AISF position paper on HCV in immunocompromised patients

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ContentslistsavailableatScienceDirect

Digestive

and

Liver

Disease

j o u r n a l ho me 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

Position

Paper

AISF

position

paper

on

HCV

in

immunocompromised

patients

Italian

Association

for

the

Study

of

the

Liver

(AISF)

1,2

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received22May2018 Accepted18September2018 Availableonline1October2018

Keywords: HCV

Immunocompromisedpatients Organtransplant

a

b

s

t

r

a

c

t

ThisreportsummarizestheclinicalfeaturesandtheindicationsfortreatingHCVinfectionin immuno-compromisedandtransplantedpatientsintheDirectActingAntiviraldrugsera.

1. Introduction

Inthelast15yearsmanyimmune-modulatingtherapieshave beenintroduced.Evenifmostlackdirecthepatictoxicity,patients withserologicalsignsofcurrentvirusC-oreitherovertor anamnes-ticB-relatedinfection(HCVandHBVrespectively)areatapotential risk for reactivation. Concerning HCV, theliver disease is usu-allyexacerbatedandmorerapidlyevolutiveinimmunosuppressed patientsandreactivationcanaffectthetreatmentplan[1].This reportsummarizestheindicationsdevelopedinaconsensus con-ference held in Italy in 2017 and aimed to deﬁne the clinical featuresandmanagementofviralhepatitisamongspeciﬁcgroups ofimmunocompromisedpatientsandspecialpopulations. 2. Methodology

AmeetingpromotedbytheItalian AssociationfortheStudy oftheLiver(AISF)wasplannedtoidentifyitemstobediscussed andansweredwithconsensusstatements;foreachareaaworking groupwasformed,composedbyatleastfourexpertsguidedbya chairman.

Thescientiﬁccommitteeselectedfourclinicalquestions, deal-ingwithbothclinicalandcontroversialissues(Table1).Emerging recommendationswereratedaccordingtoGRADEsystem(Table2) [2,3].

The statements, together witha literature review presenta-tion,werediscussedbeforetheConsensusConference.Theprocess endedwithaformalmeetingheldinTurinonDecember15–16th, 2017. A jury of clinical specialists including, epidemiologists,

1 _Authors₍_Appendix_A_). 2 _Jury₍_Appendix_B_).

Table1

Clinicalquestions.

Questionnumber

Q1 Whichpatientsshouldbescreened? Q2 Whoshouldbetreatedandhow? Q3 Whoshouldbemonitoredandhow? Q4 Howlongshouldbetreatedand/ormonitored?

methodologists,patientrepresentatives,nursesandethicistswas

selected.Asstatedinthejuryregulation,memberoftheworking

groupvotedonlythestatementsoftheothergroupsguaranteeing

theprincipleofjury’sindependence.Theareaofinterestofeach

workinggroupwasclearlydeﬁnedwithoutanyoverlapandthus

allthosewhohadtherighttovotewerebynomeansinvolvedin

theselection,preparation,anddiscussionoftopicsandstatements.

During general sessions, topics and statements proposedto

answereachquestionwerepresented.Ageneraldiscussionwas

held to reﬁne statements and identifypossible improvements.

Attheend of thegeneralsession, therevisedstatementswere

presented and voted electronically by the jury and all

mem-bersnotinvolvedintheirpreparation(twolevelsofagreement:

agree/disagree).

Allpromoters,membersofthescientiﬁcboard,workinggroups,

andjuryinvitedtoparticipatetotheConsensusConferencewere

askedtodeclareconﬂictofinterests.

3. Immunopathogenesisandgeneralassessment

3.1. Immunopathogenesis

ImmunopathogenesisissummarizedinAppendixC[4–12].

https://doi.org/10.1016/j.dld.2018.09.022

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Table2

Gradingofrecommendations,assessment,developmentandevaluation.

Gradingofevidence Notes Symbol

Highquality Furtherresearchisveryunlikelytochangeourconﬁdenceintheestimateofeffect A Moderatequality Furtherresearchislikelytohaveanimportantimpactonourconﬁdenceintheestimateofeffectandmay

changetheestimate

B Loworverylow Furtherresearchisverylikelytohaveanimportantimpactonourconﬁdenceintheestimateofeffectandis

likelytochangetheestimate.Anyestimateofeffectisuncertain

C

Gradingrecommendation Notes Symbol

Strongrecommendationwarranted Factorsinﬂuencingthestrengthoftherecommendationincludedthequalityofevidence,presumed patient-importantoutcomes,andcost

1 Weakerrecommendation Variabilityinpreferencesandvalues,ormoreuncertainty:morelikelyaweakrecommendationiswarranted

Recommendationismadewithlesscertainty:highercostorresourceconsumption

2 Forgradingevidencethesymbolisaletter:AorBorC.

Forgradingrecommendationsthesymbolisanumber:1or2.

3.2. Epidemiology

Inthelast25–30years,HCVepidemiologyinItalyhasshown

aprogressivedeclineinnewinfections,mainlyduetothechange

ofmajordrivers(i.e.iatrogenictransmission,drugabusers)witha

shiftofthehazardfromgeneraltospecialpopulationswithrisky

behaviours[13,14].AtpresenttheprevalenceofHCVinfectionin

Italy is notknown: a recentstudy conductedon4907subjects enrolledin5metropolitanareashoweda2.3%anti-HCVprevalence withHCV-RNApositivityin74.1%ofcases[14].Interestingly,the anti-HCVprevalenceinindividualsbornafter1954rangesbetween 0.2 to 1.2, conﬁrming a higher prevalencein older population [14–16].

3.3. Virology

TheHCVgenomeconsistsofapproximately9600nucleotides codifyingapolyproteinofabout3000aminoacids,cleavedbyhost andviralproteasesintothreestructuralproteins(Coreand Enve-lopeglycoproteinsE1andE2)andsevennon-structuralproteins (p7,NS2,NS3,NS4A,NS4B,NS5A,andNS5B),requiredforviral pro-cessing,replicationandparticleassembly.HCVentersthecellafter interactionwithhighafﬁnityreceptors(hCD81,SR-B1,LDLR, DC-SIGNandL-SIGN)notexclusiveofhepatocytes.Thepositive-sense single-strandedRNAgenomeinthecytoplasmservesas messen-gerRNAandtemplateforreplication,microRNA-122dependent (responsibleforthealmosthepatocyte-exclusiveHCVreplication) [17,18].Virion morphogenesisimplies a majorinteraction with apolipoproteins(ApoA,C,EandB)andVLDL[6–8]andHCV cir-culatesaslipo-viro-particles.Atpresent,therearenoevidencesfor theproductionofanintrahepaticviralreservoir[19].

Onceviralinfectionhasbeencleared,eitherspontaneouslyor byantiviraltherapy,HCVreactivation(HCVr)doesnotrecur.This eventhasbeenreportedonlyanecdotallyamongpatientswith pre-viouslyundetectableHCV-RNA,thoughasmeasuredbyassayswith lowsensitivity(600IU/ml)[20].Onthecontrary,reinfectionwith anothergenotypemayoccurbecauseoflackofcompletely steriliz-ingimmunity,inspiteofaspeciﬁcTcellresponse,whichprotects againstreinfectionfromthesameHCVstrain[21].

3.4. Pathogenesisandextrahepaticmanifestations

HCVinfectionisoftenassociatedwithextrahepatic manifesta-tions,whichcanbeclassiﬁedaccordingtotheprincipalunderlying pathogeneticprocessasautoimmune,inﬂammatory,metabolicor neoplastic.HCVcanalterthecellularfunctionsjustbyreceptorial interaction,asitoccurswhenHCVcoatedbyC3dengagesCD81 onthesurfaceofBlymphocytes,leadingtotheiractivationwith autoantibodiesandcryoglobulinsproduction[22].

Cryoglobuline-micvasculitisisthemostrelevantextrahepaticdiseaserelatedto chronicHCVinfectionandrepresentsamodelforthedevelopment ofneoplastichaematologicprocessescausedbythisvirus[23].In theliver,HCVcausesadysregulationoflipidhomeostasisfavouring trygliceridesaccumulation[24].InadditionHCVinfectionfavours bothhepaticandperipheralinsulinresistance,whichcandrive fur-thersteatosis[25].Hepaticsteatosis,affectingapproximatelyhalf ofHCV-infectedindividuals,cancontributetoliverdisease pro-gressionand, in presenceof otherco-factors(i.e.drugs),acting synergisticallythusamplifyingliverinjury[26].

