DigestiveandLiverDisease47(2015)741–743
ContentslistsavailableatScienceDirect
Digestive
and
Liver
Disease
j o ur 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
Ongoing
Clinical
Trials
PITER:
An
ongoing
nationwide
study
on
the
real-life
impact
of
direct
acting
antiviral
based
treatment
for
chronic
hepatitis
C
in
Italy
Loreta
A.
Kondili
∗,
Stefano
Vella,
and
the
PITER
Collaborating
Group
1TherapeuticResearchandMedicineEvaluation,IstitutoSuperiorediSanità,Italy
1. Rationaleandaims
Therecentdevelopmentofdirect-actingantiviralagents(DAAs) that specificallytarget thehepatitis C virus(HCV) representsa historicalbreakthrough,inthatthesecondgenerationDAAsare capableoferadicating HCVand preventingchronicliverdisease fromdevelopingintocirrhosisandhepatocellularcarcinoma(HCC)
[1–3].Thereisgreatpotentialforoverallharmreductionthrough effectivetherapy;however,manychallengesremain,beyondthat oftheexorbitantcostofthesedrugs[4–6].Inparticular,theactual clinicalimpactofDAAsonlong-termmorbidityandmortalityand inrelationtotheclinicalprofilesofchronicliverdiseaseand co-factorsofdiseaseprogression(i.e.,co-infectionsandcomorbidities) isstillunknown.
ItalyhasoneofthehighestprevalenceratesofHCVinfection inEurope,andHCVinfectionistheleadingcauseofcirrhosis,HCC, andliver-relateddeath[7–9].DAAswouldclearlyhaveahuge pub-lichealthimpactinItaly,yetdeterminingexactlywhatthisimpact wouldbe,requires evaluatingwhomtotreat basedonthe bal-ancebetweenthebenefitsoftherapyanditsaffordability.Inother words,reachingtheobjectivespromisedbytheuseofthesedrugsis linkednotonlytotheirquality,safetyandeffectivenessbutalsoto thedevelopmentofsuitableresearchforevaluatingtheirimpactin areal-lifesetting.Infact,itisnecessarytomountholdingstrategies, tomovefromtheurgentneedfortreatmentinselectedpatients toevidence-basedescalationstrategiesinotherpatientsaccording totheirdiseaseprofileandoverallbenefitfromtreatment.Inthis regard,muchcouldbelearnedfromtheexperiencewithHIV infec-tion.Inaboutthirtyyears,thankofantiviraltherapy,HIVbecomea chronicdisease,thoughthecombinedantiretroviraltreatmentcan havedifferentresultsdependingonthediseasestageduringwhich itisadministered.Moreover,itnowappearsclearthat antiretrovi-raltherapynotonlyprovidesclinicalbenefittotheindividual(in termsofrisk-benefitratioandpublichealthpolicy)buthasalsothe
∗ Corresponding authorat: TherapeuticResearch andMedicines Evaluation
Department,IstitutoSuperiorediSanità,VialeReginaElena299,00161Rome,Italy.
Tel.:+390649906580;fax:+390649902012.
E-mailaddress:loreta.kondili@iss.it(L.A.Kondili).
1 PITERCollaboratingGroupavailableathttp://www.iss.it/piter.
potentialofdecreasingtheincidenceofnewinfectionsata popu-lationlevel[10–12].InthecaseofHCVinfectionpatientscanbe curedwithDAAs,howeverthecostofprovidingearlytreatmentto allpatientswouldbeprohibitive.Itisthusimperative,considering patients’characteristicsandcomorbidities,todeterminethebest timingfortreatment,withcost-effectivenessbeingafundamental partofthisdecision.Reachingthisgoalwouldrequireaccuratedata onthelong-termeffectsofDAAtherapyforindividualsindifferent diseasestages.
To this end, a longitudinal prospective HCV cohort study knownas“PITER”(ItalianPlatformfortheStudyofViral Hepati-tisTherapies)hasbeenconducted.PITERisastructurednetwork that benefits from an integrated collaboration involvingItaly’s NationalInstituteof PublicHealth(IstitutoSuperioredi Sanità), the Italian Society for theStudy ofthe Liver (AISF), theItalian SocietyforInfectiousDiseases(SIMIT)andtheiraffiliatedclinical centres.
ThemaingoalofPITERistoevaluatetheexpectedimpactof DAAsonthenaturalcourseofinfectionandonlong-term mor-bidityandmortalityinareal-lifesetting.Thestudywilladdress such unresolved questions as: Will early treatment be able to modifylong-termoutcomeofprogression ofliverdisease?Will alternativeapproachesbeneededinpatientswithcoexisting con-ditionssuchaskidneyfailure, hepaticdecompensation,or liver transplant,aswellasthosewithpreviousfailureofaDAA com-bination?Willantiviraltreatmenthaveanimpactonextrahepatic HCV-related diseases or the natural history of other viral co-infections?
Thespecificexpectedoutcomesinclude:obtainingacontinuous updateoftheepidemiologyofHCVchronicliverdiseasethrough datafrompatientsin care;evaluationof thereal-lifelong-term impactof newDAA therapies ontheoutcomesof chronicHCV infection;monitoringoftheuseofthedifferentoptionsforDAA combinationsinareal-lifesetting,theirpossiblepharmacological interactionsandthelong-termsafety;developmentofappropriate algorithmsforcareandtherapyforspecial,difficult-to-treatand difficult-to-reachpopulations,aswellasforspecificpopulations suchastheelderly,women,non-responderstostandardtreatment protocols,patientsawaitinglivertransplantation,andliver trans-plantedpatients;evaluationoftheeconomicimpactofthe pro-gressiveintroductionofDAAsandtheircost-effectivenessthrough
http://dx.doi.org/10.1016/j.dld.2015.05.022
742 L.A.Kondili,S.Vella/DigestiveandLiverDisease47(2015)741–743
the construction of a continuously updated cost-effectiveness framework.
