Prevention, treatment and care of hepatitis C virus infection among people who inject drugs

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ContentslistsavailableatScienceDirect

International

Journal

of

Drug

Policy

jo u r n al ho m e p ag e :w w w . e l s e v i e r . c o m / l o c a t e / d r u g p o

Commentary

Prevention,

treatment

and

care

of

hepatitis

C

virus

infection

among

people

who

inject

drugs

Philip

Bruggmann

a,∗

_,

_Jason

_Grebely

b

a_Arud_Centres_for_Addiction_Medicine,_Zurich,_Switzerland

b_The_Kirby_Institute,_The_University_of_New_South_Wales_Australia,_Sydney,_Australia

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received11June2014

Receivedinrevisedform11August2014 Accepted23August2014

Keywords: HepatitisC PWID

a

b

s

t

r

a

c

t

Peoplewhoinjectdrugs(PWID)representthecoreofthehepatitisCvirus(HCV)epidemicinmany countries.HCVtransmissioncontinuesamongPWID,despiteevidencedemonstratingthathighcoverage ofcombinedharmreductionstrategies,suchasneedlesyringeprograms(NSP)andopioidsubstitution treatment(OST),canbeeffectiveinreducingtheriskofHCVtransmission.Amonginfectedindividuals, HCV-relatedmorbidityandmortalitycontinuestogrowandisaccompaniedbymajorpublichealth, socialandeconomicburdens.DespitethehighprevalenceofHCVinfection,theproportionofPWIDwho havebeentested,assessedandtreatedforHCVinfectionremainsunacceptablylow,relatedtosystems-, provider-andpatient-relatedbarrierstocare.Thisisdespitecompellingdatademonstratingthatwith theappropriateprograms,HCVtreatmentissafeandsuccessfulamongPWID.Theapproachingeraof interferon-freedirectlyactingantiviraltherapyhasthepotentialtoprovideoneofthegreatadvances inclinicalmedicine.Simple,tolerableandhighlyeffectivetherapywilllikelyaddressmanyofthese barriers,therebyenhancingthenumbersofPWIDcuredofHCVinfection.However,thehighcostofnew HCVtherapieswillbeabarriertoimplementationinmanysettings.Thispaperhighlightsthatrestrictive nationaldrugpolicyandlawenforcementarekeydriversoftheHCVepidemicamongPWID.Thispaper alsocallsforenhancedHCVtreatmentsettingsbuiltonafoundationofbothprevention(e.g.NSPand OST)andimprovedaccesstohealthcareforPWID.

Introduction

ThehepatitisCvirus(HCV)epidemichasbeencoineda“viral timebomb”bytheWorld HealthOrganization.HCVisa preva-lentchronicinfectionwithpotentiallydeadlyconsequences.Recent estimates suggest that globally, the HCV viremic (RNA posi-tive)prevalenceisforecastedat1.1%(0.9–1.4%)correspondingto 80(64–103) millionviremicinfections (Gower,Estes, Hindman, Razavi-Shaerer,&Razavi,2014).Despitetheloomingpublichealth threatthatHCVimposes, it receiveslittle publicattention.This silentdiseaseoftenprogresseswithfewsymptoms,evenduring advancedstagesofdisease.Asabloodbornevirus,themajorroute of transmissionin most countriesis injecting druguse. People whoinject drugs (PWID)areheavilyaffectedby this infectious disease.However,despitethehighprevalence,ongoing transmis-sionandincreasingHCV-relateddiseaseburdenamongPWID,HCV

∗ Correspondingauthorat:ArudCentresforAddictionMedicine,Konradstrasse 32,8005Zurich,Switzerland.Tel.:+41583605050.

E-mailaddress:p.bruggmann@arud.ch(P.Bruggmann).

testing, prevention, assessment and treatmentremain subopti-malinthis group,andthetime-bombstilltickson.Overrecent years,thedevelopmentof simple,tolerableandhighlyeffective interferon-freedirectlyactingantiviral(DAA)-basedtherapiesfor HCVinfectionhasbroughtgreatoptimismtothesector.However, inorderfortheroll-outofthesenewIFN-freeregimensto elimi-nateHCVamongPWID,drasticchangesandthebreakingofsome tabooswillberequired.

