HepaDisk

(1)

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

Liver,

Pancreas

and

Biliary

Tract

–

A

new

quality

of

life

questionnaire

for

HCV

patients

Stefano

Fagiuoli

a

_,

_Nicola

_Caporaso

b

_,

_Filomena

_Morisco

b

_,

_Fabio

_Buelli

c

_,

Giuliana

Gualberti

c,∗

_,

_Valeria

_Saragaglia

c

_,

_Luchino

_Chessa

d

_,

_Giampaolo

_Corti

e

_,

Ivana

Maida

f

_,

_Claudio

_M.

_Mastroianni

g

_,

_Mario

_Pirisi

h

_,

_Francesco

_P.

_Russo

i

_,

Francesca

Farina

j

_,

_Lydia

_{Giannitrapani}

k

_,

_Pierluigi

_Toniutto

l

_,

_Pierluigi

_Tarquini

m

_,

Paolo

Tundo

n

_,

_Jacopo

_Vecchiet

o

_,

_Maria

_Vinci

p

_,

Gloria

Taliani

q

_,

_On

_behalf

_of

_the

_HepaDisk

_Study

_Group

a_{Gastroenterology,}_Hepatology_and_{Transplantation}_Unit,_ASST-Papa_Giovanni_XXIII,_Bergamo,_Italy b_Department_of_Clinical_Medicine_and_Surgery,_University_of_Naples_Federico_II,_Naples,_Italy c_Medical_Department,_AbbVie_srl,_Rome,_Italy

d_Liver_Unit,_University_Hospital,_Monserrato,_Cagliari,_Italy e_University_Hospital_Careggi,_University_of_Florence,_Florence,_Italy f_University_Hospital_of_Sassari,_Sassari,_Italy

g_Department_of_Public_Health_and_Infectious_Diseases,_Sapienza_University_of_Rome,_Rome,_Italy h_Department_of_{Translational}_Medicine,_University_of_Eastern_Piedmont,_Novara,_Italy

i_{Gastroenterology}_Unit,_Department_of_Surgery,_Oncology_and_{Gastroenterology,}_University_Hospital_Padua,_Padua,_Italy j_Infectious_Diseases_Unit,_“ULSS_2”,_Treviso,_Italy

k_Internal_Medicine_Unit,_University_Hospital_Policlinico_P._Giaccone,_Palermo,_Italy

l_Hepatology_and_Liver_{Transplantation}_Unit,_Department_of_Medical_Area_(DAME),_University_of_Udine,_Udine,_Italy m_Infectious_Diseases_Unit,_Hospital_“G._Mazzini”,_Teramo,_Italy

n_Infectious_Diseases_Unit,_Presidio_Ospedaliero_S._Caterina_Novella_Galatina,_Galatina_(LE),_Italy o_Infectious_Diseases_Unit,_Clinical_Hospital_SS_Annunziata,_Chieti,_Italy

p_Niguarda_Great_Metropolitan_Hospital,_Milan,_Italy

q_Cronic_Infectious_Diseases_Unit,_Policlinico_Umberto_I,_Sapienza_University_of_Rome,_Rome,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received28September2018 Accepted3December2018 Availableonline23December2018

Keywords: Burdenofdisease HCV PROdevelopment Psychometricvalidation

a

b

s

t

r

a

c

t

Background:SincemostpatientswithhepatitisCvirus(HCV)infectionnowreceivetreatmentirrespective ofliverdiseaseseverity,specialattentiontopatientqualityoflife(QoL),includingpsycho-socialaspects, isrequired.NoQoLquestionnaireisspeciﬁcforpatientswithHCV.

Aims:TodevelopandvalidateashortItalianquestionnaire(HepaDisk)assessingtheQoLofpatients affectedbyHCVwithintuitivegraphicresultsthatisunderstandablebypatientsandphysicians. Methods:Aquestionnaire,draftedbyasteeringcommittee,underwentaDelphisurvey.Amulticenter, observationalstudywasconductedtovalidatethedevelopedHepaDiskversusothertools(CLDQ-I,SF-36, WPAI:HCV),andtoevaluateitscorrelationwithdiseaseseverityinItalianpatientswithHCV.

Results:The10-itemquestionnairewasvalidatedin214patients.HepaDiskshowedahighcorrelation withCLDQoverallscoreandWPAI:HCVactivityimpairment(Spearman’srankcorrelation:0.651and 0.595,respectively)andalowercorrelationwithSF-36.Stronginternalconsistency(Cronbachcoefﬁcient: 0.912),goodtest–retestreliability(Pearson’scorrelationcoefﬁcient:0.789;95%CI,0.714–0.865),and responsivenesstochangesamongimprovedpatientsweredemonstrated.

Conclusion:HepaDiskisareliableanduser-friendlytoolthatcanmonitordiseaseimpactonpatientQoL overtime,providingavisualrepresentationeasilyunderstandablebybothpatientsandphysicians.

http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ Correspondingauthorat:AbbVieSrl,Vialedell’Arte,25,00144Roma,Italy. E-mailaddress:[email protected](G.Gualberti).

