HBV最新进展.ppt

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1、HBV 治疗:用什么开始?,This program is supported by educational grants from,幻灯目录,HBV治疗目标已经公认的HBV治疗病人的入选标准初开始治疗方案:干扰素和核苷类选择核苷类选择干扰素类其他考虑,HBV 治疗目标，病人评估和入选,HBV的治疗目标,HBV感染不能完全清除达到“治愈”治疗目标预防或逆转因严重肝损害导致的综合症及死亡对IHBeAg-阳性和HBeAg-阴性病人治疗目的是降低复制使病毒量HBV DNA 10-15 IU/mL Can allow biochemical remission and prevent further

2、liver injury,GoaHBV治疗总目标ls of HBV Therapy,In HBeAg-阳性病人positive patients(cont)HBeAg 下降和血清逆转是治疗成功的二期表现loss and seroconversion represent a secondary form of treatment successAssociated with improved long-term outcomes In HBsAg-阳性和阴性HBeAg-者HBsAg 下降和血清转阴是最大的治疗成功病毒抑制的最好指标长期预后良好，发展为肝硬化程度最低大多数病人都达不到这个效果,In

3、terferon alfa-2b,Lamivudine,Adefovir,Peginterferon alfa-2a,Telbivudine,Tenofovir,1990,1998,2002,2005,2006,2008,Entecavir,随时间演变的HBV治疗,HBeAg-阳性者推荐的启动治疗,1.Lok A,et al.Hepatology.2007;45:507-539.2.Keeffe EB,et al.Clin Gastroenterol Hepatol.2008;6:1315-1341.3.EASL HBV Guidelines.J Hepatology.2009;50:227-

4、242.,*Persistent(3-6 mos).TDF not FDA approved at time of publication.,Criteria for HBV DNA,ALT and disease stage/grade must all be met If not,guidelines recommend monitoring and consideration of treatment based on individuals age,health status,and stage of infection/disease,HBeAg-阴性患者的启动治疗,*Persist

5、ent(3-6 mos).TDF not FDA approved at time of publication.Consider liver biopsy if 2000 IU/mL and treat if moderate/severe inflammation and/or fibrosis found.,Criteria for HBV DNA,ALT and disease stage/grade must all be met If not,guidelines recommend monitoring and consideration of treatment based o

6、n individuals age,health status,and stage of infection/disease,1.Lok A,et al.Hepatology.2007;45:507-539.2.Keeffe EB,et al.Clin Gastroenterol Hepatol.2008;6:1315-1341.3.EASL HBV Guidelines.Journal of Hepatology.2009;50:227-242.,某些可以考虑HBV治疗的情况,不管HBV DNA和ALT水平如何迅速发生肝坏死的病人肝硬化失代偿期DNA 2,000 IU/mL,ALT水平忽略不

7、计肝硬化失代偿经病例证实肝移植后HBV感染HBV携带者免疫抑制或cytotoxic chemotherapy,Lok A,et al.Hepatology.2007;45:507-539.Keeffe EB,et al.Clin Gastroenterol Hepatol.2008;6:1315-1341.EASL HBV Guidelines.Journal of Hepatology.2009;50:227242.Sorrell MF,et al.Ann Intern Med.2009;150:104-110.,HBeAg状态和治疗反应关系,*After seroconversion.,一

8、线核苷类和干扰素的选择,*Prolonged treatment not feasible.Newer vs older nucles(t)ides.,选择一线核苷类似物,选择影响因素,对治疗反应好的相关因素 高ALT 低 HBV DNA 特殊病人群体老年人优先治疗HIV 合并感染没有HCV合并感染,疗效,(稳定性=耐药屏障),考虑选择起始药物的几个问题,安全性,有效性(Potency),治疗1年HBV DNA测不到,*By PCR-based assay(LLD 50 IU/mL)except for some LAM studies.,Lok A,et al.Hepatology.2007

9、;45:507-539.EASL HBV Guidelines.Journal of Hepatology.2009;50:227-242.,Not head-to-head trials;different patient populations and trial designs,HBeAg 阳性,HBeAg 阴性,Undetectable*HBV DNA(%),100,80,60,40,20,0,LAM,ADV,ETV,LdT,TDF,40-44,13-21,67,60,76,60-73,51-63,90,88,91,100,80,60,40,20,0,LAM,ADV,ETV,LdT,T

10、DF,HBeAg-阳性病人1年治疗后发生HBeAg 下降/血清逆转,HBeAg Loss/Seroconversion(%),Lau GK,et al.N Engl J Med.2005;352:2682-2695.Marcellin P,et al.N Engl J Med.2003;348:808-816 Chang TT,et al.N Engl J Med.2006;354:1001-1010.Lai CL,et al.N Engl J Med.2007;357:2576-2588.Marcellin P,et al.N Engl J Med.2008;359:2442-2455.,N

