Transjugular Intrahepatic Portosystemic Shunt does not affect the efficacy and safety of direct-acting antivirals in patients with advanced cirrhosis: A real-life, case-control study

Contents lists available atScienceDirect

Digestive

and

Liver

Disease

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Liver,

Pancreas

and

Biliary

Tract

Transjugular

Intrahepatic

Portosystemic

Shunt

does

not

affect

the

efficacy

and

safety

of

direct-acting

antivirals

in

patients

with

advanced

cirrhosis:

A

real-life,

case-control

study

Stefano

Gitto

_,

_Francesco

_Vizzutti

_,

_Filippo

_Schepis

_,

_Laura

_Turco

_,

_Silvia

_Aspite

_,

Giovanni

Vitale

_,

_Umberto

_Arena

_,

_Erica

_Villa

_,

_Giacomo

_Laffi

_,

Wilma

Debernardi-Venon

_,

_Fabrizio

_Fanelli

_,

_Pietro

_Andreone

_,

Fabio

Marra

_,

_DAA-TIPS

_group

a_{DepartmentofExperimentalandClinicalMedicine,UniversityofFlorence,Italy}

b_{DivisionofGastroenterology,ModenaHospital,UniversityofModenaandReggioEmilia,Modena,Italy}

c_{DepartmentofMedicalandSurgicalSciences,CenterforStudyandResearchonChronicHepatitis,UniversityofBologna,Italy} d_{DepartmentofMedicalSciences,DivisionofGastroenterologyandHepatology,MolinetteHospital,Turin,Italy}

e_{DepartmentofInterventionalRadiology,CareggiHospital,Florence,Italy} f_{ResearchCenterDenothe,UniversityofFlorence,Italy}

a

r

t

i

c

l

e

i

n

f

o

Advancedliverdisease Antiviraltherapy Cirrhosiscomplications Portalhypertension

a

b

s

t

r

a

c

t

Background:TransjugularIntrahepaticPortosystemicShunt(TIPS)isawell-establishedtreatmentfor complicationsofportalhypertension.

Aims:ToanalyzetheimpactofTIPSonvirologicresponseandsafetyprofileinpatientstreatedwith direct-actingantivirals(DAAs).

Methods:WeanalyzeddatafromHCV-positivecirrhoticpatientstreatedwithDAAs.Twenty-onepatients withpreviousTIPSplacementwerecomparedwith42matchedsubjectswithoutTIPS.Logisticregression wasusedtoidentifypredictorsofhepaticfunctionworseningandadverseevents.

Results:Nodifferenceswerefoundbetweenthetwogroupsinparticularregardingsustainedvirologic response(92.5and97.6%inTIPSvsno-TIPS,p=0.559).ModelforEnd-stageLiverDisease(MELD)ofboth TIPSandno-TIPSgroupsdeclinedfrombaselinetoweek24offollow-up(from12.5±3.5to10.8±3.4 andfrom11.1±3.5to10.3±3.4,p=0.044and0.025).Therewerenodifferencesinadverseeventrates. Atunivariateanalysis,agewasassociatedwithMELDincreasefrombaselinetoweek24(OR1.111,95% CI1.019-1.211,p=0.017),andpatientswithhigherbaselineMELDdevelopedseriousadverseevents morefrequently(OR0.815,95%CI0.658–1.010,p=0.062).PatientswithorwithoutTIPSdidnotshow differencesintransplant-freesurvival.

Conclusion:TIPSplacementdoesnotaffectvirologicresponseandclinicaloutcomeofpatientsreceiving DAAs.

©2018EditriceGastroenterologicaItalianaS.r.l.PublishedbyElsevierLtd.Allrightsreserved.

1. Introduction

About3%oftheworldpopulationisinfectedwithhepatitisC virus(HCV)infectionand150.000newinfectionsareregistered

∗ Correspondingauthorat:DepartmentofExperimentalandClinicalMedicine, UniversityofFlorence,LargoBrambilla,3,50134Florence,Italy.

E-mailaddress:fabio.marra@unifi.it(F.Marra).

