1、难治性丙肝的治疗现状及发展趋势难治性丙肝的治疗现状及发展趋势 各种难治型患者各种难治型患者我们面临的挑战我们面临的挑战Baseline FactorSustained Virologic Response RatesPegIFN alfa-2a+RBV OR PegIFN alfa-2b+RBVHCV RNA,%1,2 2 x 106 copies/mL62-7842-53Genotype,%1,2 2 or 3 176-8242-46Genotype 1 and high viral load,%30-41Liver histology,%1,2 Stage 0-2 Stage 3-455-
2、5741-44Age1,2Older age,lower SVR*Weight1,2Higher weight,lower SVR*Race,%3,4 Black White5219-28*Logistic regression analysis,P .002.1.Manns MP,et al.Lancet.2001;358:958-965.2.Fried MW,et al.N Engl J Med.2002;347:975-982.3.Muir AJ,et al.N Engl J Med.2004;350:2265-2271.4.Conjeevaram HS,et al.2006;131:4
3、70-477.固定因素对固定因素对SVR的预测的预测非固有因素非固有因素与与 SVR预测预测 药物、剂量药物、剂量 依从性依从性 不良反应的处理不良反应的处理 治疗中的应答模式治疗中的应答模式 疗程疗程难治性患者的定义：所有治疗失败的患者难治性患者的定义：所有治疗失败的患者每一位都是特殊患者每一位都是特殊患者Probability of Achieving an SVR100806040200Patients Number12345678978974523619147CirrhosisNoNoNoNoNoNoNoYesALT quotient72222211Age in years202043
4、4343606060BMI2020262626303030HCV RNA,IU/mL x 10340404012009000900090009000Foster GR,et al.Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a(40KD)and ribavirin.Scandinavian Journal of Gastroenterology.2007;42(2):247-255.Reprinted with perm
5、ission from Taylor&Francis Ltd.SVR rate was higher in all groups when the dose of RBV was 10.6 mg/kg body weight(or 800 mg/day for a 75-kg person)IFNIFN和和RBVRBV用量显著影响用量显著影响SVRSVR200406080100579111315171921232527RBV(mg/kg)Lower-dosepegIFN alfa-2b(n=514)Higher-dosepegIFN alfa-2b(n=511)Proportion With
6、SVR(%)Reprinted from The Lancet,358,9286,Manns MP,et al,Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C:a randomised trial,958-965,2001,with permission from Elsevier.强化治疗方案强化治疗方案Fried MW,et al.Hepatology.2008;48:1033-1
7、043.Treatment-naive adults with genotype 1 HCV,HCV RNA 800,000 IU/mL,and body weight 85 kg(N=188)PegIFN 180 g/week+RBV 1200 mg/day(n=47)PegIFN 180 g/week+RBV 1600 mg/day(n=47)PegIFN 270 g/week+RBV 1200 mg/day(n=47)Week 48Week 24analysis of viral kineticsPegIFN 270 g/week+RBV 1600 mg/day(n=47)Stratif
8、ied by presence/absence of cirrhosis24-weekfollow-up for SVR难治性患者难治性患者(GT 1,High HCV RNA,85 kg)的强的强化化(Intensive)治疗方案治疗方案:Virologic Response(HCV RNA 50 IU/mL),%PegIFN 180 g/wk+RBV 1200 mg/day(n=46)PegIFN 180 g/wk+RBV 1600 mg/day(n=47)PegIFN 270 g/wk+RBV 1200 mg/day(n=47)PegIFN 270 g/wk+RBV 1600 mg/da