11、ot head-to-head trials;different patient populations and trial designs,HBeAg Loss,HBeAg Seroconversion,100,80,60,40,20,0,LAM,ADV,ETV,LdT,TDF,32,24,22,26,22,12-18,21,23,21,100,80,60,40,20,0,LAM,ADV,ETV,LdT,TDF,NR,Years of Therapy,Patients(%),HBeAg-阳性病人巩固治疗 HBeAg血清逆转,*With sustained undetectable HBV D

12、NA.,Chang TT,et al.N Engl J Med.2006;354:1001-1010.Lai CL,et al.N Engl J Med.2007;357:2576-2588.Marcellin P,et al.N Engl J Med.2003;348:808-816.Marcellin P,et al.N Engl J Med.2008;359:2442-2455.Lok AS,et al.Gastroenterology.2003;125:1714-1722.Leung NW,et al.Hepatology.2001;33:1527-1532.Dienstag JL,e

13、t al.Hepatology.2003;37:748-755.Marcellin P,et al.Hepatology.2008;48:750-758.Liaw YF,et al.Gastroenterology.2009;136:486-495.Gane E,et al.AASLD 2008.Abstract 729.Heathcote E,et al.AASLD 2008.Abstract 158.,Not head-to-head trials;different patient populations and trial designs,100,80,60,40,20,0,1,2,3

14、,4,5,22,12,21,23,21,29,31,29,27,40,37,47,50,48,LAM,ADV,ETV,LdT,TDF,HBeAg-阳性治疗后逐渐HBsAg 丢失,Not head-to-head trials;different patient populations and trial designs,*Patients generally withdrew from therapy after HBeAg seroconversion was achieved and any patients achieving HBsAg loss after this point ar

15、e not calculated in rates.Median follow-up 80 weeks.,Gish RG,et al.Gastroenterology.2007;133:1437-1444.Heathcote E,et al.AASLD 2008.Abstract 158.Hsu,et al.EASL 2009.Abstract 911.Hadziyannis SJ,et al.Gastroenterology.2006;131:1743-1751.Yao GB,et al.J Dig Dis.2009;10:131-137.Gish RG,et al.J Viral Hep.

16、2009;In press.,治疗1年ALT正常，组织学表现好转,Lai CL,et al.N Engl J Med.1998;339:61-68.Dienstag JL,et al.N Engl J Med.1999;341:1256-1263.Lau GK,et al.N Engl J Med.2005;352:2682-2695.Chang TT,et al.N Engl J Med.2006;354:1001-1010.Lai CL,et al.N Engl J Med.2007;357:2576-2588.Marcellin P,et al.N Engl J Med.2003;348

17、:808-816.Marcellin P,et al.2008;359:2442-2455.,*Significant variation in the baseline HBV DNA and ALT between trials.,耐药和治疗稳定性,什么因素决定耐药率?Potency 和基因屏障,Potency is only 1 part of the equation耐药相关的药物学屏障剂量安全性血液水平组织浓度n耐药基因屏障The number of substitutions needed for primary antiviral drug resistanceProbably

18、at least as important as potency,Allen MI,et al.Hepatology.1998;27:1670-1677.Yatsuji H,et al.Antimicrob Agents Chemother.2006;50:3867-3874.Qi X,et al.Antivir Ther.2007;12:355-362.Villeneuve JP,et al.J Hepatol.2003;39:1085-1089.Baldick CJ,et al.Hepatology.2008;47:1473-1482.Seifer M,et al.Antiviral Re

19、s.2009;81:147-155.Heathcote E,et al.AASLD 2008.Abstract 158.Marcellin P,et al.AASLD 2008.Abstract 146.,耐药率发生相关因素?Potency vs Genetic Barrier(cont),LAM:rtM204V/I and rtA181T(also possibly V)Compensatory mutations:rtL180M,rtV173L,and rtL80V/ILdT:rtM204I(not rtM204V)ADV:rtA181T and rtN236TCombination of

20、 low genetic barrier drugs:at least 2 mutations requiredETV:at least 3 mutations requiredrtL180M+rtM204V+1 of the following:rtT184G or rtS202I or rtM250V changeTDF:no signature resistance mutations identified at 2 years,Allen MI,et al.Hepatology.1998;27:1670-1677.Yatsuji H,et al.Antimicrob Agents Ch