1 _{Theseauthorscontributedequallytothepresentstudy.}

2 _{CollaboratorsoftheDAA-TIPSgroup:PasqualeApolito}a_{,ClaudiaCampani}a_,

SinanSadallaa_{,FedericaLombardo}a_,FabioContic_{,AlessandraScuteri}c_.

everyyearinWesterncountries[1].Twentypercentofpatients with chronic hepatitis C (CHC) develop cirrhosis, and 700.000 deathsassociatedwithcomplicationsofliverdiseaseoccurevery year[2].Untilafewyearsago,antiviraltherapybasedon inter-feroninassociationwithribavirin(RBV)wastheonlyapproachfor infectedpatients,withmodestratesofsustainedvirologicresponse (SVR)andsignificantsideeffects[3].Duringthelastfewyears,new antiviralmoleculeswithadirectactionagainstthevirushavebeen developed,resultinginadramaticchangeinthemanagementof CHC[3].Infact,mostdirect-actingantiviral(DAA)schedulesinduce highSVRrateswithexcellentsafetyprofiles.Atdifferencewith

https://doi.org/10.1016/j.dld.2018.11.015

interferon-basedantiviraltherapy,DAAscanbeusedinpatients withadvancedliverdiseasewithgoodSVRrates[4]andapositive impactonpatientsurvival[5].Nonetheless,Curryetal.[6]reported thatinpatientsinChild-Pugh-Turcotte(CTP)classBtreatedwith DAAs,satisfactorySVRrate(83–94%)wereassociatedwitha rel-evantnumberof seriousadverse events(SAE) comparedtothe sameregimensinpatientswithchronichepatitisorcompensated cirrhosis(16–19%vs2%)[6,7].

TransjugularIntrahepaticPortosystemicShunt(TIPS)isa lead-ingtreatmentoptionforthecomplicationsofportalhypertension. TIPSisindicatedinportalhypertensivebleeding,refractoryascites andvascularliverdiseases,resultingin improvementofpatient survival[8–12].Notably,TIPSstronglymodifiessplanchnic hemo-dynamics,determining substantial porto-systemicshunting [8]. TIPSplacementmightinfluencethepharmacokineticsofdifferent drugs[13–15],andthisistheoreticallypossiblealsoforDAAs.The safetyprofilerepresentsanotheropenissue,consideringthehigh ratesofSAEs inpatientswithadvanced liverdisease[6].These aspectshaveneverbeenpreviouslyinvestigated.

Inthisstudy,weevaluatedtheimpactofTIPSonSVRrate,drug safetyprofileandliverfunctioninHCV-positivecirrhoticpatients treatedwithDAAs.

2. Materialsandmethods

Weanalyzedbiochemical,virologicalandclinicaldataof HCV-positive cirrhotic patients with functioning TIPS, consecutively treatedwithDAA-basedtherapiesfromSeptember2014toApril 2017.Inallcases,TIPSwasplacedbeforestartingDAAtherapy. Cir-rhoticpatientswithoutTIPStreatedwithDAAsinthesameperiod oftimewereusedascomparison.TheywereselectedamongHCV positive patientsconsecutively treated in thefourtertiary par-ticipatingcenters,accordingtosex,age(±3years)andCTPclass (match1:2).DAAscheduleandtreatmentlengthwereestablished followingtherecommendationsoftheItalianMedicinesAgency committee[16].

Enrollmentcriteriawereage>18 yearsandHCVinfectionas establishedbybothpositiveserumHCVantibodyandserum HCV-RNA,usingareal-timepolymerasechainreaction-basedmethod. Patients had evidence of cirrhosis as assessed by liver biopsy, vibration-controlled transientelastography withFibroScan®, or bythepresence of complications. Othercausesof liverdisease includingalcoholabuse,andpreviouslivertransplantationwere exclusioncriteria.

InallpatientswithpreviousTIPSplacement,shuntpatencywas documentedbyradiologicfollow-up.Allenrolledpatients under-wentatleastoneDopplerultrasoundwithinsixmonthsfromthe beginningofantiviraltherapywiththefollowingsignsofoptimal function[17]:wholecolorsaturationinthreesegmentsofthestent (portal,midportion,andhepaticsites)withoutanyevidenceof fill-ingdefectsorfocalaliasing;high-velocityturbulentflowintothe stentwithagradualvelocityshiftduringrespiration;hepatofugal flowintheportalveinbranches;hepaticarteryflowincrease.

Laboratory assessment, including HCV-RNA levels, was con-ductedatbaseline,endofantiviraltreatment,and12and24weeks aftertheendofDAA.ModelforEnd-StageLiverDisease(MELD) andMELDcorrectedbyserumsodium(MELD-Na)werecalculated atalltimepoints.Deltavalueswerecalculated(week24of follow-up−baseline)forallthemainlaboratoryvalues.HCV-RNAlevels weremeasuredwithCOBAS® AmpliPrep/COBAS® TaqMan® HCV QuantitativeTest,v2.0(limit15IU/ml).

