Cost-effectiveness estimates of vaccination against rotavirus in Piedmont, Italy

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ContentslistsavailableatScienceDirect

Journal

of

Infection

and

Public

Health

j o u r n al ho me p ag e :h t t p : / / w w w . e l s e v i e r . c o m / l oc a t e / j i p h

Cost-effectiveness

estimates

of

vaccination

against

rotavirus

in

Piedmont,

Italy

Maria

R. Gualano

∗

,

Robin

Thomas,

Renata

Gili,

Giacomo

Scaioli,

Gianluca

Voglino,

Carla

Zotti

DepartmentofPublicHealth,UniversityofTurin,Turin,Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received24April2018

Receivedinrevisedform29June2018

Accepted16July2018 Keywords: Rotavirus Cost-effectiveness Economicanalysis Burdenofdisease Vaccine

a

b

s

t

r

a

c

t

Background:Rotavirus-induced gastroenteritis(RVGE)represents themostfrequent formofsevere gastroenteritisinchildren.Insuchascenario,theavailabilityofanefﬁcientanti-Rotavirus(anti-RV) vaccinerepresentsaneffectivepreventiontoolabletopreventthosecomplicationsmainlylinkedto themoderate-severeformsofthisdisease,whichrequirehospitalcare.Theaimofthepresentstudy istoestimatethecosteffectivenessofuniversalroutineinfantRVvaccinationprogramanditsbudget impactontheRegionalHealthService(RHS)ofPiedmont,Italy,inordertoevaluatetheopportunityof theimplementationofanationalanti-Rotavirusvaccinationprogramme.

Methods:Theresearchersperformedacost-effectivenessanalysiscomparingcostsandbeneﬁtsofa Rotarixtwo-dosevaccinationversusnonvaccinationandabudgetimpactanalysis(BIA),complementary tothecost-effectivenessanalysis.

Results:Ourresultsshowthatthemassimplementationofananti-RVvaccinationinPiedmont,inaddition totheexpectedpublichealthbeneﬁts,alsoallowstheRHStosaveaconsiderableamountofmoneywithin ashortperiodoftime,duetotheremarkablereductionofdirecthealthcostsassociatedwithRVGE management.Infact,astheanalysisshows,auniversalvaccinationagainstRVresultsinmoney-saving fortheRHSalreadyfromthe2ndyear(withavaccinationcoverageof50%).Duringtheﬁveyearperiod,the activeandfreeofferoftheanti-RVvaccinationwoulddetermineatotalsavingforRHSofaboutD503.000. Thecost-effectivenessanalysisresultsshowedacost-savingICER(incrementalcost-effectivenessratio) relevanttotheRHSandequalto–D12.197/QALY.

Conclusion:InconclusiontheadoptionofauniversalpreventivestrategyforalltheinfantsinthePiedmont RegionmaycontributesigniﬁcantlytowardsthecontrolofRVGEincidence,thusallowinganoteworthy savingofeconomicandsocialresourcesforboththeRHSandthegeneralpublic.

©2018 TheAuthors.PublishedbyElsevierLimitedonbehalfofKingSaudBinAbdulazizUniversity forHealthSciences.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Globally,rotavirus-induced gastroenteritis(RVGE) represents

themostfrequentformofseveregastroenteritisinchildren,

par-ticularlyforthoseundertheageoftwo.Itisestimatedthatevery

yearthepathogencausesabout25millionmedicalexaminations,

2millionhospitaladmissionsand215.000deaths[1,2].

Within the European Union (EU), rotavirus gastroenteritis

(RVGE)placesahighdemandonhealthcaresystems[3].

Surveil-lancestudiesshowedthatRotavirusrepresentsthegreatestburden

∗ Correspondingauthorat:DepartmentofPublicHealth,UniversityofTurin,Via

Santena5bis,10126Turin,Italy.

E-mailaddress:[email protected](M.R.Gualano).

of diseaseconsistently observedin children agedunder 2,and,

moreover,accountsforuptotwothirdsofadmissionstohospital

and emergency roomvisitsand onethird of primarycare

con-sultationsforAcuteGastro-Enteritis(AGE)amongchildrenunder

5years.RVGEisestimatedtooccuratarateof1symptomatic

infec-tioninevery7childreneachyear,accountingfor231deaths,more

than87,000hospitalizationsandalmost700,000outpatientvisits

[4–7].