3.5. Clinico-virologicassessment

SerumHCV-RNAmustbetested(byassaysofadequate sensitiv-ity:limitofdetection≤15IU/ml)inallanti-HCVpositiveindividuals toproveongoingHCVinfection(about25%anti-HCVpositive indi-viduals showundetectableviremia,suggesting clearance of the infection) [27].HCVgenotyping(GT)identiﬁes differentdisease patterns(riskforhepatitisﬂaresinlonglastingindolentGT2 infec-tions;severesteatosisinGT3infectedpatients),andmightwarrant (withsubtypingforGT1)individualizedantiviraltreatment.

ThecausalrelationshipbetweenHCVinfectionandliver dis-easeshouldbeestablishedineachpatient,excludingothercauses ofliverdamage.Assessmentofliverdiseasestageisneeded, inde-pendentlyof ALTlevels,since itaffects prognosis.Noninvasive techniques,suchasliverstiffnessandbiomarkersdeterminations, performwellintheidentificationofcirrhosisorabsenceoffibrosis, butarelessaccurateindefiningtheintermediatestagesoffibrosis [28].

3.6. Riskofreactivation

HCVrisdefinedasa1logincreaseinHCV-RNAlevelsover base-line.AcuteexacerbationofHCVhepatitisisdefinedasa3-foldor greaterincreaseoverbasalinserumALTlevelintheabsenceof othercausesasinfiltrationoftheliverbycancer,useofhepatotoxic drugs,HBVreactivationorothersystemicviralinfections.

HCVrduring immunosuppressive therapy hasbeen reported in about 30% of patients, particularly those with haematologic malignanciesand/ortreatedwithRituximab[29–32].Atpresent, consistent evidences of reactivation of latent HCV infection in extrahepatic organs are missing, and HCV biology makes this hypothesisunlikely[18,23].

HCVrcanbeassociatedwithALTflaresoccurringduring treat-ment or within 3 months from treatmentdiscontinuation: the outcomeoftheseflaresislessseverethanthatofHBV-related reac-tivations[31–34].Occurrenceofhepaticdecompensationappears toberare,butasignificantproportionofpatientshastodiscontinue

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chemotherapy[31,32,35].Moreover,thenaturalcourseofchronic hepatitisCcanbeworsenedbyanti-cancertreatment[36–38].

3.7. Managementandstrategies

ThegoalofantiviraltherapyistocureHCVinfectionandto pre-venthepaticcirrhosis,itscomplicationsandsevereextrahepatic manifestations.Theendpointofantiviraltherapyisundetectable serumHCVRNAbyasensitiveassay(≤15IU/ml)12or24weeks (SVR12or 24)aftertheend oftreatment[27].In patientswith advancedﬁbrosisandcirrhosis,HCVeradicationreduces,butdoes notabolishtheoccurrenceofdecompensationandHCCrisk.

DirectActingAntiviraldrugs(DAAs)inhibitingHCVreplication actingonviralproteinsrevolutionizedHCVtreatment.Atpresent 3 classes of DAAs are authorized: (1)anti-NS3-4A inhibitors (simeprevir,ritonavirboostedparitaprevir,grazoprevir, glecapre-vir,voxilaprevir);(2)anti-NS5Ainhibitors(daclatasvir,ledipasvir, ombitasvir, velpatasvir, elbasvir, pibrentasvir); (3) anti-NS5B inhibitors(dasabuvir,anon-nucleosideinhibitorandsofosbuvir, a nucleotide inhibitor). DAAs shouldnever be administered as monotherapy,butalwaysincombinationtowarrantapotentand multivalentantiviralactivity,minimizingtheemergenceof resis-tantvariants.HCVinfectioncanbeclearedbyDAAsregimensin >95%oftreatedpatients,withslightlylowerratesin decompen-satedliverdisease[27].

Drug–druginteraction(DDIs)hastobecarefullyevaluatedin eachpatient:forexample,thereareabsolutecontraindicationsfor thecombineduseofanyDAAswithcarbamazepineandfor sofosbu-virwithamiodarone.Sofosbuvirshouldalsobeusedwithcautionin patientswithsevererenalimpairment(eGFR<30ml/min/1.73m2_).

NS3-4Aprotease inhibitorsshouldnot beusedin patientswith Child–PughBdecompensatedcirrhosisorincompensatedcirrhosis butwithpreviousepisodesofdecompensation,andare contraindi-catedinChild–PughCpatients[30].

DAAsarecurrentlyrecommendedinallHCVcarrierswiththe onlyexclusionofpatientswithlimitedlifeexpectancydueto non-liver-relatedcomorbidities[27].

DataonthetreatmentofHCVinfectioninpatientswith can-cerarelimited,butshowSVRratescomparabletothoseobserved among non-neoplastic patients [38–40]. Therefore, considering thatconcomitantHCVinfectionincreasesmorbidity whichmay interferewithcancertreatmentandthatitseradicationcouldbe helpfulinthetreatmentoflymphoma[41–43],antiviraltreatment shouldbeconsideredinthissubgroupofpatients.

4. Oncology 4.1. Epidemiology

PrevalenceofHCVinfectioninpatientswithsolidcanceris sim-ilartothatobservedinthegeneralpopulation(0.6–2.9%)andthere isnoassociationbetweenHCVinfectionandrisktodevelopcancer, exceptforhepatocellularcarcinoma[31].

Scientiﬁcassociations(EASL,AASLD,ASCO,AISF)donot recom-mendtestingpatientswhoundergochemotherapy.Recentstudies reportedthatonly14%ofoncologicpatientsundergoHCVinfection testingintheUnitedStates,andalowsensitivityoftheselective testingusingaquestionnaireonHCVriskfactorsinFrance[44,45]. TestingshouldbedeﬁnedaccordingtolocalHCVinfection epidemi-ology,ideallywithintheframeworkofnationalplans,particularly amongsubjectswithbehaviours,exposuresorconditions associ-atedwithanincreasedriskofinfection[46].

4.2. Clinicalimpact

RiskofHCVrinpatientswithcanceronchemotherapyranges between5–10%andreactivationcanrarelybesymptomaticorfatal. Itcan occurafteradministrationof speciﬁcchemotherapy regi-mens(bendamustineorpurineanalogs).Longtermadministration ofhighdosesystemiccorticosteroidsmayalsoincreasetheriskof reactivationandacuteexacerbation[47].

Data onDAAstreatment arebecoming available inthis set-ting and SVR rates seem to be similar to those observed in HCV-infectedpatientswithoutcancer.Antiviraltherapyshouldbe offeredtocancerpatients,exceptthosewithuncontrolledcancer andcomorbiditiesassociatedwithalifeexpectancy<12months. Simultaneousantiviralandoncologictherapymaypreventdelays in the administration of chemotherapy [38]. Management and strategiesarethesameappliedinnon-cancerpatients.Inpatients whoachievedSVRafterDAAs,thecontinuationofchemotherapy ornewchemotherapycyclesdonot inducereactivationofHCV infection[48].

Questions

Q1.Allpatientswithsolidcancerandcandidatesto chemother-apyshouldbescreened(2C).Voteinfavour:98,1%.

Q2. Patients withsolid cancerand HCV infection shouldbe treatedwithDAAs(2C).Voteinfavour:90,9%.

Q3.PatientstreatedwithDAAsshouldbemonitoredbytesting ALTandserumHCV-RNAlevelbeforethestartoftherapy,attheend oftherapyand12-weekaftertheendoftherapyfortheevaluation ofSVR.(1B).Voteinfavour:88%.

Q4.AllpatientsshouldbetreatedwithDAAsforthetimes indi-catedaccordingtoviralgenotypesandthestageofdisease.After conﬁrmationoftheSVR,nofurtherHCV-RNAcontrolsarerequired (1B).Voteinfavour:98,1%.