9、y(n=47)RVR(Week 4)2.28.510.612.8EVR(Week 12)47.838.353.251.1Week 2456.555.359.668.1End of treatment(Week 48)45.757.455.355.3SVR(Week 72)28.331.936.246.8Null response136413Relapse*40424619Fried MW,et al.Hepatology.2008;48:1033-1043.*Among patients with end-of-treatment response.治疗应答治疗应答及时预测无应答及时预测无应答
10、治疗过程中病毒应答的监测治疗过程中病毒应答的监测HCV RNA(log10 IU/mL)012345678EVRPartial response2 log declineLimit of detectionSVRWeeksSlow responseRVRPegIFN/RBV041218243036424854606672878Early Null Response早期无应早期无应(Early Null Response,eNR)答对答对 PegIFNPegIFN/RBV SVR/RBV SVR的阴性预测的阴性预测 回顾性分析回顾性分析159例慢性丙型肝炎例慢性丙型肝炎PegIFNPegIFN/
11、RBV/RBV治疗患者治疗患者4周周HCV RNA检测结果对检测结果对SVR的预测的预测 Grouped according to HCV RNA decline by Week 4 1 log10 reduction(eNR)1-2 log10 reduction 2-3 log10 reduction 3 log10 reduction but HCV RNA detectable HCV RNA undetectable(RVR)Reau N,et al.AASLD 2008.Abstract 1247.Reau N,et al.AASLD 2008.Abstract 1247.1008
12、06040200SVRNonresponseRelapse*Does not include patients with breakthrough,those that have not completed follow-up,those who were discontinued for reasons other than NR,or those lost to follow-up.Proportion of Patients(%)Posttreatment Response*1 log10 reduction(eNR)1-2 log10 reduction2-3 log10 reduct
13、ion 3 log10 reduction but detectable HCV RNAHCV RNA undetectable(RVR)Week 4 Response8713Factors associated with Week 72 nonresponse Genotype(GT)1OR:8.77(95%CI:2.01-38.35;P .01)Log10 baseline HCV RNAOR:2.24(95%CI:1.28-3.91;P .01)Early nonresponseOR:19.45(95%CI:7.85-48.21;P .0001)，eNR has 93%NPV早期无应答对
14、早期无应答对 PegIFNPegIFN/RBV SVR/RBV SVR的阴性预测的阴性预测 EVR is an essential predictor of achieving SVR:12-week stopping rule86%(n=390)65%(n=253)SVR14%(n=63)3%(n=2)All patients(n=453)NPV=97%EVRYesNoEVR=HCV RNA negative or drop of 2 log10 NPV=negative predictive valueFried M,et al.N Engl J Med 2002;347:975PEGAS
15、YS 180 g/wk plus COPEGUS 10001200 mg/day延长疗程提高延长疗程提高SVRSVRDecrease in relapse rates with 72 weeks treatment in G1 patients without an RVRPEGASYS 180 g/wk plus COPEGUS 800 mg/day48 weeks72 weeks0SVR(%)44%28%510152025303540455062%58%55606553%28%RVR=HCV RNA 50 IU/mL at week 4ETR=end of treatment respon
