HIV pre-exposure prophylaxis (PrEP) 2017 · Melinda Tenant-Flowers Retired Consultant in HIV and...

GuidelinewritinggroupMichaelBrady(co-Chair) ConsultantinSexualHealth&HIV,King’sCollegeHospitalAlisonRodger(co-Chair) Reader&HonConsultantInfectiousDiseases&HIV,UniversityCollegeLondonDavidAsboe ConsultantHIVandSexualHealth,ChelseaandWestminsterValentinaCambiano LecturerinInfectiousDiseaseModellingandBiostatistics,UniversityCollegeLondonDanClutterbuck ConsultantHIVandSexualHealth,NHSLothianMonicaDesai ConsultantEpidemiologist,PublicHealthEnglandNigelField SeniorLecturer,ConsultantClinicalEpidemiologist,UniversityCollegeLondonJustinHarbottle ProgrammeOfficer,TerrenceHigginsTrustZahraJamal PolicyandResearchOfficer,NAZSheenaMcCormack ProfessorofClinicalEpidemiology,MRCCTUatUCLAdrianPalfreeman ConsultantHIVandSexualHealth,UniversityHospitalsofLeicesterNHSTrustMagsPortman ConsultantHIVandSexualHealth,MortimerMarketCentre,LondonKillianQuinn ConsultantHIVandSexualHealth,King’sCollegeHospital,LondonIngridYoung Chancellor'sFellow,UsherInstitute,UniversityofEdinburghMelindaTenant-Flowers RetiredConsultantinHIVandSexualHealthMedicine,King’sCollegeHospital,LondonEdWilkins ConsultantinInfectiousDiseases,NorthManchesterGeneralHospital

BHIVA/BASHH guidelines on the use of HIV pre-exposure prophylaxis (PrEP)

BHIVA/BASHHguidelinesontheuseofPrEP

Contents1.1Inclusivity..........................................................................................................................................5

2Methods..........................................................................................................................................................62.1Searchstrategy.................................................................................................................................62.2GRADEsystem...................................................................................................................................62.2.1Goodpracticepoints...........................................................................................................................7

2.3Stakeholderinvolvement,pilotingandfeedback...............................................................................72.4References........................................................................................................................................7

3Evidenceforsafetyandefficacyinkeypopulations.........................................................................................83.1Evidenceforsafetyandefficacyinmenwhohavesexwithmen(MSM)............................................83.1.1Efficacy................................................................................................................................................83.1.2AdherenceinMSMpopulations.......................................................................................................103.1.3Safety................................................................................................................................................113.1.4Riskbehaviour/STIsinMSM.............................................................................................................133.1.6References........................................................................................................................................14

3.2Evidenceforsafetyandefficacyinheterosexualpopulations..........................................................163.2.1Efficacy..............................................................................................................................................163.2.2Adherenceinheterosexualpopulations...........................................................................................193.2.3Safety................................................................................................................................................213.2.4Riskbehaviour/STIs...........................................................................................................................233.2.5References........................................................................................................................................23

3.3Evidenceforsafetyandefficacyinpeoplewhoinjectdrugs(PWID)................................................263.3.1Efficacy..............................................................................................................................................263.3.2Adherence.........................................................................................................................................273.3.3Safety................................................................................................................................................273.3.4Riskbehaviour..................................................................................................................................283.3.6References........................................................................................................................................28

3.4Evidenceforsafetyandefficacyintranspeople..............................................................................293.4.1Efficacyintranswomen....................................................................................................................293.4.3Safetyintranswomen......................................................................................................................303.4.4Transmen.........................................................................................................................................313.4.5References........................................................................................................................................32

3.5Evidenceforsafetyandefficacyinyoungpeople(15–25years).......................................................333.5.1Efficacy..............................................................................................................................................333.5.2Adherence.........................................................................................................................................343.5.3Safety................................................................................................................................................343.5.4Riskbehaviour..................................................................................................................................363.5.5References........................................................................................................................................36

3.6EvidenceforthetimelinesforstartingandstoppingPrEP................................................................383.6.1BloodPBMCs.....................................................................................................................................383.6.2Femaleandmalegenitaltract..........................................................................................................393.6.3Rectaltissues....................................................................................................................................403.6.4DurationofPrEPusefollowinglastpossibleexposure.....................................................................403.6.5References........................................................................................................................................42

4Baselinerisk-assessment...............................................................................................................................434.1HowtotargetthoseatriskofHIVtransmission...............................................................................434.2AssociationswithHIVtransmissioninUKpopulations....................................................................444.2.1MSMandtransgenderwomen.........................................................................................................444.2.2Heterosexualmenandwomen.........................................................................................................454.2.3Peoplewhouserecreationaldrugsorpeoplewhoinjectdrugs......................................................464.2.4PeoplewithHIV-positivepartnerswhoarenotonsuppressivetherapy.........................................464.2.5Vulnerabilityfactorsintranspeople................................................................................................464.2.6Sexualhealthautonomyandsexualnetworks.................................................................................464.2.7Riskassessment(Table4.2.2andproforma).SeeAppendix2.........................................................47

4.3References......................................................................................................................................48

5InitiatingPrEP................................................................................................................................................495.1Overview........................................................................................................................................495.2Education,behaviouralsupportandadherence..............................................................................495.2.1Education..........................................................................................................................................495.2.2Behaviouralsupport.........................................................................................................................505.2.3Adherence.........................................................................................................................................505.2.4References........................................................................................................................................51

5.3SettingsandcontexttoadministerPrEP..........................................................................................525.3.1References........................................................................................................................................53

5.4Baselineassessmentandtesting.....................................................................................................545.4.1Assessmentforconsiderationofpost-exposureprophylaxisfollowingsexualexposure(PEPSE)...545.4.2HIVtesting........................................................................................................................................545.4.3AcuteHIVinfection...........................................................................................................................545.4.4Assessmentofrenalfunction...........................................................................................................545.4.5STIscreen..........................................................................................................................................555.4.6.Assessmentofviralhepatitisstatus................................................................................................565.4.7References........................................................................................................................................57

5.5Otherconsiderations.......................................................................................................................585.5.1Pregnancyortryingtoconceive.......................................................................................................585.5.2Bonehealth.......................................................................................................................................585.5.3References........................................................................................................................................59

5.6PrescribingPrEP..............................................................................................................................595.6.1Whattouse......................................................................................................................................595.6.2Lead-inperiod...................................................................................................................................595.6.3Frequencyofdosingtoattainbenefit..............................................................................................595.6.4On-demanddosing...........................................................................................................................595.6.5References........................................................................................................................................61

6Clinicalfollow-upandmonitoringontreatment............................................................................................636.1Overview........................................................................................................................................636.2Continuedprescribing.....................................................................................................................636.3Assessingadherenceandadverseevents........................................................................................636.4Managementofshort-termsideeffects..........................................................................................636.5MonitoringonPrEP.........................................................................................................................65

6.5.1HIVtesting........................................................................................................................................656.5.2ManagementofHIVseroconversion................................................................................................656.5.3STIscreening.....................................................................................................................................656.5.4Viralhepatitis....................................................................................................................................666.5.5Renalmonitoring..............................................................................................................................666.5.6Pregnancytesting.............................................................................................................................666.5.7Bonemonitoring...............................................................................................................................666.5.8Codinganddatacollection...............................................................................................................67

6.6IndicationsforstoppingPrEP..........................................................................................................696.7References......................................................................................................................................69

7Buyinggenerics.............................................................................................................................................717.1Importingmedicinesboughtonline.................................................................................................717.2Authenticityoftenofovir-emtricitabineboughtonline....................................................................717.3EthicalaspectsregardingclinicianrecommendationtobuyPrEPonline..........................................727.3.1GeneralMedicalCouncil...................................................................................................................727.3.2ImperialCollegeHealthcareNHSTrustClinicalEthicsCommittee...................................................72

7.4Specificwebsites.............................................................................................................................727.5RenalmonitoringofpatientschoosingtobuyPrEPonline...............................................................737.6References......................................................................................................................................73

8CosteffectivenessofPrEPinhigh-incomecountries......................................................................................748.1Menwhohavesexwithmen...........................................................................................................748.2Peoplewhoinjectdrugs..................................................................................................................768.3Specialpopulations.........................................................................................................................768.4References......................................................................................................................................77

10.Listofabbreviations...................................................................................................................................86

Appendix1.Pre-exposureprophylaxis(PrEP)GUMCADcodes:informationforclinicsandsoftwareproviders.87Whyarethecodesneeded?..................................................................................................................87Whatcodesarebeingintroduced?........................................................................................................87Forwhomshouldcodesbecompleted?................................................................................................87Howoftenshouldthecodesbecompleted?.........................................................................................87Wherearethecodesbeingintroduced?................................................................................................90Eligibilitycriteria(withinthePrEPImpacttrial).....................................................................................90Codingscenarios...................................................................................................................................91

Appendix2:PrEPproformas:initialandfollow-upvisits...................................................................................94

1Objectives

Weaimtoprovideevidence-basedguidanceonbestclinicalpracticeintheprovision,monitoringandsupportofpre-exposureprophylaxis(PrEP)forthepreventionofHIVacquisition.Theguidelinesinclude:

(i)guidanceonriskassessmentpriortoPrEP;

(ii)baselineassessment;

(iii)dosingschedules;

(iv)monitoring;

(v)supportingadherence;

(vi)buyinggenericPrEP;and

(vii)costeffectiveness.

Theguidelinesareaimedatclinicalprofessionalsdirectlyinvolvedin,andresponsiblefor,HIVprevention,andatcommunityadvocatesandorganisationsresponsibleforsupportingHIVpreventionstrategiesinthoseatriskofHIVacquisition.

AdetailedreviewoftheevidencebaseisincludedinSection3.Sections4to6areintendedtoofferpracticalguidanceinriskassessment,startingPrEP,ongoingmanagementwhileonPrEPandstoppingPrEP.

1.1Inclusivity

Werecognisetheimportanceoftheseguidelinesbeinginclusiveandrelevanttoall,regardlessofsexualityorgenderidentityorexpression.Forthesakeofbrevityinthemaintextoftheguidelines,phrasessuchas‘menwhohavesexwithmen’referstocis-genderedornon-binaryorgender-queermenwhohavesexwithmenand‘heterosexualmenandwomen’referstocis-genderedornon-binaryorgender-queermenandwomenwhohaveheterosexualsex.Wheresectionsarespecificallyrelevanttotranspeople,weidentifythisusingthetermstranspeople,transmenortranswomen.

2Methods

2.1Searchstrategy

ThemultidisciplinaryguidelinewritinggroupdevelopedtheguidelinesbasedontheprocessoutlinedintheBHIVAGuidelinesDevelopmentManual[1].AllmembersofthegroupunderwentGRADEtraining.WeundertookacomprehensiveliteraturereviewonPrEPandHIVpreventionusingthePICOquestionshownbelow.Therecommendationsaretheresultofaseriesofface-to-faceandvirtualmeetingsofthewritinggroupandameetingofcommunityactivistsandorganisationswhocommentedonadraftoftheguidelinesinMay2017.Thewritinggroupalsoreviewedandincorporatedinputfromthepublicconsultationprocess.PICOquestionsweresetas:

• POPULATIONS:HIVnegative• INTERVENTION:PrEP• COMPARISON:Nospecificcomparatorswereappliedtoensureallwerepickedupinthesearch• OUTCOME:HIVinfection,adverseevent,riskbehavioursorriskcompensation(condomuse,numberof

sexualpartners,STIs),adherence

TheliteraturereviewwasfromJanuary2004–May2016.TheMedline,EmbaseandCochranedatabasesweresearched.OnlypapersinEnglishwereincludedandanimalstudieswereexcluded.Inaddition,relevantevidencepublishedbetweenMay2016andJuly2017hasbeenincluded

2.2GRADEsystem

AGrade1recommendationisastrongrecommendationtodo(ornotdo)something,wherebenefitsclearlyoutweighrisks(orviceversa)formost,ifnotall,patients.Mostcliniciansandpatientswouldwanttofollowastrongrecommendationunlessthereisaclearrationaleforanalternativeapproach.Astrongrecommendationusuallystartswiththestandardwording‘Werecommend’.

AGrade2recommendationisaweakerorconditionalrecommendation,wheretherisksandbenefitsaremorecloselybalancedoraremoreuncertain.Alternativeapproachesorstrategiesmaybereasonabledependingontheindividualpatient’scircumstances,preferencesandvalues.Aweakorconditionalrecommendationusuallystartswiththestandardwording‘Wesuggest’.

Thestrengthofarecommendationisdeterminednotonlybythequalityofevidencefordefinedoutcomes,butalsothebalancebetweendesirableandundesirableeffectsofatreatmentorintervention,differencesinvaluesandpreferences,andwhereappropriate,resourceuse.Eachrecommendationconcernsadefinedtargetpopulationandisactionable.

ThequalityofevidenceisgradedfromAtoDandisdefinedasfollows:

• GradeAevidencemeanshigh-qualityevidencethatcomesfromconsistentresultsfromwell-performedrandomisedcontrolledtrials(RCTs),oroverwhelmingevidencefromanothersource(suchaswell-executedobservationalstudieswithconsistentstrongeffectsandexclusionofallpotentialsourcesofbias).GradeAimpliesconfidencethatthetrueeffectliesclosetotheestimateoftheeffect.

• GradeBevidencemeansmoderate-qualityevidencefromrandomisedtrialsthatsuffersfromseriousflawsinconduct,inconsistency,indirectness,impreciseestimates,reportingbias,orsomecombinationoftheselimitations,orfromotherstudydesignswithspecificstrengthssuchasobservationalstudieswithconsistenteffectsandexclusionofthemajorityofthepotentialsourcesofbias.

• GradeCevidenceislow-qualityevidencefromcontrolledtrialswithseveralseriouslimitations,orobservationalstudieswithlimitedevidenceoneffectsandexclusionofmostpotentialsourcesofbias.

• GradeDevidenceisbasedonlyoncasestudies,expertjudgementorobservationalstudieswithinconsistenteffectsandapotentialforsubstantialbias,suchthattherecanbelittleconfidenceintheeffectestimate.

2.2.1GoodpracticepointsInadditiontogradedrecommendations,thewritinggrouphasalsoincludedgoodpracticepoints(GPP).GPParerecommendationsbasedontheclinicaljudgementandexperienceoftheworkinggroupandfeedbackfrompublicconsultation.GPPsemphasiseanareaofimportantclinicalpracticeforwhichthereisnot,noristherelikelytobe,anysignificantresearchevidence.Theyaddressanaspectoftreatmentandcarethatisregardedassuchsoundclinicalpracticethathealthcareprofessionalsareunlikelytoquestionit,andwherethealternativerecommendationisdeemedunacceptable.ItmustbeemphasisedthatGPPsarenotanalternativetoevidence-basedrecommendations.

2.3Stakeholderinvolvement,pilotingandfeedback

TheguidelinewritinggroupincludedrepresentationfromTerrenceHigginsTrustandNAZ.Inordertowidenthestakeholderinvolvement,ameetingofcommunityactivistsandorganisationswasheldinMay2017whenfeedbackwassoughtonthecontentofthedraftguidelinesandrecommendationspriortowiderpublicconsultation.Weacknowledgethefollowingfortheirhelpfulcontributions:YusefAzad(NAT),TakudzwaMukiwa(THT),WillNutland(Prepster),GregOwen(IWantPrEPNow),MichelleRoss(CliniQ),SophieStrachan(SophiaForum),MarcThompson(Prepster/BlackOutUK)andGeorgeValiotis(HIVScotland)

2.4References1. BHIVA.BHIVAGuidelinesDevelopmentManual.2012.Availableat:www.bhiva.org/GuidelineDevelopmentManual.aspx(accessedJuly2017).

3Evidenceforsafetyandefficacyinkeypopulations

3.1Evidenceforsafetyandefficacyinmenwhohavesexwithmen(MSM)

3.1.1Efficacy

Efficacy:summary

• PrEPconsistingoforaltenofovir-emtricitabine(TDF-FTC)takendailyoron-demandpriortopotentialriskexposureishighlyefficaciousinpreventingHIVinfectioninMSM.

• OnePhase3randomiseddouble-blindplacebocontrolledtrial(iPrex)andonePhase3open-labelRCT(PROUD)reportedtheefficacyofdailyoralPrEPwithTDF-FTCinpreventingHIVinfectioninMSMat44%and86%,respectively.

• OnePhase3randomiseddouble-blindplacebo controlledtrial(IPERGAY)reportedtheefficacyofon-demandPrEPwithTDF-FTCinpreventingHIVinfectioninMSMat86%.

• ThereislessevidencetosupportTDFaloneasPrEPinMSM.OnePhase2trial(theCDCMSMSafetyTrial)hasdemonstratedthesafetyofTDFaloneasPrEP.

• Open-labelextensionstudieshavedemonstratedeffectivenessofPrEPinMSMo iPrexOpen-labelExtension(iPrex-OLE)reportednoHIVseroconversionswhendruglevelswere

compatiblewithtakingfourormorepillsperweek.o IPERGAYOpen-labelExtension(IPERGAY-OLE)demonstrateda97%reductioninHIV

transmissionriskcomparedtotheplaceboarmoftheIPERGAYrandomisedphase.

3.1.1.1Phase3clinicalstudies

3.1.1.1.1iPrEx

TheiPrExstudy[1]wasaPhase3,randomised,double-blind,placebo-controlled,multi-centretrialconductedamong2499MSMandtransgendermale-to-femaleadults(n=339)inPeru,Ecuador,Brazil,Thailand,SouthAfricaandtheUnitedStates.ParticipantswererandomlyassignedtoeitheradailydoseofTDF-FTC(1251participants)orplacebo(1248participants).PrimaryoutcomewasHIVinfectionwithatotalof3324person-yearsoffollow-up.Overthecourseofthestudy,100participantsbecameinfectedwithHIV;36intheTDF-FTCgroupand64intheplacebogroup,representinga44%(95%confidenceinterval[CI]15–63)reductioninHIVincidenceusingamodifiedintention-to-treat(ITT)analysis,excludingthoseconfirmedHIVpositiveatrandomisation.Efficacywashigherintheper-protocolanalysis;atvisitswhereadherencewas>50%byself-reportandpillcount/dispensing,efficacywas50%(95%CI18–70).

3.1.1.1.2PROUD

ThePROUDstudywasaPhase3,randomised,open-label,multi-centretrialconductedamong544MSMat13sexualhealthclinicsinEngland[2].ParticipantswererandomlyassignedtoadailydoseofTDF-FTCimmediately(275participants),orafteradeferralperiodof12months(269participants).Primaryoutcomesweretimetoaccrualof500participantsandretentionat12and24months;HIVinfectionwasasecondaryoutcome.Atinterimreview,theDSMBrecommendedthatallstudyparticipantsshouldbeofferedstudydrug.Atotalof23participantsbecameinfectedwithHIVoverthecourseofthestudy;threeinthedailyTDF-FTCgroupand20inthedeferred(no-PrEP)group,representingaratedifferenceinHIVinfectionof7.8per100person-years(90%CI4.3–11.3)inthemodifiedITTanalysisremovingthethreeadditionalinfectionsatrandomisation.Therelativeriskreductionwas86%(90%CI64–96%)andthenumberneededtotreatover1yeartopreventoneHIVinfectionwas13(90%CI9–23).

3.1.1.1.3IPERGAY

TheIPERGAYstudywasaPhase3double-blind,randomised,multi-centretrialconductedamong414MSMinFranceandCanada[3].Participantswererandomlyassignedtoeitherreceivinganon-demandregimenofTDF-FTC(206participants)orplacebo(206participants).Theon-demandregimeninvolvedtakingadoubledoseofTDF-FTC2–24hoursbeforesex,andadailydoseduringperiodsofsexualriskandfor48hours(twodoses)afterceasingsexualrisk.Participantswerefollowedupevery8weeksforHIVtestingandrisk-reductionadvice,andevery6monthsforsexuallytransmittedinfection(STI)testingforatotalof431person-yearsoffollow-up.PrimaryendpointwasHIVinfection.Atinterimreview,theplacebogroupwasdiscontinuedandallstudyparticipantswereofferedstudydrug.Overthecourseofthestudy,16peoplebecameinfectedwithHIV:twointheTDF-FTCgroupand14intheplacebogroup,representingarelativeriskreductionof86%(95%CI40–98%)intheITTanalysis.

3.1.1.2Phase2clinicalstudiesOnePhase2safetytrial,theCDCMSMSafetyTrial[4]comparedtenofovir(TDF)toplaceboinarandomised,double-blind,placebo-controlled,wait-listeddesignamong400HIV-negativeMSM.Participantswererandomlyassignedina1:1:1:1designtoreceiveTDForplaceboimmediatelyorafter9months.Mainendpointsweresafetyandbehaviouraloutcomes.Therewerenoinfectionsamongthosetakingactivedrug.Sevenparticipantsseroconverted:fourintheplaceboarmandthreeamongdelayed-armparticipantswhowerenotonthestudydrug.AneighthparticipantwasHIVpositiveatenrolment.

3.1.1.3RandomisedpilotstudiesTwofurthersmallerstudiesincludeapilotfeasibilityandacceptabilitystudy,ProjectPrEPare,whichrecruited58youngMSMaged18–22intheUnitedStates.Participantswererandomlyallocatedtoreceiveabehaviouralinterventionalone,thebehaviouralinterventionandPrEP(TDF-FTC)orthebehaviouralinterventionandplacebo.Therewerenoseroconversionsamongthe58participants[5].

TheIAVIKenyaStudywasasmallsafetyandadherencestudyconductedamongKenyanMSMandfemalecommercialsexworkers(CSW).Sixty-sevenMSMandfivefemaleCSWwererandomisedtodailyTDF-FTCorplacebo,orintermittent(Monday,Fridayandwithin2hoursaftersex)TDF-FTCorplaceboina2:1:2:1ratio.Therewasoneseroconversionintheplaceboarm[6].

3.1.1.4Open-labelstudiesTheiPrExOpen-labelExtension(iPrEx-OLE)[7]enrolled1603HIV-negativemenandtranswomenwhohavesexwithmenwhowerepreviouslypartofPrEPstudies(iPrEx,ATN082/ProjectPrEPareandCDCMSMSafetyTrial).ParticipantswereoffereddailyTDF-FTCandwerefollowedupfor72weeksafterenrolment.Uptakewashighat76%,andthiswashigheramongthosereportingcondomlessreceptiveanalintercourseandthosewhowereherpessimplex-2virus(HSV-2)seropositive,suggestinguseduringperiodsofrisk.HIVincidencewas1·8infectionsper100person-years,comparedwith2·6infectionsper100person-yearsinthosewhoconcurrentlydidnotchoosePrEP(hazardratio[HR]:0.51,95%CI0.26–1.01,adjustedforsexualbehaviours)[7].ExaminationofdruglevelsbydriedbloodspottestingwasextrapolatedtopilltakingandcomparedtoHIVincidenceeachquarter.Noseroconversionswereseenwhendruglevelswerecompatiblewithtakingfourormorepillsperweek.

TheIPERGAYOpen-labelExtension(IPERGAY-OLE)enrolled362individualstotakeon-demandTDF-FTCandfollowedthemforamedianof11.7monthsandofwhom299(83%)completedfollow-upwithasingleHIVinfection(0.19per100person-years,95%CI0.01–1.08)[8].

3.1.1.5ObservationaldataAcommunity-basedclinicinSanFranciscoscreened1249MSM(andthreetransmen)andofferedPrEPwithTDF-FTCwith95.5%uptake.Condomlesssexwasreportedby93%atenrolment.Afteramaximumof16months’follow-uptherewerenonewHIVinfectionsinthemenenrolledintheprogramme[9].

AtthetimeofwritingtherehavebeenthreecasereportsofHIVtransmissionsinMSMtakingPrEPdespiteapparentconfirmedadherence.Twoindividualswereinfectedwithresistantvirusand,inonecase,transmissionoccurredwithwild-typevirussensitivetobothtenofovirandemtricitabine[10].

3.1Evidenceforsafetyandefficacyinmenwhohavesexwithmen(MSM):recommendations1. WerecommendthatPrEPwithon-demandordailyoralTDF-FTCshouldbeofferedtoHIV-negative

MSMwhoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughcondomlessanalsexintheprevious3–6monthsandongoingcondomlessanalsex.(1A)

2. WerecommendthatPrEPwithon-demandordailyoralTDF-FTCshouldbeofferedtoHIV-negativeMSMhavingcondomlessanalsexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

3. WesuggestthattenofoviraloneshouldnotcurrentlybeofferedasPrEPtoMSM.Thisrecommendationisbasedonlackofevidence,ratherthanevidenceoflackofeffect.(2C)

Goodpracticepoint• ConsiderPrEPonacase-by-casebasisinMSMwithcurrentfactorsotherthancondomlessanalsexin

previous3–6monthsthatmayputthematincreasedriskofHIVacquisition.SeeSection4.

3.1.2AdherenceinMSMpopulations

AdherenceinMSMpopulations:summary

• PrEPefficacyishighlydependentonadherence.• IniPrEXamongthosewhohaddetectableTDF-FTClevelsthereductionofHIVincidencewas92%

comparedtothosewhohadnodrugdetected.• IniPrEx-OLE,noseroconversionswereseenwhendruglevelswerecompatiblewithtakingfourormore

pillsperweek.• InPROUDsufficientstudydrugwasprescribedfor88%ofthetotalfollow-uptimeandtenofovirwas

detectedinallsamplestakenfromaconveniencesampleof52participantswhoreportedtakingstudydrug.

• InIPERGAY86%ofasubsetof113participantsintheactivetreatmentgroupwhohaddruglevelsmeasuredhadprotectivedruglevelsoftenofovir.

EfficacyofPrEPishighlydependentonadherencewithameta-analysisofPrEPstudies[11]demonstratingthatadherenceisasignificantmoderatorofPrEPeffectiveness.ThehigherthelevelsofadherencetooralPrEPinthestudypopulation,asmeasuredbydetectabledrug,thegreatertheefficacy.

IntheiPrEXstudy,adherencewasmonitoredusingpillcountandself-reportedadherence.Pharmacokineticplasmaandintracellulardrug-levelsamplingwasconductedinapre-specifiedsubgroupanalysiswheresubjectswithHIVinfectionwerematchedwithtwocontrolsselectedfromseronegativesubjects.InthosewhohaddetectabledruglevelsofTDF-FTC,thereductioninHIVincidencewas92%(95%CI40–99%)comparedtothosewhohadnodrugdetected[1],suggestingthatahighlevelofadherenceisassociatedwithahighlevelofefficacy.

InthePROUDstudy,adherencewasmonitoredusingprescriptiondata,self-reportedadherenceanddruglevelsinaconveniencesampleofstudyparticipants.Overall,sufficientstudydrugwasprescribedfor88%ofthetotalfollow-uptimeandtenofovirwasdetectedinallsamplestakenfrom52participantswhoreportedtakingstudydrugwithinthepreceding3days[2].

IntheIPERGAYstudy,adherencewasmonitoredusingpillcounts,self-reportedadherenceanddruglevelsinasubsetof113participants.Ofparticipantsintheactivetreatmentgroupwhohaddruglevelsmeasured,protectivedruglevelsoftenofovirweredetectedin86%.However,computer-assistedinterview(CASI)datacollectedin319participantsintherandomisedphasesuggestedthatonly43%ofpeopletookstudydrugcorrectlyduringlastsexualintercourse,29%tookasuboptimaldoseand28%didnottakethestudydrugatall[3].Intheopen-labelphase,adherencein362mencompleting1617CASIreturnsreported50%ofmentakingstudydrugcorrectlyduringlastsexualencounter,24%takingasuboptimaldoseand26%takingnostudydrugatall[8].

ComparisonofadherencetodifferentregimensofTDF-FTCPrEPhasbeeninvestigatedinMSMintheHPTN067(ADAPT)study.ThestudyrecruitedMSMandtranswomeninHarlem(NewYork,USA)andThailandandheterosexualwomeninSouthAfrica.Followinga4-weekphaseofdailydosing,participantswererandomlyassigned1:1:1tooneofthreeregimens:dailydosing('daily'),onetablettwiceaweekandonetabletpostsex(‘timedriven’)oronetablet24–48hoursbeforesexandonetabletwithin2hoursaftersex(‘eventbased’).Resultsfrom178ThaiMSMshowedthatcoverage(definedastakingmorethanonepillinthe4daysbeforesexandmorethanonepillinthe24hoursafterwards)wassignificantlyhigherinthedaily(85%ofeventscovered)andtime-driven(84%)armsthanintheevent-drivenarm(74%).Twoseroconversionsoccurredinthe4weekpre-randomisationphase[12].In179MSMinHarlem,figureswere66%,47%and52%,respectively,withoneseroconversioninthepre-randomisationphaseandoneintherandomisedphase[13].Adherencewashigherinthedaily-dosearms:inThailand,85%ofdailydoses,79%oftwice-weeklydoses,and65%ofevent-drivendosesweretakenasprescribed.InHarlem,therespectivefigureswere65%,46%and41%.AlthoughtheserepresenttwodiversepopulationsofMSMindifferentsettings,thestudydemonstratedsimilarcoverageofsexactsfordailyandnon-dailyregimenswithbothgroupsdemonstratingloweradherenceandcoverageratesfortheevent-drivenapproach.

HighercoverageofeventsintheThaiMSMwasassociatedwitholderageandhigherlevelofeducation.Useofstimulantdrugsandhighersexualfrequencywasassociatedwithlowercoverage[14].

3.1.3Safety

Safety:summary

• RCTshaveshowngoodsafetydata(includingrenalsafetydata)fordailyandon-demandoralTDF-FTCasPrEPinMSM.

• Whererenalfunctionhasbeenaffected,TDF-FTCwasassociatedwithmild,non-progressiveandreversiblereductionsincreatinineclearance(CrCl).

• Beingaged>40yearsorhavingaCrCl<90mL/minatbaselinepriortostartingPrEPwereindependentlyassociatedwitha(small)riskofCrClfallingto≤60mL/min.

• Wherebonemineraldensityhasbeenstudied,smallnetdecreaseshavebeennotedinthosetakingTDF-FTC.Therearenolong-termdataonbonehealthorevidenceofincreasedfracturerisk.

3.1.3.1Adverseeventsandgrade3–4safetydataTodate,studiesofTDF-FTCPrEPsuggestshort-termsafety.Ameta-analysisofPrEPstudies[11]demonstratednodifferenceintheproportionsofadverseeventscomparingPrEPtoplaceboacross10placebo-controlledRCTs(oddsratio[OR]:1.01,95%CI0.99–1.03,P=0.27)withnodifferencesseeninsubgroupanalysisthatincludedmodeofacquisition,adherence,sex,drugregimen,dosingorage.Nodifferenceswereseeningrade3or4adverseeventscomparingPrEPandplacebogroupsacross11placebo-controlledRCTs(riskratio[RR]:1.02,95%CI0.92–1.13,P=0.76).Resultswerenotpresentedbysubgroup.

IntheiPrExstudy,therewasnodifferenceinreportedadverseeventsbetweenthetwostudyarms:867/1251(67%)ofparticipantsintheTDF-FTCarmreportedanyadverseevent,comparedto877/1248(70%)inthecontrolarm.Botharmsreportedsimilarratesofgrade3and4adverseevents:151/1251(12%)ofTDF-FTCparticipantscomparedto164/1248(13%)ofcontrol-armparticipants[1].Therewasnodifferenceinpermanentortemporarydiscontinuationofstudydrugbetweenthetwoarms:25/1251(2%)permanentdiscontinuationintheinterventionarmcomparedto27/1248(2%)intheplaceboarmandatotalof79/1251(6%)permanentortemporarydiscontinuationsintheinterventionarmcomparedto72/1248(6%)intheplaceboarm.However,nauseawasmorecommonamongthosetakingTDF-FTCcomparedtoplacebointhefirstmonth(95%vs5%).Depression-relatedadverseeventswerethemostcommonsevereorlife-threateningadverseeventsreportediniPrEx,butwerenotassociatedwithbeingrandomlyassignedtoTDF-FTC(OR0.66,95%CI0.35–1.25)[15].