1. Introduction

In the past few years, the pivotalchange broughtabout by

theintroductionofdirect-actingantiviralagents(DAAs)intothe

therapeuticarmamentariumforthetreatmentofhepatitisCvirus

https://doi.org/10.1016/j.dld.2018.12.009

1590-8658/©2019TheAuthors.PublishedbyElsevierLtdonbehalfofEditriceGastroenterologicaItalianaS.r.l.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

(2)

(HCV)infectionhasgreatlycontributedtoincreasedawarenessof

themedicalcommunitytowardhepatitisC.DAAshavemarkedly

enlargedthenumber ofpossiblebeneﬁciariesof curative

treat-mentstoincludepatientspreviouslyrarelyconsidered,suchasthe

elderlyandthosewithminimalliverdisease.Therefore,theinterest

for thepsycho-socialaspects of chronichepatitis C and

associ-atedconditionsismounting.Indeed,hepatitisC,nowconsidered

adiseasethataffectsthewholebodyandnotjusttheliver,is

asso-ciatedwithmarkedpsychiatricmorbidityandsocialimpairment,

characterizedbyanxiety,depression,socialwithdrawal,signiﬁcant

reductionofthequalityoflife(QoL),feelingsofstigmatization,and

lossofproductivity[1–8].

To date, severalvalidated instruments to assess theclinical

severity of hepatitis C are available, while only a few speciﬁc

instrumentsassessingtheimpactonQoLandworkingcapability

ofliverdiseasehavebeendevelopedandvalidated[9–14].

More-over,theimpactofHCVinfectiononpatientQoLisrarely,ifever,

assessedoutsidespecializedcenters[15,16].Ithasbeensuggested

thatroutineassessmentofQoLforpatientswithHCVwouldlead

toimprovedpatientsatisfactionandclinicaloutcomes[16].

OneofthereasonsofthepoorassessmentofQoLinclinical

prac-ticemaybethelackofvisuallyintuitiveinstrumentsthatarequick

andeasytoadminister[16].Therefore,aquestionnairethatallows

aquickassessmentoftheimpactofthedisease,andatthesame

time,anintuitivegraphicvisualizationoftheoutcome,mightbe

usefulindailypractice.Inparticular,makingtheresultsofthetest

availabletothepatientfordiscussionduringthemeetingwiththe

physicianislikelytoincreasethepatient’sperceivedcontrolofthe

disease.

Therefore,we aimedtodevelop andvalidatetheﬁrstItalian

visualtool(HepaDisk)fortheassessmentofQoLinpatientswith

HCVinfection.Thistoolischaracterizedbyboththe

comprehen-sivenessofashortquestionnaireandtheintuitivenessofagraphic

representationoftheoutcome,easilyunderstoodbybothpatients

andphysicians.

2. Materialsandmethods

2.1. Delphimethod

Asteeringcommitteedraftedasetofdimensionsandrelated

questions (items)in theItalianlanguage,withtheaimof

eval-uatingtheimpactofHCVinfectionontheQoLofpatients.This

preliminaryHepaDiskversionunderwentaDelphi[17,18]survey

conductedviae-mailandmanagedbyaprivatemarketresearch

company(ThinkTank, Milan, Italy). A national panelof experts

wasprovidedwiththequestionnairebye-mail,togetherwitha

detailedinstructionsheetandtheproject’smostrelevantliterature.

Intwosequentialanonymousrounds,participantswereaskedto

indicatetheirlevelofagreementforeachitemona10-point

numer-icalratingscale(rangingfrom0=noimportance/disagreementto

9=utmostimportance/agreement)ontheappropriatenessofthe

item.Aftereachround,thesteeringcommitteereviewedthe

pan-elists’levelofagreementandcommentsandmodiﬁedthesetof

dimensions/itemsaccordingly.Consensusforinclusionofanitem

intheHepaDiskwasdeﬁnedapriorias≥70%ofpanelistsratingan

item5orabove.

Asteeringcommittee memberwasdeﬁnedasa keyopinion

leaderinHCVandanexpertin hepaticdiseaseQoLassessment

tools.An expert/panelist wasdeﬁned asa physicianwith

rele-vantclinicalexpertiseinHCVandpatientmanagement,specialized

ingastroenterology,internalmedicine,orinfectiousdisease.The

distributionoftheItalianhepatologycenterswasgeographically

balancedtoreﬂectthenationalepidemiologyofthedisease[19,20].

2.2. Validationstudy

Amulticenter,observationalstudywasconductedwiththe

pri-maryobjectiveofvalidatingthedevelopedHepaDiskquestionnaire

withrespecttootheralreadyvalidatedtools(ChronicLiverDisease

Questionnaire[CLDQ],36-itemShortFormHealthSurvey[SF-36],

andWorkProductivityandActivityImpairment–HepatitisCVirus

[WPAI:HCV])andtoevaluateitscorrelationwithdiseaseseverity,

assessedthroughMetavirscore,inItalianpatientswithHCV.

Sec-ondaryobjectivesweretoassesspatientperception/satisfactionof

theuseofthenewinstrument,toexaminetheinﬂuenceoftheuse

ofthenewinstrumentonthepatient–physicianrelationship,andto

evaluatetheimpactofHCVonworkingabilityusingtheWPAI:HCV.

