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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