4.3. Futureperspectives

Epidemiologydatashowthatover50%ofallnewcancersinthe UnitedStatesandEuropearediagnosedamongpeopleaged50–75 years,theprevalenceof HCVinfectionin thisagegroupis esti-matedtobeover2%andmanyofthesesubjectshaveachronicliver disease.Thus,screeningforHCVinfectioninpatientswithsolid can-cersshouldberecommended,facilitatedandtherapywithDAAs consideredascapableofeliminatingtheriskofHCVreactivation, hepatitisﬂareandtocompletechemotherapy.

5. Hematologyandhemopoieticcellstransplant(HCT) 5.1. Epidemiology

In endemic areasas Italy, a 17.9% (16.6–19.2,95%CI) preva-lence of HCV infection in the lymphoma population has been describedandacausativeassociationbetweenthisinfectionand Bcellnon-Hodgkinlymphomas(nHL)hasbeenreported[49].As afurtherevidenceofacausativeroleinlymphomagenesis, HCV-positiveBcellindolentnHLcaninsomeinstancesbesuccessfully treatedwithantiviraltherapyonly[40–43,50,51]andsuccessful HCVeradicationseemstoreducetheriskofsubsequentlymphoma development[52].HCVscreeningratebeforelymphomatreatment ishigh(97.8%/86%)[53,54].

5.2. Clinicalimpact

ActiveHCVinfectionhasoftenbeenconsideredasan exclu-sion criteria from trials testing anti-lymphoma treatments. However,in realworld practice,its presencein diffuse largeB cell lymphomas(DLBCL)is associated withhigher incidence of treatment-related toxicities (grade 3–4), dose reductions and

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(immune)-chemotherapy interruptions [47,48,53,54]. On the otherhand,availabledatashowthatoverallandprogressionfree survival do notseem tobeaffectedby HCVinfectionin DLBCL patients[49].Afasterprogressiontocirrhosishasbeenreported among HCV-positivepatientsundergoingHCT [31], particularly inpresenceofcomorbiditiessuchashepatic ironoverload[55]. Nonetheless,datafromspecialsubpopulations(i.e.HCV-positive patientsundergoingHCTforHIV-relatedlymphomas)donotseem toconﬁrmsuchtrend[56].

HCVrincidenceduringlymphoproliferativediseases/HCTis cur-rentlypoorlydeﬁned.Variousmedicationshavebeenassociated withHCVr,inparticularfollowingrituximabandhighdosesteroids treatments[57–59].HCVrisrarelyfatal,infactmostcasesshow anindolent course[31], butfatal cholestatichepatitis do occur [60].Intheonlyavailableprospectiveobservationalstudy,HCVr developedin36%(18/50)[95%CI:22–50]ofpatientstreatedfor lymphoproliferativediseases,withﬂaresin44%ofthecases(8/18; 47).

5.3. Treatment

TimingofHCVtreatment(concomitant,sequential,oncaseby casecriteria)inlymphoproliferativediseasespatients(BcellnHL inparticular)remainscontroversialbecauseavailabledataarestill limitedbysamplesize,mostlybasedoncaseseries[61],andeven expertopinions[23].Somegeneralindicationshoweveremerged: (1)adifferentapproachbetweenindolentandaggressive lympho-proliferativediseases(WHO2016criteria)shouldbeconsidered; (2)HCVtreatmentshouldbeofferedtoindolentBcellnHLpatients not fulﬁlling the criteria for immediate immunochemotherapy beginning (marginal zone lymphoma in particular) [27,62–65]; (3) upfront chemo-free combination of DAAs and rituximabto treatHCV-associated indolent nHLwithhightumorburdenare attractive,butneedprospectivestudies[66];(4)HCV-RNApositive patients with DLBCL/rapidly progressive/symptomatic indolent lymphomas(progressiveleukemic phase, bulky nodal or extra-nodal massesor splenomegaly,systemic symptoms),shouldbe managed according to current hematological guidelines; DAAs treatmentcouldeitherbeconcomitant[36]ordelayed[66].More dataareneededtoreﬁne strategies,consideringthedisturbing, evenifanecdotal,observationsofearlyprogressiontoaggressive lymphomaafterDAAs[61].

DAAs-obtained HCV eradication not only prevents progres-siontocirrhosisandliver-diseaserelatedevents,butalsomight hinder lymphoma relapse. Clearance of a postulated antigen-dependent low-grade clone may in fact eradicate the relapse trigger, especially in thoseBcell nHLshowing histological evi-denceofevolutionfromlowergrades[57].Viraleradicationmay protectagainstimmunochemotherapy-relatedsideeffects devel-opment[31],allowingtocompletescheduledtreatmentswithout interruptions[57].InpatientswithalimitedlifeexpectancyHCV treatmentcanreasonablybeexcluded[23].

AsfarasHCT(autologousandallogeneic)isconcerned, consid-eringthatactiveHCVinfectionisnotcurrentlyheldasanabsolute contraindication[67],andsincethistreatmentisnotconsidered a ﬁrst line strategy in lymphoproliferative diseases, HCV man-agementshouldbeconsideredin theinitialstepsof evaluation accordingtothepresentguidelines.IncaseofHCV-positivedonors, currentlynotexcludedfromdonationifnecessary,itseems rea-sonabletosuggestthat,iftimeallows,theyshouldstartantiviral therapyassoonaspossible,withtheaimtoeliminatethe infec-tious potential, ideally attaining undetectable HCV-RNA before hemopoieticcellharvest[67].HCVrastheresultofchemotherapy aftersuccessfulSVRistobeconsideredhighlyunlikely[48].

Regular monitoring is suggested for HCV-infected patients undergoingchemotherapy,HCT,depletingantibodiesandnewly

introduceddrugs(i.e.lenalidomide,BCL2andBKinhibitors).HCVr andﬂarescandevelopduringthecourseoftreatment, but usu-allyoccurweeksormonthsafterimmunosuppressionwithdrawal; accordinglyfurthersuccessivefollowupsurveillanceisalso sug-gested[31,68].

Questions

Q1.AllcandidatestoHCT,chemoorimmune-chemotherapyfor lymphoproliferativediseasesshouldbetestedforHCV(1B).Vote infavour:100%.

Q2.HCVRNApositive patientswithlymphoproliferative dis-easesshouldbetreatedforHCVinfectionwithcurrentlyapproved DAAsregiments.Antiviraltherapy:

1)shouldbeofferedasﬁrstlinetreatmenttopatientswith indo-lentBcellNHLnotfulﬁllingthecriteriaforimmediatestartof immuno-chemotherapy(1B).Voteinfavour:97,9%.

2)canbeeitherconcomitant(iffeasible)ordelayedinpatientswith rapidlyprogressiveandsymptomaticindolentlymphomasand thoseaffectedbyothersformoflymphoproliferativediseases including DLBCL who can undergo immuno-chemotherapy according to current guidelines for lymphoma (1C). Vote in favour:97,9%.

Q3.HCV-RNApositivepatientsshouldberegularlymonitored duringtreatmentwithchemo-orimmune-chemotherapy,before theinitiationofchemotherapy,at12-weekintervalsafterinitiation ofcancertreatmentandatthetimeofhepatitisﬂare.Furtherfollow upsurveillanceaftertheendoftheimmunosuppressivetreatment isalsosuggested(1B).Voteinfavour:100%.

Q4.MonitoringshouldbecontinueduptodemonstrationofHCV eradication(2C).Voteinfavour:100%.

More data are needed to deﬁne the appropriate timing of HCV treatment among patients with DLBCL, rapidly pro-gressive/symptomaticindolentlymphomasandotheraggressive lymphoproliferativediseases.Therarebutreportedcaseof progres-siontoaggressivelymphomashouldbeaddressed.Inpatientswith lymphoproliferativediseasesHCVtreatmentshouldbe acknowl-edgedasarelevantmanagementopportunity.

6. Coinfections

The strategy of treatmentin HCV/HBV coinfectionhas been describedinaspeciﬁcdocumentaimedtoHBV.

7. Livertransplantation 7.1. Epidemiology

HCVinfectionrepresentstheleadingcauseofdeathduetoliver diseaseandthecommonindicationtolivertransplantation(LT)in theUnitedStatesandEurope[69].

