慢性乙型肝炎患者的抗病毒治疗

慢性乙型肝炎治疗新 进 展UDCA,慢性乙肝的全球影响,由于乙肝的高发病率和引起的肝损伤乙肝造成了亚洲地区严重的健康和经济负担2,1.WHO and CDC fact sheets,available at and 2 .Rosmawati et al.J.Gastroenterol Hepatol 2004;19:958-969,20亿HBV感染者,全球人口60亿,3-4亿慢乙肝患者1,25-40%的患者死于肝硬化或肝癌,75%的患者在亚洲环太平洋地区2,乙型肝炎病毒基因型的地理分布,Ahn SH,et al.J Med Virol.2010;82:1126-1134;Kim BK,et al.Antivir Ther.2011;16:1169-1186,A1,A1,A1,A1,A2,A2,A2,A2,A2,A2,A2,A2,A3,B2,B2,B3,C1,C1,B1,C2,C2,D,D,D,D,D,D,D,D,D,D,D,D,B6,B6,B6,B6,A1,F4,F1,F2,H,G,F1,H,F2,F2,F3,F1,C4,D4,C3,C1,E,C1,C5,B5,B4,D2,D1,D1,D1,E,E,D3,G,慢性乙肝治疗目标,HBsAg的清除是理想的“治疗终点”,Short-Term,Long-TermHBeAg(+) and (-) patients,HBeAg(+) patients,HBeAg loss,Anti-HBeseroconversion,HBeAg(-) patients,HBeAg loss,Anti-HBsseroconversion,Histologic improvementReversal of fibrosisPrevent complicationsProlong survival,HBV DNA undetectable,ALT normalization,Treatment initiation TIME,1.Ahn SH et al.Hepatol Int 2010;4:386-395 2.Liaw Y-F,et al.2008;2(3): 263-283 3.EASL J Hepatol 2009;50:227-242,CH,LC,HCC,POTENTIAL TO STOP THERAPY,HBeAgseroconversion,乙肝治疗的两种方式,HBV Replication,Liver Function,乙肝治疗方式,大 纲,治疗方案更新-以应答为指导的慢乙肝抗病毒治疗：（1）聚乙二醇化干扰素（2）核苷类似物UDCA用于病毒性肝炎,大 纲,治疗方案更新 - 以应答为指导的慢乙肝抗病毒治疗： （1）聚乙二醇化干扰素UDCA用于病毒性肝炎,PEGASYS,0WEEKS,48WEEKS,Initiatetreatment,End oftreatment,Sustained immune control,大 纲,治疗方案更新 -以应答为指导的慢乙肝抗病毒治疗： （2）核苷类似物,为什么对核苷类似物需要应答指导的治疗（RGT）？,耐药性是慢性乙型肝炎管理的主要挑战,病毒载量升高1低基因屏障4,7-9抗病毒耐药2,次优治疗方案或者不治疗,持续的肝脏炎症和损伤1,纤维化/肝硬化8，肝衰竭1肝癌9，死亡1,抗病毒耐药性,一旦产生耐药性，就会持续 7,1.Fung SK.et al.Antivir Ther.2004;9:1013-1026. 2.Liaw Y-F,et al. N Engl J Med.2004;351:1521-1531. 3.Dienstag J.et al.N Engl J Med.2008;359:1486-1500. 4.Colonno RJ.et al.Hepatology.2006;44:1656-1665. 5.Tenney DJ.et al.Antimicrob Agents Chemother.2004;48:3498-3507.6.Baraclude(entecavir) prescribing information. Princeton,NJ:Bristol-Myers Squibb. July 2008.7.Lok AS,et al.Hepatology.2007;45:507-539. 8.Chen C-J,et al.JAMA 2006;295:65-73.,拉米夫定难治性的队列研究（HBeAg-和+）：阿德福韦酯耐药的5年积累概率,ADVr=rtA181V only (44.6%);rtA181T only(25.9%);rtA181V+T(2.7%);rtN236T only (7.1%);rtA181V/T+tN236T(19.7),N=320,N=279,N=164,N=66,N=25,Years,Lee JMAhn SH.Antiviral Therapy 2010;15(2):235-241,拉米夫定耐药患者对核酸类似物的部分病毒学应答,64%,BaselineHBV DNA,7.3 7.2,7.4 9.5 9.1,7.6 7.4,7.3 7.3,6.9,1.Lee JM,Ahn SH et al.Antivir Ther.2009;14:705-12; 2.Rapti I et al.Hepatol 2007;45:307-313;3.Sherman M et al.Gastroenterology 2006;130:2039-49 4.Chang TT et al.Gastroenterol 2005;129:1189-12095.Ryu HJ,Ahn SH et al.J Med Virol 2010;82(11):1835-42 6.Yatsuji et