InthePROUDstudy,21/275participants(8%)interruptedormissedstudydrugdosesbecauseofadverseevents,thecommonestofwhichwereheadacheandnausea[2].InIPERGAY,drug-relatedgastrointestinaladverseeventswerereportedmorecommonlyintheTDF-FTCgroupcomparedtotheplacebogroup(14%vs5%,P=0.002),buttherewasnodifferenceinthefrequencyofgrade3or4adverseevents[3].

3.1.3.2RenalfunctionPrEPtrialshaveshownmodest,butstatisticallysignificantdeclinesinrenalfunctionwithadministrationofdailyTDF-FTC,buttheincidenceofseriousrenaleventswasverylowandmostlyreversible.

InPROUD,threeparticipantsinterrupteddrugduetoelevatedcreatinineconcentrations(twowereclassedasmildelevation,definedas1.1–1.3timestheupperlimitofnormal[ULN],andoneasmoderate,1.4–1.8ULN),althoughthemostlikelyexplanationinonemanwasrecreationaldruguseandtheothertwomenwereolderwithcomorbidities[2].IntheIPERGAYstudy,18%ofactivedrugparticipantsexperiencedelevatedcreatininelevelscomparedto10%ofplacebogroup(P=0.03).Allbutonewasmildandtransient,andnoneledtodiscontinuationofstudydrug[3].

IntheiPrExstudy,useofTDF-FTCwasassociatedwithamildnon-progressivedecreaseinestimatedcreatinineclearance(CrCl)of2.4%frombaseline,whichwasreversible[13].Creatinineelevationsofgreaterthan1.1ULNweresimilarbetweenactiveandplaceboarms,occurringin32(2.6%)intheactivearmand24(2.2%)intheplaceboarm(RR:1.35,95%CI0.80–2.3).Mostexcesscreatinineelevationsintheactivearmofthestudy(medianfollow-up72weeks)occurredat12–24weeksandalloccurredatlessthan48weeks.Proteinuriabydipstickwasdetectedregularly(613/5081[12%]dipsticksperformed),buttherewasnobetween-groupdifferenceintheproportionofparticipantseverpositiveforproteinuria(20%placebovs21%TDF-FTC;P = 0.62).Inaddition,thepositivepredictivevalueofproteinuriainpredictingaconfirmedcreatinineelevationwaspoorat0.7%[13].

IniPrEx-OLEtheprobabilityofCrClfallingto≤60mL/minatleastonceoverthefirstyearonPrEPwaslow,butwasmorelikelywhenparticipantsstartedPrEPatolderages(>40years)orwithastartingCrCl≤90mL/min[14].Forparticipantsunder40yearsofage,themeandeclineinCrCloverthedurationofthestudy(median72weeks)wasmodest(−2.6%)andnopatientsexperiencedaCrCldropto≤60mL/mineveninthosewithfulladherencetodailydosingindicatingthatannualmonitoringofrenalfunctioninthisgroupshouldbesufficient.However,beingaged>40yearsorwithalowerbaselinecreatinineclearance(≤90mL/min)atinitiationofPrEPwereindependentlyassociatedwithariskofCrClfalling≤60mL/min,especiallywithdailydosing.ThissuggeststhatmorefrequentrenalmonitoringonPrEPmayberequiredinolderPrEPusers(>40years)andinthosewithmarginalrenalfunctionatbaseline,eveniftherearenootherconcomitantriskfactorsforrenaldisease.

3.1.3.3BonemineraldensityInaniPrExsub-studyof500participantswhounderwent6-monthlyDEXAscanstoassessbonemineraldensity(BMD),asmallnetdecreaseinBMDof0.7–1%wasseenamongthoserandomlyassignedtoTDF-FTC(n=247)comparedtoplacebo(n=256)after24weeksinbothspineandtotalhipmeasures[16].Therearenolong-termdataonbonehealthforpeopleonTDF-FTCPrEP.IntheCDCMSMstudy,inmultivariateanalysis,backpainwasassociatedwithuseofTDFandalsoasmalldecreaseinBMDamongasubsetof184menintheSanFranciscosite.However,TDFusewasnotassociatedwithbonefractures[17].

3.1.3.4DrugresistanceIntheiPrExtrial,FTC-relateddrugresistancedevelopedintwoparticipantswhohadunrecognisedacuteHIVinfectionatbaseline[18].TheseindividualshadanegativeantibodytestbeforestartingPrEP,butlatertestedpositive.InthePROUDstudy,twoofthethreeparticipantswithapositiveHIVtestatenrolmentorthe4-weekvisithadFTC-relateddrugresistance;noresistancewasdetectedinparticipantswhoacquiredHIVpost-randomisation[2].InIPERGAY,noneoftheincidentHIVinfectionspost-randomisationdemonstratedresistancemutationstostudydrug[3].

Inameta-analysis,Fonneretal.reviewedresultsfromsixtrialsthatreportedcasesofFTCorTDFdrugresistanceusingstandardisedgenotypiclaboratoryassays[11].AlthoughtheonlystudyofMSMincludedinthisanalysiswasiPrEx,theriskfactorsassociatedwithdevelopmentofdrugresistancewillbesimilarinMSMandpeoplewhohaveheterosexualsex.TheriskofdevelopinganFTC-relatedmutationamongthoseacutelyinfectedwithHIVatenrolmentwassignificantlyhigherinthegrouprandomlyallocatedtoreceiveTDF-FTCcomparedtoplacebo(riskratio=3.72,95%CI1.23–11.23,P=0.02).TheriskofaTDF-relatedmutationwasnotstatisticallydifferentbetweenPrEPandplaceboregardlessofPrEPregimenamongthoseacutelyinfectedatenrolment.Additionally,six(2%)TDF-orFTC-resistantinfectionsoccurredamong544post-randomisationHIVinfections;fiveinPrEPgroupsandoneinaplacebogroup.Numbersweretoosmalltocalculateapooledrelativerisk.

3.1.4Riskbehaviour/STIsinMSM

Riskbehaviour/STIsinMSM:summary

• Findingsfromplacebo-controlledtrialsofPrEPdonotpermitconclusionstobedrawnregardingtheeffectofPrEPonsexualbehaviour.

• PROUDdemonstratednodifferencebetweentheimmediateanddeferredarmsintotalnumberofsexualpartnersortheincidenceofSTIs,whichwerehighinbothgroupspriortoenrolmentandduringthetrial.Agreaterproportionoftheimmediategroupreportedreceptiveanalsexwithoutacondomwith10ormorepartnersinthe3monthspriortothe1-yearquestionnairecomparedtothedeferredgroup.

• Intheopen-labelphaseofIPERGAY(IPERGAY-OLE)therewasahighlysignificantreductioninreportedcondomuseovertime.

• AlargeobservationalcohortinSanFranciscoreportedthatcondomusereducedinasubstantialminorityofMSMonPrEP.

RiskbehaviourhasbeenmeasuredusingoutcomesincludingSTIdiagnoses,condomuseandsexualpartnernumbers.ThemostclinicallyrelevantoutcomeisSTIdiagnoses,notleastbecausetheothertwoindicatorsareself-reportedand,assuch,subjecttoreportingbias.

Intheplacebo-controlledtrials,onepurposeoftheplaceboistocontrolforbehaviour,anditisnotpossibletocommentontheimpactofPrEPonbehaviour,asparticipantsdonotknowiftheyareonactivedrug.However,itispossibletoevaluatetheimpactoftherisk-reductionsupportprovidedtoallparticipants,andthereweredemonstrablebenefitsiniPrEx,theCDCMSMSafetyTrial,butnottheIAVIKenyastudy.

IntheiPrExstudy,bothPrEPandplacebogroupsreportedincreasedcondomuseoverthecourseofthestudyandreportedcondomusedidnotdifferbetweenthearms(P=0.36)[1].Thenumberofreportedreceptivesexualintercoursepartnersinbotharmsalsodeclinedoverthecourseofthestudywithnosignificantdifferenceinthenumberofpartnersreportedineachgroupateachtimepoint(P=0.97)[1].ThereductioninriskbehavioursmayreflectthefactthatthemajorityofiPrExparticipantscamefrompopulationswithlittleaccesstorisk-reductionsupport.

InIPERGAY,therewerenosignificantdifferencesbetweenTDF-FTCandplacebogroupsintheproportionofcondomlessreceptiveanalsex(P=0.40)andincidentSTIs(P=0.10).Therewasaslightbutsignificantdecreaseinthenumberofsexualpartnersintheprevious2monthsintheplacebogroupcomparedtotheTDF-FTCgroup(7.5vs8,P=0.001)[3,19].

IntheCDCMSMSafetyTrial(alsoplacebo-controlled),meannumberofsexualpartnersintheprevious3monthsandtheproportionreportingcondomlessanalsexdeclinedover24monthsoffollow-up.

TheIAVIKenyastudy,whichincludedMSM,wastheonlytrialtoreportanincreaseinstudypartnersfrombaselinetofollow-up,butpartnersmayhavebeenunderreportedatbaseline[6].

Intheopen-labelPROUDstudy,inwhichparticipantsknewtheyweretakingPrEPandthatitwasatleastpartiallyeffective,therewasnodifferencebetweentheimmediateanddeferred(no-PrEP)groupsinthetotalnumberofsexualpartners(P=0.57)inthe3monthspriortothe1-yearquestionnaire,butagreaterproportionoftheimmediategroupreportedreceptiveanalsexwithoutacondomwith10ormorepartnerscomparedtothedeferredgroup(21%vs12%,P=0.03).TherewasnodifferenceinthefrequencyofbacterialSTIsduringtherandomisedphase(P=0.74)[2].

IntheiPrEx-OLEstudy,bothgroupsreporteddecreasesinreportedcondomlessreceptiveanalintercoursefrom34%(377/1115)to25%(232/926P=0.006)amongthoseacceptingPrEPandfrom27%(101/369)to20%(61/304;P=0.03)inthegroupwhodeclinedPrEP.Conversely,inIPERGAY-OLEtherewasamuchhigherbaselinerateandasignificantincreaseinreportedcondomlesssexatlastreceptiveanalintercoursefrom77%atbaselineto86%at18months(P=0.003fortrend)[8].Examinationofthreedifferenttrajectoriesofcondomuse(low,mediumandhigh)andfourofPrEPuseovertimeinIPERGAY-OLEshowsthatinthemajorityofmen,declinesincondomusewerecompensatedbyincreasedon-demandPrEPuse,butinaminorityofmenthisisnotthecase.Compensationbyusingon-demandPrEPwaslowerinyoungermenforallthreecondomtrajectories[20].

InalargeobservationalcohortstudyofMSMPrEPinacommunity-basedclinicinSanFrancisco,self-reportedcondomusefordifferentsubcohortsofmentakingPrEPforperiodsof1–16monthswasunchangedin38–61%,increasedin5–12%andreducedin16–48%[9].

3.1.5.1STIsBoththePROUDandIPERGAYstudiesdocumentedhighlevelsofbacterialSTIsinMSMthroughoutthecourseoffollow-up.WithinIPERGAY,participantswerescreenedatenrolmentandevery6monthsduringfollow-upforchlamydiaandgonorrhoea(withtriplesitenucleicacidamplificationtests)andsyphilis[10].OfparticipantsreceivingTDF-FTC,41%acquiredanewSTIduringfollow-up,comparedto33%intheplaceboarm;mostSTIswererectaland10%acquiredanewsyphilisinfection[3].SimilarresultswereobservedwithinthePROUDstudywhere3–6-monthlySTIscreeningwasofferedandtheproportionswithabacterialSTIwere50%and57%ofmendiagnosedwithanSTI,respectively,inthedeferredanimmediatetreatmentarmsofthestudy(P=0.74).SimilarlytoIPERGAY,10%ofindividualsinPROUDacquiredanewsyphilisinfection[2].InIPREXOLEtheincidenceofsyphiliswassimilarinbothgroups,althoughnumericallyhigheramongPrEPusers(7.2/100person-yearscomparedto5.4/100person-yearsinnon-PrEPusers,HR1.35,95%CI0.83–2.19).

InIPERGAY,incidencerateoffirstSTIwas35.2per100person-yearsinthedouble-blindphase,and40.6per100person-yearsintheopen-labelphase[3].

IncidenthepatitisChasalsobeenreportedinclinicaltrialsandPrEPaccessprojects.InAmsterdam,HIV-negativeMSMwhoenrolledintheAmsterdamPrEPdemonstrationprojecthadconsiderablyhigherhepatitisCvirus(HCV)prevalenceat4.8%thanHIVnegativeMSMinthegeneralAmsterdamSTIclinicsurveyat0.3–1.2%[21].GeneticanalysessuggestedthatcirculatingHCVstrainsinHIV-negativemenonPrEPweresimilartothoseinlocalHIV/HCVco-infectedMSM.InthePROUDstudy5/160(3.1%)participantswhohadtestedononeormoreoccasionsforHCVhadincidentHCVinfection(3.1%).TherewerethreeincidentHCVinfectionsintheimmediatearmandtwointhedeferredarm[2].InIPERGAY,overall,therewerefiveincidentHCVinfections[3].

3.1.6References1. GrantRM,LamaJR,AndersonPLetal.PreexposurechemoprophylaxisforHIVpreventioninmenwhohavesexwithmen.NEnglJMed2010;363:2587–2599.

2. McCormackS,DunnDT,DesaiMetal.Pre-exposureprophylaxistopreventtheacquisitionofHIV-1infection(PROUD):effectivenessresultsfromthepilotphaseofapragmaticopen-labelrandomisedtrial.Lancet2016;387:53–60.

3. MolinaJM,CapitantC,SpireBetal.On-demandpreexposureprophylaxisinmenathighriskforHIV-1infection.NEnglJMed2015;373:2237–2246.

4. GrohskopfLA,ChillagKL,GvetadzeRetal.RandomizedtrialofclinicalsafetyofdailyoraltenofovirdisoproxilfumarateamongHIV-uninfectedmenwhohavesexwithmenintheUnitedStates.JAcquirImmuneDeficSyndr2013;64:79–86.

5. HosekSG,GreenKR,SiberryGetal.IntegratingbehavioralHIVinterventionsintobiomedicalpreventiontrialswithyouth:lessonsfromChicago'sProjectPrEPare.JHIVAIDSSocServ2013;12.

6. MutuaG,SandersE,MugoPetal.Safetyandadherencetointermittentpre-exposureprophylaxis(PrEP)forHIV-1inAfricanmenwhohavesexwithmenandfemalesexworkers.PLoSOne2012;7:e33103.

7. GrantRM,AndersonPL,McMahanVetal.Uptakeofpre-exposureprophylaxis,sexualpracticesandHIVincidenceinmenandtransgenderwomenwhohavesexwithmen:acohortstudy.LancetInfectDis2014.

8. MolinaJM,CharreauI,SpireBetal.Efficacy,safety,andeffectonsexualbehaviourofon-demandpre-exposureprophylaxisforHIVinmenwhohavesexwithmen:anobservationalcohortstudy.LancetHIV2017;(Epubaheadofprint).

9. GibsonS,CrouchP-C,HechtJetal.EliminatingbarrierstoincreaseuptakeofPrEPinacommunity-basedclinicinSanFrancisco.InternationalAIDSConference(AIDS2016).July2016.Durban.AbstractFRAE0104.

10. HoornenborgE,deBreeGJ.Acuteinfectionwithawild-typeHIV-1virusinPrEPuserwithhighTDFlevles.ConferenceonRetrovirusesandOpportunisticInfections.Seattle,WA,USA.

11. FonnerVA,DalglishSL,KennedyCEetal.EffectivenessandsafetyoforalHIVpreexposureprophylaxisforallpopulations.AIDS2016;30:1973–1983.

12. HoltzTH,ChitwarakornA,CurlinMetal.HPTN067/ADAPTstudy:acomparisonofdailyandnon-dailypre-exposureprophylaxisdosinginThaimenwhohavesexwithmen,Bangkok,Thailand.8thInternationalAIDSSocietyConferenceonHIVPathogenesis,TreatmentandPrevention.July2015.Vancouver,Canada.

13. SolomonMM,LamaJR,GliddenDVetal.Changesinrenalfunctionassociatedwithoralemtricitabine/tenofovirdisoproxilfumarateuseforHIVpre-exposureprophylaxis.AIDS2014;28:851–859.

14. GandhiM,GliddenDV,MayerKetal.Associationofage,baselinekidneyfunction,andmedicationexposurewithdeclinesincreatinineclearanceonpre-exposureprophylaxis:anobservationalcohortstudy.LancetHIV2016;3:e521–e528.

15. LiuAY,VittinghoffE,ChillagKetal.SexualriskbehavioramongHIV-uninfectedmenwhohavesexwithmenparticipatinginatenofovirpreexposureprophylaxisrandomizedtrialintheUnitedStates.JAcquirImmuneDeficSyndr2013;64:87–94.

16. MulliganK,GliddenDV,AndersonPLetal.Effectsofemtricitabine/tenofovironbonemineraldensityinhiv-negativepersonsinarandomized,double-blind,placebo-controlledtrial.ClinInfectDis2015;61:572–580.

17. LiuAY,VittinghoffE,SellmeyerDEetal.BonemineraldensityinHIV-negativemenparticipatinginatenofovirpre-exposureprophylaxisrandomizedclinicaltrialinSanFrancisco.PLoSOne2011;6:e23688.

18. LieglerT,Abdel-MohsenM,BentleyLGetal.HIV-1drugresistanceintheiPrExpreexposureprophylaxistrial.JInfectDis2014;210:1217–1227.

19. Sagaon-TeyssierL,Suzan-MontiM,DemoulinBetal.UptakeofPrEPandcondomandsexualriskbehavioramongMSMduringtheANRSIPERGAYtrial.AIDSCare2016;28Suppl1:48–55.

20. Sagaon-TeyssierLS-M,Rojas-CastroD,DanetM,HallN,FressardL,DiCiaccioM,CapitantC,FoubertF,Chidiac,DoréV,TremblayC,MolinaJ,SpireB,ANRSIPERGAYStudyGroup.ReportedchangesinPrEPandcondomuseinMSMduringtheopen-labelextensionoftheANRSIPERGAYstudy.InternationalAIDSConference(AIDS2016).July2016.Durban,SouthAfrica.

21. HoornenborgE,PrinsM,RoelCA.HighprevalenceofhepatitisCvirusamongHIV-negativeMSMinAmsterdamPrEPproject.ConferenceonRetrovirusesandOpportunisticInfections.February2017.Seattle,WA,USA.

3.2Evidenceforsafetyandefficacyinheterosexualpopulations

3.2.1Efficacy

Efficacy:summary

• TherearenoclinicaltrialsofPrEPforheterosexualindividualsinhigh-incomecountries;whilethebiologicalefficacyislikelytobeidentical,theextenttowhichdatafromothersettingsaregeneralisabletotheUKremainsuncertain.

• FourRCTsundertakeninsub-SaharanAfrica(SSA)haveevaluatedtheefficacyofdailyoralPrEPforpreventingHIVinfectioninheterosexualmenandwomenatrisk.

• OneRCTprovidesstrongevidenceofPrEPhavinghighefficacyinpreventingHIVacquisitionbyheterosexualmenandwomenatrisk,andoneRCTprovidesweakevidenceofhighefficacy

• TwootherRCTswerelimitedbyinadequateadherencetostudydruganddonotprovidereliableevidenceaboutefficacy.

• Nostudieshaveevaluatedtheefficacyofanon-demandoralPrEPregimeninheterosexualmenandwomen

• Thereisevidencethattenofovir-basedPrEPofferssomeprotectionagainstHSV-2.

• Contraceptionisanimportantconsideration.Depotmedroxyprogesteroneacetate(DMPA)useisassociatedwithanincreasedriskofHIVacquisition,andthereisevidencethatthisiscounteractedbyPrEP.

3.2.1.1OverviewTwoRCTshavedemonstratedtheefficacyofdailyoralPrEPinpreventingHIVacquisitionamongstheterosexualindividuals.OnePhase3RCT,PartnersPrEP[1],assessedtheefficacyofdailyoralTDFversusTDF-FTCversusplaceboinserodifferentheterosexualcouplesinEastAfricaandonePhase3RCT,TDF-2[2],evaluatedTDF-FTCversusplaceboinsexuallyactiveheterosexualadultsathighriskofHIVacquisitioninBotswana.Nostudieshaveevaluatedtheefficacyofanon-demandPrEPregimeninheterosexualsandtodatetherearenoRCTsundertakeninheterosexualmenandwomeninhigh-incomecountries.Althoughthereisnoreasontothinkthebiologicalefficacywouldbedifferent,giventhelackofRCTsinheterosexualsinhigh-incomecountries,itremainsdifficulttogeneralisethefindingofhighPrEPefficacyfromthesetwotrialsinsub-SaharanAfrica(SSA)totheUKbecauseHIVincidenceismuchlower,andnowell-definedgroupofheterosexualswithhighHIVincidencecanbeidentifiedinnationalsurveillancedata.Furthermore,therearelikelytobedifferencesinculturalbeliefsandsociodemographiccircumstancesthatinfluenceadherenceandefficacyandfurthercomplicateanyextrapolationofthedata.

TwoRCTs(FEM-PrEP[3]andVOICE[4]),bothinheterosexualwomeninSSA,reportedlowefficacyratesofdailyoralPrEP.Inbothcases,thestudieswerewellconductedandthenullresults,andinconsistencyoftheresultswhencomparedtoTDF-2andPartnersPrEP,areprimarilyattributedtolowadherence(measuredusingdruglevels)tothestudydrugintheinterventionarm.

3.2.1.2Phase3clinicalstudies

3.2.1.2.1PartnersPrEP

PartnersPREPwasadouble-blind,placebocontrolledPhase3RCTfollowing4747heterosexualcouples,comparingsingleanddualagentPrEP(TDFvsTDF-FTC)withplaceboconductedfrom2008to2010[1].ParticipantsweresexuallyactiveserodifferentheterosexualcouplesinUgandaandKenya.HIV-negativeparticipantswereagedbetween18and65yearsold,sexuallyactivewithanHIV-positivepartner(³6episodesvaginalintercoursewithHIV-positivepartnerinthepast3months)withnochronicHBVinfection.HIV-negativewomenwhowerebreastfeeding,pregnantorplanningtobecomepregnantwereexcludedfromthestudy.ThestudyalsoexcludedHIV-negativeparticipantswithglycosuriaorproteinuria,ongoingtherapywithcertaindrugs,andahistoryofpathologicalbonefracturesnotrelatedtotrauma.HIV-positivesexualpartnerswere>18yearsold,sexuallyactive,withCD4cellcounts³250cells/mL,nohistoryofAIDS-definingIllnesses(ADIs)andnotusingantiretrovirals(ARVs).TheHIVincidenceinthecontrolarmwas1.99per100person-years.Overall,thestudyfoundtheefficacyofPrEPusingTDFalonewas67%(95%CI44–81;P<0.001)comparedtoplacebo,andhadcomparableefficacytoPrEPusingTDF-FTC75%(95%CI55–87;P<0.001).ThestudyteamsubsequentlyreportedananalysisofefficacystratifiedbyTDFandTDF-FTClevelsinplasmaintheinterventionarmsinthe29seroconverterscomparedto196randomlyselectedcontrolswhowereuninfected.TheestimatedprotectiveeffectofPrEPagainstHIVbasedondruglevels>40mg/mL(i.e.consistentwithdailydosing),was88%(95%CI60–96;P<0.001)forTDFand91%(95%CI47–98;P=0.008)withTDF-FTC[5].AsecondaryanalysisofPartnersPrEPdatafoundoralTDF-basedPrEPreducedHSV-2acquisitionby30%amonginitiallyHSV-2seronegativepeople[6].

3.2.1.2.2TDF-2

TDF-2wasadouble-blindplacebocontrolledPhase3RCTcomparingdualagentPrEP(TDF-FTC)withplacebo[2].ThetrialwasundertakeninBotswanafrom2007to2009wherearound40%ofadultsaged30–44yearsoldareinfectedwithHIV.ParticipantsintheRCTweresexuallyactivemenandwomenaged18–39yearsold,withoutHIVinfection,withnormalserumchemistryandhaematologyresults,negativeHBVsurfaceantigen,andwithoutanychronicillnessorlong-termmedication.Womenwererequiredtouseeffectivecontraceptionandcouldnotbepregnantorbreastfeeding.TheHIVincidenceinthecontrolarmwas3.1per100person-years.TheTDF-2studyexperienceddifficultiesingettingparticipantstocompletethestudyprotocolandwasconcludedearly,whichledtothestudybeingunderpoweredtodetermineefficacy.However,inthemodifiedintention-to-treatanalysis,theefficacyofTDF-FTCwasfoundtobe62%(95%CI21–83).However,theefficacydifferedinmenandwomen,with49%efficacyinwomen(95%CI22–81)and80%inmen(95%CI25–97).

3.2.1.2.3FEM-PrEP

FEM-PrEPwasadouble-blind,placebo-controlled,Phase3RCTcomparingPrEP(TDF-FTC)withplaceboin2120sexuallyactiveheterosexualwomenaged18–35yearsinKenya,SouthAfricaandTanzaniafrom2009to2011[3].TheHIVincidenceintheTDF-FTCarmwasnotsignificantlydifferenttotheplaceboarm(HR0.94,95%CI0.59–1.52).

3.2.1.3VOICEVOICEwasadouble-blind,placebo-controlledPhase2bRCTwithdailyoralTDF(300mg),dailyoralTDF-FTC(300mg/200mg)andvaginaltenofovirgel(1%)[4].ThetrialtookplaceinSouthAfrica,UgandaandZimbabwefrom2009to2011,in5029sexuallyactiveheterosexualwomenaged18–45years.NoneoftheinterventionsreducedHIVacquisition.Hazardratioforefficacywas1.49(95%CI0.97–2.29)forTDF,1.04(95%CI0.73–1.49)forTDF-FTC,and0.85(95%CI0.61–1.21)fortenofovirgel.

BothFEM-PrEPandVOICEexcludedpregnantandbreastfeedingwomen.BothtrialsfailedtodemonstrateefficacyofeitherTDForTDF-FTCandthisisbelievedtobeduetoinsufficientlevelsofdrugmeasuredinparticipants’plasma.Fewerthan40%ofparticipantsinFem-PrEPhadevidenceofrecentpilluse,anddrugwasdetectedinonly25–30%ofasampleofVOICEparticipants.

3.2.1.4PrEPefficacyandcontraceptionusePrEPefficacyinwomenusingdepotmedroxyprogesteroneacetate(DMPA)wasassessedintwooftheRCTs.InPartnersPrEP,Heffronetal.reporteda64.7%reductioninriskofHIVacquisitionamongwomenusingDMPAintheinterventionarmcomparedtotheplaceboarm(HR:0.35,95%CI0.12–0.1.05)[7].PrEPefficacyestimatesweresimilaramongwomenusingDMPAandthoseusingnohormonalcontraception(64.6%and75.5%,p=0.65)suggestingnoimpactofDMPAonPrEPefficacy.InFEM-PrEP,therewasnoevidencethatTDF-FTCaffectedserumDMPAlevelsinparticipantsusingDMPA[8].

InHIV-negativewomentakingPrEPinthePartnersPrEPstudy,therewasnoevidencethatPrEPaffectedhormonalcontraceptiveeffectiveness(oralcontraceptivepill,DMPAandhormonalimplants)[9].Therewasnodifferenceinpregnancyincidencebetweenwomeninthestudygroups,(10.0per100person-yearsplacebo,11.9per100person-yearsinparticipantsassignedtoTDF;P=0.22vsplacebo,and8.8per100person-yearsinparticipantsassignedtoTDF-FTC;P=0.39vsplacebo).

InaprospectivecohortstudyofSouthAfricanVOICEparticipants,Noguchietal.foundhigherriskofHIVacquisitionamongDMPAusers(incidence8.62per100person-years,95%CI6.61–8.68)thanamongnorethisteroneenanate(NET-EN)users(6.57per100person-years,95%CI4.35–7.38,HR:1.53,95%CI1.12–2.08;P=0.007)[10].Theassociationpersistedwhenadjustedforconfoundingvariables(adjustedhazardratio[aHR]:1.41,95%CI1.06–1.89;P=0.02).TheauthorssuggestthatENT-ENmightbeanalternativeinjectabledrugtoDMPAforwomeninsettingswithhighHIVincidence.GiventhelowadherencetoPrEPinVOICE,thesedataprobablyreflectthefindingsofameta-analysisthatshowsanincreasedriskofHIVacquisitioninwomenusingDMPAwhencomparedtootherformsofcontraceptionornon-use[11].

3.2.1.5ObservationaldataonefficacyofPrEPasabridginginterventiontoTasPBaetenetal.reportedonaprospectivestudywherejustover1000serodifferentheterosexualcouplesinKenyaandUgandawereofferedantiretroviraltherapy(ART)(eitherasPrEPfortheseronegativepartnerorastreatmentasprevention[TasP]fortheseropositivepartner)[12].ThestudydiscontinuedPrEPfortheseronegativepartneroncetheseropositivepartnerhadcompleted6monthsofART.Findingsdemonstratedthefeasibilityofintegrateddeliveryoftime-limitedPrEPasabridgetosuppressiveART,whichresultedinneareliminationofHIVtransmission,withanobservedHIVincidenceof<0.05%peryearcomparedtoanexpectedincidenceof>5%peryear(estimatedthroughmodelling)[12].

3.2Evidenceforsafetyandefficacyinheterosexualpopulations:recommendations4. WerecommendthatdailyoralTDF-FTCshouldbeofferedtoHIV-negativeheterosexualmen

andwomenhavingcondomlesssexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

5. WesuggestthatPrEPwithdailyoralTDF-FTCshouldbeofferedonacase-by-casebasistoheterosexualmenandwomenwithcurrentfactorsthatmayputthematincreasedriskofHIVacquisition.SeeSection4.(2B)

6. WerecommendthatTDFalonecanbeofferedtoheterosexualmenandwomenwhereFTCiscontraindicated.(1A)

Goodpracticepoint

• ForwomenusingDMPA,PrEPislikelytocounteractanincreaseinHIVacquisition.However,womenatriskofHIVacquisitionshouldbeofferedanalternativeformofcontraceptionifavailable,whetherornottheyopttotakePrEP.

3.2.2Adherenceinheterosexualpopulations

Adherenceinheterosexualpopulations:summary

• Pooradherencehasbeenreportedintwotrialsinsub-SaharanAfricaandthisrestrictedtheeffectivenessofPrEP.

• Othertrialsinsub-SaharanAfricahavedemonstratedthatgoodadherencetodailyoralPrEPispossibleandsustainable.

• GoodadherenceishelpedbyunderstandingperceivedriskofHIV,partnerandpeersupport,trustinPrEPandvariedexternalstrategiessuchasexternalreminders,drug-takingroutinesandadherencecounselling.

• Pooradherenceisassociatedwithlackofpeerandpartnersupport,lowriskperception,limitedorlackofdrug-takingroutines,mistrustofmedication,misunderstandingoftheroleofARVsinpreventionandwiderHIVstigma.

• Supportforvariedtoolsandapproachestofacilitateadherencewillberequired,includingthosethataddressfactorsatindividual,partner,peerandcommunitylevel.

• LowlevelsofPrEPliteracyforpotentialusersandthewidercommunitywillalsoneedtobeaddressedtosupportPrEPuptakeandeffectiveuse.