16、seSnchez-Tapias J,et al.Gastroenterology 2006;131:451n=142n=149ETRSVRSignificant benefit with 72 weeks therapy in G1 patients without a cEVRFerenci P,et al.57th AASLD 2006;Abstract 390SVR(%)010203040506070809010080%82%48 weeks72 weeks37%77%*n=59 19 44 13PEGASYS plus COPEGUS 10001200 mg/daycEVRNo cEV
17、R cEVR=no RVR and HCV RNA 50 IU/mL at week 12Patients had HCV RNA 50 IU/mL at end of treatment*p0.001 vs 48 weeksIncludes a small number(10%)of G4 patientsWk 4Wk 0Wk 12Wk 24Wk 4844 weeks36 weeks24 weeksHCV RNA阴性疗程决定阴性疗程决定SVR发生率发生率Time to HCV RNA negativityDuration of RNA negativityWk 7244 weeks1st R
18、egimen2nd RegimenRelative SVR rates44 weeks?难治性难治性患者患者加大剂量，强化治疗尽早达到加大剂量，强化治疗尽早达到HCV RNA阴性阴性进一步延伸进一步延伸HCV RNA的阴性时间，确保最终获得的阴性时间，确保最终获得SVR治疗时间治疗时间 HCV RNA首次阴性首次阴性标准疗程标准疗程 延长疗程延长疗程 一般一般患者患者对不能耐受患者不同治疗时期对不能耐受患者不同治疗时期采用不同的药物剂量降低方式采用不同的药物剂量降低方式 Full-dose RBV:decline in SVR when pegIFN dose decreases Full-d
19、ose pegIFN:no effect on SVR when RBV as low as 60%Stopping RBV:chance of SVR eliminatedShiffman ML,et al.Gastroenterology.2007;132:103-112.17221921141615140091519067100600102030405098%to 100%81%to 97%61%to 80%60%RBV StoppedRBV Dosage98%to 100%81%to 97%61%to 80%60%PegIFN alfa-2aDosage(N=936)SVR(%)Peg
20、IFN和和RBV早期早期(Weeks 1-20)减量对减量对SVR的影响的影响5635503360385055440646742630833805029Shiffman ML,et al.Gastroenterology.2007;132:103-112.98%to 100%81%to 97%61%to 80%60%PegIFN alfa-2aDosage(N=936)98%to 100%81%to 97%61%to 80%60%RBV StoppedRBV Dosage20406080100SVR(%)0Full-dose RBV:no change in SVR with decrease
21、d pegIFN dosageFull-dose PegIFN:no change in SVRNB:small number in many groupsAll previous nonrespondersPegIFN和和RBV后期后期(Weeks20-48)减量对减量对SVR的影响的影响难治性患者的再治疗难治性患者的再治疗Jensen D,et al.AASLD 2007.Abstract LB4.Patients with chronic HCV infection not responsive toPegIFN alfa-2b/RBV therapyPegIFN alfa-2a 180
22、 g/wk+RBV 1000/1200 mg/day(n=317)Week 48 WeeK 96 Week 72 PegIFN alfa-2a 180 g/wk+RBV 1000/1200 mg/day(n=156)PegIFN alfa-2a 180 g/wk+RBV1000/1200 mg/day(n=156)PegIFN alfa-2a 180 g/wk+RBV 1000/1200 mg/day(n=313)PegIFN alfa-2a360 g/wk+RBV1000/1200 mg/dayPegIFN alfa-2a360 g/wk+RBV1000/1200 mg/dayWeek 12