7.2. Clinicalimpactandbackground

InrecipientswhoundergoLTwithactiveHCVreplication, hep-atitisHCVrecurrenceinthegraftisuniversal[70].Liverﬁbrosis progressionduetoHCVrecurrenceinlivertransplantedpatients is fasteras compared toimmune-competentpatients[71]. This impliesthatabout30%ofHCVpositiverecipientsdevelopedgraft cirrhosisﬁveyearsafterLT[72].SevereHCVrecurrenceis respon-siblefor theworse outcomein HCV-positiverecipientsthan in patientsundergoingLTforotherindications[73].Therecent intro-ductionofnewpotentandsafeDAAshasdramaticallychangedthe

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scenarioofHCVtherapyinthecontextofLT.Thevastmajorityof HCVpositivepatientswithsevereliverdiseasecannowbetreated successfullyeitherpre-orpost-LT[70,74].Giventheirfavorable proﬁle,twodifferentapproachescannowbepursued:

• treatingHCVinfectionbeforeLT,whilethepatientisonthe wait-inglistwiththe aimtopreventHCV recurrencein thegraft, improveliverfunctiontoexplorethepossibilityofpatient delist-ingandfacilitatepost-LTmanagement;

• treatingHCVinfectionafterLT,eithersoonafterwardstotake advantageoftheremovaloftheinfectednativeliverandthe con-sequentlyverylowviralburden,oratthetimeofHCVrecurrence, topreventﬁbrosisprogression.

7.3. AntiviraltreatmentbeforeLT(strategy1)

Besides the prevention of HCV recurrence, achievement of sustained viral response (SVR) with antivirals in HCV positive patientswithdecompensatedcirrhosishasled,insomecases,to theimprovementofliversyntheticfunctionand/ortothereduction ofportalhypertensivecomplications[75–78].Thesegoalsshould improvepatientsurvivalonthewaitinglistandinsomecases,may alsoallowavoidanceofLT[79].However,itshouldbepointedout thattheachievementofSVRcouldnotpreventdisease progres-sionorliver-relatedmortalityinthesickestpatients,particularly thosewhopresentseverehepaticinsufficiencyandportal hyper-tension[80–82].Todateitisnotcompletelyclearwhichcanbe consideredthe“pointofnoreturn”dividingpatientswith decom-pensatedcirrhosiswhowillreallybenefitfromtheachievement ofSVR.It iscurrentlyacceptedandrecommendedthatpatients waitingforlivertransplantwithMELDscore>18–20willbenefit fromlivertransplantationfirstandantiviraltreatmentstartedas soonaspossibleafterlivertransplantation[83].Avery challeng-ingissueconcernspatientswithSVRandpartialimprovementof MELDwhocould,paradoxically,haveareducedpriorityaccessto LT(“purgatoryMELD”)[83].Moreover,thefailuretoachieveSVR, observedmorefrequentlyinpatientswithdecompensatedliver cirrhosis,coulddeterminetheselectionofHCVresistantvariants makingretreatmentstrategiesdifficult,particularlyinHCV geno-type3infectedpatients[84].

Questionforstrategy1(*subsectionswerevotedoverall). Q1.WhoshouldorshouldbenottreatedbeforeLT?

Q1.1aPatientswithhepatocellularcarcinoma(HCC)and com-pensatedcirrhosisshouldreceiveantiviraltherapyifthewaiting timeforLTisexpectedtobeover3months(1C).

Q1.1b.PatientswithorwithoutHCCwithdecompensatedliver cirrhosisshouldbeconsideredforantiviraltherapy iftheyhave MELDscore≤20 andarewithoutrefractoryportalhypertensive symptomsorotherconditionsrequiringmoreimmediateLT(2C).

Q1.1c. Antiviral therapy beforeLT shouldbe considered on individualbasesinwait-listedpatientswithorwithoutHCCand decompensatedcirrhosiswithintermediateMELDscores(21–29) and/orlowMELDscoresbuthavingrefractoryportalhypertensive complications(i.e.MELDexceptions)(2B).

Q1.1.Patientswithdecompensatedlivercirrhosiswithor with-outHCCandMELD≥30orthosewhoareexpectedtoreceivethe highestpriorityforLTshouldreceiveantiviraltherapyafterLT(2C).

Voteinfavour:95,7%*.

Q2.Howshouldbetreatedpatientsinthewaitinglist? Q2.1aThecombination ofHCVpolymeraseand NS5Aorthe combinationofNS5AandNS3proteaseinhibitorscanbeused(1A). Q2.1bNS5AplusNS3proteaseinhibitorscombinationshould beavoidedinChild–PughclassBandC(1A).

Q2.1cInpatientswithcreatinineclearance<30ml/min/1.73m2

sofosbuvircannotbeused.AntiviralstrategiescombiningHCVNS3

andNS5Aproteaseinhibitorsshouldbeconsideredwiththe excep-tionofthoseinChildPughclassBandC(1A).

Q2.1d. The effective prevention of post LT HCV recurrence requiresaperiodofDAAsinducedvirologicalsuppressionofatleast 30dayspriorLT(1B).

Q2.1eIfthewaitingtimeforlivertransplantationisexpectedto benotlongenoughtoreachthisgoal,theoptiontostartantiviral therapyafterlivertransplantshouldbepreferred(2B).

Q2.1f.In patientswhoareonantiviraltreatmentwithDAAs buthavenotreachedavirologicalsuppressionforatleast30days, livertransplantationshouldnotbedeniedandantiviraltreatment shouldbere-startedafterlivertransplant(2B).

7.4. AntiviraltreatmentafterLT(strategy2)

AntiviraltreatmentwithnewDAAsinrecurrentHCVrelated hepatitisafterLTallowstoobtainSVRinmorethan95%recipients [75].Thisresultwasindependentfromthedegreeofgraftfibrosis untilastageofcompensatedcirrhosisandfromthepresenceof fibrosingcholestatichepatitis[85].Recentreportsclearlyindicate thattheachievementofSVRisassociatedwithanimprovement ofpatientsandgraftsurvivalafterLT[86].Itshouldbeanticipated that theprogression to decompensatedcirrhosis willbe a rare event in the DAAs era, however, some recipients under care currentlypresentthiscondition.Thisraisesthequestionwhether itcouldbesufficienttouseantiviraltherapywithDAAasasingle strategy,expectingasignificantclinicalimprovementinalltreated patients,orifcouldbebettertoevaluatethecandidacyofthese patientsforre-transplantation.ItshouldbepointedoutthatSVRat week12aftertherapy(SVR12)isstillsuboptimalinDAA-treated patientswithdecompensatedHCVrelatedlivercirrhosisandthat theclinicalbenefitofantiviraltreatmentissignificantlyreduced bythepresenceatbaselineofascites,hepaticencephalopathyand low albuminlevels [87]. Since the baseline negativepredictive factorsofclinicalimprovementafterantiviral therapyareoften present in patients with decompensated cirrhosis due to HCV recurrence,thepotentialcandidacytore-transplantationshould beconsideredfirstly.

Questionforstrategy2

Q1.WhoshouldbetreatedafterLT?

Q1.2aAllHCV-RNApositiverecipientsshouldbetreatedasearly aspossibleafterLT.Patientswhoexperiencedﬁbrosingcholestatic variantofHCVrecurrenceshouldtakehigherpriority(1B).

Q1.2b.Inpatientswithdecompensatedgraftcirrhosisdueto HCVrecurrence,theﬁrstoptiontoconsiderisre-transplantation. Antiviraltherapyshouldonlybeofferedasaﬁrstoptiontopatients withcontraindicationsforre-transplantationwhoseadvancedliver diseaserepresentstheirmainriskofdeath(1B).

Q2.Howpatientsshouldbetreated?

Q2.2aThechoiceofdrugcombinationandtreatmentduration shouldbedecidedonthebasesofstageofliverdisease,HCV geno-type,renalfunctionandDDIs(1A).

Q2.2b.Longer(24weeks)durationoftreatmentshouldbe con-sideredinpatientsintolerantorwhohavecontraindicationsfor ribavirinuse(1B).

Voteinfavour:98%*.

Q3.Whoshouldbemonitoredandhow?