2.3. Centersandsubjects

Thestudy wasconductedinItalian centerstreating patients

withHCV,withatleast10subjectswithHCVinfectionfollowedby

theoutpatientclinicpermonth.Inclusioncriteriawere:maleand

femalepatientsaged≥18yearsold;affectedbyHCVofanygradeof

severityandeithertreatedornotwithanyantiviraldrug,andable

tounderstandandcompletestudy-relatedquestionnaires.Patients

currentlyorpreviouslyaddictedtodrugs,withrelevantpsychiatric

comorbiditiesortakingpartinaclinicaltrial,wereexcludedfrom

thestudy.Eachsubjectattendedthreevisits,whichwerecarried

outinaccordancewiththenormalclinicalpracticeateachcenter:

visit(V)2occurredbetween2to7daysafterV1,andV3tookplace

14weeks(notherapyor3-monththerapy)or26weeks(6-month

therapy)afterV2.

2.4. Questionnaires

The HepaDisk questionnaire is composed of 10 questions.

Patientsweretoanswereachquestion,togetherwiththephysician,

byindicatingtheirperceptionofHCVburdenonavisualanalogue

scale(VAS)rangingfrom0(absolutelynot)to10(deﬁnitelyyes).

ThetotalscoreisthesumofthesingleVAS(0=noimpactofthe

diseaseonQoL;100=maximumimpactofdiseaseonQoL).Itwas

providedatallvisitsonatabletdevice,developedinaccordance

withtheUSFDAPROGuidanceforIndustry[21].Thedevicedid

notpermitunansweredquestions.Theotherquestionnaireswere

providedatV1andV3ashardcopy.

TheCLDQisaspeciﬁchealth-relatedQoLassessmentdesigned

forpatientswithliverdisease[12].Inthisstudy,weusedthe

val-idated Italianversion ofthequestionnaire (CLDQ-I)[15],which

includes28itemsscoredfrom1(never)to6(always),where6

denotestheworstpossiblefunction.Itincludesasecondpartthat

inquires aboutchanges fromthelast visit in six areas: fatigue,

activity,emotionalfunction,abdominalsymptoms,systemic

symp-toms,andworry.Thetotal scoreis thesumoftheitems’score

(28=minimalimpactonQoL;168=maximumimpactonQoL).No

morethat20%ofmissingdatawereallowed.Incasesof<20%,the

missingvalueswerereplacedwiththemeanoftheavailableitems.

TheSF-36v2isamulti-purpose,36-itemgenerichealthsurvey.

The36itemsaredividedintoeightscales:physicalfunctioning,

rolephysical,bodilypain,generalhealth,vitality,social

function-ing,roleemotional,andmentalhealth.Thescalesareaggregated

intotwosummary scores,a mentalcomponentsummary anda

physical componentsummary. Allbut oneof theitems(health

transition)areusedtoscorethescales[22].SF-36isscoredonthe

QualityMetricIncorporatedWebsite(http://www.QualityMetric.

com/)[23];higherscoresindicatebetterhealth.Inthisstudy,we

usedtheItaliantranslationofthesurvey(SF-36v2standardItaly

[Italian]version2.0,3/03).Missingvalueswerenotreplaced;in

(3)

TheWPAI:HCVisa6-itemquestionnaireontheeffectofHCV

ontheabilitytoworkandperformregularactivities.Questions

exploretheeffectofHCVonpatients’abilitytoworkandperform

regularactivities: employment status, hoursmissed fromwork

duetoHCV,hoursmissedfromworkduetootherreasons,hours

actuallyworked,degreeHCVaffectedproductivitywhileworking

(scorefrom0to10),anddegreeHCVaffectedregularactivities

(scorefrom0to10)[24].WPAIoutcomesareexpressedas

impair-mentpercentages(responsescoresmultipliedby100),withhigher

numbersindicatinggreaterimpairmentandlessproductivity,as

follows:percentageofworktimemissedduetohealth;percentage

ofimpairmentwhileworkingduetohealth;percentageofoverall

workimpairmentduetohealth;andpercentageofactivity

impair-mentduetohealth[25].TheItaliantranslationusedinthisstudy

(ItalianforItaly–WPAI:HepatitisCV2.3–24/MAR/2014)was

cre-atedbyRWSLifeSciences[26].Missingvalueswerehandledasper

copyrightholderinstructions[27].

TheSubjectSatisfactionQuestionnairewascreatedbythestudy

team.The questions ask patientsabouttheir perceptionof the

severityoftheirdisease;ifthephysicianshowedinterestinthem

asaperson,ifansweringtheHepaDiskquestionnairehelpedthe

physiciantounderstandhowthepatientexperiencesthedisease,

and if the HepaDisk questionnaire has provided the physician

with a satisfactory overall understanding of the problems the

patientexperiencesbecauseofthedisease.Allquestionshaveﬁve

responses,rangingfrom“notatall”to“verymuchso.”

2.5. Samplesize

Thesamplesizewasdeterminedaccordingtofeasibility

crite-ria[28].Accordingtothesecriteria,atotalof10subjectsperitem

ofthequestionnairewasneeded.TheHepaDiskquestionnaire

con-sistsof10items;hence,aminimumsamplesizeof100subjectswas

required.Duetotheexpectedhighrate(35%)ofmissingdataor

fail-uretocompletepaperquestionnairesanddrop-outrate(basedon

previousexperiencefromPSOdiskquestionnairevalidation[29])

andinordertoreachstatisticalsigniﬁcanceincaseitwas

possi-bletoperformtheanalyseson150patientsstagedF0–F2and150

stagedF3–F4,thesamplesizewasincreasedto300subjects.