23、Follow-upFollow-upFollow-upFollow-upRandomization 2:1:1:2PegIFN 2b无应答患者的无应答患者的PegIFN 2a 再治疗再治疗42252020020406080360180Peginterferon Dose(g/wk)Percentage of Patients2 log10 declineHCV RNA*(-)Response at 12 weeksMarcellin P,et al.AASLD 2005.Abstract LB04.100*HCV RNA 600 IU/mL(quantitative)6245P .0001Pe
24、gIFN 2b无应答患者的无应答患者的PegIFN 2a再治疗再治疗仅高剂量诱导未必提高疗效仅高剂量诱导未必提高疗效Extended treatment did not increase ETR but did decrease relapse Jensen D,et al.AASLD 2007.Abstract LB4.PegIFN alfa-2a 360/180 g/wk PegIFN alfa-2a 180 g/wk 3133312849596702040608010072 wk(n=317)48 wk(n=156)72 wk(n=156)48 wk(n=313)ETRRelapseSV
25、RPatients(%)161479P=.006(OR:2.0;95%CI:1.21-3.31)78Modified ITT*Patients randomized who received at least one dose of study medication延长疗程可提高延长疗程可提高SVRJensen D,et al.AASLD 2007.Abstract LB4.Pooled 72 wks(n=473)vs 48 wks(n=469)16872 Wks(360/180 g and 180 g)48 Wks(360/180 g and 180 g)SVR(%)010203040506
26、0708010090P=.0006Modified ITT*Patients randomized who received at least one dose of study medication Overall SVR rate:17.4%GT1,pegIFN+RBV nonresponder SVR rate:10.7%SVR,%(n/N)AlbIFN alfa-2b+RBV*Every 4 WeeksEvery 2 Weeks1200 g900 g1200 g1500 g1800 gAll patients25(6/24)30(7/23)13(3/24)9(2/22)9(2/22)G
27、T1,pegIFN/RBV nonresponders15(2/13)15(2/13)13(2/16)7(1/15)6(1/18)Nelson D,et al.AASLD 2007.Abstract 51.*RBV 1000-1200 mg/day based on body weight.人血白蛋白干扰素再治疗人血白蛋白干扰素再治疗利巴韦林类似物利巴韦林类似物(taribavirin)的应用的应用Lawitz E,et al.AASLD 2008.Abstract 272.16.441.852.214.341.442.916.225.039.711.431.438.6020406080100
28、Week 4Week 12Week 24TBV 20 mg/kg/dayTBV 25 mg/kg/dayTBV 30 mg/kg/dayRBV 800-1400 mg/dayNSNSNSUndetectable HCV RNA*(%)*39 IU/mL.Hg 100 IU/mL)野生型野生型T54AV36A/MR155K/T36/155A156V/T36/156天天天天Telaprevir 定量给药定量给药Telaprevir 定量给药定量给药LODLOD=检测限检测限(100 IU/mL)1235674基线基线14天给天给药结束药结束给药后给药后710天天随访随访给药后给药后37月月长期随访
29、长期随访中位中位 log HCV RNAVX-950 给药期给药期 给药后观察给药后观察 IC50 倍数变化倍数变化野生型野生型15536361555436/155156156361555436/155野生型野生型长期随访长期随访 V36M/A/LR155K/T/S/MT54A36/155A156V/T36/1561471246466781WTKieffer T,et al.41st EASL 2006;Abstract 12 时间时间(天天)野生型野生型野生型野生型将小分子化合物与派罗欣+利巴韦林联合应用 派罗欣药代动力学的优势：起效快速、半衰期长 无交叉耐药和/或高耐药屏障的小分子化合物联
