Interim impact evaluation of the hepatitis C virus elimination program in Georgia

JosephineWalker*1,AaronLim1,HannahFraser1,LiaGvinjilia6,LieslHagan2,TinatinKuchuloria6,NatashaKMartin9,MuazzamNasrullah2,ShaunShadaker2,MalvinaAladashvili11,AlexanderAsatiani5,DavitBaliashvili5,MaiaButsashvili12,IvdityChikovani4,IrmaKhonelidze5,IrmaKirtadze3,MarkKuniholm10,DavidOtiashvili3,KetevanStvilia5,TengizTsertsvadze11,MattHickman1,JulietteMorgan7,AmiranGamkrelidze5,ValeriKvaratskhelia8,FranciscoAverhoff2,PeterVickerman1

*Correspondenceto:J.G.Walker@bristol.ac.uk

1. PopulationHealthSciences,BristolMedicalSchool,UniversityofBristol

2. DivisionofViralHepatitis,NationalCenterforHIV/AIDS,ViralHepatitis,STDandTBPrevention,CDC

3. AddictionResearchCenterAlternativeGeorgia

4. CuratioInternationalFoundation

5. NationalCenterforDiseaseControlandPublicHealthofGeorgia,Tbilisi,Georgia

6. CDCFoundation,Tbilisi,Georgia

7. GlobalDiseaseDetection,DivisionofGlobalHealthProtection,SouthCaucasusCDCOffice,Tbilisi,Georgia

8. MinistryofLaborHealthandSocialAffairsofGeorgia,Tbilisi,Georgia

9. DivisionofGlobalPublicHealth,UCSanDiego,California,USA

10. DepartmentofEpidemiologyandBiostatistics,UniversityatAlbany,StateUniversityofNewYork

11. InfectiousDiseases,AIDSandClinicalImmunologyResearchCenter,Tbilisi,Georgia

12. Neolab,Tbilisi,Georgia

NOTE:THISISADRAFTTHATISUNDERGOINGCDCCLEARANCEANDWILLBEUPDATEDWHENAPPROVED

peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not. http://dx.doi.org/10.1101/270579doi: bioRxiv preprint first posted online Feb. 24, 2018;

Abstract BackgroundandAims:GeorgiahasoneofthehighesthepatitisCvirus(HCV)prevalenceratesintheworld,with>5%oftheadultpopulation(~150,000people)chronicallyinfected.InApril2015,theGeorgiangovernment,incollaborationwithCDCandotherpartners,launchedanationalprogramtoeliminateHCVthroughscalingupHCVtreatmentandpreventioninterventions,withtheaimofachievinga90%reductioninprevalenceby2020.WeevaluatetheinterimimpactoftheHCVtreatmentprogramasof31October2017,andassessthefeasibilityofachievingtheeliminationgoalby2020.

Method:WedevelopedadynamicHCVtransmissionmodeltocapturethecurrentandhistoricalepidemicdynamicsofHCVinGeorgia,includingthemaindriversoftransmission.Usingthe2015nationalsero-surveyandpriorsurveysconductedamongpeoplewhoinjectdrugs(PWID)from1997-2015,themodelwascalibratedtodataonHCVprevalencebyage,genderandPWIDstatus,andtheagedistributionofPWID.WeusethemodeltoprojecttheinterimimpactoftreatmentstrategiescurrentlybeingundertakenaspartoftheongoingGeorgiaHCVeliminationprogram,whileaccountingfortreatmentfailure/losstofollowup,inordertodeterminewhethertheyareontracktoachievingtheirHCVeliminationtargetby2020,orwhetherstrategiesneedtobemodifiedtoensuresuccess.

Results:Atreatmentrateof2,050patients/monthwasrequiredfromthebeginningofthenationalprogramtoachievea90%reductioninprevalencebytheendof2020,withequaltreatmentratesofPWIDandthegeneralpopulation.FromMay2015toOctober2017,40,420patientsweretreated,anaverageof~1,350permonth;althoughthetreatmentratehasrecentlydeclinedfromapeakof4,500/monthinSeptember2016to2100/monthinNovember-December2016,and1000/monthinAugust-October2017,withasustainedvirologicalresponserate(SVR)of98%per-protocolor78%intenttotreat.ThemodelprojectsthatthetreatmentsundertakenuptoOctober2017havereducedadultchronicprevalenceby26%(18-35%)to3.7%(2.9-5.1%),reducedtotalincidenceby25%(15-35%),andprevented1845(751-3969)newinfectionsand93(31-177)HCV-relateddeaths.Ifthetreatmentrateof1000patientsinitiatedpermonthcontinues,prevalencewillhavehalvedby2020,andreduceby90%by2026.Inordertoreacha90%reductionby2020,thetreatmentratemustincrease3.5-foldto4000/month.

Conclusion:TheGeorgiaHCVeliminationprogramhasaccomplishedanimpressivescaleupoftreatment,whichhasalreadyimpactedonprevalenceandincidence,andaverteddeathsduetoHCV.However,extensivescaleupisneededtoachievea90%reductioninprevalenceby2020.

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Introduction HepatitisCvirus(HCV)causeslong-termliverdamageandprogressiontoendstageliverdisease1,2,withdeathsduetoHCVbeinggreaterthanmalariain2015(~400,000)3.Anestimated71millionpeopleareinfectedworld-wide,with80%concentratedinlowandmiddleincomecountries(LMIC)4.HCVisahighlytransmissibleblood-borneinfectionprimarilytransmittedbyinjectingdruguseandunsafemedicalprocedures.Untilrecently,theonlytreatmentsavailableforHCVhadpoorefficacy,longduration(24-48weeks)andwerepoorlytolerated.However,newhighlyeffectiveall-oraldirect-actingantiviral(DAA)treatmentsarenowavailable,whichhavemadeHCVaneasilycurableinfection.