TransmissionofHCVinfection

Althoughriskfactorscommonlyassociatedwithtransmissionof HCVinfectionincludebloodtransfusionfromunscreeneddonors, unsafetherapeuticinjections,andotherhealth-carerelated proce-dures,themajorityofnewandexistinginfectionsinmostcountries have occurred as a result of injection drug use (Hajarizadeh, Grebely,&Dore,2013).AmongPWID,themajorrouteof trans-missionisthroughthesharingofdrugpreparationandinjection equipment (e.g. syringes, needles, ﬁlters, water and cookers) (Pouget, Hagan, & Des Jarlais, 2012). The hepatitis C virus is resilientandiscapableofsurvivingondrugpreparationequipment http://dx.doi.org/10.1016/j.drugpo.2014.08.014

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(e.g. needles, syringes, ﬁlters and water) for several days to weeks(Doerrbeckeretal.,2013;Paintsil,He,Peters,Lindenbach, &Heimer,2010).Also,theriskofHCVtransmissionisgreaterthan forHIVinfection,consistentwithgreaterpercontaminated inject-ingexposuretransmission(2.5–5.0%forHCVvs.0.5%-2.0%forHIV), andhigherprevalenceofHCVthanHIVamongPWID(andthus,risk ofexposure)(Grebely&Dore,2011a).

EpidemiologyofHCVamongPWID

GivenanestimatedglobalHCVprevalenceof67%amongPWID (Nelsonetal.,2011),around10millionPWIDhavebeeninfected withHCV,withanadditionallargereservoirofinfectionamong formerPWID.In somecountries, theHCVprevalenceis ashigh as90%(Hagan,Pouget,DesJarlais,&Lelutiu-Weinberger,2008). Inabsolutenumbers,thecountrieswiththegreatestnumberof HCVinfectedPWIDincludeChina(1.6million),theUnitedStates (1.4million)andtheRussianFederation(1.3million)(Nelsonetal., 2011).

TheestimatedincidenceofHCVinfectionamongPWIDranges from5%to45%perannum(Grebely&Dore,2011a;Haganetal., 2008;Page,Morris,Hahn,Maher,&Prins,2013).TheriskofHCV infectionishighestamongyoungerindividualsand recent initi-atesintoinjectingdruguse(Grebely&Dore,2011a;Pageetal., 2013) (2, 3) (1, 2). However, many PWID remain unaware of theirinfectionstatus. The absenceof accuratenational surveil-lanceandnotiﬁcationsystemsalsocontributestounderreportingof HCV.

MorbidityandmortalityamongPWID

HCVis a majorcauseof liverfailureand liver-related death (Grebely &Dore,2014;Hajarizadeh etal., 2013).In theUnited States, HCV-related mortality hasnow surpassed death related toHIV(Lyetal.,2012).Globally,theburdenofHCVinfectionis expectedtosubstantially increase withinthenext fewdecades (Grebely&Dore,2014;Hajarizadehetal.,2013).

Givenaround25%ofpeopleinfectedwithHCVspontaneously clearvirus(4),∼50%ofPWIDwillhavechronicHCVinfection (rep-resents8millionPWIDglobally).InthosewithspontaneousHCV clearance,re-infectioninthesettingofongoingHCVexposureis possible(Grebelyetal.,2012).Althoughmanyofthosewith re-infectionclearrepeatedly,othersdeveloppersistentinfection.

Developmentof chronicHCV infectionmayleadto progres-sivehepatic fibrosis,cirrhosis, andcomplicationsofliverfailure orhepatocellularcarcinoma(Grebely&Dore,2011b).Progression toadvancedliverdiseaseisuncommonintheinitial10–20yearsof infection,particularlyamongPWIDwhogenerallyacquireinfection atayoungerage,butbecomesmorecommonwitheach subse-quentdecadeofinfection(Grebely&Dore,2011b).AmongPWID, factorscontributing tofibrosisprogression suchas age, contin-uedmoderate-heavyalcoholuse,andHIVareoftencompounded. AlthoughyoungerindividualswithHCVinfectionareatlowerrisk ofHCV-relatedmorbidityandmortality,anddrug-related mortal-ityissignificantamongPWID,theageingcohortnatureofPWID populationsmeansthatliverdisease-relatedmortalityis increas-ing(Grebely&Dore,2011b,2014).Thereisalsoincreasingevidence thatHCVinfectionisassociatedwithanincreaseinbothhepatic andextra-hepaticdisease,includingcirculatorydiseases,renal dis-eases, and neuropsychiatric disorders (Grebely & Dore, 2011b, 2014).However,HCVtreatmentcanattenuatehepatitisC-related diseaseconsequences,andpreventdeathassociatedwithHCV(van derMeeretal.,2012).