3.2.2.1AdherencetodailyPrEPPartnersPrEPreportedgoodadherence,measuredbycountsofreturnedbottlesandpills.Medicationwasreportedtohavebeentakenasprescribedduring92.1%oftotalstudyfollow-uptime.APartnersPrEPsub-analysisreportedhighcontinuedPrEPuseamongstthoseinserodifferentpartnerships[13].AmongstpartnershipswheretheHIV-positivepartnerhadnotyetinitiatedART,participants’continuedPrEPuseremainedhighat6-(91%)and12-(84%)monthfollow-upvisits.ReasonsfordiscontinuationofPrEPincludedARTusebyHIV-infectedpartner(41%),losstofollow-up(30%),pregnancyandbreastfeeding(9%),partnerpreference(8%)andpartnershipdissolution(6%).APartnersPrEPsub-studyreportedhighadherencewithactiveadherencemonitoringwithunannouncedhome-basedpillcounts(99.1%,interquartilerange[IQR]96.9–100%)andelectronicpillbottlemonitoring(97.2%,IQR90.6–100%)[14].Lowadherencewasassociatedwithnothavingsex,havingsexwithanotherpersonbesidesstudypartner,youngerage,andheavyalcoholuse.Asubgroupof96participantswhoreceiveddailyshortSMStextmessagingover60daysfoundthat96.9%reportedtakingPrEPon³80%ofthedays,with69.8%missingatleastonedose[15].

AdherenceratesintheTDF-2studyweresimilarforboththeTDF-FTCandplacebogroupswhenmeasuredbypillcount(84.1%inTDF-FTCgroupand83.7%inplacebogroup;P=0.79)andself-reportedadherenceoverthe

preceding3days(94.4%and94.1%,respectively;P=0.32).AswithPartnersPrEP,efficacywasdependentonadherencetomedication,asassessedbymeasureofplasmadrugconcentrationswithnon-seroconversiondruglevelsof30.5ng/mLforTDFand103.3ng/mLfor3TC.

3.2.2.2Adherencetodailyvstimeorevent-drivendosingTheADAPTRCT(HPTN067)compareddailyandnon-dailyPrEPdosingamong179womenenrolledintheSouthAfricanarmofthistrial.Regimensincluded:(i)daily(D);(ii)timedriven:twiceweeklywithpost-intercourseboost(T);or(iii)eventdriven:beforeandafterintercourse(E).Coveragewasdefinedasmorethanonepillin4daysbeforeandmorethanonepilltaken24hoursafterintercourse[16].Participantswereagedbetween18and52yearsold(medianage26),with80%unmarriedand83%unemployed.Inthisstudy,reportedadherencetoPrEPwasgreaterinDregimens,comparedwithTandE(P<0.001),andadherencetopost-intercoursedosingwaslow.Amicoetal.reportspecificchallengestonon-dailydosingintheADAPTstudy,centringonthecontextinwhichparticipantshadsex(e.g.unplanned,asavailableandtypicallyoutsidethehome)andthecontextsurroundingpost-sex(e.g.whererelaxationtakesprecedenceoveraction-orientedpreventionbehaviourssuchasdosing)[17].

3.2.2.3LessonslearnedfromlowadherencetodailyPrEPinVOICEandFEM-PrEPAlthoughVOICEandFEM-PrEPdonotprovideevidenceabouttheefficacyofTDF-basedPrEP,theydoofferimportantinsightsintosomeofthebarriersandfacilitatorstotakingdailyoralPrEPinsub-SaharaAfricanpopulations.ResearchfrombothtrialsidentifiedarangeofbarrierstoinitiatingandsustainingadherencetoPrEP,whichmayhaverelevancetoaUKcontext.

• PerceivedharmofARVs:withintheVOICEtrial,takingARVswasperceivedtobeassociatedwithillness,andseenasharmfultothosewhowereHIVnegative,inspiteofacknowledgedbenefitsforpeoplewithHIV.

• Distinguishingbetweenpreventionandtreatment:femaleparticipantsdescribeddifficultiesindistinguishingbetweenARVsforpreventionandtreatment,forboththemselvesandtheirsexualpartners[18].

• Social/communitypressures:FEM-PrEPparticipantsdescribedbeingdiscouragedfromtakingPrEPbymembersoftheirsocialnetworkbecauseoftheinvestigationalnatureofthestudyandpotentialdrugside-effects[19].

Thesestudies,whicharesupportedintheirfindingsbyasystematicreviewofadherenceinterventions[20],highlighttheimportanceofclearcommunicationwithpatientsandcommunitygroupsaboutwhatPrEPis,andhowitworks,toensureappropriateandsuccessfuluptakeandcontinueduse.

3.2.2.4FacilitatorsforadherenceCornelietal.usedqualitativesemi-structuredinterviewstoidentifyfacilitatorslinkedtoadherencetoPrEPintheFEM-PrEPstudyincludingpersonalmotivation(HIVriskreductionandgeneralinterestintheoutcomeoftheresearch)andadherencestrategies[21,22].Thesestrategiesincluded:externalcues,remindersandsupportsuchaspartnerawareness,encouragementandsupportorassistance,establishedroutinesandtools,andadherencecounselling.

Highadherence(measuredusingapill-dispensingdevicethatrecordedopening,andweeklyinterviews)inAfricanwomeninHPTN067wasassociated,inaqualitativestudy,with:levelsofperceivedsafetyandefficacyofPrEP;trustinthoseprovidingPrEP;andinvestmentinprotectingone’scommunitywithPrEP[17].Adherencestrategies(e.g.dailytimeronmobilephone,aligningdailyroutinetotelevisionprogrammes,social/familysupport)werereportedtosupportadherence.Theauthorssuggestwidercommunityengagement,transparencyindiscussionsaroundsafetyandefficacy,andpeer-ledprogrammesofdebateandengagementinimplementationmightcontributetosustainedengagementincareandadherence.

Guestetal.reportedonadherenceinarandomised,double-blind,placebo-controlled,TDFtrialconductedinGhanawithwomenwhoengagedinsexworkandtransactionalsex[23,24].Findingshighlighttheimportanceinallowingtimeforuserstoestablishgoodpatternsofuse(upto6months),whichwasassociatedwithgoodadherenceinthestudy.

3.2.2.5AcceptabilityofPrEPtoheterosexualpopulationsinhigh-resourcesettingsAcceptabilitystudiesintheUKandUSAinheterosexualpopulationsreiteratefindingsfromRCTstudiesinrelationto:

• TheneedforclearunderstandingsofwhatPrEPisandhowitworksforpotentialusers;and• TheneedtoaddresspotentialsocialbarrierstocontinuedPrEPuseamongstsexualpartners,peersand

thewidercommunity.

InastudywithAfricanmenandwomenlivinginScotland,Youngetal.identifiedinequalitiesinHIVliteracythatmightaffectuptakeandsustaineduseofPrEP.Limitedawarenessandmistrustofpharmaceutical-basedpreventionledtoscepticismofPrEPasaviableHIVpreventionoption.ConcernsabouthowsexualpartnersandthewidercommunitymightviewPrEPwereseenasasignificantbarriertoPrEPuse,highlightingtheneedtoaddresswidercommunityconcernsaroundsexualnormsandHIVprevention[25].Similarly,inastudywithAmericanwomenacrossmultiplesitesintheUS,Auerbachetal.identifiedlackofcommunicationamongcommunitymembers,mistrustofmedicalinstitutionsandpotentialHIV-stigmarelatedtoanunfamiliarHIVpreventionmethodaskeybarrierstosupportingPrEPuptakeandadherence[26].

3.2.3Safety

Safety:summary

• RCTsinsub-SaharanAfricahaveshowngoodsafetydatafordailyoralTDF-FTCasPrEPinmenandwomen,withanysmallchangesoccurringinrenalfunctionorbonemineraldensitylikelytoreversefollowingdiscontinuationofPrEP.

• TheexistingdatasuggestthatPrEPcanbeusedsafelyinwomenwhoarepregnantorbreastfeedingandwithcurrentfactorsthatmayputthematincreasedriskofHIVacquisition.

3.2.3.1Adverseeventsandgrade3–4safetydataTodate,studiesofTDF-FTCPrEPsuggestevidenceforshort-termsafety.

3.2.3.2RenalfunctionTDFexposurehasbeenassociatedwithasmallbutstatisticallysignificantdeclineinestimatedglomerularfiltrationrate(eGFR)inHIV-uninfectedpersonsreceivingTDF-basedPrEPforHIVprevention.InPartnersPrEP,allparticipantshadcreatinineclearanceof≥60mL/minatstudyentry[1],andtherewere3924individualswithserumcreatininemeasurementsinwhomdifferenceswerenotedbetweenstudygroupswhich,althoughstatisticallysignificant,wereunlikelytobeclinicallysignificant.MeaneGFRatlaston-studydrugvisitwas129mL/min/1.73m2forTDF,128mL/min/1.73m2forTDF-FTC,and131mL/min/1.73m2forplacebogroups,suchthattheoverallmeandeclineforthosereceivingPrEPcomparedtoplacebowasestimatedtobe2–3mL/min/1.73m2(P≤0.01)[27],andthedifferenceshaddisappearedontesting4weekslater.Overall,inPartnersPrEP,theproportionsofparticipantswithaconfirmed>25%declineineGFRfrombaselineby12and24monthswere1.3%and1.8%forTDF,1.2%and2.5%forTDF-FTC,and0.9%and1.3%forplacebo(notstatisticallysignificant)[28].

Asubgroupanalysisof1549menandwomenparticipatinginPartnersPrEPassessedtheeffectofTDFonrenalproximaltubulardysfunctionthatwaspredefinedas≥2ofthefollowing:tubularproteinuria,euglycaemicglycosuria,increasedurinaryphosphate,anduricacidexcretion.EvenusingtheseverydetailedmarkersoftubularproteinuriatheyfoundthattherewasnodifferenceintubulopathyfrequencybetweenthegroupreceivingdailyoralTDF-FTCandtheplacebogroupoveramedianof2years’follow-up(1.7%forTDF-FTCversus1.3%forplacebo,OR:1.30,95%CI0.52–3.33;P=0.68).TheauthorsalsoreportthattubulopathydidnotpredictaclinicallyrelevanteGFRdecline(definedas≥25%eGFRdeclinefrombaseline)[29].

Althoughthesedataarereassuring,cliniciansprescribingPrEPshouldconsiderwhetherpatientshaveanypre-existingrenaldiseaseorriskfactorsforfuturerenaldisease,andensureappropriatemonitoringinthesecases.

3.2.3.3BonemineraldensityAsubsetof220womenenrolledinTDF-2(108TDF-FTCand112placebo)hadbonemineraldensity(BMD)measurementswithlowbaselinescoresfoundamong7%[30].InthegroupreceivingTDF-FTC,therewasaslight,butstatisticallysignificantreductioninthemeanpercentagechangeinBMDfrombaselinecomparedtothecontrolgroupatmonth30(forearm–0.84%,spine–1.62%,hip–1.51%).IntheVOICEstudy,BMDdatawereavailableforasubsetof81womenwithdetectabledruginserumsamplesinthecombinedactivearmsand158intheplacebogroup[31].Similarfindingswerereported,showingthatthemeanpercentageBMDchangefrombaselineat48weekswas1.4%lowerforthosereceivingactivedrugthanforplacebo.Thisdifferencehadreversedwhenmeasurementswererepeated48weeksafterceasingtreatment.Nobonefractureswerereported.ThesedatamirrorfindingsfromstudiesinMSMandothergroups.

3.2.3.4PrEPsafetyinpregnancyAmongHIV-negativewomentakingPrEPinthePartnersPrEPstudy,therewasnodifferenceinpregnancyincidencebetweenwomeninthestudygroups:10.0per100person-yearsintheplaceboarm,11.9per100person-yearsinparticipantsassignedtoTDFarm(P=0.22)and8.8per100person-yearsinparticipantsassignedtoTDF-FTC(P=0.39).Therewasalsonodifferenceinpregnancyoutcomes(pretermbirth,congenitalanomalyandgrowth)betweenthosereceivingPrEPandthosereceivingplaceboinPartnersPrEP[32].However,therelativelysmallsamplesizesresultedinwideconfidenceintervalsforsomepregnancyoutcomes,includingpretermbirthandcongenitalanomalies.Inaddition,inPartnersPrEP,PrEPwasdiscontinuedoncepregnancywasconfirmed,sothatinuteroexposureafterconceptionwastypicallyshort(average35daysinearlypregnancy)andthereforethesefindingscanonlybegeneralisedtopericonceptionexposuretoPrEP[33].ThereisnoevidencethatTDF-FTCadverselyaffectsmalefertility[34].

AlthoughtherearenoformalstudiesinvestigatingsafetyoforalTDF-basedPrEPthroughoutpregnancy,twoclinicsfromtheUSAhavereportedonofferingPrEPtowomenathighriskofacquiringHIVthroughpreconception,duringpregnancyandpostpartum.Ofthe27womenreferredtotheirservice,18womenchosetotakePrEPwithamedianlengthoftimeonPrEPof30weeks.NoPrEP-relatedpregnancycomplicationswereidentified[35].

InasystematicreviewexaminingthesafetyofTDFduringpregnancyformotherandfoetusinwomenwithHIVand/orhepatitisBinfection,theauthorsconcludethatTDFissafeinpregnancy[36].Inaddition,asystematicreviewandmeta-analysisinvestigatingthesafetyofTDFinHIV-negativewomenonantiretroviralsforchronichepatitisBinfectionfoundnosignificantdifferencesincongenitalmalformations,prematurityrateorApgarscores[37].

3.2.4.5PrEPsafetyduringbreastfeedingInaprospectivestudyofdailyTDF-FTCtakenfor10daysby50HIV-negativebreastfeedingwomenwhowerebetween1and24weekspostpartum,TDFconcentrationswereextremelylowinbreastmilkandbelowthelevelofdetectionininfantplasma.FTClevels,ontheotherhand,werehigherinbreastmilkanddetectableininfantplasma,butstillmorethan200-foldlowerthanproposedinfanttherapeuticdoses[38].AlthoughmoreresearchiswarrantedtounderstandtheclinicalsafetyforinfantswhoarebreastfedbywomenonPrEP,thereisextensiveexperienceofFTC-TDFuseinwomenwithHIVwhoarebreastfeeding.ThesedataconfirmverylowmedianconcentrationsofFTCandTDFsecretedinbreastmilk(2%and0.03%respectivelyofproposedoralinfanttreatmentdosesforHIVinfection)[39].

3.2.3.6DrugresistanceThemeta-analysisbyFonneretal.reviewedsixstudiesthatreportedcasesofTDForFTCdrugresistanceusingstandardisedgenotypiclaboratoryassays[26].RCTsconductedinheterosexualpopulationsfoundthatselecteddrugresistanceoccursrarely,andthatthismaybeeitherinsubjectsinitiatingPrEPwithanundetectedHIVinfectionorinthosewithbreakthroughinfectionsafterstartingPrEP.Forexample,inTDF-2,onecaseofTDFandFTCdrugresistancewasreported.TheparticipantwassubsequentlyfoundtohavehadundetectedHIVinfectionatenrolment[2].InPartnersPrEP,amongthosereceivingPrEP,threeof12subjectssubsequentlyfoundtobeHIVpositiveatenrolmenthadTDForFTCresistancedetected,andfourof51whoacquiredHIVafterenrolmenthadresistancedetected[40,41].

3.2.4Riskbehaviour/STIs

Riskbehaviour:summary

• TherearefewdataavailabletounderstandwhetherriskcompensationmightoccurinheterosexualpopulationsandthelikelyeffectonSTIrates.

IthasbeensuggestedthatbehaviourchangeleadingtoincreasedacquisitionofSTIsmightoccurduetoriskcompensationassociatedwiththeefficacyofPrEP.However,datatoassessthisriskarelimited.ToinvestigatewhetherknowledgeofPrEPefficacymightinfluencesexualbehaviour,aPartnersPrEPsubgroupanalysiscomparedreportedsexualbehaviourduringthe12monthsbeforeandthe12monthsafterthestudywasunblindedandtheefficacyofPrEPwasreportedpublicly.Overall,3024menandwomencontributed56,132person-monthstothisstudy,andthefrequencyofcondomlesssexwiththeHIV-infectedstudypartnerfellfrom59actsper100-personmonthsto53actsper100-personmonths(non-significant),andtherewerenochangesinSTIsorpregnanciesdetected[42].Therewasasmallbutsignificantincreaseintheestimatedfrequencyofcondomlesssexactswithpartnersotherthanthestudypartner(predictedusingacounterfactualscenariohadunblindingnotoccurred).Overall,thereisalackofdataavailabletounderstandwhetherriskcompensationoccursinheterosexualpopulationsand,ifso,whattheimpactisonratesofSTIinfections.

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3.3Evidenceforsafetyandefficacyinpeoplewhoinjectdrugs(PWID)

Evidenceforsafetyandefficacyinpeoplewhoinjectdrugs(PWID):summary• TherearenodataontheefficacyofPrEPinPWIDintheUK.• Thereislimitedevidenceforsafetyandefficacyinpeoplewhoinjectdrugs(PWID)withonlyone

reportedRCT(TDFvsplacebo)performedinPWIDinBangkok,whichdemonstrateda49%reductioninHIVincidence.

• Efficacywasstronglylinkedtoadherence.• ItisdifficulttoseparatetheimpactofPrEPonparenteralHIVtransmissionfromsexualtransmissionin

PWID.• TheauthorsoftheBangkokTenofovirStudyacknowledgethat,althoughthestudywasdesignedto

measuretheimpactonparenteraltransmission,participantsmayhavebecomeinfectedsexually.• In2015,PWIDmadeup3%(210)ofnewHIVdiagnosesintheUK,butoverall,thenumberofpeople

acquiringHIVthroughinjectingdruguseintheUKremainslow.• Chemsexandslamming(theactofinjectingthedrugsusedinchemsex)aremorecommonlyseenin

MSMandareassociatedwithriskbehavioursforHIVacquisition.

3.3.1Efficacy

3.3.1.1Phase3clinicalstudyOnerandomised,double-blind,placebo-controlledPhase3trial(TheBangkokTenofovirStudy)assessedtheefficacyofdailyTDFversusplaceboinPWIDinThailand[1].ParticipantswereenrolledfromdrugtreatmentcentresinBangkokandwereeligibleiftheywereaged20–60years,wereHIV-negative,andreportedinjectingdrugsduringthepreviousyear.Participantswererandomised1:1toreceiveeitherTDForplaceboandcouldchoosedailydirectlyobservedtreatment(DOT)ormonthlyvisitsandcompletedanadherencediary.ThemajoritywereonDOTforwhichattendancewasreimbursed,whichwouldnotbethecaseinroutinepractice,soadherencemaybeoverestimated.ParticipantsreceivedmonthlyHIVtestingandindividualisedrisk-reductionandadherencecounselling,bloodsafetyassessmentsevery3months,andwereofferedcondomsandmethadonetreatment.Thestudyenrolled2413participants,assigning1204toTDFand1209toplacebo.Themedianageof

enrolledparticipantswas31years(20–59),80%weremale,and63%reportedthattheyinjecteddrugsduringthe3monthsbeforeenrolment.Amongthosewhoinjected,53%injectedmethamphetamineand35%heroin.Anopen-labelextensionstudyofferedstudyparticipantsasubsequent1yearofTDF,whichwastakenupby787(35%)participants.

TwoparticipantshadHIVatenrolmentand50becameHIVinfectedduringfollow-up;17intheTDFarm(incidence:0.35,95%CI0.21–0.56,per100person-years)and33intheplaceboarm(incidence:0.68,95%CI0.47–0.96,per100person-years),indicatinga48.9%reductioninHIVincidence(95%CI9.6–72.2).

3.3.1.2DataonPWIDintheUKTherearenodataontheefficacyofPrEPinpeoplewhoinjectdrugsintheUK.GeneralisabilityofotherstudiestoaUKpopulationisdifficultastheinjectingriskbehavioursdifferandtheUKhaseffectiveneedle-exchangeandopiatesubstitutionprogrammes,whichhavesuccessfullycontainedtheHIVepidemicinPWID.

In2015,PWIDmadeup3%(210)ofnewHIVdiagnosesintheUK[2].Thiswasanincreaseonthepreviousyear(160newinfections)andwaslargelyduetoanHIVoutbreakamongPWIDinGlasgow,whichledtothediagnosisofover50people.Overall,thenumberofpeopleacquiringHIVthroughinjectingdruguseintheUKremainslowandPrEPuseintheUKrelatestosexualtransmissionrisksexceptinanoutbreaksituationinPWIDsuchasinGlasgowin2015.

3.3.2AdherenceAsinotherstudies,efficacywascloselycorrelatedwithadherenceintheBangkokTenofovirStudy(asmeasuredbyastudydrugdiary)[1].TheriskreductionforpeopleonTDFPrEPwas84%inthosewithatleast98%adherence[3].Participantstookstudydruganaverageof84%ofdays;84%whileindailyfollow-upand89%whileinmonthlyfollow-up.Inmultivariateanalysis,menwerelessadherent(94%,95%CI79–99%)thanwomen(96%,95%CI81–99%;P=0.04).Adherencewasbetterinparticipantsaged40yearsandolder(median98%,95%CI94–99.5%)thanitwasinparticipants30–39yearsold(median94.2%,95%CI82.2–98.6%)andthoseaged20–29yearsold(median90%,95%CI69%–98%;P<0.001).Otherfactorssignificantlyassociatedwithpooradherenceincludedincarcerationinprison(OR:1.3,95%CI1.1–1.7;P=0.02),andinjectingmethamphetamine(OR:1.2,95%CI1.0–1.5;P=0.04).Participantsinamethadoneprogrammeatenrolmentweremorelikelytoreportatleast95%adherence(OR:0.7,95%CI0.6–0.9;P=0.003)[4].Intheopen-labelextensionstudy,oneparticipantbecameHIV-infectedafterstartingPrEPgivinganestimatedHIVincidenceof2.1(95%CI0.05–11.7)per1000person-years[5].Thisparticipanthadnottakentenofovirduringthe60daysbeforethereactiveHIVtest.Intheopen-labelstudy28%ofparticipantsdidnotreturnforanyfollow-upvisits,whichsuggestsengagementandadherenceremainachallengeinthisgroup.

3.3.3SafetyIntheBangkokRCTtheoccurrenceofseriousadverseeventswassimilarbetweenthetwogroups(P=0.35).RenalfunctionwasassessedusingtheCockcroft–Gault,ModificationofDietinRenalDisease(MDRD),andChronicKidneyDiseaseEpidemiologyCollaboration(CKD-EPI)equations[6].Thereweresmallbutsignificantdecreasesincross-sectionalmeasuresofcreatinineclearance(CrCl)andeGFRat24,36,48and60monthsintheTDFgroupcomparedwiththeplacebogroup.Creatinineclearancemeasuredwhenstudydrugwasstoppedwaslowerinthetenofovirgroup(89.7mL/min,95%CI86.7–92.7)thantheplacebogroup(97.9mL/min,95%CI95.1–100.7;P<0.001),butthedifferenceresolvedwhentestedamedianof20monthslater.Nauseawasmorecommoninparticipantsinthetenofovirgroup(8%)thanintheplacebogroup(5%;P=0.002).

TherewerenoreportedTDFresistancemutationsinanyoftheparticipantsintheBangkokTenofovirStudywhowereeitherHIVpositiveatenrolmentorwhosubsequentlyseroconvertedineithergroup[1].

3.3.4RiskbehaviourIntheBangkokTenofovirStudytheproportionofparticipantsinjectingdrugs,sharingneedles,andreportingsexwithmorethanonepartnersignificantlydeclinedduringfollow-up[7].Multivariableanalysisshowedthatyoungerage(i.e.20–29years;HR:1.9,95%CI1.1–3.4;P = 0.02),sharingneedles(HR:8.9,95%CI4.1–19.3;P<0.001),andincarcerationinprison(HR:2.7,95%CI,1.4–4.9;P= 0.002)wereindependentlyassociatedwithincidentHIVinfection.SexualactivitywasnotassociatedwithHIVinfection,suggestingthatthereductioninHIVincidenceamongparticipantstakingdailyoralTDFwasasaresultofpreventingparenteraltransmission.Participantsreportingsexwithapartneroftheoppositesex(OR:1.1,95%CI0.6–1.9;P = 0.79),sexwithalive-inpartner(OR:0.6,95%CI0.4–1.1,P = 0.11),sexwithacasualpartner(OR:1.6,95%CI0.9–3.0;P= 0.13),ormenreportingsexwithmalepartners(OR:0.0,95%CI0.0–5.9;P=0.50)werenotatahigherriskofHIVinfectioncomparedtothosewhodidnotreportthesebehaviours.

3.3.4.1ChemsexandslammingChemsexistheuseofthreespecificdrugs('chems')inasexualcontext.Thesethreedrugsaremethamphetamine(crystal,meth,Tina),mephedrone(meph/drone,miaowmiaow,m-cat)andGHB/GBL(G,Gina).Chemsexandslamming(theactofinjectingthedrugsusedinchemsex)shouldbedistinguishedfrominjectingdruguseinvolvingheroinasthedrugs,demographicsofusersandrisksforSTIs,HIVandotherblood-bornevirusesaredifferent.ChemsexisfrequentlyreportedinMSMwhoareatriskofHIV[8,9].InthePROUDstudy,atbaseline,drugscommonlyassociatedwithdruguseinasexualcontext(mephedrone,GHB/GBLandmethamphetamine)wereusedby231/525(44%)participantsintheprevious3months[10].StrategiestoidentifytothoseatriskandtoprovidesupportandinterventionsshouldformpartofPrEPconsultation[11].

3.3Evidenceforsafetyandefficacyinpeoplewhoinjectdrugs(PWID):recommendations7. PrEPisnotrecommendedforpeoplewhoinjectdrugswhereneedleexchangeandopiate

substitutionprogrammesareavailable.(2C)8. Werecommendthatexistingharm-reductionstrategiessuchasneedleexchangeandopiate

substitutionprogrammesshouldbeencouragedforpeoplewhoinjectdrugs.(1D)Goodpracticepoints• ConsiderPrEPonacase-by-casebasisinpeoplewhoinjectdrugsinanoutbreaksituationorwith

otherfactorsthatputthematincreasedriskofHIVacquisition.SeeSection4.

• InterventionsforchemsexshouldbeencouragedforpeoplewhoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughreportofinjectingdruguseduringchemsex(slamming).

3.3.6References1. ChoopanyaK,MartinM,SuntharasamaiPetal.AntiretroviralprophylaxisforHIVinfectionininjectingdrugusersinBangkok,Thailand(theBangkokTenofovirStudy):arandomised,double-blind,placebo-controlledphase3trial.Lancet2013;381:2083–2090.

2. KirwanPD,ChauC,BrownAEetal.HIVintheUK:2016report.2016.Availableat:www.gov.uk/government/uploads/system/uploads/attachment_data/file/602942/HIV_in_the_UK_report.pdf(accessedJuly2017).

3. MartinMT,VanichseniS,SuntharasamaiPetal.Preliminaryfollow-upofinjectingdrugusersreceivingpreexposureprophylaxis.TopicAntiviralMed2015;23:445–446.

4. MartinM,VanichseniS,SuntharasamaiPetal.TheimpactofadherencetopreexposureprophylaxisontheriskofHIVinfectionamongpeoplewhoinjectdrugs.AIDS2015;29:819–824.

5. MartinM,VanichseniS,SuntharasamaiPetal.FactorsassociatedwiththeuptakeofandadherencetoHIVpre-exposureprophylaxisinpeoplewhohaveinjecteddrugs:anobservational,open-labelextensionoftheBangkokTenofovirStudy.LancetHIV2017;4:e59–e66.

6. MartinM,VanichseniS,SuntharasamaiPetal.RenalfunctionofparticipantsintheBangkoktenofovirstudy–Thailand,2005–2012.ClinInfectDis2014;59:716–724.

7. MartinM,VanichseniS,SuntharasamaiPetal.RiskbehaviorsandriskfactorsforHIVinfectionamongparticipantsintheBangkoktenofovirstudy,anHIVpre-exposureprophylaxistrialamongpeoplewhoinjectdrugs.PLoSOne2014;9:e92809.

8. HicksonF,ReidD,HammondG,WeatherburnP.Stateofplay:findingfromtheEnglandgaymen’ssexsurvey.2014.Availableat:www.sigmaresearch.org.uk/files/GMSS-2014-State-of-Play.pdf(accessedJuly2017).

9. SchmidtAJ,BourneA,WeatherburnPetal.Illicitdruguseamonggayandbisexualmenin44cities:FindingsfromtheEuropeanMSMInternetSurvey(EMIS).IntJDrugPolicy2016;38:4–12.

10. DollingDI,DesaiM,McOwanAetal.AnanalysisofbaselinedatafromthePROUDstudy:anopen-labelrandomisedtrialofpre-exposureprophylaxis.Trials2016;17:163.

11. DeanStreet.Chemsexresourcesforprofessionals.Availableat:www.dean.st/for-professionals/(accessedJuly2017).

3.4Evidenceforsafetyandefficacyintranspeople

Evidenceforsafetyandefficacyintranspeople:summary

• Transgenderwomen(TGW)onlyformedaminorityofPrEPRCTparticipants.

• InasubgroupanalysisofiPrExandiPrEx-OLE,dailyoralTDF-FTChadlowereffectivenessinTGWthanMSM,primarilylinkedtoloweradherenceasmeasuredbydrugconcentrations.

• AninteractionbetweenTDF-FTCandfeminisinghormonesisunlikelytobeduetodifferingmetabolismandclearance.

• Thepossibilityofadrug–druginteractionbetweenPrEPandfemalehormonesremainsaconcernforTGWandcliniciansshouldbeawarethatTGWmayprioritisethisoverotherhealthconcerns,whichmayimpactonPrEPadherence.

• TherearenodataonPrEPeffectivenessintransgendermen(TGM).• TherearenodataonPrEPeffectivenessforfrontal(vaginal)sexineitherTGWorTGM.

3.4.1EfficacyintranswomenWhiletherearenodatafromtheUK,itisestimatedthattransgenderwomen(TGW)are49timesmorelikelytobeinfectedwithHIVthanthegeneralpopulationworldwide[1].Globally,TGWalsoexperiencehighlevelsofdiscrimination,structuralbarrierstohealthcare,violence,poverty,highunemploymentandhousinginstability,whichallcontributetothehighburdenofHIVamongTGW[2].

3.4.1.1Phase3clinicalstudiesAlthoughanumberofPhase3RCTsincludedtheoptiontorecruitTGW[3-5],inreality,TGWhaveformedonlyaminorityoftrialparticipants.In2015,theiPrExstudygroupcarriedoutanunplannedsubgroupanalysisconsideringefficacyspecificallyinthisgroup[6].TherandomisedphaseofiPrEXcompareddailyoralTDF-FTCwith

placebo.Ofthe2499participantsiniPrEx,339(14%)wereclassifiedasTGW.AmongstTGWtherewere11HIVinfectionsinthePrEPgroupandtenintheplacebogroup(HR:1.1,95%CI0.5–2.7),indicatingminimalefficacyofPrEPinTGW.ItisnotablehoweverthatnoneoftheTGWintheactivearmwhobecameinfectedwithHIVhaddetectabledrugatthetimeofseroconversion.

TherearenostudiesinTGWofintermittentoron-demanddosing.

3.4.1.2OtherstudiesThesubgroupanalysisofiPrEx[6]alsoconsideredtheopen-labelextensionofthestudy.Duringthisphase,192TGWenrolledandwereeligibletotakePrEP.OfthosereceivingPrEP,TGWhadlowerdrugconcentrationsthandidMSMoverall[7].Protectivedrugconcentrations(indicatinguseoffourormorepillsperweek)weredetectedin17%ofperson-yearsoffollow-upintransgenderwomencompared35%ofperson-yearsfollow-upinMSM(P<0.0001).TherewerenoseroconversionsinTGWwithdrugconcentrationscommensuratewith4ormoretabletsperweek.SeroconversionoccurredonlyamongTGWhavingdrugconcentrationscompatiblewithlessthantwotabletsofTDF-FTCperweek.ThestudyauthorsconcludedthatthelackofPrEPefficacyinTGWwasprimarilyaresultoflowadherenceasmeasuredbydrugconcentrations.

