干扰素核苷类似物

干扰素核苷类似物第1页，共28页，2023年，2月20日，星期四Peginterferonas

First-LineTreatmentin

HBeAg-PositivePatientsRobertP.Perrillo,MDAssociateDirector,HepatologyCoordinator,LiverFellowshipProgramHepatologyDivisionBaylorUniversityMedicalCenterDallas,Texas第2页，共28页，2023年，2月20日，星期四MagnitudeofHBVDNADecline

DoesNotPredictHBeAgOutcomeFriedM,etal.EASL2005.Abstract488.MeanHBVDNAReduction(log10copies/mL)Week48HBVDNAReduction

(Ontreatment)HBeAgSeroconversion

24WeeksPosttreatment-8-6-4-202-4.5-5.8PercentageofPatientsPegIFNalfa-2aLAM32P<.0119020406080100PegIFNalfa-2aLAM第3页，共28页，2023年，2月20日，星期四HBeAg+patientsreceivedpegIFNalfa-2a180ug/week,pegIFN+LAM100mg/dayorLAMfor48weeks(N=814)24-weekoff-treatmentfollow-upHBeAgSeroconversionRatesOverTimeWithPeginterferonLauGK,etal.NEnglJMed.

2005;352:2682-2695.27242032271901020304050PegIFN(n=271)PegIFN+LAM(n=271)LAM(n=272)HBeAgSeroconversion(%)Endoftreatment(Week48)Off-treatmentfollow-up(Week72)P<.001P=.023第4页，共28页，2023年，2月20日，星期四LossofHBsAg,HBeAgSeroconversionAfter1YearofTreatmentPegIFN

LAMTBVETVADV3-5001222-2717232112010203040Datafromindividualstudies,notdirectcomparisons(differentpopulations,baselinevalues)LauG,etal.NEnglJMed.2005;352:2682-2695.JanssenH,etal.Lancet.2005;365:123-129.

DienstagJ,etal.NEnglJMed.1999;341:1256-1263.Baraclude[packageinsert].Tyzeka[packageinsert].Hepsera[packageinsert].ChangTT,etal.NEnglJMed.2006;354:1001-1010.PerrilloRP,etal.NEnglJMed.1990;323:295-301.LokAS,etal.Gastroenterology.1987;92:1839-1843.HBeAgSeroconversion(%)HBsAgloss(%)0UntreatedHBeAgseroconversionHBsAgloss10第5页，共28页，2023年，2月20日，星期四P<.001Long-termFollow-upAfterInterferonTherapy:NIHExperience103patientsreceivedinterferonbetween

1984-199130%wereresponders(lostHBeAgandHBVDNA[bybDNAassay])Analysisreviewedlong-termoutcomesinrespondersandnonrespondersMeanfollow-uptime:6.2years(range:1-11)RespondersNonrespondersPercentage020406080100Normal

ALTHBVDNA

Negative(PCR)HBeAg

NegativeHBsAg

Negative867210065861153*8LauDT,etal.Gastroenterology.1997:113;1660-1667.P=.0001P=.0001*PvaluenotprovidedOutcomesatLong-termFollow-up第6页，共28页，2023年，2月20日，星期四165HBeAg-positivepatientstreatedwithIFN75%ofwhiteraceMedianfollow-up:8.8years(range:0.3-24.0)HBsAglossatfollow-up52%ofresponders9%ofnonrespondersHBsAglossfollowedHBeAgseroconversionLong-termFollow-upAfterInterferonTherapy:RotterdamExperiencevanZonnenveldM,etal.Hepatology.2004:39;804-810.第7页，共28页，2023年，2月20日，星期四FlinkHJ,etal.AmJGastro.2006;101:297-303.HBsAgandHBeAgLossDuringFollow-upAccordingtoGenotypeHBeAg+patientstreatedfor32weekswithpegIFNalfa-2b100μg/week±LAM100mg/day,thenpegIFN50ug/week±LAMfor20weeks

26-weekposttreatmentfollow-upPosttreatmentOutcome(pooledtreatmentgroups)HBVGenotypeA

