Post on 18-Dec-2021
TheShort-TermIncidenceofHepatocellularCarcinomaIsNot
IncreasedAfterHepatitisCTreatmentwithDirect-ActingAntivirals:
AnERCHIVESStudyDKLi,YJRen,DSFierer,SRutledge,OSShaikh,VLoReIII,T
Simon,AAbou-Samra,RTChung,AAButtMassachusettsGeneralHospital,Boston
VAPittsburghHealthcareSystem,PittsburghIcahnSchoolofMedicine,MtSinai,NewYork
PerelmanSchoolofMedicine,UniversityofPennsylvania,PhiladelphiaHamadMedicalCorporation,Doha,Qatar
WeillCornellMedicalCollege,Doha,Qatar&NewYork
AcceptedforPublicationinHEPATOLOGY2018HKASLDBi-monthlyScientificMeetingJournalReview
JamesY.Y.Fung18thJan2018
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Introduction• IFN-inducedSVRhasbeenshowntoreduceHCCriskbyabout4-fold,regardlessofstageofliverdisease
• TheextrapolationofthisbenefittoDAAsandtheexpectationofgreaterreductionhasnotbeenconsistent
• ParadoxicalincreasedriskofHCCinpatientstreatedwithDAAtherapy
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• 7/16hadbeentreatedinitiallywithresectionand9/16withablation
• MediantimefromHCCtreatmenttoDAAwas11.2m(25%-75%:3.6-23.2)
• MediantimefromCRtoDAAwas1.7and1.3forHCCrecurrentpatient
• MediantimefromCRtorecurrencewas3.5months(1.1-8)
• RecurrencerateishigherthanobservedinhistoricalnonDAAtreatedcontrols
Reigetal.JHepatol2016;65:719-726
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• Retrospectivecohortstudy• 344cirrhoticswithoutHCCat
timeofDAAs• TreatedwithDAAsandFUfor24
weeks• SVR91%• 59withHCChistory
– 19resections– 2resections+RFA– 2resections+TACE– 18RFA– 4RFA+TACE– 6PEI– 5TACE– 3Datanotcomplete
• MedianintervalbetweenHCCtreatmentandDAA376days(range,45-2706)
ContiFetal.JHepatol2016;65:727-733
17/599/28526/344
7.6%
3.2%
28.8%
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ANRSC022HEPATHERCohort ANRSC012CirvirCohort
ANRSC023CUPILTCohort
13% 21%1/13(8%)31/66(47%)
2.2%
NoincreaseriskofrecurrenceofHCCwithDAA-treatedpatientscompared
withnon-treatedpatients
TheANRScollaborativestudygrouponHCC.JHepatol2016
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StudyAim
• WhetherDAAtreatmentisassociatedwithhigherratesofincidentHCCusingalarge,well-establishednationalcohortofHCV-infectedUnitedStatesVeteranswithoutapriordiagnosisofHCC
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Design&DataSource(I)• RetrospectivecohortstudyofHCV-infectedpersonsinthe
ElectronicallyRetrievedCohortofHCVInfectedVeterans(ERCHIVES)database
• AllHCV-infectedVeteransatanyUS-wideDeptofVeteranAffairsmedicalfacilitieswithanti-HCV+between2002and2016wereidentified
• Demographic,clinical,labdatawereobtainedfromtheNationalPatientCareDatabaseandtheCorporateDataWarehouseHKASLD HKASLD
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Design&DataSource(II)
• Pharmacyinformation,includingallprescriptionswritten,doses,duration,numberofpills,numberofrefills,anddateofrefills,wasretrievedfromthePharmacyBenefitsManagementdatabase.
• Datamergedonestablishedalgorithms
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StudyParticipants
• Inclusioncriteria– Anti-HCV+
• Exclusioncriteria– HBV(HBsAg+)orHIVco-infection– Priortobaseline
• DiagnosisofHCC• MissingHCVRNAorFIB-4score• IncompletedataforFIB-4calculationatleast12weeksafterbaseline• MissingHCVRNAdataforcalculationofSVR12HKASLD HKASLD
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CohortGroups• GroupA(IFN):– ReceivedPEG+RBVfor≥28days– IfmultiplecoursesofPR–1sttreatmentcourseusedasbaseline
– StandardIFNexcluded
• GroupB(DAA)– ReceivedSOF/SMV±RBV;SOF/LED±RBV;SOF/DCL±RBV;PRoD±RBVfor≥28days
– OthernewerDAAsnotincluded(smallnumbers)
• GroupC– NoHCVtreatmentfor≥28days
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BaselineDefinitions• Fortreatedgroups– BaselinewasthedateofHCVtreatmentinitiation
• Foruntreatedgroups– BaselineequaltothedurationofHCVinfectionpriortotreatmentinitiationinthecorrespondingtreatedperson• Determiningtheaveragetimebetweenthefirstanti-HCV+dateandtreatmentinitiationdateforthetreatedgroup• Addingthesamedurationtothetimebetweenthefirstanti-HCV+dateineachuntreatedpersonandassigningthatdateasbaselineHKASLD HKASLD
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DefinitionofCirrhosis
• FIB-4score>3.5– FIB-4=(age[years]xAST[IU/L]/(plateletcount[plateletsx109/L]xALT½[IU/L])
• Labdataobtainedatyearlyintervals– FIB-4scorerecalculatedateachinterval
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StudyOutcomes
• Primaryoutcome– DevelopmentofincidentHCC