PreventionofHCVinfectionamongPWID

There is currently no HCV vaccine. But, HCV infection is a preventabledisease,especiallyamongPWID.Basicrequirements for successful HCV preventionaccording tothe WHO guidance are access to health care and justice, health literacy and need adaptedservicesforPWID(WorldHealthOrganisation,2012).Key measurements for effective HCV preventionare needle syringe programs (NSPs, including provision of sterile injection equip-ment) and opioid substitution treatment (OST) (Turner et al., 2011).With the combination of these two preventive stepsat highcoverage,thoseinneedandatrightscaletheindividualrisk can be minimized(Hagan, Pouget, & Des Jarlais,2011; Martin, Hickman,Hutchinson,Goldberg,&Vickerman,2013;Turneretal., 2011).Inmanycountries, thecoverageofOSTandsterile injec-tion equipment provision is insufﬁcient (Mathers et al., 2010). AsPageand colleagueshave highlighted,evenin acountrylike theUnitedStates,“publichealthandpoliticaleffortstoincrease cleansyringe/needleavailabilityhavebeenmetwithideological, social,andpoliticalbarriers,effectivelythwartingthedeliveryof oneofthemostefﬁcaciousbiomedicaltechnologiesforpreventing injection-relatedinfections”(Pageetal.,2013).

Most prevention programs, ifavailable at all, are driven by insightsfromthefieldofHIVprevention,wherea lower cover-ageofneedleandsyringesissufficienttostemHIVtransmission comparedtoHCV(Grebely&Dore,2011a).However,thehigher infectivity of HCV compared to HIV and greater prevalence demands broaderinjecting equipment provision (cooker, filter, water),highercoverageandgreaterscale-up.Therequirementsfor injectingequipmentmayvarybythetypeofdrugusedandthetype ofusers(e.g.aheroinuserneedsupto6setsofinjection equip-mentperday,whilea“krokodil(desmorphine)”usermayrequire 12sets).

InanattempttoaddresstheHCVepidemicandreduce preva-lence ofinfectionin thecommunity,preventionmeasuressuch as NSP and OST may becoupled withHCV treatment (Martin, Vickerman,etal.,2013).Ithasbeensuggestedthatwitheven mod-estratesofHCVtreatmentuptakeitwillbepossibletosubstantially reducetheviralreservoirinthecommunityanddecreasethe num-berofpotentialsourcesfortransmission,particularlyin theera ofIFN-freeHCVtherapy (Martin,Vickerman,etal.,2013). How-ever,HCVtreatmentaspreventionwillrequireastrongfoundation ofharmreductionprograms,suchasNSPandOST programsto reduce ongoing transmission.As such, countrieswithlow cov-erage of OST and sterile injection equipment provision should ﬁrstconcentrateonthescale-upthesetwoimportantprevention strategies, given their importancein preventingHCV transmis-sion(Haganetal.,2011;Martin,Vickerman,etal.,2013;Turner etal.,2011;Vickerman,Martin,Turner,&Hickman,2012). Success-fulHCVpreventionstrategiesamongPWIDcanalsopreventHIV infection,giventhesimilarroutesoftransmission,highercoverage andincreasedscalethatarerequired.However,furtherresearch isneededtobetterunderstandtheoptimalcombinationofHCV preventionstrategiesforreducingHCVtransmission.

Any combination of prevention strategies must take into accountthatthehighestriskofHCVinfectionisatthebeginningof aninjectingcareer.Assuch,comprehensivepreventionmeasures shouldensuretargetingtonewinitiatestoinjectingand young peoplewhoinjectdrugs(Pageetal.,2013).