21、emother.2006;50:3867-3874.Qi X,et al.Antivir Ther.2007;12:355-362.Villeneuve JP,et al.J Hepatol.2003;39:1085-1089.Baldick CJ,et al.Hepatology.2008;47:1473-1482.Seifer M,et al.Antiviral Res.2009;81:147-155.Heathcote E,et al.AASLD 2008.Abstract 158.Marcellin P,et al.AASLD 2008.Abstract 146.,第一次口服核苷类患者

22、耐药率的累积,Not head-to-head trials;different patient populations and trial designs,EASL HBV Guidelines.J Hepatol.2009;50:227-242.Tenny DJ,et al.EASL 2009.Abstract 20.,Year,0,24,49,67,70,38,1,2,3,4,5,Patients(%),80,40,60,20,100,0,3,11,18,29,0.2,1.2,1.2,4,0,0,17,1.2,6,1.2,LAM,ADV,ETV,LdT,TDF,0.5,小结药力和基因屏障

23、对耐药的影响,LAM and LdT Potent agents with low genetic barriers and high rates of resistanceADV Less potent agent with low pharmacologic barrier with intermediate rate of resistanceETVPotent agent with high pharmacologic and genetic barriers and low rates of resistanceTDF Potent agent with high pharmacol

24、ogic and low rates of resistance,genetic barrier not yet defined,复合治疗,复合药物治疗组合方式?,No combination therapy has convincingly shown increased short-term efficacy in nucleos(t)ide-naive patientsLdT+LAM vs LdT vs LAM1LAM+ADV vs LAM2FTC+ADV vs ADV3TDF+FTC vs TDF4Currently available drugs have excellent res

25、istance profileStudy to generate data sufficient for approval of frontline combination treatment unlikely to be performedWould have to be very large,very long,require shorter-term endpoints than resistance alone,and expensive,1.Lai CL,et al.Gastroenterol.2005;129:528-536.2.Sung JJ,et al.J Hepatol.20

26、08;48:728-735.3.Hui CK,et al.J Hepatol.2008;48:714-720.4.Berg T,et al.EASL 2009;Abstract 903.,推荐使用复合治疗的特殊病人,肝硬化发耐药高危和肝坏死高危HIV/HBV 双重感染选择对两中感染都有抑制作用的药物预防耐药已经存在耐药Rates of infection with resistant virus low but increasing没有数据表明，选择复合治疗优于单一新药的治疗,Lok AS,et al.Hepatology.2007;45:507-539.Jacobson IM.J Hepat

27、ol.2008;48:687-691.,小结FDA批准的口服HBV治疗,*Approximate and relative.Number of mutations needed for primary antiviral drug resistance.Only includes reported adverse events that may differ in historical incidence associated with LAM and,therefore,potentially affecting selection vs other agents.Pancreatitis

28、has been reported as a class effect and all agents have to be dose adjusted for renal insufficiency.From HIV databases,初开始治疗最佳核苷类选择,Use nucleos(t)ides as monotherapy with Highest antiviral potency and genetic barrier to resistanceLow incidence of resistance over time Rapid and sustained to maximize

29、cumulative benefitLAM/LdT/ADV not generally recommended as first-line therapyCombination therapy may be considered in patients where avoiding resistance is especially important Currently no data supporting this approach vs newer monotherapiesConsider individual patient characteristics in relation to

30、 safetyComorbidities(ie,compromised renal function)Coinfections(ie,anti-HIV activity of agents)Conception planning,Keeffe EB,et al.Clin Gastroenterol Hepatol.2008;6:1315-1341.EASL HBV Guidelines.J Hepatol.2009;50:227-242.Lok AS,et al.Hepatology.2007;45:507-539.,小结：选择干扰素做为初始治疗,选择干扰素的相关因素,适合用药者基因型 A o

31、r B C or D 基线低HBV DNA(baseline and on treatment)基线高ALT(baseline)特殊人群年轻人将来有生育欲望的年轻女性病人自己选择没有HIV合并感染合并HCV感染,培干扰素治疗相关的副作用,Patients should be carefully monitored for adverse eventsMost common adverse events:flu-like symptoms(fever,chills,headache,malaise,and myalgia)as well as psychological impairment,M

32、onths,Depression,Fatigue,Flu-like symptoms,Anxiety,1,2,3,4,0,Increase in Incidence/Severity,Keeffe EB,et al.Clin Gastroenterol Hepatol.2008;6:1315-1341.,0,20,40,60,80,100,PegIFN 180 g(n=271),PegIFN+LAM(n=271),LAM 100 mg(n=272),27,24,20,HBV DNA 105 copies/mL(20,000 IU/mL),ALTNormal,HBeAgLoss,HBeAgSer