TheWorldHealthOrganization(WHO)adoptedthefirstglobalhealthsectorstrategyonviralhepatitis(SVH)in2016,whichrecognizedviralhepatitisasaninternationalpublichealthpriorityandproposedeliminatingitasamajorpublichealththreatby20303.Priortothis,therepublicofGeorgia,whichhasoneofthehighestprevalencesofHCVglobally(5.4%chronicinfectionprevalenceamongadultsin20155),launchedthefirstnationalHCVeliminationprogram6,aimingtoreduceHCVprevalenceby90%by2020.

Georgiahasapopulationof3.7millionpeople,withanestimated150thousandchronicinfectionsofHCVamongadults.RecentadvancesintreatmentforHCV,alongwiththecountry’ssmallpopulation,andpoliticalandpublicsupportledtothedevelopmentofaHCVeliminationprogrammeforGeorgia,supportedbyGilead6.Tohelpguidetheeliminationprogramme,anationalserosurveywasconductedin20157.TheserosurveyfoundheterogeneouslevelsofHCVinfectionbygenderandage.Thehighestlevelofchronicinfection(>15%)wasamongstmenaged30-49years,withmuchlowerprevalenceratesinfemales(adultprevalence2.2%).ThisheightenedHCVtransmissionamongstmenisthoughttohaveoccurredduringtheperiodofunrestaroundthecollapseoftheSovietUnionin1991,whentwocivilwarsandgeneraleconomiccollapse8resultedinhighratesofdrugtraffickingandinjectiondruguse(IDU)inGeorgia9.Sincethen,druguseisthoughttohavediminished,althoughrecentestimates(2007-2016)stillsuggestabout2%ofadultsarepeoplewhoinjectdrugs(PWID,40-52,500)10–12,whichishighcomparedtoaglobalaverageof0.33%???.Transmissionisalsothoughttohavebeendrivenbyiatrogenictransmission,withtheoverallqualityofmedicalcareandbloodtransfusionsafetyremaininglowuntilatleast200913.TheagedistributionandpresumedhistoricalpatternsoftransmissionsuggestthattheHCVepidemicisindecline,butthatacohortofadultsinfected20-30yearsagoarelikelytobeprogressingtowardsadvancedliverdiseasesoneedingurgenttreatment.

WedevelopedadynamicHCVtransmissionmodeltocapturetheevolvingepidemicofHCVinGeorgia,incorporatingthemaindriversoftransmission.WeusethemodeltoestimatetheinterimimpactoftheGeorgianHCVeliminationprogram,andthendeterminewhethertheyareontracktoachievingtheirHCVeliminationtargetsby2020orwhetherstrategiesneedtobemodifiedtoensuresuccess.

peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not. http://dx.doi.org/10.1101/270579doi: bioRxiv preprint first posted online Feb. 24, 2018;

Methods

Model description and initialisation

WedevelopedamodelofHCVtransmissionincorporatingthechangingdemographicsofPWIDandthegeneralpopulationinGeorgia(Figure1).TheframeworkofthemodelusedisbasedonatraditionalSI(susceptible-infected)model,becausethemajorityofHCVexposuresleadtolife-longchronicinfection14.Curativetreatmentisincorporated(representedbyacompartmentT),whichifsuccessfulleadstoindividualsbecomingsusceptibleagain.Themodelalsoincludesgender,nineageclasses(Figure1C),anddividesallindividualsintonon-PWID,activePWID,andex-PWID.

Individualsenterthemodelintheyoungestagegroupassusceptiblenon-PWID,equallydividedbetweenmalesandfemales.Individualsthentransitionthroughtheagecategories,withaproportiontransitioningtoIDUfromallagecategoriesuptoage39,atageandgender-specificrecruitmentrates.PWIDexperiencedrug-relatedmortality,andcessatefrominjectingatage-specificratestobecomeex-PWID,whodieatthesameage-specificratesasnon-PWID.

SusceptibleindividualsbecomeinfectedataratethatisproportionaltoHCVprevalence,witharateoftransmissionthatappliestothewholepopulation,andanadditionalrateoftransmissionamongstcurrentPWID.BoththesetransmissionrisksareallowedtovaryovertimetoaccountforchangesininterventioncoverageinGeorgia.Themodelalsoallowedforthepossibilityofassortative‘like-with-like’mixingwhenyoung(<30years)andolder(>30years)PWIDformtransmissioncontacts,varyingbetweenrandommixingacrosstheseagegroupstopreferentialmixingonlybetweenPWIDofthesameagegroup.

Uponinfection,someindividualsspontaneouslycleartheirinfection,withtheremainderdevelopingchronicinfectionandgraduallyprogressingthroughdifferentstagesofliverdisease(Figure1B).Individualswithdecompensatedcirrhosis(DC)orhepatocellularcarcinoma(HCC)experienceheightenedmortality.Treatmentoccursatatime-varyingrate,withsuccessfullycuredindividualsreturningtothesusceptiblestatewiththeircorrespondinglevelofliverdisease,whilethosefailingtreatmentreturntotheinfectedstate.Aftersuccessfultreatment,liverdiseaseprogressionhaltsforindividualscuredwithmildormoderateliverdisease,whileitcontinuesataslowerrateforthosewithcompensatedcirrhosisormoreprogresseddisease.IndividualswithdecompensatedcirrhosisorHCCarenoteligiblefortreatment.