WeregisteredDAA-relatedandunrelatedadverseevents(AEs) (untowardmedicaloccurrenceassociatedwiththeuseofantiviral therapy)andSAEs(death,alife-threateningAE,inpatient hospital-izationorprolongationofexistinghospitalization,apersistentor

significantincapacityorsubstantialdisruptionoftheabilityto con-ductnormallifefunctions)[18].Thestudyprotocolconformedto theethicalguidelinesofthe1975DeclarationofHelsinki.Patients gavetheirwritteninformedconsenttoundergoantiviraltherapy withDAAs.

2.1. Statisticalanalysis

Aphysiciantrainedinstatisticsencodedallsamplesintoa ded-icateddatabaseinananonymousform.Dataareexpressedasthe mean(±standarddeviation)ormedian(withrange),asapplicable. Confidenceinterval(CI)isshownwhereappropriate.Comparisons betweengroupsweremadebyChisquare-testandFisher’sexact testforqualitativevariables,andMann–WhitneyU-testfor con-tinuousordinaldata,respectively.Wilcoxontest wasutilizedto assesstendenciesandspecificranktestforsignificance. Logistic regressionwasperformedtoidentifythepredictorsofliver func-tionimpairment,AEsandSAEs.PresenceofTIPSwasanalyzedas potentialpredictorinalloutcomeanalyses.Asignificancelevelof 0.05wasconsideredforalltests.TheSPSSsoftwareversion21.0 (MJNorusis,Chicago,US)wasusedforallstatisticalanalyses. 3. Results

3.1. Baselinecharacteristics

Weenrolled21HCV-positivecirrhoticpatientswithprevious TIPSplacementand42cirrhoticsubjectswithoutTIPS,matched forgender,ageandCTPclass.Themaindemographicand base-lineclinicalcharacteristicsofthetwogroups(TIPSandno-TIPS) aresummarizedinTable1.Additionalclinicalandtechnicaldata ofpatientsincludedintheTIPSgrouparereportedin Supplemen-taryTable1.Notably,afractionofpatientshadunder-dilatedTIPS accordingtoanapproachdescribedinarecentlypublishedstudy

[19].PatientswithTIPSandthecounterpartswerecomparablefor allotherclinicalandvirologiccharacteristics.Genotype1bwasthe mostrepresented,andsofosbuvir/ledipasvirthemostfrequently usedantiviralschedule.RBVwasaddedtoDAAinapproximately halfofthecases,inbothgroups.

3.2. Virologicresponse

Allpatientsconcludedtheantiviraltherapy.Allpatients, regard-less of the presence of TIPS, reached the SVR12 but not all maintainedthevirologicresponseat24weeksoffollow-up(SVR24 92.5%vs97.6%inTIPSand no-TIPS,respectively,p=0.559).One patientineachgrouphadavirologicrelapse:intheTIPSgroup,a 49yearsoldmale,genotype4,CTPclassA,treatedfor24weeks withsofosbuvir/ledipasvirwithoutRBV;intheno-TIPSgroup,a42 yearsoldmale,genotype1a,CTPclassB,treatedfor24weekswith sofosbuvir/ledipasvirwithoutRBV.

3.3. Changesinlaboratoryparametersandliverfunction

Thebehavioroflaboratorytestsatbaseline(T0),endof treat-ment(EOT)andweek24offollow-up(W24)isreportedinTable2. PatientswithTIPS and no-TIPSwerein generalcomparable for alllaboratoryassessments,althoughthosewithTIPShadhigher medianvaluesoftotalbilirubinatEOTandatW24incomparison withpatientswithoutTIPS.

Analyzingthemodificationsalongthethreetimepoints, amino-transferasesand␥GTlevelsdecreasedinbothgroups,whiletotal bilirubinsignificantlydeclinedonlyinpatientswithoutTIPS.Mean MELDscoresateachtimepointandtheirtrendduringandafter antiviraltherapyarereportedinTable2andinFig.1.Patientsof thetwogroupshad statisticallyequivalentMELDand MELD-Na

Table1

BaselinecharacteristicsofpatientsincludedintheTIPSandno-TIPSgroups.

TIPS no-TIPS ␹2-Fisher/MW-U

Pvalue

N 21 42

Malen(%) 18(85.7) 36(85.7) 1.000

Age(years,mean±SD) 58±10 61±10 0.385

Genotypen(%) 1a 4(19) 8(19) 1.000 1b 9(42.9) 21(50) 0.395 2 1(4.8) 2(4.8) 1.000 3 3(14.3) 8(19) 0.564 4 4(19) 3(7.1) 0.160

