.5mg/d治疗，平均随访349个月。研究的主要终点为累积病毒学应答率。治疗12个月， 2 例患者原发无应答，114例（25.9%）患者出现部分病毒学应答,Wong GL, Wong VW, Chan HY, et al. Undetectable 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.,*病毒学应答：HBV DNA300拷贝/ml,ETV治疗至3年的病毒学应答率*,ETV：恩替卡韦,p300拷贝/ml或出现拉米夫定耐药患者本研究中拉米夫定难治性患者共187例，其中84.5%的患者检出拉米夫定基因型耐药#病毒学突破是指患者HBV DNA较治疗中的最低点升高1 log10拷贝/ml,Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-nave patients is rare through 5 years of therapy. Hepatology,2009,49(5):1503-1514.,ETV治疗LAM难治性慢性乙肝患者的累积耐药率,LAM治疗失败#患者换用韦瑞德治疗,一项回顾性队列研究纳入197例 慢性乙肝患者，接受TDF单药或联合LAM中位治疗29个月主要研究终点为达到完全病毒学应答*的患者比例,Baran B, Soyer OM, Ormeci AC, et al. Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-nave patients with chronic hepatitis B. Antimicrob Agents Chemother, 2013, 57(4):1790-1796.,#拉米夫定治疗失败定义为经拉米夫定治疗6个月后产生耐药或部分病毒学应答者（HBV DNA 50 IU/ml）*完全病毒学应答：HBV DNA20 IU/ml,LAM治疗失败患者，换用韦瑞德治疗24个月，病毒学应答率达89%,Baran B, Soyer OM, Ormeci AC, et al. Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-nave patients with chronic hepatitis B. Antimicrob Agents Chemother, 2013, 57(4):1790-1796.,p=0.23,韦瑞德或韦瑞德联合LAM治疗 LAM治疗失败患者24个月累积完全病毒学应答率,LAM耐药患者的挽救治疗,一项前瞻性、随机、双盲、多中心、240周研究（Gilead 121 研究，ClinicalT No. NCT00737568） ，入选280例LAM耐药慢性乙肝患者（HBV DNA 3log 10 IU/ml)，随机分为TDF组（n=141）和FTC/TDF组（n=139）主要研究终点为治疗96周达到HBV DNA69 IU/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. Gastroenterology,2014,146(4):980-988.,FTC：恩曲他滨,FTC 在中国未被批准用于治疗HBV感染,入组患者基线特征,Fung S, Kwan P, Fabri M, et al. Randomized Comparison of Tenofovir Disoproxil Fumarate vs Emtricitabine and Tenofovir Disoproxil Fumarate in Patients with Lamivudine-Resistant Chronic Hepatitis B. Gastroenterology,2014,146(4):980-988.,LAM耐药患者，换用韦瑞德治疗96周病毒学应答率达89.4%,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,2014,146(4):980-988.,韦瑞德或FTC/TDF治疗LAM耐药患者96周病毒学应答率*,数据来自ITT人群,*病毒学应答：HBV DNA60 IU/ml）的患者，分三组进行挽救治疗ETV+ADV（n=5）TDF（n=6）ETV+TDF（n=31）,Yip B, Chaung K, Wong 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.,ADV：阿德福韦酯,ETV应答不佳患者，换用韦瑞德单药疗效优于ETV+ADV，且与韦瑞德 +ETV疗效相当,Yip B, Chaung K, Wong 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.,*完全病毒学应答指HBV DNA60 IU/ml,6个月时，三组比较，p=0.00112个月时，三组比较，p=0.01,ETV应答不佳后分别联合ADV，韦瑞德或换用韦瑞德单药的累积完全病毒学应答率*,出现应答不佳的患者，更换治疗方案时应考虑耐药率的问题,韦瑞德具有高耐药基因屏障,Corrigendum to: “EASL clinical practice guidelines: Management of chronic hepatitis B virus infection” J Hepatol 2012;57:167185. J Hepatol, 2013, 58:201.,S：敏感；I：中度敏感/敏感性降低；R：耐药*在临床实践中，单一M204V突变通常检测不到，其交叉耐药特征主要在体外试验中研究,最常见的HBV变异株交叉耐药位点,迄今为止，众多循证医学证据显示韦瑞德在各类慢性乙肝患者长期治疗耐药率为0,1.Patrick Marcellin, Edward J. Gane, 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 Detectable Resistance. 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 Favorable 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 Disoproxil 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 tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol,2014,60(4):715-22.,韦瑞德 长期治疗的耐受性如何？,韦瑞德长期治疗慢性乙肝患者耐受性良好,*肾脏不良事件：肌酐清除率50ml/min或血磷2mg/dl或血清肌酐较基线升高0.5mg/dl # DXA：双能X线吸收法,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,2014,146(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(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