Hepatitis C disease burden and strategies for elimination by 2030 in Brazil. A mathematical modeling approach

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Hepatitis

C

disease

burden

and

strategies

for

elimination

by

2030

in

Brazil.

A

mathematical

modeling

approach

Adele

Schwartz

Benzaken

_,

_Renato

_Girade

_,

_Elisa

_Catapan

_,

Gerson

Fernando

Mendes

Pereira

_,

_Elton

_Carlos

_de

_Almeida

_,

_Simone

_Vivaldini

_,

Neide

Fernandes

_,

_Homie

_Razavi

_,

_Jonathan

_Schmelzer

_,

_Maria

_Lucia

_Ferraz

_,

Paulo

Roberto

Abrão

Ferreira

_,

_Mario

_Guimarães

_Pessoa

_,

_Ana

_Martinelli

_,

Francisco

José

Dutra

Souto

_,

_Nick

_Walsh

_,

_Maria

_Cassia

_{Mendes-Correa}

a_{MinistryofHealth,PreventionandControlofSTI,HIV/AIDSandViralHepatitis,DepartmentofSurveillance,Brasília,DF,Brazil}

b_{CenterforDiseaseAnalysisFoundation,PolarisObservatory,Lafayette,CO,USA}

c_{FederalUniversityofSãoPaulo,GastroenterologyDivision,SãoPaulo,SP,Brazil}

d_{FederalUniversityofSãoPaulo,InfectiousDiseasesDivision,SãoPaulo,SP,Brazil}

e_{UniversityofSãoPauloSchoolofMedicine,DivisionofGastroenterologyandHepatology,SãoPaulo,SP,Brazil}

f_{UniversityofSãoPauloSchoolofMedicine,DepartmentofMedicine,RibeirãoPreto,SãoPaulo,SP,Brazil}

g_{FederalUniversityofMatoGrosso,SchoolofMedicine,Cuiabá,MT,Brazil}

h_{PanAmericanHealthOrganization(PAHO),DepartmentofCommunicableDiseasesandEnvironmentalDeterminantsofHealth,}

Washington,DC,USA

i_{UniversityofSãoPauloSchoolofMedicine,Lim/52,TropicalMedicineInstitute,SãoPaulo,SP,Brazil}

j_{TropicalMedicinaFoundationHeitorVieiraDourado,Manaus,Amazon,AM,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received23February2019 Accepted19April2019 Availableonline27May2019

Keywords:

HepatitisC

HepatitisCelimination HepatitisCdiseaseburden Brazil

a

b

s

t

r

a

c

t

Introductionandaim:HepatitisCisakeychallengetopublichealthinBrazil.Theobjectiveof

thispaperwastodescribetheBrazilianstrategyforhepatitisCtomeetthe2030elimination goalproposedbyWorldHealthOrganization(WHO).

Methods:AmathematicalmodelingapproachwasusedtoestimatethecurrentHCV-infected

Brazilianpopulation,andtoevaluatetherelativecostsoftwodifferentscenariostoaddress HCVdiseaseburdeninBrazil:(1)ifnofurtherchangesaremadetotheHCV treatment programinBrazil;(2)wheretheWHOtargetsfor2030eliminationaremetthroughdiagnosis andtreatmenteffortspeakingbefore2024.

Results:Ananti-HCVprevalenceof0.53%wascalculatedforthetotalpopulation.Itwas

estimatedthatthenumberofHCV-RNA+individualsinBrazilin2017was632,000(0.31%of thepopulation).Scale-upoftreatmentanddiagnosisovertimewillbenecessaryinorderto achieveWHOtargetsbeginningin2018.Directcosts(diagnostic,treatmentandhealthcare costs)areprojectedtoincreasesignificantlyduringthescale-upoftreatmentanddiagnosis

∗ _{Correspondingauthor.}

E-mailaddress:cassiamc@uol.com.br(M.C.Mendes-Correa). https://doi.org/10.1016/j.bjid.2019.04.010

1413-8670/©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

intheinitialyearsoftheinterventionscenario,butthenfallbelowthebasecaseonan annualbasisby2025–2036,onceHCViseliminated,duetohealthsectorssavingsfromthe preventionofHCVliver-relatedmorbidityandmortality.

Conclusion: AchievingtheWHOtargetsistechnicallyfeasibleinBrazilwithascale-upof

treatmentanddiagnosisovertime,beginningin2018.However,eliminationofhepatitisC requirespolicychangestosubstantiallyscale-upprevention,screeningandtreatmentof HCV,togetherwithpublichealthadvocacytoraiseawarenessamongaffectedpopulations andhealthcareproviders.