2.6. Psychometricevaluation

Theevaluationwasperformedusingthedatacollectedatthree

differentvisits:V1,V2andV3.Thefaceandcontentvaliditywas

assessedusingtheDelphimethodasdescribedabove.Theconstruct

validitywasevaluatedclinicallyandpsychometricallyatV1.First,

differencesinscoresingroupsdifferinginseverityofHCVinfection

andinQoLwereanalyzedusingtheSpearman’srankcorrelation,

hypothesizingthatpatientswithahigherlevelofdiseaseseverity

andaworseQoLwouldalsohaveahigherHepaDiskscore.

Sec-ondly,anexploratoryfactoranalysiswasperformedtoidentifythe

factorstructureunderlyingtheHepaDiskitems.Underthe

hypoth-esisthattheunderlyingfactorsarecorrelated,mainlyinphysical,

mental,andsocialsubdomains,principalaxesfactoranalysis,

fol-lowedbyanobliquerotation,wasapplied.Thenumberoffactors

wasdeterminedbyretainingonlythosefactorswithaneigenvalue

>1afterfactor rotation.The internalconsistency reliabilitywas

evaluatedatV1usingtheCronbach’scoefﬁcientalpha,aparameter

calculatedfromthepairwisecorrelationsbetweenthe10itemsof

theHepaDiskquestionnaire.Internalconsistencyrangesbetween

zeroandone:0.6–0.7indicatesacceptablereliabilityand≥0.8

indi-catesgoodreliability.

For test–retest reliability assessment, the same respondents

completed thequestionnaire twiceat V1 and V2. The

correla-tionbetweenthetwosetsofresponseswasprovidedintermsof

Pearson’scorrelationcoefﬁcient.Thelessscatteredtheresults,the

greaterthetest–retestreliabilityofthestudyinstrument.

TheresponsivenesstochangewastestedatV3usingthepaired

ttesttocomparethechangesinscoresinpatientswhose

clini-calconditionhadoverallimproved,stayedthesame,orworsened

sinceV1.Clinicalimprovementwasassessedthroughviralloadand

aspartateaminotransferase(AST)/alanineaminotransferase(ALT)

changes.

3. Results

3.1. Delphimethod

Thesteeringcommitteethatdraftedtheinitialsetofdimensions

anditemsoftheHepaDiskwasmadeupoffourclinicalexperts,

withtheaidofarepresentativeoftheItalianpatientassociationfor

hepatitisC(EpaC);attheendofround2,thesteeringcommittee

(fourclinicalexperts)developedtheﬁnalHepaDiskversion.

Ofthe100HCVexpertsselected,77agreedtoparticipate;69

experts(mediannumberofnewpatients/year:90;medianyearsof

clinicalexperienceinHCV:20years,95%CI,3–40years)returned

theﬁrstroundofthesurveyand55completedthesecondround.

Thegeographicaldistributionofthecentersinvolvedinround1

and2was14and11innorthernItaly,13and11incentralItaly,

and42and33insouthernItaly,respectively.

TheDelphiprocesswasconductedbetweenNovember2014

andMay2015,withround1and2datacollectedover2months

and3weeks,respectively.Aftereachround,ThinkTankprovided

areporttothesteeringcommitteewithgraphssummarizingthe

resultsforeachitemaswellasthecomments.Thesteering

com-mitteereviewedtheresultsina1-daymeetingandmodiﬁedthe

questionnaireaccordingly.

Theﬂowchartoftheevolvingofconsensusovertheroundsis

detailedinFig.1andthedescriptionoftheresultsispresentedin

thesupplementarymaterials.ThedevelopedHepaDiskisa10-item

questionnaire(Fig.2).

Thestudy protocol wasapproved byeach local ethics

com-mittee.All patientssigned the informed consent formand the

authorizationtothetreatmentofpersonaldatapriortoany

study-relatedactivity.Ofthe301patientsenrolledin23centers,265(88%)

wereeligibleforthestudy(eligiblepopulation)andattendedV1

andV2;263patientsattendedV3.Twopatientsdidnotcomplete

thestudy(1losttofollow-up;1withdrawal).Theper-protocol

pop-ulation(allvisitsfullycompleted)consistedof214patientsenrolled

in22centers.Thebaselinedemographicsandclinical

characteris-ticsoftheeligibleand per-protocolpopulationare describedin

Table1.

The per-protocol population perception of HCV severity,

measured through the Subject Satisfaction Questionnaire, was

severe/verysevere(23.8%and15.0%),fair(38.3%and40.2%),and

mild/verymild(37.9%and44.4%)atV1andV3,respectively.

ThesecondpartoftheCLDQ-Iwasnotused,asitwasnotneeded

forthevalidationoftheHepaDisk.

3.3. Psychometricevaluation

Thepsychometricevaluationandsecondaryanalysiswere

per-formedusingdatafromtheper-protocolpopulation.

3.3.1. Constructvalidity

Allquestionnairesshowednosigniﬁcantcorrelationwiththe

physician’sand Metavirevaluationof HCVseverityand asmall

(4)

Fig.1.StagesoftheDelphiprocessandattainmentofconsensus.

(Table2),asconﬁrmedbyHepaDiskscoresstratiﬁedbygradeof

subjects’perception(Fig.3).