HCV-RNA(UI/ml)(median,R) 352977.8740–12723486 380000.2750–12295107 0.683 CTPscoren(%) A6 9(42.8) 18(42.8) 1.000 B7 3(14.3) 15(35.7) 0.137 B8 8(38.1) 5(11.9) 0.023 B9 0(0) 2(4.8) 0.548 C10 1(4.8) 2(4.8) 1.000 MELD(mean±SD) 12.5±3.5 11.1±3.5 0.177 MELD-Na(mean±SD) 13.6±3.5 12.4±5.2 0.055 DAAregimenn(%) SOF/SIM 0 2(4.8) 0.441 SOF/LPV 11(52.4) 18(42.9) 0.327 SOF/DCV 7(33.3) 14(33.3) 1.000 SOF 2(9.5) 3(7.1) 0.545 OBV/PTV/RTV/DSV 0 4(9.5) 0.188 OBV/PTV/RTV 1(4.8) 1(2.4) 0.559 RBVn(%) 9(42.9) 20(47.6) 0.465

Lengthoftherapy12/24weekn(%) 0(0)/21(100%) 6(14.3)/36(85.7) 0.077

TIPS:TransjugularIntrahepaticPortosystemicShunt;␹2:Chisquare;MW-U:Mann–WhitneyUtest;SD:standarddeviation;R:range;CTP:Child-Turcotte-Pugh;MELD: ModelforEnd-stageLiverDisease;SOF:sofosbuvir;SMV:simeprevir;LPV:ledipasvir;DCV:daclatasvir;OBV:ombitasvir;PTV:paritaprevir;RTV:ritonavir;DSV:dasabuvir; RBV:ribavirin.

Table2

LaboratoryparametersincirrhoticpatientswithorwithoutTIPSundergoingtherapywithDAA.

TIPS no-TIPS

T0 EOT W24 T0 EOT W24

PLT(×109_{/mmc)(median,R) 79.36–161 78.33–172 78.36–164 98.19–222 92,19–259 98.20–206}

Bilirubin(mg/dl)(median,R) 1.8.0.8–7.2 1.7.1.1–4.6b _{1.3.0.5–3.4}b _{1.3.0.4–8.6 1.3,0.2–6.7}a _1.0.4–5.5a

AST(IU/ml)(median,R) 61.28–154 31.14–63a _30.17–55a _{73.21–519 28,16–66}a _25.13–71a

ALT(IU/ml)(median,R) 47.21–151 23.9–48a _21.10–52a _{60.11–405 20,11–48}a _21.10–58a

␥GT(IU/ml)(median,R) 53.10–303 36.7–246a _33.8–120a _{67.16–303 41,12–121}a _42.12–119a

ALP(IU/ml,median,R) 100.62–233 99.46–193 104.57–200b _{126.58.490 123,59–635}a _157.22–801

Creatinine(mg/dl,mean±SD) 0.9±0.2 0.8±0.3 1±0.4 0.9±0.3 0.9±0.3 0.9±0.3

MELDscore(mean±SD) 12.5±3.5 12.7±3b _10.8±3.4a _{11.1±3.5 10.5±3.4}a _10.3±3.4a

MELD-Nascore(mean±SD) 13.6±3.5 13.7±3.2b _11.7±3.4a _{12.4±5.2 11±4.2 10.4±3.4}a

T0:startofDAAtreatment;EOT:endofantiviraltherapy;W24:week24offollow-upaftertheendofantiviraltherapy;R:range;PLT:platelets;AST:aspartate aminotrans-ferase;ALT:alanineaminotransferase;␥GT:gammaglutamyltransferase;ALP:alkalinephosphatase;MELD:ModelforEnd-StageLiverDisease.

a_{SignificantdifferencewithrespecttoT0(Wilcoxontest,p<0.05).}

b_{Significantdifferencecomparedtothesametimepointinno-TIPS(Mann–WhitneyUtest,p<0.05).}

Table3

ComparisonofchangesinlaboratoryparametersbeforeandafterantiviraltreatmentincirrhoticpatientswithorwithoutTIPS.

Deltavalue(W24−T0) TIPS no-TIPS Pvalue

PLT(×109_{/mmc)median(R) +2(−61to+54) +4(−42to+49) 0.406}

Bilirubin(mg/dl)median(R) −0.4(−6.7to+2.5) −0.3(−15to+1) 0.994 AST(IU/ml)median(R) −29(−137to+9) −48(−448to−1) 0.055 ALT(IU/ml)median(R) −25(−144to+12) −41(−347to+35) 0.079 ␥GT(IU/ml)median(R) −20(−141to+37) −22(−218to+99) 0.569 ALP(IU/ml)median(R) −6(−141to+39) +8(−153to+347) 0.354