Inlightoftheabove,itisclearthatRVGErepresentsanimportant

worldwidepublichealthissue.Since2006,twoRVvaccines,Rotarix

andRotaTeq,havebeenlicensedandwidelyusedinmanycountries

aroundtheworld[8].

Morethan10yearsaftertheauthorizationoftwovaccinesof

demonstrated efﬁcacyand with a strongly positive beneﬁt-risk

https://doi.org/10.1016/j.jiph.2018.07.008

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Table1

Epidemiologicaldata.

Variable Number Sources

Totalof2014cohort(PiedmontRegion) 34637 Demo-Istat[17]

Referencepercentage Novaccination

RVGEcases/RV-speciﬁcdiarrhoea 45.45% 15742 Soriano-Gabarróetal.,Vitaleetal.[3,29]

Medicalconsultations/paediatricexaminations 22% 7606 Matteietal.,Giletal.[18,19]

Emergencyroomvisits 9.8% 3391 Giaquintoetal2008[20]

Hospitaladmissions 2.74% 951 Giaquintoetal.[20]

AdmissionsfornosocomialinfectionofRV-speciﬁcdiarrhoea 1.51% 521 HealthforAll,IstatMinisterodellaSalute,numeroricoveri[21]

Deaths 0% 0 Marchettietal.[11]

Table2

Unitcostsandsources.

Costitems Values Sources

Familypediatricianvisits D18 EstimatefromGrossannualsalaryconsideringanaveragetimeof10min/visit Emergencyroomvisitcost D241 MinisterodellaSalute,2011ProgettoMattoni[22]

Hospitaladmissioncost D1222.50 Ministerodellasalute–Decreto18ottobre2012–GUn.23del28gennaio2013.Mean

ofDRG422(D1660)eDRG184(D785)[23]

Hospitaladmissioncostfornosocomialinfections D2156 Ministerodell’EconomiaedelleFinanze,Gianinoetal.,Biermanetal.[24–26]

Rotarixvaccinecost(perdose) D33.50 CostconsistentwithPiedmontRegiontenderprice

Administrationcost D0 Vaccineadministrationscheduledtogetherwithhexavalentandpneumococcal

conjugatevaccinations

proﬁle,uptake inEuroperemainslow:around40%ofcountries

currentlyhavenoexistingnationalrecommendations[9].

Insuchascenario,theavailability ofananti-Rotavirus

(anti-RV)vaccinerepresentsaneffectivepreventiontoolabletoprevent

thosecomplicationsmainlylinkedtothemoderate-severeformsof

thisdisease,whichrequirehospitalcare[3,10–12].Asamatterof

fact,scientiﬁcliteraturehasdemonstratedhowhygienestandards,

suchashandwashinganddisinfectionofsurfaces,albeiteffective,

arestillnotadequatetohaltthespreadingandthemanifestation

oftheviraldisease[13].

Thenew“PianoNazionaleperlaPrevenzioneVaccinale(PNPV)

2017–2019”[14],approved in Italy inJanuary 2017withinthe

approvalplanofthenew“LivelliEssenzialidiAssistenza”,

antic-ipates theintroductionof theanti-Rotavirus vaccinationfor all

childrenintheirﬁrstyearoflife(Lawn.119,31July2017).

Inthiscontext,thePNPVneedsstrongevidencetobe

scientif-icallysupportedbydataandﬁndingsreportedfromthecurrently

availableliterature.

Inordertoadequately assesstheavailablevaccination

tech-nologiesandtheirimpact,in2005theWorldHealthOrganization

(WHO)publishedadocumentthatpointsoutthecriteriathatmust

befollowedtoevaluateanddecideontheintroductionofnew

vac-cineswithinthehealthsystems.Thesecriteriahighlighttheneed

toinvestigatethevaccine’sefﬁcacyproﬁle,securityandeconomic

sustainability.TheWHOalsosuggestsconsideringtheassessments

onthefeasibilityofthevaccinationprogramme,frombotha

tech-nicalandlogisticalpointofview[15].Themostsuitableapproach

tothisevaluationframeworkappearstobethatoftheHealth

Tech-nologyAssessment (HTA),which consistsin a multidisciplinary

assessmentthat includes allthebestavailable evidenceonthe

impactofanewhealthtechnologyuponitsintroductioninahealth

system.

