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1、1RoadmapforManagementofPatientswithChronicHepatitisB(CHB)Prof.XinxinZhangRuiJinHospitalJiaoTongUniversity2IntroductionPresentationObjectivesDataReview:AssociationsofHBVDNAwithOutcomesi.Naturalhistorystudiesii.ImpactoftreatmentKeyroleofHBVDNAinOn-TreatmentManagementi.TimingandmagnitudeofHBVDNAsuppres
2、sionOn-TreatmentRoadmapConceptSummaryandConclusionsContents3IntroductionTreatmentchallengeshighlightneedfornewmanagementapproachTreatinghepatitisBvirus(HBV)infectioncontinuestobeachallengeforphysiciansduetoComplicationsarisingfromchronicHBV(CHB)TheincreasingnumberofavailabletherapeuticoptionsTreatme
3、ntguidelinesrecognizetheimportanceofmonitoringandevaluationoftreatmentresponse;however,astandardon-treatmentmanagementapproachdoesnotexistToestablishanewtreatmentparadigm,weshouldaskDoeslong-termsuppressionofHBVreplicationachievethegoalsoftreatmentinCHB?Canthedegreeofon-treatmentviralsuppressionpred
4、ictoutcomes?Doesprofound,earlyviralsuppressionatweek24predictclinicaloutcomes?CanaRoadmapconcepthelpachievethegoalsoftreatmentinCHB?4PresentationObjectivesToexploretheassociationbetweenpersistentviraemiaandhepatitisdiseaseprogressionToassesstherelationshipbetweenthedegreeofviralsuppressionandclinica
5、loutcomeToassesstheroleofearlyandeffectiveviralloadreductionandtheassociationwithclinicaloutcomes*Toreviewanon-treatmentmanagementstrategytheroadmapconceptthatmayofferavaluableopportunityforenhancedtreatmentresponse*For safety information on the products referred to,please refer to the Product Infor
6、mation.5DataReview:AssociationsofHBVDNAwithOutcomesi.Naturalhistorystudies6CorrelationBetweenHBVDNAandHistologicActivityIndex(HAI)inUntreatedPatientsReviewof26prospectiveclinicaltrialsfoundastatisticallysignificantcorrelationbetweenviralloadlevelandhistologicalgrading246810120024681012BaselineHBVDNA
7、level,log10copies/mLr=0.78;P=0.0001HAIatbaselineMommeja-Marinetal200372.51.41.05.66.5P1,000,00010,000999,99910009999300999300HBVDNAatentry,copies/mL:Cirrhosis:AssociationwithBaselineHBVDNATaiwannaturalhistorystudyIloejeetal20068HepatocellularCarcinoma(HCC)AssociationwithbaselineHBVDNA:Taiwannaturalh
8、istorystudyCumulativeincidenceofHCC,%HBVDNAatbaseline,copies/mLHBsAg-positive,untreatedparticipants(n=3,653)Chenetal20061069EvidenceforAssociationBetweenHBVDNAandClinicalOutcomesNaturalhistorystudiesdemonstrateLowerHBVDNAlevelsareassociatedwithbetterunderlyinghistologyHighHBVDNAmaybeanindependentpre
9、dictorforcirrhosisandHCCSustainedsuppressionofHBVmayreducelong-termriskofcirrhosisandHCCHypothesisneedstobeprovenprospectively10DataReview:AssociationsofHBVDNAwithOutcomesii.Impactoftreatment11ConsistentrelationshipintreatedanduntreatedpatientsHBVDNAcouldbeusedasamarkerofefficacyMedianHBVDNAleveldec
10、reasefrombaseline,log10copies/mLHAIimprovementfrombaseliner=0.96;P0.0000031234521012345Mommeja-Marinetal2003CorrelationBetweenHBVDNAandHistologicActivityIndex(HAI)inTreatedPatients12P0.001HBVDNAatweek72,copies/mLHBeAg-negativepatients(n=537)treatedwithlamivudine,peg-interferonalfa-2a,orbothcombinedf
11、or48weeksPatientswithhistologicalresponseatweek72,%Marcellinetal2004ViralSuppressionatWeek72isAssociatedwithHistologicImprovement105/329116/20813Months051015202506121824303613%21%5%Liaw2005Patientswithdiseaseprogression,%ViralSuppressionSignificantlyImpactsDiseaseProgressionLamivudineWildtypeLamivud
12、ineYMDDmPlaceboHBeAg-positivepatients(n=651)treatedwithlamivudineorplacebo14ViralSuppressionImprovesOutcomesStudiesreportingassociationswithoutcomesOutcomeCitation(s)Improvedclinicaloutcomesafterresponsetointerferonalfa(HBeAg+orHBeAg-)Niederauetal1996Papatheodoridisetal2001vanZonneveldetal2004Lineta
