乙肝抗病毒治療進展

1、乙肝抗病毒治療進展,北京佑安醫(yī)院陳新月 教授,慢性乙肝需要長期治療，治療目標是長期抑制病毒復制，阻止疾病進展,首要目標：清除或永久性抑制乙肝病毒近期臨床治療目的終止或減少肝臟的壞死炎癥。減輕肝臟的炎癥，預防肝臟纖維化和/或肝臟失代償的發(fā)生，能持續(xù)保持HBV DNA陰性和ALT的正常遠期臨床治療目的避免ALT的活動及導致的肝臟失代償，以及預防肝硬化和/或肝細胞肝癌(HCC)的發(fā)生，最終延長生存期。,參考文獻：慢性乙肝處理亞太共識

2、：更新Journal of Gastroenterology and Hepatology (2003) 18,239–245,,,,慢性乙型肝炎治療的展望,1. 核苷類似物- 拉米夫定- 阿德福韋- L-nucleosides (LdT, LdC) - 恩替卡韋- Emtricitabine (FTC)- Clevudine (L-FMAU)- LY582563 (Eli Lilly)2. 病毒包裝抑制劑- AT-6

3、1; AT 130 (作用于RNA包裹過程 )- Bay 41- 4109 (加速核心蛋白降解)3. 基因治療 -小分子干擾RNA(siRNA)- 反義寡核苷酸,干擾素-alpha - 常規(guī)干擾素 - 復合干擾素 - 聚乙二醇干擾素,A. 直接抗病毒藥物,B. 抗病毒/免疫調節(jié)劑,C.免疫調節(jié)劑1. 非特異性免疫治療

4、- 白介素-12、 白介素-18- 胸腺肽-alpha2. HBV特異性免疫治療- 抗HBsAg抗體- HBV蛋白疫苗 (表面抗原、核心抗原)- HBV DNA 疫苗- T細胞體外擴增- 樹突狀細胞免疫治療,,單磷酸腺苷的核苷酸類似物HBV DNA鏈合成的終止物有效抑制HBV野生株和拉米夫定耐藥株10mg，一天一次48周安全性與安慰劑相似持續(xù)抑制HBV DNA，耐藥發(fā)生的閾值高,,阿德福韋酯,阿

5、德福韋治療HBeAg (-)慢性乙肝96周對病毒學，生化學及組織學的改善,研究設計,* Patients in ADV 10 mg group re-randomized in a 2:1 fashion at week 48** All patients who received ADV 10 mg in second 48 week period,,,,,,0,Week 48,Week 96,Randomized,,ADV 10

6、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% comp

7、leted,92% completed,,,,ADV 10 mg,*LLQ = 1000 copies/mL,平均血清 HBV DNA,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,40,60,80,100,120,0,12

8、,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,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

9、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,10,20,30,40,50,60,70,80,90,100,0,4,8,12,24,36,48,60,72,84,96,Patients (%),Weeks,80%,76%,32%,

10、,,1ULN for males = 43 IU/L, females = 34 IU/L,病人96周時肝活檢 Knodell評分從基線變化情況,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

11、,Weeks,,,,,,,,惡化,改善,Median Change,,PLB - ADV,ADV - ADV,ADV - PLB,48,96,96,96,48,48,Weeks,,,,,,,,,,,,,,,,40,20,0,20,40,60,80,35%,74%,38%,30%,63%,50%,改善,惡化,n = 19,n = 19,n = 20,n = 20,n = 8,n = 8,Patients (%),40%,25%,0%,0%

12、,0%,13%,48 / 96周時肝纖維化評估情況,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: 膽紅素 ? 2.

