乙肝肝硬化抗病毒治療的現(xiàn)狀和思考河南會乙肝肝硬化抗病毒治療的現(xiàn)狀和思考河南會代償性乙型肝炎肝硬化是HBV感染相關(guān)疾病中的特殊人群，但其抗病毒治療指征、藥物選擇、療程、治療終點、停藥指征等均和慢性乙型肝炎普通人群一致，并無特殊，只是抗病毒治療的指征更寬，停藥指征應(yīng)更嚴(yán)。這里不做討論，而重點討論失代償乙肝肝硬化的抗病毒治療的有關(guān)問題。代償性乙型肝炎肝硬化是HBV感染相關(guān)疾病中的特殊人群，但核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：YaoFY,etal.Lamivudinetreatmentisbene?cialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-4162001：美國加州Yao等用拉米夫定治療23例HBV相關(guān)終末期肝病患者，并與55例患者歷史對照。拉米夫定治療患者肝移植需求減少（35%比74%），隨訪1-44個月無患者死亡。InastudyfromtheUniversityofCaliforniaSanFrancisco,Yaoandcoworkerscomparedacohortof23patientswithHBV-relatedend-stageliverdiseasereferredforlivertransplantationandwhoweretreatedwithlamivudine,toagroupof55historicalcontrols.Thelamivudine-treatedpatientshadmarkedlyimprovedsurvival,beginning6monthsafterstartinglamivudinewithadecreasedneedforlivertransplantation(35%versus74%:P＜0.04).Excludingpatientswhounderwentlivertransplant,noneofthelamivudine-treatedpatientsdied(follow-upfor1-44months)comparedtosixhistoricalcontrols(within3-12months)(P＜0.009).早期探索：藥物、療效、安全YaoFY,etal.LamivudinetreaYaoFY,etal.Lamivudinetreatmentisbene?cialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-416早期探索：藥物、療效、安全YaoFY,etal.Lamivudinetrea2001：Perrillo等用拉米夫定治療等待肝移植的77例失代償肝硬化患者，病毒等各項指標(biāo)好轉(zhuǎn)，且4年生存率70%，明顯高于2項先期報道的約60%和30%。

PerrilloandcolleaguesfrommultiplelivertransplantcentersthroughoutNorthAmericatreated77livertransplantcandidateswithend-stagechronichepatitisBwithlamivudine(100mgdaily).Nocontrolgroupwasused,butresultswerecomparedtooutcomesintwopreviouslypublishedstudiesofdecompensatedcirrhosisduetohepatitisB.HBVDNAlevelsdecreasedonlamivudinetherapy,butlevelswerenotreported.Alanineaminotransferase(ALT)valuesdecreasedandbecamenormalinmorethanhalfofpatientswithelevationsbeforetreatment.Averageserumbilirubin,albumin,andprothrombintimesimprovedwithtreatment.The4-yearsurvivalrateamongamivudine-treatedpatientswas70%,whichwashigherthanhistoricalcohorts(~60%and30%).Lamivudinewaswelltolerated.Antiviralesistancedevelopedinaproportionofpatients,andappearanceofresistancewasgenerallyfollowedbyreversalofthevirologicalandclinicalbene?t.Perrillo,etal.Amulti-centerUnitedStates-CanadiantrialtoassesslamivudinemonotherapybeforeandafterlivertransplantationforchronichepatitisB.HEPATOLOGY2001;33:424-432早期探索：藥物、療效、安全2001：Perrillo等用拉米夫定治療等待肝移植的77例2003：Schiff等報道阿德福韋酯治療等待肝移植的肝硬化患者128例，48周時HBVDNA下降4.1log、ALT復(fù)常率76%、Child-Pugh穩(wěn)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).Therapywasassociatedwithsigni?cantdeclinesinHBVDNAlevels(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：藥物、療效、安全2003：Schiff等報道阿德福韋酯治療等待肝移植的肝硬化核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：2007：Schiff等報道,等待肝移植患者226例和肝移植后患者241例在拉米夫定耐藥后改阿德福韋酯治療39-99周，等待肝移植者48周和96周時HBVDNA<1,000者為59%和65%。生化和肝功指標(biāo)同時改善。因不良事件中斷治療者4%，48周、94周、144周耐藥發(fā)生率0、2%和2%。