TheHepaDiskquestionnairescoresshowedamoderatelyhigh

correlationwithCLDQ-IoverallandWPAI:HCVscoresandalower

correlationwithSF-36scores(Table3).

ThefactoranalysisidentiﬁedtwofactorsatV1(the

percent-ageoftotalvarianceexplainedbybothfactorswas>65%),andit

waspossibletogrouptheitemsintotwodomains:onedeﬁnedby

psychologicalpatterns(sociallife,peaceofmind,relationships,

sex-uality,lifehabits,andcapabilitytoplanthefuture),andtheotherby

physicalones(health,lackofenergy,sleep,andwork);eachfactor

wasstronglycorrelatedtoallitsindividualitemsexceptforwork.

AtV3,onlyonelatentfactorwasidentiﬁedthatexplainedaround

70%ofthetotalvariance,anditwasstronglycorrelatedtoallofthe

individualitems.

3.3.2. Internalconsistencyreliability

TheCronbach’scoefﬁcientalphawas0.912,indicatingverygood

internalconsistencyreliability.

3.3.3. Test–retestreliability

Good test–retestreliability betweenV1 (39.2±26.8) and V2

(36.9±26.5)wasobserved,withaPearson’scorrelationcoefﬁcient

(5)

Fig.2.TheItalianHepaDiskquestionnaire,withanexampleofpolygonsderivedfromanswerstothe10items.

Health(salute):hepatitisCdamagesmyhealthstatus;lackofenergy(calodienergia):hepatitisCmakesmefeeltiredduringnormaldailylife;sleep(sonno):hepatitisC damagesthequalityofmysleep;sociallife(vitasociale):hepatitisCdamagesmysociallife(i.e.,convivialevents,kindofsportactivities,kindofholidays);peaceofmind (serenitàmentale):hepatitiscpreventsmefromfacingmydailylifeuntroubled;work(lavoro):hepatitisCdamagesmyworkinglife;relationships(vitaaffettiva):hepatitis Cinﬂuencesmydecisionsonmyrelationships;sexuality(vitasessuale):hepatitisCinﬂuencesmysexuality;lifehabits(abitudinidivita):hepatitisCdamagesmylifehabits (i.e.,goingtothehairdresser,barber,beautician,dentist,bodypiercing,tattooing);capabilitytoplanfuture(progettareilfuturo):hepatitisCdamagesmywilltomakefuture plans.

Fig.3. HepaDiskscoresbysubject’sperceptionoftheseverityofthedisease.

3.3.4. Responsivenesstochange

Amongimprovedpatientsfor viralloaddecrease(n=141)at

V3,astatisticallysigniﬁcantdecrease(−9.96±26.77,p<0.001)was

notedontheHepaDiskquestionnaire;nostatisticallysigniﬁcant

changeswerenotedamongstable(n=53,−2.08±21.84,p=0.49)

orworsenedpatients(n=20;2.90±21.70,p=0.56).

AmongimprovedpatientsforAST/ALTdecrease(n=125)atV3,

astatisticallysigniﬁcantdecrease(−11.73±25.28,p<0.001)was

notedontheHepaDiskquestionnaire;nostatisticallysigniﬁcant

changeswerenotedamongstable(n=41;_−2.68_±21.95,p=0.44)

orworsenedpatients(n=48;2.48±26.16,p=0.52).

3.4. Secondaryanalysis

Seventypercentto89%ofpatientswere“Quitealot”to“Very

muchso”satisﬁedwiththeuseoftheHepaDiskandconsideredit

important,givingtheirphysicianabetterunderstandingof

HCV-relatedconcerns.

Themeanimpact(%±SD)ofHCVonworkingabilitythrough

theWPAI:HCV was22.8±28.9foractivityimpairment,4.0±9.2

forabsenteeism,19.6±26.3forpresenteeism,and17.2±22.9for

(6)

Table1

Demographicsandclinicalcharacteristicsatbaseline.

Eligiblepopulation(N=265) Per-protocolpopulation (n=214)

n % n %

Sex Male_Female 128₁₃₇ 48.3_51.7 101₁₁₃ 47.2_52.8

Age(years) Mean±SD(range) 61.4±12.5(25–84) 61.7±12.7(25–84)

Civilstatus

Single 31 11.7 25 11.7

Marriedorlivingtogether 195 73.6 155 72.4

Separatedordivorced 19 7.2 18 8.4 Widow/widower 20 7.5 16 7.5 Educationlevel Primaryschool 61 23.0 43 20.1 Secondaryschool 107 40.4 87 40.7 Highschool 63 23.8 55 25.7 University 34 12.8 29 13.5 Smokinghabits Smoker 66 24.9 53 24.8 Neversmoked 148 55.8 115 53.7 Ex-smoker(>6months) 51 19.2 46 21.5 Alcoholconsumption Drinker 27 10.2 25 11.7

Drinkermean±SD(range) alcoholconsume (units/day)

3.7±9.9(1–50) 4.0±10.3(1–50)

Non-drinker 186 70.2 141 65.9

Ex-drinker(>6months) 52 19.6 48 22.4

BMI,kg/m2 _Mean_±_SD_(range) _25.4_±_4.0_(17–39) _25.3_±_3.9_(17–39)