Themodelwasinitializedin1900withapopulationsizeof4million,allsusceptible,non-PWID,andwithnoliverdisease,distributedequallyacrossgenderandagecompartments.Injectingdruguseisassumedtostartin1960.TogeneratearapidincreaseininfectionamongstPWID,HCVisseededinthispopulationwitha10%annualrateofinfectionforsusceptiblePWID<30yearsoldinthefirstfiveyearsafter1960.

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Model parameterization and calibration

Calibration and validation data

Themodelwascalibratedto,andcomparedagainstavailabledataontheprevalenceofHCVfromthe2015NationalSerosurveyandsevenIntegratedBiologicalandBehavioralSurveillance(IBBS)surveysofPWIDfrom1997-2015(Table3).Sero-prevalenceestimatesfromIBBSsurveyswereconvertedtochronicprevalencebasedontheratioofchronictoantibodyprevalenceintheNationalSerosurvey(72%).TheNationalSerosurveyprovidedgender-specificHCVprevalencesinthegeneralpopulation,groupedintothreeagecategories(18-29,30-49,and50+),whiletheIBBSprovidedyearspecificHCVprevalenceestimatesforallPWID,youngPWID(18-24)andolderPWID(25+).TheHCVprevalenceestimatesusedtocalibratethemodelaregiveninTable3,withspecificprevalenceratiosbeingusedtocalibratethemodeltoensureitcapturesincreasesinHCVprevalenceamongstallPWID(16%relativeincreaseover2006-2015),andthelargevariationsinHCVprevalencebyageamongstmales.DatafromtheotherIBBSsurveys(2001,2007-2012)wereusedformodelvalidation.InadditiontoHCVprevalencedata,themodelwasalsocalibratedtotheoverallpopulationsizeinGeorgiain2015(estimatedfrom2014nationalcensus15),theestimatednumberofPWIDin2014(estimatedasaconsensusofalternativesizeestimates11),andtheproportionofPWIDthatare18-29and30-49inthe1998and2015IBBS(Table3).ThislastdatawasincludedtoensurethemodelcapturesthedecreaseinrecruitmentofnewPWIDbetweenthesedates.

Tocomparewithourmodelpredictions,wealsoestimatedtheobservedincidenceinPWIDbetween1997-2001basedonpreviouslyunpublisheddatafromacohortofPWIDinGeorgia(seesupplementarymaterials).

Model Parameterisation

ThemodelwasparameterisedusingdatafromthePWIDIBBSsurveys,theNationalSerosurvey,thetreatmentdatabasefortheGeorgianeliminationprogram,publishedliteratureandWHOdatabases.Allmodelparameters,uncertaintydistributionsandtheirdatasourcesaregiveninTable1andTable2.

DiseaseprogressionandHCV-relateddeathrateswereobtainedfromtheliterature16–18.DataonHCVtreatmentrates(seenextsection)werenotusedinthemodelfittingbecauseitbeganafterthelastprevalencedatausedinthemodelfitting(mid-2015).

Gender-andage-specificmortalityrateswereobtainedfrom2015lifetablesforGeorgia19,withPWIDhavinganelevatedmortalityratiobasedonPWIDmortalitydatafromEasternEurope20.Themodeldoesnotaccountforimmigration/emigrationorchangesinpopulationsize.

ThenumberofPWIDinGeorgiaisunderstoodtohaveincreaseddramaticallyalongsidethefalloftheUSSRandresultingsocial,political,andeconomiccrises9,21.Officialrecordsofdrugusers(diagnosedasdrugdependentbypolice)increasedeighttimesbetween1990and2004,from2,700to21,000,butunfortunatelyunbiasedestimatesofthenumberofPWIDoverthistimeperiodarenotavailable21.Recentestimatesfrom2007-2014suggesta

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stablePWIDpopulationinGeorgiaofabout50,00011,whileIBBSdatafrom1998-2015suggestanagingPWIDpopulation,likelyduetoreducedinitiationofinjecting(SupplementaryFigure3).ToaccountforthelikelychangingdynamicsofIDUinGeorgia,weassumedatransientpeakintheinitiationofIDU,allowingconsiderableuncertaintyinwhenthisoccurredanditsmagnitude(Table1).UncertaintyalsoexistsaroundthedurationthatPWIDinjectfor,whichwasgivenwideuncertaintyboundsandallowedtovaryacrossagegroups.ThewidepriorrangesfortheserecruitmentandcessationparameterswereconstrainedthroughfittingthemodeltoIBBSdataontheproportionofPWID18-29and30-49in1998and2015,theestimatedpopulationsizeofPWIDin2014,andtheproportionofPWIDthatarefemale(fromNationalSerosurvey).

Harmreduction(HR)interventionsintheformofneedleandsyringeprovisionprograms(NSP)waswerefirstintroducedinGeorgiain1999,andopioidsubstitutiontherapy(OST)wasintroducedin200522.Sincethen,bothinterventionshavescaledup,with4.5millionsyringekitsand30,330PWIDreachedbyNSPin2016(GeorgiaHarmReductionNetwork,unpublisheddata)and4450PWIDonOSTin201523,24.TheimpactofOSTisincludedinthemodelbyreducingtheriskofHCVacquisition(basedonarecentCochranereview25)fortheproportionofPWIDonOSTovertime23,24.However,becauseuncertaintyexistsintheimpactofNSPinGeorgia,weallowedNSPtohavegreaterimpactonpopulation-levelHCVtransmission.ThiswasdonetocapturethehalvinginHCVprevalenceamongstyoungPWID(<30years)inIBBSsurveysbetween1997and2006,whichsuggeststhatHCVincidenceinPWID,particularlyinyoung/newPWID,mayhavedeclinedoverthisperiod(SupplementaryFigure4).WealsoundertookasensitivityanalysiswheretheimpactofNSPisuseddirectlyfromtheCochranereview25.