In2014acompleteeconomicanalysisontheuniversalroutine

infantRVvaccinationprogramwiththeRotarixvaccinewas

pub-lished,withina HTAreportontheanti-RVvaccinationwiththe

Rotarixvaccine[10].Thisassessmentwasconductedonanational

scalewiththeaimofevaluatingthecost-effectivenessofa

univer-salroutineinfantRVvaccinationprogramanditsbudgetimpacton

theNationalHealthService(NHS),inordertoguidethe

decision-makingprocessesinthelightofthebestexistingevidence.

Inthisstudy,asimilarapproach[10]wasappliedtothe

Pied-mont Region, in order to conduct an evaluation adapted to a

regionalcontext,withtheaimofestimatingtheRVGEassociated

costsandthehealthandeconomicbeneﬁtsoftheuniversal

vaccina-tionwiththeRotarixvaccine,inordertoevaluatetheopportunity

oftheimplementationofanationalanti-Rotavirusvaccination

pro-gramme.

WhenthepresentanalysiswasperformedinItalythere was

astrongdebateonmandatoryvaccinationprogrammesandthe

opportunityof the implementationof a nationalanti-Rotavirus

vaccinationprogrammealso.Currently,theantiRotaviurs

vacci-nationhasbeenintroducedinthenew“Piano Nazionaleperla

PrevenzioneVaccinale(PNPV)2017–2019”[14]asrecommended

one.

Materialsandmethods

Thevaccine

ROTARIXisavaccineindicatedforthepreventionofrotavirus

gastroenteritiscausedbyG1andnon-G1types(G3,G4,andG9).

ROTARIXisapprovedfororaluseininfants6weeksto24weeksof

age[16].

Theanalysis

The methodology used to conduct the present analysis is

inspiredbytheoneusedfor thenational evaluation[10]but it

considersthespeciﬁcdataofthePiedmontRegion[17].

Starting fromthenumber ofdeaths atthenational level,as

reportedintheliterature[11],theserepresentapercentageequal

to0.00038%(2deaths)comparedtotheentireItalianpopulation.By

reportingthisvaluetotheonlycohortconsideredinthePiedmont

Region,inthe“non-vaccination”scenario,thisnumbertranslates

intoanabsolutevalueofabout0.13stillequalto0.00038%ofthe

regionalpopulation.

Nationaldatawereusedforallotherparametersassummarized

inTables1,2and4.Thereferencesofthesourcesincludedinthe

tablesarethefollowing:Refs.[3,17–26].

Onthisbasis,twoanalyseswereconducted:

-Acost-effectivenessanalysiscomparingcostsandbeneﬁtsofa

Rotarixtwo-dosevaccinationadministeredconcomitantlywith

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Table3

Utilityvalues(qualityoflife).

Event QoLvalue(agedependent) Children (>12months) Infants(0–12 months) Diarrhoea 0.844 0.891 Severediarrhoea 0.200 0.425 Paediatricexamination 0.688 0.781 Emergencyroomvisit 0.425

HospitalizationforRV 0.200 0.425 Severediarrhoea(nosocomial

infection)

0.200 0.425

ofage(hexavalentandpneumococcalconjugate)versusnon

vac-cination.

-Budget impact analysis (BIA), complementary to the

cost-effectiveness analysis,which estimates the potentialﬁnancial

consequencesoftheintroductionoftheanti-RVvaccinationby

consideringthecostburdenontheRegionalHealthService(RHS)

ofPiedmont,Italy.

Cost-effectivenessanalysis

TheanalysiswasconductedusingaMarkovmodelwhichisa

deterministic(notrandom)andstatic(notdynamic)

characteriza-tion.ThismodelsimulatestheepidemiologicaltrendofRVinfection

anditspossibleconsequences,thecostsassociatedtothedifferent

kindsofmanagementandtreatment,andthevaccinationbeneﬁts.