AccessandprovisionofHCVpreventionservicesishinderedin countrieswithrestrictivedruglawenforcement.The criminaliza-tionofdruguseandthefearofarrestdrivespeopleaway from HCVpreventionservices,resultinginincreasedriskbehaviorsand increasedtransmissionofHCVinfection.RestrictionsinOST pro-visionleadstolowcoverage,therebylimitingthepotentialeffect onHCVprevention.Incountrieswithrepressivedrugpolicy,PWID

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oftenend upinprison, wheretheriskofHCVinfectionisoften higher,givenahighprevalenceofHCVinfectionandtheabsence ofeffectivepreventionmeasures.

TreatmentofHCVinfectionamongPWID

HepatitisCvirusinfectionisacurablechronicdisease.Although new DAA-based HCV therapies are already available in some countries,formostareas,thecurrentstandardofcareconsistsof treatmentwithpegylated-interferon(oneinjectionperweek), riba-virin(1–3tabletstwiceaday)andtelaprevirorboceprevir(6–12 tablets,2–3timesaday)for thosewithHCVgenotype 1.These treatmentsarearduous(6–12months),poorlytoleratedandcure only60–70%ofindividuals.

Initially,HCVtreatmentguidelinesexcludedPWIDfrom consid-eration,citingconcernsaboutadherence,increasedsusceptibility tosideeffects(e.g.depression)andre-infection(NIH,1997). How-ever,thereisnowcompellingevidencethatHCVtreatmentissafe andeffectiveamong PWID(Aspinall etal., 2013;Dimova etal., 2012).Intwosystematicreviewsofstudiesassessingtreatment forPWID(onespeciﬁcallyfocusingonthosewithrecent inject-ingatthetimeoftreatmentinitiation),theoverallproportionwith viralcurewas56%(Aspinalletal.,2013;Dimovaetal.,2012).These responseratesarecomparabletolargerandomizedcontrolledtrials ofHCVtreatment(Manns,Wedemeyer,&Cornberg,2006). Inter-nationalguidelinesnowrecommendtreatmentforPWIDfollowing individualisedassessment(Robaeysetal.,2013).

AlthoughthereisconcernthatHCVre-infectionmaynegatethe potentialbeneﬁtsoftreatment, thereportedratesofreinfection followingsuccessfulHCVtreatmentamongPWIDarelow(1–5% peryear)(Aspinalletal.,2013).TreatmentofHCVinfectionamong currentandformerPWIDhasalsobeendemonstratedtobe cost-effective(Martinetal.,2012).

NewtherapiesforthetreatmentofHCVinfection

NumerousantiviralagentstargetingspecificHCVviralfunctions havebeendeveloped(directactingantivirals[DAAs])(5).Overthe next2–3yearsseveral,interferonfreecombinationDAAregimens shouldbelicensed.Theseregimensofferincreasedefficacy(>90%), reduced toxicity, shortened treatment durations (8–12 weeks), simplifieddosing(alloral,possiblyonce-dailyregimens)and moni-toringschedules.Theavailabilityofsuchregimensshouldmarkedly improvethe feasibilityof enhanced HCV treatmentuptake and responsesamongPWID,furtherenhancingtheprevention poten-tialofHCVtherapy,makingeliminationofHCVinfectionamong PWIDapossibility(Grebely&Dore,2014;Martin,Vickerman,etal., 2013).

ModelsofcareforthetreatmentofHCVinfectionamong

PWID

Traditionally,theprovisionofHCVcareandtreatmenthasbeen providedathospital-basedspecialistservices(Bruggmann,2012). ThissettingisoftennotsuitableforPWID,giventheriskof stigma-tization,exclusionduetoprejudicesandtheabsenceofexpertisein addictiontreatment(Bruggmann&Litwin,2013).Furthermore,the limitedinfrastructurefordeliveryofHCVtherapiesandthelackof HCVknowledgeindrugandalcoholclinicsandprimarycarecentres maylimittheabilitytoprovidetreatmentsettingsthataresuitably adaptedfortheneedsofthisvulnerablepopulation(Bruggmann, 2012).Amultidisciplinaryapproachisthefoundationofa need-adaptedHCVcaresettingforPWID(Bruggmann&Litwin,2013). Closecollaborationofallinvolvedhealthprofessionalsiscrucialfor everymodeltobesuccessful.Toadoptanonjudgmentalattitude

