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1、乙肝抗病毒治疗进展,北京佑安医院陈新月 教授,慢性乙肝需要长期治疗，治疗目标是长期抑制病毒复制，阻止疾病进展,首要目标：清除或永久性抑制乙肝病毒近期临床治疗目的终止或减少肝脏的坏死炎症。减轻肝脏的炎症，预防肝脏纤维化和/或肝脏失代偿的发生，能持续保持HBV DNA阴性和ALT的正常远期临床治疗目的避免ALT的活动及导致的肝脏失代偿，以及预防肝硬化和/或肝细胞肝癌(HCC)的发生，最终延长生存期。,参考文献：慢性乙肝处理亚太共识：更新Journal of Gastroenterology and Hepatology (2003) 18,239245,慢性乙型肝炎治疗的展望,1. 核苷类似物-
2、拉米夫定- 阿德福韦- L-nucleosides (LdT, LdC) - 恩替卡韦- Emtricitabine (FTC)- Clevudine (L-FMAU)- LY582563 (Eli Lilly)2. 病毒包装抑制剂- AT-61; AT 130 (作用于RNA包裹过程 )- Bay 41- 4109 (加速核心蛋白降解)3. 基因治疗 -小分子干扰RNA(siRNA)- 反义寡核苷酸,干扰素-alpha - 常规干扰素 - 复合干扰素 - 聚乙二醇干扰素,A. 直接抗病毒药物,B. 抗病毒/免疫调节剂,C.免疫调节剂1. 非特异性免疫治疗- 白介素-12、 白介素-18- 胸
3、腺肽-alpha2. HBV特异性免疫治疗- 抗HBsAg抗体- HBV蛋白疫苗 (表面抗原、核心抗原)- HBV DNA 疫苗- T细胞体外扩增- 树突状细胞免疫治疗,单磷酸腺苷的核苷酸类似物HBV DNA链合成的终止物有效抑制HBV野生株和拉米夫定耐药株10mg，一天一次48周安全性与安慰剂相似持续抑制HBV DNA，耐药发生的阈值高,阿德福韦酯,阿德福韦治疗HBeAg (-)慢性乙肝96周对病毒学，生化学及组织学的改善,研究设计,* Patients in ADV 10 mg group re-randomized in a 2:1 fashion at week 48* All pat
4、ients who received ADV 10 mg in second 48 week period,0,Week 48,Week 96,Randomized,ADV 10 mg*,Placebo (n = 62),ADV 10 mg (n = 60),Placebo (n = 62),ADV 10 mg (n = 80),Placebo (n = 40),Placebo,Liver Biopsy,Liver Biopsy,Liver Biopsy(optional),ADV 10 mg (n = 125) 3 additional years*,97% completed,92% co
5、mpleted,ADV 10 mg,*LLQ = 1000 copies/mL,平均血清 HBV DNA,0,40,60,80,100,120,0,12,24,36,48,60,72,84,96,Weeks,ALT (IU/L),PLB - ADV,ADV - ADV,ADV - PLB,平均血清 ALT (IU/L),1ULN for males = 43 IU/L, females = 34 IU/L,ULN1,4,8,保持ALT 正常的病人比例,0,10,20,30,40,50,60,70,80,90,100,0,4,8,12,24,36,48,60,72,84,96,Patients
6、(%),Weeks,80%,76%,32%,1ULN for males = 43 IU/L, females = 34 IU/L,病人96周时肝活检 Knodell评分从基线变化情况,PLBn = 20,n = 19ADV,n = 9ADV,-5,-4,-3,-2,-1,0,+1,+2,0%,n = 20ADV,n = 19ADV,n = 9PLB,PLB - ADV,ADV - ADV,ADV - PLB,48,96,96,96,48,48,Weeks,恶化,改善,Median Change,PLB - ADV,ADV - ADV,ADV - PLB,48,96,96,96,48,48,W
7、eeks,40,20,0,20,40,60,80,35%,74%,38%,30%,63%,50%,改善,恶化,n = 19,n = 19,n = 20,n = 20,n = 8,n = 8,Patients (%),40%,25%,0%,0%,0%,13%,48 / 96周时肝纤维化评估情况,Intent to treat population of patients with biopsies at baseline, week 48 and week 96,ALT 升高 10 x ULN,ALT 10 x ULN 13% 5% 35%ALT 10 x ULN with: 胆红素 2.5 m
8、g/dL 或 5%a 0% 3%b 1 mg/dL 高于基线值 白蛋白 3 g/dL 2%a 0% 0% PT 延长 1.5 秒 2%a 0% 0% above ULN,a Events for the PLB to ADV group took place during year one on PLB b Events for the ADV to PLB group took place during year two while on PLB,PLB - ADV,n=60,ADV - ADV,n=79,ADV - PLB,n=40,耐药评估,0，48，96周时进行HBV DNA 聚合酶序
9、列分析发现rtN236T位点变异48周发生率0%96周时发生率2.5%1rtN236T变异株对阿德福韦敏感性下降但无论体内/体外试验均显示对lamivudine仍具敏感性,1 Yang et al AASLD (2003) poster # 1141,结论,96周阿德福韦的治疗使HBV DNA与 ALT持续降低 组织学改善 中断阿德福韦的治疗出现HBV DNA 和 ALT抑制的丧失 组织学改善出现反复 48周安全性与安慰剂相似 96周安全性与48周时相似阿德福韦耐药现象出现的晚且发生率低,Three year of Adefovir demonstrates sustained efficac