3.4.1.2AdherenceInbothiPrExandiPrEx-OLE,adherenceinTGWwaslow.Ofconcern,thesubgroupanalysisofiPrEx[6]showedthatMSMwiththehighestriskbehavioursweremoreadherenttoPrEP,butthiswasnotthecaseinTGWathighestrisk.LowerTDFconcentrationswereobservedamongTGWusingfeminisinghormonescomparedwithotherTGWnotusinghormones(OR:0.32,95%CI0.16–0.66;P=0.002). ThismayreflectlessPrEPadherenceamongTGWwhoseconcernsaboutdrug–druginteractionswerenotfullyaddressedduringthetrial.However,nosystemicdrug–druginteractionsareexpectedbetweenTDF-FTC,whichisclearedinthekidney,andoestrogensandprogestogens,whicharemetabolisedintheliver.

3.4.3Safetyintranswomen

3.4.3.1Adverseeventsandgrade3–4safetydataTheiPrEXsubgroupanalysis[6]showedthatmoderateandsevereadverseeventsinTGWwererare,andtherewasnodifferencebetweenthePrEPandtheplacebogroup(31vs28events;P=0.73).

3.4.3.2RenalfunctionIniPrEx,therewasanon-significantmeandifferencefrombaselineinestimatedcreatinineclearanceatweek24of–1.0mL/min(95%CI–3.8–1.8;P=0.48)inTGWintheactivearm,whichwassimilartodifferencesinMSM[8].However,presenceofTDFintheactivearmwaslowamongTGW.

3.4.3.3BonemineraldensityDual-energyX-rayabsorptiometry(DEXA)scanswereperformedinasubsetofparticipantsenrolledintheiPrExstudy(246TDF-FTC,251placeboarms)ofwhom11%wereTGW.Bonemineraldensityatthehipincreasedby0.5%(95%CI-0.5–1.5)frombaselineinTGWatweek24,comparedwithadecreaseof0·4%(95%CI-0.7–-0.2)amongMSMandatthespine,bonemineraldensityincreasedby0.3%(-0.8–1.3)frombaselineinTGWanddecreased0.7%(–0.3–1.2)amongMSM(P=0.08)[6].Atweek24,intracellulartenofovirdiphosphate (TFV-DP)wasdetectedinonly53%ofsub-studyparticipantsrandomisedtoTDF-FTCandTFV-DPlevelsexhibitedastatisticallysignificantinverserelationshipwithchangesinBMD.

3.4.3.4InteractionwithfemalehormonesInteractionbetweenPrEPandfemalehormonesisaconcernforTGW,andmanywillprioritisehormoneuseoverotherhealthconcernssuchasaquisitionofHIV.InaPrEPacceptabilitystudycomprising107TGWinThailand[9],three-quartersfearedthatPrEPmightinteractwithothermedications,includingfemalehormones.

Co-administrationofTDF-FTCandoestradiolhasnotbeenstudied,butbasedonmetabolismandclearance,aclinicallysignificantinteractionisunlikely[10].OestradiolismetabolisedbyCYP1A2andCYP3A4,whereasbothTDFandFTCdonotimpactcytochromeP450activity,andareexcretedviathekidney.

InthePartnersPrEPstudy,therewasnodifferenceinPrEPefficacybetweenwomenusinghormonalcontraceptionversusthosewhowerenot[8].Notrialstodatehavestudiedefficacyathormonallevelsusedforfeminisation.TherearetwodemonstrationprojectsplannedfortranswomeninCaliforniaandBrazil.ThesestudieswillincludeanexaminationofpossibledruginteractionsbetweenPrEPuseandfeminisinghormones[11,12].

TheUniversityofLiverpool(www.hiv-druginteractions.org)hasreleasedanupdatedguideoninteractionsbetweenARVsandoestrogenandanti-androgenpreparationsusedinmale-to-femalegenderreassignmenttherapy,indicatingthereisnoclinicallysignificantinteractionexpectedbetweenTDForFTCandhormonetherapiesusedforgendertransitioningexceptforethinylestradiol.(Seelinkformoredetails:https://liverpool-web-production.s3.amazonaws.com/printable_charts/pdfs/000/000/024/original/Hormone_Chart_2017_Apr.pdf?1491312832).

Anyconcernsaboutdrug–druginteractionsshouldbefullyexploredandaddressedwithreassurancegiventooptimiseadherence.Forfurtherinformationandcurrentnationalgoodpracticeguidelinesforgeneralassessmentandtreatmentoftransadultsseethefollowingdocument[13].

3.4.3.5DrugresistanceAmongtheTGWparticipantswithincidentinfectionsintheiPrExstudy,nonehadFTCorTDFselectedmutationsorreducedphenotypicsusceptibility.AmongthetwoTGWwithacuteHIVinfectionatrandomisationtotheactivearm,M184VorImutationswerepredominantatseroconversion,butwanedtobackgroundlevelswithin24weeksafterdiscontinuingdrug[14].

3.4.3.6RiskbehaviourIntheiPrExsubgroupanalysis,TGWmorefrequentlyreportedtransactionalsexorcommercialsexworkwhichcanbeassociatedwithahigherriskofHIVacquisition,receptiveanalintercoursewithoutacondom,ormorethanfivepartnersinthepast5monthswhencomparedwithMSM.ThestudyauthorsdidnotcommentuponriskcompensationovertimeorSTIincidence[6].

3.4.4TransmenTodate,therearenoclinicaltrialsthatincludetransgendermen(TGM)asparticipants.PrEPefficacyinthisgroupisthereforeunknown.TransgenderMSMsolelyhavinganalsexcouldbeassumedtohavesimilarlevelsofprotectionfromPrEPascisgenderMSM,ifachievingsimilarlevelsofadherence.

Undertheinfluenceoftestosteronetherapy,theremaybevaginalatrophy,theoreticallyincreasingtheriskofHIVtransmission.ThereisevidencetosuggestthatdailydosingofTDF-FTCisneededtoachieveeffectiveconcentrationsinvaginaltissueandthelead-intimetoachievesteadystateislonger[15].

3.4Evidenceforsafetyandefficacyintranspeople:recommendations9. WerecommendthatPrEPwithdailyoralTDF-FTCshouldbeofferedtoHIV-negativetrans

womenwhoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughcondomlessanalsexintheprevious3–6monthsandongoingcondomlesssex.(1A)

10. WerecommendthatdailyoralTDF-FTCshouldbeofferedtoHIV-negativetranswomenandtransmenhavingcondomlesssexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

Goodpracticepoints• PrEPcouldbeconsideredonacase-by-casebasisintranswomenandtransmenwithcurrent

factorsotherthancondomlessanalsexthatmayputthematincreasedriskofHIVacquisition.SeeSection4.

• ForbothtranswomenandtransmenadiscussionshouldbehadregardingunknownPrEPefficacyforfrontal(vaginal)sex.

• Adiscussionshouldbehad,bothatPrEPinitiationandmaintenancevisits,thattherearenoknowninteractionsbetweenTDF-FTCandfeminisingormasculinisinghormonesexceptforethinylestradiol.

3.4.5References1. BaralSD,PoteatT,StromdahlSetal.WorldwideburdenofHIVintransgenderwomen:asystematicreviewandmeta-analysis.LancetInfectDis2013;13:214–222.

2. PoteatT,ScheimA,XavierJetal.GlobalepidemiologyofHIVInfectionandrelatedsyndemicsaffectingtransgenderpeople.JAcquirImmuneDeficSyndr2016;72Suppl3:S210–219.

3. GrantRM,LamaJR,AndersonPLetal.PreexposurechemoprophylaxisforHIVpreventioninmenwhohavesexwithmen.NEnglJMed2010;363:2587–2599.

6. DeutschMB,GliddenDV,SeveliusJetal.HIVpre-exposureprophylaxisintransgenderwomen:asubgroupanalysisoftheiPrExtrial.LancetHIV2015;2:e512–519.

7. GrantRM,AndersonPL,McMahanVetal.Uptakeofpre-exposureprophylaxis,sexualpractices,andHIVincidenceinmenandtransgenderwomenwhohavesexwithmen:acohortstudy.LancetInfectDis2014;14:820–829.

9. YangD,ChariyalertsakC,WongthaneeAetal.Acceptabilityofpre-exposureprophylaxisamongmenwhohavesexwithmenandtransgenderwomeninNorthernThailand.PLoSOne2013;8:e76650.

10. MurnanePM,HeffronR,RonaldAetal.Pre-exposureprophylaxisforHIV-1preventiondoesnotdiminishthepregnancypreventioneffectivenessofhormonalcontraception.AIDS2014;28:1825–1830.

11. CaliforniaHIV/AIDSResearchProgram.AnHIVpreventionpillfortransgenderpersons:UClaunchesfirstinthenationdemonstrationproject(pressrelease).2016.Availableat:www.californiaaidsresearch.org/files/chrp-press-releases/prep-for-transgender-persons-april-2016.pdf(accessedJuly2017).

12. NúcleodeDireitosHumanoseCidadaniaLGBT(NUH).PrEParadas:MulheresTransexuaisetravestissãoalvodepesquisasobreprepnoBrasil.2016.Availableat:www.fafich.ufmg.br/nuh/2016/12/28/preparadas-mulheres-transexuais-e-travestis-sao-alvo-de-pesquisa-sobre-prep-no-brasil/(accessedJuly2017).

13. RoyalCollegeofPsychiatrists.CR181.Goodpracticeguidelinesfortheassessmentandtreatmentofadultswithgenderdysphoria.2013.Availableat:www.rcpsych.ac.uk/usefulresources/publications/collegereports/cr/cr181.aspx(accessedJuly2017).

14. LieglerT,Abdel-MohsenM,BentleyLGetal.HIV-1drugresistanceintheiPrExpreexposureprophylaxistrial.JInfectDis2014;210:1217–1227.

15. CottrellML,YangKH,PrinceHMetal.Atranslationalpharmacologyapproachtopredictingoutcomesofpreexposureprophylaxisagainsthivinmenandwomenusingtenofovirdisoproxilfumaratewithorwithoutemtricitabine.JInfectDis2016;214:55–64.

3.5Evidenceforsafetyandefficacyinyoungpeople(15–25years)

Evidenceforsafetyandefficacyinyoungpeople(15–25years):summary

• DataregardingsafetyandefficacyfororalTDF-FTCPrEPinyoungpeopleisavailableonlyforMSMage15–22yearsthroughProjectPrEPare,whichhadtwophases:arandomisedplacebo-controlledfeasibilityandacceptabilityphase(ATN082);andanopen-labelPrEPdemonstrationproject(ATN110).

• Adherenceasmeasuredbyselfreportanddriedbloodspotsdecreasedovertime.Byweek48inATN110,only34%ofparticipantshaddruglevelsconsistentwithfourormorepillsperweek.

• IndicesofrenalfunctioninATN117didnotdifferbetweenhigh-orlow-TDFexposuregroupssupportingtheshort-termrenalsafetyofTDF-basedPrEPinadolescentboysandyoungmen.

• BonedensityshowedprogressivedeclineinhighvslowTDFexposuregroupsover48weeks,butdiscontinuationofTDF-FTCledtorecoveryofbonemineraldensitychangesovera48-weekfollow-upperiod.ThissuggestsPrEP-relatedbonelossinyoungmenisreversible.

• However,thepersistentlylowerZscoresinthespine,evenat48weeksoffPrEP,suggestthattheuseofTDFPrEPmaybeaparticularriskforadolescentsasthisisacriticalperiodforattainmentofpeakbonemass.

3.5.1EfficacyDespitethemajorityoflargePrEPstudiesrecruitingfromtheageof18years,fewweredesignedtoreportsafetyandefficacyspecificallyintheyoungeragegroup.Whenreported,youngerageisassociatedwithpooreradherenceandlowerTDF-FTClevels[1,2].Thisisnotsurprising,asadherencetomedicationisknowntobeachallengeforyoungpeople,whetherfortreatmentofdiseaseorpregnancyprevention[3-7].RecentPhase3studiesofthedapavirineringreportedthatefficacywaslowerintheyoungeragegroups[8,9].

TheonlystudytodatetoreportonadherenceandsafetyspecificallyinyoungpeopleisProjectPrEPare.Thisiscomposedoftwophases:arandomisedplacebocontrolledfeasibilityandacceptabilityphase(ATN082)[10];andProjectPrEPare2(ATN110)[11],anopen-labelPrEPdemonstrationprojectandPhase2safetystudyinMSM.ForProjectPrEPare2(ATN110),HIV-negativeyoungmenwhohavesexwithmen(YMSM)age18–22yearswererecruitedfrom12urbancitiesintheUnitedStates.Of2186screened,400wereeligibleand200wereenrolledintothestudy(meanage20.2years;54.5%Black,26.5%Latino).ElevenindividualswerediagnosedwithHIVat

baseline(4%)andtwoparticipantswereprematurelydiscontinuedduetodiagnosisofacuteHIVviaRNAatenrolmentvisit.

TherewerefourHIVseroconversionsduringthestudygivinganHIVincidencerateof3.29per100person-years(95%CI0.07–6.52).Noneoftheparticipantswhoseroconvertedhaddetectablelevelsoftenofovirdiphosphate(TFV-DP)inthesamplethatwasdrawnclosesttotheseroconversiondate.

3.5.2AdherenceProjectPrEPare(ATN082)[10]andProjectPrEPare2(ATN100)[11],bothreportedadherence.Bothstudiesincludedanevidence-basedbehaviouralHIVpreventionintervention,ManyMenManyVoices(3MV)[12],withparticipantsinPrEPare2alsoreceivingpersonalisedcognitivecounselling[13].

Follow-upofthe58participantsrandomlyrecruitedtoProjectPrEPare,occurredevery4weeksfor24weeks.Self-reportedadherencetostudypillfluctuated,rangingfromfivemisseddoses(weeks16and20)to17misseddoses(week24).TheratesofdetectableTFV-DPintheplasmaoftheTDF-FTCarmdecreasedoverthestudyvisits:63.2%atweek4to20%atweek24.

StudyvisitsforProjectPrEPare2occurredmonthlyforthefirstquarterandthenquarterlyto48weeks.TFV-DPwasmeasuredusingdriedbloodspots:themajorityofparticipantshaddetectabledrugoverthecourseofthestudy;90%haddetectabledrugat12weeks;81%atweek24;and69%atweek48.Byweek48,only34%ofparticipantshadadruglevelconsistentwithatleastfourpillsperweek,thelevelconsistentwithnoHIVinfectionsiniPrEx-OLE[1].Ofnote,themedianlevelforAfricanAmericanparticipantswasbelowthisprotectivethresholdatalltimepoints.ParticipantsreportingrecentcondomlesssexhadconsistentlyhigherTFV-DPlevels(P=0.01).

ATN113(ProjectPrEPare)wasademonstrationprojectandPhase2safetystudythataimedtoobtaindataonsafetyandtoevaluateratesofadherence,andpatternsofsexualriskbehaviouramongyoungMSMaged15–17[14].ThestudycombinedPrEPwithbehaviouralriskreductionandadherencesupportin78HIV-uninfectedMSMaged15–17years[14].Morethan95%haddetectabledruglevelsandmorethanhalfhadhighlyprotectivelevels(atleastfourdosesperweek)duringthefirst3months,butthisdroppedtoabout75%and32%,respectively,aftertheyswitchedtoquarterlyfollow-up.

3.5.3Safety

3.5.3.1Overalladverseeventsandgrade3–4Of258participantsinProjectPrEPare[10]andProjectPrEPare2[11],thereweresevengrade3adverseeventsthoughttobepossiblyorprobablyrelatedtostudydrug:oneincreasedbilirubin,twoheadache(onemigrainous),onenausea,oneweightlossandtwoinstancesofdecreasedcreatinineclearanceinthesameparticipant.Forthatparticipant,theestimatedcreatinineclearancewas180mL/min/1.73m2atbaselineandshowedconsiderablevariationoverthecourseofthestudy,butneverdeclinedbelow110mL/mindespitecontinuationofstudydrug.MorenauseawasnotedintheTDF-FTCgroup(23.5%)ofProjectPrEParevsplacebo(0%)andno-pill(5.9%)groups.

TheATN110extensionstudyfollowedBMDinyoungmenwhoeitherlostorfailedtogainbonemineralcontentorBMDatweek48oftheinitialstudy(n=102)foranadditional48weeks,ofwhom72patientsdiscontinuedPrEPandwereeligibleforinclusioninthefinalboneextensionanalysis[15]).Asmenreachpeakbonemassatapproximately25yearsofage,itwouldbeabnormalnottogainboneduringthisperiodofearlyadulthood,andimportanttodetermineifanyeffectsofTDFonBMDarereversibleupondiscontinuation.

3.5.3.2RenalfunctionMetabolicdatawerecollectedfromasubsetofparticipantsinATN110[11]andATN113[14](15–17yearoldparticipantsinProjectPrEPare).Thissub-study(ATN117[16]),aimedtocharacterisetherelativerolesofrenal(glomerularandtubular)versusendocrine(calciumphosphate–vitaminDmetabolism)changesinTDF-associatedbonetoxicity.UsingTFV-DPconcentrationsindriedbloodspots,theycategorisedparticipantsintohigh(>861fmol/punch),moderate(≤861–≥345fmol/punch)andlow(<345fmol/punch)exposurecategories.Serumcreatinineroseslightlyduringthefirst12weeks,buteGFRdidnotdeclinesignificantlyatanytimepoint.Therewerenosignificantchangesinanyothermeasureofrenaltoxicity.Noneoftheindicesofrenalfunction(urineglucose,retinol-bindingprotein,β2-microglobulin,protein/creatinineorcalcium/creatinineratio;serumcreatinine,calcium,orphosphate;orcalculatedeGFR)differedbydrug-exposurecategory.

Theauthorsconcludethatthesefindingssupporttheshort-termrenalsafetyofTDF-basedPrEPinHIV-negativeadolescentboysandyoungmen.TheycommentthatalackofrenaleffectcouldresultfromhigherbaselineeGFRintheyoungstudygroup,andalsothatdurationoffollow-upwasshort,postulatingthatalongerexposuremayberequiredtorevealarelationshipbetweentubularimpairmentandboneloss.

3.5.3.3BonemineraldensityComparedtothelowdrug-exposuregroup,thehighdrug-exposuregroup(asmeasuredbymeasuredbyredbloodcellTFV-DPconcentrations)exhibitedgreaterandmoreconsistentchangeinbiochemicalmarkersofcalcium(PTH),phosphate(FGF23),andboneturnover(osteocalcin)thanmarkersofrenalglomerularortubulardysfunctionover48weeksofTDF-FTCPrEP,suggestingthatendocrinedisruption(PTH-FGF23)isaprimarycontributortoTDF-associatedBMDdeclineinthisagegroup[16].

IntermsofBMD,theabilityofTDFtodecreaseorimpairaccrualofBMDinthisyoungstudycohortwasdemonstratedbythegreaterthan3%differenceinchangeinBMD(percentagedifferencefromthebaselinevalue)andBMDZ-scoreinthetotalhipandfemoralneckfrombaselinetoweek48inthehighdrug-exposuregroupcomparedtothelowdrug-exposuregroup(−1.59[2.77]%vs+1.54%[3.34]%,respectively;P=0.001).SpineBMDchangesfollowedasimilarpattern,butdidnotachievestatisticalsignificance(P=0.19atweek48).TheauthorssuggestthatthispatternofBMDchangesuggestsastrongereffectofTDFoncorticalbone(thehipisapredominantlycorticalsite)andalessereffectontrabecularbone(predominantinthespine)inyoungmen,someofwhomwereaged15years.

FollowingdiscontinuationofTDF-FTC,changesinbonemassof72participantsofATN110(meanage20.1years),wasassessedat24and48weekspostdiscontinuationviaDEXAscanning[15].Amongthisgroup,averageBMDchangesfrombaselinetoweek48ofthePrEPtreatmentphasewere:spine−0.25%(P=0.23);hip−1.43%(P=0.002);wholebody(WB)−0.63%(P=0.03).

However,inthe48weeksafterPrEPwasstoppedattheendoftheextensionphase(48weeksonTDF-FTCfollowedby48weeksoffTDF-FTC),BMDincreasedsignificantlyatallsites:+1.15%inthespine(P=0.003),+1.02%inthehip(P=0.04),and+0.64%inthewholebody(P=0.01).

WhencomparingnetchangesinBMDfrombaselinetotheendoftheextensionphase,thesewerenotsignificantinthehip−0.35%orwholebody−0.11%,butasignificantincreaseinBMDforthespine(+0.87%,P<0.05)wasreportedattheendof48weeksoffPrEPwhencomparedtobaseline[15].

IntermsofZ-scores,whichmeasurethenumberofstandarddeviationsapersonisawayfromanage-,sex-,andrace-matchedpopulation,withanormalZ-scorebeing0,therewashoweverasuggestionofsomepersistenteffectsofPrEPonBMDatendoffollow-up(48weekspostPrEP),withsmall,butstatisticallysignificantnetdecreasesfrombaselineinZ-scoresinthespine(−0.164,P<0.001)withnosignificantchangeinthehip(−0.03)orwholebody(−0.07).ThereisthereforesomeevidenceofimpactonbonedensitycausedbyexposuretoTDF-FTC

over48weeksin18–22-year-oldmales,butdiscontinuationofTDF-FTCledtorecoveryofbonemineraldensitychangesovera48weekfollow-upperiod.TheseresultssuggestthattheeffectofPrEPonbonelossinyoungmenisreversible.However,thepersistentlylowerZscoresinthespine,evenat48weeksoffPrEPattheendoffollow-up,suggeststhattheuseofTDFPrEPmaybeaparticularriskforadolescentsasthisisacriticalperiodforattainmentofpeakbonemass.

Theauthorssuggestthatendocrine-focusedinterventionsmightbereasonabletoconsiderforyoungmentakingTDF-FTCforPrEP,andthatsupplementationwithcalciumandvitaminDmaylessenTDF-relatedBMDdecline,butthedataislackinginHIV-negativeindividualsandastudyoftheeffectofvitaminDsupplementationonBMDdeclineinTDF-FTCPrEPiswarranted,particularlyasvitaminDandcalciumsupplementationlessensBMDdeclineatTDF-containingARTinitiation[17].

3.5.4RiskbehaviourInProjectPrEPare[10],sexual-riskbehaviourdeclinedinallstudyarmsfrombaselinethroughtoweek24.ThebaselineratesofHIVtransmissionriskbehaviourandSTIprevalencewerehighinProjectPrEPare2[11];thesebehavioursremainedlargelystableovertime.However,thefactthatongoingHIVtransmissionriskbehaviourremainedhigh,PrEPadherencecounsellinginthisgroupwasextremelyimportant.

3.5Evidenceforsafetyandefficacyinyoungpeople(15–25years):recommendations11. WerecommendthatPrEPwithdailyoralTDF-FTCshouldbeofferedtoyoungMSMandTGW

women(15–25years)whoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughcondomlessanalsexintheprevious3–6monthsandongoingcondomlessanalsex.(1A)

12. WerecommendthatPrEPwithTDF-FTCshouldbeofferedtoyoungpeoplehavingcondomlessanalsexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

13. RoutineBMDscanninginyoungpeopleinitiatingPrEPisnotrecommended.(1D)Goodpracticepoints• ConsiderPrEPwithdailyoralTDF-FTConacase-by-casebasistoyoungpeoplewithcurrent

factorsotherthancondomlessanalsexthatmayputthematincreasedriskofHIVacquisition.SeeSection4.

• TheriskandbenefitsofprovidingPrEPforadolescentsshouldbeweighedcarefullyinthecontextofUKlawsandjudgementsaboutautonomyinhealthcaredecision-making(e.g.Frasercompetency),andbalancedagainstprotectingyoungpeoplefromharm.

• AdiscussionaboutsideeffectsincludingimpactuponbonedensityinyoungpeopleshouldbeheldatPrEPinitiationandmaintenancevisits.

3.5.5References1. GrantRM,AndersonPL,McMahanVetal.Uptakeofpre-exposureprophylaxis,sexualpractices,andHIVincidenceinmenandtransgenderwomenwhohavesexwithmen:acohortstudy.LancetInfectDis2014;14:820–829.

2. MarrazzoJM,RamjeeG,RichardsonBAetal.Tenofovir-basedpreexposureprophylaxisforHIVinfectionamongAfricanwomen.NEnglJMed2015;372:509–518.

3. deOliveiraBM,VianaMB,ZaniCL,RomanhaAJ.Clinicalandlaboratoryevaluationofcomplianceinacutelymphoblasticleukaemia.ArchDisChild2004;89:785–788.

4. HallKS,WhiteKO,ReameN,WesthoffC.Studyingtheuseoforalcontraception:areviewofmeasurementapproaches.JWomensHealth2010;19:2203–2210.

5. LindseyJC,BoschRJ,RudyBJ,FlynnPM.Earlypatternsofadherenceinadolescentsinitiatinghighlyactiveantiretroviraltherapypredictlong-termadherence,virologic,andimmunologiccontrol.AIDSPatientCareSTDS2009;23:799–801.

6. RudyBJ,MurphyDA,HarrisDRetal.Patient-relatedrisksfornonadherencetoantiretroviraltherapyamongHIV-infectedyouthintheUnitedStates:astudyofprevalenceandinteractions.AIDSPatientCareSTDS2009;23:185–194.

7. ZindaniGN,StreetmanDD,StreetmanDS,NasrSZ.Adherencetotreatmentinchildrenandadolescentpatientswithcysticfibrosis.JAdolescHealth2006;38:13–17.

8. BaetenJM,Palanee-PhillipsT,BrownERetal.UseofavaginalringcontainingdapivirineforHIV-1preventioninwomen.NEnglJMed2016;375:2121–2132.

9. KapigaS,BekkerLG,BridDevlinBetal.SafetyandefficacyofdapivirinevaginalringforHIV-1preventioninAfricanWomen.ConferenceonRetrovirusesandOpportunisticInfections.Boston,MA,USA.

10. HosekSG,SiberryG,BellMetal.TheacceptabilityandfeasibilityofanHIVpreexposureprophylaxis(PrEP)trialwithyoungmenwhohavesexwithmen.JAcquirImmuneDeficSyndr2013;62:447–456.

11. HosekSG,RudyB,LandovitzRetal.AnHIVpreexposureprophylaxisdemonstrationprojectandsafetystudyforyoungMSM.JAcquirImmuneDeficSyndr2017;74:21–29.

12. WiltonL,HerbstJH,Coury-DonigerPetal.EfficacyofanHIV/STIpreventioninterventionforblackmenwhohavesexwithmen:findingsfromtheManyMen,ManyVoices(3MV)project.AIDSBehav2009;13:532–544.

13. DilleyJW,WoodsWJ,LoebLetal.BriefcognitivecounselingwithHIVtestingtoreducesexualriskamongmenwhohavesexwithmen:resultsfromarandomizedcontrolledtrialusingparaprofessionalcounselors.JAcquirImmuneDeficSyndr2007;44:569–577.

14. HosekS,LandovitzR,RudyBetal.AnHIVpre-exposureprophylaxis(PrEP)demonstrationprojectandsafetystudyforadolescentMSMages15–17intheUnitedStates(ATN113).InternationalAIDSConference(AIDS2016).Durban,SouthAfrica.

15. MulliganK,HosekS,KapogiannisGetal.ChangesinbonemassafterdiscontinuationofPrEPwithtenofovirdisoproxilfumarate/emtricitabine(TDF/FTC)inyoungmenwhohavesexwithmen:extensionphaseresultsofAdolescentTrialsNetwork(ATN)110(abstractWEAC0305LB).JIntAIDSSoc2016;19(6Suppl5):21264.

16. HavensPL,StephensenCB,VanLoanMDetal.Declineinbonemasswithtenofovirdisoproxilfumarate/emtricitabineisassociatedwithhormonalchangesintheabsenceofrenalimpairmentwhenusedbyHIV-uninfectedadolescentboysandyoungmenforhivpreexposureprophylaxis.ClinInfectDis2017;64:317–325.

17. OvertonET,ChanES,BrownTTetal.VitaminDandcalciumattenuatebonelosswithantiretroviraltherapyinitiation:arandomizedtrial.AnnInternMed2015;162:815–824.

3.6EvidenceforthetimelinesforstartingandstoppingPrEP

EvidenceforthetimelinesforstartingandstoppingPrEP:summary

• Thetimetoachieveaprotectiveconcentrationisdeterminedbythedrugsused,thedose,thefrequencyofdosingandthetargettissue.

• AvailabledatasuggestthattimetoclinicalprotectionforTDFandFTC(andactivemetabolites)isshortestinthelowergastrointestinaltract,followedbyperipheralbloodmononuclearcells(PBMCs)andtheninthefemalegenitaltract(FGT).

• TheactivemetaboliteofTDFconcentratestomuchhigherlevelsinthelowergastrointestinalmucosarelativetoPBMCswhereasFTCconcentratesintheFGT.

• ThetimetoclinicalprotectionforanalsexhasbeenevaluatedinasingleRCT(IPERGAY),startingwithdouble-doseofTDF-FTC2–24hrsbeforesex.Thisissupportedbypharmacokineticdatainanimalstudies.

• ThetimetoclinicalprotectionforvaginalsexhasbeenextrapolatedfrompharmacokineticstudiesofTDF-FTCandthereisconsensusforalead-intimeforprotectionof7days.

• DatafromIPERGAYdemonstratesthat,whenPrEPistakentopreventHIVacquisitionfromanalsex,dosingcanbestoppedwhenanoraldosehasbeentaken24hoursand48hoursafterthelastepisodeofpotentialexposure.Thisissupportedbyanimalandpharmacokineticstudieswhenthepersonisreceptive,buttherearefewerdataforforeskinandurethra.

• Thereisconsensusthat,whentakentopreventHIVacquisitionfromvaginalsex,TDF-FTCcanbestoppedwhenadailyoraldosehasbeentakenfor7daysafterthelastepisodeofpotentialexposure.

Thereareseveralwell-conductedpharmacokineticstudieswhichhaveuseddiversemethodologytoaddressthequestionoftimetoclinicalprotection.Thereisconsiderableheterogeneityacrosstheresults,butaconsensuswithrespecttotheconcentrationoftheactivemetabolitesofTDFandFTCincolonicandcervico-vaginaltissuerelativetoPBMCs,theshortertimeittakestoachievethepeakconcentrationofFTC-TPcomparedtoTFV-DP,andthelongerhalf-lifeofTFV-DPinalltissues.Thereisalsoconsensusthatconcentrationsofactivemetabolitesinthegenitalandcolonictissuesareprobablythemostimportantinavertinginfection.

3.6.1BloodPBMCsAndersonetal.combineddatafromtheiPrEXeffectivenesstrialandtheSTRANDpharmacokineticstudytodeterminetherelationshipbetweenPrEPefficacyandTFV-DPconcentrationinPBMCs.TheydeducedthatanintracellularconcentrationofTFV-DP(theactivemetabolite)of16fmolpermillionincryopreservedPBMCswasassociatedwitha90%reduction(EC90)inHIVacquisitionrelativetotheplaceboarm,andderivedeffectsizesof76%fortwodosesaweek,96%forfourdosesand99%forsevendoses,respectively[1].AsimilarapproachwasusedtoevaluatethetimetoclinicalprotectioninPBMCsandrectalmononuclearcells,andthedurationofprotectionafterstoppingPrEPbySeifertetal.[2].TFV-DPconcentrationsinPBMCs(andrectalmononuclearcells)weremeasuredintwenty-oneHIV-uninfectedadultsinanintensivepharmacokineticstudyof30daysofdailyTDF-FTCfollowedby30daysoffdrug.UsingtheiPrExdrug-detectionefficacymodeldescribedabove,theinferredHIVriskreductionderivedfromPBMCTFV-DPconcentrationreached99%(95%CI,69–100%)afterfivedailydoses,andremained>90%for7daysafterstoppingdrugfromsteady-stateconditions.IncontrasttotheeffectdescribedbyAndersonetal.(describedabove)andusingthesamedrug-detectionefficacymodel,theproportionofparticipantsreachingtheEC90was77%afterfivedosesand89%aftersevendoses[3].