Themodelconsiderssixhealthconditionsoreventsthat

high-light the changes occurring in terms of costs and/or Quality

AdjustedLifeYears(QALYs)overtime:

1.Healthy.

2.Diarrhoea.

3.Pediatricexamination.

4.Emergencyroomaccess.

5.Hospitaladmission.

6.Death.

Theanalysisobservesthevaccineeffectsoveraﬁveyeartime

frame(higherinfectionriskperiod)inabirth-cohortofchildren

bornin2014.Morespeciﬁcally,themodelfollowsthisbirth-cohort

andsimulatesthedevelopmentofRVdiseaseuntiltheageofﬁve,

dividing it into “monthly” time cycles [27]. Every month, each

individual present in the model may or may not experience a

ﬁrstepisodeofdiarrhoeacausedbyRVinfection.Thereafter,the

episodeofdiarrhoeamayormaynotleadtoamedicalconsultation

and/ortoanemergencyroomaccessand/ortoahospital

admis-sion.RVGEcasesareclassiﬁedasmild,moderateandsevere,each

involvingdifferentmanagementprocedures(homemanagedcare,

pediatricvisits,emergencyroomvisits,hospitalizations)anda

rel-ativeimpactonqualityoflife,employmentofresourcesanddeath

risk.Thechild’sage(withaprogressivelydecreasingprobabilityof

contractingthediseaseasthechildreachestheﬁfthyearoflife)

andthemonthoftheyear(periodicityofthedisease)constitute

themainparametersforthevariationofthetransitionprobability

introducedinthemodel,whichregulatetheshiftfromonehealth

conditiontoanother.Theseprobabilitiesalsotakeintoaccountthe

protectiveeffectofbreastfeedingandthedifferencesbetweenthe

ﬁrstandthesecondRVinfection.Afteraﬁrstevent,thesame

indi-vidualmightexperienceasecondepisodeofRVinfection,withor

withoutdiarrhoea,generallylesssevereandthereforepresumed

nottoleadtohospitalization(Fig.1).

Theanalysismodelassumesanannualvaccinationcoverageof

100%andthecostvaluesofthemodelrefertothecurrentratesin

use(vaccinecost:D33.5/dose,entirelyattheexpenseoftheRHS).

Fig.1. ICER.

Sincetheanti-rotavirusvaccinationisprovidedbythe

Vacci-nationCentresoftheLocalHealthUnit,thecostofadministration

wasnotconsideredintheanalysisasattributabletotheordinary

managementexpensesoftheRegionalHealthServices.

TheanalysiswasconductedfromaNHSperspective(by

assum-ingadiscountrateof3%forbothcostsandbeneﬁts).Themain

outcomes considered, resulting from the anti-RV vaccination,

aretheincremental cost-effectiveness ratio(ICER) expressedas

D/QALYandareductioninepisodesofdiarrhoea,numberof

hos-pitaladmissionsandnosocomialinfections.

Table1includesRVGEepidemiologicaldataestimatedinthe

PiedmontRegion.

Theanalysedcostitemsandtheirrelativesourcesarepresented

inTable2.

Becauseof alackof datarelativetotheItalian scenario,the

quality scores(QALY)used tomeasurethevaccination beneﬁts

(as shown in Table 3) are derived from a study conducted in

GreatBritainwhereEQ-5Dquestionnaires,concerningtheir

RVGE-affectedpatients,wereadministeredtopaediatriciansandgeneral

practitioners[28].

Budgetimpactanalysis(BIA)

Thisanalysisconsideredtwodifferentscenarios,onewiththe

Rotarixanti-RVvaccinationandonewithout,andusedthesame

dataenteredinthecost-effectivenessmodeldescribedinthe

pre-viousparagraph.Theacquisitioncostofthevaccine(equaltoD

33.50,foratotalofD 67)wasconsideredasbeingentirelyatthe

expenseoftheRHS.Asopposedtothecost-effectivenessmodel,

thevaccinationcoveragewasassumedasavariablefromtheﬁrst

tothefifthyear(withagradualgrowthfromthefirsttothefifth

yearfrom40%to95%,morespeciﬁcally:40%,50%,65%,80%and

95%).Furtherreferenceonthemethodologicaldetailsandthecost

valuesascribedinthemodelcanbefoundintheHTAreportonthe

anti-RVvaccinationwithRotarix[1].

