慢性乙型肝炎患者管理（英文版）.ppt

RoadmapforManagementofPatientswithChronicHepatitisB(CHB)Prof.XinxinZhangRuiJinHospitalJiaoTongUniversity,2,IntroductionPresentationObjectivesDataReview:AssociationsofHBVDNAwithOutcomesi.Naturalhistorystudiesii.ImpactoftreatmentKeyroleofHBVDNAinOn-TreatmentManagementi.TimingandmagnitudeofHBVDNAsuppressionOn-TreatmentRoadmapConceptSummaryandConclusions,Contents,3,IntroductionTreatmentchallengeshighlightneedfornewmanagementapproach,TreatinghepatitisBvirus(HBV)infectioncontinuestobeachallengeforphysiciansduetoComplicationsarisingfromchronicHBV(CHB)TheincreasingnumberofavailabletherapeuticoptionsTreatmentguidelinesrecognizetheimportanceofmonitoringandevaluationoftreatmentresponse;however,astandardon-treatmentmanagementapproachdoesnotexistToestablishanewtreatmentparadigm,weshouldaskDoeslong-termsuppressionofHBVreplicationachievethegoalsoftreatmentinCHB?Canthedegreeofon-treatmentviralsuppressionpredictoutcomes?Doesprofound,earlyviralsuppressionatweek24predictclinicaloutcomes?CanaRoadmapconcepthelpachievethegoalsoftreatmentinCHB?,4,PresentationObjectives,ToexploretheassociationbetweenpersistentviraemiaandhepatitisdiseaseprogressionToassesstherelationshipbetweenthedegreeofviralsuppressionandclinicaloutcomeToassesstheroleofearlyandeffectiveviralloadreductionandtheassociationwithclinicaloutcomes*Toreviewanon-treatmentmanagementstrategytheroadmapconceptthatmayofferavaluableopportunityforenhancedtreatmentresponse,*Forsafetyinformationontheproductsreferredto,pleaserefertotheProductInformation.,DataReview:AssociationsofHBVDNAwithOutcomes,i.Naturalhistorystudies,6,CorrelationBetweenHBVDNAandHistologicActivityIndex(HAI)inUntreatedPatients,Reviewof26prospectiveclinicaltrialsfoundastatisticallysignificantcorrelationbetweenviralloadlevelandhistologicalgrading,BaselineHBVDNAlevel,log10copies/mL,r=0.78;P=0.0001,HAIatbaseline,Mommeja-Marinetal2003,7,Cirrhosis:AssociationwithBaselineHBVDNATaiwannaturalhistorystudy,Iloejeetal2006,8,HepatocellularCarcinoma(HCC)AssociationwithbaselineHBVDNA:Taiwannaturalhistorystudy,CumulativeincidenceofHCC,%,HBVDNAatbaseline,copies/mL,HBsAg-positive,untreatedparticipants(n=3,653),Chenetal2006,9,EvidenceforAssociationBetweenHBVDNAandClinicalOutcomes,NaturalhistorystudiesdemonstrateLowerHBVDNAlevelsareassociatedwithbetterunderlyinghistologyHighHBVDNAmaybeanindependentpredictorforcirrhosisandHCCSustainedsuppressionofHBVmayreducelong-termriskofcirrhosisandHCCHypothesisneedstobeprovenprospectively,DataReview:AssociationsofHBVDNAwithOutcomes,ii.Impactoftreatment,11,ConsistentrelationshipintreatedanduntreatedpatientsHBVDNAcouldbeusedasamarkerofefficacy,MedianHBVDNAleveldecreasefrombaseline,log10copies/mL,HAIimprovementfrombaseline,Mommeja-Marinetal2003,CorrelationBetweenHBVDNAandHistologicActivityIndex(HAI)inTreatedPatients,12,P0.001,HBVDNAatweek72,copies/mL,HBeAg-negativepatients(n=537)treatedwithlamivudine,peg-interferonalfa-2a,orbothcombinedfor48weeks,Patientswithhistologicalresponseatweek72,%,Marcellinetal2004,ViralSuppressionatWeek72isAssociatedwithHistologicImprovement,105/329,116/208,13,Months,13%,21%,5%,Liaw2005,Patientswithdiseaseprogression,%,ViralSuppressionSignificantlyImpactsDiseaseProgression,HBeAg-positivepatients(n=651)treatedwithlamivudineorplacebo,14,ViralSuppressionImprovesOutcomesStudiesreportingassociationswithoutcomes,0,KeyRoleofHBVDNAinOn-TreatmentManagement,i.TimingandmagnitudeofHBVDNAsuppression,16,RapidandProfoundHBVSuppression:aCriticalGoalofTherapy,Outcomes,Primarygoaloftreatment,DelayinprogressiontocirrhosisandHCCImprovedsurvivalReducedresistanceIncreasedseroconversionImprovedliverhistologyNormalisedalanineaminotransferase(ALT)levels,SustainedsuppressionofHBVreplicationtothelowestpossiblelevel,Fontana2003;Gauthieretal1999;Keeffeetal2006;Liawetal2004;Liawetal2005;Mommeja-Marinetal2003;Niederauetal1996;Yuenetal2001,17,PatientswithHBVDNA20,000copies/mLat72weeks(%),SerumHBVDNAlevelat12weeks,copies/mL,HBeAg-negativepatients(n=176)treatedwithpeg-interferonalfa-2afor48weeks,P4log,203,146,57,63,83,79,107,165,178,157,18,20,16,24,10,20,19,Profound,EarlyViralSuppressionWeek24viralloadand1-yearoutcomeswithentecavir,HBVDNAatweek24,copies/mL,PCR-negativeatweek48,%,HBeAg-positive,HBeAg-negative,400,4003log,35log,5log,400,4003log,35log,5log,153/195,28/34,47/118,6/15,240/247,20/21,32/38,1/4,BMSEntecavirAVDACBriefingDocument2005,20,HBeAgseroconversionoccurredonlyinthisgroup,Weeks,MedianHBVDNA,log10copies/mL,Potentialassessmentofearlyvirologicalresponsetopredictoutcome,Gauthieretal1999,MagnitudeofViralResponsetoLamivudineAssociationwithhigherratesofHBeAgseroconversion,21,n=183,n=54,n=81,n=107,Seroconversionat2years,%,SerumHBVDNAlevelat24weeks,log10copies/mL,EarlyViralSuppressionwithTelbivudineAssociationwith2-yearHBeAgseroconversion,HBeAg-positivepatients,Hanetal2007,Preliminarydatafromlockeddatabase,22,47/159,8/34,14/117,2/15,Seroconversionat48weeks,%,HBVDNAat24weeks,copies/mL,HBeAg-positivepatients,BMSEntecavirAVDACBriefingDocument2005,EarlyViralSuppressionwithEntecavirAssociationwith1-yearHBeAgseroconversion,23,Profound,EarlyViralSuppressionCorrelateswithLowerRiskofResistance,Hadziyannisetal2006;Yuenetal2001,Patientswithlamivudineresistance,%,HBeAg-positivepatients(n=159),median30monthsfollowup,HBVDNAlevelatweek24,copies/mL,1/12,3/23,13/41,76/118,PatientswithADVresistanceatweek192,%,HBeAg-negativepatients(n=125),HBVDNAlevelatweek48,copies/mL,24,HBeAg-negativepatients,Patientswithtelbivudineresistanceweek92,%,n=178,n=16,n=18,n=10,DiBisceglieetal2006,EarlyViralSuppressionwithTelbivudineAssociationwithresistance,Preliminaryanalysisofpatientswithviralreboundatweek92,HBVDNAlevelatweek24,copies/mL,300,3003log10,3log104log10,5log10,25,HBeAg-positive,HBeAg-negative,GoalsofHBVtherapyPreventcirrhosis,liverfailureandHCCImprovesurvival,Signpost,Signpost,EarlyViralSuppressionCanBeaSignpostforFutureTherapeuticResponse,StartRx.,On-TreatmentRoadmapConcept,27,PotentialFoundationforBuildingaCHBTherapeuticRoadmap,On-treatnentearlyvirologicalresponsemonitoringCanhelptoidentifysuboptimalrespondersProvidesopportunitiestomodifytreatmenttoenhanceantiviralefficacyCanhelpsupportindividualisedtreatmentmapsHasthepotentialtoimprovelong-termoutcomes,Responsemarkersactassignpostsforclinicalmanagement,28,UnresolvedquestionsWhatIsthebeston-treatmentmarker?WhenIsthebesttimingfordecisionpoints?WhatCut-offlevelforon-treatmentdecisions?WhichTypeofinitial/add-ontherapy?,?,Expertpanelconvenedtoevaluateevidenceanddeveloptreatmentrecommendations,ReportofanInternationalWorkshop:RoadmapforManagementofPatientsReceivingOralTherapyforChronicHepatitisBKeeffeEBetal.ClinicalGastroenterologyandHepatology2007,ProposedNewTreatmentAlgorithmforCHBRecentexpertpanelandRoadmappublication,Keeffeetal2007,29,Starttreatment,1log10copies/mLdecreasefrombaseline:primaryresponse,RoadmapConceptManagementalgorithmaccordingto12-weekvirologicresponse,Continue,1log10copies/mLdecreasefrombaseline:primaryfailure,Non-compliant,Compliant,Counsel,ChangeTx,Week12:assessmentforprimarynon-response,Keeffeetal2007,30,Starttreatment,RoadmapConceptOn-treatmentresponses,CompleteresponsePCRnegative,Partialresponse602000IU/mLor3002000IU/mLor10,000copies/mL,Week12:assessmentforprimarynon-response,Week24:earlypredictorsofefficacy,Keeffeetal2007,Definedas300copies/mL,31,RoadmapConceptManagementalgorithmforcompleteresponseat24weeks,CompleteresponsePCRnegative,ContinueMonitor6-monthly,Definitionofcompleteresponse:PCRnegative(300copies/mL)Intervalformonitoringcanbeprolongedtoevery6monthsInpatientswithmoreadvanceddisease,monitoringevery3monthsormorefrequently,Week24:earlypredictorsofefficacy,Keeffeetal2007,Definedas300copies/mL,32,RoadmapConceptManagementalgorithmforpartialresponseat24weeks,Week24:earlypredictorsofefficacy,Keeffeetal2007,Partialresponse602000IU/mLor30010,000copies/mL,Addanotherdrugwithoutcross-resistanceorcontinueMonitor3-monthly,33,Inadequateresponse2000IU/mLor10,000copies/mL,Adaptregimen,Completeresponse,Partialresponse,Inadequateresponse,RoadmapConceptManagementalgorithmforinadequateresponseat24weeks,Week24:earlypredictorsofefficacy,Keeffeetal2007,Definedas300copies/mL,34,HBVRoadmapProposal:Monitoring,Monitorevery3monthsIfpatientachievescompleteresponseby48weeks,followmonitoringrecommendation(6-monthly)Ifpatientshowscontinuousdeclineupto48weeks,butstillhashigherviralloadthanacompleteresponder,continuetomonitorevery3monthsIfpatientshowsanincreaseorplateauingofvirallevel,theyshouldbetreatedbasedonroadmaprecommendationforinadequateornon-responderInpatientswithmoreadvanceddisease,morefrequentmonitoringmaybeindicated,Keeffeetal2007,35,SummaryandConclusionsImportanceofearlymonitoringofvirologicresponsetotherapy,EarlyandsustainedviralsuppressionhasbeenassociatedwithpreventionofdiseaseprogressionHBVDNAisacriticalsignpostintheon-treatmentmanagementofCHBOn-treatmentmanagementoffersopportunitiestooptimisetreatmentresponseEssentialtoidentifysuboptimalresponsesModifymanagementtoenhanceantiviralefficacyPotentialtoimprovelong-termoutcomes,Howshouldtheroadmapbeappliedtotelbivudine?,37,ConclusionfromReportofanInternationalWorkshop:RoadmapforManagementofPatientsReceivingOralTherapyforChronicHepatitisB,EarlymonitoringofthevirologicresponsetotherapyinchronichepatitisBtreatedwithoralnucleos(t)idesisessentialUseofthisroadmapshouldpermitimprovedindividualizedon-treatmentmanagementdesignedtoenhancelong-termpatientoutcomes,1.KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.,38,Adaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.,StartTelbivudine,EarlyVirologicResponseEfficacyatWeek24,PCRNegative(10，000copies/mL,AssessmentofPrimaryResponseatweek12,MaintainTelbivudine,HowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?,39,ViralLoadAchievedbyWeek24:Telbivudinevs.Lamivudine,DiBisceglieA,etal.PresentedatAASLD2006,HBeAgPositive,HBeAgNegative,*,*,*P0.05,40,TelbivudineIsAGoodOptionforTherapyforHBeAg-PositivePatients,49%ofTelbivudineTreatedPatientsAchievePCRNegativity(300copies/mL)atWeek24,86%PCRNegativeWeek104,49%SeroconversionWeek104,2%ResistanceWeek92,BaselineALT2xULNN=558,85%ALTNormalizationWeek104,41,TelbivudineIsAGoodOptionforTherapyforHBeAg-NegativePatients,80%ofTelbivudineTreatedPatientsAchievePCRNegativity(300copies/mL)atWeek24,88%PCRNegativeWeek104N=78/86,2%Resistanceat92weeks,49%SeroconversionWeek104,Alltelbivudine-treatedHBeAg-NegativePatientsN=588,42,StartTelbivudine,EarlyVirologicResponseEfficacyatWeek24,HBVDNAPCRNegative(300copies/mL),HBVDNA30010，000copies/mL,MaintainTelbivudineWeek52-MonitorHBVDNAclosely,HowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?,IfPCRNegativeMaintainTelbivudineMonotherapy,IfPCRPositiverevisetreatmentstrategy,Adaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.,43,StartTelbivudine,EarlyVirologicResponseEfficacyatWeek24,PCRNegative(300copies/mL),HBVDNA30010,000copies/mL,AssessmentofPrimaryResponseatweek12,HowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?,Revisetreatmentstrategy,Adaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.,44,Thankyouforyourattention!,