13、5 mg/dL 或 5%a 0% 3%b ? 1 mg/dL 高于基線值 白蛋白< 3 g/dL 2%a 0% 0% PT 延長 ? 1.5 秒 2%a 0% 0% above ULN,,a Events for the PLB to ADV group

14、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,,耐藥評估,0，48，96周時進行HBV DNA 聚合酶序列分析發(fā)現rtN236T位點變異48周發(fā)生率0%96周時發(fā)生率2

15、.5%1rtN236T變異株對阿德福韋敏感性下降但無論體內/體外試驗均顯示對lamivudine仍具敏感性,1 Yang et al AASLD (2003) poster # 1141,結論,96周阿德福韋的治療使HBV DNA與 ALT持續(xù)降低 組織學改善 中斷阿德福韋的治療出現HBV DNA 和 ALT抑制的喪失 組織學改善出現反復 48周安全性與安慰劑相似 96周安全性與48周時相似阿德福韋耐藥現象出

16、現的晚且發(fā)生率低,Three year of Adefovir demonstrates sustained efficacy in presumed precore mutant chronic CHB patients in a long term safety and efficacy study,EASL 2004,Result,Study 435研究目的,評價阿德福韋在肝移植前或后的病人中的療效及安全性評價阿德福韋對于

17、肝移植前已經出現拉米夫定耐藥病人的療效,Schiff et al. Hepatology, in press,Study 435Study Design,開放，多中心，國際臨床研究需要進行肝移植的病人或肝移植后的病人（均為拉米夫定治療失?。〩BV DNA ? 6 log10 copies/mL ALT ? 1.2 x ULN在原有用藥基礎上加用ADV 10 mg /天根據醫(yī)生判斷繼續(xù)使用拉米夫定和 HBIg,Study 43

18、5研究終點,HBV DNA較基線的變化(%)病人無法檢測出HBV DNA Roche Amplicor MonitorTM PCR (LLQ < 400 copies/mL*)ALT的變化及 ALT正常的比例 Child-Pugh-Turcotte (CPT) 評分變化,*The LLQ was changed from 400 to 1,000 copies/mL during the course of the st

19、udy,Study 435基線情況,,,,Study 435HBV DNA的平均變化,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0 4 8 12 24 36 48,Weeks,Post-OLT n = 169 161 156 149

20、 116 88 57 Pre-OLT n = 103 98 91 84 52

21、 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

22、-OLT,,Pre-OLT,,,,Study 43548周時其他研究終點,*Roche Amplicor MonitorTM PCR assay (LLQ 400 copies/mL or 1,000 copies/mL)?In patients with abnormal values at baseline?24 week data,,,移植前病人回顧性調查結果Retrospective Survey of Patient

23、Outcomes (Pre-OLT),Study 435 Survey Questions,開始使用阿德福韋治療后病人接受肝移植了嗎?病人的病情是否得到改善從而允許接受移植?從等待移植的名單上去除?,Pre-OLT patientsn=100*,,Yes43 (43%),No57 (57%),,病人在接受阿德福韋治療后接受肝移植了嗎?,,,*Surveys returned for 102 of 128 pre-OLT

24、patients; 2 NA,病人使用阿德福韋后病情是否改善并允許接受移植手術,Received OLTn=43,,,,,,*Remained on ADV therapy?3 of 6 were either on ADV < 4 weeks prior to OLT or began ADV after OLT,Yes*37 (86%),No?6 (14%),阿德福韋改善病情是否可以使病人從等待移植的名單上去除?,,

25、,沒有接受 OLTn=57,,,,,Removed from OLT wait-list*21 (37%),Remained on OLT wait-list*36 (63%),*Remained on ADV therapy,仍然在等待移植名單上的病人狀況,*Death within 24 weeks on therapy?Lost to follow-up,,,Conclusions,應用ADV 48周無論對于移植

26、前還是移植后病人都有很好的抗病毒療效及臨床益處等待移植的病人獲得明顯的臨床益處 病情改善允許接受OLT病情改善從肝移植名單上去除仍在等待移植的病人病情改善明顯提高生存率,接受肝移植的拉米夫定耐藥病人使用阿德福韋96周后耐藥情況分析,阿德福韋耐藥情況,阿德福韋耐藥通常出現的晚且發(fā)生率低沒有接受移植的病人耐藥發(fā)生率：0% （48周） 1.6% （96周）主要是rtN236T變異無論體內體外實驗均顯示變異病毒對拉米夫定