InadditiontointerventioneffectsonHCVtransmissionamongstPWID,theriskofHCVtransmissioninthegeneralpopulationwasallowedtoreducedatapointintimetoaccountforotherpreventionmeasures,suchastheintroductionofdonorbloodscreening.

Model Calibration

WeusedamodifiedMarkovChainMonteCarloApproximateBayesianComputation(MCMC-ABC)approachtocalibratethemodel26,27inRversion3.3.228(seesupplementarymaterial).Themethodobtainsaprobabilitydistributionofparametervalues(theposterior)thatconstraintheinitialpriorrangesformodelparameters,producingmodelfitsthatincorporatetheuncertaintyinthemodelparametersandthecalibrationdata.Allparametersaresimultaneouslyindependentlysampledfromtheirprioruncertaintyranges,withtheparametersamplingdistributionsbeingadjustediterativelybasedonhowwelleachsampledrunagreeswiththecalibrationdata.Importantly,thisincludeshighlyuncertainparameters,suchastransmissionrates,whichwillbenarroweddownbasedonfittingthemodeltodata.

TheparametersetsidentifiedthroughMCMC-ABCwerefurtherfilteredtoonlyretainthosethatagreed(layin95%confidenceintervals)withtheoverallHCVprevalence(4.51-6.32%)andtotalfemaleHCVprevalence(1.55-2.86%)fromthe2015NationalSerosurvey,andtheHCVprevalenceamongstPWIDfromthe2015IBBS(45.5-56.1%)29.Thesefilteredmodelrunsweredenotedasthebaselinemodelfits.

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Intervention analyses

Thebaselinemodelfitswerefirstlyusedtoestimatetheinterimimpactoftheexistingscale-upintreatmentfromMay2015toOctober2017inGeorgia.Thisutiliseddatafromthetreatmentprogramonthenumberofinfectedindividualsinitiatingtreatment,includingtreatmentstargetedtopatientswithcirrhosisbeforeJune2016(Table4).BeforeMarch2016,sofosbuvirwithribavirinwasused,achievingper-protocolSVR(sustainedviralresponse)of80.4%,whileafterthis,ledipasvirwithsofosbuvir(Harvoni,Gilead)wasused,resultinginanSVRof98.5%(GeorgiaMinistryofLabor,Health,andSocialAffairs[MoLHSA],unpublisheddata).WecalculatedITTSVRratesforpre-cirrhoticandcirrhoticpatients,andanintermediatecureratetakingintoaccountpatientswhowereknowntohavecompletedtreatmentbutdidnotreturnforSVRtesting12weeksafterfinishingtreatment(seesupplementarymaterialsandTable4).

Duetodatalimitations,therewasuncertaintyoverthenumberofPWIDthatweretreated.Inthebasecase,weassumedPWIDweretreatedatthesamerateastherestofthepopulation,andcomparedtheseresultstoscenarioswherePWIDreceivednegligibletreatment,orweretreatedatdoubletherateoftherestofthepopulation.

ImpactwasestimatedintermsoftherelativedecreaseinincidenceandprevalencefromMay2015toOctober2017,aswellasthenumberofdeathsandinfectionsavertedoverthisperiod,comparedtoifnotreatmenthadoccurred.Thenumberofinfectionsanddeathsavertedwerealsoestimateduptotheendof2030,assumingtreatmentstoppedafterOctober2017.

Followingthis,weevaluatedtheimpactofalternativeinterventionstrategiesgoingforward(fromNovember2017),toassesswhatisrequiredtoensuretheeliminationprogramreduceschronicprevalenceby90%by2020,comparedtoprevalencelevelsinMay2015.Weconsidereddifferenttreatmenttargetingscenarios,withtreatmentseitherdistributedequallyacrossriskgroupsanddiseasestagesoralternativelytargetedtoPWID(attwicetherateofothergroups)ornot(PWIDnotbeingtreated),ortocirrhotics(80%ofinfectedindividualswithcirrhosis(F4)treatedannually).Foreachscenario,weconsideredtheimpactupto2020ofeithermaintainingthecurrenttreatmentrateachievedbetweenAugust-October2017(1000permonth),orscalinguptoachievetheGeorgiangovernment’sestimateofthenumberoftreatmentsnecessary(128,250)todiagnose90%ofcasesandtreat95%oftheseinfections(90-95target).Foreachtreatmenttargetingscenario,welastlyestimatedthetreatmentraterequiredfromNovember2017toachievetheGeorgianeliminationtargetofreducingprevalenceby90%byDecember2020(comparedtoJanuary2015levels).Wealsoestimatedwhatthiswouldachieveintermsofdecreasingincidence,andnumberofinfectionsanddeathsavertedby2020.

Sensitivity analysis

Weundertookasensitivityanalysistodeterminehowtherequiredtreatmentrateforachievinga90%decreaseinprevalenceby2020wouldchangeif:harmreductioninterventionswerealsoscaledupoverthisperiodto75%coverageforOSTandNSP;thetreatmentprogramachievedthehigherperprotocolSVRratesamongstallpatients;orif

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existingharmreductioninterventionshadalowerimpactasestimatedbyaCochranereview25(seemodelparameterizationsection).