Wait-listed(n=226)orpost–livertransplantation(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).HepatitisBsurfaceantigenwasdetectedonthe?rstmeasurementonlyin6%and9%ofpatientswhodidordidnotreceiveHBIg,respectively.SerumHBVDNAwasdetectedonconsecutivevisitsin6%and0%ofpatientswhodidordidnotreceiveHBIg,respectively.Treatment-relatedadverseeventsledtodiscontinuationofadefovirdipivoxilin4%ofpatientsCumulativeprobabilitiesofresistancewere0%,2%,and2%atweeks48,96,and144,respectively.Inconclusion,adefovirdipivoxiseffectiveandsafeinwait-listedorposttransplantationCHBpatientswithlamivudine-resistantHBVandpreventsgraftreinfectionwithorwithoutHBIg.EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPost–LiverTransplantationPatientsWithLamivudine-ResistantHepatitisB:FinalLong-TermResults.LiverTranspl13:349-360,2007當(dāng)前熱點：更優(yōu)治療方案選擇2007：Schiff等報道,等待肝移植患者226例和肝移植EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPost–LiverTransplantationPatientsWithLamivudine-ResistantHepatitisB:FinalLong-TermResults.LiverTranspl13:349-360,2007當(dāng)前熱點：更優(yōu)治療方案選擇EugeneSchiff,etal.Adefovir

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聯(lián)合阿德福韋酯治療79例HBeAg陽性患者104周，聯(lián)合組病毒突破率更低（19%比44%），耐藥率更低（15%比43%）；HBeAg血清轉(zhuǎn)化率無顯著差異（13%比20%），HBVDNA抑制程度和臨床改善無差異。聯(lián)合治療的理由是預(yù)防耐藥。當(dāng)前熱點：更優(yōu)治療方案選擇Inastudyof79HBeAgpos