10、y in presumed precore mutant chronic CHB patients in a long term safety and efficacy study,EASL 2004,Result,Study 435研究目的,评价阿德福韦在肝移植前或后的病人中的疗效及安全性评价阿德福韦对于肝移植前已经出现拉米夫定耐药病人的疗效,Schiff et al. Hepatology, in press,Study 435Study Design,开放，多中心，国际临床研究需要进行肝移植的病人或肝移植后的病人（均为拉米夫定治疗失败）HBV DNA 6 log10 copies/mL
11、ALT 1.2 x ULN在原有用药基础上加用ADV 10 mg /天根据医生判断继续使用拉米夫定和 HBIg,Study 435研究终点,HBV DNA较基线的变化(%)病人无法检测出HBV DNA Roche Amplicor MonitorTM PCR (LLQ 400 copies/mL*)ALT的变化及 ALT正常的比例 Child-Pugh-Turcotte (CPT) 评分变化,*The LLQ was changed from 400 to 1,000 copies/mL during the course of the study,Study 435基线情况,Study 43
12、5HBV DNA的平均变化,0 4 8 12 24 36 48,Weeks,Post-OLT n = 169 161 156 149 116 88 57 Pre-OLT n = 103 98 91 84 52 28 13,Log10copies/mL,0,- 1,- 2,- 3,- 4,- 4.3 log10 copies/mL,- 4.1 log10 copies/mL,- 5,Week 48 pre- and post-transplantation (p 0.001 as compared to baseline),Post-OLT,Pre-OLT,Study 43548周时其他研究终点
13、,*Roche Amplicor MonitorTM PCR assay (LLQ 400 copies/mL or 1,000 copies/mL)In patients with abnormal values at baseline24 week data,移植前病人回顾性调查结果Retrospective Survey of Patient Outcomes (Pre-OLT),Study 435 Survey Questions,开始使用阿德福韦治疗后病人接受肝移植了吗?病人的病情是否得到改善从而允许接受移植?从等待移植的名单上去除?,Pre-OLT patientsn=100*,Y
14、es43 (43%),No57 (57%),病人在接受阿德福韦治疗后接受肝移植了吗?,*Surveys returned for 102 of 128 pre-OLT patients; 2 NA,病人使用阿德福韦后病情是否改善并允许接受移植手术,Received OLTn=43,*Remained on ADV therapy3 of 6 were either on ADV 4 weeks prior to OLT or began ADV after OLT,Yes*37 (86%),No6 (14%),阿德福韦改善病情是否可以使病人从等待移植的名单上去除?,没有接受 OLTn=57,R
15、emoved from OLT wait-list*21 (37%),Remained on OLT wait-list*36 (63%),*Remained on ADV therapy,仍然在等待移植名单上的病人状况,*Death within 24 weeks on therapyLost to follow-up,Conclusions,应用ADV 48周无论对于移植前还是移植后病人都有很好的抗病毒疗效及临床益处等待移植的病人获得明显的临床益处 病情改善允许接受OLT病情改善从肝移植名单上去除仍在等待移植的病人病情改善明显提高生存率,接受肝移植的拉米夫定耐药病人使用阿德福韦96周后耐药
16、情况分析,阿德福韦耐药情况,阿德福韦耐药通常出现的晚且发生率低没有接受移植的病人耐药发生率：0% （48周） 1.6% （96周）主要是rtN236T变异无论体内体外实验均显示变异病毒对拉米夫定敏感不知阿德福韦对已经发生拉米夫定变异并同时接受免疫抑制剂的病人疗效及耐药状况？,Angus et al. Gastroenterology 2003; Xiong et al. EASL 2003,研究设计,Study GS-98-435开放研究, ADV 10 mg /天用于拉米夫定治疗失败并进行肝移植的慢性乙肝病人98% 的病人基线时有 YMDD变异大部分病人继续拉米夫定治疗48周时没有发现阿德福
17、韦耐药1共有114名病人随访至96周,1. Westland et al. Therapies for Viral Hepatitis, 2002,Patients Included for Evaluation,*Attributable to low serum HBV DNA,随访96周的病人 n = 114,96周时PCR ( 1000 c/mL) 检测到HBV DNA n = 34,96周时 HBV DNA 1000 c/mL n = 80 (70%),Genotypedn = 33,PCR failure* n = 1,Results,2名病人出现rtN236T 变异 (1.8%,
18、 2/114) 2人均接受ADV单药治疗并在出现rtN236T变异之前 YMDD变异消失1人出现 ALT 波动加用LAM后DNA明显下降,出现rtN236T 变异的A病人血清HBV DNA水平,rtN236T at wk96,Serum HBV DNA (Log10 copies/mL),ADV,ALT (IU/L),5004003002001000,rtL180M+rtM204V,LAM,ALT,DNA,Wild-type in YMDD,LAM,出现rtN236T 变异的B病人血清HBV DNA水平,rtN236T at wk76,Serum HBV DNA (Log10 copies/m
19、L),ADV 10 mg,ALT (IU/L),5004003002001000,Wild-type in YMDD,rtL180M+rtM204V,LAM,ALT,DNA,LAM,In Vitro Drug Susceptibility,rtN236T demonstrated 4-fold reduced susceptibility to adefovir but remained susceptible to lamivudine in vitroConsistent with data obtained from a different assay in Huh7 cells1,1.