Results

Baseline epidemic projections without treatment

Aftermodelcalibration,554parametersetswereretainedwhichfittheobservedPWIDdemographicsandHCVprevalenceforGeorgia(Figure2,Figure3,SupplementaryFigure2).PriorandposteriorparameterdistributionsarepresentedinSupplementaryFigure1.

ThebaselinemodelfitssuggestthatHCVprevalenceinPWIDisdecliningovertime(Figure5,middlepanel)andHCVincidenceinPWID(Figure6,middlepanel)isdecreasingorstayingstable(percentdecrease10%(-110-99%from2010to2015).ThepopulationofactivePWIDisalsodecliningfromapeakof128815(50583-325756)in2002,withacurrentpopulationsizeof64420(17598-152152).ThemodelisconsistentwithrecentestimatesoftheadultPWIDpopulation,butthemodelledestimatesforthepopulationofformerPWIDismorethandoubletheestimatefromthe2015nationalsurvey,inwhich4.2%(3.5-5.2%)ofadultsreportahistoryofinjectingdruguse,indicatingapopulationof116,760formerPWID(Figure4).However,thisriskfactorislikelytobeunderreported.

ThealternativemodelcalibrationestimatesamuchgreaterdeclineinHCVincidenceamongstPWID,whilethepopulationsizeofPWIDshowslessfluctuationthaninthemaincalibrationscenario(seesupplementarymaterialforresultsusingthismodelcalibration).

WiththesizeofthePWIDpopulationandHCVdecreasing,themodelalsoprojectsthattheHCVpopulationattributablefractionforinjectingdruguse(PAF)hasdecreaseddramatically,withPWIDbeingthemaindriversoftheHCVepidemicinthepast,butnotnow.TheHCVproportionattributablefraction(PAF)hasdeclinedfrom71%(38-92%)overtheperiod1985-2000to37%(13-65%)over2000-2015andisprojectedtobe15%(0-46%)over2015-2030.

Intheabsenceofanytreatmentintervention,themodelpredictsthatoverallincidenceandprevalencewilldeclinefrom2015to2030(Figure5,bottompanelandFigure6,bottompanel).Incidencewilldeclineinthegeneralpopulationfrom0.2(0.07-0.39)infectionsper100person-yearsin2015to0.13(0.04-0.27)in2030.InPWID,incidencechangesfrom2.69(0.07-10.04)to1.99(0-8.63)overthesametimeperiod.HCVrelatedmortalitywouldincreasefrom607(165-1159)in2015to711(265-1251)in2030.Annualnewinfectionswoulddecreasefrom7009(2324-13214)in2015to4620(1439-10358)in2030.Totalprevalence(allagegroups)woulddeclinefrom4.2(3.51-4.92)in2015to2.91(1.94-4.43)in2030.

FromthebeginningoftheprograminMay2015,atreatmentrateofatleast2050/monthwouldhavebeenrequiredtoreacha90%reductioninprevalencebytheendof2020.Inthistimeperiod,40,420patientsweretreated,anaverageof~1,350permonth.Thetreatmentratedeclinedfromapeakof4,500/monthinSeptember2016to2100/monthinNovember-December2016,and1000/monthinAugust-October2017.

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Interim impact assessment

The40,420treatmentsgivenarepredictedtoavert2654(1134-4419)deathsduetoHCVand16035(5592-37026)newHCVinfectionsby2030.AsofNovember2017,thetreatmentprogramhasaverted98(31-167)deathsduetoHCVand1517(596-3585)newHCVinfections.

Basedonthistreatmentrate,theHCVadultprevalenceisestimatedtobe3.91%(2.87-4.85%)inNovember2017,adecreaseof28%(18-37%)sincetheintroductionoftheprogramin2015.Similarly,HCVincidencehasdeclinedby27%(16-37%)from0.19(0.07-0.39)per100person-yearsin2015to0.14(0.05-0.27)inNovember2017.

TheaboveestimatesassumethatPWIDhavebeenreachedfortreatmentatthesamerateasthegeneralpopulation.IfnoPWIDhavebeenreachedfortreatment,theoverallHCVadultprevalenceandHCVincidencehavesimilarlydecreasedby28%(18-37%)and27%(17-36%).However,whileifPWIDareequallytreatedtheprevalenceinPWIDwillreduceby25%(1-39%)inthistimeperiodandincidenceassociatedwithinjectingdrugusewillreduceby24%(-10-38%),ifPWIDarenottreated,prevalenceinPWIDwillhaveapercentreductionof3%(-23-17%).Incidenceduetoinjectingdrugusewillreduceby4%(-24-20%).Asofnow,theprevalenceinPWIDwouldbe49%(39-67%)andincidenceduetoinjectingdrugusewouldbe2.28(0.02-12.43).

Ongoing impact assessment

Atthecurrenttreatmentrateof1000patients/month,a53%(34-69%)reductioninadultprevalenceand52%(32-69%)reductioninincidencewillbereachedby2020,anda90%reductionreachedduringtheyear2025(Figure8,Figure10).

Scalinguptoreachthe90-95targetwillachievea81%(58-92%)reductioninadultprevalenceand80%(52-92%)reductioninincidenceby2020,anda90%reductionreachedin2021.

Reachinga90%reductioninprevalenceandincidenceby2020willrequirescaleupto3500treatments/monthwiththeintermediateSVRestimate.Theupperbound(basedonintenttotreatSVR)requiresatreatmentrateof4000/month,whilethelowerbound(perprotocolSVR)achievesa90%reductionby2020with2500treatments/month(Figure10).