2010：韓國Shim等用恩替卡韋治療失代償性肝硬化70例，對其中治療1年時有病毒學(xué)應(yīng)答的55例患者與144例代償性肝病有病毒學(xué)應(yīng)答者進行比較。治療1年時免于肝移植者87.1%，Child-Pugh下降至A級者66%（36/55)、Child-Pugh下降2.0分以上者49%(27/55)。HBVDNA陰轉(zhuǎn)率、生化指標(biāo)和HBeAg消失率與對照組無差別。Cox回歸分析提示，HBeAg陽性患者的應(yīng)答比陰性患者較低。提示恩替卡韋治療代償性與失代償性肝硬化患者同樣有效，安全。JHShim,etal.Ef?cacyofentecavirintreatment-na?vepatientswithhepatitisBvirus-relateddecompensatedcirrhosis.JHepatology2010,52:176–182當(dāng)前熱點：更優(yōu)治療方案選擇2010：韓國Shim等用恩替卡韋治療失代償性肝硬化70Yun-FanLiaw,etal.EFFICACYANDSAFETYOFENTECAVIRVERSUSADEFOVIRINCHRONICHEPATITISBPATIENTSWITHEVIDENCEOFHEPATICDECOMPENSATION.HEPATOLOGY,2009,50(SUPPL):505A,poster422Ratesofadverseevents,seriousadverseevents,anddiscontinuationsduetoadverseeventswerecomparablebetweenthetreatmentgroups.DeathratesthroughWeek24forbothETVandADVwere12%.當(dāng)前熱點：更優(yōu)治療方案選擇Yun-FanLiaw,etal.EFFICAC當(dāng)前熱點：更優(yōu)治療方案選擇本文報道恩替卡韋治療16例肝硬化和慢性乙型肝炎患者，其中5例發(fā)生乳酸酸中毒。這些患者均有肝功能嚴(yán)重受損，終末期肝病模型評分（ModelforEnd-StageLiverDisease[MELD]score）≥20。乳酸酸中毒(乳酸鹽26-200mg/dL,pH7.02-7.40,剩余堿-5mmol/L到-18mmol/L)發(fā)生于恩替卡韋治療后4-240天。有1例患者的乳酸酸中毒是致命的，另4例在終止恩替卡韋治療后緩解。其余11例慢性乙型肝炎和肝硬化患者MELD評分均低于18，患者的乳酸鹽血清濃度均未升高。MELD評分及其單個指標(biāo)膽紅素、國際標(biāo)準(zhǔn)化比率和肌酐與乳酸酸中毒的發(fā)生相關(guān)(P<0.005)。相反，Child-Pugh評分與乳酸酸中毒的發(fā)生不相關(guān)。我們的數(shù)據(jù)提示恩替卡韋應(yīng)當(dāng)謹(jǐn)慎用于肝功能受損患者.EntecavirisapotentnucleosideinhibitorofthehepatitisBvirus(HBV)polymerasewithahighantiviralefficacyandahighgeneticbarriertoviralresistance.Afterapprovalin2006,knowledgeonthesideeffectprofileinpatientswithadvancedliverdiseaseandimpairedliverfunctionisstilllimited.Here,wereporton16patientswithlivercirrhosisandchronichepatitisBwhoweretreatedwithentecavir.Fiveofthesepatientsdevelopedlacticacidosisduringentecavirtreatment.Allpatientswhodevelopedlacticacidosishadhighlyimpairedliverfunction(ModelforEnd-StageLiverDisease[MELD]score>20).Lacticacidosis(lactate26-200mg/dL,pH7.02-7.40,baseexcess5mmol/Lto18mmol/L)occurredbetween4and240daysaftertreatmentinitiationwithentecavir.Lacticacidosiswaslethalinonepatientbutresolvedintheothercasesaftertermination/interruptionofentecavirtreatment.Noincreasedlactateserumconcentrationswereobservedduringtreatmentwithentecavirintheother11patientswithchronichepatitisBandlivercirrhosiswhoallhadMELDscoresbelow18.TheMELDscorecorrelatedwiththedevelopmentoflacticacidosis(P<0.005)aswellasitssingleparametersbilirubin,internationalnormalizedratio,andcreatinine.Incontrast,Child-PughScoredidnotcorrelatewiththedevelopmentoflacticacidosis.Ourdataindicatethatentecavirshouldbeappliedcautiouslyinpatientswithimpairedliverfunction.ChristianM.Lange,etal.SevereLacticAcidosisDuringTreatmentofChronicHepatitisBwithEntecavirinPatientswithImpairedLiverFunction.HEPATOLOGY2009;50:2001-2006當(dāng)前熱點：更優(yōu)治療方案選擇本文報道恩替卡韋治療16例肝硬化和2009：Liaw等使用替諾福韋、替諾福韋/恩曲賽他平（另2組治療24周時如HBVDNA≥400拷貝者也入該組）、恩替卡韋治療失代償肝硬化患者45、45、22例。治療168周設(shè)計中的48周初步安全性評估，不能耐受者為6.7%、4.4%、9.1%；腎功指標(biāo)異常8.9%、6.7%、4.5%；病死率4%、4%、9%，6例肝移植。48周時，維持在原治療組中患者32例、40例、16例，HBVDNA<400拷貝者71%、88%、73%；HBeAg消失/轉(zhuǎn)換者21%/21%、27%/13%、0/0。各治療組均有效和安全，聯(lián)合治療更優(yōu)。Yun-FanLiaw,etal.INTERIMRESULTSOFADOUBLE-BLIND,RANDOMIZEDPHASE2STUDYOFTHESAFETYOFTENOFOVIRDISOPROXILFUMARATE,EMTRICITABINEPLUSTENOFOVIRDISOPROXILFUMARATE,ANDENTECAVIRINTHETREATMENTOFCHRONICHEPATITISBSUBJECTSWITHDECOMPENSATEDLIVERDISEASE.HEPATOLOGY.2009,50(SUPPL):409A,poster222當(dāng)前熱點：更優(yōu)治療方案選擇2009：Liaw等使用替諾福韋、替諾福韋/恩曲賽他平（另2替比夫定對照拉米夫定治療失代償性慢性乙型肝炎肝硬化隨機雙盲試驗當(dāng)前熱點：更優(yōu)治療方案選擇EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)當(dāng)前熱點：更優(yōu)治療方案選擇EJGane,etal:T研究設(shè)計目的:評估替比夫定對照拉米夫定治療失代償性乙型肝炎肝硬化患者的臨床和病毒學(xué)療效雙盲治療Days-35to-4