27、敏感不知阿德福韋對已經發(fā)生拉米夫定變異并同時接受免疫抑制劑的病人療效及耐藥狀況？,Angus et al. Gastroenterology 2003; Xiong et al. EASL 2003,研究設計,,Study GS-98-435開放研究, ADV 10 mg /天用于拉米夫定治療失敗并進行肝移植的慢性乙肝病人98% 的病人基線時有 YMDD變異大部分病人繼續(xù)拉米夫定治療48周時沒有發(fā)現阿德福韋耐藥1共有114

28、名病人隨訪至96周,1. Westland et al. Therapies for Viral Hepatitis, 2002,Patients Included for Evaluation,*Attributable to low serum HBV DNA,隨訪96周的病人 n = 114,96周時PCR (? 1000 c/mL) 檢測到HBV DNA n = 34,96周時 HBV DNA <1000 c/mL

29、n = 80 (70%),Genotypedn = 33,PCR failure* n = 1,,,,,Results,2名病人出現rtN236T 變異 (1.8%, 2/114) 2人均接受ADV單藥治療并在出現rtN236T變異之前 YMDD變異消失1人出現 ALT 波動加用LAM后DNA明顯下降,出現rtN236T 變異的A病人血清HBV DNA水平,,rtN236T at wk96,Serum HBV DNA (

30、Log10 copies/mL),,ADV,ALT (IU/L),5004003002001000,rtL180M+rtM204V,,,,LAM,,,ALT,DNA,,,Wild-type in YMDD,LAM,出現rtN236T 變異的B病人血清HBV DNA水平,,rtN236T at wk76,Serum HBV DNA (Log10 copies/mL),ADV 10 mg,ALT (IU/L),50040

31、03002001000,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 vitroC

32、onsistent with data obtained from a different assay in Huh7 cells1,1. Zoulim et al. EASL 2003,,In Vitro Cross-Resistance,rtN236T remained susceptible to entecavir and emtricitabine in vitro,1. Ono et al. JCI, 2001, 107:4

33、49,Conclusions,肝移植病人應用阿德福韋長期治療耐藥發(fā)生率低rtN236T 變異率1.8% (2/114) 伴隨HBV DNA及ALT反跳rtN236T變異株仍對拉米夫定及恩替卡韋敏感對于發(fā)生rtN236T 變異的病人重新使用拉米夫定可以再次抑制HBV DNA,慢乙肝病人的聯合治療,核苷酸類似物+細胞因子 拉米夫定+干擾素拉米夫定+白介素-12 核苷酸類似物的聯合治療拉米夫定+阿德福韋LdT (te

34、lbivudine)+拉米夫定,Response,Lamivudine,(n=75),Lamviudine,+ IFN (n=76),p,HBeAg 血清轉換,19%,35%,<0.05,持續(xù)ALT 與HBV DNA應答,14,33,0.011,改善Knodell HAI,27,46,0.021,YMDD變異發(fā)生率,16,13,NS,,,,拉米夫定+ 普通IFN-? 的治療效果,Barbaro et al, J Hepatol 2

35、001; 35: 406-411,,,,,,,,,,,,,52 weeksend of 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+ patient

36、s,Janssen et al., AASLD 2003,Studies with lamivudine plus IFN-a in HBeAg+ CHB,HBeAg 血清轉換Standard IFNSchalm et al.(Gut 2000)NoBarbaro et al.(J Hep 2001)YesPegylated IFNSung et al. (EASL 2003)Y

37、esJanssen 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 e

38、t al. Hepatol 2000; 32 (4), Abstr. 868,,Serum HBV DNA levels during treatment withlamivudine alone vs lamivudine plus interleukin-12,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

39、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0.1,1,10,100,0,4,5,6,7,8,12,16,,,weeks,Log10 HBV DNA copies/ml,慢乙肝的聯合治療,核苷酸類似物+細胞因子 拉米夫定+干擾素拉米夫定+白介素-12 目前結果抗病毒效果有所提高不能持續(xù)控制病毒的復制,慢乙肝病人的聯合治療,核苷酸類似物+細胞因子 拉米夫定

40、+干擾素拉米夫定+白介素-12 核苷酸類似物的聯合治療拉米夫定+阿德福韋LdT (telbivudine)+拉米夫定,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,,% Pati

41、ents 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 AD