©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

HepatitisCisthemajorcauseofdeathamongviral hep-atitisinfected patientsin Brazil and representsone ofthe keychallengestopublichealthinthecountry.1_The introduc-tionofinterferon-freedirect-actingantivirals(DAAs),withits highratesofsustainedvirologicalresponse,hasmade fea-sibletheeliminationofhepatitisCasaglobalepidemic,as recommendedbytheWorldHealthOrganization(WHO).2

InBrazil,thepublichealthsystemprovidesfree-of-charge anduniversaltreatmentforallHCV-infectedpatients, accord-ingtotheprinciplesofthecountry’sUnifiedHealthSystem (SUS),whichwasinstitutedbytheFederalConstitutionof1988 basedontheprincipleofhealthasacitizen’srightandastate duty.3_{Thus,Brazil’sMinistryofHealth(MoH)decidedto} pro-videaccesstoDAAsandtoupdatehepatitisCtreatmentinthe countrystartingin2014.4_{FromthatdateuntilDecember2017,} approximately70,000peoplereceivedtreatmentwithDAAs,at anapproximatecostofUS$1billion.5,6

In order to guarantee universal, unrestricted access to hepatitisCdiagnosis and treatmentand inlinewithWHO eliminationgoal,theMoHoutlinedaspecificnational strat-egytoachievethistarget.1_{Thisexperiencecouldbeusefulas} aguideforothercountrieswithsimilarepidemiologic, eco-nomic,orculturalcharacteristics.Theobjectiveofthispaper was todescribe the origins and outcomes ofthe Brazilian strategyincludingananalysisofthenationalhepatitisC dis-easeburdenandeconomicmodelingofpotentialstrategiesfor achievingWHOtargets.

Amathematicalmodelingapproachwasusedtoestimate the current HCV-infected Brazilian population, to forecast future disease progression as well as to evaluate possible strategiesandcoststoeliminateHCVinBrazilby2030.

The

model

AdiseaseprogressionMarkovmodel,constructedinMicrosoft Excel® (MicrosoftCorp.,Redmond,WA,USA),wasutilizedto quantifythesizeoftheHCV-infectedpopulation,bytheliver disease stages, from 1950 to2030. Themodel is described indetailelsewhere.7 _{Itwas populatedand calibratedusing} BrazilianspecificepidemiologicdatatoforecasttheHCV dis-easeburdenunderdifferentscenarios.Theflowofpatientsin theMarkovmodelisshowninFig.1.

HepatitisCdiseaseburdeninputs

ThehistoricalepidemiologyofHCVwasgatheredthrougha literaturesearch,analysisofunpublisheddataanddiscussion withexpertpanels,asdescribedpreviously.8_Areviewofthe literaturewasconductedtoidentifyindexedarticles report-ingepidemiology,ageandsexdistributionsofHCVinfection andtotalnumberofHCVcasesdiagnosed,treatedandcured. ThereviewencompassedallstudiesbetweenJanuary1990and March2017.Inaddition,non-indexedsourceswereidentified throughtheMoHandnon-indexedjournals.Finally,anexpert panel providedproceedingsoflocalconferencesor unpub-lisheddata.Individualswereidentifiedtoparticipatebasedon contributiontopriorpublishedresearchonthesubject, perti-nentexpertiseandrelevantresponsibilitieswithintheMoH. Twoface-to-facemeetingswereconductedtoreviewinputs, findingsandanalyseswiththeexpertpanelandincorporate theirfeedback.

Whennoinputdatawereavailable,itwasexplicitlystated, and analogs(datafromcountrieswithasimilarhealthcare practiceand/orriskfactors)orexpertinputswereused.The annual number oflivertransplantswas collected from the MoHdatabase9_{andadjustedforthepercentageattributedto} HCV.

HCVantibodyprevalenceandviremicprevalence

In2016,0.76%of484,300anti-HCVAbrapiddiagnostictests conductedacrossBrazilamong15–69yearoldswereantibody positive(unpublisheddata).Afteradjustingforregional pop-ulationsandfactoringinprevalenceandthesizeofvarious at-riskgroups(e.g.,prisoners,peoplewhoinjectdrugs,crack users,menwhohavesexwithmen,andHIV-infected individ-uals),the anti-HCVprevalenceamong15–69yearsoldswas estimatedtobe0.70%.