52周104周共隨訪4個月拉米夫定100mg+安慰劑替比夫定600mg+安慰劑篩選n=116n=116EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)研究設(shè)計目的:評估替比夫定對照拉米夫定治療失代償性乙型肝炎肝患者人群和統(tǒng)計學(xué)方法患者人群:232例失代償性CHB患者(Child-Pugh評分>7和肝硬化或門靜脈高壓)按基線Child-Pugh評分和ALT水平分層49例患者繼續(xù)治療到4年(數(shù)據(jù)將在Q3/2010公布)目前可用的是199例隨機患者數(shù)據(jù)最后數(shù)據(jù)分析在Q2/2010

統(tǒng)計學(xué)分析:

療效結(jié)果基于ITT人群.漏失數(shù)據(jù)視為失敗(治療失敗,死亡或AE)目前的結(jié)果是基于2009年9月完成的初步分析最終分析將對臨床應(yīng)答(HBVDNA<4logcopies/ml&ALT復(fù)常&Child-Pugh評分穩(wěn)定或改善)作非劣效性分析

EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)患者人群和統(tǒng)計學(xué)方法患者人群:EJGane,eta基線人口統(tǒng)計學(xué)特征

所有人群(ITT*)

ITT人群替比夫定拉米夫定N=114*N=114*平均年齡(±SD)49.6(±10.88)51.9(±9.98)男性87(76.3)81(71.1)人種–亞洲n(%)74(64.9)74(64.9)高加索人10(8.8)17(14.9)基線HBeAg狀態(tài)陰性n(%)63(55.3%)68(59.6%)基線HBVDNA(Log10copies/ml)均值(±SD)7.6(±1.91)7.6(±1.92)基線Child-Pugh評分均值(±SD)8.1(±1.58)8.5(±1.76)基線MELD評分均值(±SD)14.8(±3.7)15.9(±4.73)基因型B/Cn(%)74(64.9%)73(64.1%)Dn(%)33(28.9%)29(25.4%)*ITT人群:患者接受至少一次藥物治療和一次基線后的復(fù)查EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)基線人口統(tǒng)計學(xué)特征

所有人群(ITT*)替比夫定拉米夫初步結(jié)果：

患者分布(隨機人群*)隨機人群*替比夫定N=100*拉米夫定N=99*藥物暴露中位數(shù)時間(周)104100完成104周n/N(%)56/100(56%)47/99(47%)早期終止治療原因(停藥)死亡12(12)16(16)病毒學(xué)突破12(12)16(16)患者,研究者或發(fā)起方要求8(8)6(6)依從性差/失訪5(4)3(3)不良事件4(4)4(4)肝移植3(3)3(3)治療失敗3(3)4(4)肌酐清除率<30或透析0(0.0)1(0.9)*隨機人群:至少參加基線訪視的患者EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)初步結(jié)果：

患者分布(隨機人群*)隨機人群*替比夫定拉米夫定治療104周替比夫定與拉米夫定療效比較

<300copies/mL

<4log10copies/mLp=0.615p=0.6866p=0.7291p=0.4753EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)治療104周替比夫定與拉米夫定療效比較<300copies104周兩組患者穩(wěn)定肝功能作用相似且無腎功能改變**Patientswhodiscontinuedpre-maturelylaston-treatmentresultisreported.