GTatdiagnosis GT1a 32 12.1 25 11.7 GT1b 144 54.3 114 53.3 GT2 57 21.5 49 22.9 GT3 16 6.0 14 6.5 GT4 15 5.7 11 5.1 GT5 1 0.4 1 0.5 Metaviratdiagnosis F0 70 26.4 58 27.1 F1 68 25.7 53 24.8 F2 43 16.2 36 16.8 F3 47 17.7 40 18.7 F4 37 14.0 27 12.6 Routeoftransmission Unknown 185 69.8 156 72.9 Bloodtransfusion 43 16.2 29 13.6 Bloodcontact 16 6.0 9 4.2 Sexual 13 4.9 12 5.6 Other 7 2.6 7 3.3 Mothertochild transmission 1 0.4 1 0.5 Livertransplantation 2 0.7 2 0.9 Cirrhosis 49 18.5 36 16.8 Decompensation 0 0.0 0 0.0

BMI,bodymassindex;GT,genotype;SD,standarddeviation.

Table2

Correlationbetweenquestionnairesandseverityofdiseaseevaluatedbyphysician,Metavirscoreandsubject.

Physicianevaluation Metavir Subjectperception

Spearman’srankcorrelation Pvalue Spearman’srankcorrelation Pvalue Spearman’srankcorrelation Pvalue

HepaDisk −0.011 0.878 0.004 0.949 0.48 <0.001 SF-36:PCS −0.167 0.015 0.079 0.252 −0.403 <0.001 SF-36:MCS 0.103 0.132 −0.017 0.807 −0.327 <0.001 CLDQ:overallscore −0.013 0.847 −0.041 0.547 0.425 <0.001 CLDQ:abdominalsymptoms −0.062 0.365 −0.119 0.084 0.3 <0.001 CLDQ:fatigue 0.013 0,855 −0.056 0.416 0.397 <0.001 CLDQ:systemicsymptoms 0.037 0,588 −0.053 0.438 0.357 <0.001 CLDQ:activity 0.09 0,191 0.029 0.679 0.369 <0.001 CLDQ:emotionalfunction −0.106 0.121 −0.017 0.798 0.343 <0.001 CLDQ:worry 0.048 0.485 0.04 0.561 0.384 <0.001

WPAI:HCV:activityimpairment 0.002 0.976 −0.044 0.528 0.462 <0.001

CLDQ,ChronicLiverDiseaseQuestionnaire;MCS,mentalcomponentsummary;PCS,physicalcomponentsummary;SF-36,36-itemShortFormHealthSurvey;WPAI:HCV, WorkProductivityandActivityImpairment:HepatitisCVirus.

4. Discussion

4.1. Delphimethod

The10-itemquestionnairethatwasdevelopedisintendedtobe ﬁlledoutbythepatientwiththephysicianduringaroutinevisit, fosteringabettercommunicationbetweenthem,whichmay

posi-tivelyinﬂuencetreatmentadherence.Theanswerstothequestions arerepresentedgraphicallyonacoloreddiskasapolygon(Fig.2).

Whentheburdenofthediseasedecreases,theareaofthe

poly-gonshrinks,providingboththephysicianandthepatientwithan

immediateandintuitiverepresentationoftheprogressachieved.

(7)

Table3

Correlationbetweenquestionnairescores.

CorrelationofHepaDiskwith: Spearman’srankcorrelation Pvalue CLDQ:overallscore 0.651 <0.001 CLDQ:abdominalsymptoms 0.509 <0.001 CLDQ:fatigue 0.571 <0.001 CLDQ:systemicsymptoms 0.54 <0.001 CLDQ:activity 0.535 <0.001 CLDQ:emotionalfunction 0.555 <0.001 CLDQ:worry 0.562 <0.001 SF-36:PCS −0.432 <0.001 SF-36:MCS −0.552 <0.001

WPAI:HCV:activityimpairment 0.595 <0.001 CLDQ,ChronicLiverDiseaseQuestionnaire;MCS,mentalcomponentsummary; PCS,physicalcomponentsummary;SF-36,36-itemShortFormHealthSurvey; WPAI:HCV,WorkProductivityandActivityImpairment–HepatitisCVirus.

andeasy-to-readresponsefortheirroutineclinicalpracticeorfor clinicalstudies.

A possible limitation of the Delphi process is the panel of expertsinvolvedpotentiallynotrepresentingtheviewofall Ital-ianphysicianstreatingpatientswithHCVinfection.Tominimize thislimitation,weincludedexpertsingastroenterology,internal medicine,andinfectiousdiseaseandbalancedthegeographical dis-tributionofthecenterstoreﬂectthenationalepidemiologyofthe disease.