Theageand sexdistributionwerecalculatedusing noti-fication data from the MoH, which was published in the 2016BoletimEpidemiologicoreport.10_{Theannualdatafrom} 2004to2016werecalibratedtotheprevalenceestimateand agedthrough the modeltoaccountfor curedpatients and mortality.Duetolackofdata,itwasassumedthatthe preva-lencedecreasedby50%witheach5-yearagecohortforthose olderthan65–69yearsandthoseyoungerthan15–19years.

Acute hepatitis Chronic hepatitis−F0 Chronic hepatitis−F1 Chronic hepatitis−F2 Chronic hepatitis−F3 Compensated cirrhosis Decompensated cirrhosis Liver related death Liver transplantation Hepatocellular carcinoma Spontaneously cured

Fig.1– TheHCVdiseaseprogressionintheMarkovmodel.

Additionally,theanti-HCVprevalenceamong15–24yearolds wascalibratedto0.18%tomatchtheresultsfromalargestudy (n=36,818)ofmilitaryconscripts.11

Aviremicrateof60.7%wascalculatedthroughaweighted averageoffivestudiesinBrazil.12–15

Althoughanumberofinternationalstudiesreportviremic rates,thoseresultswereinfluencedbythetypeofanti-HCV testsandtheageofthepopulationbeingdiagnosed.Forthe purposesofthisanalysis,onlystudiesinBrazilwere consid-ered.

Genotypedistribution

The genotype distribution was provided by experts from nationalnotificationdata.6

IncidenceofnewHCVinfections

In this analysis, the term “incidence” refers to the abso-lute number of new infections occurring in a given year, rather than newly diagnosed cases. The incidence was back-calculated using the known prevalence as described previously.7_{Thisanalysiswassupplementedbyananalysisof} HCVinfectionamongpeoplewhoinjectdrugs(PWID).There areanestimated286,000peoplewhoinjectdrugs(PWID)in Brazil,withanHCVseroprevalenceof26%correspondingto 73,000HCVinfectionsamongPWID.16,17_{Aturnoverof10%was} usedtoestimateincidenceamongPWID.Theprison popula-tionhadnoimpactontheoverallanalysis.Thereare700,000 prisonerswithanestimatedHCVprevalenceof13.6%.18_The majorityoftheseinfectionsareduetothePWIDpopulation, alreadycapturedabove,aswellastattoosandhighrisk behav-iorinprisons.

Previouslyandannuallydiagnosedcases

Dataonthenumberofnewlydiagnosedcasesperyearwere providedbyexpertsfromthenational,(unpublished) notifica-tiondata.Theywereadjustedforunder-reporting,mortality andtreatedcuredtoestimatethefinalnumberofdiagnosed casesalive todayand annual number ofnewly diagnosed. The analysis also took into consideration the number of

individualsdiagnosedthroughanationalscreeningcampaign. In2017,anationalcampaigntested6.1millionBraziliansvia rapidtestingandanother2.9millionviatraditional serologi-caltesting.Anestimated30,000caseswereidentifiedinthis campaign.6

Numberneededtobescreened

Thenumberofindividualsthatneededtobescreenedwas calculatedusingthenewlydiagnosedratefromthehistorical screeningcampaign.Itwasassumedthatfuturescreenings willhaveasimilarproductivity.For screeningsinhighrisk population,itwasassumedthatHCVprevalencewillbefive timeshigherinthehighriskpopulations;thus,fivetimeas manyHCVpositivecaseswillbeidentified.

Treatedandcuredpatients

Theexpertpanelalsoprovidedthenumberoftreatedpatients in Brazilbyyear from national unpublisheddata(Table3). Accordingtoexpertconsensus,theDAAsachieveda95%SVR onaverageacrossallgenotypesanddiseasestages.

Scenario

analysis

Basescenario

WecalculatedtheimpactontheHCVinfectionsand mortal-ityifthereisnochangetoHCVtreatmentpoliciesfrom2017 to2030.In2016,thefollowingpatientswereeligiblefor treat-ment:patientsstaged≥F3,patientswithconfirmedstageF2 inthepreviousthreeyears,andpatientswithcomorbidities suchasHIVco-infection,chronickidneydiseaseorextra hep-aticmanifestations.Thoughtherewasasubstantialincrease inthenumberofpatientstreatedbetween2015(∼14,000)and 2016 (∼37,000), the number of patients treateddropped to 23,000in2017.Weassumedacontinuingdeclinebetween2018 and2020duetoashrinkingpoolofeligiblepatients.In2017, nationaltreatmentguidelineswereexpandedtoincludeallF2 patients.AsfromMarch2018treatmentaccesswasexpanded toallinfectedpatients.

