乙肝肝硬化抗病毒治疗的现状和思考.ppt

失代偿性乙型肝炎肝硬化抗病毒治疗的现状与思考,.,代偿性乙型肝炎肝硬化是HBV感染相关疾病中的特殊人群，但其抗病毒治疗指征、药物选择、疗程、治疗终点、停药指征等均和慢性乙型肝炎普通人群一致，并无特殊，只是抗病毒治疗的指征更宽，停药指征应更严。这里不做讨论，而重点讨论失代偿乙肝肝硬化的抗病毒治疗的有关问题。,核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状,早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”基本共识：指征、目标、策略,.,核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状,早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”基本共识：指征、目标、策略,.,YaoFY,etal.LamivudinetreatmentisbenecialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-416,2001：美国加州Yao等用拉米夫定治疗23例HBV相关终末期肝病患者，并与55例患者历史对照。拉米夫定治疗患者肝移植需求减少（35%比74%），随访1-44个月无患者死亡。InastudyfromtheUniversityofCaliforniaSanFrancisco,Yaoandcoworkerscomparedacohortof23patientswithHBV-relatedend-stageliverdiseasereferredforlivertransplantationandwhoweretreatedwithlamivudine,toagroupof55historicalcontrols.Thelamivudine-treatedpatientshadmarkedlyimprovedsurvival,beginning6monthsafterstartinglamivudinewithadecreasedneedforlivertransplantation(35%versus74%:P0.04).Excludingpatientswhounderwentlivertransplant,noneofthelamivudine-treatedpatientsdied(follow-upfor1-44months)comparedtosixhistoricalcontrols(within3-12months)(P0.009).,早期探索：药物、疗效、安全,YaoFY,etal.LamivudinetreatmentisbenecialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-416,早期探索：药物、疗效、安全,2001：Perrillo等用拉米夫定治疗等待肝移植的77例失代偿肝硬化患者，病毒等各项指标好转，且4年生存率70%，明显高于2项先期报道的约60%和30%。,PerrilloandcolleaguesfrommultiplelivertransplantcentersthroughoutNorthAmericatreated77livertransplantcandidateswithend-stagechronichepatitisBwithlamivudine(100mgdaily).Nocontrolgroupwasused,butresultswerecomparedtooutcomesintwopreviouslypublishedstudiesofdecompensatedcirrhosisduetohepatitisB.HBVDNAlevelsdecreasedonlamivudinetherapy,butlevelswerenotreported.Alanineaminotransferase(ALT)valuesdecreasedandbecamenormalinmorethanhalfofpatientswithelevationsbeforetreatment.Averageserumbilirubin,albumin,andprothrombintimesimprovedwithtreatment.The4-yearsurvivalrateamongamivudine-treatedpatientswas70%,whichwashigherthanhistoricalcohorts(60%and30%).Lamivudinewaswelltolerated.Antiviralesistancedevelopedinaproportionofpatients,andappearanceofresistancewasgenerallyfollowedbyreversalofthevirologicalandclinicalbenet.,Perrillo,etal.Amulti-centerUnitedStates-CanadiantrialtoassesslamivudinemonotherapybeforeandafterlivertransplantationforchronichepatitisB.HEPATOLOGY2001;33:424-432,早期探索：药物、疗效、安全,2003：Schiff等报道阿德福韦酯治疗等待肝移植的肝硬化患者128例，48周时HBVDNA下降4.1log、ALT复常率76%、Child-Pugh稳定或改善90%以上、1年存活率84%。肝移植率43%，36%等待移植，21%不需移植，5%死亡。,Inathirdstudy,SchiffandcolleaguesfrommultipleclinicalcentersinNorthAmerica,Europe,andAsiatreated128patientswithHBV-relatedcirrhosisawaitinglivertransplantationwithadefovir(10mgdaily).TherapywasassociatedwithsignicantdeclinesinHBVDNAlevels(mediandeclineof4.1log10byweek48)andserumaminotransferaselevels(normalALTin76%byweek48).TheChild-Pughscorestabilizedorimprovedinmorethan90%ofpatientsandthe1-yearsurvivalratewas84%.Atotalof43%ofpatientsunderwentlivertransplantation,36%werestillonthewaitinglist,21%hadbeenremovedfromthewaitinglist,and5%ofpatientsdiedwithoutundergoinglivertransplantation.,SchiffER,etal.Adefovirdipivoxiltherapyforlamivudine-resistanthepatitisBinpre-andpost-livertransplantationpatients.HEPATOLOGY2003;38:1419-1427.,早期探索：药物、疗效、安全,核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状,早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”基本共识：指征、目标、策略,.,2007：Schiff等报道,等待肝移植患者226例和肝移植后患者241例在拉米夫定耐药后改阿德福韦酯治疗39-99周，等待肝移植者48周和96周时HBVDNA1,000者为59%和65%。