TheHPTN066studysoughttoestablishdrugconcentrationswithinPBMCs(andalsoreproductiveandgastrointestinaltracts)whenoralTDF-FTCwasgivenatdifferentdosesandatdifferentdoseschedulesunderdirectobservationfor5weeks.Forty-ninestudyparticipants(29femalesand20males)wererandomlyassignedtooneoffouroralregimensoffixed-doseFTC-TDF.Participantsreceivedonetabletweekly(1/week),onetablettwiceweekly(2/week),twotabletstwiceweekly(4/week),oronetabletdaily(7/week)withsamplingpriortotheseconddose,atday7andevery7daysthroughtoday49.Allregimensachievedsteady-stateconcentrationsfortheactivemetabolitesinPBMCsat7days,earlierthanpredictedfromsimilarstudiesinHIVpositivepopulations.Withdailydosing,iPrEXEC90concentrationsofTFV-DPinunfractionatedPBMCswerealsoachievedinallparticipantsafter7days.Twoweeksafterthefinaldose,TFV-DPinPBMCswasabovethelowerlimitofquantificationinsevenofeightinthe4/weekgroupandeightof10inthedailygroupwhereasFTC-TPwasonlydetectedinthedailygroupatthistimepoint[4].

Comparableresultswereseeninanintensive60-daypharmacokineticstudyof40individuals(19HIV-negativeand21HIV-positiveindividuals)receivingdailyTDF-FTCwheredrugconcentrationswereanalysedinblood,genitalandrectalcompartments.Thisstudyincludedanearliersamplingtimepointinallparticipantsatday3.TheestimatedtimetosteadystateinPBMCwas3daysforFTC-TPand11daysforTFV-DP.ThereweresmalldifferencesbetweenHIV-negativeand-positivepopulationsbutthesewerenotthoughttobeclinicallymeaningful[2].

3.6.2FemaleandmalegenitaltractSimilarEC90valuesfor‘protectiveconcentrations’arenotwelldefinedforthefemalegenitaltract(FGT),urethra,glansorforeskin,andmayvaryfromthatinbloodPBMCs.SeveralpapershaveshownthatTFV-DPachievesmuchhigherconcentrationsinrectaltissuesrelativetovaginaltissues.

Patersonetal.evaluatedtheconcentrationsinbloodandgenitalsecretionsofTFVandTFV-DPplusFTCandFTC-TPin15HIV-negativeindividuals,includingsevenwomen,givenasingleoraldoseofTDF-FTC[5].Druglevelsandtheiractivemetaboliteswerealsomeasuredinhomogenatespreparedfromvaginalandcervicaltissuesandcomparedwithrectalhomogenates.FollowingsingledoseofTDF-FTC,theareaundertheconcentration–timecurvefrom24hoursto14days(AUC1–14days)forFTCingenitalsecretionswas27-foldgreaterthaninbloodplasmaand10-to15-foldhigherthaninrectaltissue.LevelsofFTC-TPwere,however,onlydetectedfor2daysafterdosinginvaginalandrectaltissues[5].Thus,FTCandFTC-TPlevelsseemtoaccumulaterapidlyincervicovaginaltissuesandfluidbutdecayrapidly(terminalhalf-lifeofFTC,T1/2=40hours).Inaddition,resultssuggesttheroleofFTCinprotectioninvaginaltissuesmaybeofgreatersignificance,particularlyintheearlystagesafterstartingoralTDF-FTC.

IncontrasttoFTC,followingasingledoseofTDF-FTC,theAUC1–14daysforTFVwasonly2.5-foldgreateringenitalsecretionsthaninbloodplasmawhereasinrectaltissue,TFVandTFV-DPconcentrationswere100-foldhigherthantheconcentrationsinvaginalandcervicaltissues[5].Inaddition,TFV-DPlevelsweredetectableoutto14days(terminalhalf-lifeT1/2=71hours),againsuggestingtheactivemetaboliteplaysamoreimportantrolethanFTC-DPinavertinginfectionaftercessationoforalTDF-FTCafterlasttimeofexposure[5].

Time-to-steadystateintheFGThasbeenextrapolatedfrompharmacokineticdatastudiesonsamplestakenfromtheFGTfollowingasingleoraldoseofTDF300mgandmicrodoseofradiolabelled14C-TDFtosixHIV-negativewomen[6].Bloodwascollectedatmultipletimepointswithinthefirst24 hours,thenat4,8,11,and15dayspost-dosing.Rectalandvaginalbiopsiesplusluminalfluidandbloodondays1,8and15wereassayedforTFVandTFV-DP;nodatawerecollectedonFTC.Datawereusedtoestimatetherateofabsorption,andrateofformationanddecayofTFV-DP.ResultsdemonstratedanatomicalvariationinpharmacokineticsacrossCD4cellsextractedfromPBMCs,colonbiopsiesandfemalegenitaltractbiopsies.Respectively,theT1/2ofTFV-DPwasmarkedly

longerinvaginaltissuesthanPBMCs(139hoursvs112hours)andalsolongerthanthatseenincolonicsamples(139hoursvs60hours),underlyingtheimportanceoftheterminaldecayofTFV-DPinavertinginfection[6,7].

HPTN066alsosoughttoestablishdrugconcentrationswithinreproductivetissuewhenoralTDF-FTCwasgivenatdifferentdoses[4].Of49studyparticipantsrecruited,29werefemale.Samples,includingvaginaltissue(biopsy)andcervicovaginalfluid(directaspirate),werecollectedfordrugassessmentatendofdosingand2weekslaterinasubsetofparticipantswhounderwenta‘washoutperiod’[4].

Althoughnoassessmentoflead-intimeswasperformedintheFGT,HPTN066didestablishthat,exceptforvaginalhomogenateTFVandFTCconcentrationswithdailydosing,nearlyallvaginalsampleswerebelowquantitativelimits,implyingthatonlydailydosingislikelytobeeffectiveandbyinference,lead-intimeislikelyatleastaweek[4].

Finally,bycombininganinvitroefficacymodelwithmucosaltissuePKdataandmathematicalmodelling,Cottrelletal.attemptedtodeterminethenumberofdosesrequiredforeffectivePrEP.MucosalconcentrationsofTDFandFTC(includingvaginal,cervicalandcolorectalsamples)andtheirmetabolitesweremeasuredin47HIV-negativewomenadministeredasingledoseofTDF-FTC.Resultswerecomparedwithcompetingendogenousnucleotides.Invitromodels(usingTZM-blandCD4+cells)werethenusedtoidentifyEC90ratiosforprotection[8].BycontrasttoHPTN066,themodelpredictedthatintheFGT,atleast98%ofthepopulationachievedprotectivemucosaltissueexposurebythethirddailydoseofTDF-FTC.AligningwithconclusionsofHPTN066,however,aminimumadherencetosixofsevendoses/week(85%)wasrequiredtoprotectlowerFGTfromHIV[4].

Nodataexistondoubledosingonday1oflead-inforwomenwishingtousePrEP;however,suchanapproachisbiologicallyplausibleinordertoloadmorerapidly.NodataexistonpenetrationofTDForFTCintothemalegenitaltract.

3.6.3RectaltissuesSeifertetal.examinedTFV-DPconcentrationsinrectalmononuclearcellsamong21HIV-negativeadultsover30daysofdailyTDF-FTCfollowedby30daysoffdrug[3].ThepercentageofsteadystatereachedforTFV-DPinrectaltissuewas71%afterthreedoses,88%afterfiveand94%aftersevendoses;itisspeculated,however,thatprotectiveconcentrationsofTDFintherectalmucosawillbeachievedmorerapidly.

EarliertimetoachievingprotectiveconcentrationsissupportedbyresultsinastudybyPattersonetal.inwhich15HIV-negativeindividualsweregivenasingleoraldoseofTDF-FTC[4].Here,bothdrugsweremeasuredinhomogenatespreparedfromrectal(andvaginalandcervicaltissues).Inrectaltissue,highpenetrationofTFV-DPwasdemonstratedattheendofthefirst24-hourperiodafterdosing(median206,950fmol/g);FTC-TPconcentrations,however,weresubstantiallylowerthanTFV-DPat24hours(124ng/g).RectalTFV-DPconcentrationswere100-foldhigherthanthevaginalandcervicalconcentrations.

FurtherdataontimetosteadystateforFTCandTDFinrectaltissuescomesfromtheCell-PrEPstudy;inthe60-daypharmacokineticstudywithdailyoralTDF-FTC,steadystateconcentrationsforTFV-DPwereachievedinrectalmononuclearcellsbyday5andwas10-foldthatseeninPBMCs.Significantly,however,FTCappearedtoreachsteadystate2hoursintothefirstdosewithinrectalmononuclearcells[2].

ThisrapidaccumulationofFTCinrectaltissuesmayexplainthefindingswithintheIPERGAYstudywhereanapparentlead-intimeof2–24hourswithadoubledoseofTDF-FTCconferred86%riskreductioninHIVacquisitionandthusmayplayanimportantroleinevent-baseddosing[9].

3.6.4DurationofPrEPusefollowinglastpossibleexposureDurationofcontinuedPrEPdependsonsiteoflastpotentialexposure.DatafromIPERGAYsuggeststhatwhereexposureoccursthroughanalsex,ahighprotectiveeffectisachievedwhendailyoraldosesaretaken24hours

and48hoursafterthefirstdoubledose(incasesofmultipleconsecutivesexualintercourse,participantswereinstructedtotakeonepillperdayuntilthelastsexualintercourseandthentotakethetwopost-exposurepills)[9].Evidenceinrelationtodurationofcontinuedusefollowingexposuresatotheranatomicalsites,however,remainslessclearandhasnotbeenclearlyaddressedinclinicaltrialsettings.Importantly,thedurationoftimeforHIVtobeclearedfrommucosalsitesfollowinglastpotentialexposureisunknownandassuch,thedurationoftimethatPrEPshouldbecontinuedtocoverthistimecanonlybeinferred.Althoughitisrecommendedtocontinuepost-exposureprophylaxisfor28daysafterexposure,thisisbasedonthepremisethattheearlystagesofHIVlifecyclemayhaveoccurredbythetimePEPSEhasbeeninitiatedandconsequently,alongerdurationoftreatmentisrequireduntiltheviruscanbecleared.IntheinstancewhereapersonisreceivingPrEPhowever,earlystagesofthevirallifecycleareinhibitedandthus,ashorterdurationofcontinuedPrEPuseislikelytoberequiredfollowinglastpotentialHIVexposure.

DatafromCottrelletal.suggestshighadherenceisneededinwomen(atleastsixofsevendoses/week)becausedrugconcentrationsquicklydrop(particularlyFTC-DP)invaginaltissuethussuggestingalongerdurationofcontinuationisneededinfollowingpotentialvaginalexposure[8];todate,expertopinionestimatesacontinueddurationofTDF-FTCof7daysafterlastpotentialexposure.

SeifertetalestimatedthetimetakenforTFV-DPlevelstofallbelowtheprotectivethresholdafterstoppingPrEPinPBMCsextrapolatedfromiPrExdata[3].At2daysafterstoppingdrug,80%ofTFV-DPconcentrationsremainedaboveprotectivethresholds(EC90),decreasingto48%at7daysafterdiscontinuation.Insensitivityanalyses,theproportionofconcentrationsabovetheEC90rangedfrom86%to91%at2daysafterstoppingdrug,and48%to63%at7daysafterstoppingdrug.

3.6EvidenceforthetimelinesforstartingandstoppingPrEP:recommendations

14. WerecommendthatiftheriskofHIVacquisitionisthroughanalsex,PrEPcanbestartedwithadoubledoseofTDF-FTCtaken2–24hoursbeforesexandcontinueddailyuntil48hoursafterthelastsexualrisk.(1B)

15. WerecommendthatifPrEPforanalsexhasbeeninterruptedanditislessthan7dayssincethelastTDF-FTCdosethenPrEPcanbere-startedwithasingledoseofTDF-FTC.(1B)

16. WerecommendthatiftheriskofHIVacquisitionisthroughvaginalsex,PrEPshouldbestartedasadailyregimen7daysaheadofthelikelyriskandcontinueddailyfor7daysafterthelastsexualrisk.(1C)

Goodpracticepoints

• IndividualswhoseriskisthroughvaginalsexshouldstillbeinformedaboutstartingoralPrEPwithadoubledoseofTDF-FTCincasetherearetimeswhenitisnotpossibletotakeforafull7daysbeforeapotentialrisk,butadvisedthattheevidencecurrentlyonlysupportsthisregimenforanalsex.

• Individualsatriskthroughinjectingdruguseaswellassexualriskshouldbeinformedthatittakeslongertoachieveprotectiveconcentrationsintheblood,andthat7daysbeforeand7daysafterisadvisable.

3.6.5References1. AndersonPL,GliddenDV,LiuAetal.Emtricitabine-tenofovirconcentrationsandpre-exposureprophylaxisefficacyinmenwhohavesexwithmen.SciTranslMed2012;4:151ra125.

2. SeifertSM,ChenX,MeditzALetal.Intracellulartenofovirandemtricitabineanabolitesingenital,rectal,andbloodcompartmentsfromfirstdosetosteadystate.AIDSResHumRetroviruses2016;32:981–991.

3. SeifertSM,GliddenDV,MeditzALetal.DoseresponseforstartingandstoppingHIVpreexposureprophylaxisformenwhohavesexwithmen.ClinInfectDis2015;60:804–810.

4. HendrixCW,AndradeA,BumpusNNetal.Dosefrequencyrangingpharmacokineticstudyoftenofovir-emtricitabineafterdirectlyobserveddosinginhealthyvolunteerstoestablishadherencebenchmarks(HPTN066).AIDSResHumRetroviruses2016;32:32–43.

5. PattersonKB,PrinceHA,KraftEetal.Penetrationoftenofovirandemtricitabineinmucosaltissues:implicationsforpreventionofHIV-1transmission.SciTranslMed2011;3:112re114.

6. LouissaintNA,CaoYJ,SkipperPLetal.Singledosepharmacokineticsoforaltenofovirinplasma,peripheralbloodmononuclearcells,colonictissue,andvaginaltissue.AIDSResHumRetroviruses2013;29:1443–1450.

7. AVAC(GlobalAdvocacyforHIVPRevention).TImetoProtectionForPrEPWebinar.Availableat:www.avac.org/event/webinar-time-protection-prep(accessed

4Baselinerisk-assessment

4.1HowtotargetthoseatriskofHIVtransmission

PrEPisindicatedforthoseatgreaterriskofHIVacquisitionandthereforecomprehensivehistorytakingandriskassessment,includingbothsexualanddrugtakinghistories,isrequiredtoidentifythosemostlikelytobenefit.ClinicianswillneedtomakepragmaticdecisionswithpatientsaboutfutureHIVrisk,theirneedforPrEPandindividual–levelassessmentofthebenefitversuspotentialharmsofPrEP.Atapopulationlevel,givenlimitedresourcesandadesiretoachievethemaximumimpactofPrEP,cliniciansshoulduseclinicalcriteriaandrecommendationsasoutlinedintheseguidelines,alongwithlocalandnationalcriteriaforNHSorclinicaltrialeligibilitytoprovidePrEPtothoseathighestriskofHIVacquisition.

ItiswellrecognisedthatthereareotherriskbehavioursandvulnerabilityfactorsthatincreasetheriskofHIVacquisitionandtheseshouldbetakenintoconsiderationonacase-by-casebasisbyclinicianswhenconsideringeligibilityforPrEPandassessingHIVrisk.Althoughthislacksaclearevidencebase,thewritinggrouphasconsideredthisintermsofthosewhoare‘highrisk’andthereforePrEPwouldberecommendedandthosewhoareat‘mediumrisk’wherePrEPshouldbeconsidered(Tables4.1.1and4.1.2).

Table4.1.1.SummarytableofrecommendationsforPrEPHighrisk:recommendPrEP(i)HIV-negativeMSMandtranswomenwhoreportcondomlessanalsexintheprevious3–6monthsandongoingcondomlessanalsex.(1A)(ii)HIV-negativeindividualshavingcondomlesssexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies.(1A)Mediumrisk:consideronacase-by-casebasisPrEPmaybeofferedonacase-by-casebasistoHIV-negativeindividualsconsideredatincreasedriskofHIVacquisitionthroughacombinationoffactorsthatmayincludethefollowing:Population-levelindicators

• HeterosexualblackAfricanmenandwomen• RecentmigrantstotheUK• Transgenderwomen• Peoplewhoinjectdrugs• Peoplewhoreportsexworkortransactionalsex

Clinicalindicators• RectalbacterialSTIinthepreviousyear• BacterialSTIorHCVinthepreviousyear• Post-exposureprophylaxisfollowingsexualexposure

(PEPSE)inthepreviousyear;particularlywhererepeatedcourseshavebeenused

Sexualbehaviour/sexual-networkindicators• High-risksexualbehaviour:reportingcondomlesssex

withpartnersofunknownHIVstatus,andparticularlywherethisiscondomlessanalsexorwithmultiplepartners

• CondomlesssexwithpartnersfromapopulationgrouporcountrywithhighHIVprevalence(seeUNAIDdefinitions)[1]

• Condomlesssexwithsexualpartnerswhomayfitthecriteriaof‘highriskofHIV’detailedabove

• Engagesinchemsexorgroupsex• Reportsanticipatedfuturehighrisksexualbehaviour• Condomlessvaginalsexshouldonlyconsideredhigh

riskwhereothercontextualfactorsorvulnerabilitiesarepresent

Druguse• Sharinginjectingequipment• Injectinginanunsafesetting(outsidesafeinjection

facilities)

Sexualhealthautonomy• Coerciveand/orviolentpowerdynamicsin

relationships(e.g.intimatepartnerviolence)• Inabilitytonegotiateand/orusecondoms(oremploy

otherHIVpreventionmethods)withsexualpartners

Table4.1.2.EstimatedHIVprevalence(diagnosedandundiagnosedinfection)inadultsaged15–59yearsintheUKin2015[2]

Populationgroup*HIVprevalence(per1000)(95%credibleinterval,CrI)

Totalpopulation • Allages 1.6(1.5–1.6)• Thoseaged15–74 2.1(2.0–2.2)• Men 2.3(2.2–2.5)• Women 0.98(0.95–1.02)

Menwhohavesexwithmen(MSM) • UK 58.7(51.2–68.0)• London 135(101–184)• ElsewhereintheEnglandandWales 39.1(33.4–46.5)

Heterosexuals • All 1.0(1.0–1.1)• BlackAfricanheterosexualmen 22.2(21.3–23.6)• BlackAfricanheterosexualwomen 42.6(41.0–44.3)

*ThesedataareforEnglandandWalesonly

4.2AssociationswithHIVtransmissioninUKpopulations

4.2.1MSMandtransgenderwomenInclusioncriteriaforPROUDwereMSMandTGWwhoreportedcondomlessanalsexononeormoreoccasionsintheprevious90daysandthelikelihoodoffuturecondomlessanalsex[3].IPERGAYincludedMSMandTGWwhoreportedanalsexwithatleasttwosexualpartners,withoutsystematiccondomuse,intheprevious6months[4].InthePROUDstudythebaselinepredictorsofHIVinfectioninthedeferredPrEPgroup(overallHIVincidenceof9.1per100person-years)were:havingarectalSTI(incidence17.4/100person-years),twoormorecondomlessanalsexpartnersintheprevious90days(incidence13.6/100person-years),takingPEPSEinprevious90days(incidence12.5/100person-years)andparticipatinginchemsex(incidence11.6/100person-years).

IntheIPrEXstudy,wheretheoverallnumberneededtotreat(NNT)was62(95%CI44–147),NNTswerelowestforMSMandTGWwhoreportedreceptiveanalintercoursewithoutacondominthe3monthsbeforescreening(NNT36),cocaineuse(12),orasexuallytransmittedinfection(41)[5].ThereisalsoaclearcorrelationbetweenpreviousSTIsandsexualbehaviourandon-goingriskofHIVacquisition.UsingGUMCADdata(EnglandandWales)from2014,HIVincidenceoverallinMSMwas1.8per100person-years(Table4.2.1).Thisincreasedto3.3/100person-yearsinthosewhohadabacterialSTIand4.9/100person-yearsinthosewitharectalbacterialSTIintheprevious12months(S.DesaiandH.Mitchell,personalcommunication).

Table4.2.1.HIVincidenceinMSM

MSMGUMclinicattendees Numbers(2014) HIVincidenceper100person-years(95%confidenceinterval)

HIVnegativeorunknown 104,480 1.8(1.7–2.0)*

HIVtestinpreviousyear

(42–365daysprior)[A]

24,235 1.9(1.6–2.2)

• Subsetof[A]withrecent*bacterialSTI[B]

7,949 3.3(2.7–4.0)

• Subsetof[B]withrecent**rectalbacterialSTI[C]

2,125 3.9(2.8–5.6)

RecentbacterialSTI** 21,002 3.3(2.9–3.9)

RecentrectalbacterialSTI** 5,425 4.9(3.9–6.2)

*HIVincidenceestimatedinEnglandandWalesusingMay2016GUMCADextract.Analysesincluded36,541repeattestersand421seroconversions

**RecentSTIisoneintheprioryearand/oratfirstattendancein2014

4.2.2HeterosexualmenandwomenTheevidencetosupportPrEPefficacyandinformdetailedriskassessmentinheterosexualpopulationsintheUKsettingisnotasrobustasthatforMSM.TherearenoPrEPstudiesinUKheterosexualpopulationsorinhigh-incomecountries.TheRCTsevaluatingtheefficacyofPrEPamongheterosexualshavebeenundertakeninsub-SaharanAfricawhereHIVprevalenceisveryhighandthissubstantiallylimitstheabilitytogeneralisethesefindingstotheUKsetting.

TheestimatedprevalenceofHIVamongallheterosexualsintheUKislowat1.0per1000(95%credibleinteral[CrI]1.0–1.1),butgreateramongblackAfricanadults;22.2(95%CrI21.3–23.6)per1000amongblackAfricanheterosexualmenand42.6(95%CrI41.0–44.3)per1000amongblackAfricanheterosexualwomen[2].TheclinicalandcosteffectivenessofPrEPdependsuponprovidingPrEPtothoseathighriskofHIVacquisition.However,itisquitedifficulttoidentifyusingsufficientlyspecificclinicalcriteriaforanygroupofheterosexualpeopleintheUKwhowouldbeatsufficientrisk.TheWHOrecommendsPrEPforthoseat'substantialrisk'ofHIVacquisition,whichisdefinedasanHIVincidencegreaterthan3per100person-years[2].EvenamongGUMclinicblackAfricanattendees,theincidenceofHIVis0.17per100person-years[6],whichisfarlowerthanthe2–5%reportedintheRCTs.However,weknowthatblackAfricanwomenareatsubstantiallymoreriskoftransmissionthanmenandthoseatriskmaynotattendGUMclinics.

FactorsthatmayindicatetheuseofPrEPisappropriateincludehavinganHIV-positivepartnernotonsuppressiveART,recentbacterialSTIandmultiplesexualpartnerswherecondomsarenotused.Inaddition,cliniciansshouldconsidertheriskofanyofthepatients’sexualpartnersbeingHIVpositive,asHIVtransmissionisnotdeterminedsolelyattheindividuallevelbutisaffectedbyamorecomplexinteractionwithinsexualnetworksandatapopulationlevelespeciallyifapatient'ssexualpartnersarefromacommunityordemographicgroupwithahigherHIVprevalence.

4.2.3PeoplewhouserecreationaldrugsorpeoplewhoinjectdrugsInconsideringHIVriskinpeoplewhoinjectdrugs,wehaveconsideredseparatelythosewhoinjectheroininparticularfromthosewhoengageindrugtakingspecificallywithsex(chemsex).AsdiscussedinSection3.3HIVincidenceinpeoplewhoinjectdrugsintheUKislow,outsidespecificoutbreaksituations.Peoplewhoengageinchemsexhowever,especiallyMSM,oftenengageinhigher-risksexualpractices.

ParticipantsinthePROUDandIPERGAYstudiesreportedhighlevelsofrecreationaldruguseand,inparticular,drugsassociatedwithchemsex[4,7].Chemsexisassociatedwithhigh-risksexualpractices,includinggroupsex,highpartnernumbersandcondomlessanalsex.

InPROUD,thosereportingchemsexweresignificantlymorelikelytobediagnosedwithabacterialrectalSTIcomparedtonon-users(41%vs28%;P=0.003)andintheno-PrEPgrouphadahigherHIVincidence(11.6/100person-years).

AcohortstudyundertakeninCaliforniaon8905HIV-negativeMSMdemonstratedthatthe754/8905menwhoreportedmethamphetamineuseintheprevious12monthsscoredsignificantlyhigheronanevaluatedsexualriskbehaviourscorethanthe5922MSMwhoreportedneverusingmethamphetamine(P<0.001).TheauthorsconcludedthatmethamphetamineuseincreasessexualriskbehaviourandthesepatientsmayrepresentidealcandidatesforPrEP[8].

4.2.4PeoplewithHIV-positivepartnerswhoarenotonsuppressivetherapyBothHPTN052andthePARTNERstudydemonstratedtheefficacyofsuppressiveARTtherapyatpreventingHIVtransmissionsthroughcondomlesssexinheterosexualandMSMcouples[9,10].ThePartnersPrEPstudydemonstratedthatPrEPcanbeaneffectivestrategytopreventHIVtransmissioninHIVserodifferentcoupleswherethepositivepartnerhasrecentlystartedtherapyandnotyetachievedasuppressedHIVviralload.PartnersPrEPdemonstratedarelativereductionof67%intheincidenceofHIV-1withTDF(95%CI44–81;P<0.001)andof75%withTDF-FTC(95%CI55–87;P<0.001)inheterosexualHIV-1serodifferentcouplesfromKenyaandUganda[11].

InthePartnerDemonstrationproject1013serodifferentheterosexualcouplesinKenyaandUgandawereofferedART(asPrEP)fortheHIV-negativepartnerandasTasPfortheHIV-positivepartner.ThestudydiscontinuedPrEPforthepartnerwithoutHIVoncethepartnerwithHIVhadcompleted6monthsofART.Findingsdemonstratedthefeasibilityofintegrateddeliveryoftime-limitedPrEPasabridgetosustainedART,whichresultedinneareliminationofHIVtransmission,withanobservedHIVincidenceof<0.05%peryearcomparedtoanexpectedincidenceof>5%peryear(estimatedthroughmodelling)[12].

4.2.5VulnerabilityfactorsintranspeopleTransgenderwomenhaveahighestimatedworldwideHIVprevalenceof19%[13].Fewdataareavailablefortransgendermenorothertransgenderpopulations.However,transMSMarelikelytohavethesameorsimilarriskforHIVacquisitionasotherMSMpopulations.TransgenderpeoplehavelowratesofaccesstohealthandHIVservicesowingtoarangeofsocio-economicandculturalissues.Transandnon-binarypeoplecommonlyexperienceviolenceandstigma(including,abuseperpetratedbyclientsofsexworkersandintimatepartnerviolence)andmayexperiencerejectionfromfamilyandlackofculturalsupport.Transcommunitiesalsoexperiencehigherratesofunemployment,poverty,housinginsecurity,marginalisationandsocialisolation.Allthesefactorscanhaveanegativeimpactonmentalhealthandwellbeing,couldpotentiallyincreasevulnerabilitytoHIVandshouldinformadherencesupportandengagementwithserviceswhiletakingPrEP[14].

4.2.6SexualhealthautonomyandsexualnetworksAnassessmentofanindividual’ssexualhealthautonomyandtheirinvolvementinwidersexualnetworks,whichbothmayimpactonHIVrisk,shouldbeundertakenwiththepatientwhenassessingtheireligibilityforPrEP.Inparticular,considerationshouldbegivento:

• Theexistenceofanycoerciveand/orviolentpowerdynamicsintheirrelationship(s)(e.g.intimatepartnerviolence);

• Whethertheyengageinanypaidortransactionalsex;• Whethertherearedrugandalcoholormentalhealthissuesthatmaynegativelyimpactontheir

autonomy;• Theircurrentabilitytonegotiateand/orusecondoms(oremployotherHIVpreventionmethods)

withsexualpartners;• AnypotentialimpactofPrEPonfutureabilitytonegotiatecondomuse(oremployotherHIV

preventionmethods).

ConsiderationshouldalsobegiventothosewhoseHIVriskmaybeelevatedasaresultofengagingwithinahigher-risksexualnetwork.IndividualsmaybeatelevatedriskofHIVacquisitionwhenengagingincondomlesssexwithpartnersfromapopulationgrouporcountrywithhighHIVprevalence.Inaddition,anindividualmayhaveanelevatedHIVriskasaresultofcondomlesssexwithpartnerswhofitthecriteriaof‘highriskofHIV’asdetailedabove.

4.2.7Riskassessment(Table4.2.2andproforma).SeeAppendix2

Table4.2.2.Atbaseline(andduringfollow-up)detailedhistoryandriskassessmentisrequiredtoinclude:

Sexualbehaviour • Genderandsexualityofpartners• Numberofsexualpartnersinprevious3–6months• Condomlesssexinprevious3–6months(analorvaginal)• SexualpartnerswhoareHIVpositiveandnotonARTfor>6

monthswithanHIVviralload<200copies/mL• Historyofchemsex

STIhistory • HistoryofbacterialSTI• HistoryofrectalbacterialSTI• HIVandSTItestinghistory• HistoryofPEPintheprevious12months

Medicalandotherrelevanthistory

• Pastmedicalhistory(withparticularreferencetorenalandboneproblems)

• Drughistory(withparticularreferencetonephrotoxicdrugs)• Historyofinjectingdruguseincludingdetailsofsharingneedles

orinjectingequipment

4.1HowtotargetthoseatriskofHIVtransmission:recommendations

17. WerecommendthatPrEPwithregularorevent-basedoralTDF-FTCisofferedtoMSMandTGWatelevatedriskofHIVacquisitionthroughrecent(3–6months)andongoingcondomlessanalsex.(1A)

18. WerecommendthatPrEPwithdailyoralTDF-FTCisofferedtoHIV-negativepeoplehavingcondomlesssexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

Goodpracticepoint

• ConsiderPrEPwithoralTDF-FTConacase-by-casebasisforpeoplewithotherfactorsthatplacethematincreasedriskofHIVacquisition.

4.3References1. UNAIDS.Availableat:www.unaids.org/en/regionscountries/countries(accessedAugust2017).

2. KirwanPD,ChauC,BrownAEetal.HIVintheUK:2016report.2016.Availableat:www.gov.uk/government/uploads/system/uploads/attachment_data/file/602942/HIV_in_the_UK_report.pdf(accessedJuly2017).

6. WorldHealthOrganization.ConsolidatedguidelinesontheuseofantiretroviraldrugsfortreatingandpreventingHIVinfection.2016.Availableat:www.who.int/hiv/pub/arv/arv-2016/en/(accessedJuly2017).

7. DollingDI,DesaiM,McOwanAetal.AnanalysisofbaselinedatafromthePROUDstudy:anopen-labelrandomisedtrialofpre-exposureprophylaxis.Trials2016;17:163.