towardPWIDisessentialforallpartiesinvolved.Ahighlevelof acceptanceoftheindividuallifecircumstancesofPWIDratherthan rigidexclusioncriteriawilldeterminethelevelofsuccessofany modelofhepatitisCmanagement.IntegratingHCVtreatmentin aprimarycare-based,multidisciplinaryOSTclinichasprovento bean efﬁcientwaytotreat a poly-morbid populationofPWID (Bruggmann&Litwin,2013).

BarrierstothetreatmentofHCVinfectionamongPWID

DespitethehighprevalenceofHCVinfection,provenfavourable HCV treatment responses, available guidelines recommending treatmentamong PWID, and hightreatmentwillingness, treat-mentuptakeremainaslowas1–2%peryear,even incountries wheretreatmentisavailableandaffordableforeveryone(Grebely &Dore,2014).Furtherresearchis neededtobetterunderstand the best interventions to enhance HCV screening, assessment and treatment to reduce the burden of HCV infection among PWID.

Anyattempttoavertthepublichealthcarethreatposedbythe loomingburdenofHCVamongPWIDwillurgentlyrequire ground-breakingchangestoalterthecurrentlyinefﬁcientsystemforthe careof HCV infectionamong this vulnerable population. A rel-evantscale-upoftreatmentamong PWIDis impossiblewithout massivelyreducing thebarrierstocare.Lowawareness(among patients,healthcareproviders,policymakers,politicalleadership andgeneralpublic),aswellaslowHCVliteracy(amonghealthcare professionalsandpatients)anddiscriminationandstigmatization ofdruguseare allmajorbarriersfor PWIDtoaccessHCVcare (Bruggmann, 2012;Paterson, Hirsch, &Andres, 2013).Many of thosebarriersarearesultofthecriminalizationofdruguse(The GlobalCommissiononDrugPolicy, 2013).Repressive drug pol-icy is hinderingeffective publichealthmeasures for PWIDand thereforefuellingtheHCVand HIVepidemicin thispopulation. De-penalizationofdrugusewouldthereforebeanimportantstep towardeliminatinghepatitisC(Bruggmann,2013).

Anothermajorbarrier totreatmentforPWIDis thepriceof medication.HCVtreatmentforbothactiveandformerPWIDis cost-effective(drivenbythepreventionbeneﬁtamong activePWID) (Martinetal.,2012;Martin,Vickerman,Miners,&Hickman,2013). However,thecostoftoday’sstandard-ofcareHCVtreatmentis pro-hibitivelyexpensivefor middle-andlow-incomecountries.Even in Western European countries, access to current therapies is restrictedbecauseoftheexorbitantcostofthemedication.High tolerabilityofthoseregimenswillbringthepotentialofhigh appli-cability.But,theirextortionatecostwillexceedeventhehealthcare budgetsofrich countries. OfferingHCV treatmentataffordable pricesiscrucialintheﬁghtoftheglobalHCVcrisis(Bruggmann, 2013).

ItisuncertainwhetherHCVtreatmentforPWIDwillbe cost-effective, particularly in the initial era of DAA-based therapy. Newer, more effective regimens will undoubtedly come at an increasedcost.Price reformandenhancedaccesstotherapyfor thosewithHCVinfectionwillrequireconsiderablepublichealth advocacyfromallsectorsintheHCVcommunity,including com-munity organizations representing PWID. The involvement of severalpharmaceuticalcompaniesindevelopmentofDAA-based therapymayenablemorecompetitivedrugpricinginhigh-income countries. In low- and middle-income countries, production of genericDAA regimenswillberequired,similartoantiretroviral therapyforHIV.

Ultimately,markedlyenhancedglobalpublichealthadvocacy andinvestmentalongthelinesoftheGlobalFundforHIV, tuber-culosisandmalaria,willberequiredtoenablebroadenedaccessto highlyeffectiveHCVtherapy,includingforPWID.

