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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,慢性乙型肝炎治疗的进展,HBV,感染的流行情况,全世界,HBV,感染者,:,3.5亿,中国,HBV,感染者,: 1.2,亿,慢性乙型肝炎: 3 000 万, 20%,可发展为肝硬化, 1%5%,可发展为肝癌,慢性乙型肝炎的特点,慢性乙型肝炎,HBV,持续复制,肝脏病变持续存在和发展,慢性乙型肝炎的抗HBV治疗,一.干扰素,二.,核苷类似物,三.免疫调节剂,(一) 非特异性免疫调节剂,胸腺肽、胸腺素,1,、左旋咪唑、中药等。,(二),HBV,特异性免疫调节剂,Pre-S,2,和,S,蛋白疫苗,CTL,多肽疫苗,DNA,疫苗,干扰素,对慢性乙型肝炎治疗的进展,干扰素,的疗效,干扰素,对慢性乙型肝炎治疗结束(即时),应答率为40%60%,持久应答率为20%40%,干扰素治疗能显著减轻肝组织炎症,Knodell,指数下降,Hepatology, 1997,26:1621-1625,10.3,9.3,5.3,9.8,0,2,4,6,8,10,12,背景资料,42例慢性乙肝患者,6,MU, tiw 24,月,随访12月以上,*治疗组治疗前后对比,P=0.01,治疗前,治疗后,干扰素 对照组,治对照组疗组 对照组 对照组对照组 对照组,干扰素治疗慢性乙型肝炎,根据5,项长期随访（5-10年）研究结果,：,干扰素治疗完全应答者的长期持续应答率：,80,%-90%,HBsAg,阴转率：25%-65%，但亚洲患者极少阴转,Korenman J et al, Ann Intern Med 1991;114:629,Lau DT,et al, Gastroenterology 1997;113:1660,niederau,c et al, N Engl J Med 1996;334:1422,Lok ASF,et al, Gastroenterology 1993;105:1833,Lin SM, et al, Hepatology 1999;29:976,N Eng J Med 1996;334:1422,Gastroenterology 1997;113:1660,Hepatology 1997;26:1338,Hepatology 1999;30:257,Gastroenterology 1993;105:1833,Hepatology 1999;29:971,Hepatology 1997;26:1621,干扰素治疗患者,原发性肝癌发生率降低,HCC,累积发病率,(%),50,25,0 2 4 6 8 10 12,(年份),对照组,P=0.013,治疗组,随访时间（年）,Hepatology, 1999,29:971-975,干扰素治疗患者的生存率更高,累积生存率,(%),0 2 4 6 8 10 12,(年份),50,75,100,治疗组,P=0.018,对照组,随访时间（年）,Hepatology, 1999,29:971-975,干扰素治疗慢性乙肝小结,持久完全应答率： 2,0-40%,几点共识：,适应证：,ALT,升高(3-5,ULN)、HBeAg,和,HBV DNA,阳性的慢性乙型肝炎,禁忌证：重型肝炎和失代偿期,肝硬化,不宜用于慢性,HBV,携带者和,HBeAg,阴性的,慢性乙型肝炎,剂量和疗程：5,MU tiw ,疗程：,6,个月,完全应答者多数可获持久疗效,干扰素应答者可降低肝硬化和肝细胞性肝癌的发生,不良反应较多、,较大,PEG,干扰素,的特点和对慢性乙型肝炎治疗的临床研究,PEG干扰素的特性,水溶性，易迅速吸收,无毒性,分子量大，从肾脏排泄慢，半衰期明显延长达,40 h(一般干扰素为3-4 h),随PEG逐渐降解缓释干扰素，使血清干扰素维持恒定的有效浓度达168 h，可每周注射1次,降低抗原性，减少干扰素抗体的产生,A Phase II Open Label Study Evaluating the Safety and Efficacy of Peginterferon alfa-2a (40KD)vs Interferon alfa-2ain Interferon-Nave Patientswith Chronic Hepatitis B,Graham Cooksley, M.D.,AASLD Annual Meeting,Dallas, November 2001,Study Design,48,weeks,24,week,follow-up,EOF,Study weeks,48,194,IFN-naiverandomised,90 ,g,PEG-IFN,a,-2a,(40KD),qw,180 ,g,PEG-IFN,a,-2a,(40KD),qw,270 ,g,PEG-IFN,a,-2a,(40KD),qw,24,weeks,EOT,0,6,12,18,24,4.5,MIU IFN,-2a tiw,Demographics,PEG-IFN,-2a,270,gn = 48,PEG-IFN,-2a,180,gn = 46,PEG-IFN,-2a,90,gn = 49,IFN,-2a 4.5 MIUn = 51,Male38 (75%)34 (69%) 35 (76%)36 (75%),Oriental48 (93%)48 (98%)46 (100%)47 (98%),Mean age (y) 31 31 32 30,Weight (kg) 67 64 63 65,Cirrhotic (%) 8% 8% 9% 10%,Baseline ALT 