8. HoeniglM,ChaillonA,MooreDJetal.Clearlinksbetweenstartingmethamphetamineandincreasingsexualriskbehavior:acohortstudyamongmenwhohavesexwithmen.JAcquirImmuneDeficSyndr2016;71:551–557.

9. CohenMS,ChenYQ,McCauleyMetal.PreventionofHIV-1infectionwithearlyantiretroviraltherapy.NEnglJMed2011;365:493–505.

10. RodgerAJ,CambianoV,BruunTetal.SexualactivitywithoutcondomsandriskofhivtransmissioninserodifferentcoupleswhentheHIV-positivepartnerisusingsuppressiveantiretroviraltherapy.JAMA2016;316:171–181.

11. KahleE,DonnellD,JamesHetal.PrEPhashighefficacyforHIV-1preventionamonghigher-riskHIV-1serodiscordantcouples:asubgroupanalysisfromthePartnersPrEPStudy(abstractTUAC0102).JIntAIDSSoc2012;15(Suppl3):138–139.

12. BaetenJ,HeffronR,KidoguchiLetal.NeareliminationofHIVtransmissioninademonstrationprojectofPrEPandART.ConferenceonRetrovirusesandOpportunisticInfections.February2015.Seattle,WA,USA.

13. BaralSD,PoteatT,StromdahlSetal.WorldwideburdenofHIVintransgenderwomen:asystematicreviewandmeta-analysis.LancetInfectDis2013;13:214–222.

14. OperarioD,NemotoT.HIVintransgendercommunities:syndemicdynamicsandaneedformulticomponentinterventions.JAcquirImmuneDeficSyndr2010;55:S91–S93.

5InitiatingPrEP

5.1Overview

InitiationofPrEPshouldoccurwithinthecontextacomprehensivepackageofpreventionservicesincludinglevel3sexualhealthservicesandaccesstosubstancemisuseandcounsellingservices.ProvisionofPrEPshouldbeprecededbyaddressingriskfactors(e.g.inconsistentcondomuse,recreationaldruguse),screeningandreferralfortreatmentforotherSTIsandviralhepatitis,vaccinationagainsthepatitisAandB(ifindicated),educationonlimitationsofPrEP(includingadherenceandlead-intimes),managementofpossiblesideeffects,educationonlong-termsafetyofmedications,drugresistanceandsymptomsofprimaryHIVinfection(PHI).

InadditiontoconfirmingthatanypersonstartingPrEPmedicationisnotinfectedwithHIV,assessmentsofrenalfunctionandtestingforinfectionwithhepatitisBvirus(HBV)arerequiredbecausebothdecreasedrenalfunctionandactiveHBVinfectionarepotentialsafetyissuesfortheuseofTDF-FTCasPrEP.Adherencemaybepromotedthroughtextmessageremindersoruseofmobileappdevicestorecordtakingmedications.TheneedforPEPSEshouldbeexcludedinallindividualsconsideringstartingPrEP.

5.2Education,behaviouralsupportandadherence

Education,behaviouralsupportandadherence:summary

• EducationpriortostartingPrEPshouldincludeinformationonHIVtransmission,howPrEPworks,potentialsideeffectsofPrEPmedication,adherenceandefficacy,dosingschedule,lead-intimetoprotection,STI/HIVtestingandotherHIVpreventionstrategies.

• PrEPefficacyisstronglylinkedtoadherence.PeoplestartingPrEPwhomayneedgreateradherencesupportshouldbeidentifiedandofferedenhancedadherencesupportinterventions.

• Accesstoahealthadvisor,orpsychosexualsupportthroughcounselling,shouldbeavailableandoffered.• Referralsintospecialistservicesshouldalsobeusedwhereappropriatetosupportandcompliment

clinicaladvicearoundPrEP,includingMSM,blackAfricanortranspeople,sexualhealthpeersupport,drug(includingchemsex),alcoholandmentalhealthservices.

5.2.1EducationEducationhasbeenakeycomponentofmanyPrEPtrials.EducationalinterventionsinthePROUDstudycoveredHIVprevention,HIVtesting,treatment,sideeffectsofTDF-FTCadherence,PEP,STItestingandotherHIVpreventionstrategies[1].InservicessupportingPrEPuse(generic,privateorNHS),thefollowingtopicsshouldbecoveredinbrieftoensurethepatienthassufficientknowledgebeforestartingPrEP:

• HIVtransmission;• HIVtestingandwindowperiods;• SideeffectsofTDF-FTC• EfficacyofPrEPandlinktoadherence;• Dailydosingandevent-basedregimens;• PEPforriskswithsuboptimalPrEPadherence;• WiderPrEPprovision,includinggenerics,nationalprogrammesandtrials;• STItesting• PrEPinformationresources(seebelow)

BothinternationallyandwithintheUKPROUDstudy,uptakeofPrEPhasbeengreateramongstMSMwithhigherlevelsofformaleducationandassociatedsocioeconomicresources(e.g.caucasian,full-timeemployment).EducationalneedsofMSMbeyondthoseseeninthePROUDstudymaybegreater.

Similarly,itseemslikelythatothercommunities,particularlythosewhoexperiencemorestigmaorhavelessengagementwithHIV,mayhavesignificantlydifferentandgreatereducationalneeds[2,3].MoreresearchisneededinaUKcontextaroundknowledge,attitudesandacceptabilityofPrEPwithinothergroupsatriskofHIVacquisition,especially,butnotlimitedto,blackAfricanortranspeople.

Usefulresourcestosignpostpeopletoinclude:

i-base http://i-base.info/prepandhttp://i-base.info/guides/prep

Prepster http://prepster.info/

IWantPrEPNow https://www.iwantprepnow.co.uk/

5.2.2BehaviouralsupportIntheUKPROUDstudy,alltrialparticipantswereofferedtheopportunitytoseeahealthadvisororaccesspsychosexualsupportthroughcounsellingatthelevel3sexualhealthservices.AhighproportionofPROUDtrialparticipantsalsoreportedrecreationaldruguse,particularlythosecloselyassociatedwithchemsex.Itisimportant,therefore,thatpeopleaccessingPrEPhaveaccesstobehaviouralchangeservices,whichmayhaveanimpactontheirwider,holisticsexualhealth(andwhicharenotsolelyfocusedoncondomlesssex).

ItisrecommendedthatallserviceseitherprescribingPrEPorsupportingitsuseareabletoofferbehaviouralchangeservices,including:(i)healthadvisorornurse-ledbriefinterventions(withoptionaluseofmotivationalinterviewing);and(ii)psychologicalsupportservices.Althoughtheserepresenttheideal,itisrecognisedthatsomeclinicsmaynothavetheirowncounsellingservices,andthisshouldnotbeabarriertoaclinicprovidingsupportaroundPrEP.

ReferralpathwaysintorelevantcommunityorspecialistservicesshouldalsobeusedtosupportandcomplementclinicaladvicearoundPrEP,i.e.:

• Sexualhealthpeersupport;• Communitybehaviouralchange(e.g.motivationalinterviewing)ortherapeuticchange(e.g.counselling)

services;• Chemsexservices;• Communityonlinesupportandtransspecificclinicswhereavailable;• Drugandalcohol,and/ormentalhealthservices.

5.2.3AdherenceSpecificculturalorsituationalcontextsremainanimportantfactorindeterminingadherence.WithinAfricanheterosexualstudies,ahugevariationinadherencewasseenbetweentheFem-PrEPstudy[4],whichwasdiscontinuedduetopooradherence,andtheserodifferentAfricanPartnersstudy[5],whichreportedgoodlevelsofadherenceandefficacy.Variationsincohortswithinacommunity,aroundissuessuchasperceivedrisk,gender,HIVstigmaorknowledge,mayallhaveprofoundimpactsonadherenceandthefeasibilityofPrEPasanintervention.Differentpopulationsorindividualsmayneedsignificantlydifferentorgreaterinterventionstosupportadherence.

WhileadherencewasnothighlightedasaconcernintheUKPROUDstudyinMSM,itwasnotedthattrialparticipantshadhigherlevelsoffurthereducation,andengagementwithsexualhealthservices(seenintestingfrequencyandPEPusage)comparedtothewiderMSMpopulation[6].ConcernsaboutsideeffectsofPrEPorlow

perceptionofneedforPrEPmayreflectthatextraadherencesupportisrequired.Similarly,theIPERGAYstudyreportedgoodlevelsofadherenceamongasimilarcohorttothatrecruitedtoPROUD.ExpansionofPrEPusetodifferentpopulationsorbeyondthedemographicsseenwithinthePROUDstudymayseegreaternumbersofuserswhorequiremoresupportaroundadherence.Forexample,thesubgroupanalysisofiPrEx[7]reportedlowTDFconcentrationsamongtransgenderwomenwhousefeminisinghormones,possiblyreflectingconcernsaboutdruginteractions.

RobustadherencesupportisrequiredatPrEPinitiationandfollow-up,butsomeindividualsstartingPrEPmayrequireextensivecounsellingandsupporttoexplorepotentialbarrierstoadherenceandtoprovidesupportandstrategiestoimproveadherence.Thismaybeparticularlyrelevanttotransgendermenandwomen,youngpeopleandsomeheterosexualmenandwomentoensurePrEPliteracyandmaximiseadherence.

5.2.3.1AdherenceinterventionsInareviewofadherenceinterventionsthatmightbeadaptedtosupportPrEPadherenceintheUK[8],thestrongestevidencefortwotypesofinterventionswasfound.

1.Complex,resource-intensiveinterventionsshowntobeeffectivecombinedmultipleadherencesupportapproaches.InthecaseofPrEP,thiscouldinclude:educationaboutPrEPandtheimportanceofadherence;counsellingtoimproveadherenceskills,suchasincorporatingpilltakingintoadailyroutineanddevelopingstrategiesforrememberingdoseswhentravelling;and/orprovisionoffeedbackonmedicationadherence(e.g.providingresultsfromdrug-leveltesting).

2.Effective,low-cost,low-intensityinterventionswiththestrongestevidenceincludedtheprovisionofeducationortelephonecallsforadherencesupport.Education-basedinterventionsforPrEPusers,intheformofeitherprintedmaterialsorbriefdiscussionwithaprovider,couldfocusonimprovingusers’understandingandself-perceptionofHIVinfectionrisk,informationaboutthedrug,theregimen’srequirements,potentialsideeffects,andthesignsandsymptomsofacuteHIVinfection.

Forthosewhoexpressmoderateconcernsordifficultieswithadherence,thefollowingadherencesupportinterventionsshouldbeused:

• Useofsupporttools,morecommonlyusedbypeoplelivingwithHIV:o Alarmsorremindersonphones;o Routineplanning(takenatsettimeseachdayorwithanactivity(e.g.bedtime,orwhenbrushing

teeth);o Storageoptions(keyringpillcapsules,suppliesinmultiplelocations);

• Accesstobehaviouralchangeservices(seeabove).

5.2.4References1. ParticipantinformationsheetforthePROUDstudy.2012.Availableat:www.proud.mrc.ac.uk/97173/97177/proud_pis_sept_10_2012(accessedAugust2017).

2. ParkerK,EustacheS,JohnsonBetal.Evaluationofanindividual-levelinterventiontoincreaseknowledgeandthelikelihoodofuseforprep:Resultsfromapilotstudy.SexTransmDis2014;41:S6.

3. Perez-FigueroaRE,KapadiaF,BartonSCetal.AcceptabilityofPrEPuptakeamongracially/ethnicallydiverseyoungmenwhohavesexwithmen:theP18study.AIDSEducPrev2015;27:112–125.

4. VanDammeL,CorneliA,AhmedKetal.PreexposureprophylaxisforHIVinfectionamongAfricanwomen.NEnglJMed2012;367:411–422.

5. NdaseP,CelumC,CampbellJetal.SuccessfuldiscontinuationoftheplaceboarmandprovisionofaneffectiveHIVpreventionproductafterapositiveinterimefficacyresult:thepartnersPrEPstudyexperience.JAcquirImmuneDeficSyndr2014;66:206–212.

7. DeutschMB,GliddenDV,SeveliusJetal.HIVpre-exposureprophylaxisintransgenderwomen:asubgroupanalysisoftheiPrExtrial.LancetHIV2015;2:e512–519.

8. MarcusJL,BuiskerT,HorvathTetal.HelpingourpatientstakeHIVpre-exposureprophylaxis(PrEP):asystematicreviewofadherenceinterventions.HIVMed2014;15:385–395.

5.3SettingsandcontexttoadministerPrEP

IntheUK,thePROUDstudydemonstratedthefeasibilityofadministeringPrEPinlevel3sexualhealthclinics.TheclinicsofferedPrEP,monitoringofrenalandotherdrugtoxicityandmedicationadherenceembeddedintoaroutinerisk-reductionsupportpackageincludingtestingforHIVandSTIs[1].

ProvisionofPrEPinthesesettingsalsoprovidesopportunitiestodeliveracombinationpreventionpackage,whichincludesotherspecialistservicesthatmayonlybeavailableinthissetting,suchasdrugandalcoholservicesandpsychologicalsupport.

DatafromtheGayMen’sSexualHealthcross-sectionalsurveyofMSMindicatesthatmorethanhalfofMSMsurveyed(54.8%)reportedattendingasexualhealthclinicinthepastyear[2].Thosewhoreportedhigh-risksexualbehaviourssuchas10ormorepartnersorcondomlessanalintercoursewithcasualpartnersinthepastyearweremorelikelytohaveattendedasexualhealthclinic,suggestingthatsexualhealthclinicsareasuitablesettingforthedeliveryofPrEP.However,datafromcross-sectionalsurveysinScotlandshowthattwo-fifths(34/78)ofMSMnewlydiagnosedwithHIVhadneverpreviouslyengagedwithspecialistsexualhealthservicesandone-thirdhadneverpreviouslytestedforHIVpriortodiagnosis[3].

Inaddition,limitingprovisionofPrEPtolevel3sexualhealthclinicsriskswideninghealthinequalities,disproportionatelyamongblack,Asian,andminorityethnic(BAME)populations.InarecentsurveybyPublicHealthEnglandof1379MSMand362blackAfricanrespondents,oneinseven(14%)MSMandaquarter(23%)ofblackAfricanshadneverhadanHIVtest[4].ThesecommunitiescouldbeenabledtoaccessPrEPandpreventionservicesthroughcollaborationwithoutreachandcommunity-basedsupportforPrEPservicesandofferedalternativeHIVtestingstrategiessuchasself-samplingandself-testing.

Inotherhigh-incomesettings,suchastheUSA,PrEPhasbeensuccessfullydeliveredacrossavarietyofsettings,includingcommunity-basedHIV/STItestingsites,healthmaintenanceorganisations(HMOs),HIVclinics,LGBTclinics,primarycareandSTIclinics[5].AlthoughexperienceofdeliveringPrEPinarangeofsettingsiscurrentlylackingintheUK,theseoptionsshouldbeexploredandevaluatedtoensurewidestpossibleaccess.

5.3SettingsandcontexttoadministerPrEP:goodpracticepoints• RobustadherencesupportisrequiredatPrEPinitiationandmaintenance.Someindividualsstarting

PrEPmayrequireextensivecounsellingandsupporttoexplorepotentialbarrierstoadherenceandtoprovidesupportandstrategiestoimproveadherence.Thismaybeparticularlyrelevanttosometranspeople,someyoungpeopleandsomeheterosexualmenandwomentoensurePrEPliteracyandmaximiseadherence.

• Informationshouldbeprovidedtoallpatientson:o PrEPmedicationdoseandschedule;o Lead-intimetoprotection;o PotentialsideeffectsofPrEPmedicationandmanagementofcommonsideeffects;o RelationshipofadherencetoPrEPefficacy;o RisksofHIVinfectionandantiretroviralresistancefromsuboptimaladherence;o SymptomsofHIVseroconversionthatrequireassessment.

• PrEPprovisionshouldincludecondomprovisionandbehaviouralsupport.• PeoplereceivingPrEPshouldreceiveadviceonthepotentialriskofotherSTIsandtheneedforregular

testing.• Althoughlevel3sexualhealthservicesarerecognisedaspreferableforPrEPdeliverythesesettings

mayrestrictaccessforsomeand,whereappropriate,alternativemodelsofdeliveryshouldbeexplored.

5.3.1References1. McCormackS,DunnDT,DesaiMetal.Pre-exposureprophylaxistopreventtheacquisitionofHIV-1infection(PROUD):effectivenessresultsfromthepilotphaseofapragmaticopen-labelrandomisedtrial.Lancet2016;387:53–60.

2. HicksonF,BourneA,WeatherburnPetal.Tacticaldangers.FindingsfromtheUnitedKingdomGayMen’sSexSurvey2008.2010.Availableat:www.sigmaresearch.org.uk/files/report2010b.pdf(accessedJuly2017).

3. CoiaNDM,McAdamsR,MorrisonCetal.HIVpreventionneedsassessmentofmenwhohavesexwithmen.MOREDETAILSNEEDED.2014.Availableat:(accessed

4. RomanouE,DownerM.‘ItStartswithMe’Evaluation.November–December2015.2016.Availableat:www.tns-bmrb.co.uk/sites/tns-bmrb/files/ISWM-Evaluation-Report.pdf(accessedAugust2017).

5. MarcusJL,VolkJE,PinderJetal.SuccessfulimplementationofHIVpreexposureprophylaxis:lessonslearnedfromthreeclinicalsettings.CurrHIV/AIDSRep2016;13:116–124.

5.4Baselineassessmentandtesting

5.4.1Assessmentforconsiderationofpost-exposureprophylaxisfollowingsexualexposure(PEPSE)Ifanindividualhashadahigh-riskexposurewithintheprevious72hours,itmaybeappropriatetoconsideracourseofPEPSE[1]priortotransitioningtoPrEP.TestingforHIVshouldbeperformedinlinewithcurrentPEPSEguidelines[1].IfimmediatelytransitioningtoPrEPafteracourseofPEPSE,HIVtestingshouldbeperformedattheendofthe4weeksofPEPSEandagain4weeksafterstartingPrEP.

5.4.2HIVtestingBaselineHIVtestingismandatorypriortostartingPrEPsinceinitiationinthecontextofundiagnosedHIVinfectioncouldleadtodevelopmentofantiretroviralresistance.Allindividualsmusthavea4thorlatergenerationlaboratoryHIVenzyme-linkedimmunoassay(EIA)testatbaselineorarecordednegativetestwithintheprevious4weeks.Serviceprovidersmayobtainrapidresultsthroughblood-basedpoint-of-caretests(POCTs)toallowsame-dayinitiation,althoughcautionmustbegiventothehigherpossibilityofbothfalse–positive,and,inearlyinfection,false–negativeresults.Ifblood-basedPOCTisnegative,andthepatienthasnosymptomssuggestiveofseroconversionillness,clinicianscanconsiderstartingsame-dayPrEPwhileawaitingtheresultsofthelaboratory4thgenerationHIVantigen/antibodytest.OralPOCTtestsshouldnotbeusedbecauseoflowersensitivityparticularlyduringthewindowperiod.Cliniciansshouldnotacceptself-reportednegativeresults.

Whereahigh-riskexposure(e.g.condomlessanalsex)hasoccurredwithintheprevious4weeks,anHIVviralloadcouldbeconsideredinadditiontosendinga4th/5thgenerationtest.IntheabsenceofsymptomsofPHI[2]andinthepresenceofanegative4th/5thgenerationorblood-basedPOCTtestandongoingriskofHIV,PrEPcanbestartedimmediatelytomitigateagainsttheriskofinfection.A4th/5thgenerationHIVtestresultcanberepeated4weeksafterPrEPinitiationinthosewhereariskoccurredinthe4weekspriortoinitiatingPrEP.

ApersonwithapositiveHIVtestatbaselineshouldbemanagedinaccordancewithcurrentguidelineswithreferralforspecialistHIVcare[3].

5.4.3AcuteHIVinfectionPrEPisindicatedforindividualsatriskofHIVacquisition.CliniciansshouldthereforehaveahighlevelofsuspicionforacuteHIVinfection(AHI)andtakeanappropriatesymptomhistory,notingthataproportion(40–90%)withAHIwillbesymptomatic.ThesymptomsmoststronglyassociatedwithPHIarefeverandrash[2].Othersymptomsincludeheadache,malaise,arthralgiaandsorethroat.SymptomsofAHImaybenon-specific,however,andpatientsmayfailtoreportthem,sodiligenceisrequiredtoexcludeAHIatthetimeofstartingPrEP.

AhistoryofcondomlessanalsexwithintheHIVwindowperiodofthetestisnotanexclusioncriteriontostartingPrEP,althoughstartingPrEPshouldbedeferredinthosewithsignsorsymptomsconsistentwithAHIcurrently,orintheprevious4weeks,untilHIVinfectioncanbereliablyexcludedwithadditionalHIVviralloadnucleicacidamplificationtesting(NAAT)toavoiddevelopmentofdrug-resistantvirus.

5.4.4AssessmentofrenalfunctionAmongHIV-positivepersonsprescribedTDF-containingregimens,tenofovircancausedecreasedrenalfunctionandoccasionalcasesofacuterenalfailure,includingFanconi’ssyndrome[4].InthecontextoftreatingHIV,theTDF'SummaryofProductCharacteristics'recommendsstandarddosinginmildrenalimpairment(creatinineclearanceof50–80mL/min)anddosereductionswherecreatinineclearanceislessthan50mL/min[4].Insome

ofthePrEPtrialsamongotherwisehealthy,HIV-negativeadults,anestimatedGFR≥60mL/min/1.73m2wasaneligibilitycriterion[5,6]).

AlthoughagoodrenalsafetyprofileforTDFhasbeendemonstratedacrossallPrEPtrials,safetydataforTDF-FTCprescribedtoHIV-negativepersonswithreducedrenalfunctionarenotavailable.MildprogressiverenalimpairmenthasbeenseeninPrEPstudies,whichreversedonstoppingstudymedication[5-10]

Itisnecessarytoassesstheriskofchronickidneydiseaseatbaseline.FactorsthatmayindicateanindividualisathigherriskofCKDincludebeingaged40yearsoldormorebeingonconcomitantmedicationassociatedwithrenalimpairment,orthepresenceofcomorbiditiessuchashypertension,anddiabetes[11,12].PriortoinitiatingPrEP,cliniciansshoulddiscussthepossibilityofkidneydiseasewithindividualswhohavepre-existingriskfactors.AthoroughmedicationhistoryshouldbeobtainedtoascertainanyconcomitantnephrotoxicdrugsordrugsthathaveinteractionswithTDF-FTC.

SerumcreatinineandeGFRshouldthereforebeperformedatbaseline.PrEPmaybestartedpendingresultsofserumcreatinineandeGFR,butresultsshouldbereviewedatthesoonestpossibletime.

AnumberofstudieshavedemonstratedthatCKD-EPIequationismoreaccuratethantheCockcroft–GaultformulaortheMDRDestimate,especiallyathigherGFR>60mL/min/1.73m2[11].ThemosteffectivewaytocalculateeGFRisthereforeusingtheCKD-EPIequation.

TheCKD-EPIequation(www.kidney.org/professionals/kdoqi/gfr_calculator)

Forwomenwithaplasmacreatinine≤0.7:

(plasmacreatinine/0.7)−0.329×(0.993)age(×166(ifblack)×144(ifwhiteorother))

Forwomenwithaplasmacreatinine>0.7:

Formenwithaplasmacreatinine≤0.9:

Formenwithaplasmacreatinine>0.9:

ItisrecognisedthatmostclinicianswillbelikelytouselabeGFR,butCKD-EPIequationcanbecalculatedusinganonlinecalculator(e.g.https://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi).ItshouldalsobenotedthattheCKD-EPIdoesnottakeweightintoaccount,andinpeoplewithextremesofmusclemass,forexampleinbodybuilders,theeGFRmayneedtobeinterpretedwithcaution[12]. Baselineurinalysisisnotrecommendedasdetectionofproteinuria,asmeasuredinroutinedipstickurinalysis,hasaverylowPPV(0.7%)inpredictingelevationofcreatinine[8].

5.4.5STIscreenSTItestingisrecommendedatbaselineincludingNAATforgonococcalandchlamydialinfectionatsitesofexposure(genital,rectal,pharyngeal)andsyphilisserologyinaccordancewithnationalrecommendationsandguidelines[13].

5.4.6.AssessmentofviralhepatitisstatusTDF-FTCmaybeusedsimultaneouslyastreatmentforchronicactiveHBVinfectionandasPrEP.However,discontinuationofTDF-FTCrequiresclosemonitoringinpatientswithchronichepatitisBinfectionbecauseoftheriskofreboundviraemiaandfulminantliverdamage.

ScreeningforhepatitisBshouldbeundertakenatbaseline,ifnoevidenceofcurrentorpreviousinfectionorimmunitythenHBVvaccinationshouldbeofferedaspercurrentguidelines[14].PrEPmaybestartedpendingresultsofHBsAg,butresultsshouldbereviewedatthesoonestpossibletimeasbothTDFandFTCareactiveagainstHBVandstoppingthesedrugsmaycauseseverehepaticflares.IndividualsfoundatbaselinetohaveundiagnosedHBVinfectionshouldbereferredtospecialisthepatologyservicesforassessment.IndividualswithchronicHBVonPrEPshouldbecounselledregardingadherencetoPrEPtopreventpossiblehepaticflares.Event-basedorondemandPrEPdosingshouldnotbeconsideredinpeoplewithchronicHBVinfection.

HighbackgroundprevalenceofHCVhasbeenreportedinHIV-negativeMSMbeforestartingPrEPinbothclinicaltrialsandPrEPdemonstrationprojects[15,16].ScreeningforHepatitisCshouldbeundertakenatbaseline.PeoplewithpreviouslyundiagnosedHCVshouldbereferredtospecialistservicesforassessmentandconsiderationofdirectlyactingantiviral(DAA)treatment,ifappropriate.

RoutinehepatitisAvirusscreeningandimmunisationisnotrecommendedexceptincontextofriskoroutbreak(e.g.inMSMwhereincreasedratesofinfectionhavebeenrecognisedlocally)[14].AllMSMattendingGUMservicesshouldbevaccinatedagainstHAV(unlesstheyhaveareliablehistoryofvaccinationorinfection)andadefaultscreeningstepisnotrequired.

5.4Baselineassessmentandtesting:recommendations

19. WerecommendthatbaselineHIVtestingwith4thgenerationserologytestisundertakenpriortocommencingPrEP.(1A)

20. Werecommendthatsame-dayinitiationofPrEPmayoccurwhereanindividualhasanegativeblood-basedPOCTontheday,or4thgenerationtestwithinthepast4weeks.(1A)

21. WerecommendthatanHIVviralloadshouldbeconsideredwhereahigh-riskexposurehasoccurredwithin4weeks.(1B)

22. WerecommendthatinitiationofPrEPisdeferredinpeoplereportingcondomlessanalsexintheprevious4weekswhohavesymptomssuggestiveofHIVseroconversionuntilanHIVRNAresultisavailable.(1A)

23. WerecommendthatbaselinescreeningforhepatitisBshouldbeundertakeninthoseofunknownhepatitisBstatustoexcludeactivehepatitisBinfectionwithvaccinationinitiatedinthosewhoarenon-immune.(1A)

24. WerecommendthatbaselinescreeningforhepatitisCshouldbeundertaken.(1B)

25. WerecommendafullSTIscreenatbaselineincludingsyphilisserologyforall,STItestingNAATforgonococcalandchlamydialinfectionatsitesofexposure(genital,rectal,pharyngeal).(1A)

26. WerecommendthatbaselinerenalfunctionisassessedwithaserumcreatinineandeGFRbutPrEPcanbecommencedwhilewaitingfortheresultsofbaselinecreatininemeasurements.(1A)

27. WesuggestthattheeGFRforindividualsstartingTDFis>60mL/min/1.73m2.(2A)28. WesuggestthatindividualswitheGFR<60mL/min/1.73m2shouldbestartedonPrEPonlyonacase-

by-casebasisandafterafullassessmentanddiscussionwiththepatientoftheriskandbenefitsandobtainingspecialistrenaladvice.(2B)

Goodpracticepoints• AthoroughmedicalhistorybeforeinitiatingPrEPisessentialtoidentifypatientsatgreaterriskof

adverseeventswhomightrequirecloserrenalorbonemonitoring.• DiscusspossibilityofkidneydiseasewithTDF-FTCwithindividualswhohavepre-existingchronickidney

diseaseorriskfactors(>40yearsofage,eGFR<90mL/min/1.73m2atbaseline,hypertension,ordiabetes).

• ObtainathoroughmedicationhistoryforconcomitantnephrotoxicdrugsordrugsthathaveinteractionswithTDF-FTC.Discussriskandbenefits.

• PrEPshouldbeofferedaspartofapackageofcareincludingregularHIVandSTItestingandmonitoringofrenalfunction.

5.4.7References1. BritishAssociationforSexualHealthandHIV.UKnationalguidelinefortheuseofhivpost-exposureprophylaxisfollowingsexualexposure(PEPSE).2015.Availableat:www.bhiva.org/PEPSE-guidelines.aspx(accessedAugust2017).

2. HechtFM,BuschMP,RawalBetal.UseoflaboratorytestsandclinicalsymptomsforidentificationofprimaryHIVinfection.AIDS2002;16:1119–1129.

3. BritishHIVAssociation.BHIVAguidelinesfortheroutineinvestigationandmonitoringofadultHIV-1-positiveindividuals.2016.Availableat:www.bhiva.org/PEPSE-guidelines.aspx(accessedAugust2017).

4. HallAM,HendryBM,NitschD,ConnollyJO.Tenofovir-associatedkidneytoxicityinHIV-infectedpatients:areviewoftheevidence.AmJKidneyDis2011;57:773–780.

5. BaetenJM,DonnellD,NdasePetal.AntiretroviralprophylaxisforHIVpreventioninheterosexualmenandwomen.NEnglJMed2012;367:399–410.

9. MugwanyaKK,WyattC,CelumCetal.ReversibilityofglomerularrenalfunctiondeclineinHIV-uninfectedmenandwomendiscontinuingemtricitabine-tenofovirdisoproxilfumaratepre-exposureprophylaxis.JAcquirImmuneDeficSyndr2016;71:374–380.

10. MugwanyaKK,WyattC,CelumCetal.ChangesinglomerularkidneyfunctionamongHIV-1-uninfectedmenandwomenreceivingemtricitabine-tenofovirdisoproxilfumaratepreexposureprophylaxis:arandomizedclinicaltrial.JAMAInternMed2015;175:246–254.

11. KidneyDisease:ImprovingGlobalOutcomes(KDIGO)ChronicKidneyDiseaseWorkGroup.Clinicalpracticeguidelinefortheevaluationandmanagementofchronickidneydisease.KidneyInt2013;3(Suppl):1–150.

12. NationalInstituteforHealthandCareExcellence.Chronickidneydiseaseinadults:assessmentandmanagement.CG182.2014.Availableat:www.nice.org.uk/guidance/cg182(accessedAugust2017).

13. BritishAssociationforSexualHealthandHIVClinicalEffectivenessGroup.Guidanceontestsforsexuallytransmittedinfections.2015.Availableat:https://www.bashhguidelines.org/media/1084/sti-testing-tables-2015-dec-update-4.pdf(accessedAugust2017).

14. BrookG,BhaganiS,KulasegaramRetal.UKnationalguidelineonthemanagementoftheviralhepatitidesA,BandC2015.IntJSTDAIDS2016;27:501–525.