生化和肝功指标同时改善。因不良事件中断治疗者4%，48周、94周、144周耐药发生率0、2%和2%。,Wait-listed(n=226)orpostlivertransplantation(n=241)chronichepatitisB(CHB)patientswithlamivudine-resistanthepatitisBvirus(HBV)weretreatedwithadefovirdipivoxilforamedianof39and99weeks,respectively.Amongwait-listedpatients,serumHBVDNAlevelsbecameundetectable(1,000copies/mL)in59%and65%atweeks48and96,respectively.After48weeksalanineaminotransferase(ALT),albumin,bilirubin,andprothrombintimenormalizedin77%,76%,60%,and84%ofwait-listedpatients,respectively.Amongposttransplantationpatients,serumHBVDNAlevelsbecameundetectablein40%and65%atweek48and96,respectively.After48weeks,ALT,albumin,bilirubin,andprothrombintimenormalizedin51%,81%,76%,and56%ofposttransplantationpatients,respectively.Amongwait-listedpatientswhounderwenton-studylivertransplantation,protectionfromgraftreinfectionoveramedianof35weekswassimilaramongpatientswhodid(n=34)ordidnot(n=23)receivehepatitisBimmunoglobulin(HBIg).HepatitisBsurfaceantigenwasdetectedontherstmeasurementonlyin6%and9%ofpatientswhodidordidnotreceiveHBIg,respectively.SerumHBVDNAwasdetectedonconsecutivevisitsin6%and0%ofpatientswhodidordidnotreceiveHBIg,respectively.Treatment-relatedadverseeventsledtodiscontinuationofadefovirdipivoxilin4%ofpatientsCumulativeprobabilitiesofresistancewere0%,2%,and2%atweeks48,96,and144,respectively.Inconclusion,adefovirdipivoxiseffectiveandsafeinwait-listedorposttransplantationCHBpatientswithlamivudine-resistantHBVandpreventsgraftreinfectionwithorwithoutHBIg.,EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPostLiverTransplantationPatientsWithLamivudine-ResistantHepatitisB:FinalLong-TermResults.LiverTranspl13:349-360,2007,当前热点：更优治疗方案选择,EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPostLiverTransplantationPatientsWithLamivudine-ResistantHepatitisB:FinalLong-TermResults.LiverTranspl13:349-360,2007,当前热点：更优治疗方案选择,Inastudyof79HBeAgpositive,treatment-naivepatientswhocompleted104weeksofarandomizedcontrolledstudyoflamivudineandplaceboversuslamivudineandadefovir,thecombinationwasassociatedwithlowerrateofvirologicalbreakthrough(19%versus44%),lessantiviralresistantmutations(15%versus43%),andahigherrateofALTnormalization(45%versus34%)thanlamivudinealone.ThecombinationdidnotresultinahigherrateofHBeAgseroconversionthanmonotherapy(13%versus20%).CombinationtherapydoesnotappeartoincreasetherateofdeclineofHBVDNAorresultinamorerapidclinicalimprovement,evenindecompensatedpatients.Thus,themajorreasonforusingcombinationnucleosideanalogtherapyistopreventantiviralresistancetooneorbothoftheagents.,SungJJ,etal.LamivudinecomparedwithlamivudineandadefovirdipivoxilforthetreatmentofHBeAg-positivechronichepatitisB.JHepatol2008;48:728-735.,2008：Sung等用拉米夫定或拉米夫定联合阿德福韦酯治疗79例HBeAg阳性患者104周，联合组病毒突破率更低（19%比44%），耐药率更低（15%比43%）；HBeAg血清转化率无显著差异（13%比20%），HBVDNA抑制程度和临床改善无差异。联合治疗的理由是预防耐药。,当前热点：更优治疗方案选择,2010：韩国Shim等用恩替卡韦治疗失代偿性肝硬化70例，对其中治疗1年时有病毒学应答的55例患者与144例代偿性肝病有病毒学应答者进行比较。治疗1年时免于肝移植者87.1%，Child-Pugh下降至A级者66%（36/55)、Child-Pugh下降2.0分以上者49%(27/55)。HBVDNA阴转率、生化指标和HBeAg消失率与对照组无差别。Cox回归分析提示，HBeAg阳性患者的应答比阴性患者较低。提示恩替卡韦治疗代偿性与失代偿性肝硬化患者同样有效，安全。