(n=90)B

(n=23)C

(n=39)D*

(n=103)HBeAgLoss/HBsAg+,%47442825HBeAgLoss/HBsAgLoss,%14932P=.006forgenotypeAvsD第8页，共28页，2023年，2月20日，星期四SustainedHBsAgSeroconversionandLossOverTimeinHBeAg-CHBHBeAg-negativepatientstreatedfor48weekswithpegIFNalfa-2a,pegIFN+LAM,orLAM;thenfollowedposttreatmentMarcellinP,etal.EASL2007.Abstract53.HBsAgLoss36845800005101520Year1Year2Year3Patients(%)PegIFNalfa-2a(n=116)PegIFN+LAM(n=114)LAM(n=85)HBsAgSeroconversion34432300005101520Year1Year2Year3P=.009第9页，共28页，2023年，2月20日，星期四QualitativeDifferencesBetweenHBsAgLossandHBeAgSeroconversionDurabilityofvirologicresponseLowerlevelsofgenomictemplate(cccDNA)Betterlong-termprognosisLivercancerCirrhosisLesschanceofviralreactivationSpontaneousChemotherapyFattovichG,etal.AmJGastroenterol.1998;93:896-900.第10页，共28页，2023年，2月20日，星期四CostofCurrentlyAvailableTherapiesforTreatmentofHepatitisBLamivudine100mg/dayCost/day:$6.80Cost/year:$2482Adefovir10mg/dayCost/day:$18.11Cost/year:$6647Entecavir0.5mg/dayCost/day:$23.82Cost/year:$8694Telbivudine600mg/dayCost/day:$16.23Cost/year:$5924Peginterferonalfa-2a180ug/weekCost/day:$385.00Cost/year:$18,480Tenofovir*300mg/dayCost/day:$15.92Cost/year:$5811HoofnagleJ,etal.Hepatology.2007;45:1056-1075.*unlabeledfortreatmentofHBVinfection.第11页，共28页，2023年，2月20日，星期四PegIFNbestinthefollowingpatientgroupsYoungerthan60yearsofageandotherwisehealthyBaselineHBVDNA

≤109copies/mLBaselineALT>2-3xULNHBVgenotypeAorBAbsenceofcirrhosisNucleos(t)ideanaloguebestinthefollowingpatientgroupsAdultofanyageBaselineHBVDNA

≥2x108IU/mLBaselineALT>5xULNAnyHBVgenotypeCirrhosiswithorwithoutdecompensationHBsAg(+)chemotherapypatientProperPatientSelectionIsKeyPerrilloRP.Hepatology.2006;43:S182-S193.第12页，共28页，2023年，2月20日，星期四ConclusionsIFNhasdualantiviralandimmunomodulatoryrolePotentialforHBsAgclearanceshouldnotbedisputed,diminished,ordismissed,particularlyinHBeAg+diseaseResponsesaredurableandclinicalbenefitscontinueafterdiscontinuationoftreatmentNoresistanceobservedMorecostlyinitially,butcostequivalenttooraltherapiesat2-3years第13页，共28页，2023年，2月20日，星期四Nucleos(t)ideAnaloguesas

First-LineTreatmentin

HBeAg-PositivePatientsJulesL.Dienstag,MDHarvardMedicalSchoolGastrointestinalUnitMassachusettsGeneralHospitalBoston,Massachusetts第14页，共28页，2023年，2月20日，星期四≥100,00010,000-99,999HBVDNAAssociatedWith

IncreasedRiskofHCCandCirrhosisREVEAL:Long-termfollow-upofuntreatedHBsAgpositiveindividualsinTaiwanBaselineHBVDNA(copies/mL)Patients(%)CumulativeIncidenceofHCCat

Year13Follow-up[1](N=3653)5040302010012.214.9CumulativeIncidenceofCirrhosisat

Year13Follow-up[2](N=3582)23.536.2<300300-9991000-9999<300300-999910,000-99,999100,000-999,999≥1million1.ChenCJ,etal.JAMA.2006;295:65-73.

2.IloejeUH,etal.Gastroenterology.2006;130:678-686.第15页，共28页，2023年，2月20日，星期四REVEAL:PersistentHBVDNAAssociatedWithIncreasedHCCRisk*Coxproportionalhazardsmodels.Riskisrelativeto<104copies/mLatentry/nottestedatfollow-up.

Dataadjustedforsex,age,cigarettesmoking,andalcoholconsumption.AdjustedHazardRatio*forHCC(95%CI)Low<104Mid104-105High≥105HBVDNA(copies/mL)High≥105High≥105High≥105DNAatentry:DNAatfollow-up:0481216n=146120537ChenCJ,etal.

JAMA.2006;295:65-73.