Thegradeofcorrelationoftheseverityofdiseaseversus ques-tionnairescoresrecordedfortheHepaDiskscoreswassubstantially similartotheotherquestionnaires.Thegradeofcorrelationofthe HepaDiskscoresversusotherquestionnaireswasmoderatelyhigh versusCLDQ-I(overallscore)andWPAI:HCV(activityimpairment) andlowerversusSF-36;thiscouldbeimputabletothedifferent natureofthetwoquestionnaires,asHepaDiskinvestigatesthe sta-tusofthepatientswithaspecificpathology(HCV),whiletheSF-36 aimstoevaluatethegeneralstatusofhealthofthepatients.This evidencesupportstheclinicalvaluethattheHepaDiskcanbringto clinicalpractice.ThefactoranalysisshowedthatHepaDiskis com-posedofasingledomainwithoutanysubdomain,thusallowing calculatingthetotalscoreasthesumofthescoresofeach ques-tion.TheHepaDiskalsodemonstratedstronginternalconsistency reliability,themeasureofhowwelltheitemsonatestmeasurethe sameconstructoridea.Thegoodtest–retestreliabilityresults high-lightedthehighreproducibilityofourtoolinashorttimeinterval, whentheclinicalconditionsareexpectedtobethesameand there-foretheQoLshouldbealmostthesame.Finally,HepaDiskdetected astatisticallysignificantdifferencewhenthepatient’sHCVseverity improved,similartotheCLDQ-IandSF-36instruments,asassessed ina14/26weeks’timeframe(V3).Therewasastatistically sig-nificantdecrease inscores(p<0.001)among improvedpatients (n=141);therewasnostatisticallysignificantchangeamongstable (n=53;p=0.49)orworsenedpatients(n=20;p=0.56).

A possible limit of this study could be the use of “non-disease-specific” QoL tools, CLDQ-I and SF-36, as comparison questionnaires;furtheranalysiscomparingHepaDiskscoresversus otherHCV-specificQoLtoolsmightprovideadeeper understand-ingofthenewquestionnaireefficacy.Anotherlimitationofour studymaybethequestionnaire’sdevelopmentbasedonand tar-getedfortheItalianpopulationanditslocallanguage.Inorderto spreaditsuseinternationally,HepaDiskshouldbetranslatedandits psychometricpropertiestestedinotherpopulationsaccordingly.

Inconclusion,thedevelopmentandvalidationoftheHepaDisk questionnaireprovidespatientsandclinicianswithareliableand user-friendlytoolthatshouldhelpmonitortheimpactofHCVon differentaspectsofapatient’sQoLovertimebymeansofan

intu-itivegraphicrepresentation.Moreover,theHepaDiskmightallow for thecorrelation of treatmentoutcomes and QoL, potentially increasingthecontrolofdiseaseperceivedbypatients.

Conﬂictsofinterest

GiulianaGualbertiandValeriaSaragagliaareemployeesofAbbVie andmayownAbbViestocks/options.FabioBuelliwasanAbbVie employeeandmayownstocks/options.

SFagiuolideclaresspeakerbureausandadvisoryboardsforBMS, MSD,AbbVie,Gilead,Novartis,Grifols,Kedrion,andBayer.

NCaporasodeclares researchgrants,lecturingfees,advisory boards,andscientiﬁcconsultancyforAbbVie,BMS,GileadScience, Janssen,andMSD.

FMoriscodeclaresadvisoryboardsandcongressparticipation forAbbVie,Gilead,BristolandMSD.

LChessadeclaresparticipationinadvisoryboardsforAbbVie andspeakerfeesforAbbVieandGilead.

CM Mastroianni receivedgrants from Janssen-Cilag, AbbVie, MSD,ViiV,andGilead.

MPirisideclareslecturefeesfromGilead,Bayer,AbbVie,and AlfasigmaandparticipationinadvisoryboardsforBayerandMSD. FPRussodeclaresspeakerbureausandadvisoryboardsforBMS, MSD,AbbVie,Gilead,Biotest,grantsfromAbbvieandBMS.

PTarquinireceivedgrantsfromAbbVie.

LGiannitrapani declaresparticipation toadvisoryboardsfor AbbVie.

JVecchietreceivedgrantsfromAbbVie.

MVincireceivedgrantsfromAbbvie,declaresparticipationin advisoryboardsforAbbVie,speakerfeesforAbbvieandGilead.

GTalianideclaresspeakingandteachingfeesfromAbbVie,BMS, Gilead,MSDItalia.

PToniuttodeclaresspeakerbureausandadvisoryboardsfor BMS,MSD,AbbVie,Gilead,Novartis,Kedrion.

Thefollowingauthorsdeclarenoconﬂictsofinterest:GCorti,P Tundo,FFarinaandIMaida.

Noauthorwaspaidforwritingthismanuscript.

Funding

AbbViefundedthestudyandparticipatedinthedesign,study conduct, as well as in interpretation of the data, review, and approvalofthemanuscript.

Acknowledgements

TheauthorswishtothankEpaCforthecriticalcontributionto thedevelopmentoftheHepaDiskquestionnaireandDaria Nuccia-relliofAbbViefordraftingthemanuscript.

Theauthorsalsowishtothankthefollowingindividualsfordata collection:DrIrenePozzetto,DrElisaCeriani,DrFrancescaMori Ubaldini,DrMariaCristina Rossi,DrValentinaIuri,DrGabriella Girinelli,DrFaniaPuccia,DrDanilaTeco,DrVivianaPicciotto,Dr ElisaBiliotti,andDrEnricaFranceschet.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttps://doi.org/10.1016/j.dld.2018.12.009.

References

[1]YounossiZM,KiwiML,BoparaiN,etal.Cholestaticliverdiseasesand health-relatedqualityoflife.AmJGastroenterol2000;95:497–502.

[2]YounossiZM,BoparaiN,PriceLL,etal.Heath-relatedqualityoflifeinchronic liverdisease:theimpactoftypeandseverityofdisease.AmJGastroenterol 2001;96:2192–9.