Creatinine(mg/dl)mean±SD +0.1±0.2 +0.05±0.2 0.331

MELDscoremean±SD −1.7±3.4 −0.7±2.6 0.039

MELD-Nascoremean±SD −2±3.9 −2±5.1 0.433

T0:startofDAAtreatment;W24:week24offollow-upaftertheendofantiviraltherapy;MW-U:Mann–WhitneyUtest;R:range;PLT:platelets;AST:aspartate amino-transferase;ALT:alanineaminotransferase;␥GT:gammaglutamyltransferase;ALP:alkalinephosphatase;MELD:ModelforEnd-StageLiverDisease;MELD-Na:Modelfor End-StageLiverDiseasecorrectedbyserumsodium.

scoresatT0andW24.PatientswithTIPSshowedasignificantly highermeanMELDandMELD-NaatEOTincomparisonwith sub-jectswithno-TIPS.MeanMELDscoredroppedfromT0toEOTand

fromT0toW24inthecontrolgroup.PatientswithTIPSshoweda significantdecreaseofmeanMELDfromT0toW24butnotfrom T0toEOT.Inbothgroups,MELD-Nasignificantlydecreasedfrom

Fig.1.DistributionofMELDscore(rangingfrom6to40,withhighervalues indicat-ingmoreadvancedliverdisease)accordingtothepreviousTIPSplacement.MELD atbeginningofantiviraltreatment(darkgreybar),MELDcalculatedattheendof antiviraltherapy(lightgreybar),MELDatweek24fromtheendoftreatment(white bar).Thehorizontalbarinsidetheboxindicatesthemedianvalue.Thepoints rep-resenttheoutliers,definedasvaluesnotfallingintheinnerfences.Theasterisks aretheextremeoutliers,definedasvaluesmorethanthreetimestheheightofthe boxes.

T0to W24.Delta values (W24−T0) ofthe analyzedlaboratory parametersarereportedinTable3.PatientswithTIPSshoweda significantlygreatermeandelta-MELDthanpatientswithoutTIPS. MELDscoredeclinedfromT0toW24inthevastmajorityof patientswhileitincreasedin14.3%ofpatientswithTIPS(3/21)and in16.7%ofno-TIPS(7/42)(p=0.559).Atunivariateanalysis,only patients’agewassignificantlyassociatedwiththeincreaseinMELD score(fromT0toW24)[OddsRatio(OR)1.111,95%CI1.019–1.211, p=0.017]. In particular, mean age was 67±7 in patientswith increasedMELD,and59±10yearsinthosewhodecreasedMELD. ThepresenceofTIPSortimebetweenTIPSplacementandstartof DAAtherapydidnotemergeassignificantvariableseitherinthe preliminaryunivariatetestorinthemultivariatemodel.

3.4. Safety

ThemainsafetyoutcomesaresummarizedinTable4. Compar-ingTIPSandno-TIPS,nosignificantdifferenceswerefoundinthe incidenceofAE.ThemostcommonDAA-relatedAEwasfatigue. HCCoccurrenceduringantiviraltherapy wasthemostfrequent SAEunrelatedtoDAA.NoDAA-relatedSAEswereregistered.No patientsdiscontinuedtreatmentprematurelybecauseofanAEor SAE.

Malegenderwastheonlyfeaturethattendedtobeassociated withtheoccurrenceofAE(OR0.148,95%CI0.018–1.241,p=0.078). AEswerereportedin40.4%ofmales(21/52)andin9.1%offemales (1/11).NopredictorsofDAA-relatedAEweredetected.

AtunivariateanalysisforthepredictorsofSAE,MELDscoreat T0emergedastheonlyfactorwithaPvalue<0.1(OR0.815,95%CI 0.658–1.010,p=0.062).PatientswhoexperiencedaSAEshoweda meanbaselineMELDscoreof14±5,comparedto11±3intheother patients.ThepresenceofTIPSortimebetweenTIPSplacementand startofDAAtherapydidnotemergeassignificantvariableseither inthepreliminaryunivariatetestorinthemultivariatemodel. 3.5. Long-termoutcome

Nopatientdiedorwastransplantedduringtheantiviral ther-apy.Duringthe2-yearfollow-upperiod,1patientdied(no-TIPS group)while3patientswithTIPSand1no-TIPSweretransplanted. Two-yearcumulativesurvivalofpatientswithTIPSwas100%while

Table4

AdverseeventsincirrhoticpatientswithorwithoutTIPSundergoingtreatmentwith DAA.