al.J Hepatol 2008;48:923-931.,预防抗病毒耐药性应对策略,一线治疗,二线治疗,预防耐药 使用强效抗病毒药物 治疗伊始即避免耐药,添加第二种药物治疗 或耐药发生时，更换药物,Preemptive SwitchRGT with potent antiviral drugs orCombination theapy,Locarnini S,et al.Antiver Ther 2004;9:679-693;Keefe EB,et al.Clin Gastroenterol Hepatol 2008;6:1315-1341.,Switch To ENT(STENT) Study,HBV DNA levles.Drug-resistant mutations.HBeAg status,Liver biochemistry,服用拉米夫定100mg至少6个月,筛选,随机分组,每日一次，服用96周,每日一次，服用96周,RGTN=72,N=36,N=36,HBeAg+HBV DNA60IU/ml by PCR,Yonsei University College of MedicinePusan National University School of MedicineYeungnam University College of MedicineKyungpook National University College of MedicineKorea University College of Medicine,Ahn SH et al.APASL 2010.AASLD 2011.,4W,12W,24W,36W,48W,60W,72W,84W,96W,A prospective randomized trial,迅速从LAM转换到ETV能够增强抗病毒的效果,P35IU/ml at week 48 Favorable VR: HBV DNA12 IU/ml) at week 96,N=175 (100%),N=41(23.4%),N=13476.6%),N=35(20.6%),N=139(79.4%),Week 12Responder assessment,Responder(1log10 decline in HBV DNA ),Primany non-responder(1log10 decline in HBV DNA ),Week 48Responder assessment,Compliant-identify HBV resistant mutations-Add or switch to potent drug,Non-compliantCounsel on adherence,Favorable virologic response(HBV DNA 35IU/ml),Partial virological Response(HBV DNA 35IU/ml),Continue ETV therapy with Regular monitoring,Compliant,Non-compliantCounsel on adherence,Baseline low viral load(Baseline HBV DNA1.77E+08IU/ml),Baseline low viral load(Baseline HBV DNA1.77E+08IU/ml,Continue ETV therapy with Regular monitoring,Add or switch to potent drug,乙肝病毒的发现,Barush S Blumberg,M.D.,Ph.D.The Nobel Prize in Physiology and Medicine 1976,NIH:Double diffusion in agar gel (Ouchterlony) method to detect antibodies in multiply transfused patients. Au-antigen from hemophiliacs(Mt.Sinai Hospital in New York)“Why did precipitin band has developed between the serum of hemophilia Patients in NY and that of an aborigine from Australia?” Association between Au and acute hepatitis (Ann Int Med 1967;66:924-931),Subsequent study found the Australian Antigen to be the HBs antigen.,HBsAg定量 / HBV DNA定量,HBsAg定量和HBV DNA 定量提供了互补信息,HBsAg定量是对HBV DNA 定量的一个补充！