20、 Zoulim et al. EASL 2003,In Vitro Cross-Resistance,rtN236T remained susceptible to entecavir and emtricitabine in vitro,1. Ono et al. JCI, 2001, 107:449,Conclusions,肝移植病人应用阿德福韦长期治疗耐药发生率低rtN236T 变异率1.8% (2/114) 伴随HBV DNA及ALT反跳rtN236T变异株仍对拉米夫定及恩替卡韦敏感对于发生rtN236T 变异的病人重新使用拉米夫定可以再次抑制HBV DNA,慢乙肝病人的联合治疗,核苷
21、酸类似物+细胞因子 拉米夫定+干扰素拉米夫定+白介素-12 核苷酸类似物的联合治疗拉米夫定+阿德福韦LdT (telbivudine)+拉米夫定,Response,Lamivudine,(n=75),Lamviudine,+ IFN (n=76),p,HBeAg 血清转换,19%,35%,0.05,持续ALT 与HBV DNA应答,14,33,0.011,改善Knodell HAI,27,46,0.021,YMDD变异发生率,16,13,NS,拉米夫定+ 普通IFN- 的治疗效果,Barbaro et al, J Hepatol 2001; 35: 406-411,52 weeksend of
22、 therapy,78 weeksend of follow-up,Peg-IFN,Peg-IFN + Lam,HBeAg loss,36%,29%,44%,35%,p 0.01,NS,0,10,20,30,40,50,Peg-IFN-a2b + LamivudineNaive, HBeAg+ patients,Janssen et al., AASLD 2003,Studies with lamivudine plus IFN-a in HBeAg+ CHB,HBeAg 血清转换Standard IFNSchalm et al.(Gut 2000)NoBarbaro et al.(J Hep
23、 2001)YesPegylated IFNSung et al. (EASL 2003)YesJanssen et al. (AASLD 2003)NoH.L.Y Chan et al. (EASL 2004)Yes,Peg-IFN-a2a + LamivudineNaive, HBeAg- patients,Study week,Mean HBV DNA (log10 cp/mL),Marcellin et al. Hepatology 2003; 38 (suppl1): 724A,Naoumov et al. Hepatol 2000; 32 (4), Abstr. 868,Serum
24、 HBV DNA levels during treatment withlamivudine alone vs lamivudine plus interleukin-12,0.1,1,10,100,0,4,5,6,7,8,12,16,weeks,Log10 HBV DNA copies/ml,慢乙肝的联合治疗,核苷酸类似物+细胞因子 拉米夫定+干扰素拉米夫定+白介素-12 目前结果抗病毒效果有所提高不能持续控制病毒的复制,慢乙肝病人的联合治疗,核苷酸类似物+细胞因子 拉米夫定+干扰素拉米夫定+白介素-12 核苷酸类似物的联合治疗拉米夫定+阿德福韦LdT (telbivudine)+拉米夫定
25、,平均HBV DNA log10(copies/ml),J Sung et al. EASL 2003,Reduction in Serum HBV DNA at Week 24,Phase IIb Trial: LdT or LdT + Lamivudine, vs Lamivudine,% Patients HBV,DNA Negative by,PCR,Median log,change from,baseline,Adefovir + lamivudine:平均HBV DNA,Perrillo et al., Gastroenterolgy 2004; 126:81-90,37% frequency of transient grade3 ALT flare in switchover to ADV alone,Adefovir alone or added to lamivudine:Median HBV DNA by week of study,慢乙肝病人的联合治疗目前结论,经验性联合治疗并未显著增加持久应答率联合治疗减少耐药的发生对于已经耐药的病毒有显著疗效,联合治疗的优势或许表现在：,虽未经治疗但可能是难治性的慢性乙肝已经发生耐药的病例逆转纤维化耗竭cccDNAHBsAg/anti-HBs,