Table1–Diagnosticcosts(2016).

Costperdiagnosedandtreated patient(US$)

#oftestsfortreating–present #oftestsfortreating–2022

Anti-HCV 3 1 1

RNATest/PCR 16 4 2

Genotyping 32 1 1

Staging/Liverbiopsy/fibroscan 54 1 1

Table2–Healthcarecosts(2016).

Annualcostper diagnosedpatient (US$) Annualfollow-upF0–F2 185 F3tocompensatedcirrhosis 219 Decompensatedcirrhosis 3340 Hepatocellularcarcinoma 5886 livertransplant 38,202

Livertransplant–subsequentyears 2385

Table3–DALYparameters.

Age-weightingmodulation constant(K)

0(noage-weighting) Disabilityweightbydisease

stage

Usedpreviouslypublished estimateswhenavailable19

F0–F4 0

Decompensatedcirrhosis 0.178 Hepatocellularcarcinoma 0.466a

LiverTransplant 0.024b

DALY,disability-adjustedlifeyear.

a _{Weightedaverageofdisabilityweightsforterminalandcontrolled}

phasesoflivercancerduetohepatitisC.Weassumed85%of hep-atocellularcarcinomacaseswereterminal(disabilityweightof 0.54)and15%ofcaseswerecontrolled(disabilityweightof0.049).

b _{Disabilityweightforend-stagerenaldisease,whenkidney}

trans-plantwasused.

Nationalstrategyplanscenario(NSP)

An intervention scenario was modeled to determine the degreetowhichthenumberofpatientstreatedanddiagnosed mustincreasestartingin2018inordertoreachtheWHO tar-getsby2030.

HepatitisCeconomicanalysis

Amodelingapproachwasusedtoevaluatetherelativecosts oftwo differentstrategies tocontrolthe HCV disease bur-deninBrazil:(1)ifnofurtherchangesaremadetotheHCV treatmentprograminBrazil;(2)wheretheWorldHealth Orga-nization(WHO)targetsfor2030eliminationaremetby2030. Data regardingdirect costs were obtainedfrom the Brazil-ianUnifiedHealthSystem,andaDelphiprocesswasapplied inordertogainexpertconsensusandvalidateinputs. HCV-relatedcostingdataaredetailedinTables1and2.

Theeconomicanalysisfactoredindirectcostsofscreening, diagnosingandtreatingHCV;healthcarecostsassociatedwith HCVandadvancedliverdisease;andindirectcoststothe soci-etyfromyearsoflifelost(YLL)andyearslivedwithdisability (YLD)duetoHCV-relatedmorbidityandmortality.

Average cost of DAAs (across genotypes) for a 12-week courseoftreatmentwasestimatedatUS$4600in2017and wasestimatedtodecreasedtoUS$2700by2019perexpert input.

Directcosts

Directcostswerethoseassociatedwithscreening, diagnos-ingandmanagingchronicHCVinfection,cirrhosisandliver cancer(intheabsenceofantiviraltherapy)andtreatingHCV.

Indirectcosts

Disability-adjustedlifeyears(DALYs)werecalculatedbasedon yearslivedwithdisability(YLDs)weightedbydiseasestage (minimum disability impact until cirrhosis, liver cancer or transplant)andYLLs.Weightingofdisabilitybydiseasestage wastakenfromthehealthliteratureasshowninTable3. Dis-abilityweightswereappliedonlytodiagnosedcasesforF0–F3 andforallprevalentcasesinF4andadvanceddiseasestages. Indirectcostsweretakenaseconomicproductivitylosses toBraziliansocietycausedbyHCVandrelatedliverdisease andmortality.Weassumedthevalueofastatisticallifeyear (VSLY)wasequaltothegrossnationalincome(GNI)percapita inBrazil,US$7772in2015(fromtheWorldBank2015).Indirect costswerecalculatedonlyforDALYsincurredamongcases aged20–69years

Results

HepatitisCdiseaseburden

Aftertakinginto considerationallages,ananti-HCV preva-lenceof0.53%wascalculatedforthetotalpopulation(0–85+) corresponding to1,091,000 antibodypositive casesin2016. ItwasestimatedthatthenumberofHCV-RNA+individuals inBrazilin2017was632,000(0.31%ofthepopulation).The prevalenceandtotalinfectionsbyageareshowninFig.2.