Results

Cost-effectivenessanalysisinthePiedmontRegion

Inacohortof34.637individualsborninPiedmontin2014,the

numberofhospitalizationscausedbyRVinabsenceofavaccination

was951.Assumingthat100%oftheinfantsreceivetwodosesofthe

anti-RVvaccine,thevaccinationwouldleadtoan84%reductionof

RVGEcases,a99%reductionofRVGE-relatedhospitalizationsand

an89%reductionofnosocomialRV-infections,thusinﬂuencingthe

qualityoflifeanddeathrateofthepopulationanalysed.(Table4).

Theintroductionofthevaccinewouldbringaproﬁtof0.0216

QALMs(QualityAdjustedLifeMonths)resultingin0.0018QALYs

perchildcomparedtoascenariowithoutvaccination.

Theeffectonhealthoutcomesdeterminesastrongeconomic

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hospitaliza-Table4

RVGE-relatedepidemiologicaldata,hospitalizationsanddeaths,estimatedinthePiedmontRegionbeforeandaftervaccination.

Reference percentage Numberofcases (Novaccination) Numberofcases (vaccination) Numberofcases (differencevaccination vsnovaccination) %Difference vaccinationvsno vaccination Total2014cohort(PiedmontRegion) 34637 100%Coverage

RVGEcases/RV-speciﬁcdiarrhoea 45.45% 15742 2518 13224 −84%

Medicalconsultations/paediatricexaminations 22% 7606 238 7368 −97%

Emergencyroomvisits 9.8% 3391 104 3287 −97%

Hospitaladmissions 2.74% 951 10 941 −99%

AdmissionsfornosocomialinfectionofRV-speciﬁcdiarrhoea 1.51% 521 55 466 −89%

Deaths 0% 0 0 0 0

Table5

Costspercategory,includingtotalcosts,withandwithoutvaccination.

Novaccination(D) Vaccination(D) Costdifference(D)

Vaccinecost 0 2,320,679 2,320,679

Medicalconsultations/paediatricvisits 136,908 4284 132,624

Emergencyroomvisits 817,231 25,064 792,167

HospitalizationsforRV 1,162,598 12,225 1,150,373

AdmissionsfornosocomialRV-diarrhoea 1,123,276 118,580 1,004,696

Totalcosts 3,240,013 2,480,832 759,181

Costperindividual 93.54 71.62 21.92

Table.6

Budgetimpactanalysis—economicimpact.

Economicimpact Novaccination(D) 1styear(D) 2ndyear(D) 3rdyear(D) 4thyear(D) 5thyear(D)

Vaccinecost – 1,040,455 1,271,667 1,502,879 1,849,698 2,196,516

Residualpathologycost 3,240,013 2,400,845 1,839,300 1,444,210 1,045,357 622,416

Totalcost 3,240,013 3,441,300 3,110,967 2,947,089 2,895,055 2,818,932

Total 297,942 −32,391 −196,269 −248,303 −324,426

Budgetdifferenceafter5years(D) −503,447

tionsandemergencyroomvisits.Theincrementalcostresulting

fromthevaccineappearstobeabundantlycompensatedbythe

reductionofthehealthcare-relatedcostsandthisismainlydueto

reducedhospitaladmissionsandemergencyvisitscosts.Theannual

costoftheRVpathologyattheexpenseofthePiedmontRegionisof

D3.242.936;theintroductionofthevaccinationplanwouldresult

inacostreductionofD761.291(Table5).

Thecost-effectiveness analysisresults showed a cost-saving

ICER(incrementalcost-effectivenessratio)relevanttotheRHSand

equaltoD12.197/QALY.

Hence,theintroductionofthevaccineappearstobethebest

option,asitleadstoanincreaseofQALYs(moreeffective)andtoa

reductionofcostsfortheRHS(lessexpensive).