TIPS no-TIPS ␹2-Fisher Pvalue N 21 42 AEs(overall)n(%) 9(42.9) 13(31) 0.255 AEs(DAA-related)n(%) 3(14.3) 10(23.8) 0.297 Fatigue 3(100) 7(70) Skinrash 0 2(20) Nausea 0 1(10)

AEs(notDAA-related)n(%) 6(28.6) 3(7.1) 0.031

Ascites 2(33.3) 0 Rectalbleeding 1(16.7) 0 Skininfection 1(16.7) 0 HepaticHencephalopathy 1(16.7) 0 Depression 1(16.7) 2(66.7) Anaemia 0 1(33.3)

WithdrawalofantiviralforAE 0 0 1.000 SAEs(overall)n(%) 1(4.8) 6(14.3) 0.248 SAEs(DAA-related)n(%) 0 0 1.000 SAEs(notDAA-related)n(%) 1(4.8) 6(14.3) 0.248

HCC 1(100) 3(50)

Liverfailure 0 1(16.7)

SBP 0 1(16.7)

Portalthrombosis 0 1(16.7)

WithdrawalofantiviralforSAEn(%) 0 0 1.000 Deathduringtreatmentn(%) 0 0 1.000 Deathduring2-yearfollow-upn(%) 0 1(2.4) 0.667 LTduringtreatmentn(%) 0 0 1.000 LTduring2-yearfollow-upn(%) 3(14.3) 1(2.4) 0.104 ␹2:Chisquare;AE:adverseevent;DAA:directactingantivirals;SAE.seriousadverse event;HCC:hepatocellularcarcinoma;SBP:spontaneousbacterialperitonitis;LT: LiverTransplant.

survivalofno-TIPSwas97.4%(p=0.549).Deathand transplanta-tionoccurredinallcasesforprogressionoftheunderlyingliver disease,andwerenotrelated toDAAtherapy. Thepatientwho diedwasa 60yearsoldmale,genotype 1b,CTPB,treated with ombitasvir/paritaprevir/ritonavirplus dasabuvirand RBV for 12 weekswithachievementofRVR,SVR12andSVR24.Thecauseof deathwasacomplicationofbowelobstruction.

4. Discussion

PatientswithHCV-relatedadvancedliverdiseasemightbenefit frombothTIPSplacementandDAAtherapy[6,8–12].However,TIPS leadstoporto-systemicshunting[8]anditsimpactondrug phar-macokineticsandconsequentlyonefficacyandsafetyisuncertain. WhileDAAtherapyisgenerallysafeinCHCandcompensated cir-rhosis[6,7],inpatientswithadvancedliverdisease,relevantrates ofSAEwereobserved[6,7].Inthisstudy,wedemonstratedforthe firsttimethatpatientswithpreviousplacementofTIPScanachieve optimalratesofSVR24(92.5%)andasignificantdecreaseinMELD andMELD-NascorefromT0toW24.Inparticular,bothSVRrate andtheimprovementofliverfunctioninpatientswithprior place-mentofTIPStreatedwithDAAarecoherentwithpreviousstudies inpatientswithadvancedcirrhosiswithoutTIPS[6,20].Itshouldbe notedthatinpatientswithTIPSthedeclineofMELDwassomehow slowerthaninpatientswithoutTIPS.However,inpatientswithTIPS asignificantlyhigherdelta-MELDthaninpatientswithoutTIPSwas observed.

Notably,attwoyearsoffollow-up,patientswithandwithout TIPSshowedacomparablepercentageofhardclinicaloutcomes (LTanddeath).Surprisingly,patientswithTIPStendedtodevelopa lowernumberofDAA-relatedAEsandSAEswithrespecttopatients withoutTIPS,althoughthisdifferencewasnotsignificant.Whileit isconceivablethatthereductioninportalpressurecouldhavean impactonsomeoftheAEs,datafromlargerseriesofpatientsare necessarybeforedefinitiveconclusionsonthisissuemaybedrawn.

Wealsoanalyzedthewholepopulationofpatientswithsevere liverdisease,irrespectiveofTIPS,tryingtoidentifyindependent predictorsofMELDincreasefromT0toW24,andofAEsandSAEs. Indeed,whileinthemajorityofpatientsMELDscoredecreased fromT0totheendoffollow-up(W24),inasubgroupofpatients thescoreincreased(14.3%ofpatientswithTIPSand16.7%without TIPS).ElderlypatientswereathigherriskofMELDincrease, con-firmingthatageisadeterminantofthelikelihoodtoimproveliver function,possibleduetodifferencesinhepaticfunctionalreserve. TheseresultsareinagreementwiththoseofContietal.[21],who demonstratedthatpatientswithadvancedfibrosisorcirrhosisaged ≥65years,andtreatedwithDAA,hadaworseningofCTPclass,at differencefromyoungerpatients.Genderemergedasaborderline predictoroftheappearanceofAEduringDAAtreatment.Infact, malesshowedfourtimesasmanyAEsasfemales.Althoughthisis anoriginalandpotentiallyinterestingfinding,thelownumberof femalesenrolledinthisstudydoesnotallowtodrawany defini-tiveconclusions.Furtherstudiesshouldexplorepossiblegender differencesintermsofSVRandsafetyprofileinthispopulation.

