慢性丙型肝炎治疗的现在将来课件.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,慢性丙型肝炎,治疗的现在与将来,DAA,时代的聚乙二醇干扰素联合利巴韦林,由最近发表的一篇文章想到的,HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV,especially in those with mild disease.,丙肝病毒的清除能改善中枢代谢以及神经认知功能，由此成为丙肝病人（特别是病变程度轻的患者）开展抗病毒治疗的重要决定因素。,V.Byrnes,et al.J Hep.2012,受益,获得,SVR,的患者肝纤维化改善,72,周时不同治疗应答的纤维化情况,Everson GT,et al.Aliment Pharm Ther.2008;27:542-551.,平均纤维化改善,(Metavir Stage),0,-0.2,-0.4,-0.6,-0.8,-1.0,-1.2,SVR,复发,NR,纤维化改善,1,的患者比例,(%),90,SVR,复发,NR,100,80,70,60,50,40,30,20,10,0,Camma C,et al.Journal of Hepatology,2001,34:593-602,受益,获得,SVR,的患者肝癌发生率下降,6,4,2,0,受益,获得,SVR,的患者肝病相关死亡率下降,Cardoso AC et al.,J Hepatol 2010,100,80,60,40,20,0,8,10,年,无需移植的比例,(%),SVRs,p,11,25,国际肝移植学会专家组,关于肝硬化应用干扰素的建议指南（,2003,）,治疗受益,获得,SVR,的患者恶性淋巴瘤发生率下降,Kawamura Y,et al.Am J Med 2007;120:1034-1041,累积恶性淋巴瘤发生率,(%),年,0,1,2,3,4,0,5,10,15,Log-rank test p=0.0159,0.36%,0%,1.49%,0%,0%,2.56%,SVR(n=1048),持续感染,(n=2161),ALT,正常的慢性丙肝患者接受派罗欣,联合,利巴韦林治疗获得和,ALT,升高患者相似的,SVR,13%,40%,p0.001,PEG-IFN,a,-2a,+,利巴韦林,24,周,PEG-IFN,a,-2a,+,利巴韦林,48,周,*,意向性治疗分析，,未经治疗的患者没有自行清除病毒,n=144,n=141,72%,78%,p0.45,SVR(%),0,20,40,60,80,100,n=59,n=58,基因,1,型,基因,2/3,型,PEG-IFN,a,-2a,+,利巴韦林,24,周,PEG-IFN,a,-2a,+,利巴韦林,48,周,Zeuzem S,et al.Gastroenterology.2004;127(6):1724-32.,12%,n=285,20%,n=286,40%,n=289,APRICOT,研究,证实了派罗欣,联合利巴韦林治疗合并,HIV,感染的丙肝患者同样有效,p=0.008,p,0.001,p,0.001,SVR,：,72,周时,HCV RNA 50 IU/mL,；意向性治疗分析,SVR(%),0,10,20,30,40,50,普通干扰素,+,利巴韦林,派罗欣,+,安慰剂,派罗欣,+,利巴韦林,Torriani F,et al.N Engl J Med 2004;351:438,随机分组,随访,随访,派罗欣,180 g/1.73 m,2,/wk,+,RBV,15 mg/kg/d,派罗欣,180 g/1.73 m,2,/wk,+,安慰剂,周,0,48,24,72,儿科慢性丙肝初治患者，年龄,5-17,岁,(n=114),设计：美国多中心、随机、对照临床试验,Schwarz KB,et al;Peds-C Clinical Research Network.Gastroenterology.2011;140(2):450-458.,PEDS-C,研究评价派罗欣,+RBV,治疗青少年丙肝患者的疗效和安全性,PEDS-C,研究,证实派罗欣,联合利巴韦林治疗,青少年慢性丙肝同样有效,p=0.044,p 30%,和其它合并用药之间的相互作用尚不明了,Boceprevir,与,Telaprevir,的常见不良事件,Boceprevir,三联方案与,pegIFN/RBV,相比最常见的不良事件是贫血、中性粒细胞减少和味觉障碍,不良事件,%,Boceprevir+PegIFN,/RBV,PegIFN,/RBV,初治患者,贫血,中性粒细胞减少,味觉障碍,(n=1225),50,25,35,(n=467),30,19,16,经治患者,贫血,味觉障碍,(n=323),45,44,(n=80),20,11,Boceprevir package