13、l2005Improvedclinicaloutcomeswithlamivudinelong-termviralsuppressionDiMarcoetal2004Liawetal2004Papatheodoridisetal2005Decreasedclinicalevents,improvedChild-Pughscores,decreasedHCCinpatientswithadvancedliverdiseasetreatedwithlamivudineLiawetal2004Improvedvirological,biochemical,andclinicalparametersi
14、nlamivudine-resistantpatientswithdecompensatedcirrhosistreatedwithadefovirSchiffetal200415KeyRoleofHBVDNAinOn-TreatmentManagementi.TimingandmagnitudeofHBVDNAsuppression16RapidandProfoundHBVSuppression:aCriticalGoalofTherapyOutcomesPrimarygoaloftreatmentDelayinprogressiontocirrhosisandHCCImprovedsurv
15、ivalReducedresistanceIncreasedseroconversionImprovedliverhistologyNormalisedalanineaminotransferase(ALT)levelsSustainedsuppressionofHBVreplicationtothelowestpossiblelevelFontana2003;Gauthieretal1999;Keeffeetal2006;Liawetal2004;Liawetal2005;Mommeja-Marinetal2003;Niederauetal1996;Yuenetal200117Patient
16、swithHBVDNA20,000copies/mLat72weeks(%)SerumHBVDNAlevelat12weeks,copies/mLHBeAg-negativepatients(n=176)treatedwithpeg-interferonalfa-2afor48weeksP0.001Farcietal2005ViralSuppressionwithPeg-Interferonalfa-2aAssociationwithsubsequentHBVDNAresponse18Profound,EarlyViralSuppressionWeek24viralloadand2-yearo
17、utcomeswithtelbivudineandlamivudineQL=quantificationlimit(polymerasechainreaction(PCR)-undetectableat4logQL3003log34log4logTelbivudineLamivudine203 14657638379107 165178 15718201624102019Profound,EarlyViralSuppressionWeek24viralloadand1-yearoutcomeswithentecavirHBVDNAatweek24,copies/mLPCR-negativeat
18、week48,%HBeAg-positiveHBeAg-negative4004003log35log5log4004003log35log5log153/19528/3447/1186/15240/24720/2132/381/4BMSEntecavirAVDACBriefingDocument200520HBeAgseroconversionoccurredonlyinthisgroup468102Baseline81624324048566472WeeksMedianHBVDNA,log10copies/mLMedian104(n=11)Median5log1025HBeAglossLi
19、verinflammationandfibrosisHBeAg-positiveHBeAg-negativeReduceserumHBVDNANormalALTPCRnegativeAnti-HBeAgsero-conversionHBsAglossReduceserumHBVDNANormalALTPCRnegativeHBsAglossGoalsofHBVtherapya)Preventcirrhosis,liverfailureandHCCb)ImprovesurvivalSignpostSignpostEarlyViralSuppressionCanBeaSignpostforFutu
20、reTherapeuticResponseStartRx.26On-TreatmentRoadmapConcept27PotentialFoundationforBuildingaCHBTherapeuticRoadmapOn-treatnentearlyvirologicalresponsemonitoringCanhelptoidentifysuboptimalrespondersProvidesopportunitiestomodifytreatmenttoenhanceantiviralefficacyCanhelpsupportindividualisedtreatmentmapsH
21、asthepotentialtoimprovelong-termoutcomesResponsemarkersactassignpostsforclinicalmanagementChosentherapyiseffectiveandwelltoleratedAdditionalinterventionsrequired28UnresolvedquestionsWhatIsthebeston-treatmentmarker?When Isthebesttimingfordecisionpoints?WhatCut-offlevelforon-treatmentdecisions?Which T
22、ypeofinitial/add-ontherapy?ExpertpanelconvenedtoevaluateevidenceanddeveloptreatmentrecommendationsReportofanInternationalWorkshop:RoadmapforManagementofPatientsReceivingOralTherapyforChronicHepatitisBKeeffeEBetal.Clinical Gastroenterology and Hepatology2007ProposedNewTreatmentAlgorithmforCHBRecentex
23、pertpanelandRoadmappublicationKeeffeetal200729Starttreatment1log10copies/mLdecreasefrombaseline:primaryresponseRoadmapConceptManagementalgorithmaccordingto12-weekvirologicresponseContinue1log10copies/mLdecreasefrombaseline:primaryfailureNon-compliantCompliantCounselChangeTxWeek12:assessmentforprimar
24、ynon-responseKeeffeetal200730StarttreatmentRoadmapConceptOn-treatmentresponsesCompleteresponsePCRnegativePartialresponse602000IU/mLor3002000IU/mLor10,000copies/mLWeek12:assessmentforprimarynon-responseWeek24:earlypredictorsofefficacyKeeffeetal2007Definedas300copies/mL31RoadmapConceptManagementalgori
25、thmforcompleteresponseat24weeksCompleteresponsePCRnegativeContinueMonitor6-monthlyDefinitionofcompleteresponse:PCRnegative(300copies/mL)Intervalformonitoringcanbeprolongedtoevery6monthsInpatientswithmoreadvanceddisease,monitoringevery3monthsormorefrequentlyWeek24:earlypredictorsofefficacyKeeffeetal2