• DefinedaspresenceofatleastoneinpatientortwooutpatientICD-9/10codesforHCCmade≥3monthsafterbaseline• TimetodevelopmentofHCCdeterminedrelativefrombaseline• GiventhatadvancedfibrosisisoneofthestrongestpredictorsofHCCdevelopment,primaryanalysiswasperformedonpersonswithbaselinecirrhosis(FIB-4>3.5)HKASLD HKASLD
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PatientCharacteristics
Age(yrs)
Sex,%maleRace,%WhiteBlack
HispanicOthers
Diabetes,%BMI,median
Alcohol,%
Smoking,%CurrentFormerNeverHKASLD HKASLD
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HCVGT,%123
4,5,6Missing
BaselineHCVRNAlog
PPIuseduringtreatment
StatinusepriortobaselineFIB-4baseline,%<1.45nofibrosis
>3.5cirrhosis1.45-3.5
MedianAFP
RBVuse,%Treatment,%
<8weeks8weeks12weeks24weeksSVR,%
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IncidenceRateofHCCbyTreatmentGroupandSVRStatus(EntireCohort)
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IncidenceRateofHCCbyTreatmentGroupandSVRStatus(CirrhoticsOnly)
TreatmentGroup
AllcirrhoticsIFN
DAAregimensUntreatedcontrols
SVR12subgroupIFN
DAAregimens
NonSVR12subgroupIFN
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ProbabilityofHCCDevelopmentinCirrhoticPersonwhoachievedSVR
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BaselineCohortCharacteristicsfromFIB-4SensitivityAnalysis
(Limiting
definitionofbaselineFIB-4towithin12monthspriortobaseline)
Overall1933FIB-4valuesexcluded209IFN82DAA
1642untreated
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IncidenceRateofHCCinPersonswithCirrhosis,byTreatmentGroupandSVR
StatusinFIB-4SensitivityAnalysis
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BaselineCharacteristics
ofDAASubgroups
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IncidenceRateofHCCinPersonswithCirrhosis,byDAATreatmentandSVRStatus
TreatmentGroup
CirrhoticsIFN
SOF/SMVSOF/LED
SVR12subgroupIFN
SOF/SMVSOF/LED
NonSVR12subgroupIFN
SOF/SMVSOF/LED
p=0.07
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Age,per10yearincreaseMalesex
RaceWhite(comparator)
BlackHispanic
Other/MissingDiabetes
BMI(per1unitincrease)Alcoholabusehistory
SmokinghistoryNon-smoker(comparator)
CurrentsmokerFormersmoker
MissingHCVgenotype,%1(comparator)
23
4,5,6Missing
HCVRNA,per1logincreasePPIuse(baselineonwards)
StatinuseAFP>20(vs20orbelow)
TreatmentregimenPeg/RBV(comparator)
AnyDAAAttainmentofSVR
PredictorsfortheDevelopmentofHCCinPersonswithCirrhosisbasedon
Multivariate,CoxProportional
HazardsAnalysis
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PredictorsfortheDevelopmentofHCCinCirrhotics
BasedonMultivariateCoxProportional
HazardsAnalysisinFIB-4
SensitivityAnalysis
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Discussion• DAA-treatedpersonsdidhaveasignificantlyhigherHCC
ratethanIFN-treatedpersons(overallgroup)– Higherrateofknownriskfactors
• Cirrhosis,olderage,higherbaselineAFP
• AnalyzingcirrhoticpatientsaloneshowednodifferenceinHCC-freesurvivalbetweenDAAandIFNgroups– LowerHCCincidenceinsensitivityanalysis
• Pre-treatmentriskofHCCisthemaindriverofpost-treatmentriskofHCCHKASLD HKASLD
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Discussion• HigherprevalenceofunderlyingHCCrisks
amongDAApatientsdueto“warehousing”?• TreatmentwithearliestDAAregimensmay
besurrogateforhigherbaselineHCCrisk• Failedtherapy,cirrhotics
• PersonstreatedwithSIM/SOFhadhigherratesofcirrhosis(c/wIFN/laterDAAs)
• PreviousstudieshavenotprovidedbaselinedataincombinationwithDAAregimens
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Discussion
• Incontrasttopreviousstudies,DAAtreatmentisnotassociatedwithhigherriskofHCCcomparedtoIFNtreatmentwhencontrollingfordifferencesinbaselineHCCriskfactors
• AchievementofSVRwithantiviralregimenisthemostimportantdeterminantofalowerHCCrisk
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StudyLimitations• Relativelyshortfollow-uptimeinDAAcohort• Potentialforlimitedgeneralizability– Veterans,males,highersmoking&alcoholuse
• Retrospectivecohortstudy– Prospectivestudiesunlikely
• Lackofliverhistologyfordiagnosingcirrhosis• LackofinforegardingHCCsurveillancepractices
• ExcludedthosewithpriorHCCHKASLD HKASLD
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StudyConclusion
• IncirrhoticswithchronicHCVinfection,therewasnoassociationbetweenHCCincidenceratesandDAAtreatmentcomparedtoIFN
• InsufficientcontrollingforbaselinerisksforHCCandselectionbiaslikelydrovepreviouslyreportedassociationsbetweenDAAtreatmentandincreasedHCCrisk
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