33、oconversion,30,27,22,52,86,62,39,46,62,Patients(%),HBsAg seroconversion:0%in all 3 arms,HBV DNA 400 copies/mL(80 IU/mL),25,69,40,Lau GK,et al.N Engl J Med.2005;352:2682-2695.,HBeAg-阳性病人：培干扰素alfa-2a或拉米夫定或同时使用两种治疗48周比较,Lau GK,et al.N Engl J Med.2005;352:2682-2695.,HBeAg Seroconversion(%),32,27,19,0,10

34、,20,30,40,50,PegIFN(n=271),PegIFN+LAM(n=271),LAM(n=272),P.001,P=.023,HBsAg seroconversion:3%of pegIFN groups/0%in LAM group(P=.001),60,70,80,90,100,Off-Treatment Follow-up(Week 72),HBeAg Seroconversion After EOT(Week 48)停药后随访,HBeAg-阴性者使用培干扰素 PegIFN-2a 拉米夫定治疗病毒抑制情况,Marcellin P,et al.AASLD 2006.Abstra

35、ct.972.Marcellin P,et al.EASL 2007.Abstract 53.Marcellin P,et al.EASL 2008.Abstract 103.,*80 IU/mL,missing data considered a nonresponse.,Years After Therapy Completed,Patients with HBV DNA 400 copies/mL(%)*,100,90,80,70,60,50,40,30,20,10,0,1,2,3,4,13,13,18,17,HBeAg(-)患者HBsAg水平是长期耐受干扰素治疗与否的指标,4-yr a

36、nd 6-mo response rates higher with Wk 12 HBsAg level 1500 IU/mL vs 1500 IU/mL in long-term cohort,Marcellin P,et al.AASLD 2008.Abstract 919.,6 mos posttreatment,4 yrs posttreatment,HBsAg 1500 IU/mL,HBV DNA 10,000 copies/mL,HBV DNA 400 copies/mL,HBsAg Clearance,Patients With Response(%),59,39,39,31,7

37、,23,60,40,20,0,6 mos posttreatment,4 yrs posttreatment,HBsAg 1500 IU/mL,HBV DNA 10,000 copies/mL,HBV DNA 400 copies/mL,HBsAg Clearance,Patients With Response(%),34,12,9,8,2,4,60,40,20,0,100,80,100,80,早期 HBsAg 动力学反应是长期干扰素治疗成功与否的预期指标,治疗12周发生病毒抑制对的HBsAg监测 提示病人可能是长期耐受者 病人可能成为无反应者这群人需换药,Lau GK,et al.APAS

38、L 2009.Abstract PE083.Moucari R,et al.Hepatology.2009;49:1151-1157.Brunetto MR,et al.Hepatology.2009;49:1411-1150.Moucari R,et al.J Hepatol.2009;50:1084-1092.Perillo RP.Hepatology.2009;49:1063-1065.,关于使用培干扰素alfa-2a作为一线治疗的小结,利处持久的治疗耐受，持久治疗反应，不发生耐药弊处：需要粘膜下给药，很多患者发生明显毒副作用HBeAg 和HBsAg 血清逆转率，耐受性，和跟核苷类治疗比

39、较等是决定治疗的因素HBsAg 动力学分析可以对治疗反应提供前期评估,其他跟启动治疗相关因素,对有生育欲望HBV女性治疗推荐,有肝损害，低病毒量先怀孕，后治疗中度肝损害，没有肝硬化怀孕前治疗，如果起效，受孕前停止治疗严重肝损害孕前或孕中治疗，直到分娩前轻度肝损害，高病毒量在妊娠后期使用“B”类药治疗,Wedemeyer H,et al.Dtsch Med Wochenschr.2007;132:1775-1782.EASL HBV Guidelines.J Hepatol.2009;50:227-242.,血透和肾移植病人,ADV and TDF have been linked to wor

40、sening renal function and should be used with caution in renally impaired patientsTDF can be used if dose adjustments are made in response to changes in glomerular filtration rates No specific renal toxicity associated with entecavirDose-adaptation should be used with any agentShould be made accordi

41、ng to the prescribing informationMonitoring of renal function before and during therapy particularly important in patients who have multiple risk factors for renal impairment,EASL HBV Guidelines.J Hepatology.2009;50:227-242.Ha NB.AASLD 2008.Abstract 901.,小结,选择初始治疗方案强调高效和治疗稳定性一旦 HBV复制受抑制，丢失和血清逆转表明治疗好

42、转 分析治疗反应的预期因素核苷类选择耐药屏障最高的药物合并组合治疗大多数人不适用干扰素alfa-2a评估HBsAg动力学越来越重要,Go Online for Additional Components of This Program!,CME/CE-certified Text Module:of all the key data,plus discussions exploring the clinical implicationsCME/CE-certified Interactive Case Challenges:follow along and test your learning on cases with expertsDownloadable PowerPoint slides,