Genotype1accountedfor71.3%ofallcases,followedby Genotype3,whichaccountedfor24.4%ofcases.

The back-calculations of incidence estimated7500 new acuteHCVinfectionsin2016.Thiswasconsistentwith esti-matingnewinfectionsamongPWID.Assumingaturnoverof 10%ofHCVinfectionsamongPWID,anincidenceof7300per yearwasestimatedamongthispopulation.

Thetotalreporteddiagnosedcaseswere319,000antibody positive cases in 1999–2016. After adjusting for under-reporting,anestimated362,000antibodypositivecaseswere diagnosed inthe same period.The annualdata were then adjusted for mortality and cured cases, resulting in an

Vire mic ca s e s Re port e d pre valen ce 2.5 % 2.0% 1.5% 1.0 % 0.5% 0.0% 0-4 0-4 5-9 5-9 10-14 10-14 15-19 15-19 20-24 20-24 25-29 25-29 30-34 30-34 35-39 35-39 40-44 40-44 45-49 45-49 50-54 50-54 55-59 55-59 60-64 60-64 65-69 65-69 70-74 70-74 75-79 75-79 80-84 80-84 85 + 85 +

HCV Prevalence by age and sex—Brazil,2016 HCV Infected population by age group—Brazil,2017 120,000 100,000 80,000 60,000 40,000 20,000 Male Female

Fig.2–HepatitisCprevalencebyageandsex.

Table4–Epidemiologicdatausedasinputsinthe model.

Input Estimateyear

RNA+HCVinfections 662,000 2016

Totaldiagnosed(RNA+) 97,000 2016

Annualnewlydiagnosed 30,000 2017

Annualnumbertreated 23,000 2017

estimated224,000antibodypositivediagnosedcaseswhoare alivetoday.Treatedandcuredcaseswereamongtheviremic populationonly.Thus,itwasestimatedthat97,000viremic diagnosedcases(notcuredandalive)remainedin2016.The estimatednumberofnewlydiagnosedviremiccasesin2016, accountingforunder-reporting, wasestimatedat18,800. A summaryofthemodelinputsisshowninTable4.

Scenarioanalysis

Thenumbersofpeoplewhoneedtobescreened,diagnosed andtreatedundereachscenarioareshowninTable5.The numberofrapidteststhatwillbeneededtomeetthe diagno-sistargetwascalculatedforeachyearwiththeassumption thatscreeningcontinuestofindpositivecasesatthecurrent positivityrate(0.55%anti-HCV).InordertoachievetheWHO targetsby2030,treatmentaccesswasexpandedtoall fibro-sisstagesbeginningin2018.Patientsaged15–79continued tobeeligiblefortreatment.Thenumberoftreatedpatients increasedtoapeakof50,000in2019–2020,andthenumber ofannuallydiagnosedpatientsincreasedtoamaximumof 40,000startingin2019.

Thescreeningstrategywouldbemoreefficientiftesting targetedhighriskpopulations.Table5showsthenumberof people whoneedtobescreenedifthescreeningcampaign targetedhighprevalencepopulations(definedashaving five-fold higherprevalence than thecurrent rate) forthe same strategiesconsideredabove.

AsshowninTable6,theanalysisprojectedthatintheBase Scenariothetotal numberofHCV infectionswoulddecline from2015to2030,butHCCwouldincreaseby25%and decom-pensatedcirrhosiswouldbe45%higherthanin2015asthe population ages.Thenumber ofliver relateddeathswould be30%higherin2030thanin2015.Comparedwiththebase case,theNSPscenariodrasticallyreduceshepatocarcinoma, decompensatedcirrhosisandliverrelateddeaths.

Economicanalysis

WeaggregatedthedirectcostsforthebasecaseandtheNSP scenario andcompared themacross time. Screening, diag-nosticandtreatmentannualcostsareprojectedtoincrease significantlywiththescale-upoftreatmentanddiagnosisin theinitialyearsoftheNSPscenario,butthendropbelowthe basecaseonanannualbasisby2035,onceHCViseliminated (Fig.3).

IndirectcostsintheNSPscenarioremainapproximately evenwiththebasecaseforthefirstcoupleyearsbefore drop-ping(Fig.4).Asmorepatientsreceivetreatmentandarecured, reducedmortalityanddisabilitywillresultinfewerYLLsand YLDs.Asaresult,DALYsareavoidedintheNSPscenario, cre-atingsavingsinindirectcosts.