Scalingupharmreductionincreasesthereductioninincidence,whiletargetingPWIDatdoubletherateoftherestofthepopulationincreasesthelowerboundoftheprevalencereductionthatwillbeachievedby2020(Figure7).

AlthoughHCVmortalitydeclinesrapidlywiththeinterventionitwillnotachievea65%reductionby2020.Targetingpatientswithcirrhosisbytreating80%ofcirrhoticpatientseachyouincreasesthereductioninmortalitybutitstilldoesnotachievethegoalby2020(Figure7,bottompanel).Inthefirstphaseoftheprogram,patientswithadvancedliverdiseaseweretargeted,whichimprovedtheachievedmortalityreductioncomparedtoequalratesoftreatment(Figure8)

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Discussion GeorgiahasimplementedanambitioustreatmentprogramwhichaimstoreducetheprevalenceofHCVby90%by2020,andtobethefirstcountrytoachievetheHCVeliminationgoalssetoutintheWHOSVH.ByexploringpathwaystoeliminationinGeorgiaoverthenextfewyears,therearemanylessonstobelearnedforHCVeliminationglobally.

NotallHCVepidemicsarecreatedequal.WhileinmanywesterncountriesHCVincidenceisdominatedbytransmissionthroughinjectingdruguse[sources–Australiaetc].IntheUnitedStatesanopioidepidemicisgrowingandleadingtoagrowingnumberofHCVcasesinyoungpeople.InPakistan,agrowingpopulationandincreasingHCVprevalencewillrequireanenormousscaleupintreatmenttoreducetheburdenofHCV30.Incontrast,evidencesuggeststhattheoverallHCVepidemicaswellasthecontributionofPWIDtoHCVinGeorgiaisdeclining.ThelatestageoftheepidemicinGeorgiameansthatreducingtheprevalenceandincidenceofHCVispotentiallyeasierthaninothersettings.However,becausemanypeoplehavebeenlivingwithHCVfor20yearsormoreandhavealreadysufferedextensiveliverdamage,nomatterhowquicklytreatmentisscaledup,itwillbeimpossibletoavertordelaydeathtoHCVformanyanda65%reductioninmortalityisunlikelytobeachievedby2020.Treatmentratesmustbeincreased,likelytripledorquadrupled,inordertoreacha90%reductioninprevalenceandincidenceby2020.

Oneoftheprimarylimitationsoftheresultspresentedhereisthatthemodeldoesnotaccountforcase-finding,orotherbarrierstomaintainingaconstantandhighrateofHCVtreatmentasprevalencedeclines.Intheearlystagesoftheprogram,manyHCVcaseshadalreadybeenidentifiedandpatientswhowereinterestedintreatmentcameforward.Infectedpatientsmaybecomehardertofindaspatientsremainingarethosethataretheleastlikelytobelinkedtocare.Goingforward,itwillbenecessarytoscreenalargenumberofindividualstoidentifypatientswhoareinfectedwithHCVbutdonotknow.Furthermore,theendgameofeliminationwillresultinanincreasedpoolofsusceptible(cured)individualswhoareabletobere-infected31ifconcurrenteffortsarenotmadealongsidetreatmenttoreducetransmissionthroughpreventivemeasures.Allofthesefactorswillcontributetoareductionintheratiobetweenthenumberofindividualscuredandtheresourcesexpended.

Case-findingandlinkagetocaremaybeparticularlydifficultinPWIDandformerPWID,andalthoughthePWIDcontributiontotheHCVepidemichasdeclinedovertime,reachingactivePWIDforHCVtreatmentisessentialtoreduceprevalenceandincidencetothetargetby2020orshortlyafterwards.WhiletheeliminationprogramhasincludedadramaticincreaseinPWIDaccesstoHCVtestingandtreatmentoverthepastfewyears,andaprograminTbilisihasdemonstratedthefeasibilityofreachinghighratesofHCVtreatmentsuccessamongPWID32,barrierstoHCVtreatmentaccessforPWIDincludecontinuedstigmatizationandcriminalizationofdruguse.ThisalsoledtohighuncertaintyinthenumberofPWIDwhohavealreadybeenreachedbytheprogram.TheGeorgiaeliminationprogrammustcontinuetomakeeveryefforttoreachPWIDinordertoachieveHCVelimination.

peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not. http://dx.doi.org/10.1101/270579doi: bioRxiv preprint first posted online Feb. 24, 2018;

Thereareseverallimitationstothismodel,includingthenecessityoffittingtolimitedanduncertaindata.Toaccountforthis,wehavepresentedtwomodelstructureswhichalthoughtheydifferinthewaythatincidence,particularlyinPWID,haschangedovertime,bothresultinsimilarconclusionsregardingtheimpactoftreatment.Additionalwaysofstructuringthemodelcouldbedevelopedasmoreinformationcomestolightonhistoricalpatternsofrisk,andongoingmonitoringduringeliminationmayhelptorevealthetruetrajectoryofHCVincidence.OtherstudiescouldbedonetoestimateuncertainparameterssuchasthedegreeofassortativemixinginPWID,theeffectivenessofharmreductionmeasuresinGeorgiainparticular,orspatialheterogeneityintransmission,forexample.

TheGovernmentofGeorgiaandpartnershavemadeanadmirablecommitmenttoeliminateHCVfromthecountry,andtheprogramtheyhaveestablishedincludesongoingmonitoringandevaluation.ThedatathattheycollectwillhelptosteertheeliminationprogramandlessonslearnedthroughoutwilllikelybetransferrabletoothercountriesscalingupinterventionsforHCV.