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HCV infection is widely ignored politically, resultingin low attention,resourcesandcommitment.Politicaleffortstoimprove preventionandaccesstocareandtosecureaffordabletreatmentlag farbehindthoseofHIV.Withtheavailabilityofnovel,highly effi-caciousHCVtherapies,theeliminationofHCVamongPWIDisnow feasible.Atthismoment,evidence-basedharmreductionmeasures andspecificcareelementsneedtobeoptimizedandexpandedin ordertoefficientlypreventthefurtherspreadandsecondaryliver diseaseburdenofHCVandtohaltthegrowingindividual,social andeconomicharmoftheepidemic.

Conclusion

HCVinfectionishighlyprevalentamongPWID.Globally,67%of PWIDareHCVpositive.

Awareness is low among policy makers, political leadership and generalpublic, particularlyin theregions mostaffectedby theHCVepidemicamong PWID.Despitethis, thepublichealth threat is considerable and will manifest itself in the next ﬁve years.

Overall,only10–50%ofallPWIDworldwidereceiveHCV test-ing,lessthan10%haveaccesstoassessmentandtreatmentofthe disease,despitetheevidencethattreatmentiseffective. Restric-tivedrugpolicyandlawenforcementarekeydriversoftheHCV epidemicamongPWID,ineven greatermagnitudethan ofHIV, asHCV is morecontagious and 3.5 timesmore prevalent. Suc-cessfulHCVpreventionstrategiescombinehighcoverageofharm reduction measures withHCV treatmentprovision at theright scale.The integrationofneeds-adaptedHCV treatmentservices intoharmreductionsserviceslikeopioidsubstitutiontreatment hasthepotentialtoenhancetherapyuptakeandcurerates.Novel, well-tolerated,andefficaciousinterferon-freeHCVtreatment regi-mensadministeredoncedailyasapillover8–12weeksbringalong thepotentialtocurethemajorityofinfectedpeoplewhoinject drugs.Withthesenewmedicines,theeliminationofHCVamong PWIDbecomesachievable.The contentsand conclusionsofthe paperreflectabroadconsensusamongsocialandclinical scien-tistsparticipatinginaUNODCScientificConsultationonHIV/AIDS (UNODC,2014).

ConclusionStatements:

-HCVprevalenceishighamongPWID.Globally,67%ofPWID areHCVpositive.

-ThepublichealththreatbytheHCVepidemicisconsiderable andwillcontinuouslyincreaseinthenextyears.Still, Hep-atitisCawarenessisgenerallylow,evenamonghealthcare providersand healthministries,particularly intheregions mostaffectedbytheHCVepidemicamongPWID.

-Accesstotesting,assessmentandtreatmentforPWIDispoor, despitetheevidencethattreatmentiseffective.

-The HCV epidemic among PWID is relevantly driven by restrictivedrugpolicyandlawenforcement.

-HCVcanbepreventedbyacombinationofhighcoverageof harmreductionmeasureswithHCVtreatmentprovisionat therightscale.

-Treatmentuptakeandcureratescanbeenhancedbythe pro-visionofHCVcareintegratedintoharmreductionsservices likeopioidsubstitutiontreatment.

-Newinterferon-freeHCVtreatmentregimenshavethe poten-tialtocurethemajorityofinfectedpeoplewhoinjectdrugs. Withthesewelltoleratedandeasytoadministermedicines, theeliminationofHCVamongPWIDbecomesachievable.

Conﬂictofintereststatement

P.B.servedasanadvisorand/orspeakerforandhasreceived grantsfromRoche,MSD,Janssen,Abbvie,GileadandBMS.

JGissupportedbyaNationalHealthandMedicalResearch Coun-cil(NHMRC)CareerDevelopmentFellowship.TheKirbyInstituteis fundedbytheAustralianGovernmentDepartmentofHealthand Ageing.Theviewsexpressedinthispublicationdonotnecessarily representthepositionoftheAustralianGovernment.

JGisaconsultant/advisorandhasreceivedresearchgrantsfrom Abbvie,BristolMyersSquibb,Gilead,Janssen,andMerck.

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