30、合应用不断优化治疗方案，提高患者的依从性244872961201441680192216PEGASYS 180 g qwHCV RNA检测检测限限血药浓度血药浓度HCV RNA 病毒病毒载载量量小分子敏感病毒小分子敏感病毒自然产生的耐药突变变异体自然产生的耐药突变变异体小分子化合物小分子化合物时间时间(小时小时)干扰素敏感患者可能无需小分子化合物治疗 防止额外的不良事件，节省支出，降低耐药风险Kwo et al,AASLD 2009,oral(62)随机、安慰剂对照、临床II期试验Telaprevir 750 mg/8小时小时+派派罗欣罗欣+RBV(n=79)派罗欣派罗欣+RBVTelapre
31、vir+派罗欣派罗欣+RBV(n=79)Telaprevir+派罗欣派罗欣+RBV(n=17)派罗欣派罗欣+RBV 基因1型初治患者*(N=250)12周周*患者根据随机分组，接受telaprevir 1250-mg负荷剂量或安慰剂。24周周48周周48周随访周随访安慰剂安慰剂+派罗欣派罗欣180 g/周周+RBV1000/1200 mg QD(n=75)随访随访24周周McHutchison J,et al.EASL 2008.Abstract 4.60周随访周随访随访随访24周周ABCDMcHutchison J,et al.N Engl J Med 2009;360:1827-38.平均
32、平均Log10 HCV RNA(IU/mL)01234567836912151821240HCV RNA检测限周周PR48对照组对照组T12PR48T12PR12T12PR24T:Telaprevir;P:派罗欣派罗欣;R:RBV治疗治疗24周平均周平均Log10 HCV RNA水平水平41%23%67%6%61%2%35%33%0%20%40%60%80%100%SVR复发复发 病毒学应答率（%）PR48T12PR48T12PR24T12PR12T:Telaprevir;P:派罗欣派罗欣;R:RBVMcHutchison J,et al.N Engl J Med 2009;360:1827-
33、38.P=0.02P=0.00248周随访周随访（周）（周）480安慰剂安慰剂+派罗欣派罗欣180 g/周周+RBV1000/1200 mg QD(n=82)Telaprevir 750 mg/8小时小时+派派罗欣罗欣+RBV(n=81)Telaprevir 750 mg/8小时小时+派派罗欣罗欣+RBV(n=82)2412派罗欣派罗欣+RBVTelaprevir 750 mg/8小时小时+派派罗欣罗欣(n=78)4ABCD*患者根据随机分组，接受telaprevir 1250-mg负荷剂量或安慰剂。C、D组：若在第4周至第10周未获得RVR或HCV RNA仍为阳性，患者应在研究药物结束治疗后
34、，开始接受派罗欣+RBV治疗直至48周。A组：若12周下降2log，且24周HCV RNA仍未转阴，则停止治疗。基因1型初治患者*(N=323)随访随访24周周60周随访周随访60周随访周随访Zeuzem S,et al.AASLD 2008.Abstract 243.治疗治疗12周平均周平均Log10 HCV RNA水平水平Hezode C,et al.N Engl J Med 2009;360:1839-50.369120012345678PR48对照组对照组T12PR12T12P12T12PR24平均平均Log10 HCV RNA(IU/mL)周 HCV RNA检测限T:Telaprev
35、ir;P:派罗欣派罗欣;R:RBV14%22%69%46%60%30%36%48%0%20%40%60%80%SVR率率 复发率复发率患者比例（%）PR48 T12PR24 T12PR12T12P12Hezode C,et al.N Engl J Med 2009;360:1839-50.T:Telaprevir;P:派罗欣派罗欣;R:RBVP=0.004P=0.003Everson et al,AASLD 2009,poster(1565)1%8%32%54%32%22%0%20%40%60%80%皮疹贫血患者比例（%）T12/PR24 PR48 T:Telaprevir;P:派罗欣派罗欣;
36、R:RBV严重的皮疹T12/PR24组与组与PR48组间存在显著性差异组间存在显著性差异随机分组(1:1:1:1)周周480安慰剂安慰剂+派罗欣派罗欣+RBV TVR 750mg q8h+派罗欣派罗欣+RBVTVR 750mg q8h+派罗欣派罗欣基因1型慢性丙肝peg-IFN+RBV无应答或复发患者，n=45324$12 180 g/wk 1000-1200 mg/d 首剂的负荷剂量为1125 mg 若未获得EVR(下降2 log)则中止治疗,A组患者符合VX06-950-107交叉研究的条件$若HCV RNA仍为阳性，则中止治疗派罗欣派罗欣+RBVTVR 750mg q8h+派罗欣派罗欣+