Table5–Thenumberofpeoplewhoneedtobescreened,diagnosedandtreatedforeachscenario.

2016 2017 2018 2019 2020 2025

Base

Treated 36,600 23,000 19,000 12,900 12,500 12,500

Newlydiagnosed 18,800 30,000 30,000 30,000 30,000 30,000

Numberneededtoscreen(gen.pop.) 3,889,000 9,000,000 9,585,000 10,246,000 10,991,000 16,763,000 Numberneededtoscreen(highrisk.pop.) 778,000 1,800,000 1,917,000 2,049,000 2,198,000 3,353,000

NSP

Treated 36,600 23,000 19,000 50,000 50,000 32,000

Newlydiagnosed 18,800 30,000 30,000 40,000 40,000 40,000

Numberneededtoscreen(gen.pop.) 3,889,000 9,000,000 9,598,000 13,975,000 15,469,000 30,997,000 Numberneededtoscreen(highrisk.pop.) 780,000 1,800,000 1,920,000 2,795,000 3,094,000 6,199,000 NSP,nationalstrategyplan.

Table6–Projectedprevalence,morbidityandmortalityineachscenarioin2020and2030.

Prevalentviremiccases IncidentHCC Incidentdecompensated cirrhosis

Incidentliverrelated deaths Basecase 2020 607,000 2500 1900 2500 2030 469,000 2800 2200 3600 NSP 2020 531,000 2400 1800 2300 2030 125,000 910 730 970 An n u a l co s t (BR L M illi on s ) 1,000 900 800 700 600 500 400 300 200 100 2016 2018 2020 2022 2024 2026 2028 2030 2032 2034 -Direct costs

Base 2017 National strategy plan

Fig.3–DirectcostsintheNSPscenarioandthebasecase scenarios. 1,400 1,200 1,000 800 600 400 200 -Indirect costs

Base 2017 National strategy plan

2016 2018 2020 2022 2024 2026 2028 2030 2032 2034

Fig.4–IndirectcostsintheNSPscenarioandthebasecase scenarios.

The20-yearaveragecostperDALYavertedwasUS$486in theNSPscenario,wellundertheGNIpercapitaofUS$7838, indicatingcost-effectiveness.

Wealsocalculatedtheannualtotalcost(direct+indirect costs)toBrazil andfoundthe NSPscenariowillresultina lowercost,relativetothebasescenario,startingin2022(Fig.5). Additionally,thecumulative(2017forward)directand indi-rect coststo Braziliansociety under the NSP scenariowas costsavingwithapositivereturnoninvestment(ROI) start-ingin2025.Theproportionofthetotalpublichealthbudget (estimatedinUS$53billion)spentonHCVmanagement is projectedtodeclineinfutureyearsinthebasescenarioasthe numberoftreatedpatientsdeclines(Fig.6).Asaresult,theNSP scenarioisexpectedtorequirealargerpercentageofthetotal publichealthbudgetinitially.After2028,theNSPscenariowill costlessthanthebasescenarioandafter2030itwillrequire

An n u a l co s t (BR L M illi on s ) 2,000 1,800 1,600 1,400 1,200 1,000 800 600 400 200

-Direct & indirect costs

Base 2017 National strategy plan

2016 2018 2020 2022 2024 2026 2028 2030 2032 2034

Fig.5–ComparingdirectandindirectcostsintheNSPand basescenarios. 0.60% 0.50% 0.40% 0.30% 0.20% 0.10% 0.00%

Base 2017 National strategy plan

Public health insurance budget utilization

2016 2018 2020 2022 2024 2026 2028 2030 2032 2034

Fig.6–Comparingpublichealthbudgetutilizationinthe NSPscenariowiththebasecasescenario.

lessthan0.2%ofthebudgetastheeliminationtargetsaremet andtherearefewerpatientswithadvancedliverdisease.