Budgetimpactanalysis(BIA)inthePiedmontRegion

AsshowninTable6,havingassumedanincreasingvaccination

coveragerate,theacquisitioncostofthevaccineincreasesfrom

theﬁrsttotheﬁfthyear.Atthesametime,withthegradual

intro-ductionoftheanti-RVvaccination,aprogressivecostreductionwas

observed.Thisisduetotheriseinthevaccination’sclinicalbeneﬁts,

whichleadstoaconsequentreductioninthehealthcare-related

medicalcostsandtomoney-savingfromthesecondyearonwards.

Thecostreductionrelatedtothevaccinationprogrammeand

theconsequentsavingsfromthesecondyearonisclearlyshown

inTable6;thetotalexpectedsavingisaboutD 503.000.

Discussion

Thepresentstudyevaluated,throughacost-effectiveness

anal-ysisand a budgetimpact analysis,theeconomic impactof the

introductionofauniversalanti-RV vaccinationin thePiedmont

Region,i.e.itseconomicsustainabilityforRHS.

Our resultsshow that the mass implementationof an

anti-RVvaccinationin Piedmont, in additiontotheexpected public

healthbeneﬁts,alsoallowstheRHStosaveaconsiderableamount

ofmoney withina shortperiodof time,due totheremarkable

reductionofdirecthealthcostsassociatedwithRVGEmanagement.

Infact,astheanalysisshows,auniversalvaccinationagainstRV

resultsinmoney-saving fortheRHSalreadyfromthe2ndyear

(withavaccinationcoverageof50%).Duringtheﬁveyearperiod,

theactiveandfreeofferoftheanti-RVvaccinationwoulddetermine

atotalsavingfortheRHSofaboutD503.000.

Therefore,theseresultsappeartobeinlinewithsimilar

evalua-tionsperformedbothonanational[29,30]andEuropeanscale,thus

reportingaquitereassuringpictureofthepreventionperspective

ofthepathologiesrelatedtothepathogenexamined.Other

eco-nomicevaluationsshowacostsavingproﬁleofthevaccines,as

results[31,32].

In thecurrent literature somestudies have investigatedthe

impactofRVvaccination.Inparticular,Austriawastheﬁrst

coun-tryinEuropeimplementingauniversalmassvaccinationprogram

againstRVGEforallinfants. Publisheddatashowthatincidence

ratesofchildrenhospitalizedwithRVGEdecreasedin2009

com-paredtotheprevaccinationperiod[33].

ThesamewasobservedinBelgiumandEngland[34,35].

Moreover,fromastrictlyorganizationalpointofview,the

vacci-nation,beingorallyadministeredandco-administrablewithother

vaccines,would alsoaddanumber ofotherlogistical/economic

advantages,withoutfurtherweighingdownthevaccine

organi-zationsystem.

Interestingly,anincreasedrisk of intussusception(∼1–6per

100,000vaccinated infants) afterRV vaccinationhasbeen

doc-umentedinsomecontexts,but thisis outweighedby thelarge

beneﬁtsofvaccination[36].

Inconsequenceofthis,theroleoftheintussusceptionafterthe

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hospitalization ratefor intussusception had a slightincrease in

trendfrom2009to2014(18%)buttheroleplayedbydifferentrisk

factors,includingacutegastroenteritis,havetobeinvestigated[37],

especiallyinordertoﬁghtthepossible“fear”ofintussusception

amongpaediatriciansandvaccinationunitsphysiciansthatcould

representaproblemforvaccinationacceptance[38].

Inconclusion,consideringthewelldocumentedclinical

effec-tivenessofthecurrentlyavailableanti-RVvaccinesandtheirgood

safetyand tolerability proﬁles,theadoption ofa universal

pre-ventivestrategy foralltheinfantsin thePiedmontRegionmay

contributesigniﬁcantlytowardsthecontrolofRVGEincidence,thus

allowinganoteworthysavingofeconomicandsocialresourcesfor

boththeRHSandthegeneralpublic.

Funding Nofundingsources. Competinginterests Nonedeclared. Ethicalapproval Notrequired. References

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