,JHShim,etal.Efcacyofentecavirintreatment-navepatientswithhepatitisBvirus-relateddecompensatedcirrhosis.JHepatology2010,52:176182,当前热点：更优治疗方案选择,Yun-FanLiaw,etal.EFFICACYANDSAFETYOFENTECAVIRVERSUSADEFOVIRINCHRONICHEPATITISBPATIENTSWITHEVIDENCEOFHEPATICDECOMPENSATION.HEPATOLOGY,2009,50(SUPPL):505A,poster422,Ratesofadverseevents,seriousadverseevents,anddiscontinuationsduetoadverseeventswerecomparablebetweenthetreatmentgroups.DeathratesthroughWeek24forbothETVandADVwere12%.,当前热点：更优治疗方案选择,当前热点：更优治疗方案选择,本文报道恩替卡韦治疗16例肝硬化和慢性乙型肝炎患者，其中5例发生乳酸酸中毒。这些患者均有肝功能严重受损，终末期肝病模型评分（ModelforEnd-StageLiverDiseaseMELDscore）20。乳酸酸中毒(乳酸盐26-200mg/dL,pH7.02-7.40,剩余碱-5mmol/L到-18mmol/L)发生于恩替卡韦治疗后4-240天。有1例患者的乳酸酸中毒是致命的，另4例在终止恩替卡韦治疗后缓解。其余11例慢性乙型肝炎和肝硬化患者MELD评分均低于18，患者的乳酸盐血清浓度均未升高。MELD评分及其单个指标胆红素、国际标准化比率和肌酐与乳酸酸中毒的发生相关(P20).Lacticacidosis(lactate26-200mg/dL,pH7.02-7.40,baseexcess5mmol/Lto18mmol/L)occurredbetween4and240daysaftertreatmentinitiationwithentecavir.Lacticacidosiswaslethalinonepatientbutresolvedintheothercasesaftertermination/interruptionofentecavirtreatment.Noincreasedlactateserumconcentrationswereobservedduringtreatmentwithentecavirintheother11patientswithchronichepatitisBandlivercirrhosiswhoallhadMELDscoresbelow18.TheMELDscorecorrelatedwiththedevelopmentoflacticacidosis(P0.005)aswellasitssingleparametersbilirubin,internationalnormalizedratio,andcreatinine.Incontrast,Child-PughScoredidnotcorrelatewiththedevelopmentoflacticacidosis.Ourdataindicatethatentecavirshouldbeappliedcautiouslyinpatientswithimpairedliverfunction.,ChristianM.Lange,etal.SevereLacticAcidosisDuringTreatmentofChronicHepatitisBwithEntecavirinPatientswithImpairedLiverFunction.HEPATOLOGY2009;50:2001-2006,2009：Liaw等使用替诺福韦、替诺福韦/恩曲赛他平（另2组治疗24周时如HBVDNA400拷贝者也入该组）、恩替卡韦治疗失代偿肝硬化患者45、45、22例。治疗168周设计中的48周初步安全性评估，不能耐受者为6.7%、4.4%、9.1%；肾功指标异常8.9%、6.7%、4.5%；病死率4%、4%、9%，6例肝移植。48周时，维持在原治疗组中患者32例、40例、16例，HBVDNA7和肝硬化或门静脉高压)按基线Child-Pugh评分和ALT水平分层49例患者继续治疗到4年(数据将在Q3/2010公布)目前可用的是199例随机患者数据最后数据分析在Q2/2010统计学分析:疗效结果基于ITT人群.漏失数据视为失败(治疗失败,死亡或AE)目前的结果是基于2009年9月完成的初步分析最终分析将对临床应答(HBVDNA4logcopies/mlLOKANDMCMAHON.,AASLD指南（2009）推荐意见,慢性乙型肝炎的抗病毒治疗推荐意见32.核苷（酸）类似物的疗程。1.HBeAg阳性者治疗到HBeAg血清转换，继续治疗至少6个月（）。停药后密切监测（）。2.HBeAg阴性患者，应持续治疗直至HBsAg清除（）。3.代偿性肝硬化患者应长期治疗。HBeAg阳性患者治疗到HBeAg血清转换，并在巩固治疗至少6个月后或者HBeAg阴性患者治疗到HBsAg清除（-3）。停药后必须密切监测是否复发和肝炎发作。4.失代偿性肝硬化和肝移植后复发者，应终生治疗。,LOKANDMCMAHON.HEPATOLOGY,Vol.50,No.3,2009;LOKANDMCMAHON.,建议4.11.2：失代偿性肝硬化应当在肝病专科治疗，抗病毒治疗同时可根据患者具体情况考虑肝移植。只要能检出HBVDNA的患者，都应立即抗病毒治疗，应当选用强效和低耐药的核苷（酸）类似物，如恩替卡韦或替诺福韦治疗，但关于这些药物的安全性尚需进一步研究（B1）。4.11.2.Patientswithdecompensatedcirrhosisshouldbetreatedinspecializedliverunits,astheapplicationofantiviraltherapyiscomplex,andthesepatientsmaybecandidatesforlivertransplantation.End-stageliverdiseaseshouldbetreatedasamatterofurgency.TreatmentisindicatedevenifHBVDNAlevelislowinordertopreventrecurrentreactivation.PotentNUCswithgoodresistanceproles(entecavirortenofovir)shouldbeused.However,therearelittledataforthesafetyoftheseagentsindecompensatedcirrhosis.(B1),EuropeanAssociationfortheStudyoftheLiver.EASLClinicalPracticeGuidelines:ManagementofchronichepatitisB.JHepatology，2009，50:227-242,Yun-FanLiaw,etal.Asian-PacicconsensusstatementonthemanagementofchronichepatitisB:a2008updateHepatolInt(2008)2:263283,Asian-Pacificconsensusstatementonthem