Discussion

HepatitisCeliminationplaninBrazil

TheMinistryofHealthofBrazil,inlinewiththe WHOgoal toeliminatehepatitisCasaglobalhealththreatby2030,has outlinedanationalstrategytoachievethistarget.A mathe-maticalmodelingapproachwasusedtoestimatethecurrent HCV-infectedBrazilianpopulation,toprojectfuture disease progressionincludinglivercanceranddeaths,andto evalu-atepossiblestrategiesandcoststoeliminateHCVinBrazilby 2030.In2016,itwasestimatedthattheanti-HCVprevalence was0.53%amongthetotalpopulationandthatthenumberof

HCV-RNA+individualswas632,000(0.31%ofthepopulation). Itwasalsopossibletoprojectthatifnochangeweremadeto Brazil’sHCVtreatmentstrategy(althoughover70,000 Brazil-ianpatientshadbeentreatedwithnewDAAsasofDecember 2017),therewouldbeanincreaseincasesoflivercancerand advancedliverdiseaseby2030.

Accordingtothemodeledintervention,itwouldbe neces-sarytocombineanincreaseoftreatmentanddiagnosisover timeinordertoreachWHOtargetsby2030.Anotherinsight that the modeling provided was that WHO targets would requiresignificantup-frontinvestmentintreatmentand diag-nosis.However,savingsfromhealthcareandindirectcostsas thediseaseburdenisreducedwouldoffsetthesecosts, result-inginlowertotalannualcostsby2022andapositivereturn oninvestment(ROI)by2025whencomparedagainsttheBase Scenario.

Theresultsofthisstudy allowedthe MoH’sDepartment ofSTIs,HIV/AIDS and Viral Hepatitistooutlinethe

Hepati-tisCElimination Plan in Brazil,which wasthen approvedby

theMoH’sTripartiteCommission(representedbythe Brazil-ianfederal,stateandmunicipalgovernments)inOctober2017. Since then, the MoH’s Department of STIs, HIV/AIDS and ViralHepatitishasbeenensuringthefeasibilityofthisplan, establishingauniversaltreatmentpolicyforallviremiccases, updatingtherapeuticguidelines,simplifyingtestsand imple-mentinginterventionsforlinkagetocare,andestablishinga sustainablepricenegotiationpolicyovertime.

HepatitisCdiseaseburdeninBrazil

The estimates assumed following the construction of this model demonstrate a significantly lower HCV prevalence whencomparedtoapreviousstudyconductedfrom2005to 2009in arepresentative sampleof 19,503adolescents and adults in all Brazilian macro-regions. That study demon-stratedananti-HCVAbprevalenceof1.38%,15 _aprevalence notsincereplicated inother studies.Additionally, the pub-lishedviremicrateof35.7%suggests arelatively highHCV Abfalsepositivityrate.Itisalsopossiblethatthereductionof seroprevalenceobservedinthepresentstudyreflectsachange inthepatternofHCVtransmissioninBraziloverthepast20 years.

Beforebloodscreeningbeganin1992inBrazil,transfusion ofblood and bloodproductswasthe predominantrouteof HCVtransmission.20_{Themodelestimatesthatmorethan90%} ofthe infectedpopulation wasborn priortoblood screen-ing.Injectiondrugusehasalsobeenanimportantmodeof hepatitis C transmission in the past.20,21 _{Today blood and} bloodproductstransfusionsaresafe.22_Inaddition,a signif-icant reductionintheoverall frequenciesofdrug injection andneedle-sharinghasbeenobservedinthecountry.17,23_All thesefactorscouldhavecontributedtoareductioninhepatitis Ctransmissionandviremiccases.Nevertheless,nosocomial transmission (particularly hemodialysis), as well as trans-missionthroughneedlesharingfortherapeuticinjectionsin nonmedicalsettings,couldcontributetoongoinghepatitisC transmissioninthecountry.24,25

InordertopreventthespreadofHCVindialysisunits,MoH hasestablishedspecificguidelines.Despitetheseguidelines, patientsonhemodialysistreatmentare stillathighriskfor

HCVinfection.23,24_{InBrazil,theriskofexposuretoHCVhas} alsobeenassociatedwiththepracticeoftattooingandbody piercing withoutattention tosterilization oruse of dispos-ableequipmentaswellaswithsexbehavior.21_However,the frequencyoftheseeventsseemstobelowandwithalower impactontheoverallinfections.1_{Ourdataestimatethatthe} majorityofpatientswithhepatitisCinBrazilareagedbetween 40and65.Thesedatareinforcetheneedforapriority diagno-sisinpeopleinthisagegroup.