(8)

[3]MonacoS,MariottoS,FerrariS,etal.HepatitisCvirus-associated neurocogni-tiveandneuropsychiatricdisorders:advancesin2015.WorldJGastroenterol 2015;21:11974–83.

[4]NegroF,FortonD,CraxìA,etal.Extrahepaticmorbidityandmortalityofchronic hepatitisC.Gastroenterology2015;149:1345–60.

[5]YounossiZ,BrownA,ButiM,etal.ImpactoferadicatinghepatitisCvirusonthe workproductivityofchronichepatitisC(CH-C)patients:aneconomicmodel fromﬁveEuropeancountries.JViralHepat2016;23:217–26.

[6]NaggieS.HepatitisCvirus,inﬂammation,andcellularaging:turningbacktime. TopAntivirMed2017;25:3–6.

[7]CartaMG,AngstJ,MoroMF,etal.AssociationofchronichepatitisCwith recur-rentbriefdepression.JAffectDisord2012;141(2):361–6.

[8]RagusaR,BertinoG,BrunoA,etal.Evaluationofhealthstatusinpatientswith hepatitisCtreatedwithandwithoutinterferon.HealthQualLifeOutcomes 2018;16(1):17.

[9]Marchesini G, BianchiG, Amodio P,et al. Factorsassociated with poor health-related qualityof life of patientswith cirrhosis. Gastroenterology 2001;120:170–8.

[10]SampJC,PerryR,PiercyJ,etal.Patienthealthutility,workproductivity,and lifestyleimpairmentinchronichepatitisCpatientsinFrance.ClinResHepatol Gastroenterol2015;39:307–14.

[11]YounossiZM,JiangY,SmithNJ,etal.Ledipasvir/sofosbuvirregimensforchronic hepatitisCinfection:insightsfromaworkproductivityeconomicmodelfrom theUnitedStates.Hepatology2015;61:1471–8.

[12]YounossiZM,GuyattG,KiwiM,etal.Developmentofadiseasespeciﬁc ques-tionnairetomeasurehealthrelatedqualityoflifeinpatientswithchronicliver disease.Gut1999;45:295–300.

[13]GralnekIM,HaysRD,KilbourneA,etal.Developmentandevaluationofthe LiverDiseaseQualityofLifeinstrumentinpersonswithadvanced,chronicliver disease—theLDQOL1.0.AmJGastroenterol2000;95:3552–65.

[14]WareJrJE,BaylissMS,MannocchiaM,etal.Health-relatedqualityoflifein chronichepatitisC:impactofdiseaseandtreatmentresponse.Hepatology 1999;30:550–5.

[15]RucciP,TalianiG,CirrincioneL,etal.ValidityandreliabilityoftheItalian ver-sionoftheChronicLiverDiseaseQuestionnaire(CLDQ-I)fortheassessmentof health-relatedqualityoflife.DigLiverDis2005;37:850–60.

[16]WhiteleyD,ElliottL,Cunningham-BurleyS,etal.Health-relatedqualityof lifeforindividualswithhepatitisC:anarrativereview.IntJDrugPolicy 2015;26:936–49.

[17]SteurerJ.TheDelphimethod:anefﬁcientproceduretogenerateknowledge. SkeletalRadiol2011;40:959–61.

[18]GentiliniP,BernardiM,BolondiL,etal.Therationaluseofalbumininpatients withcirrhosisandascites.ADelphistudyfortheattainmentofaconsensuson prescribingstandards.DigLiverDis2004;36:539–46.

[19]BellentaniS,MiglioliL,MasuttiF,etal.EpidemiologyofhepatitisCvirus infec-tioninItaly:theslowlyunravelingmystery.MicrobesInfect2000;2:1757–63.

[20]GaetaGB,CuomoG.EpidemiologiadelleepatitiviraliinItalia.LigandAssay 2006;11(4):314–8.

[21]USFDA.Guidanceforindustry.In:Patient-reportedoutcomemeasures:usein medicalproductdevelopmenttosupportlabelingclaims.SilverSpring,MD: U.S.DepartmentofHealthandHumanServices;2009.December.

[22]WareJrJE.SF-36healthsurveyupdate.Spine2000;25:3130–9.

[23]WareJEJr,KosinskiS,BjornerJB,etal,editors.User’smanualfortheSF36v2®

healthsurvey,2nded.Lincoln:QualityMetricIncorporated;2007.

[24]ReillyMC, ZbrozekAS, Dukes EM. The validityand reproducibility of a workproductivityandactivityimpairmentinstrument.Pharmacoeconomics 1993;4:353–65.

[25]http://www.reillyassociates.net/WPAIScoring.html.[AccessedJune2018]. [26]http://www.reillyassociates.net/WPAITranslations.html. [Accessed June

2018].

[27]http://www.reillyassociates.net/WPAICoding.html.[AaccessedJune2018]. [28]StreinerDI,NormanGR.Validity.In:StreinerDL,editor.Healthmeasurement

scales.Apracticalguidetotheirdevelopmentanduse.NewYork:Oxford Uni-versityPress;1995.p.104–62.

[29]SampognaF,LinderD,RomanoGV,etal.Resultsofthevalidationstudyofthe Psodiskinstrument,anddeterminationofthecut-offscoresforvaryingdegrees ofimpairment.JEurAcadDermatolVenereol2014;29:725–31.