26、007Definedas300copies/mL32RoadmapConceptManagementalgorithmforpartialresponseat24weeksWeek24:earlypredictorsofefficacyKeeffeetal2007Partialresponse602000IU/mLor30010,000copies/mLAddanotherdrugwithoutcross-resistanceorcontinueMonitor3-monthly33Inadequateresponse2000IU/mLor10,000copies/mLAdaptregimenC
27、ompleteresponsePartialresponseInadequateresponseRoadmapConceptManagementalgorithmforinadequateresponseat24weeksWeek24:earlypredictorsofefficacyKeeffeetal2007Definedas300copies/mL34HBVRoadmapProposal:MonitoringMonitorevery3monthsIfpatientachievescompleteresponseby48weeks,followmonitoringrecommendatio
28、n(6-monthly)Ifpatientshowscontinuousdeclineupto48weeks,butstillhashigherviralloadthanacompleteresponder,continuetomonitorevery3monthsIfpatientshowsanincreaseorplateauingofvirallevel,theyshouldbetreatedbasedonroadmaprecommendationforinadequateornon-responderInpatientswithmoreadvanceddisease,morefrequ
29、entmonitoringmaybeindicatedKeeffeetal200735SummaryandConclusionsImportanceofearlymonitoringofvirologicresponsetotherapyEarlyandsustainedviralsuppressionhasbeenassociatedwithpreventionofdiseaseprogressionHBVDNAisacriticalsignpostintheon-treatmentmanagementofCHBOn-treatmentmanagementoffersopportunitie
30、stooptimisetreatmentresponseEssentialtoidentifysuboptimalresponsesModifymanagementtoenhanceantiviralefficacyPotentialtoimprovelong-termoutcomes36Howshouldtheroadmapbeappliedtotelbivudine?3737ConclusionfromReportofanInternationalWorkshop:RoadmapforManagementofPatientsReceivingOralTherapyforChronicHep
31、atitisBEarly 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,Esteb
32、an-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.3838Adaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.StartTelbivudineEarlyVirologicR
33、esponseEfficacyatWeek24PCRNegativePCRNegative(300copies/mL)(1010，000copies/mL000copies/mLAssessmentofPrimaryResponseatweek12MaintainTelbivudineMaintainTelbivudineHowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?3939ViralLoadAchievedbyWeek24:Telbivudinevs.LamivudineDiBisceglieA,etal.Presen
34、tedatAASLD20064LogHBeAgPositiveHBeAgPositiveHBeAgNegativeHBeAgNegative*P 0.054040TelbivudineIsAGoodOptionforTherapyforHBeAg-PositivePatients49%49%ofTelbivudineTreatedPatientsofTelbivudineTreatedPatientsAchievePCRNegativity(AchievePCRNegativity(300copies/mL)300copies/mL)atWeek24atWeek2486%86%PCRNegat
35、ivePCRNegativeWeek104Week10449%49%SeroconversionSeroconversionWeek104Week1042%2%ResistanceResistanceWeek92Week92BaselineALT2xULNN=55885%85%ALTNormalizationALTNormalizationWeek104Week1044141TelbivudineIsAGoodOptionforTherapyforHBeAg-NegativePatients80%80%ofTelbivudineTreatedPatientsofTelbivudineTreat
36、edPatientsAchievePCRNegativity(AchievePCRNegativity(300copies/mL)300copies/mL)atWeek24atWeek2488%88%PCRNegativePCRNegativeWeek104Week104N=78/86N=78/862%2%ResistanceatResistanceat92weeks92weeks49%49%SeroconversionSeroconversionWeek104Week104Alltelbivudine-treatedHBeAg-NegativePatientsN=5884242StartTe
37、lbivudineEarlyVirologicResponseEfficacyatWeek24HBVDNAHBVDNAPCRNegativePCRNegative(300copies/mL)(300copies/mL)HBVDNAHBVDNA3001010，000copies/mL000copies/mLMaintainTelbivudineWeek52-MonitorHBVDNAcloselyHowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?IfPCRNegativeIfPCRNegativeMaintainTelbivu
38、dineMonotherapyMaintainTelbivudineMonotherapyIfPCRPositiverevisetreatmentstrategyAdaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.4343StartTelbivudineEarlyVirologicResponseEfficacyatWeek24PC
39、RNegativePCRNegative(300copies/mL)(300copies/mL)HBVDNAHBVDNA30010,000copies/mLAssessmentofPrimaryResponseatweek12HowMaytheHBVTreatmentRoadmapbeAppliedtoTelbivudineTreatment?RevisetreatmentstrategyAdaptedform:KeeffeEB,ZeuzemS,KoffRS,DieterichDT,Esteban-MurR,GaneE,JacobsonIM,LimSG,NaoumovNN,MarcellinP,PiratvisuthT,ZoulimF.ClinGastroenterolHepatol.Inpress.4444
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