Q3.1. The efﬁcacy of antiviral treatment must be done by serum HCV-RNA measurement using high-sensitivity real-time PCR.PatientsshouldbetestedforHCVRNAatleast12and24weeks afterthecompletionoftreatmenttodeterminetheachievementof SVR(1A).

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Q3.2.InpatientswhofailtoachieveSVR,resistancetestingin HCVNS3,NS5AandNS5Bregionsismandatorybeforetodecide theretreatmentschemetoadopt(1A).

Q3.3. Serum levels of immune-suppressive drugs shouldbe checkedfrequentlyduringandattheend ofantiviraltreatment whileserumlevelsofhemoglobinandcreatinineclearanceshould beassessedtoevaluatetheimpactofribavirin(1B).

Voteinfavour:100%*. 7.5. Futureperspectives

DespitethehighefficacyandsafetyofnewDAAscombinations, therearestillseveralissuesthatshouldbeclarified:(1)the mini-mumdurationofpre-LTHCVRNAnegativitynecessarytoprevent HCVrecurrence;(2)inpatientswithHCC,thepossibleinfluenceof antiviraltherapyontherateofHCCrecurrenceafterLT, particu-larlyinpatientstransplantedoutsideMilancriteriaaftereffective tumordownstaging;(3)theclearidentificationofthe“pointof noreturn”,beyondwhichtheachievementofSVRdoesnotyield substantial clinicalimprovement to allowpatient delisting; (4) howtoconsiderpatientswhoachievedSVRand“purgatoryMELD” condition.Itisstillunclearifthesepatientsshouldreceiveany pri-oritytoLTascompared toHCVnegatives withthesameMELD score.

Afurtherareaofgreatinterestistoevaluatethefeasibilityand safetyofusinganti-HCV-positiveorHCVRNApositivedonorsin anti-HCV-negative recipients[88]. Theoretically,newDAAswill allowtocureHCVinfectioneasilyinalltheserecipients,butbesides clinicalissues,thisscenariowillimplylegalandethical considera-tions[89].

Inthepost-LTsetting,avoidanceofribavirinisdesirablegiven the reduction in renal perfusion due tothe use of calcineurin inhibitorsandreducedhemoglobinlevels.Studiesaimedto eval-uatetheefﬁcacyofribavirin-freecombinationstotreatrelapsers or HCV genotype 3 infected recipients are needed. While efﬁ-cacydataareexpectedtobesimilartonon-LTpopulations,the combinationsofgrazoprevir/elbasvirandglecaprevir/pibrentasvir should be studied more extensively in patients with renal impairmentafterLTand,includingthecombinationof sofosbu-vir/velpatasvir/voxilaprevir,inthose whofaileda previousDAA regimen.

8. Solidorgantranplants(SOTs) 8.1. Epidemiology

TodayprevalenceofHCVinfectioninnon-renalSOTcandidates appearstoapproximatethatofthebackgroundpopulation.Inolder studies,HCVinfectionincardiactransplantrecipientswasinitially reportedtobeashighas11–18%anddroppedfrom28%to4.2%in transplantrecipientstransplantedbeforeandafter1990[89–95] (Table3).

8.2. Clinicalimpact

TheimpactofHCVinfectionontheoutcomeofnon-hepaticSOT hasbeenstudiedmostextensivelyinrenaltransplantrecipients.

Table3

HCVprevalenceinpreandposttransplantheart-transplant(HTx)recipients (*anti-HCV+,6%HCV-RNA*). HCVprevalence Pre-HTx Post-HTx Cadranel,[127] – 18.0% Zein,1994 – 7.0% Lunel,1995 – 10.4% Preiksaitis,[97] 2.3% 10.2% Fagiuoli,[94] 0.6% 8.0% Cotler,[91] 1.9% – Lunel,[92] 1.7% 10.6% Fagiuoli,[98] 2.7% 9.4% Gasink,[90] 12.5%* –

Indeed,justafewlong-termstudieshaveexploredtheoutcomeof heart,lung,smallbowelorpancreasrecipients.

8.3. Heart

Contradictoryevidencesareavailablelikelyduetoshortterm follow up and relativelysmall number of patientsin the stud-ied cohorts [92,96,97]. In two small series, HCV infection did notimpactpatientsandgraftsurvivalontheshortterm[98,99]. However,a recent retrospectiveanalysis ofthe UNOSdatabase (1991–2014)demonstratedthatHCVpositiverecipientspresented aworseoutcome(4yearsfollowup)ascomparedtoHCV nega-tiverecipients,sincelaterenalandliverdysfunctionoccuredmore frequentlyinpositiverecipients[100].Differentmechanismshave beenproposedtoexplainreducedsurvivalandincreasemorbidity inHCV-infectedcardiacrecipients,suchasearlieronsetofcirrhosis anditscomplication,andacceleratedcoronaryheartdisease[101] (Table4).

8.4. Lung

Intwosmallcohortsfromsinglecentreexperiencesandina ret-rospectiveanalysisoftheUNOSdatabase,the5-yearsurvivalwas similarinHCVpositiveandnegativerecipients[102–104]. How-ever,theresultsofthesestudieswerelimitedbythelackofdataon HCV-RNAstatus.Bycontrast,arecentretrospectiveanalysisfrom scientiﬁcregistryoftransplantrecipient(1995–2011)haveshown a moderatemortalityincrease in HCVpositive recipients[105]. Despitethelimiteddata,HCVinfectionisstillarelative contraindi-cationtolungtransplantationfortheInternationalSocietyforHeart andLungTransplantation(2015).Itissuggestedthattransplantcan beconsideredinpatients“withoutevidenceofcirrhosis”andon “appropriatetherapy”andthatsuchpatientsshouldbemanaged incentreswithexpertiseinviralhepatitis.

8.5. Pancreas

Availabledataonpancreasandpancreas-kidneyarepoor,but thesepatientsappeartobeathigherriskofgraftdysfunctionand morbidity(sepsis,higherriskofrenaldysfunctionwithproteinuria Table4

PrevalenceofHCVinfectionandchronicliverdiseaseinhearttransplantrecipients.

HCVprevalence CLD Cirrhosis Liverfailure Meanfollow-upyears

Cadranel,[127] 18% 63% – 5 Zein,1994 7% – – – Lunel,1995 10.4% 62% 0% 0 5 Fagiuoli,[94] 8% 66% 15% 15% 5 Lunel,[92] 10.6% 100% – 0 8 Fagiuoli,[98] 12% 58% 28% 7% 8

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andpoorglycemiccontrol)[106].Nodataexistsregardingsurvival insmallboweltransplantrecipientswithHCVinfection.

Inthepre-DAAera,IFN-basedtherapywascontraindicatedin patientswithend-stageheartfailure,duetotheincreasedriskof arrhythmiaandcardiotoxicity.Furthermore,theriskof ribavirin-related anaemia was bound to worsen any underlying cardiac ischemia.Additionally,theresultsofIFN-basedregimensinsmall seriesofpatientswerecontradictory[107,108].

TheadventofDAAshasdramaticallychangedtheclinical sce-nario.However,limitedexperienceontheiruseinpatientswith SOTisavailable.DAAshavedemonstratedtobeextremelyeffective andsafeinfewcasereportsinthepre-andpost-hearttransplant setting,butsafetyinpatientswithcongestiveheartfailureremains veryinadequate[109,110].Noevidenceisreportedontheuseof DAAsinlungorpancreastransplantrecipients.However,the expe-riencefromkidneytransplantstudiesrecommendsearlytherapy forHCVinfection.Patientsshouldbereferredtoexpertcentresand DDIscarefullyevaluated.

Finally,nowadaystheshortageoforgansfortransplantationis amajorimpedimentandtheuseofHCV-positivedonorsmay rep-resentapotentialapproachtosafelyexpandthedonorpoolinthe DAAera.

Questions

Q1.AllSOTrecipientsshouldbetestedforanti-HCVmarkers, includingHCVRNA, genotype and fullassessment of liver dys-function.Liverbiopsyornon-invasiveevaluationofliverﬁbrosis (elastometryorserummarkersdiagnosis)isrecommendedto con-ﬁrmortoruleoutthepresenceofcirrhosis(1A).Voteinfavour: 100%.