,HBV,Virion,preS1,Peg-interferon,HBsAg=Marker ofImmunological response,HBc,3.2 kb DNA,Oral antiviral agents(NAs),HBV DNA=Marker ofVirus replication,Lee JM,Ahn SH.World J Gastroenterol 2011 B;runetto Editorial.J Hepatol 2010,降低HBsAg水平PEG-IFN比恩替卡韦疗效更佳,In HBeAg(+) patients,HBV DNA decline,HBeAg decline,Week,PEG-IFN(N=61),ETV(N=33),-2.2,-4.5,Reijnders et al.J Hepatology 2010,Week,ETV(N=33),PEG-IFN(N=61),-0.38,-0.94,qHBsAg的基线水平能预示恩替卡韦的完全病毒学应答,For VR (HBV DNA60 copies/ml),baseline log qHBeAg level:3.98IU/ml(sensitivity,86.8%;specificity,78.9%)(sensitivity,75.0%;specificity,89.8%),Month,P0.005,HBeAg(+),Lee JM,Ahn SHPark JY.Hepatology 2011;53(5):1486-93,A,qHBsAg水平的快速下降能预示恩替卡韦治疗期间， HBsAg转阴,For Serologic Response (HBeAg loss at 24 months),the reduction of logqHBeAg:1.00 PE IU/ml at 6 months(sensitivity, 75.0%;specificity,89.8%),P0.05,Month,Lee JM,Ahn SHPark JY.Hepatology 2011;53(5):1486-93,B,何时停用核苷类药物？ Prediction of off-treatment durability,乙肝治疗停用核苷类药物的原则,EASL guidelines state a durable response can be expected in 80% Of HBeAg+ve patients1,*AASLD recommendations on finite treatment differ for each NUC therapy,1.EASL Clinical Practics Guidelines.J Hepatol 2009;50:227-242. 2.Lok A.et al.Hepatology 2009;50(3):1-363.Liaw YF,et al.Hepatol Int.2008;2:263-283,HBsAg下降可预测 HBsAg 的转阴,N=266 patient treated with tenofovir(or adefovir-tenofovir) for 2 years.,HBeAg levels during treatment,HBV DNA levels during treatment,Weeks of study,Weeks of study,Healthcote et al.EASL and AASLD 2009.,N=266 overall,N=16 cleared HBsAg,监测HBsAg 水平能指导HBsAg阴性的慢性乙肝患者拉米夫定的停药时间,53 HBeAg-CHB on lamivudine for a mean of 19 mo.,At the end of lamivudine treatement,SR-12:HBV DNA 200IU/ml,at month 12 post-treatment,Chan HL et al.Hepatol Int 2011;5:abst PPO5-102,UDCA的发展历史,中国黑熊胆汁的主要组成成分： 被用于传统中药；Hydrophilic From In 1927,first isolation of UDCA In 1954,development of synthetic method In 1957,作为利胆剂首次上市1975年，UDCA被报道用于胆固醇性结石的溶解主要治疗领域是包括PBC在内的胆汁淤积性肝病 US FDA 批准用于PBC的唯一药物 收录于“2009版AASLD，EASL 指南”在Japan,Korea 增加了丙肝的适应症,Shoda et al.,J Biochem.,1927;7:505-17Iwasaki et al.,Z Physiol.Chem.,1936;244:181-93Makino et al.,J.Gastroenterol.Hepatol.,1998;13:659-64Makino et al.,Jpn.J.Gastroenterol.,1975;72:690-702Leuschner et al.Dig.Dis.Sci.,1985;30:642-9,UDCA:作用机制,3种主要的作用机制 1. 保护胆管细胞对抗胆汁酸毒性 2. 刺激胆汁分泌 3. 保护肝细胞拮抗胆汁酸引起的凋亡,Gustav Paumgartner,Clin.Liver.Dis.,2004;8:67-81,UDCA,Stimulation of biliary secretion,UDCA,UDCA,Stimulation of detoxification,Inhibition of apoptosis,HEPATOCYTEBile acids Apoptosis Necrosis,Bile acids,Metabolites,UDCA,Protection of cholangiocytes,CHOLANGIOCYTE,UDCA对急性病毒性肝炎的疗效,- UDCA改善肝脏炎性反应 -,Source:Jan Gslsky et al.,J Clin Gastroentroentrol 1999;28(3):249-253,N=40,N=38,P=0.037,Time(month),UDCA 能延缓乙肝由急性到慢性的病程进展,Source:Jan Gslsky et al.,J Clin Gastroentroentrol 19