16. TiraboschiJ,BrodnickiE,BradyMetal.AcutehepatitisCinthePROUDpilotstudy(AbstractO45).HIVMed2014;15(Suppl3):1–16.

5.5Otherconsiderations

5.5.1PregnancyortryingtoconceivePrEPmaybeoneoptiontopreventHIVseronegativepartnersfromacquiringHIVinfectioninserodifferentcouplesduringattemptstoconceiveifthepositivepartnerisnotonsuppressiveART.Assessmentforpregnancystatusshouldbeundertakenifindicatedatbaseline.IfapersonispregnantwhenstartingPrEPorbecomespregnantwhileonPrEP,discusstheknownrisksandbenefitsoftakingTDF-FTCduringpregnancy.AfterdiscussingthepotentialrisksofTDF-FTC,recommendcontinuationofPrEPduringpregnancyorbreastfeedingforthosewithongoingriskforHIV.ReportinformationregardinguseofPrEPduringpregnancytotheAntiretroviralPregnancyRegistry.

5.5.2BonehealthBonelossisassociatedwithtenofoviruse.Inaddition,lowbonemineraldensity(BMD)hasbeenreportedinparticipantsinPrEPtrialsatbaseline[1].Pre-existingriskfactorsforbonelossinclude:ageover50years(particularlywomen);useofsomemedicationsincludingsteroids;havingalowbodyweight;smokingandexcessalcoholuse[2].Cliniciansshoulddiscussriskofbonelosswithindividualswithpre-existingriskfactorsordemonstratedosteoporosis,osteomalaciaorosteopenia.IndividualswithlowBMDorriskfactorsshouldbecounselledtoreducefactorsassociatedwithlowBMDsuchasreducingalcoholintakeandstoppingsmokingaswellasensuringadequatelevelsofvitaminDandcalciuminthedietandundertakingweight-bearingexercise.ApersonwithosteoporosisonTDF-basedPrEPwillrequirecarefulmonitoringatcliniciandiscretion.

5.5Otherconsiderations:recommendations

29. WesuggestthatifanindividualispregnantwhenstartingPrEPorbecomespregnantwhileonPrEP,wesuggestcontinuationofPrEPduringpregnancyorbreastfeedingforthosewithongoingriskforHIVafterdiscussingthepotentialrisksofTDF-FTC.(2B)

Goodpracticepoints

• ReportinformationregardinguseofPrEPduringpregnancytotheAntiretroviralPregnancyRegistry.

• Discussriskofbonelosswithindividualswithpre-existingriskfactorsoryoungpeopleordemonstratedosteoporosis/osteomalacia/osteopenia.

5.5.3References1. LiuAY,VittinghoffE,SellmeyerDEetal.BonemineraldensityinHIV-negativemenparticipatinginatenofovirpre-exposureprophylaxisrandomizedclinicaltrialinSanFrancisco.PLoSOne2011;6:e23688.

2. KanisJA,OdenA,JohnellOetal.TheuseofclinicalriskfactorsenhancestheperformanceofBMDinthepredictionofhipandosteoporoticfracturesinmenandwomen.OsteoporosInt2007;18:1033–1046.

5.6PrescribingPrEP

5.6.1WhattouseWerecommendthatTDF-FTCisusedforPrEPforMSM,TGW,TGM,andheterosexualmenandwomen.Forheterosexualmenandwomenonly,TDFalonemaybeconsidered.

WhenfirststartingPrEP(andwhenre-starting),dispensinga90-daysupplyofmedicationisrecommended.Follow-upshouldbeplannedfor4weekslater(eitherfacetofaceorbytelephone)toreviewadherenceandsideeffects.

5.6.2Lead-inperiodFTC-DPconcentratesmorerapidlythanTFV-DPinalltissues.Ingeneral,timetoprotectionofTFV-DPisshortestinlowergastrointestinaltracttissues,followedbybloodPBMCsandthenthefemalegenitaltracttissues(FGT).ThetimetoclinicalprotectionhasonlybeenevaluatedforanalsexinasingleRCT(IPERGAY),startingwithdouble-doseofTDF-FTC2–24hoursbeforesexandstoppingwithasingletablettakenat24hoursandagainat48hoursafterthefirstdose[1].Thetimetoclinicalprotectionisestimatedas7daysforvaginaltissue[2-4].Thereisnodataintranswomenortransmen.

5.6.3FrequencyofdosingtoattainbenefitAlthoughcompleteadherencetodailyPrEPisnotrequiredtoattainbenefitforanalsex,protectiveeffectsdiminishincrementallyasadherencedeclines.InIPrEX,whenTDFistakentwice,fourtimesandseventimesaweek,estimatedHIVriskreductionis76%,90%and99%,respectively[5].IntheiPrEx-OLEstudy,plasmadruglevelscorrespondingwithadherenceoftwotothreetabletsperweekwereassociatedwithan84%riskreduction(95%CI21–99)whereasmorethanfourdosesperweekwereassociatedwith100%riskreduction[6].WherethereisapreferencetoavoiddailydosingbyaPrEPuserhavingonlyanalsex,andintheknowledgethateffectiveprotectionisobtainedbyatleastfourdosesperweek,consensusopinionisthatTDF-FTCshouldbetakenonalternatedaysratherthanfourconsecutivedayswiththenthreedaysoff.Forexposuresotherthananalsex,intermittentuseTDF-FTChasnotbeenstudiedanditiscurrentlyrecommendedthatTDF-FTCshouldbetakendaily.

5.6.4On-demanddosingOndemand,or‘event-based’,PrEPdosingledtoan86%reductioninnewHIVinfectionsinMSMintheIPERGAYstudy[1],similartodailydosing.AloadingdoseoftwoTDF-FTCwastaken2to24hoursbeforesex,followedbyathirddoseat24hoursandafourthat48hours.Intheeventofmultipleconsecutiveepisodesofsexualintercourse,participantswereinstructedtotakeonepillperdayuntilthelastsexualintercourseandthentwopostexposurepillsfrequentsexualintercourse,participantsareinstructedtocontinuetakingonetabletdaily

until48hoursafterthelastsexualintercourse.WhenrestartingPrEP,participantswereadvisedtotakealoadingdoseoftwopillsunlessthelastPrEPdosewaslessthan1weekearlier,inwhichcasetheywereinstructedtotakeonlyonepill[1].Event-baseddosinghasnotbeeninvestigatedinheterosexualmenandwomenandbasedonthisandpharmacokineticconcernswedonotrecommendevent-basedPrEPinthesegroups.Intheabsenceofdata,transwomenandtransmenshouldalsonotbeofferedevent-basedPrEP.

Table5.6.1.Optionsfordosingschedulesandlead-intimes[references]

Insertiveanalsex

Receptiveanalsex

Insertivevaginalsex

Receptivevaginalsex*

Dosingschedule

Dailydosing ü [6-8] ü [6-8] ü [9,10] ü [9,10]

Event-baseddosing

(≥4tabletsaroundsex)

ü [1]

Notrecommended Notrecommended

Intermittentdosing

(≥4tabletsperweek)

ü [6] ü [6] Notrecommended Notrecommended

StartingandstoppingPrEP

Leadintimestoprotection

2–24hoursbeforecondomlesssex[1]

StoppingPrEP Onetablet24hoursandone48hoursafterlastcondomlesssex

Onetablet24hoursandone48hoursafterlastcondomlesssex

7daysafterlastcondomlesssex

*Includesfrontalsexintranswomenandtransmen.

5.6PrescribingPrEP:recommendations

30. Werecommendthattenofovir/emtricitabine(TDF-FTC)fixed-dosecombination,dosedappropriately,isusedforHIVpre-exposureprophylaxisformenwhohavesexwithmen(MSM),transgenderwomen(TGW)andheterosexualmenandwomenwhoareathighriskofHIVacquisition.(1A)

31. Werecommendthatforheterosexualmenandwomenonly,tenofoviralonemaybeconsidered.(1A)32. Werecommendthefollowingleadinperiods:

o Forevent-basedordailydosinginanalsex,thetimetoclinicalprotectioninrectaltissuesisestimatedas2–24hoursfollowingadoubledoseofTDF-FTC.(1A)

o Fordailydosing(withsingledoseTDF-FTC),thetimetoprotectionforvaginalsexisestimatedas7days.(1B)

33. Frequencyofdosing:o WerecommenddailyPrEPcanbeofferedtoMSM,transmen,transwomenandheterosexual

menandwomenathighriskofHIV.(1A)o MSMandTGWshouldbeadvisedthatminimalbenefitfromdailydosingwillnotbeattainedif

fewerthanfourdosesaretakenperweek.Thereisnoevidenceinotherpopulationsthatfourdosesinsteadofsevenperweekisadequate.(1B)

o Werecommendthatevent-basedPrEPcanbediscussedandofferedtoMSM.AloadingdoseoftwotabletsofTDF-FTCtaken2–24hoursbeforesex,followedbyathird(single)tablet24hoursandafourth(single)tablet48hourslaterisadvised.Wherepotentialexposureissustainedovermorethana24-hourperiod,onepillperdayshouldbetakenuntilthelastsexualintercourseandthentotakethetwopostexposurepills.(1A)

o Intheabsenceofdata,wedonotrecommendevent-baseddosinginheterosexualmenandwomen,transmenortranswomen.

5.6.5References1. MolinaJM,CapitantC,SpireBetal.On-demandpreexposureprophylaxisinmenathighriskforHIV-1infection.NEnglJMed2015;373:2237–2246.

3. LouissaintNA,CaoYJ,SkipperPLetal.Singledosepharmacokineticsoforaltenofovirinplasma,peripheralbloodmononuclearcells,colonictissue,andvaginaltissue.AIDSResHumRetroviruses2013;29:1443–1450.

4. PattersonKB,PrinceHA,KraftEetal.Penetrationoftenofovirandemtricitabineinmucosaltissues:implicationsforpreventionofHIV-1transmission.SciTranslMed2011;3:112re114.

5. AndersonPL,GliddenDV,LiuAetal.Emtricitabine-tenofovirconcentrationsandpre-exposureprophylaxisefficacyinmenwhohavesexwithmen.SciTranslMed2012;4:151ra125.

6. GrantRM,AndersonPL,McMahanVetal.Uptakeofpre-exposureprophylaxis,sexualpractices,andHIVincidenceinmenandtransgenderwomenwhohavesexwithmen:acohortstudy.LancetInfectDis2014;14:820–829.

9. BaetenJM,DonnellD,NdasePetal.AntiretroviralprophylaxisforHIVpreventioninheterosexualmenandwomen.NEnglJMed2012;367:399–410.

10. ThigpenMC,KebaabetswePM,PaxtonLAetal.AntiretroviralpreexposureprophylaxisforheterosexualHIVtransmissioninBotswana.NEnglJMed2012;367:423–434.

6Clinicalfollow-upandmonitoringontreatment

6.1Overview

Inadditiontoundertakingmonitoringinvestigations,regularreviewpermitsreviewofadherence(e.g.throughpillcounts,reviewofpillappreminder),sideeffectsandfacilitatesdiscussionsaroundchangesinriskbehaviourtodeterminetheneedforongoingPrEPuse.InprovidingrepeatcoursesofPrEP,providersshouldobtainathoroughsexualanddrugusehistory,andassistinthedecisionofwhentousePrEP(especiallyincasesofeventbaseduse)andwhentodiscontinueuse.

Inmostcircumstancesa3-monthsupply(90tablets)ofTDF-FTCshouldbeprovidedinordertopromotereturnforreviewofadherence,tolerabilityandtoensure3-monthlyHIVtestingisconductedtominimiseprolongeduseofPrEPinthepresenceofanewHIVinfection.

MonitoringofindividualsreceivingPrEPshouldfocusonexcludingHIV,monitoringforsideeffectsandtoxicities,screeningforandtreatingsexuallytransmittedinfections,riskreductionandpromotingadherence.Atapopulationlevel,surveillanceisrequiredtounderstandhowPrEPisusedandmonitorclinicattendanceandothercharacteristicsofPrEPusersandnon-users,andwillenablefollow-uptoestimateHIVincidenceinthesegroups.

6.2Continuedprescribing

WhenfirststartingPrEP(andwhenre-starting),dispensinga90-daysupplyofmedicationissuggested.Furthermaintenanceprescriptionsfor90daysshouldbegivenafterobtaininganegative4th/5thgenerationHIVtestresult.Followingvisitsshouldbeevery3months.PrEPshouldbecontinuedwherethereisongoinghigh-riskforHIVtransmissionasperthebaselineassessment.Thelengthofusewilldependontheindividual’sbehavioursandchoices,whicharelikelytochangeovertime.ForthosewhostartedPrEPbecausetheyhaveapartnerwhoisHIVpositive,anongoingassessmentshouldbemadeofwhenPrEPcanbestopped(partneronARTfor6monthsandHIVviralload<200copies/mL).Thisshouldtakeaccountofriskstakenoutsidetheprimaryrelationship.

6.3AssessingadherenceandadverseeventsAssessment1monthaftercommencingPrEP(face-to-face,telephone,emailortext)providestheopportunitytoreviewadherence,adverseeventsandHIV/STIwindowperiods.Reasonsfornon-adherenceincludingadverseeventsshouldbeelicitedanddocumentedateachfollow-upvisit.Additionalsupport,practicalorpsychologicalmayberequired.Adherencemustbereviewedateachfollow-upvisit.ForMSMandTGWonevent-basedPrEP,providersshouldensurethisisbeingtakencorrectlyandthataswitchtodailyPrEP(andviceversa)isnotappropriate.InMSMandTGWtakingthedailyPrEPregimenwhoarehavingonlyanalsex,providersshouldensurethataminimumoffourtabletsaweek(onalternatedaysnotconsecutively)arebeingtakentoensurecontinuedefficacy.

6.4Managementofshort-termsideeffects

TDF-FTCcanhaveshort-termsideeffects,althoughinclinicaltrialsthesewereshort-lived.Sideeffectscanincludenausea,flatulence,abdominalpain,dizzinessandheadache.Thesesymptomsusuallyoccurearlybutmostlydisappearwithinthefirstmonth.Theycanoftenbemanagedwithsimpleanalgesiaoranti-emetics,butpatientsshouldalsobemadeawareofsymptomsthatmayindicatemoreserioustoxicitiessuchasrenalinjury.

Flowchart

WantingtostartPrEP

Firstvisitassessmentanddocumentation• ReasonsforseekingPrEP• MedicalhistoryrelevanttoTDF-FTCincludingboneandrenalhealth,concomitantmedications• RiskassessmentandeligibilityforPrEP• ConsiderationofAHIandeligibilityforPEPSE• DetailsofHIV/STIscreenslast12months• Timingofcondomlesssexactslast3months• IfMSM:discussionofbothregimens(dailyandondemand)• Reasonsadherenceisimportantbeforeandafterriskofexposure• Potentialtoxicitiesandhowtomanage• Risksandbenefitsofonlinepurchaseandcommunitywebsiteswithinformationaboutonlinepurchaseif

required• ResultsHIV/STIscreen• Decisiontostartandtimetostart• Recommendedfollow-upat1or3monthsafterstartingPrEPforHIV/STIscreen,adherencecheckand

serumcreatinineandeGFR• CodeusingGUMCADcodes(SeeAppendix1)

Baselinetesting• HIVtestingusing4thgeneration(POCTifsamedayinitiationispreferable)• STIscreenincludingHCVandHBVtesting• SerumcreatinineandeGFR• Pregnancytestingifindicated

Quarterlyvisitdocumentation• ReasonforcontinuingPrEP• Regimenfollowedandreasonsfornon-adherenceincludingadverseevents• Supportprovidedformedicationadherence• HIVrisk-reductionadvice• Recreationaldrugoralcoholusewithreferraltosupportservices,ifrequired• ResultsHIV/STIscreen• Prescriptionfor90days• Arrangefollowupfor3months• CodeusingGUMCADcodes(Appendix1)

Monitoring• ResultofHIVtestingusing4thgeneration• ResultsofSTIscreen(includinganti-HCVinMSM/TGW)• SerumcreatinineandeGFRannuallyif>90mL/min/1.73m2andaged<40,morefrequentlyif60–90

mL/min/1.73m2or>40yearsorriskfactorsforrenaldisease.

6.Clinicalfollow-upandmonitoringontreatment:goodpracticepoints

• WhenfirststartingPrEP(andwhenre-starting),dispensinga90-daysupplyofmedicationissuggested.

• Follow-upshouldbeplannedfor4weekslaterifindicated–viaphoneoremailissufficient–toreviewsideeffects,adherenceandthatdailyandon-demandbasedregimesarebeingtakenappropriately.

• Reasonsfornon-adherenceincludingadverseeventsshouldbeelicitedanddocumentedateachfollow-upvisit.Additionalsupport,practicalorpsychologicalmayberequired.

• PrEPshouldcontinuewherethereison-goinghigh-riskforHIVtransmission.

• Recipientsshouldbeadvisedofthepossibilityoftransientnausea,vomiting,orheadacheandencouragedtomanagethisthroughtheuseofsimpleanalgesicsandanti-emetics

6.5MonitoringonPrEP

Thefollowingmonitoringguidanceisthesameforbothon-demanddosinganddailydosing(Table6.5.1).

6.5.1HIVtestingHIVtestingshouldbeundertakenevery3-monthswithalaboratory4thgenerationtestorblood-basedPOCT.FurtherPrEPprescriptionsshouldnotbeissuedwithoutrepeatHIVtestingevery90days.Atypicaltestingresultsshouldbediscussedwitharegionalexpert,forpossiblefurtherinvestigationforseroconversion.

6.5.2ManagementofHIVseroconversionComprehensiveadherencesupportshouldminimisetheriskofHIVseroconversiononPrEPandregularHIVtestingshoulddetectanynewinfectionsasearlyaspossible.HIVseroconversionshouldbeconsideredinanyindividualpresentingwithsymptomssuggestiveofprimaryHIVinfectionandinvestigatedwithanHIVviralloadinadditiontoa4thgenerationHIVtest.

AfullassessmentofthosewhoseroconvertwhilebeingprescribedPrEPshouldincludeintendedPrEPuse(dailyversusevent-baseddosing),adherencetointendedregimenandassessmentandtimingofrecentrisksforHIVtransmission.Baselineresistancetestingshouldbeundertakenasearlyaspossibletolookforevidenceofresistance-associatedmutationstotenofoviroremtricitabine.Therapeuticdrugmonitoringshouldbeconsideredinordertoassesswhethertheindividualhasdetectablelevelsoftenofovirandemtricitabine.AnynewHIVinfectionsshouldbemanagedinlinewithexistingBHIVAHIVtreatmentguidelines[1].

Inaddition,PublicHealthEnglandhaveintroducedenhancedpublichealthsurveillancetofurtherinvestigatefactorsassociatedwithseroconversionamongPrEPusers.CliniciansareadvisedtocompletethequestionnaireinforallpatientswhoseroconvertwhilsttakingPrEPorforpatientswhoseroconvertandhaveahistoryofhavingtakenPrEPinthepast.

6.5.3STIscreeningGiventhehighratesofbacterialSTIsobservedinPROUDandIPERGAYandaspartofacomprehensiveriskreductionstrategy,3-monthlySTIscreening(chlamydia,gonorrhoeaandsyphilis)areadvocatedforMSMandTGW.ForheterosexualindividualsreceivingPrEP,STIscreeningshouldbeofferedateach3-monthreviewinparticular,iftherehasbeenachangeinpartnerorotherrisksforSTIacquisition[2].

6.5.4ViralhepatitisThereisrecognitionoftheriskofHCVincidenceamongstHIVnegativeMSMusingPrEP[3].WithinthePROUDstudy,incidentHCVinfectionswerefoundin3.1%[4].Similarly,withintheIPERGAYstudy,therewasa1%incidenceofnewHCVinfections[5].NodataexistforheterosexualPrEPstudieshowevertheincidenceisunlikelytobeincreasedintheabsenceofspecificriskfactorssuchasintravenousdruguse.

AmongstMSMandTGWusingPrEP,itisrecommendedtoscreenforHCVevery3months.Ifanti-HCVispositivethenHCVRNAshouldbetestedand,ifpositive,thepatientreferredtospecialistservicesforfurtherinvestigationandconsiderationofearlytreatment.

6.5.5RenalmonitoringTodate,largeclinicaltrialsinvestigatingtheuseofPrEPhavenotdemonstratedanymajorclinicalconcernswithregardstorenaltoxicities.Asmall,butstatisticallysignificantdecreaseincreatinineclearance(CrCl)maybeseenfrombaseline,whichresolvesafterstoppingPrEP.However,therearenodataforpeoplewitheGFR<60mL/min/1.73m2socontinuingPrEPifeGFRfallstobelow60mL/min/1.73m2isnotadvisedandshouldonlybedoneonacase-by-casebasiswithafulldiscussionoftheriskandbenefitsandongoingmonitoringofrenalfunction.Referraltospecialistrenalserviceforinvestigationandmanagementisadvised.

ItisadvisedtomeasureserumcreatinineandeGFRatbaselineandifeGFR>90mL/min/1.73m2andthepersonisagedunder40yearswithnoconcomitantfactorsforrenaldisease,theneGFRcanbeconductedannually[6].

Whereadditionalriskfactorsforrenaldiseasearepresent(e.g.agedover40years,useofnephrotoxicdrugs,hypertensionordiabetes)morefrequentmonitoringofeGFRandcreatinineisrequired(atleast6monthly).Ariseinserumcreatinineand/orfallineGFRisnotareasontostopPrEPtreatmentifeGFRremains≥60mL/min/1.73m2,butmorefrequentmonitoringisindicated.

ItisrecognisedthatmostclinicianswilluselabeGFR,butCKD-EPIequationcanbecalculatedusinganonlinesuchashttps://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi.ItshouldalsobenotedthattheCKD-EPIdoesnottakeintoaccountweightandinpeoplewithextremesofmusclemass,forexampleinbodybuilders,theeGFRmayneedtobeinterpretedwithcaution[7].

Routineurinalysisforproteinuriaisnotrecommendedduringfollow-up,asdetectionofproteinuriahasaverylowpositivepredictivevalue(PPV)forcreatinineelevation(0.7%)[8].Inaddition,testingforspecificrenalproximaltubulardysfunctionseenwithTDF,usingdetailedmarkersoftubularproteinuria,isalsonotrecommendedasitdoesnotpredictaclinicallyrelevanteGFRdecline[9].

6.5.6PregnancytestingAssessmentforpregnancystatusshouldbeundertakenifindicated.

6.5.7BonemonitoringBMDinHIV-negativeMSMhasbeenexaminedwithiniPrEx,iPrEx-OLEandCDCsafetystudies[10-13].Patientsagedunder25yearssufferedthegreatestlossinBMDalthoughBMDatbothhipandspinerecoveredfollowingPrEPdiscontinuation,slowerrecoverywasobservedinthoseover25yearsoldversusthoseunder25years[10].BMDchangesinyoungHIV-negativeAfricanwomenwhohaddetectableTDFin75–100%ofplasmasamples,was1.4%lowerinthosereceivingTDForTDF-FTCafter48weeksoffollow-up.Importantly,48weeksaftertreatmentdiscontinuation,effectsonBMDappearedtobereversible[12,13].

Basedontheabove,noroutinebonedensitymonitoringisrecommendedforPrEPusers,althoughsupplementationwithvitaminDandcalciummaybeconsidered,particularlyifadditionalrisksforosteopeniaorosteoporosisasagoodpracticepointalthoughthereisnoevidencecurrentlytosupportthis.

Table6.5.1.MonitoringandclinicalfollowofpeopleprescribedPrEP

*Ifriskin4weekspriortostartingPrEP.

6.5.8CodinganddatacollectionPublicHealthEnglandhasdevelopednewSexualHealthandHIVActivityPropertyType(SHHAPT)codestobereturnedaspartoftheGenitourinaryMedicineClinicSurveillanceSystem,whichshouldbecompletedforallpatientstoallownationalmonitoringoftheeligibility,uptake,anddurationofuseofHIVpre-exposureprophylaxis(PrEP).Thecodeshavebeendesignedtominimisethedata-entryburdenonclinicianswhilecapturingessentialpublichealthinformationabouttheuseofPrEPamongGUMclinicattendees,includingthosewhomaybeenrolledinaPrEP-relatedtrialorwhohavepurchasedPrEPdrugsovertheinternet.ThesecodeswillbeusedtounderstandclinicattendanceandothercharacteristicsofPrEPusersandnon-users,andwillenablefollow-uptoestimateHIVincidenceinthesegroups.FordetailsofthecodesseeAppendix1.

ThenewPrEPcodesshouldonlybeconsideredforclinicattendeeswhobelongtosub-populationsathighHIVriskincludingcis-andtransgendermenandtransgenderwomenwhohavesexwithmen,blackAfricanheterosexuals,peopleinserodiscordantrelationships,andotherswhoseriskofHIVmaybegreaterthanorequalto2%per

(Baseline)

Follow-up

Month1 Month3 Everysubsequent3monthsonPrEP

FrequencywhileonPrEP

HIVtesting X X* X X 3monthly

AssessmentforsymptomsofAHI

X X X X 3monthly

HepatitisB(+vaccinationifnonimmune)

STIscreentoincludehepatitisC(MSM,TGW,otherrisksforHCV)

X X X 3monthly

STIscreen(nonMSM/TGW) X X 3monthly

Serumcreatinine/eGFR X AnnualifeGFR>90mL/min/1.73m2andaged<40.Morefrequentmonitoringrequired(atleast6/12)ifeGFR60–90mL/min/1.73m2oraged>40yearsorconcomitantriskfactorsforrenalimpairment.If<60mL/min/1.73m2seekspecialistrenaladvice.

Urinepregnancytest(ifindicated)

X X X X 3monthlyifindicated

annum.ThecodesshouldbecompletedateachPrEPvisitorforeachnewepisodeofcare.PrEPcodesshouldberecordedforallpatientswhoareeligibleforPrEPandincludearecordofstartingPrEP,continuingonPrEP,stoppingPrEP,declininganofferofPrEP,ortakingPrEPfromanothersource.WherePrEPisbeingprescribed,thenumberoftabletsbeingprescribedshouldalsobecoded.ParallelcodeshavebeenadoptedinScotlandandareenteredusingtheSTISSmoduleoftheNaSHsystem,althoughmedicationdataisderiveddirectlyfromtheprescribingmodule.

6.5MonitoringonPrEP:recommendations

34. WerecommendHIVtestingshouldbeundertakenevery3monthswithalaboratory4thor5thgenerationtest(1A)orablood-basedPOCT.(1B)

35. Werecommendpatientswithsymptomssuggestiveofseroconversionshouldbeinvestigatedwitha4thgenerationHIVtestandHIVviralload.Atypicaltestingresultsshouldbediscussedwitharegionalexpert.(1C)

36. WerecommendthatinconfirmedprimaryHIVinfection,baselineresistancetestingshouldbeundertaken.Thisistolookforevidenceofresistance-associatedmutationstotenofoviroremtricitabinealongwithothertransmittedmutations.(1B)

37. Werecommend3-monthlyscreeningforbacterialSTIs(chlamydia,gonorrhoeaandsyphilis)andforHCVisrecommendedforMSMandTGW.(1B)

38. WerecommendSTIscreeningshouldbeofferedannuallyforheterosexualmenandwomen,ormorefrequentlyifchangeofpartnerorotherrisksforSTIacquisitionarepresent.(1B)

39. Renalrecommendations:o IfeGFR>90mL/min/1.73m2atbaseline(andfollowup)andthepersonisaged<40yearsthen

annualeGFRshouldbeconducted.(1A)o IfeGFR60–90mL/min/1.73m2,aged>40yearsorconcomitantriskfactorsforrenal

impairmentrecommendmorefrequentmonitoringofrenalfunctionatphysiciandiscretion,butatleast6monthly.(1B)

o IfeGFR<60mL/min/1.73m2,therisksandbenefitsofcontinuingPrEPshouldbeassessedonacase-by-casebasis.Specialistrenalinputshouldbeobtainedtodeterminefurtherinvestigationsandfrequencyofmonitoring.(1C)

Goodpracticepoints

• Assessmentofpregnancystatusinpeoplenotusingreliablecontraceptionshouldbeconductedifindicated.

• Bonehealth:o PatientsshouldbeinformedoftheriskofreductioninBMDofaround1.5–2%atthehipand

spinefollowing48weeksoftreatment.o RoutinemonitoringofBMDisnotrecommendedinindividualstakingTDFforPrEPwithno

otherriskfactorsforreducedBMD.

• Adverseeventsshouldbereportedthroughtheyellowcardscheme(https://yellowcard.mhra.gov.uk/).

• PrEPSexualHealth&HIVActivityPropertyType(SHHAPT)codesshouldbecompletedforallpatientstoallownationalmonitoringoftheeligibility,uptake,anddurationofuseofHIVpre-exposureprophylaxis(PrEP).

6.6IndicationsforstoppingPrEP

ContraindicationstocontinuedPrEPuseincludeareductioninriskofHIVacquisitionasdefinedbyeligibilitycriteria,HIVinfectionandpooradherencewhereattemptsatadherencesupporthavefailed.Relativecontraindicationsincludesideeffectsandchangeinriskbehaviour(i.e.PrEPisnolongerindicated).ContinuationofPrEPifeGFRdeclinestobelow60mL/min/1.73m2shouldbeconsideredonacase-by-casebasiswithspecialistrenalinput.PregnancyisnotanindicationtostopPrEPespeciallyifthereisongoingriskofHIV.

BothTDFandFTCareactiveagainstHBV.Thus,inindividualswhodonothavevaccine-inducedHBVimmunity,HBVinfectionshouldbeexcludedbeforestoppingPrEP.IfHBVinfectionisidentified,TDF-FTCshouldbecontinued,aslongasnocontraindicationsexist,andreferredtoaphysicianwithexpertiseinmanagementofhepatitisB.IfpatientswithactiveHBVinfectiondecidetostoptakingTDF-FTC,liverfunctionmustbecloselymonitoredbecausereactivatedHBVinfectioncanresultinhepaticdamage.

6.6IndicationsforstoppingPrEP:recommendations40. WerecommendthatapositiveHIVtestisanabsolutecontraindicationtocontinuedPrEP.Referralto

specialistHIVservicesshouldbeundertakenimmediatelyforinvestigationandmanagementincludingintensificationofARTregimen.(1A)

41. WesuggestthatforthoseathighriskofHIVacquisition,suboptimaladherenceisarelativecontraindicationtocontinueduse.(2B)

42. Werecommendthatinthosewithoutvaccine-inducedimmunity,HBVinfectionshouldbeexcludedpriortostoppingTDF-FTC.(1B)

6.7References1. ChurchillD,WatersL,AhmedNetal.BritishHIVAssociationguidelinesforthetreatmentofHIV-1-positiveadultswithantiretroviraltherapy2015.HIVMed2016;17Suppl4:s2–s104.

2. BritishAssociationforSexualHealthandHIVClinicalEffectivenessGroup.Guidanceontestsforsexuallytransmittedinfections.2015.Availableat:https://www.bashhguidelines.org/media/1084/sti-testing-tables-2015-dec-update-4.pdf(accessedAugust2017).

4. TiraboschiJ,BrodnickiE,BradyMetal.AcutehepatitisCinthePROUDpilotstudy(AbstractO45).HIVMed2014;15(Suppl3):1–16.

6. GandhiM,GliddenDV,MayerKetal.Associationofage,baselinekidneyfunction,andmedicationexposurewithdeclinesincreatinineclearanceonpre-exposureprophylaxis:anobservationalcohortstudy.LancetHIV2016;3:e521–e528.

7. NationalInstituteforHealthandCareExcellence.Chronickidneydiseaseinadults:assessmentandmanagement.CG182.2014.Availableat:www.nice.org.uk/guidance/cg182(accessedAugust2017).

9. MugwanyaK,BaetenJ,CelumCetal.Lowriskofproximaltubulardysfunctionassociatedwithemtricitabine-tenofovirdisoproxilfumaratepre-exposureprophylaxisinmenandwomen.JInfectDis2016;29:29.