Q2(Recipients).Thedecisiontoperformanti-HCVtherapy pre-orpost-transplantationshouldbediscussedattheindividuallevel (2C).

Q2a.Ifadoptingapre-transplantantiviraltreatmentstrategyall patientsshouldbetreatedregardlessofﬁbrosisstage(1B).

After-transplantallnewand“long-term”SOTrecipientsshould betreatedafterwithDAAsregardlessoftheﬁbrosisstage(DDIs withimmunosuppressivedrugmustbetakenintoaccount)(1B). Voteinfavour:93,2%*.

Q2.(Donors).HCVpositivegraftsshouldbeutilized in HCV-positive(“viremic”)recipients.GraftingofHCV-viremicorgansinto non-viremicrecipientsshouldonlybeconductedunderapproved studyprotocols(1C).Voteinfavour93.6%.

TheuseofHCV-positiveorgandonorsinnegativerecipientsisan intriguingpossibility.Indeed,withtheavailabilityofDAAsbetween 2015and2016,theallocationofHCV-positiveorgansinto HCV-negativerecipientstripledinlivertransplantanddoubledinkidney transplants.Thistrendhasalsobeenobservedinthoracic trans-plants[107].Althoughitstilloccursinsmallnumbers,thisoption isanemergingtrendduetodifferentreasons:(1)thewidespread useofDAAshasincreasedthenumberofnon-viremiccandidates; (2)theincreasingconﬁdencein thesuccessofcuringHCVafter transplant;(3)therecentexperienceinrenaltransplant, conﬁrm-ingtheexcellentresultsofapre-emptivetreatmentwithDAAin caseofuseofpositiveHCVdonorsinnegativerecipients[108,109]. 9. Nephrology

9.1. Epidemiology

PrevalenceofHCVinfectionamongdialysispatientsandrenal transplantrecipientshashistoricallybeenhighasaconsequence ofnosocomialHCVtransmissionbyrepeatedhaemodialysis,blood

transfusionsandHCV-infectedkidneygraftstransplantation.Due toimprovementsofmedicalstandards,prevalenceofHCVinfection inthedialysispopulationdecreasedfrom10to13%intheearly90s, toapproximately7–8%intheearly2000sindevelopedcountries, withanestimated0.2%peryeartransmission.Conversely,in devel-opingcountries,upto80%prevalenceand15%yearlytransmission ratehavebeenreportedinsinglecentrestudies[110,111].

9.2. Clinicalimpact

HCVinfectionisassociatedwithincreasedmorbidityand mor-talitybothinthedialysisandthepost-transplantsettings,where HCVisanestablishedriskfactorforgraftloss[111–113].Moreover, HCV infectionaddsfurther non-kidneyrelated mortality,being associatedwithincreasedliver-relatedcomplications,diabetesand cardiovascularevents,aswellascancer-relateddeaths[114–117]. ChronicHCVinfectionin dialysispatientsisoften character-izedbypersistentlynormalaminotransferase(ALT)values,since repeatedhaemodialysisreduceALTlevels.Consequently,ALTare notreliablemarkersofliverdiseaseactivityandprogressiveliver diseasehasbeendemonstratedinpatientswithpersistentlynormal ALT.Inrenaltransplantrecipients,HCVinfectionisassociatedwith acceleratedliverdiseaseprogressionandkidneygraftimpairment [112].

Alldialysispatientsandrenaltransplantationcandidatesshould be screened for this infection by anti-HCV testing. Although currently available assays provide optimal sensitivity, reduced antibodyresponsetoHCVantigenshasbeenreportedindialysis patients[116].HCVRNAassessmentshouldthusbeperformedinall patientscandidatestotransplantation,soasthepoorerprognosisof kidneytransplantrecipientswithhepatitisC.Duetothepersistent riskofHCVtransmission,HCVscreeninginhaemodialysispatients shouldberegularlyrepeatedovertime.

AvailabilityofDAAshaschangedHCVtreatmentindialysisand renaltransplantrecipients,providingincreasedSVRratesandsafer treatmentoptions among those withprior contraindicationsto IFN-basedregimens.AllviremicHCVdialysispatientsandrenal transplantrecipientsshouldbeconsideredforantiviraltherapy: indialysispatients,treatmentoptionsarecurrentlyavailablefor allHCVgenotypes.Asstatedabove,sofosbuvir-basedregimensare currentlynotrecommendedifeGFRis<30ml/min,althoughthey havebeenusedinreal-lifesettings[27].

In renal transplant recipients, antiviral treatment shouldbe performedafterrenal function stabilization.Arandomized trial demonstratedoptimalefﬁcacyandsafetyofsofosbuvir/ledipasvir in HCV genotype 1 and 4 patients, and sofosbuvir/velpatasvir or sofosbuvir+daclatasvir combinations are approved in the post-transplant,althoughdataarestill limited [117].DDIs with patient’s concomitantmedicationsshouldbecarefullyassessed. The decision totreat beforeor after transplant should be dis-cussedatanindividuallevel,accordingtolocaldrugavailability, patient comorbidities and access to waitlist for renal trans-plant.

HCVdialysispatientsshouldbereferredforspecialistcareto stageliverdiseaseand antiviraltreatmentevaluation.Eligibility to antiviral therapy should be regularly reassessed in patients withoutcurrenttreatmentoptions.MonitoringofALTvaluesand liverfunctiontestsshouldberegularlyperformedinHCV dialy-sispatientsandrenaltransplantrecipientsnotreceivingantiviral treatment.

Questions

Q1. All dialysis and renal transplant recipients should be screenedforHCVinfection(1A).Voteinfavour:100%.

Q2.AllHCVdialysisandandkidneytransplantrecipientsshould beevaluatedforantiviraltreatment(1B).

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Q2a.Thedecisiontoperformanti-HCVtherapy pre-or post-renaltransplantationshouldbediscussedattheindividuallevel; patientsshouldbereferredtoexpertcenterstomanageaccessto antiviraltreatmentand/orrenaltransplant(2C).

Q2b.AllHCVrenaltransplantrecipientsshouldreceiveantiviral treatment(1B).Voteinfavour:100%*.

Q3.Monitoringofliverfunctiontestsshouldberegularly per-formedinHCVdialysispatientsandrenaltransplantrecipientsnot receivingantiviraltreatment(1C).Voteinfavour:100%.

9.3. Futuredirectionsandresearchpriorities

LargescaletreatmentofHCVinfectionwithDAA-based regi-mensisexpectedtodeeplyaffectHCVprevalenceworldwideinthe nextdecades.Thepossibilitytoextensivelytreatdialysispatients andrenaltransplantrecipientswillleadtonewscenarios:access toHCV-positivekidneygraftpoolinordertoreducetimeonthe waitinglistcouldbesystematicallypursedconsideringthe avail-abilityofantiviraltreatmentsin thepost-transplantphase.This strategyhasalreadybeenappliedtoHCV-positiverecipients,and futuredevelopmentscouldalsoextendit toHCV-negativerenal transplantcandidates[118].

10. Rheumatology 10.1. Epidemiology

Prevalenceof HCV infectionamong patientswithrheumatic diseases ispoorly known.Althoughepidemiological studiesare limited to speciﬁc population or geographic areas, prevalence seemstobeslighthigherthan,oratleastcomparableto,thatof thegeneralpopulation[119,120].Thesepatientsmayneedlong termandoftenmultipleimmunosuppressivetherapiestoobtain clinicalremission.Immunosuppressivetreatmentsplacethemat riskofviralreactivation.

10.2. Clinicalimpact

HCVrseemstobearareevent.SerumHCVRNAmayincrease duringimmunosuppressivetherapies,howeverwithoutclinically signiﬁcanthepatitis [121].Immunosuppressivetherapiesdo not seemtohaveadetrimentaleffectonthecourseofHCVinfection. Experiencesontheconcomitanttreatmentwithboth immunosup-pressivedrugsandDAAarelimited[122].

Questions

Q1.Allrheumatologic patientsshouldbetestedforanti-HCV (plus HCV RNA if positive) before starting immunosuppressive therapy(1C).Voteinfavour:97,7%.

Q2.ThedetectionofachronichepatitisCshouldpromptlylead totreatmentwithDAAs.CarefulcheckofDDIsbetween immuno-suppressiveregimensandHCVdrugsisrecommended(1C).Vote infavour:97,6%.

Q3.Alluntreatedpatientsshouldbemonitoredwithlivertest every3-6months.HCVRNAmonitoringhasnoclinicalutility(1C). Voteinfavour85%.

Q4.Nomodiﬁcationsofthestandardhepatologicalfollowup is neededin HCVpatientsaftertheend of immunosuppressive therapy(1A).Voteinfavour:97,8%.

Thetherapeuticscenarioforrheumaticdiseaseisrapidly evolv-ingandnewdrugswithpotentialgreatefﬁcacywillbeavailable inthenextfuture.Theeffectsofthesenewdrugsonthecourseof chronicviralhepatitisareunknown.

11. Gastroenterology 11.1. Epidemiology

UlcerativecolitisandCrohn’sdisease(IBD)mainlyaffectyoung subjects,reachingtheirpeaksinthethirddecadeoflife[123].As aconsequence,theburdenofconcurrentchronicviralhepatitisin ItalianIBDpatientsislimitedbythelowprevalenceofHCVinfection amongyoungsubjects.

11.2. Clinicalimpact

Thereisgeneralconsensusaboutthefactthat immunosuppres-santsorbiologicsusedinIBDdonotseemtohaveasigniﬁcant effectonthecourseofHCV infection,becausetherisk ofHCVr duringtheseimmunosuppressivetherapiesappearstobeverylow andtheydonotinﬂuencetheprogressionofchronicliverdisease [124,125].However,althoughthesedrugsdonotseemtohavea detrimentaleffectonthecourseofHCVinfection,theawarenessof aconcomitantchronichepatitisCisimportantduetothe poten-tialriskofworseningliverfunctionandtobetterdiscriminatethe alterationsofliverfunctiontestsasduetotheuseofdrugswith potentialhepatotoxicity(azathioprine,methotrexate,biologics)or HCVinfection[126].

Questions

Q1.AllIBDpatientstobetreatedwithimmunosuppressantsor biologicsshouldbetestedforanti-HCV(HCVRNAifpositive).The idealtimetoscreenisatthediagnosisofthedisease,regardlessof itsseverityatonset(1B).Voteinfavour:95,1%.

Q2. The detection of a chronic hepatitis C should lead to treatmentwiththenewDAAs.CarefulcheckofDDIswith immuno-suppressiveregimensisrecommended(1A).Voteinfavour:100%. 11.3. Futureperspectives

ThetherapeuticscenarioforIBDisrapidlyevolving.Overthe past20years,drugresearchhasfocusedonthedevelopmentof large-moleculebiologics,includinganti-TNF-␣monoclonal anti-bodiesand,morerecently,antibodieswithdifferenttargets(suchas vedolizumab,ustekinumab,andothers).Furthermore,neworally administeredsmallmoleculedrugswithpotentialgreat efﬁcacy willbeavailableinthenextfuture.Theeffectofthesenewdrugson thecourseofchronicviralhepatitisisunknownandthisreinforces theindicationtoscreenandtreatviralhepatitisinthesepatients. Conﬂictofinterest

Estensor Pharmaceutical company

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s.r.l.,GileadSciences S.r.l.,Bristol-Myers SquibbS.r.l.,Novartis, KedrionS.p.A.,Bayer S.p.A.

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Merck AdvisoryBoards, Speakerfees,Meeting organization GileadSciencesS.r.l. Advisoryboards,

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Busca

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AppendixA.

AlfredoMarzano.DivisionofGastroenterology,SanGiovanni Bat-tistaHospital,UniversityofTorino(Projectcoordinator)

EmanueleAngelucci.HaematologyandTransplantCenter,San MartinoHospital,Genova

MarcoAstegiano.DivisionofGastroenterology,SanGiovanni Bat-tistaHospital,UniversityofTorino

ChiaraBaratelli.DepartmentofOncology,MaurizianoHospital, Torino

LuigiBiancone.DivisionofNephrologyDialysisTransplantation, SanGiovanniBattistaHospital,Torino

PaoloBironzo.DepartmentofOncology,SanLuigiGonzaga Hos-pital,Orbassano,UniversityofTorino

GiuseppinaBrancaccio.InfectiousDisease,UniversityofPadua andUniversityofCampania,Napoli

MauriziaRossanaBrunetto.InternalMedicine,Departmentof ClinicalandExperimentalMedicine,UniversityofPisa

RaffaeleBruno.DepartmentofInfectiousdisease,IRCCSSan Mat-teo,UniversityofPavia

PatriziaBurra. MultivisceralTransplantUnit, Gastroenterology Departmentof Surgery,OncologyandGastroenterology,University Hospital,Padova

MariaGiuseppinaCabras.DepartmentofHaematology,Hospital Businco,Cagliari

PaoloCaraceni.DepartmentofMedicalandSurgicalSciences, Uni-versityofBologna

ClaudiaChialà.DivisionofGastroenterology,SanGiovanni Bat-tistaHospital,UniversityofTorino

MariaGraziaClemente.PediatricClinic,DepartmentofClinical andExperimentalMedicine,UniversityofSassari

Agostino Colli. Internal Medicine Unit “A,Manzoni“ Hospital, Lecco(MethodologyandPresidentoftheJury)

BrunoDaniele.MedicalOncologyUnit,G.RummoHospital, Ben-evento

ElisabettaDeGasperi.CRC ¨A.M.eA.Migliavacca¨CenterforLiver Diseases, Division of Gastroenterology and Hepatology, IRCCS Ca’ GrandaOspedaleMaggiorePoliclinico,UniversityofMilano

VitoDiMarco.SezionediGastroenterologiaeEpatologia, Dipar-timentoBiomedicodiMedicinaInternaeSpecialistica,Universityof Palermo

Maria Chiara Ditto. Rheumatology, Città della Salute e della ScienzadiTorino,SanGiovanniBattistaHospital,Torino

StefanoFagiuoli.GastroenterologyHepatologyand Transplantol-ogyandDepartmentofMedicineandTransplantation-PapaGiovanni XXIIIHospital-Bergamo

ClodoveoFerri.RheumatologyUnit,AziendaPoliclinicodi Mod-ena,UniversityofModenaeReggioEmilia

GiovanniBattistaGaeta.InfectiousDiseases,Campania Univer-sity ¨Luigi_{Vanvitelli¨,}NapoliStefanoGinanniCorradini.LiverTransplant Unit,DepartmentofClinicalMedicine,SapienzaUniversityofRoma

PaoloAntonioGrossi.DepartmentofTransplantationand Infec-tious and Tropical Diseases Unit, University Hospital “ASST Sette Laghi”,Varese

BarbaraImperatrice. DigestiveandLiverDiseaseDepartment, AUOS.AndreaRomaandDivisionofGastroenterology,SanGiovanni BattistaHospital,UniversityofTorino

PietroLampertico.CRC ¨A.M.eA.Migliavacca¨CenterforLiver Dis-eases,DivisionofGastroenterologyandHepatology,IRCCSCa’Granda OspedaleMaggiorePoliclinico,UniversityofMilano

FabioSalvatoreMacaluso.IBDUnit,“VillaSoﬁa-Cervello” Hospi-tal,Palermo

SalvatoreMadonia.Internal MedicineDepartment,V.Cervello Hospital,Palermo

MassimoMarignani. Digestive andLiverDisease Department, LiverDiseaseSection,AUOS.Andrea,Roma

Chiara Mazzarelli. Hepatology and Gastroenterology, ASST GrandeOspedaleMetropolitanoNiguarda,Milano

AlbertoMella.DivisionofNephrologyDialysisTransplantation, SanGiovanniBattistaHospital,UniversityofTorino

GabrieleMissale.UnitofInfectiousDiseaseandHepatology- Uni-versityHospitalofParma

SimoneParisi.Rheumatology,CittàdellaSaluteedellaScienzadi Torino,SanGiovanniBattistaHospital,Torino

LuisaPasulo.GastroenterologyHepatologyandTransplantology, PapaGiovanniXXIIIHospital,Bergamo