ITT人群替比夫定n=98拉米夫定n=97p-值LSMeanChange±SEChild-Pugh評分0.4±0.3-0.6±0.30.6166MELD評分-0.2±0.7-1.0±0.70.3125GFR(CockroftGault)0.3±3.62-4.1±3.350.2230GFR(MDRD)3.3±3.26-4.3±3.070.0223EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)104周兩組患者穩(wěn)定肝功能作用相似且無腎功能改變**Pati

104周替比夫定組與拉米夫定組病死率比較存活率:24周 96%替比夫定 91%拉米夫定(p=ns)104周 83%替比夫定 75%拉米夫定(p=ns)104968472604836241200.00.41.0Week拉米夫定替比夫定0.60.5病死率%EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)104周替比夫定組與拉米夫定組病死率比較存活率:2因SAE/AEs終止研究藥物治療，兩治療組無差異安全性人群*

替比夫定N=99拉米夫定N=99P-值死亡n15(13%)22(19%)0.2198SAEs(包括死亡)54(55%)60(61%)0.338藥物相關(guān)2

1(0.9%)0非藥物相關(guān)253(55%)60(59%)0.3149AE導(dǎo)致研究終止4(4%)4(4%)1AE導(dǎo)致研究藥物終止9(9%)10(10%)0.8093SAEs與重癥肝病嚴(yán)重程度相關(guān)無藥物相關(guān)性死亡病例2無橫紋肌溶解或乳酸性酸中毒病例報告1安全性人群:任何接受1劑研究藥物的患者2研究者判斷EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)因SAE/AEs終止研究藥物治療，兩治療組無差異安全性人替比夫定拉米夫定安全性人群*N=99*N=99*任何AEs患者n(%)94(94.9)95(96.0)腹水43(43.4)37(37.4)周圍性水腫28(28.3)17(17.2)腹脹22(22.2)12(12.1)發(fā)熱17(17.2)16(16.2)咳嗽16(16.2)7(7.1)肝性腦病15(15.2)20(20.2)疲勞14(14.1)14(14.1)黃疸14(14.1)10(10.1)凹陷性水腫14(14.1)12(12.1)上呼吸道感染14(14.1)11(11.1)消化不良13(13.1)12(12.1)104周期間兩組患者不良事件發(fā)生率相似*安全性人群:任何接受1劑研究藥物的患者EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)替比夫定拉米夫定安全性人群*N=99*N=99*任何AEs核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：初步印象循證級別不夠高；研究人數(shù)不夠多；治療時間不夠長；設(shè)計分組不夠嚴(yán)；結(jié)論得出不夠硬。初步印象循證級別不夠高；核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：AASLD指南（2009）推薦意見慢性乙型肝炎的抗病毒治療推薦意見24.失代償性肝硬化應(yīng)選快速抑制病毒、耐藥風(fēng)險低的核苷（酸）類似物立即治療（Ⅱ-1）。1.初始治療時可選拉米夫定或替比夫定聯(lián)合阿德福韋酯或替諾福韋酯，以減少耐藥風(fēng)險（Ⅱ-2）。2.也可選恩替卡韋或替諾福韋酯治療，但尚缺乏治療失代償性肝硬化的安全和有效的臨床資料（Ⅲ）。3.失代償性肝硬化治療應(yīng)與肝臟移植中心協(xié)同進行（Ⅲ）。4.不應(yīng)選普通或聚乙二醇干擾素α治療（Ⅱ-3）。LOKANDMCMAHON.HEPATOLOGY,Vol.50,No.3,2009;LOKANDMCMAHON.AASLD指南（2009）推薦意見慢性乙型肝炎的抗病毒治療LAASLD指南（2009）推薦意見慢性乙型肝炎的抗病毒治療推薦意見32.核苷（酸）類似物的療程。1.HBeAg陽性者治療到HBeAg血清轉(zhuǎn)換，繼續(xù)治療至少6個月（Ⅰ）。停藥后密切監(jiān)測（Ⅰ）。2.HBeAg陰性患者，應(yīng)持續(xù)治療直至HBsAg清除（Ⅰ）。3.代償性肝硬化患者應(yīng)長期治療。HBeAg陽性患者治療到HBeAg血清轉(zhuǎn)換，并在鞏固治療至少6個月后或者HBeAg陰性患者治療到HBsAg清除（Ⅱ-3）。停藥后必須密切監(jiān)測是否復(fù)發(fā)和肝炎發(fā)作。4.失代償性肝硬化和肝移植后復(fù)發(fā)者，應(yīng)終生治療。LOKANDMCMAHON.HEPATOLOGY,Vol.50,No.3,2009;LOKANDMCMAHON.AASLD指南（2009）推薦意見慢性乙型肝炎的抗病毒治療L建議4.11.2：失代償性肝硬化應(yīng)當(dāng)在肝病專科治療，抗病毒治療同時可根據(jù)患者具體情況考慮肝移植。只要能檢出HBVDNA的患者，都應(yīng)立即抗病毒治療，應(yīng)當(dāng)選用強效和低耐藥的核苷（酸）類似物，如恩替卡韋或替諾福韋治療，但關(guān)于這些藥物的安全性尚需進一步研究（B1）。4.11.2.Patientswithdecompensatedcirrhosisshouldbetreatedinspecializedliverunits,astheapplicationofantiviraltherapyiscomplex,andthesepatientsmaybecandidatesforlivertransplantation.End-stageliverdiseaseshouldbetreatedasamatterofurgency.TreatmentisindicatedevenifHBVDNAlevelislowinordertopreventrecurrentreactivation.PotentNUCswithgoodresistancepro?les(entecavirortenofovir)shouldbeused.However,therearelittledataforthesafetyoftheseagentsindecompensatedcirrhosis.