PatientswithhigherMELDscoreatT0displayedahigherrisk ofSAE.Thisfindingisnotsurprisingsince onlySAEsassociated withadvancedliverdiseaseitselfandnotrelatedtoDAAswere registered.Notably,wecouldnotanalyzethepossiblepredictors ofSVRoroftransplantordeathduetothelownumberofevents.

Wehavetoacknowledgeafewlimitationsofthisstudy, includ-ing therelatively small number of patientsenrolled.However, thisisthefirstreal-lifestudyanalyzingwholelaboratory, virolog-ical,andclinicaloutcomesofpatientstreatedwithDAAafterTIPS. BecauseDAAshavebeenintroducedinclinicalpracticeonlyfew yearsago,thelengthoffollow-upreportedinthepresentstudy(2 years)isadequatetoconfirmtheexcellentresultsofDAA-based therapyalsoinpatientswithadvancedliverdisease.The observa-tionaldesignofthestudyrepresentsafurtherlimitation,although the1:2matchingcanassureanacceptablestrengthofthestudy design.Thestudyaddsreallife-basedknowledgeinthecontextof advancedcirrhosis,aconditionwhereadditionalpost-registration informationmaystillbeofvalue[22].Futurestudiesshouldbe undertakentoevaluatewhethertheoutcomesobserved inTIPS patientstreatedwithDAAaredifferentfromthoseofpatientswith TIPSnotundergoingantiviraltherapy.Inthecohortsavailablein ourcenters,these latterpatients had TIPSplaced severalyears beforeandthiswouldcreateabiasinthecomparison.Another lim-itationofthisstudyisthelackofpharmacokineticdatainthetwo groupsofpatients.Thesedata,whichcouldestablishwhether,and towhatextent,DAAsplasmalevelsaredifferentinpatientswith TIPS,deservetobeobtainedinfuturestudies.

Inconclusion,DAA-basedantiviraltherapymaybesafelyand effectivelyusedafterTIPSplacement.Cirrhoticpatientswithand withoutTIPStreatedwithDAAhavesimilarlong-termoutcomes andcomparablechancestoimprovetheirliverfunction.

Conflictofinterest

FVhasreceivedundisclosedresearchgrantandlecturefeesfrom Gore.

FShasreceivedundisclosedresearchgrantandsupportgrant fromGore.

EVhasbeenconsultantandspeakerforMSD,AbbVie,Gilead Science,BMS.

PAhasbeeninadvisoryboardforMSD,GileadSciences,AbbVie, BMS,InterceptandhasreceivedresearchgrantformMSD,AbbVie, GileadSciences,BMS.

FMhasbeenconsultantforAbbVie,GileadScience,Menarini, ViiV,NovoNordisk,Astrazeneca,Bayer,Allergan,Interceptandhas receivedsupportgrantfromAlphaSigma,Bayer,AbbVie,Kedrion.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttps://doi.org/10.1016/j.dld.2018.11.015. References

[1]GlobalBurdenofHepatitisCWG.Globalburdenofdisease(GBD)forhepatitis C.JClinPharmacol2004;44:20–9.

[2]Guidelinesforthescreening,careandtreatmentofpersonswithhepatitisC infection.http://www.who.com.[Accessed3October2016].

[3]EuropeanAssociationfortheStudyoftheLiver.EASLrecommendationson treatmentofhepatitisC2018.JHepatol2018;69:461–511,http://dx.doi.org/ 10.1016/j.jhep.2018.03.026,pii:S0168-8278(18)31968-8.

[4]MangiaA,LosappioR,CenderelloG,PotenzaD,MazzolaM,DeStefanoG,etal. Realliferatesofsustainedvirologicalresponse(SVR)andpredictorsofrelapse followingDAAtreatmentingenotype3(GT3)patientswithadvanced fibro-sis/cirrhosis.PLoSOne2018;13:e0200568,http://dx.doi.org/10.1371/journal. pone.0200568.

[5]BackusLI,BelperioPS,ShahoumianTA,MoleLA.Impactofsustained viro-logicresponsewithdirect-actingantiviraltreatmentonmortalityinpatients withadvancedliverdisease.Hepatology2019;69:487–97,http://dx.doi.org/10. 1002/hep.29408.

