HBV Drug Resistance

ProfessorStephenLocarniniVictorianInfectiousDiseasesReferenceLaboratory,NorthMelbourne,Victoria3051,AUSTRALIA(VirtualVirology)PtyLtdInnogeneticsGileadSciencesPharmassetBristol-MyersSquibbRoyaltyyesConsultantyesyesyesyesFeesforNon-CMEServicesyesContractualResearchyesShareHolderyesWhatisHepatitisB?TheEyesoftheTreater:•ImmunologicalversusVirologicaldiseaseprocess•DiseaseandtreatmentcanbemonitoredbyserumALTversusHBVDNA•Only20%ofpatientswillhaveliver-relatedmorbidity/mortalitydirectlyattributedtoHBVinfection•Long-termmonotherapywithlamivudineisareasonabletherapeuticapproachbecause20%ofpatientsrespondwellinthefirstinstanceandresistantHBVnotespeciallypathogenic•Sequentialmonotherapyisstandardofcarewhenpatientsfailtherapy•CombinationtreatmentistooexpensiveandprobablytoxicModifiedfromIloejeUH,etal(2006)Gastroenterology;130:678-686SerumHBVDNALevel(copies/mL)SerumALTLevelAdjustedRelativeRisk*(95%CI)1041ULN1.0(referent)≥104to1051ULN2.1(1.5–2.9)‡≥1051ULN6.4(4.9–8.3)‡104≥1ULN2.2(1.0–5.1)≥104to105≥1ULN1.8(0.2–12.7)≥105≥1ULN10.4(7.1–15.1)‡Multivariate-AdjustedRelativeRiskofLiverCirrhosisbySerumHBVDNAandALTLevelsAmongAnti-HCV-SeronegativeSubjects(N=3,582)*Adjustedforgender,age,habitsorcigarettesmokingandalcoholconsumption.‡P0.001AdjustedRelativeRiskofLiverCancerforVariousSerumHBVDNAandALTLevelsHBVDNALevelNumberofSubjectsNumberofLiverCancerCasesAdjustedRelativeRisk*(95%CI)ALT1ULNUndetectable*105≥10590818258681337931.01.6(0.9–3.0)10.2(5.7–18.4)‡ALT≥1ULNUndetectable*105≥105436114633274.3(1.2–15.9)†4.3(1.2–15.1)†16.9(8.1–33.7)‡†P0.05;‡P0.001*102ModifiedfromIloejeUH,etal(2006)Gastroenterology;130:678-686SummaryandConclusionHBVviralloadisariskpredictoroflivercirrhosisandHCCdevelopment,inadose-dependentmannerstartingat104copies/mlReductioninHBVDNAlevelovertimewasassociatedwithanupto6-foldreductioninHCCriskSuccessfulantiviraltherapywillbeabletoreduceorslowtheprogressionofliverdiseaseHepatitisB:MolecularPathogenesis•HBVreplicatesitsDNAgenomeviareversetranscriptionofpregenomicRNA•HBVisnotgenerallycytopathictohepatocytes•Precoreprotein/HBeAgessentialforestablishingpersistentinfection•Hostimmuneresponses(generallyinadequateand/orinappropriate)areresponsiblefortheliverdiseaseofchronichepatitisB•Twotherapeuticapproaches:(i)directantiviralagents:lamivudine,adefovirandentecavir.(ii)immunemodulation:interferonalphaandthymosin-alphaGenomicReplication:ReverseTranscriptionCCCDNAHBVRNAtranscriptsDNArepairMINICHROMOSOMEAttachmentandPenetrationuncoatingHBVpolymeraseproteinpregenomicRNANucleusnucleustransporttocellcoreproteins(HBcAg)O-5’Cap(A)n3’TranslocationdAdAdGnew(-)strandDNAsynthesispgRNAHBVDNASYNTHESISInhibitionofReverseTranscription:Nucleos(t)ideAnaloguesDelaneyetal(2001)AntiviralChemChemother.12:1-35CCCDNAHBVRNAtranscriptsDNArepairMINICHROMOSOMEAttachmentandPenetrationuncoatingcoreproteinsenvelopeproteinsS,M,LGolgicomplexReleaseHBVpolymeraseproteinpregenomicRNANucleusnucleustransporttocellO-5’Cap(A)n3’TranslocationdAdAdGnew(-)strandDNAsynthesispgRNAHBVDNASYNTHESISRe-entryNucleos(t)ideAnalogueseg.LMV,ADV,ETVChainTerminationIFN-:(i)25-OASynthetase:RNaseL(ii)PKRCCCDNAHBVRNAtranscriptsDNArepairMINICHROMOSOMEAttachmentandPenetrationuncoatingcoreproteinsenvelopeproteinsS,M,LGolgicomplexReleaseHBVpolymeraseproteinpregenomicRNANucleusnucleustransporttocellO-5’Cap(A)n3’TranslocationdAdAdGnew(-)strandDNAsynthesispgRNARe-entryHBVDNAReplicationReentryLAPROTEINIncidenceofHBVResistanceLamivudineresistance(rtL180M+rtM204V/I)Adefovirresistance(rtN236T/rtA181V)LaiCL,ClinInfectDis2003;36:687.Locarninietal.,EASL2005.0%10%20%30%40%50%60%70%80%year1year2year3year40%24%3%42%11%53%70%IncidenceofResistance18%29%70%year5LoketalGastroenterology2003HepaticFlaresDuringLong-TermLamivudineinRelationtoAbsenceorPresenceandDurationofLMV-ResistantHBVIncidenceofClinicalEndpointsbyYMDDVariantHBVStatusPatientGroupNoCP↑HCCCEPDeathLamivudine43015(3.5%)17(4.0%)34(7.9%)10(2.3%)•YMDDw2211(0.5%)8(3.6%)11(5.0%)2(0.9%)•YMDDm20914(6.7%)9(4.2%)23(11.0%)8(3.8%)Placebo21419(8.9%)16(7.5%)38(17.8%)4(1.9%)FromLiawetal,2004NEJM351:1521WhatCausesAntiviralDrugResistance?•Antiviraldrugresistancereflectsreducedsusceptibilityofavirustotheinhibitoryeffectofadrug•AntiviraldrugresistanceresultsfromaprocessofadaptivemutationsundertherapyHighreplicationratesLowfidelityoftheviralpolymeraseSelectivepressureofthedrugRoleofreplicationspace(liverturnover)FitnessofmutantLMV-Resistance&HBVInfectionsRiskFactors•Pre-therapyHBVDNAlevel(PersistentViralReplication)•Pre-therapyserumALTlevel(CreationofReplicationSpace)•InadequateHBVDNAsuppressionduringtherapy(103vge/mlafter6months)•DurationofLMVtreatment•BodymassindexLaiC-L.etal.2003Clin.Inf.Dis.36:687ViralReplicationandMutationalFrequency•Highvirionproduction:1012-13virionsperday•Wild-typeHBVPollacksproof-readingfunction•Highmutationalrate:10-5substitution/base/cycle•1010-11pointmutationsproducedperday•Allpossiblesinglebasechangescanbeprodu