(B1)EuropeanAssociationfortheStudyoftheLiver.EASLClinicalPracticeGuidelines:ManagementofchronichepatitisB.JHepatology，2009，50:227-242建議4.11.2：失代償性肝硬化應(yīng)當(dāng)在肝病專科治療，抗病毒治Yun-FanLiaw,etal.Asian-Paci?cconsensusstatementonthemanagementofchronichepatitisB:a2008updateHepatolInt(2008)2:263–283Asian-PacificconsensusstatementonthemanagementofchronichepatitisB:a2008updateYun-FanLiaw,etal.Asian-PacYun-FanLiaw,etal.Asian-Paci?cconsensusstatementonthemanagementofchronichepatitisB:a2008updateHepatolInt(2008)2:263–283Asian-PacificconsensusstatementonthemanagementofchronichepatitisB:a2008update失代償性肝病的治療：禁用干擾素，建議立即使用強效快速的直接抗病毒藥抑制病毒。建議13：對于明顯肝臟失代償?shù)某踔位颊哌x用拉米夫定治療(II)，也可選用恩替卡韋和替比夫定(IV)。Patientswithdecompensatedliverdisease：IFNisusuallycontraindicatedinpatientswithdecompensatedliverdisease.DirectantiviralagentwithpotentandpromptHBVsuppressiveactionshouldbeusedimmediately.Recommendation13:Lamivudineistheagentofchoicefortreatment-naivepatientswithobviousorimpendinghepaticdecompensation(II).Entecavirandtelbivudinecanalsobeused(IV).Yun-FanLiaw,etal.Asian-Pac基本共識指征：檢出病毒，立即治療；藥物：核苷（酸）類，有效安全；目標(biāo)：亡羊補牢，防治惡化；療程：長期治療，甚至終生；策略：強效、聯(lián)合，預(yù)防耐藥；結(jié)局：減少移植，延長生命。基本共識指征：檢出病毒，立即治療；核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的思考單藥治療還是聯(lián)合治療？個體化優(yōu)化治療還是起始聯(lián)合治療？有限療程治療還是終生治療？單純抗病毒治療還是綜合治療？核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的思考單藥治療還思考一單藥治療還是起始聯(lián)合治療低載量(<6log）：單藥（拉米夫定或阿德福韋酯）？高載量(>6log)：強效單藥（恩替卡韋或替比夫定）或起始聯(lián)合（拉米夫定聯(lián)合阿德福韋酯）？思考一單藥治療還是起始聯(lián)合治療思考二個體優(yōu)化還是起始聯(lián)合低載量、一過性失代償、Child-Pugh<8：根據(jù)早期病毒學(xué)應(yīng)答個體化優(yōu)化治療？高載量、頑固性失代償、Child-Pugh>8：起始聯(lián)合、長期治療？思考二個體優(yōu)化還是起始聯(lián)合思考三有限療程還是終生治療HBeAg陽性、一過性失代償、Child-Pugh<8：對血清學(xué)應(yīng)答患者可能實施有限療程？HBeAg陰性、頑固性失代償、Child-Pugh>8：長期治療直至HBsAg血清轉(zhuǎn)換，甚至終生治療？思考三有限療程還是終生治療思考四單純抗病毒治療還是綜合治療一過性失代償、Child-Pugh<8：抗病毒治療結(jié)合內(nèi)科綜合治療？頑固性失代償、Child-Pugh>8：抗病毒治療結(jié)合綜合治療，必要時考慮肝移植和抗病毒終生治療？思考四單純抗病毒治療還是綜合治療乙肝肝硬化抗病毒治療的現(xiàn)狀和思考河南會乙肝肝硬化抗病毒治療的現(xiàn)狀和思考河南會代償性乙型肝炎肝硬化是HBV感染相關(guān)疾病中的特殊人群，但其抗病毒治療指征、藥物選擇、療程、治療終點、停藥指征等均和慢性乙型肝炎普通人群一致，并無特殊，只是抗病毒治療的指征更寬，停藥指征應(yīng)更嚴(yán)。這里不做討論，而重點討論失代償乙肝肝硬化的抗病毒治療的有關(guān)問題。代償性乙型肝炎肝硬化是HBV感染相關(guān)疾病中的特殊人群，但核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：YaoFY,etal.Lamivudinetreatmentisbene?cialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-4162001：美國加州Yao等用拉米夫定治療23例HBV相關(guān)終末期肝病患者，并與55例患者歷史對照。拉米夫定治療患者肝移植需求減少（35%比74%），隨訪1-44個月無患者死亡。InastudyfromtheUniversityofCaliforniaSanFrancisco,Yaoandcoworkerscomparedacohortof23patientswithHBV-relatedend-stageliverdiseasereferredforlivertransplantationandwhoweretreatedwithlamivudine,toagroupof55historicalcontrols.Thelamivudine-treatedpatientshadmarkedlyimprovedsurvival,beginning6monthsafterstartinglamivudinewithadecreasedneedforlivertransplantation(35%versus74%:P＜0.04).Excludingpatientswhounderwentlivertransplant,noneofthelamivudine-treatedpatientsdied(follow-upfor1-44months)comparedtosixhistoricalcontrols(within3-12months)(P＜0.009).早期探索：藥物、療效、安全YaoFY,etal.LamivudinetreaYaoFY,etal.Lamivudinetreatmentisbene?cialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-416早期探索：藥物、療效、安全YaoFY,etal.Lamivudinetrea2001：Perrillo等用拉米夫定治療等待肝移植的77例失代償肝硬化患者，病毒等各項指標(biāo)好轉(zhuǎn)，且4年生存率70%，明顯高于2項先期報道的約60%和30%。