2. Studydesign
2.1. Studypopulation
Thecohortwillconsistofarepresentativesampleof approxi-mately10,000consecutivepatientswithchronichepatitisC(CHC) receivingcarein over 100publicgeneralhospitalsand univer-sitymedicalcentresinItaly.Thefollow-upofenrolledpatientsis expectedtolastatleast10years.Thegeographicdistributionofthe participatingcentresisavailableat:www.iss.it/piter
Inclusion criteria: all HCV-infected patients (any stage, any genotype,includingHBV,HDV,orHIVco-infected)atleast18years ofageconsecutivelyreferredtotheoutpatientclinicsofthe partic-ipatingclinicalcentresduringenrolmentphases(approximately 6months),whoareuntreatedatthetimeofenrolment.Eligible patientsarethosewhowillreceiveDAAsasfirsttherapy,orwho havefailedapriorpeginterferon/ribavirin-basedtherapy;thestudy willalsofollowpatientseligiblefortreatmentwhocannotbe pre-scribed DAAs(i.e. for non-advancedstages of fibrosis), and are warehoused.
2.2. Studyprocedures
Anad-hocweb-basedplatform,certifiedtointernational stan-dards, is used to collect data on enrolled patients, enabling interoperability, sharing of information and development of specificstudies(SupplementaryFigureS1). Theelectronic data-collectionsystemcoversallclinicalandtherapeuticaspectsofCHC ofthePITERstudy;however,thissystemwillalsobeusedforall spin-offstudiesandotherfuture researchrelatedtoPITER. The qualityofdataischeckedusingqueriesspecificallydesignedto controlforincorrectdataentryandclinicalcongruencies.Aclose interactionbetweenthecoordinatingcentreandtheparticipating clinicalcentreswillensurethequalityoffollow-updata.
2.3. Mainstudyendpointsandstatisticalanalysis
Throughacrosssectionalanalysisofenrolledpatients,the fol-lowingendpointswillbeevaluated:
(a)PrevalenceofthemainclinicalcharacteristicsofCHC:fibrosis stage;complicationsofcirrhosissuchasportalhypertension, livercancerand end-stageliverfailurerequiringliver trans-plantation.
(b)PrevalenceofextrahepaticHCV-relateddisorders,specifically, cryoglobulinemiaandlymphoproliferativedisorders(at base-lineandduringanti-HCVantiviraltherapy).
(c)VirologicalcharacterisationofHBV,HDVandHIVco-infections (baselineandduringanti-HCVandotherantiviraltherapies). (d)Prevalenceofliverandextrahepaticco-morbidities.
(e)Prescription of types of anti-HCV treatment regimens,their treatment efficacy based on rates and speed of sustained virologicalresponse(SVR),andadverseeffectsindifferent sub-groupsofpatients.
The longitudinal prospective analysis will evaluate morbid-ityandmortalityoutcomesin treatedandnon-treatedpatients. Theprogressionof liverdiseasewillbedeterminedby evaluat-ing:changesinfibrosisstage;developmentofportalhypertension, decompensatedliverdisease,andHCC;theneedforliverand/or otherorgantransplantation;theoutcomeofextrahepatic HCV-relateddisordersandco-morbidities;hospitalizationsandoverall
mortality in association with clinical profiles of liver disease and comorbidities at enrolment. The efficacy of treatmentwill be determined based on long-term effectiveness; this evalu-ation will focus on assessing the residual risk (after SVR is achieved)of life-threateningcomplicationssuchasliverfailure, portalhypertension,HCCandtheneedforlivertransplantation. Pharmaco-economicmodelsofthedirectandindirectcostsof mor-bidityduetochronic HCVinfectionversusthecost ofthenew treatmentswillbedeveloped.
2.4. Ethicalconsiderations
Themainprotocolofthestudyhasbeenapprovedbythe cen-tralethicscommitteeand theethicscommitteeof eachclinical centre.Clinicalcentresareinvolvedinthestudyona voluntary basis.Thestudystart-upwassupportedby“ResearchProjectPITER 2010”RF-2010-2315839,NationalInstituteofPublicHealthfunds forstart-upstudiesand byun-conditionedpartialsupportfrom Bristol-MyersSquibb,RocheandMerck(MSDItalia).Eachprivate financialsupporthasbeenevaluatedbytheEthicsCommitteeof theNationalInstituteofPublicHealthaccordingtostrictconflictof interestpolicies,toensureimpartialityandintegrity.Future pub-licand/orprivatefundswillberequiredforthecoordinationand conductionofthestudy.
2.5. Currentenrolmentstatus
ThefirstroundofenrolmentbeganinMay2014andlastedfor 6months.Enrolmentwillbere-openedregularlyforthree-month periodsduringthespringandfallofsubsequentyearsinorderto keepupwiththechangingoftheepidemiologicalsituationand withtheintroductionofnewDAAsandnewcombinationsinthe reallife.Todate,80%ofparticipatingclinicalcentreshavebegun enrolment,and theyhave alreadyenrolledapproximately6000 patients;theremainingcentresarepreparingforenrolment (Sup-plementaryFigureS2).ThePITERStudywillbethebackbonefor furtherspecificresearchstudiesandisexpectedtoprovidemuch neededguidancein evidence-basedhealth policyfor thebetter managementofchronicHCVinfectionandforprudentresource allocationinordertoguaranteeequityinaccesstotreatment.
Conflictofinterest
Nonedeclared.
AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.dld.2015.05.022
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