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Figures

Figure1:Flowchartsofstate-transitionsinthemodel.A,infectioncompartments,B,liverdiseasestatecompartments,C,PWIDandagecompartments.Redlettersindicatewhichdimensionstheparametersvarywith,withtrepresentingtime,vrepresentinginfectionstate,wrepresentingagegroup,xrepresentingliverdiseasestate,yrepresentingPWIDstate,andzrepresentingsex.Sexcompartmentsarenotshown.

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Figure2:ModelfitstoPWIDagedistributionsin1997(A)and2015(B),andtoPWIDpopulationsize(C)andgeneralpopulationsizeinGeorgia(D)

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Figure3:FitstopercentchronicHCVinfectionbyageanddemographicgroupin2015,totalistotaladultpopulation(≥ 18).Total,male,andfemaleobserveddatafromnationalserosurvey,PWIDobserveddatafrom29.Nosurveydataareavailableforprevalenceinindividuals<18yearsold.

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Figure4:Projectedpopulationsizeofcurrent,former,andever(current+former)PWID(adultsonly)overtime.Circlesandcrossesshowavailabledata,withcrossesindicatingdatapointsusedforfitting.

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Figure5:HCVprevalenceovertime,inPWID,generalpopulationandtotal.TotalandPWIDprevalenceareforadultonlytomatchavailabledatapoints,generalpopulationisforallages.Circlesandcrossesshowavailabledata,withcrossesindicatingdatapointsusedforfitting.

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Figure6:HCVincidenceovertime,inPWID,generalpopulationandtotal.Circlesshowavailableincidenceestimates,thesevalueswerenotusedformodelfitting.

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Figure7:Percentreductioninincidence,adultprevalence,andmortalityovertimeforselectedscenarios.Dashedlineshowseliminationtargetof90%reductionforincidenceandprevalenceand65%reductionformortality

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Figure8:InterimimpactandprojectedchangesinHCVwiththetreatmentprogram.(A)CumulativeHCVtreatmentsovertime,(B)AdultHCVprevalenceovertime,(C)HCVmortalityrateovertime,(D)TotalHCVincidenceovertime.Therighthandaxisshowsthe%reductionforB,C,D,withhorizontaldashedlineshowingtheeliminationtarget.Thegreyboxshowsindicatesprojectionsintothefuture.Theredlineshowsnotreatment,withuncertaintybounds,thebluelineshowstheconstanttreatmentratethatwouldhavebeenrequiredfromprograminitiationtoreachtheprevalencetargetby2020,andtheblack,purple,andorangelinesshowexistingratesoftreatmenttoOctober2017andprojectedratesof1000/month,2311/month(toreachthe90-95target),and3,000/month

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Figure10:Yearinwhich90%prevalencereductionwillbereachedforlevelsoftreatmentscaleupfromNovember2017,withalternativeSVRrates:perprotocol,intenttotreat,andintermediate.

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Tables Table1:Parametersvariedinmodelfittingprocess

Parameter Description Unit EstimatePriorrange Source

B Populationrecruitment

annualbirths

57000 51000-62000

averageof1995-2020birthnumbers33

𝜏% Yearinjecting&HCVstart

Year 1960 - FirstyearreportedinjectinginallavailableIBBS

𝜏& YearInjectingscalesup

Year 1991 1980-1995

BreakdownofUSSR;9,21

𝛥 Lengthofheightenedperiod

timeinyears

- 1–30 Nodata-calibratedthroughfitting

𝜓 Baselineinitiationratetoinjecting

annualrate - 0.0001-0.1

Nodata-calibratedthroughfitting

𝜓) Relativeinjectingrecruitmentrateforfemales

ratio 0.02 0-0.045

ProportionoffemalePWIDinIBBSandproportionfemaleofthosereportingeverinjectinginserosurvey

𝛿% Factorincreaseininjectingrecruitmentduringpeak

ratioofpre-peakvalue

- 2–10 -

𝛿& Factordecreaseininjectingrecruitmentafterpeak

ratioofpeakvalue

- 2–20 -

𝜙% Durationofinjectingforage15-29PWID

timeinyears

- 5–50 -

𝜙& Durationofinjectingforage30-49PWID

timeinyears

- 5–50 -

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𝜙, Durationofinjectingforage50+PWID

timeinyears

- 5–50 -

𝜈 StandardizedmortalityratioforPWID

ratio 9.25 7.22-11.28

20

𝜌/ EffectivenessofOST ratio 0.5 0.4-0.63

25globalestimate

𝜌0 EffectivenessofNSP[lowinterventioneffectmodel]

ratio 0.24 0.09-0.62

25Europeestimate

𝜌&11& ReductioninPWIDHCVtransmission2002[highinterventioneffectmodel]

ratio - 0-1

𝜌&1%& ReductioninPWIDHCVtransmission2012[highinterventioneffectmodel]

ratio - 0-1

𝛽 Generalpopulationtransmission

annualeffectivecontactrate

- 0.001-0.2

-

𝜖 Reductionin𝛽 ratio - 0.01-0.5

-

𝜏, Year𝛽changes Year 1997 1994-2000

Bloodsafetyprogramintroducedin1997

𝜃1 PWIDtransmission annualeffectivecontactrate

- 0.001-0.5

-

𝛾% Progressionmildtomoderatefibrosis

annualtransitionprobability

0.025 0.018-0.033

16(took95%rangeofbetadistributioninthemodeltheyuse)