PerrilloandcolleaguesfrommultiplelivertransplantcentersthroughoutNorthAmericatreated77livertransplantcandidateswithend-stagechronichepatitisBwithlamivudine(100mgdaily).Nocontrolgroupwasused,butresultswerecomparedtooutcomesintwopreviouslypublishedstudiesofdecompensatedcirrhosisduetohepatitisB.HBVDNAlevelsdecreasedonlamivudinetherapy,butlevelswerenotreported.Alanineaminotransferase(ALT)valuesdecreasedandbecamenormalinmorethanhalfofpatientswithelevationsbeforetreatment.Averageserumbilirubin,albumin,andprothrombintimesimprovedwithtreatment.The4-yearsurvivalrateamongamivudine-treatedpatientswas70%,whichwashigherthanhistoricalcohorts(~60%and30%).Lamivudinewaswelltolerated.Antiviralesistancedevelopedinaproportionofpatients,andappearanceofresistancewasgenerallyfollowedbyreversalofthevirologicalandclinicalbene?t.Perrillo,etal.Amulti-centerUnitedStates-CanadiantrialtoassesslamivudinemonotherapybeforeandafterlivertransplantationforchronichepatitisB.HEPATOLOGY2001;33:424-432早期探索：藥物、療效、安全2001：Perrillo等用拉米夫定治療等待肝移植的77例2003：Schiff等報道阿德福韋酯治療等待肝移植的肝硬化患者128例，48周時HBVDNA下降4.1log、ALT復(fù)常率76%、Child-Pugh穩(wěn)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).Therapywasassociatedwithsigni?cantdeclinesinHBVDNAlevels(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：藥物、療效、安全2003：Schiff等報道阿德福韋酯治療等待肝移植的肝硬化核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：藥物、療效、安全當(dāng)前熱點：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識：指征、目標(biāo)、策略核苷（酸）類似物治療