3.2 4.2 3.5 3.4,(x ULN),On-Treatment Quantitative HBeAg,4.5,MIU IFN,-2a,90,g,PEG-IFN,-2a (40KD),180,g,PEG-IFN,-2a (40KD),270,g,PEG-IFN,-2a (40KD),Study Weeks,Median HBeAg reduction,0,200,400,600,800,1000,1200,1400,1,2,4,8,12,16,24,Baseline,20,Mean Log,10,Reduction in HBV DNA,Log,10,HBV DNA (copies/ml),Study weeks,Baseline,5,6,7,8,9,10,1,2,4,8,12,16,20,24,4.5,MIU IFN,-2a,90,g,PEG-IFN,-2a (40KD),180,g,PEG-IFN,-2a (40KD),270,g,PEG-IFN,-2a (40KD),HBeAg Loss at End of Follow-up,Patients with HBeAg loss,Treatment Group N %,4.5 MIU IFN,-2a,13 / 51 25%,90,g,PEG-IFN,-2a (40KD),18 / 49 37%,180,g,PEG-IFN,-2a (40KD),16 / 46 35%,270,g,PEG-IFN,-2a (40KD),14 / 48 29%,HBeAg Seroconversionat End of Follow-up,Patients with HBeAg seroconversion,Treatment Group N %,4.5 MIU IFN,-2a,13 / 51 25%,90,g,PEG-IFN,-2a (40KD),18 / 49 37%,180,g,PEG-IFN,-2a (40KD),15 / 46 33%,270,g,PEG-IFN,-2a (40KD),13 / 48 27%,0,5,10,15,20,25,30,Patients with response(%),End-of-Follow-up Combined Response*,*,HBeAg loss, HBV DNA 500,000 copies/ml, ALT normalization,4.5,MIUIFN,-2a,90,g,PEG-IFN,-2a (40KD),180,g,PEG-IFN,-2a (40KD),270,g,PEG-IFN,-2a (40KD),12%,26%,28%,19%,n = 51,n = 49,n = 46,n = 48,Withdrawals,2 (4%),1,1,1 (2%),0,1,1 (2%),0,1,1 (2%),0,1,Non-Safety,Failure to return,Other,1 (2%),1,0,1 (2%),1,0,1 (2%),0,1,2 (4%),2,0,Safety,Adverse event,Abnormal lab,2 (4%),3 (6%),2 (4%),3 (6%),Total,Reason for withdrawal,PEG-IFN,-2a,270,gn = 48,PEG-IFN,-2a,180,gn = 46,PEG-IFN,-2a,90,gn = 49,IFN,-2a 4.5 MIUn = 51,Dose Modifications,Reason for dose modification,14 (29%),15 (33%),16 (33%),10 (20%),N (%) requiring modification,1,14,11,3,2,3,2,11,10,0,1,4,2,11,5,6,0,5,2,5,2,2,1,5,Adverse event,Lab abnormality,Neutrophils,ALT,Platelets,Other,PEG-IFN,-2a,270,gn = 48,PEG-IFN,-2a,180,gn = 46,PEG-IFN,-2a,90,gn = 49,IFN,-2a 4.5 MIUn = 51,Absolute Neutrophil CountBefore, During, and After Therapy,4.5,MIU IFN,-2a,90,g,PEG-IFN,-2a (40KD),180,g,PEG-IFN,-2a (40KD),270,g,PEG-IFN,-2a (40KD),Mean neutrophils,Weeks,0,0.5,1,1.5,2,2.5,3,3.5,4,0,4,8,12,16,20,24,28,32,36,Platelet CountBefore, During, and After Therapy,Weeks,Mean platelets,0,50,100,150,200,250,0,4,8,12,16,20,24,28,32,36,4.5,MIU IFN,-2a,90,g,PEG-IFN,-2a (40KD),180,g,PEG-IFN,-2a (40KD),270,g,PEG-IFN,-2a (40KD),评议,PEG-IFN alfa-2a (40KD),抗,HBV,疗效略优于,IFN alfa-2a，,但尚无明显统计学差异,PEG-IFN alfa-2a (40KD),对中性粒细胞减少作用较,IFN alfa-2a,明显,PEG-IFN alfa-2a (40KD),对慢性乙型肝炎的疗效和安全性，尚须进一步临床验证。