MassimoPuoti.NiguardaHepatitisCenter,DivisionofInfectious Diseases,ASSTGrandeOspedaleMetropolitanoNiguarda,Milano

MariaRendina.GastroenterologyandDigestiveEndoscopy,Liver OutpatientClinic-UniversityHospitalBari

Davide Ribaldone.Divisionof Gastroenterology, SanGiovanni BattistaHospital,UniversityofTorino

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GiuseppeRossi.HematologyDivisionandOncologyDepartment -SpedaliCiviliBrescia

PierluigiToniutto.MedicalLiverTransplantSection,Department ofMedicalSciencesExperimentalandClinical,University ofUdine, Udine

AlessandraTucci.DivisionofGastroenterology,SanGiovanni Bat-tistaHospital,UniversityofTorino

Pietro Vajro. Department of Medicine, Surgery and Dentistry ¨

ScuolaMedicaSalernitana¨/PediatricsSection,UniversityofSalerno MauroViganò.HepatologyDivision,OspedaleSanGiuseppe, Uni-versityofMilano

Riccardo Volpes. Hepatology and Gastroenterology Unit ISMETT/IRCCS-Palermo

Anna Linda Zignego. Interdepartmental Hepatology Center MaSVE-DepartmentofExperimentalandClinicalMedicine- Univer-sityofFlorence

AppendixB.

ProjectCoordinator:AlfredoMarzano(Torino)

Promoters and Scientiﬁc board: Maurizia Rossana Brunetto (Pisa),RaffaeleBruno(Pavia),VitoDiMarco(Palermo),Stefano Fag-iuoli(Bergamo),PietroLampertico(Milano),AnnaLindaZignego (Firenze)andtheAISFgoverningboard:EdoardoG.Giannini(Genova) (AISFSecretary),LucaMiele(Roma),FrancescoPaoloRusso(Padova), SalvatorePetta(Palermo),MauroViganò(Milano)

JURY

StefanoBonora,Torino,InfectiousDiseases EnricoBrignardello,Torino,Oncology. AlessandroBusca,Torino,Haematology GiuseppeCariti,Torino,InfectiousDiseases FedericaCavallo,Torino,Haematology

MassimilianoConforti,EpaCOnlus,ItalianLiverPatient Associ-ation

MartaCoscia,Torino,Haematology

AntonioCraxì,Palermo,Hepatology,Palermo DanieleCurci,Torino,Nephrologynurse

StefanoCusinato,Borgomanero(Novara),Nephrology MassimoDiMaio,Torino,Oncology

RossellaDellaValle,Torino,Nephrologynurse EnricoFusaro,Torino,Rheumatology

AldoGiacardi,A.I.T.F.(AssociazioneItalianaTrapiantatidiFegato), ItalianLiverTransplantedPatientAssociation

LuisaGiaccone,Torino,Haematology MarcoLagget,Torino,Gastroenterology

DanielaLibertucci,Torino,PneumologyandLungTransplantation RobertoMinutolo,Napoli,Nephrology

GiuseppeMontrucchio,Torino,InternalMedicine AmbrogioOrlando,Palermo,Gastroenterology LorellaOrsucci,Torino,Haematology

CarlaPasquina,Torino,Gastroenterologynurse AngeloPera,Torino,Gastroenterology ClaraLisaPeroni,Torino,Rheumatology MarioPirisi,Novara,InternalMedicine PatriziaRacca,Torino,Oncology

FrancoRiccardini,Torino,InternalMedicine MarioRizzetto,Torino,Hepatology

MauroSalizzoni,Torino,LiverTransplantationSurgery MarioSalomone,Chieri(TO),Nephrology

GiorgioMariaSaracco,Torino,Gastroenterology LucaScaglione,Torino,InternalMedicine

GiulianoTorre,Roma,PediatricGastroenterology, RitaTozzi,Torino,Gastroenterologynurse

UmbertoVitolo,Torino,Haematology GiorgioVerme,Torino,Gastroenterology

AppendixC.

ImmunopathogenesisofHCVreactivation

ImmuneresponsetoHCVinfectioncanleadtoself-limited infec-tionwithviraleliminationandhepatocellularinjury.Thevirusis knowntobeastronginterferonactivatorbutitisalsoresponsible foraseriesofmechanismsinterferingwiththeintracellular inter-feronpathways,contributingtoviralpersistenceduringtheearly stageofinfection[4–6].

Inspiteofeffectiveactivationofﬁrstlineimmuneresponse, HCVinfectionresultsinahighrateofpersistence,andevenifthe strengthandbreadthofHCV-speciﬁcT-cellresponsehasbeen asso-ciatedwithvirusclearance[5–7],theexactroleofdifferentimmune mechanismsinviralcontrolandimmunopathogenesis havenot thoroughlyunderstood. Severalmechanisms of impairedT and NKcellresponsehavebeendescribedtoexplainviralpersistence, comprisingT-cellexhaustion,Tregexpansionwithintheliver,and suboptimalactivationofT-cellsbyliverantigenpresentingcellsin thehepaticsuppressiveenvironment[4].

InpatientsundergoinginterferontreatmentforchronicHCV infection,ahigherlevelofCD8cellresponsehasbeenassociated withsustainedviralresponse(SVR)[6].Howevertheexact role ofT-cellresponseinachievingviralclearanceandSVR,eitherby peg-interferonordirectlyactingantivirals(DAAs)iscurrentlynot completelyclear.Interestingly,DAAshaveshowntobevery effec-tivealsointransplantrecipientswithsevereimmunosuppression [7],questioningthetrueroleofimmuneresponseinviralclearance inthissetting.

Evenifithasbeenclearlydemonstratedthatlivercellinjuryis immunemediated,andthatT-cellresponsecancontrolandclear HCVinfectionduringtheacutephase,theexactroleofimmune responseincontrollingviralreplicationduringchronicinfection hasnotbeenentirelyclariﬁed.

TheimmunepathogenesisofHCVreactivationseemstobe sim-ilartothatofHBV.However,differencesexistinvirusbiologyand roleofT-andB-cellmediatedresponseincontrollingthetwo infec-tions.Indeed,evenifimmunosuppressivetreatmentsinpatients withchronicHCVinfectionmayinduceenhancedviralreplication, transaminasesincreasedevelopsinalimitednumberofcases,and severehepatitisisarareevent.

EvenifneutralizingantibodiesdonotprovidecontrolofHCV replication,andself-limitedHCVinfectiondoesnotleadto neutral-izingprotectiveantibodies,similarlytoHBVimmunosuppressive treatments targetingB-cells can befollowed by enhanced HCV replicationandseverehepatitis. However,in thegreatmajority ofcasesthesephenomenadonotseemtoaffectoverallsurvival [8].Insomestudiestherateofhepatitisunderpharmacological immunosuppressiondidnot differ betweenHCV-positiveand -negativepatients[9].Actually,inmanyreportedcasesitwasnot entirelyclearifthetransaminasesﬂareswereduetoeitherHCV, drug-inducedliverinjury,ormetastaticliverdisease[10].

Recentreportshave raisedwarningonthepossibleeventof HBVreactivationamongHCV-coinfectedpatientsundergoingDAAs therapy[11],leadingtotransaminaseflaresandevenfulminant hepatic failure. Whether viral-viral interference or immune-mediatedmechanismsareresponsibleforthiseventitisnotknown. Thecombinedeffectsofnegativeviral-viralinterferenceloss,along withanenhancedimmunemediatedliverinjurycouldinfluence reactivation.Moreover,HCVclearancecouldleadtotherestoration andenhancementofcellmediatedimmuneresponseastheresult ofasuddendropofendogenousIFN-Ilevels,persistentlyelevated inchronicHCVinfection.IthasbeenshownthatIFN-Icanplaya negativeregulatoryroleonvirus-specificT-cellresponseduetoa counterregulatoryactionontheimmuneresponsethatwouldbe suddenlyabolished[12].However,thesepossibleinterpretations

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ofimmunopathogenetic mechanismsresponsiblefor thesevere HBVreactivationdescribed inthissubgroupofpatientsdeserve dedicatedstudiesaimedatdissectingviralreplicationkineticsand antigen-speciﬁccellmediatedimmuneresponse.

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