失代償性乙型肝炎肝硬化的現(xiàn)狀早期探索：2007：Schiff等報道,等待肝移植患者226例和肝移植后患者241例在拉米夫定耐藥后改阿德福韋酯治療39-99周，等待肝移植者48周和96周時HBVDNA<1,000者為59%和65%。生化和肝功指標(biāo)同時改善。因不良事件中斷治療者4%，48周、94周、144周耐藥發(fā)生率0、2%和2%。

Wait-listed(n=226)orpost–livertransplantation(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).HepatitisBsurfaceantigenwasdetectedonthe?rstmeasurementonlyin6%and9%ofpatientswhodidordidnotreceiveHBIg,respectively.SerumHBVDNAwasdetectedonconsecutivevisitsin6%and0%ofpatientswhodidordidnotreceiveHBIg,respectively.Treatment-relatedadverseeventsledtodiscontinuationofadefovirdipivoxilin4%ofpatientsCumulativeprobabilitiesofresistancewere0%,2%,and2%atweeks48,96,and144,respectively.Inconclusion,adefovirdipivoxiseffectiveandsafeinwait-listedorposttransplantationCHBpatientswithlamivudine-resistantHBVandpreventsgraftreinfectionwithorwithoutHBIg.EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPost–LiverTransplantationPatientsWithLamivudine-ResistantHepatitisB:FinalLong-TermResults.LiverTranspl13:349-360,2007當(dāng)前熱點：更優(yōu)治療方案選擇2007：Schiff等報道,等待肝移植患者226例和肝移植EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPost–LiverTransplantationPatientsWithLamivudine-ResistantHepatitisB:FinalLong-TermResults.LiverTranspl13:349-360,2007當(dāng)前熱點：更優(yōu)治療方案選擇EugeneSchiff,etal.Adefovir

Inastudyof79HBeAgpositive,treatment-naivepatientswhocompleted104weeksofarandomizedcontrolledstudyoflamivudineandplaceboversuslamivudineandadefovir,thecombinationwasassociatedwithlowerrateofvirologicalbreakthrough(19%versus44%),lessantiviralresistantmutations(15%versus43%),andahigherrateofALTnormalization(45%versus34%)thanlamivudinealone.ThecombinationdidnotresultinahigherrateofHBeAgseroconversionthanmonotherapy(13%versus20%).CombinationtherapydoesnotappeartoincreasetherateofdeclineofHBVDNAorresultinamorerapidclinicalimprovement,evenindecompensatedpatients.Thus,themajorreasonforusingcombinationnucleosideanalogtherapyistopreventantiviralresistancetooneorbothoftheagents.SungJJ,etal.Lamivudinecomparedwithlamivudineandadefovir