第16页，共28页，2023年，2月20日，星期四ReversalofFibrosisWithLong-term

Nucleos(t)ideAnalogueTherapyPairedbiopsiesfrombefore,after3yearsoflamivudine

(N=63)HAInecroinflammatoryscores56%improvedby≥2points33%hadnochange11%hadworsening(YMDDmutationsbluntedtheresponse)Fibrosis63%(12/19)hadimprovementinbridgingfibrosisby≥173%(8/11)hadimprovementincirrhosis(score4→≤3)Only2%(1/52)hadprogressiontocirrhosisand9%(3/34)tobridgingfibrosis—allwithYMDDmutationsDienstagJ,etal.Gastroenterology.2003;124:105-117.第17页，共28页，2023年，2月20日，星期四LauG,etal.NEnglJMed.2005;352:2682-2695.PegIFNalfa-2avsLAMvsCombinationat48WeeksinHBeAg+Patients020406080100EndofTreatment(Week48)PegIFN180µg(n=271)PegIFN+LAM(n=271)LAM100mg(n=272)272420HBVDNA<105copies/mLALTNormalHBeAgLossHBeAgSeroconversion302722528662394662Patients(%)HBsAgseroconversion

0%inall3armsHBVDNA<400copies/mL256940第18页，共28页，2023年，2月20日，星期四PegIFNalfa-2avsLAMvsCombinationat48WeeksinHBeAg(+)Patients-5.8-4.5-7.2HBVDNAReductionatWeek48Meanlog10HBVDNAreduction-8.0-7.0-6.0-5.0-4.0-3.0-2.0-1.00.01.0PegIFN180µg(n=271)PegIFN+LAM(n=271)LAM100mg(n=272)LauG,etal.NEnglJMed.2005;352:2682-2695.第19页，共28页，2023年，2月20日，星期四PegIFNalfa-2avsLAMvsCombination:Off-TreatmentFollow-up-2.0-2.4-2.6HBVDNAReductionatWeek72(24WeeksOff-Treatment)Follow-upLauG,etal.NEnglJMed.2005;352:2682-2695.Meanlog10HBVDNAreduction-8.0-7.0-6.0-5.0-4.0-3.0-2.0-1.00.01.0PegIFN180µg(n=271)PegIFN+LAM(n=271)LAM100mg(n=272)第20页，共28页，2023年，2月20日，星期四LimitationsofPegIFNStudiesAssessingtheimpactofLAM6monthsafterdiscontinuationsubjectsLAMtoanewstandardforanucleoside,usuallynotstoppedat48weeksInthistrial,ALT≥2xULNforentryformajorityInthisAsiancohort,2potentialcandidateswereexcludedforeveryparticipantincludedOnlylamivudinehasbeenstudiedasacomparatorLamivudinehasinferiorantiviraleffectscomparedwithothernucleos(t)ideanalogues第21页，共28页，2023年，2月20日，星期四Telbivudine“vs”Entecavir“vs”LamivudineinChronicHepatitisBMeanHBVDNAReduction(log10copies/mL)-6.5-5.5TBVvsLAM52WeeksTBV*22%LAM46%ETV<1%Resistanceat2Years-8.00-6.00-4.00-2.000.00ETVvsLAM48Weeks-6.9-5.4*Week92dataLaiC,etal.AASLD2005.AbstractLB1.LaiC,etal.AASLD2006.Abstract91.Baraclude[packageinsert].ColonnoRJ,etal.EASL2007.Abstract781.第22页，共28页，2023年，2月20日，星期四Patients(%)PegIFNalfa-2aTelbivudineWeek52Week76(OnTreatment)Week48Week72(OffTreatment)LauG,etal.NEnglJMed.2005;352:2682-2695.LaiCL,etal.AASLD2005.AbstractLB01.27320204060801002233HBeAgSeroconversionRatesat

1Year,24-WeekFollow-up第23页，共28页，2023年，2月20日，星期四HBeAgSeroconversionAfterExtendedNucleos(t)ideAnalogueTherapy1.LeungN.JGastroenterolHepatol.2002;17:409-414.2.LaiC,etal.AASLD2006.Abstract91.3.ChangTT,etal.NEnglJMed.2006;354:1001-1010.4.GishR,etal.AASLD2005.Abstract992.5.ChangTT,etal.AASLD2006.Abstract109.PatientsWithHBeAgSeroconversion(%)LAM[1]ETV[3-5]

TBV[2]2222212940473031020406080Year1

Year2Year3Year410039第24页，共28页，2023年，2月20日，星期四0RatesofResistanceinNucleos(t)ide-NaivePatientsLaiCL,etal.ClinInfectDis.2003;36:687-696.LokAS,etal.Gastroenterology.2003;125:1714-1722.Hepsera[packageinsert].FosterCity,Calif:GileadSciences;2006.ColonnoR,etal.EASL2007.Abstract781.LaiCL,etal.Gastroenterology.2005;129:528-536.LaiCL,etal.AASLD2006.Abstract91.2355716546Year12345Patients(%)8040602010003111930<1<1

<1<1522*9*

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?LamivudineAdefovirEntecavirTelbivudine,allpatientsTelbivudine,HBeAg-positivepatientsTelbivudine,HBeAg-negativepatients*Week92第25页，共28页，2023年，2月20日，星期四AdverseEffectsofPegIFNTherapy1.HadziyannisS,et