乙肝肝硬化抗病毒治疗的现状和思考河南会课件

乙肝肝硬化抗病毒治疗的现状和思考河南会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.LamivudinetreatmentisbeneficialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation:acomparativestudyusingamatched,untreatedcohort.HEPATOLOGY2001;34:411-4162001：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%:P＜0.04).Excludingpatientswhounderwentlivertransplant,noneofthelamivudine-treatedpatientsdied(follow-upfor1-44months)comparedtosixhistoricalcontrols(within3-12months)(P＜0.009).早期探索：药物、疗效、安全YaoFY,etal.LamivudinetreatmentisbeneficialinpatientswithseverelydecompensatedcirrhosisandactivelyreplicatinghepatitisBinfectionawaitinglivertransplantation: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,andappearanceofresistancewasgenerallyfollowedbyreversalofthevirologicalandclinicalbenefit.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).TherapywasassociatedwithsignificantdeclinesinHBVDNAlevels(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HBVDNA<1,000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)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).HepatitisBsurfaceantigenwasdetectedonthefirstmeasurementonlyin6%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当前热点：更优治疗方案选择EugeneSchiff,etal.AdefovirDipivoxilforWait-ListedandPost–LiverTransplantationPatientsWithLamivudine-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.Efficacyofentecavirintreatment-naïvepatientswithhepatitisBvirus-relateddecompensatedcirrhosis.JHepatology2010,52:176–182当前热点：更优治疗方案选择Yun-FanLiaw,etal.EFFICACYANDSAFETYOFENTECAVIRVERSUSADEFOVIRINCHRONICHEPATITISBPATIENTSWITHEVIDENCEOFHEPATICDECOMPENSATION.HEPATOLOGY,2009,50(SUPPL):505A,poster422Ratesofadverseevents,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-StageLiverDisease[MELD]score）≥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(P<0.005)。相反，Child-Pugh评分与乳酸酸中毒的发生不相关。我们的数据提示恩替卡韦应当谨慎用于肝功能受损患者.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;50:2001-20062009：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HBVDNA≥400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，HBVDNA<400拷贝者71%、88%、73%；HBeAg消失/转换者21%/21%、27%/13%、0/0。各治疗组均有效和安全，联合治疗更优。Yun-FanLiaw,etal.INTERIMRESULTSOFADOUBLE-BLIND,RANDOMIZEDPHASE2STUDYOFTHESAFETYOFTENOFOVIRDISOPROXILFUMARATE,EMTRICITABINEPLUSTENOFOVIRDISOPROXILFUMARATE,ANDENTECAVIRINTHETREATMENTOFCHRONICHEPATITISBSUBJECTSWITHDECOMPENSATEDLIVERDISEASE.HEPATOLOGY.2009,50(SUPPL):409A,poster222当前热点：更优治疗方案选择替比夫定对照拉米夫定治疗失代偿性慢性乙型肝炎肝硬化随机双盲试验当前热点：更优治疗方案选择EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)研究设计目的:评估替比夫定对照拉米夫定治疗失代偿性乙型肝炎肝硬化患者的临床和病毒学疗效双盲治疗Days-35to-4

52周104周共随访4个月拉米夫定100mg+安慰剂替比夫定600mg+安慰剂筛选n=116n=116EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)患者人群和统计学方法患者人群:232例失代偿性CHB患者(Child-Pugh评分>7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(HBVDNA<4logcopies/ml&ALT复常&Child-Pugh评分稳定或改善)作非劣效性分析

EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)基线人口统计学特征

所有人群(ITT*)

ITT人群替比夫定拉米夫定N=114*N=114*平均年龄(±SD)49.6(±10.88)51.9(±9.98)男性87(76.3)81(71.1)人种–亚洲n(%)74(64.9)74(64.9)高加索人10(8.8)17(14.9)基线HBeAg状态阴性n(%)63(55.3%)68(59.6%)基线HBVDNA(Log10copies/ml)均值(±SD)7.6(±1.91)7.6(±1.92)基线Child-Pugh评分均值(±SD)8.1(±1.58)8.5(±1.76)基线MELD评分均值(±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:患者接受至少一次药物治疗和一次基线后的复查EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)初步结果：