,拉米夫定5年治疗的结果,40%,47%,50%,27%,16-18%,Lai Schiff,Dienstag Schalm,Liaw,Chang,Leung,Guan,HBeAg seroconversion over 5 years of,treatment in patients with elevated ALT,Seroconversion = HBeAg-ve and HBeAb+ve,Guan, APDW 2001,拉米夫定治疗慢性乙型肝炎的几个重要问题,1.拉米夫定的疗程应该多长？如何减少复发，提高疗效？2.,YMDD,变异的观察和处理？,3.拉米夫定停药后的观察和处理？,疗程,总疗程至少1年。,治疗前,HBeAg,阳性的患者，治疗1年后达到完全应答,建议继续用药6个月,期间每3个月1次复查,ALT、HBV DNA、HBeAg,和 抗-,Hbe,仍完全应答可停药观察。,YMDD,变异的观察,拉米夫定治疗过程中出现,ALT,升高须除外以下病因：,有无合并其他病毒感染,有无酗酒，合并酒精性或非酒精性脂肪肝,有无同时使用其他导致肝脏损害的药物,患者有无非正规用药,是否是疾病本身的波动或,HBeAg,血清转换,在,除外以上病因后，,疗程6个月以上出现,ALT,升高者,应考虑出,现,YMDD,变异株，并进行,HBV DNA,定量检测和,YMDD,变异株检测,ALT,5XULN，HBV DNA,低于治疗前水平可继续使用拉米夫定，加强保肝治疗,仍可获得疗效,ALT,和,HBV DNA,高于治疗前水平或持续不降，可停用拉米夫定改用或加用其他抗病毒治疗,ALT5XULN，,或合并总胆红素等生化指标明显异常，有肝脏失代偿迹象,*,，,不能轻易停药,*,肝脏失代偿：血清总胆红素,5,mg/dL (85.5umol/L)；,血清白蛋白,35,g/L；,凝血酶原活动度,60%(或较正常对照延长4秒)；出现明显失代偿的临床表现，如明显厌食、乏力、恶心和呕吐、腹水、自发性腹膜炎、黄疸(进行性加深)、皮肤粘膜出血倾向、肝脏进行性缩小、肝性脑病及上消化道出血等。,YMDD,变异的处理,阿地福韦(Adefovir),腺嘌呤核苷类似物,阿地福韦双酯(,adefovir dipivoxil),为阿地福韦前体药及口服剂,口服吸收后，不需磷酸化，转化为阿地福韦，能抑制病毒,DNA,多聚酶和逆转录酶活性，并能掺入病毒,DNA,链，终止,DNA,链合成，阻止病毒复制,体外能抑制,HBV、HIV、HSV、CMV,的作用,治疗慢性乙型肝炎的疗效,国外一组多中心随机对照试验，,阿地福韦30,mg,每日1次，疗程12周，治疗53例慢性乙型肝炎病人，血清,HBVDNA,转阴率67、27,HBeAg,阴转，20出现,HBeAg,血清转换,推荐治疗剂量为10,mg/d,剂量30,mg/d,可出现肾毒性,阿地福韦与拉米夫定联用，能增加抗,HBV,的疗效。,阿地福韦对拉米夫定和泛昔洛韦耐药的慢性乙,肝病人治疗有效。,对拉米夫定耐药株,HBV,多聚酶的抑制,阿地弗韦,拉米夫定,酶,抑制常数,K,i,(M),升高倍数,K,i,(M),野生型,0.10,1,0.25,1,M552I,0.13,1.3,2.0,8.0,M552V,0.22,2.2,4.9,19.6,L528M,0.23,2.3,0.64,2.6,L528M/M5,52I,0.18,1.8,3.8,15.2,L528M/M552V,0.079,0.79,6.3,25.2,耐药指,K,i,成 5倍以上升高,抑制常数,升高倍数,Addition of adefovir to lamivudine in YMDD variant +ve decompensated CHB with clinical breakthrough (n=40),Perrillo,et al,AASLD 2000: Abstract 708,Addition of adefovir to lamivudine in YMDD variant +ve decompensated CHB with clinical breakthrough (n=40),*,p100pg/ml),11,例,HBeAg,阳性，均经肝组织学证实。,治疗方法：先用拉米夫定0.1,QD.20W,，与,IFN,-2,b,5MU tiw,联用4,W，,单用,IFN,-2b,5MU tiw,24,W,治疗结束后随访24周,结果： 治疗48,W(%),停药后随访24,W(%),ALT,复常 6/14(42.9) 8/14(57.1),HBVDNA,阴转 9/14(64.3) 8/14(57.1),HBeAg,血清转换 5/11(45.5) 5/11(45.5),HBsAg,血清转换,3/14(27.3) 3/14(27.3),无一例病人发生,YMDD,变异和,breakthrough。,评论：减少和防止拉米夫定长期治疗引起病毒变异，可能提高抗,HBV,的疗效。但本文病例数较少，缺乏对照。但延长序贯疗程或可增加疗效。值得进一步研究。,慢性乙型肝炎抗毒治疗存在的问题,1.疗效不满意,抑制,HBV,复制，很难消除,HBV, 免疫耐受,HBVcccDNA,很难清除, 病毒变异，对抗病毒药耐药,HBV DNA,与宿主细胞整合,2.不良反应,3.治疗费用较高,研制新的有效、低毒的抗,HBV,药及治疗方法：,PEG-,干扰素，新的核苷类似物，治疗性疫苗(多肽疫苗、蛋白质疫苗、,DNA,疫苗)、反义核酸等,联合治疗(,Combination treatment)：,-,抗病毒药+抗病毒药联合治疗,- 抗病毒药+免疫调节剂联合治疗,序贯治疗(,Sequential treatment),
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