HepatitisCeconomicanalysis

ThemodeloutputsrevealedthatthecurrentBrazilian strat-egytoconfrontthisepidemiccanbemadesignificantlymore cost-effectivewhileacceleratingthe eliminationofthe dis-easeburden,andthusmodificationisurgentlyneeded.From 2005 to 2015 an extraordinary increase of MoH expendi-tureonmedicinesforhepatitisCwasobserved,mainlydue to an increase ofvolumes purchased as well as the need to incorporate alfa-pegylated interferon in the early DAA combinations.26In2015theadoptionofthenewDAAledtoan increaseof230%(US$255million)inMoHspending,as com-paredto2014.26_{ThecurrentBrazilianstrategy,despiteitshuge} investment,wouldnotbeabletoguaranteeinthemedium and long termthe eliminationofthisdisease.Onthe con-trary,maintainingthesametypeofpublichealthpolicycould leadtoasignificantincreaseinthenumberofadvancedliver diseasecasesandtheneedforfurtherincreasedinvestment. Based on our estimates, achieving the WHO targets demands a scale-upoftreatmentand diagnosis over time, beginningin2019.Amajorchallengewillbetosustain strate-gicactionsand toincreasethenumber ofnewlydiagnosed patientsinordertomaintainapoolofpatientswhoareeligible fortreatmenttoreducethesizeoftheepidemic.

Theeliminationscenarioprojectsthatantiviralwill consti-tuteasubstantialproportionofpublichealthexpenditureto addressHCV.AnyfurtherreductionsinDAApricesfromthose assumed inthe model willimprove cost-effectiveness and ultimatelyreducebudgetimpact,strengtheningtheeconomic caseforelimination.Thecriticalnatureofachievingaffordable DAApricingforthenationcannotbeunderestimated.

Itisimportanttonotethatthe resultsofthis study are influenced byseveral limitations inherenttomathematical modeling.Inputsusedinthemodel,concerningthe epidemi-ology of hepatitis C in Brazil, were not always published or availableintheliterature.Todealwiththis,the authors applied the Delphi process, relying on a panel of experts wheneverthe informationwasnotbasedonpeer-reviewed published literature. Secondly, we have assumed that the numberofnewcaseswouldremainconstantintothefuture. Thisisaconservative approachthatassumes statictrends inriskbehaviorintheabsenceofmoreinformation.Thirdly, we have assumed that screening campaigns will continue todeliver thesame rateofnewlydiagnosedcases. In real-ity, itispossiblethatasthediagnosisrateincreases,itwill become more difficultto find undiagnosed patients. Addi-tionally,wehaveassumedacontinuousavailabilityofDAAs todiagnosedpatients. Inreality,challengesassociatedwith pricenegotiationanddrugdistributionmaypreventdiagnosed

patientsfromaccessingmedicationaspredictedbythemodel. Finally,themodeldoesnottakeintoconsiderationthe pos-sibleimpact, oneitherHCV disease burdenoron theHCV economicanalysis,oftheprogressionofcuredHCVpatients, reinfection,comorbiditiesandextrahepaticmanifestationsof HCVinfection.Thesecouldleadtoincreasedfuturehealthcare costs.However,theselimitationsaretypicalofsimilar stud-iesandwebelievetheydonotsignificantlycompromisethe relevanceandmagnitudeoftheresultspresented.

Conclusion

Inconclusion,ourstudyindicatesthateliminationof hepati-tisCinBrazilistechnicallyfeasible,andHCVdiseaseburden would not be controlled by the previous treatment strat-egy.However,theeliminationofhepatitisCrequirespolicy changestosubstantiallyscale-upprevention,screening,and treatmentofHCV, together withpublic healthadvocacy to raiseawarenessamongaffectedpopulationsandhealthcare providers.Healthcareproviders,includingprimaryhealthcare practitioners,willneedspecifictraininginthediagnosisand treatmentofHCV.Testingandcounselingmustbescaledup andalsodirectedatprioritizedgroupswithhigherHCV preva-lenceincludingHIVinfectedpatients,diabetics,adultsover40 years,orpatientsonhemodialysis.Giventhesespecific pop-ulationsarealreadyengagedwiththenation’sUnifiedHealth System(SUS),theycouldbeeasilyidentifiedandreferredfor HCVtreatment.

Government,medicalsocietiesandindustryneednowto worktogetherinordertoassurefullaccesstothenewantiviral regimensand healthservicesforeveryonewhoisinfected. Accessmustnotbecompromisedbyexcessivelyhighprices orlackofpoliticalwill.EliminationofhepatitisCinBrazilis possiblebutwillrequireurgent,strongandsustainedpolitical andsocietalcommitmenttoachievethisgoal.

Funding

The mathematical model was funded by The Ministry of HealthinBrazil.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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