10. GliddenDV,MulliganK,McMahanVetal.Recoveryofbonemineraldensityfollowingdiscontinuationoftenofovir-basedhivpre-exposureprophylaxis.JAcquirImmuneDeficSyndr2017.

11. LiuAY,VittinghoffE,SellmeyerDEetal.BonemineraldensityinHIV-negativemenparticipatinginatenofovirpre-exposureprophylaxisrandomizedclinicaltrialinSanFrancisco.PLoSOne2011;6:e23688.

12. MirembeBG,KellyCW,MgodiNetal.Bonemineraldensitychangesamongyoung,healthyafricanwomenreceivingoraltenofovirforHIVpreexposureprophylaxis.JAcquirImmuneDeficSyndr2016;71:287–294.

13. MulliganK,GliddenDV,AndersonPLetal.Effectsofemtricitabine/tenofovironbonemineraldensityinhiv-negativepersonsinarandomized,double-blind,placebo-controlledtrial.ClinInfectDis2015;61:572–580.

7Buyinggenerics

• Therearenopeerreviewedpapersonthissubject.

• Informationinthissectionisdrawnfromconferencepresentationsandpersonalcommunicationwithmembersofthewritinggroup,BASHHMSMSpecialInterestGroup,CliniciansPrEPSupportGroupandCommunityGroupconsultation

7.1Importingmedicinesboughtonline

TheMedicinesandHealthcareproductsRegulatoryAgency(MHRA)advisethatitislegaltobuyupto3monthsofmedicinesfromoutsidetheEuropeanUnionforpersonaluse.Thereisnorequirementforacertificateorauthorisation.TheMHRAalsoadvisethataprescriptionand/oraletterfromthepatient'sdoctorexplainingwhytheproduct(s)arerequiredishelpful.Theysuggestthatthepackageisclearlylabelledontheoutsidestatingthecontentsofthepackageandthattheproductsareforpersonaluse.MHRAstronglyadvisethatthemedicinesarekeptintheiroriginalpackagingandthattheyaretransportedinaccordancewithstorageconditionsspecifiedbythemanufacturerbecausethisnotonlyhelpsidentifythemedicines,butalsohelpsensuretheproduct'sstability.

ItispossibletoimportgenericPrEPfromcertainsupplierswithouttheneedforaprescription.

TherehavebeensomeoccasionswhenmedicineshavebeenimpoundedbytheUKBorderAgencyandcustomsdutycharged.ThisisincreasinglycommonandshouldbetakenintoconsiderationwhenorderinggenericPrEPonline.

TherearereportsofdelaysindeliveryofTDF-FTCboughtonline,andoccasionalissueswithstockrunningout.

7.2Authenticityoftenofovir-emtricitabineboughtonline

ThereareseveralmanufacturersofgenericTDF-FTCwhoimportintotheUK.ThesegenericmanufacturershavetheirownqualitycontrolinplaceandmeetstandardssatisfactorytotheWHOandtheFDA[1].

Despitetheabove,therehavebeenconcernsthatPrEPboughtonlinecouldbesubstandard(containlessorvariableamountsofactiveingredients)orbecounterfeit.TosupportpeoplechoosingtobuygenericPrEPonlinecertaincliniciansandTrustshavecarriedouttherapeuticdrugmonitoring(TDM).ThelargestcohortofPrEPusershavingTDMwasseenat56DeanStreet.Whencomparingpharmacokinetic(PK)dataforbrandedTruvadafromhistoriccontrols,withPKdatafor212genericPrEPusers,thePKlevelsareequivalentforbothtenofovirandemtricitabine[2].

ClinicaltrialsofPrEPwereundertakenusingtenofovirdisoproxilfumarate.InOctober2016theEuropeanMedicinesAgencyreportedthetenofovirdisoproxilmaleatesalt,whichiscontainedingenericformulations,tobebioequivalenttotenofovirdisoproxilfumarate[3].

ThewritinggroupisnotawareofanyreportstodatestatingthatgenericPrEPiscounterfeit.

7.3EthicalaspectsregardingclinicianrecommendationtobuyPrEPonline

7.3.1GeneralMedicalCouncilCommunicationfromtheGMCstatesthat

• Doctorsareresponsiblefortheirdecisionsandactionswhentheysupplyandadministermedicinesorauthoriseorinstructotherstodoso.

• RaisingthepossibilityofobtainingmedicinesforPrEPonlineaspartofthewiderdiscussionofHIVpreventionoptionsforpatientswithhigh-riskbehavioursisconsistentwithGMCguidanceonconsentanddecision-making[4].Inparticular,theGMCstatesthat'doctorsshouldgivepatientstheinformationtheywantandneedaboutoptionsfortreatingandmanagingtheircondition,thepotentialbenefits,burdensandrisksforeachoption,andanytreatmentsthattheythinkhasgreaterpotentialbenefitforthepatientthantheyortheirorganisationcanoffer.'

7.3.2ImperialCollegeHealthcareNHSTrustClinicalEthicsCommitteeCliniciansatImperialCollege(StMary’s)askedthespecificquestionoftheirClinicalEthicsCommittee(CEC)aboutprovidingPrEPsupportservicesforpeopleaccessinggenericPrEPandtheirresponsewas(O.DosekunandN.Mackie,personalcommunication):

• TheCECagreesthattheHIV/GUMclinicalteamshaveadutyofcaretoholdinformeddiscussionsaboutPrEPwithpatientswhoareathighriskofHIVinfection(wherePrEPwouldnotbeotherwisecontraindicated),inadditiontoofferingothercorerisk-reductionstrategies.

• TheCECagreesthatthecliniciansproactivelyandroutinelyaskonlythehigh-riskcohortofpatientsiftheyareawareof,alreadytaking,orwouldconsidertakingPrEPinadditiontootherpreventativepractices.

• TheCECadvisesthatitistheclinicalteam’sdutyofcaretofullymonitorindividualsundertheircarewhohavepurchasedandaretakingPrEP.EngagingandsupportinghighriskpatientstakingPrEPwouldbeanopportunitytopromoteriskreduction,andenableregularSTItestinginlinewithnationalguidelines.

7.4Specificwebsites

TheGMCadvicestatesthat:

• Asregardsdirectingpatientstospecificwebsites,muchwilldependonhowsureyoucanbethatthemedicinesobtainedfromaparticularsourcewillbesafeandeffective.

TheynotethatwhethertheexistinginformationgainedfrommonitoringpatientswhohaveindependentlyacquiredmedicinesforPrEPonlineprovidessufficientassuranceisamatterforindividualprofessionaljudgement.

Anumberofclinicians(includingmembersofthewritinggroup)approachedtheirdefenceunionsforadvicewithregardtogenericPrEPboughtonline.Defenceunionshaveconcernsaboutcliniciansendorsingaspecificwebsite,becausequalityassurancecannotbeabsolutelyguaranteed,andthiscouldbeariskintheeventofanadverseincident.ThisisalsothestanceoftheImperialCollegeHealthcareClinicalEthicsCommittee.

Itistheexperienceofthewritinggrouphowever,thatifpatientschoosingtosourcegenericPrEPdonotbuyviaacceptedwebsites,thentheyaremorelikelytoobtainmedicinesthatarenotrecommended.ExamplesincludeobtainingtenofoviraloneratherthanTDF-FTC,thereforepotentiallyputtingthemselvesatincreasedriskofHIV

acquisition.Patientsshouldthereforebeencouragedonlytousesellerslistedoniwantprepnow.co.ukassellingFDA-approvedTDF-FTC.

Iwantprepnow.co.uk(IWPN)istheonlywebsiteintheUKwhichhasa‘clicktobuy’section.ThissiteonlylinkstoanonlinesellerifthewebsitefoundersknowthatusershavepurchasedTDF-FTCviathatseller,andhavehadasatisfactoryTDMresult.Theyalsoonlylinktoasellerifthesales/deliveryprocesshasbeentestedanddeemedsatisfactory.TheonlysellerslistedonIWPNarethosesellingFDA-approvedTDF-FTC.

7.5RenalmonitoringofpatientschoosingtobuyPrEPonline

ThewritinggroupagreeswiththeImperialCollegeHealthcareNHSTrustClinicalEthicsCommittee,thatdenyingfullmonitoringofcarewhileonPrEPwouldbeinbreachofthemedicalprofession’sdutyofcare.

7.6References1. USFoodandDrugAdministration(FDA).ApprovedandtentativelyapprovedantiretroviralsinassociationwiththePresident'sEmergencyPlan.2017.Availableat:www.fda.gov/InternationalPrograms/PEPFAR/ucm119231.htm(accessedAugust2017).

2. WangX,NwokoloN,Korologou-LindenRetal.InterPrEP:internet-basedpre-exposureprophylaxis(PrEP)withgenerictenofovirDF/emtricitabine(TDF/FTC)inLondonanalysisofpharmacokinetics,safetyandoutcomes.InternationalCongressofDrugTherapyinHIVInfection.October2016.Glasgow,UK.Abstract0315.

3. EuropeanMedicinesAgency.CommitteeforMedicinalProductsforHumanUse.Assessmentreport:tenofovirdisoproxilMylan.2016.Availableat:www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/004049/WC500218306.pdf(accessedAugust2017).

4. GeneralMedicalCouncil.Consent:patientsanddoctorsmakingdecisionstogether.2008.Availableat:www.gmc-uk.org/Consent___English_0617.pdf_48903482.pdf(accessedAugust2017).

8CosteffectivenessofPrEPinhigh-incomecountries

8CosteffectivenessofPrEPinhigh-incomecountries:summary• Overall,thecost-effectivenessofPrEPamongMSMpopulationsinhigh-incomecountrieswasfoundto

behighlydependentonHIVincidenceofthepopulationtakingupPrEP(andthereforetheirageandlevelofcondomuse),HIVprevalence,PrEPdrugcost,PrEPefficacy(sometimesexpressedintermsofadherencetoPrEP),rateofHIVdiagnosisinthepopulationandcostofantiretroviraltreatmentfortheHIV-positivepopulation.

• TwoofthefouranalysessetinEurope(bothusingdynamicmodels)foundthattheintroductionofPrEPinaselectedgroupofMSMathighriskofHIVcouldnotonlybecost-effectivebutcost-savingwhenappropriatelyusedconsideringalongtimehorizon,highPrEPeffectivenessandevent-baseduse.Giventheefficacyofevent-basedPrEPwasfoundtobesimilartotheeffectivenessofthedailyregimen,butwithalowernumberofpills,anevent-basedregimenisconsideredmorecost-effectivethanthedailyregimen.

• Cost-effectivenessofPrEPamongpeoplewhoinjectdrugshasbeeninvestigatedonlyintheUS.BothstudiesconcludedthatPrEPshouldnotbeprioritisedtothisgroup.

• AmongcoupleswhowishtoconceivewherethewomanisHIVnegativeandthemanisHIVpositiveandvirologicallysuppressedontreatment,PrEP,evenlimitedtofertiledays,doesnotrepresentacost-effectiveoptionatthecurrentcostgiventheverylowriskoftransmissioniftheHIV-positivemalepartnerisvirologicallysuppressed.

8.1Menwhohavesexwithmen

Severalstudiesassessedthecost-effectivenessofPrEPamongMSMinhighincomecountries:mostlookedatPrEPdeliveredtoatargetgroupofhigh-riskMSM,withJuusolaetal.[1],Schneideretal.[2]andCambianoetal.[3]alsoevaluatingthecost-effectivenessofPrEPgiventoMSMatriskofHIV,butwithouttargetingspecifichigher-risksubgroups.

Inordertoevaluatethecost-effectivenessofinterventionsitisnecessarytousemathematicalmodels.Modelsforinfectiousdiseasesaregenerallyclassifiedasdynamicorstatic.Dynamicmodelsreproduceexplicitlythetransmissionofthedisease(bymodellingtheinteractionsbetweencontactsthroughwhichinfectioncanhappen)andcanthereforetakeintoaccountthesecondaryinfectionsaverted.Staticmodelsarethosecommonlyusedtoassessthecost-effectivenessofnon-communicablediseasesanddonotcapturethetransmissionofthedisease,thereforetheydonotconsiderthebenefitforpeoplewhoarenotdirectlyreceivingthepreventionintervention.ItisimportanttobearinmindwhichtypeofmodelisusedbecausestaticmodelsbydefinitiondonotcapturethefullbenefitofinterventionssuchasPrEPthatpreventnewtransmissions.

Ninecost-effectivenessstudieswerebasedondynamicmodels[1-9],fourusedastaticmodel[10-13],twousednumberneededtotreat,respectivelybasedontheiPrExtrialandtheANRSIPERGAYtrialtoestimatecost-effectiveness[14,15]andforoneitwasnotclear(onlyavailableasanabstract)[16].

TheidentifiedstudiesconsideredtheMSMpopulationintheUSgenerally[1,4,5,10,11,13]orinspecificcities(NewYorkCity[7,8]andLosAngelesCounty[16],Canada[14],Australia[6]andinparticularNewSouthWales[2],theNetherlands[9],France[15]andtheUK[3,12]).ThesettingstowhichtheyreferarecharacterisedbydifferentHIVincidenceintheMSMpopulation,anddifferentcostsfortreatmentofpeoplelivingwithHIVandfor

PrEP,andthesefactorshavebeenfoundtobecrucialindeterminingthecost-effectivenessofthispreventionintervention.

Anothercrucialparameterindeterminingthecost-effectivenessofPrEPisclearlytheefficacyassumed.ThestudiesconductedbeforethePROUDandIPERGAYtrialsreported,whereindicated,assumedalevelofPrEPefficacyinlinewithwhatwasreportedatthetime:basecaserangingfromaround44%to50%,althoughinsensitivityanalysesadditionallevelsofefficacywereconsidered(e.g.92%[10];10–90%[11],90%[6]).Morerecentstudies[3,5,9,12,15]consideredhigherlevelsofefficacy(80–86%)consistentwiththenewtrials.

IntermsofthePrEPregimen,moststudiesassumedadailyregimen,andonlysomeoftherecentstudiesalsoconsideredevent-basedPrEPuse[5,9,15].(Ouelletetal.investigatedtheuseofdailydosingforon-demandPrEP,themostexpensiveon-demandscenario).Allofthepeer-reviewedpaperswerethoughttobeofhigh/acceptablequalityusingtheSIGNchecklist(www.sign.ac.uk/checklists-and-notes.html),itwasnotpossibletoassessitfortheconferenceabstracts[3,6,12,13,15,16]andthecorrespondence[7].

Incost-effectivenessanalysesthecostsandhealthbenefitsofalternativeoptionsarecomparedandtheratiobetweenthedifferenceincost(betweenthetwoalternatives)andthedifferenceinhealthisreported.Thisratioiscalledtheincrementalcost-effectivenessratio(ICER)andisexpressedusuallyasthecostperquality-adjustedlifeyear(QALY)gained.

InthepapersthatevaluatedPrEPtargetedatMSMonly,theICERdependedonassumptionsaboutthetargetpopulation:theirage,HIVincidence,HIVprevalence,PrEPdrugcost,levelofcondomuse,adherencetoPrEPorefficacy,rateofHIVdiagnosisinthepopulationandPrEPtoxicity.

Eightofthem[1-3,9-12,15]explicitlyinvestigatedtheimpactofreductioninthecostofPrEPandallagreeditcouldhavealargeimpactontheICER.Desaietal.[4]inparticularnotedthattheICERwasinverselyproportionaltothecostoftreatinganHIV-positivepatient:thehigherthecostoftreatmentthemorePrEPiscost-effective.ReductioninthecostofPrEPcouldbeachievedbyusingevent-basedPrEPratherthandailyPrEP(inIPERGAYonaverage16pills/monthsweretaken)orduetotheintroductionofgenerictenofovirorTDF-FTC.ThepatentforFTCexpiredin2016.Thepatentfortenofovirdisoproxil(TD)expiresinJuly2017.ThepatentforTDF(withthesalt)expiresinthemiddleof2018.TherearegrantedSupplementaryProtectionCertificates(SPCs)basedonthispatentthatisforcombinationsofTDandFTCandgenerallytheSPCsexpirearoundFebruary2020.

AfewpapershighlightedexplicitlytheimportanceoftargetingPrEPinordertomakeitcost-effective[1,2,5,8].TheyalsofoundthatPrEPcoveragehadimportantimplicationsfortheepidemiologicalimpact,budgetimpactandtheICER:thegreaterthenumberofpeopleonPrEP,thehigherthenumberofHIVinfectionsavertedandthebudgetimpact(theadditionalcostinthefirstyearsofimplementation).Thecost-effectivenessofPrEPislargelydependentontheHIVincidenceinthegroupofPrEPuptakers,thereforeiftheofferPrEPtoalargernumberofpeopleisduetolessstringentcriteriaintermsofHIVrisk(orinotherwordslowerHIVincidenceinthegrouptakinguptheofferofPrEP)thecost-effectivenessofPrEPtendstobereduced.Nicholsetal.andCambianoetal.foundthattargetingtosmallergroupathigherriskwasmorecost-effectivethanifprovidedtoalesstargetedbutlargergroup[3,9].However,Desaietal.reportedthataPrEPprogrammewithalowcoverage(2.5%oftheveryhigh-riskMSMpopulationofNewYorkCity,n=1500)hadlimitedimpactonthenumberofinfectionsprevented,whichwouldnotprovidesufficientjustificationforinvestinginaPrEPprogramme.

ApotentialchallengethatwasraisedwaswhetheritwouldberealistictoofferPrEPbyrisklevel,thepotentialchallengeofidentifyingthetargetpopulation,andhowpolicycouldbeimplementedselectivelytoprioritiseaccesstoPrEPgiventhesubstantialbudgetaryimplications[1].

Twoanalyses[3,12]specifictotheUKMSMcontexthavebeendevelopedtoestimatePrEPcosteffectivenessandtoexplorethesensitivityofcost-effectivenesstochangesincriticalconditions.TheabstractbyCambianoetal.[3]wasbasedonaUK-baseddynamicmodel.TheauthorsconcludedthatPrEPuseamongMSMwascost-effective

whentargetedatMSMreportingfiveormorecondomlesssexpartnersinthelastyear,whenpresentingwithabacterialSTI,orinmenhavingcondomlesssexifthecostofantiretrovirals(fortreatmentandforuseasPrEP)wasreducedby50%ofthecurrent(2015)BritishNationalFormularylistpriceorinthecontextofPrEPbeingavailableformenhavingCLSinthepast3monthsifthereisnoincreaseinCLSandmendonotactivelyseekanHIVtest,asaconsequenceofPrEPbecomingavailable.TheabstractbyOngetal.[12]usedastaticmodeltoevaluatecost-effectivenessofa1-yearprogrammeofferedtoselectedGUMclinicattendeesinEngland.TheauthorsconcurredwithCambianoetal.inconcludingthatasubstantialpricereductionofantiretroviraldrugsusedforPrEPwouldprovidethenecessaryassuranceofcost-effectivenessforanaffordablepublichealthprogrammeofsufficientsize.

8.2Peoplewhoinjectdrugs

Onlytwostudiesconsideredthecost-effectivenessofPrEPamongPWID:oneintheUS,wherePWIDrepresentlessthan1%ofthepopulation,butwithaconsiderableHIVprevalence(9.8%)[17]andonethatconsidereddifferentsubgroupsofthepopulationsathighriskofHIVincludingPWIDinNewYorkCity[8].Theybothconsideredanefficacyaround50%withawiderangeandbothfoundthatPrEPshouldnotbeprioritisedtothisgroup.

AsthispopulationintheUSischaracterisedbyaverylowlevelofARTcoverage(10%intheearlystagesofthedisease),theauthors[17]investigatedthecost-effectivenessnotonlyofPrEPonitsownandwithfrequentscreeningbutalsowithenhancedART(50%ofnewlydiagnosedintheearlystagesofHIVreceivepromptsustainedART)andfoundthislastscenariotodominatetheothersandtopreventasubstantialnumberofHIVinfectionsamongPWIDandthewholeUSpopulation.However,theyconcludedthatatcurrentdrugprices(costofTruvadaofUS$10,000/year[range:US$7,150–13,320]),thisstrategyistooexpensivebothinabsolutetermsandintermsofcostperQALYgained($253000/QALYgained),butifdrugcostsarereducedby65%(possiblyduetotheintroductionofgenericdrugs),thentheICERwouldbereducedtoaround$100,000perQALYgained.

Kessleretal.[8]consideredtheintroductionofPrEPindifferentgroupathighriskofHIV:MSM,high-riskMSM,high-riskheterosexuals,PWIDandtheircombinationsandfoundthattheintroductionofPrEPonlyinPWIDhadasmallepidemiologicalimpact(2%ofinfectionsavertedover20yearscomparedtoaround20%whentargetingMSM)andatahighcost-per-infectionaverted(morethan$9millioncomparedtoaround$2.1millionwhentargetingMSM).

8.3Specialpopulations

TworecentstudiesevaluatedPrEPasaconceptionstrategyforheterosexualserodiscordantcoupleswherethemalepartnerisHIVpositiveandvirologicallysuppressedonantiretroviraltherapy:oneinCanada[18]andoneinFrance[19].

Inparticular,Letchumananetal.[18]consideredcondomlesssexrestrictedtotimeofovulationwithPrEPandasotherconceptionstrategies:condomlesssexrestrictedtotimeovulation,sperm-washingwithintrauterineinsemination.Similarly,Mabileauetal.[19]consideredfouroptions:condomlesssex(notethattheHIV-positivepartnerissuppressedandontreatment),condomlesssexrestrictedtofertiledays,condomlesssexwiththeuseofPrEP,condomlesssexwithPrEPrestrictedtofertiledaysandmedicallyassistedprocreation(MAP),suchasintrauterineinsemination.

BothconcludedthattheuseofPrEPasaconceptionisnotacost-effectiveoption.Letchumananetal.foundbothcondomlesssexrestrictedtotimeovulationwithPrEPandsperm-washingwithintrauterineinseminationweretooexpensiveintermsofabsolutecost(respectively$438and$14,910moreexpensivethancondomlesssex

restrictedtotimeovulation)andcostperQALYgained(bothdominatedbycondomlesssexrestrictedtotimeovulationwhichhasanICERof$101/QALYgained).Mabileauetal.recognisedthattheconceptionoptionswiththelowestriskofHIVtransmissionarecondomlesssexrestrictedtofertiledays(withthepositivepartnersuppressedonART)withPrEPduringthosedaysandMAP.However,theyconcludethattheseoptionsarenotcost-effectiveatthecurrentcosts.

8.4References1. JuusolaJL,BrandeauML,OwensDK,BendavidE.Thecost-effectivenessofpreexposureprophylaxisforHIVpreventionintheUnitedStatesinmenwhohavesexwithmen.AnnInternMed2012;156:541–550.

2. SchneiderK,GrayRT,WilsonDP.Acost-effectivenessanalysisofHIVpreexposureprophylaxisformenwhohavesexwithmeninAustralia.ClinInfectDis2014;58:1027–1034.

3. CambianoV,MinersA,DunnDetal.Ispre-exposureprophylaxisforHIVpreventioncost-effectiveinmenwhohavesexwithmenwhoengageincondomlesssexintheUK?SexTransmDis2015;91:A1.

4. DesaiK,SansomSL,AckersMLetal.ModelingtheimpactofHIVchemoprophylaxisstrategiesamongmenwhohavesexwithmenintheUnitedStates:HIVinfectionspreventedandcost-effectiveness.AIDS2008;22:1829–1839.

5. RossEL,CintiSK,HuttonDW.Acost-effective,clinicallyactionablestrategyfortargetingHIVpreexposureprophylaxistohigh-riskmenwhohavesexwithmen.JAcquirImmuneDeficSyndr2016;11:11.

6. AndersonJ,CooperD.Cost-effectivenessofpre-exposureprophylaxisforHIVinanMSMpopulation.HIVMed2009;10:39.

7. KoppenhaverRT,SorensenSW,FarnhamPG,SansomSL.Thecost-effectivenessofpre-exposureprophylaxisinmenwhohavesexwithmenintheUnitedStates:anepidemicmodel.JAcquirImmuneDeficSyndr2011;58:e51–52.

8. KesslerJ,MyersJE,NuciforaKAetal.Evaluatingtheimpactofprioritizationofantiretroviralpre-exposureprophylaxisinNewYorkCity.AIDS2014;10:10.

9. NicholsBE,BoucherCAB,vanderValkMetal.Cost-effectivenessanalysisofpre-exposureprophylaxisforHIV-1preventionintheNetherlands:amathematicalmodellingstudy.LancetInfectDis.

10. ChenA,DowdyDW.Clinicaleffectivenessandcost-effectivenessofHIVpre-exposureprophylaxisinmenwhohavesexwithmen:riskcalculatorsforreal-worlddecision-making.PLoSOne2014;9:e108742.

11. PaltielAD,FreedbergKA,ScottCAetal.HIVpreexposureprophylaxisintheUnitedStates:impactonlifetimeinfectionrisk,clinicaloutcomes,andcost-effectiveness.ClinInfectDis2009;48:806–815.

12. OngK,DesaiS,DesaiMetal.Thecost-effectivenessofpre-exposureprophylaxis(PrEP)topreventHIVacquisitionbyhigh-riskMSMinEngland–preliminaryresultsofastaticdecisionanalyticalmodel.Posterpresentation.PublicHealthEnglandAnnualConference.September2015.WarwickUniversity,UK.

13. VaidyaN,CampbellJD.Acost-effectivenessanalysisofpre-exposureprophylaxisforHIV:Auspayerperspective.ValueinHealth2015;18(3):A236–A237.

14. OuelletE,DurandM,GuertinJRetal.Costeffectivenessof'ondemand'HIVpre-exposureprophylaxisfornon-injectiondrug-usingmenwhohavesexwithmeninCanada.CanJInfectDisMedMicrobiol2015;26:23–29.

15. Durand-ZaleskiI,MutuonP,CharreauIetal.CosteffectivenessofondemandPrEPinmenwhohavesexwithmen(MSM)intheANRSIPERGAYstudy.InternationalAIDSConference(AIDS2016).July2016.Durban,SouthAfrica.

16. DraboEF,HayJW,VardavasRetal.Rollingoutoralpre-exposureprophylaxis(PREP)isacost-effectiveHIVpreventionstrategyamongtheLosAngelescounty(LAC)menwhohavesexwithmen(MSM).ValueinHealth2015;18(3):A237.

17. BernardCL,BrandeauML,HumphreysKetal.Cost-effectivenessofHIVpreexposureprophylaxisforpeoplewhoinjectdrugsintheUnitedStates.AnnInternMed2016;26:26.

18. LetchumananM,CoytePC,LoutfyM.AneconomicevaluationofconceptionstrategiesforheterosexualserodiscordantcoupleswherethemalepartnerisHIV-positive.AntivirTher2015;20:613–621.

19. MabileauG,SchwarzingerM,FloresJetal.HIV-serodiscordantcouplesdesiringachild:'treatmentasprevention,'preexposureprophylaxis,ormedicallyassistedprocreation?AmJObstetGynecol2015;213:341.e341–312.

9Summaryofrecommendations

3.1Evidenceforsafetyandefficacyinmenwhohavesexwithmen(MSM):recommendations1. WerecommendthatPrEPwithon-demandordailyoralTDF-FTCshouldbeofferedtoHIV-negative

MSMwhoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughcondomlessanalsexintheprevious3–6monthsandongoingcondomlessanalsex.(1A)

2. WerecommendthatPrEPwithon-demandordailyoralTDF-FTCshouldbeofferedtoHIV-negativeMSMhavingcondomlessanalsexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

3. WesuggestthattenofoviraloneshouldnotcurrentlybeofferedasPrEPtoMSM.Thisrecommendationisbasedonlackofevidence,ratherthanevidenceoflackofeffect.(2C)

Goodpracticepoint• ConsiderPrEPonacase-by-casebasisinMSMwithcurrentfactorsotherthancondomlessanalsexin

previous3–6monthsthatmayputthematincreasedriskofHIVacquisition.SeeSection4.

3.2Evidenceforsafetyandefficacyinheterosexualpopulations:recommendations4. WerecommendthatdailyoralTDF-FTCshouldbeofferedtoHIV-negativeheterosexualmenand

womenhavingcondomlesssexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

5. WesuggestthatPrEPwithdailyoralTDF-FTCshouldbeofferedonacase-by-casebasistoheterosexualmenandwomenwithcurrentfactorsthatmayputthematincreasedriskofHIVacquisition.SeeSection4.(2B)

6. WerecommendthatTDFalonecanbeofferedtoheterosexualmenandwomenwhereFTCiscontraindicated.(1A)

Goodpracticepoint

• ForwomenusingDMPA,PrEPislikelytocounteractanincreaseinHIVacquisition.However,womenatriskofHIVacquisitionshouldbeofferedanalternativeformofcontraceptionifavailable,whetherornottheyopttotakePrEP.

3.3Evidenceforsafetyandefficacyinpeoplewhoinjectdrugs(PWID):recommendations7. PrEPisnotrecommendedforpeoplewhoinjectdrugswhereneedleexchangeandopiatesubstitution

programmesareavailable.(2C)8. Werecommendthatexistingharm-reductionstrategiessuchasneedleexchangeandopiate

substitutionprogrammesshouldbeencouragedforpeoplewhoinjectdrugs.(1D)Goodpracticepoints• ConsiderPrEPonacase-by-casebasisinpeoplewhoinjectdrugsinanoutbreaksituationorwithother

factorsthatputthematincreasedriskofHIVacquisition.SeeSection4.

• InterventionsforchemsexshouldbeencouragedforpeoplewhoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughreportofinjectingdruguseduringchemsex(slamming).

3.4Evidenceforsafetyandefficacyintranspeople:recommendations9. WerecommendthatPrEPwithdailyoralTDF-FTCshouldbeofferedtoHIV-negativetranswomen

whoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughcondomlessanalsexintheprevious3–6monthsandongoingcondomlesssex.(1A)

10. WerecommendthatdailyoralTDF-FTCshouldbeofferedtoHIV-negativetranswomenandtransmenhavingcondomlesssexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

Goodpracticepoints• PrEPcouldbeconsideredonacase-by-casebasisintranswomenandtransmenwithcurrentfactors

otherthancondomlessanalsexthatmayputthematincreasedriskofHIVacquisition.SeeSection4.• ForbothtranswomenandtransmenadiscussionshouldbehadregardingunknownPrEPefficacyfor

frontal(vaginal)sex.• Adiscussionshouldbehad,bothatPrEPinitiationandmaintenancevisits,thattherearenoknown

interactionsbetweenTDF-FTCandfeminisingormasculinisinghormonesexceptforethinylestradiol.

3.5Evidenceforsafetyandefficacyinyoungpeople(15–25years):recommendations

11. WerecommendthatPrEPwithdailyoralTDF-FTCshouldbeofferedtoyoungMSMandTGWwomen(15–25years)whoareidentifiedasbeingatelevatedriskofHIVacquisitionthroughcondomlessanalsexintheprevious3–6monthsandongoingcondomlessanalsex.(1A)

12. WerecommendthatPrEPwithTDF-FTCshouldbeofferedtoyoungpeoplehavingcondomlessanalsexwithpartnerswhoareHIVpositive,unlessthepartnerhasbeenonARTforatleast6monthsandtheirplasmaviralloadis<200copies/mL.(1A)

13. RoutineBMDscanninginyoungpeopleinitiatingPrEPisnotrecommended.(1D)Goodpracticepoints• ConsiderPrEPwithdailyoralTDF-FTConacase-by-casebasistoyoungpeoplewithcurrentfactorsother

thancondomlessanalsexthatmayputthematincreasedriskofHIVacquisition.SeeSection4.• TheriskandbenefitsofprovidingPrEPforadolescentsshouldbeweighedcarefullyinthecontextofUK

lawsandjudgementsaboutautonomyinhealthcaredecision-making(e.g.Frasercompetency),andbalancedagainstprotectingyoungpeoplefromharm.