[6]CurryMP,O’LearyJG,BzowejN,MuirAJ,KorenblatKM,FenkelJM,etal. Sofos-buvirandvelpatasvirforHCVinpatientswithdecompensatedcirrhosis.NEngl JMed2015;373:2618–28,http://dx.doi.org/10.1056/NEJMoa1512614. [7]FeldJJ,JacobsonIM,HézodeC,AsselahT,RuanePJ,GruenerN,etal.

Sofosbu-virandvelpatasvirforHCVgenotype1,2,4,5,and6infection.NEnglJMed 2015;373:2599–607,http://dx.doi.org/10.1056/NEJMoa1512610.

[8]BoyerTD,HaskalZJ.Theroleoftransjugularintrahepaticportosystemicshunt inthemanagementofportalhypertension.Hepatology2005;41:386–400. [9]FagiuoliS,BrunoR,DebernardiVenonW,SchepisF,VizzuttiF,ToniuttoP,

etal.AISFTIPSspecialconference.ConsensusconferenceonTIPSmanagement: techniques,indications,contraindications.DigLiverDis2017;49:121–37. [10]SalernoF,CammàC,EneaM,RössleM,WongF.Transjugularintrahepatic

por-tosystemicshuntforrefractoryascites:ameta-analysisofindividualpatient data.Gastroenterology2007;133:825–34.

[11]García-PagánJC,CacaK,BureauC,LalemanW,AppenrodtB,LucaA,etal. EarlyuseofTIPSinpatientswithcirrhosisandvaricealbleeding.NEnglJMed 2010;24:2370–9.

[12]BureauC, ThabutD, ObertiF, DharancyS,CarbonellN,Bouvier A,etal. Transjugularintrahepaticportosystemicshuntswithcoveredstentsincrease transplant-freesurvivalofpatientswithcirrhosisandrecurrentascites. Gas-troenterology2017;152:157–63.

[13]ChalasaniN,GorskiJC,PatelNH,HallSD,GalinskyRE,etal.Hepaticand intestinalcytochromeP4503Aactivityincirrhosis:effectsoftransjugular intrahepaticportosystemicshunts.Hepatology2001;34:1103–8.

[14]SprietI, MeyfroidtG, MaleuxG, VerslypeC,Willems L.Theimpactofa transjugularintrahepaticportosystemicshuntonthepharmacokineticsof caspofungininacriticallyillpatient.Pharmacology2012;90:247–50,http:// dx.doi.org/10.1159/000342906.

[15]DeWinterS,VerelstS,WautersJ,VanderLindenL,VerslypeC,WillemsL, etal.Pharmacokineticchangesafterplacementofatransjugularintrahepatic portosystemicshunt.EurJClinPharmacol2014;70:377–8,http://dx.doi.org/ 10.1007/s00228-013-1629-y.

[16]http://www.agenziafarmaco.gov.it/.

[17]RicciP,CantisaniV,LombardiV,AlfanoG,D’AmbrosioU,MenichiniG,etal.Is color-DopplerUSareliablemethodinthefollow-upoftransjugular intrahep-aticportosystemicshunt(TIPS)?JUltrasound2007;10:22–7,http://dx.doi.org/ 10.1016/j.jus.2007.02.005.

[18]https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch. cfm?fr=312.32.[Accessed1April2017].

[19]SchepisF, VizzuttiF, Garcia-Tsao G, Marzocchi G, Rega L, De Maria N, etal.Under-dilatedTIPSassociatewithefficacyandreduced encephalopa-thyinaprospective,non-randomizedstudyofpatientswithcirrhosis.Clin GastroenterolHepatol2018;16,http://dx.doi.org/10.1016/j.cgh.2018.01.029, 1153–62.e7.

[20]JiF,WangW,DangS,WangS,LiB,BaiD,etal.Outcomesafter sofosbuvir-containingregimensforhepatitisCvirusinpatientswithdecompensated cirrhosis:areal-worldstudy.InfectAgentsCancer2017:48,http://dx.doi.org/ 10.1186/s13027-017-0158-1.

[21]ContiF,BrillantiS,BuonfiglioliF,VukoticR,MorelliMC,LalanneC,etal.Safety andefficacyofdirect-actingantiviralsforthetreatmentofchronichepatitisCin areal-worldpopulationaged65yearsandolder.JViralHepat2017;24:454–63. [22]BaroneM,IannoneA,ShahiniE,IppolitoAM,BrancaccioG,MoriscoF,etal.A differentperspectiveonsofosbuvir-ledipasvirtreatmentofpatientswithHCV genotype1bcirrhosis:theital-cnetworkstudy.JViralHepat2018;25:56–62.