1RoadmapforManagementofPatientswithChronicHepatitisB(CHB)Prof.XinxinZhangRuiJinHospitalJiaoTongUniversityIntroductionPresentationObjectivesDataReview:AssociationsofHBVDNAwithOutcomesi.Naturalhistorystudiesii.ImpactoftreatmentKeyroleofHBVDNAinOn-TreatmentManagementi.TimingandmagnitudeofHBVDNAsuppressionOn-TreatmentRoadmapConceptSummaryandConclusionsContents2IntroductionTreatmentchallengeshighlightneedfornewmanagementapproachTreatinghepatitisBvirus(HBV)infectioncontinuestobeachallengeforphysiciansduetoComplicationsarisingfromchronicHBV(CHB)TheincreasingnumberofavailabletherapeuticoptionsTreatmentguidelinesrecognizetheimportanceofmonitoringandevaluationoftreatmentresponse;however,astandardon-treatmentmanagementapproachdoesnotexistToestablishanewtreatmentparadigm,weshouldaskDoeslong-termsuppressionofHBVreplicationachievethegoalsoftreatmentinCHB?Canthedegreeofon-treatmentviralsuppressionpredictoutcomes?Doesprofound,earlyviralsuppressionatweek24predictclinicaloutcomes?CanaRoadmapconcepthelpachievethegoalsoftreatmentinCHB?3PresentationObjectivesToexploretheassociationbetweenpersistentviraemiaandhepatitisdiseaseprogressionToassesstherelationshipbetweenthedegreeofviralsuppressionandclinicaloutcomeToassesstheroleofearlyandeffectiveviralloadreductionandtheassociationwithclinicaloutcomes*Toreviewanon-treatmentmanagementstrategytheroadmapconceptthatmayofferavaluableopportunityforenhancedtreatmentresponse* For safety information on the products referred to, please refer to the Product Information.45DataReview:AssociationsofHBVDNAwithOutcomesi.NaturalhistorystudiesCorrelationBetweenHBVDNAandHistologicActivityIndex(HAI)inUntreatedPatientsReviewof26prospectiveclinicaltrialsfoundastatisticallysignificantcorrelationbetweenviralloadlevelandhistologicalgrading246810120024681012BaselineHBVDNAlevel,log10copies/mLr=0.78;P=0.0001HAIatbaselineMommeja-Marinetal200362.51.41.05.66.5P1,000,00010,000999,99910009999300999300HBVDNAatentry,copies/mL:Cirrhosis:AssociationwithBaselineHBVDNATaiwannaturalhistorystudyIloejeetal20067HepatocellularCarcinoma(HCC)AssociationwithbaselineHBVDNA:TaiwannaturalhistorystudyCumulativeincidenceofHCC,%HBVDNAatbaseline,copies/mLHBsAg-positive,untreatedparticipants(n=3,653)Chenetal20061068EvidenceforAssociationBetweenHBVDNAandClinicalOutcomesNaturalhistorystudiesdemonstrateLowerHBVDNAlevelsareassociatedwithbetterunderlyinghistologyHighHBVDNAmaybeanindependentpredictorforcirrhosisandHCCSustainedsuppressionofHBVmayreducelong-termriskofcirrhosisandHCCHypothesisneedstobeprovenprospectively910DataReview:AssociationsofHBVDNAwithOutcomesii.ImpactoftreatmentConsistentrelationshipintreatedanduntreatedpatientsHBVDNAcouldbeusedasamarkerofefficacyMedianHBVDNAleveldecreasefrombaseline,log10copies/mLHAIimprovementfrombaseliner=0.96;P0.0000031234521012345Mommeja-Marinetal2003CorrelationBetweenHBVDNAandHistologicActivityIndex(HAI)inTreatedPatients11P0.001HBVDNAatweek72,copies/mLHBeAg-negativepatients(n=537)treatedwithlamivudine,peg-interferonalfa-2a,orbothcombinedfor48weeksPatientswithhistologicalresponseatweek72,%Marcellinetal2004ViralSuppressionatWeek72isAssociatedwithHistologicImprovement105/329116/20812Months051015202506121824303613%21%5%Liaw2005Patientswithdiseaseprogression,%ViralSuppressionSignificantlyImpactsDiseaseProgressionLamivudineWildtypeLamivudineYMDDmPlaceboHBeAg-positivepatients(n=651)treatedwithlamivudineorplacebo13ViralSuppressionImprovesOutcomesStudiesreportingassociationswithoutcomesOutcomeCitation(s)Improvedclinicaloutcomesafterresponsetointerferonalfa(HBeAg+orHBeAg-)Niederauetal1996Papatheodoridisetal2001vanZonneveldetal2004Linetal2005Improvedclinicaloutcomeswithlamivudinelong-termviralsuppressionDiMarcoetal2004Liawetal2004Papatheodoridisetal2005Decreasedclinicalevents,improvedChild-Pughscores,decreasedHCCinpatientswithadvancedliverdiseasetreatedwithlamivudineLiawetal2004Improvedvirological,biochemical,andclinicalparametersinlamivudine-resistantpatientswithdecompensatedcirrhosistreatedwithadefovirSchiffetal20041415KeyRoleofHBVDNAinOn-TreatmentManagementi.TimingandmagnitudeofHBVDNAsuppressionRapidandProfoundHBVSuppression:aCriticalGoalofTherapyOutcomesPrimarygoaloftreatmentDelayinprogressiontocirrhosisandHCCImprovedsurvivalReducedresistanceIncreasedseroconversionImprovedliverhistologyNormalisedalanineaminotransferase(ALT)levelsSustainedsuppressionofHBVreplicationtothelowestpossiblelevelFontana2003;Gauthieretal1999;Keeffeetal2006;Liawetal2004;Liawetal2005;Mommeja-Marinetal2003;Niederauetal1996;Yuenetal200116PatientswithHBVDNA20,000copies/mLat72weeks(%)SerumHBVDNAlevelat12weeks,copies/mLHBeAg-negativepatients(n=176)treatedwithpeg-interferonalfa-2afor48weeksP0.001Farcietal2005ViralSuppressionwithPeg-Interferonalfa-2aAssociationwithsubsequentHBVDNAresponse17Profound,EarlyViralSuppressionWeek24viralloadand2-yearoutcomeswithtelbivudineandlamivudineQL=quantificationlimit(polymerasechainreaction(PCR)-undetectableat4logQL3003log34log4logTelbivudineLamivudine203 14657638379107 165178 15718201624102018Profound,EarlyViralSuppressionWeek24viralloadand1-yearoutcomeswithentecavirHBVDNAatweek24,copies/mLPCR-negativeatweek48,%HBeAg-positiveHBeAg-negative4004003log35log5log4004003log35log5log153/19528/3447/1186/15240/24720/2132/381/4BMSEntecavirAVDACBriefingDocument200519HBeAgseroconversionoccurredonlyinthisgroup468102Baseline81624324048566472WeeksMedianHBVDNA,log10copies/mLMedian104(n=11)Median5log1024HBeAglossLiverinflammationandfibrosisHBeAg-positiveHBeAg-negativeReduceserumHBVDNANormalALTPCRnegativeAnti-HBeAgsero-conversionHBsAglossReduceserumHBVDNANormalALTPCRnegativeHBsAglossGoalsofHBVtherapya)Preventcirrhosis,liverfailureandHCCb)ImprovesurvivalSignpostSignpostEarlyViralSuppressionCanBeaSignpostforFutureTherapeuticResponseStartRx.2526On-TreatmentRoadmapConceptPotentialFoundationforBuildingaCHBTherapeuticRoadmapOn-treatnentearlyvirologicalresponsemonitoringCanhelptoidentifysuboptimalrespondersProvidesopportunitiestomodifytreatmenttoenhanceantiviralefficacyCanhelpsupportindividualisedtreatmentmapsHasthepotentialtoimprovelong-termoutcomesResponsemarkersactassignpostsforclinicalmanagementChosentherapyiseffectiveandwelltoleratedAdditionalinterventionsrequired27UnresolvedquestionsWhatIsthebeston-treatmentmarker?When Isthebesttimingfordecisionpoints?WhatCut-offlevelforon-treatmentdecisions?Which Typeofinitial/add-ontherapy?ExpertpanelconvenedtoevaluateevidenceanddeveloptreatmentrecommendationsReportofanInternationalWorkshop:RoadmapforManagementofPatientsReceivingOralTherapyforChronicHepatitisBKeeffeEBetal.Clinical Gastroenterology and Hepatology2007ProposedNewTreatmentAlgorithmforCHBRecentexpertpanelandRoadmappublicationKeeffeetal200728Starttreatment1log10copies/mLdecreasefrombaseline:primaryresponseRoadmapConceptManagementalgorithmaccordingto12-weekvirologicresponseContinue1log10copies/mLdecreasefrombaseline:primaryfailureNon-compliantCompliantCounselChangeTxWeek12:assessmentforprimarynon-responseKeeffeetal200729StarttreatmentRoadmapConceptOn-treatmentresponsesCompleteresponsePCRnegativePartialresponse602000IU/mLor3002000IU/mLor10,000copies/mLWeek12:assessmentforprimarynon-responseWeek24:earlypredictorsofefficacyKeeffeetal2007Definedas300copies/mL30RoadmapConceptManagementalgorithmforcompleteresponseat24weeksCompleteresponsePCRnegativeContinueMonitor6-monthlyDefinitionofcompleteresponse:PCRnegative(300copies/mL)Intervalformonitoringcanbeprolongedtoevery6monthsInpatientswithmoreadvanceddisease,monitoringevery3monthsormorefrequentlyWeek24:earlypredictorsofefficacyKeeffeetal2007Definedas300copies/mL31RoadmapConceptManagementalgorithmforpartialresponseat24weeksWeek24:earlypredictorsofefficacyKeeffeetal2007Partialresponse602000IU/mLor30010,000copies/mLAddanotherdrugwithoutcross-resistanceorcontinueMonitor3-monthly32Inadequateresponse2000IU/mLor10,000copies/mLAdaptregimenCompleteresponsePartialresponseInadequateresponseRoadmapConceptManagementalgorithmforinadequateresponseat24weeksWeek24:earlypredictorsofefficacyKeeffeetal2007Definedas300copies/mL33HBVRoadmapProposal:MonitoringMonitorevery3monthsIfpatientachievescompleteresponseby48weeks,followmonitoringrecommendation(6-monthly)Ifpatientshowscontinuousdeclineupto48weeks,butstillhashigherviralloadthanacompleteresponder,continuetomonitorevery3monthsIfpatientshowsanincreaseorplateauingofvirallevel,theyshouldbetreatedbasedonroadmaprecommendationforinadequateornon-responderInpatientswithmoreadvanceddisease,morefrequentmonitoringmaybeindicatedKeeffeetal200734SummaryandConclusionsImportanceofearlymonitoringofvirologicresponsetotherapyEarlyandsustainedviralsuppressionhasbeenassociatedwithpreventionofdiseaseprogressionHBVDNAisacriticalsignpostintheon-treatmentmanagementofCHBOn-treatmentmanagementoffersopportunitiestooptimisetreatmentresponseEssentialtoidentifysuboptimalresponsesModifymanagementtoenhanceantiviralefficacyPotentialtoimprovelong-termoutcomes3536Howshouldtheroadmapbeappliedtotelbivudine?36慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）3737ConclusionfromReportofanInternationalWorkshop:RoadmapforManagementofPatientsReceivingOralTherapyforChronicHepatitisBEarly monitoring of the virologic response to therapy in chronic hepatitis B treated with oral nucleos(t)ides is essentialUse of this roadmap should permit improved individualized on-treatment management designed to enhance long-term patient outcomes1.KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）3838Adaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.StartTelbivudineEarlyVirologicResponseEfficacyatWeek24PCRNegativePCRNegative(300copies/mL)(1010，000copies/mL000copies/mLAssessmentofPrimaryResponseatweek12MaintainTelbivudineMaintainTelbivudineHowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）3939ViralLoadAchievedbyWeek24:Telbivudinevs.LamivudineDiBisceglieA,etal.PresentedatAASLD20064LogHBeAgPositiveHBeAgPositiveHBeAgNegativeHBeAgNegative* P 0.05慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）4040TelbivudineIsAGoodOptionforTherapyforHBeAg-PositivePatients49%49% ofTelbivudineTreatedPatientsofTelbivudineTreatedPatientsAchievePCRNegativity(300copies/mL)AchievePCRNegativity(300copies/mL)atWeek24atWeek2486%86% PCRNegativePCRNegativeWeek104Week10449%49% SeroconversionSeroconversionWeek104Week1042%2% ResistanceResistanceWeek92Week92BaselineALT2xULNN=55885%85% ALTNormalizationALTNormalizationWeek104Week104慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）4141TelbivudineIsAGoodOptionforTherapyforHBeAg-NegativePatients80%80% ofTelbivudineTreatedPatientsofTelbivudineTreatedPatientsAchievePCRNegativity(300copies/mL)AchievePCRNegativity(300copies/mL)atWeek24atWeek2488%88% PCRNegativePCRNegativeWeek104Week104N=78/86N=78/862%2% ResistanceatResistanceat92weeks92weeks49%49% SeroconversionSeroconversionWeek104Week104Alltelbivudine-treatedHBeAg-NegativePatientsN=588慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）4242StartTelbivudineEarlyVirologicResponseEfficacyatWeek24HBVDNAHBVDNAPCRNegativePCRNegative(300copies/mL)(300copies/mL)HBVDNAHBVDNA3001010，000copies/mL000copies/mLMaintainTelbivudineWeek52-MonitorHBVDNAcloselyHowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?IfPCRNegativeIfPCRNegativeMaintainTelbivudineMonotherapyMaintainTelbivudineMonotherapyIfPCRPositiverevisetreatmentstrategyAdaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）4343StartTelbivudineEarlyVirologicResponseEfficacyatWeek24PCRNegativePCRNegative(300copies/mL)(300copies/mL)HBVDNAHBVDNA30010,000copies/mLAssessmentofPrimaryResponseatweek12HowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?RevisetreatmentstrategyAdaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）4444慢性乙型肝炎患者管理（英文版）慢性乙型肝炎患者管理（英文版）