37、RBVABCD安慰剂安慰剂+派罗欣派罗欣+RBV派罗欣派罗欣+RBV随访随访随访随访随访随访随访随访McHutchison et al,AASLD 2009McHutchison et al,AASLD 200914%53%24%51%0%20%40%60%80%SVR率率 患者比例（%）PR48 T24PR48 T24P24T12PR24T:Telaprevir;P:派罗欣派罗欣;R:RBV复发率复发率 52%4%53%28%P0.05P0.05McHutchison et al,AASLD 20090%1%4%4%6%25%3%1%9%5%1%10%0%10%20%30%3级皮疹级皮疹 3
38、级贫血级贫血 不良事件停药不良事件停药 患者比例患者比例(%)PR48 T24PR48 T24P24T12PR24T:Telaprevir;P:派罗欣派罗欣;R:RBVTelaprevir治疗具有显著更高的早期病毒学应答率Telaprevir必须联合足量派罗欣+RBV才能获得最佳疗效未足量使用派罗欣或RBV的治疗组中，复发率和突破率明显上升皮疹、贫血在Telaprevir治疗组中较为严重，且用药时间越长不良反应越明显派罗欣是三联疗法的基础用药McHutchison et al,AASLD 2009;Everson et al,AASLD 2009,poster(1565);Hezode C,e
39、t al.N Engl J Med 2009;360:1839-50;McHutchison J,et al.N Engl J Med 2009;360:1827-38.*因为因为Alb-IFN alfa-2b 1200 g 治疗组严重肺部不良反应，根据治疗组严重肺部不良反应，根据Data Monitoring Committee 的建议，将剂量调整至的建议，将剂量调整至900 g 随随访访随访随访派派罗罗欣欣 180 g q1wkplus RBVAlb-IFN -2b 900 g q2wkplus RBV慢性丙肝初治慢性丙肝初治患者患者G1(n=1323)或或 G3/2(n=932)随访随访
40、ACHIEVE 1(G1)1ACHIEVE 2/3(G2/3)2研究周数研究周数 04824720241248Alb-IFN -2b 1200 g q2wk plus RBVAlb-IFN -2b 900 g q2wk plus RBV*随机化随机化 1.Zeuzem S,et al.44th EASL 2009;Abstract 10412.Nelson D,et al.44th EASL 2009;Abstract 1042p=0.0008，非劣效性分析，非劣效性分析225/441213/442208/440p=0.0029，非劣效性分析，非劣效性分析Zeuzem et al,EASL 2
41、009,oral,late-breaker51.0%48.2%47.3%0%20%40%60%80%100%SVR(HCV RNA 900 g23.1%4.1%24.0%10.4%28.2%10.0%0%10%20%30%40%严严重不良事件重不良事件严严重不良重不良事件停事件停药药 PEGASYS 180 gAlbinterferon 900 g Albinterferon 1200 g-900 gZeuzem S,et al,EASL 2009;Tietz A,et al.AASLD 2009,#794.1.1%0.5%1.8%2.5%严严重肺部感染重肺部感染严严重呼吸道、胸部重呼吸道、胸
42、部或或纵纵隔部感染隔部感染 全球全球93万使用派罗欣治疗的万使用派罗欣治疗的患者中，报告发生间质性肺患者中，报告发生间质性肺病的比例仅为病的比例仅为 0.02%Nelson et al,EASL 2009,oral,late-breaker0%20%40%60%80%100%SVR(HCV RNA 10 IU/mL)%p=0.009，非劣效性分析，非劣效性分析 p=0.0059，非劣效性分析，非劣效性分析 84.8%79.8%80.0%派罗欣派罗欣180 gAlb-IFN 900 g Alb-IFN1200 g 900 g派罗欣派罗欣180 gAlb-IFN 900 g Alb-IFN1200
43、 g 900 g亚洲患者是派罗欣治疗获得亚洲患者是派罗欣治疗获得SVR的的阳性预测因子阳性预测因子(p=0.01)总体患者分析总体患者分析95.579.881.8 Albuferon的总体疗效与派罗欣相似 III期临床研究Albuferon 1200 g治疗组的肺部不良事件发生率非常高，促使专家委员会建议所有患者均减量至900 g治疗全体1200 g治疗组剂量调整时：基因基因1型仅有约型仅有约1/2患者仍维持剂量治疗患者仍维持剂量治疗 基因基因2/3型仅有约型仅有约2/3患者仍维持剂量治疗患者仍维持剂量治疗 较高的停药率和剂量调整，可能严重影响实际治疗效果，临床价值如何还有待深入研究Nelson D,et al.Oral.44th EASL.2009.Zeuzem S,et al.Oral.44th EASL.2009.良好的安全性良好的安全性用药方便相同的相同的SVR率率谢谢 谢！谢！