𝛾& Progressionmoderatefibrosistocompensatedcirrhosis

annualtransitionprobability

0.037 0.025-0.052

16

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𝜒% Progressioncompensatedcirrhosistodecompensatedcirrhosis

annualtransitionprobability

0.039 0.022-0.0461

16

𝜒78% HazardratioofprogressiontoDCafterSVR

ratio 0.07 0.03-0.20

17

𝜒& ProgressioncompensatedcirrhosisordecompensatedcirrhosistoHCC

annualtransitionprobability

0.014 0.0016-0.039

16

𝜒78& HazardratioofprogressiontoHCCafterSVR

ratio 0.23 0.16-0.35

18

𝜁% Progressiondecompensatedcirrhosistodeath

annualtransitionprobability

0.13 0.11-0.15

16

𝜁& ProgressionHCCtodeath

annualtransitionprobability

0.43 0.37-0.49

16

M Assortativemixingbetween<30vs30+PWID

ratio - 0-1 -

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Table2:Age-varyingparameters.Agingrate𝛼inverseofdurationofcategory.MortalityratesfromWHO.RelativePWIDrecruitmentfromagedistributionofPWID(seeSupplementaryFigure2).

Agegroup 𝛼 𝜇)<=>?< 𝜇=>?< PWIDrecruitment<15 0.067 0.0005 0.0005 0.02𝜓15-17 0.333 0.0005 0.0010 0.24𝜓18-24 0.143 0.0005 0.0010 0.62𝜓25-29 0.2 0.0005 0.0010 0.09𝜓30-34 0.2 0.0010 0.0020 0.02𝜓35-39 0.2 0.0010 0.0020 0.01𝜓40-44 0.2 0.0010 0.0040 045-49 0.2 0.0020 0.0070 050+ NA 0.0400 0.0700 0

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Table3:Summarystatisticsusedtofitmodel.∗RatioofHCVprevalenceinyoungPWIDonlyusedinhighinterventioneffectmodel.AntibodyprevalencefromPWIDserosurveysconvertedtochronicprevalenceat72%basedonchronicprevalenceamongantibodypositivein2015generalpopulationserosurvey.

Statistic Year Targetvalue SourcePopulationsize 2015 3.72million GovtofGeorgia

PopulationofPWID 2014 49.7thousand

11

ProportionPWIDage30-49 1998 0.368 34ProportionPWIDage18-29 1998 0.632 34ProportionPWIDage30-49 2015 0.603 29ProportionPWIDage18-29 2015 0.194 29

FemalePWID 2015 2.00% 29PWIDHCVprevalence 2015 51% 29

PWIDHCVprevalenceage18-24 2015 15.50% 29PWIDHCVprevalenceage25+ 2015 53.70% 29

PWIDHCVprevalence2006/PWIDHCVprevalence2015

NA 0.86 29,35

OverallHCVprevalenceage≥18 2015 5.40% Serosurvey2015

HCVprevalenceage18-29 2015 1.40% Serosurvey2015

HCVprevalenceage30-49 2015 8.80% Serosurvey2015

OverallHCVprevalenceage50+ 2015 4.20% Serosurvey2015

FemaleHCVprevalenceage≥18 2015 2.20% Serosurvey2015

FemaleHCVprevalenceage18-29 2015 0.80% Serosurvey2015

FemaleHCVprevalenceage30-49 2015 2.10% Serosurvey2015

FemaleHCVprevalenceage50+ 2015 2.80% Serosurvey2015

OverallMaleHCVprevalenceage≥18 2015 9.00% Serosurvey2015

MaleHCVprevalenceage18-29 2015 1.90% Serosurvey2015

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MaleHCVprevalenceage30-49 2015 15.70% Serosurvey2015

MaleHCVprevalenceage50+ 2015 6.00% Serosurvey2015

RatiomaleHCVprevalenceage30-49toage50+ 2015 2.6 Serosurvey2015

RatioHCVprevalenceinPWID<302015/1997*

NA 0.5 29,34

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Table4:Treatmentsbymonthfromdata,byliverdiseasestate.Perprotocol,intenttotreat,andintermediateSVRratesforMay2015-February2016,andMarch2016toOctober2017arealsoshown.

Month None/mild Moderate Cirrhosis TotalMay-15 1 57 241 298Jun-15 1 119 441 562Jul-15 9 318 673 1000Aug-15 1 416 709 1126Sep-15 1 138 148 287Oct-15 6 529 601 1136Nov-15 11 322 305 638Dec-15 20 479 392 891Jan-16 0 6 8 15Feb-16 18 350 261 629Per-protocolSVR 89.20% NA 75.80% 80.40%IntenttotreatSVR 62.60% NA 51.60% 55.30%IntermediateSVR 80.20% NA 73.00% 75.50%Mar-16 8 274 235 518Apr-16 25 753 568 1346May-16 22 463 327 811Jun-16 16 753 393 1163Jul-16 468 593 204 1264Aug-16 1806 1276 215 3297Sep-16 2483 1793 318 4594Oct-16 1989 1444 258 3691Nov-16 1105 904 179 2188Dec-16 1074 854 213 2141Jan-17 950 823 196 1969Feb-17 682 636 143 1461Mar-17 615 603 166 1384Apr-17 601 534 129 1264May-17 624 570 161 1354Jun-17 531 503 129 1163Jul-17 558 482 121 1161Aug-17 475 412 117 1004Sep-17 487 440 114 1041

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Oct-17 488 407 129 1024Per-protocolSVR 98.70% NA 96.70% 98.50%IntenttotreatSVR 80.40% NA 64.40% 77.70%IntermediateSVR 90.70% NA 85.60% 89.90%

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