insert.May 2011.Telaprevir package insert.May 2011.,不良事件,%,Telaprevir+PegIFN,/RBV(n=1797),PegIFN,/RBV(n=493),皮疹,56,34,贫血,36,17,肛直肠症状,29,7,Telaprevir,三联方案与,pegIFN/RBV,相比最常见的不良事件是贫血、皮疹和肛直肠症状,TVR,：基因,1,型初治患者的停药原则,初治患者治疗,12,周后，停用,TVR,，继续,PegIFN/RBV,肝硬化患者不采用,RGT,停药原则,时间点,标准,Wk 4 or 12,HCV RNA 1000 IU/mL,停止治疗,Wk 24,HCV RNA,检测阳性,停用,PegIFN/RBV,任何时候,停用,PegIFN/RBV,停止,TVR,Telaprevir package insert.2011.,中国丙肝患者以基因,1b,型为主,HCV,基因型的地区分布存在显著差异,即使存在地区差异，基因,1b,型仍是中国最常见的基因型,基因,6,型主要位于南部和西部地区,总体,AASLD 2011,4.6,3.3,2.6,2.0,G6,1.4,2.1,0.6,5.7,5.2,3.5,0.2,3.4,1b,HCV,基因型,1a,2b,2a or 2c,3b,3a,6c,6a or 6b,多种基因型,未确定基因型,中国丙肝患者,IL-28B,以,CC,型为主,IL28B,基因型的比例和分布,CC,CT,TT,西部,南部,北部,东部,中部,总体,86.2,86.2,86.2,83.0,80.1,84.1,12.9,13.8,13.3,16.5,19.1,15.3,0.9,0.5,0.5,0.8,0.6,ITPA,基因型的比例和分布,CC,CT,TT,69.6,64.5,76.8,74.8,70.1,71.3,29.0,30.9,18.8,24.3,27.4,26.1,1.4,4.4,1.0,2.5,2.6,0%,20%,40%,60%,80%,100%,4.6,AASLD 2011,In all regions,IL28,genotype CC(rs12979860)and ITPA genotype CC(rs1127354)were most common,with little regional variation,西部,南部,北部,东部,中部,总体,SVR(%),0,20,40,60,80,100,Chen W,et al,2010,Yu ML,et al,2008,派罗欣联合利巴韦林治疗中国基因,1,型丙肝患者的,SVR,80%,79,83,Yu ML,et al.Hepatology 2008;47:1884Chen W,et al.Chin J Hepatol 2010;18:585,基因,1,型,Peg-IFN,-2a 180,g/wk,联合,RBV 10001200 mg/d,治疗,48,周,第一代,DAA,药物对中国患者的临床意义有待探讨,中国感染控制杂志,2009;8(2):107-9.,临床荟萃,2008;23(1):49-50.,中国临床医学,2007;14(6):815-6.,中原医刊,2006;33(8):76-7.Clin Infect Dis.2008;47(10):1260-9.,中华传染病杂志,2008;26(9):560-563.Yu ML,et al.Hepatology.2008;47(6):1884-93.,华西医学,2009;24(3):646-8.,35-45,70-80,=?,未来中国丙型肝炎的个体化治疗方案？,第一代,DAA,从安全性及疗效提高角度而言，对中国初治丙肝患者意义有限,DAA,药物的作用靶点以及研发时间表,2011,2012,2013,2014,2015,2016+,US approval,boceprevir,telaprevir,ProjectedAsia-Pacific approval,*,EMA approvalboceprevir,telaprevir,*,日本已批准,Teleprevir,Protease,Inhibitors,NSSA,NS3-4A,Protease,NSSA,Inhibitors,NS5B,Polymerase,Polymerase,Inhibitors,C,E1,E2,P7,NS2,NS3,A,NS4B,NS5A,NS5B,Core,Envelope Glyciproteins,Protease,Serine Helicase,Protease,Serine Protease Cofactor,RNA-dependent,RNA-polymerase,DAA今后在中国丙肝的应用,进一步缩短丙肝初治患者的疗程（,12,周？）,提高经治患者的,SVR,（,30%,？）,未来,DAA,药物的应用将会更加个体化,谢 谢,