患者分布(随机人群*)随机人群*替比夫定N=100*拉米夫定N=99*药物暴露中位数时间(周)104100完成104周n/N(%)56/100(56%)47/99(47%)早期终止治疗原因(停药)死亡12(12)16(16)病毒学突破12(12)16(16)患者,研究者或发起方要求8(8)6(6)依从性差/失访5(4)3(3)不良事件4(4)4(4)肝移植3(3)3(3)治疗失败3(3)4(4)肌酐清除率<30或透析0(0.0)1(0.9)*随机人群:至少参加基线访视的患者EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)治疗104周替比夫定与拉米夫定疗效比较

<300copies/mL

<4log10copies/mLp=0.615p=0.6866p=0.7291p=0.4753EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)104周两组患者稳定肝功能作用相似且无肾功能改变**Patientswhodiscontinuedpre-maturelylaston-treatmentresultisreported.

ITT人群替比夫定n=98拉米夫定n=97p-值LSMeanChange±SEChild-Pugh评分0.4±0.3-0.6±0.30.6166MELD评分-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周替比夫定组与拉米夫定组病死率比较存活率: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)104968472604836241200.00.10.20.30.41.0Week拉米夫定替比夫定0.90.80.70.60.5病死率%EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)因SAE/AEs终止研究药物治疗，两治疗组无差异安全性人群*

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药物相关2

1(0.9%)0非药物相关253(55%)60(59%)0.3149AE导致研究终止4(4%)4(4%)1AE导致研究药物终止9(9%)10(10%)0.8093SAEs与重症肝病严重程度相关无药物相关性死亡病例2无横纹肌溶解或乳酸性酸中毒病例报告1安全性人群:任何接受1剂研究药物的患者2研究者判断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患者n(%)94(94.9)95(96.0)腹水43(43.4)37(37.4)周围性水肿28(28.3)17(17.2)腹胀22(22.2)12(12.1)发热17(17.2)16(16.2)咳嗽16(16.2)7(7.1)肝性脑病15(15.2)20(20.2)疲劳14(14.1)14(14.1)黄疸14(14.1)10(10.1)凹陷性水肿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周期间两组患者不良事件发生率相似*安全性人群:任何接受1剂研究药物的患者EJGane,etal:TREATMENTOFDECOMPENSATEDHBV-CIRRHOSIS:RESULTS:FROM2-YEARSRANDOMIZEDTRIALWITHTELBIVUDINEORLAMiVUDINE.JHEPATOLOGY2010,52:S4(ORALPRESENTATIONS)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、策略初步印象循证级别不够高；研究人数不够多；治疗时间不够长；设计分组不够严；结论得出不够硬。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AASLD指南（2009）推荐意见慢性乙型肝炎的抗病毒治疗推荐意见24.失代偿性肝硬化应选快速抑制病毒、耐药风险低的核苷（酸）类似物立即治疗（Ⅱ-1）。1.初始治疗时可选拉米夫定或替比夫定联合阿德福韦酯或替诺福韦酯，以减少耐药风险（Ⅱ-2）。2.也可选恩替卡韦或替诺福韦酯治疗，但尚缺乏治疗失代偿性肝硬化的安全和有效的临床资料（Ⅲ）。3.失代偿性肝硬化治疗应与肝脏移植中心协同进行（Ⅲ）。4.不应选普通或聚乙二醇干扰素α治疗（Ⅱ-3）。LOKANDMCMAHON.HEPATOLOGY,Vol.50,No.3,2009;LOKANDMCMAHON.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（Ⅰ）。停药后密切监测（Ⅰ）。2.HBeAg阴性患者，应持续治疗直至HBsAg清除（Ⅰ）。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（Ⅱ-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.PotentNUCswithgoodresistanceprofiles(entecavir