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Name: Same day HIV testing with initiation of antiretroviral therapy versus standard care for persons
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Year: 2017
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group,156(44%)participantswereretainedincarewith12 monthHIV 1RNA50copies, and184(52%)had1,000copies/ml;20participants(6%)died.Inthesame dayARTgroup, 184(53%)participantswereretainedwithHIV 1RNA50copies/ml,and212(61%)had 1,000copies/ml;10(3%)participantsdied.Theunadjustedriskratio(RR)ofbeingretained at12monthswithHIV 1RNA50copies/mlwas1.21(95%CI:1.04,1.38;p=0.015)forthe same dayARTgroupcomparedtothestandardARTgroup,andtheunadjustedRRfor beingretainedwithHIV 1RNA1,000copieswas1.18(95%CI:1.04,1.31;p=0.012).The mainlimitationofthisstudyisthatitwasconductedatasingleurbanclinic,andthegeneraliz abilitytoothersettingsisuncertain.ConclusionsSame dayHIVtestingandARTinitiationisfeasibleandbeneficialinthissetting,asit improvesretentionincarewithvirologicsuppressionamongpatientswithearlyclinicalHIV disease.TrialregistrationThisstudyisregisteredwithClinicalTrials.govnumberNCT01900080AuthorsummaryWhywasthisstudydone? Multiplevisitsforcounseling,laboratorytesting,andotherprocedurestoprepare patientsforinitiationofantiretroviraltherapy(ART)areburdensomeandcontributeto thehighrateofattritionduringtheperiodfromHIVtestingtoARTinitiation. TheWorldHealthOrganization(WHO)recentlychangedtheirguidelinestorecom mendARTforallpersonslivingwithHIV,facilitatingARTinitiation. ThisstudywasconductedtodetermineifARTinitiationonthedayofHIVdiagnosis couldimprovetreatmentinitiationrates,retentionincare,andHIVviralsuppression forpatientswithasymptomaticorminimallysymptomaticHIVdisease.Whatdidtheresearchersdoandfind? WerandomlyassignedpatientswhopresentedforHIVtestingataclinicinPort au Prince,HaititostandardARTinitiationorsame dayHIVtestingandARTinitiation (356inthestandardand347inthesame daygroups). Thestandardgrouphad3weeklyvisitswithasocialworkerandphysicianandthen startedART21daysafterthedateofHIVdiagnosis;thesame dayARTgroupinitiated ARTonthedayofHIVdiagnosis. Allparticipantsinthesame dayARTgroupand92%ofparticipantsinthestandard groupinitiatedART. Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,20172/15Competinginterests:Theauthorshavedeclared thatnocompetinginterestsexist. Abbreviations:ART,antiretroviraltherapy; GHESKIO,HaitianGroupfortheStudyofKaposi's SarcomaandOpportunisticinfections;IQR, interquartilerange;LTFU,losttofollow up;PPD, purifiedproteinderivative;RR,riskratio;SEARCH, SustainableEastAfricaResearchonCommunity Health;UNAIDS,TheJointUnitedNations ProgrammeonHIV/AIDS;WHO,WorldHealth Organization.

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At12monthsafterHIVtesting,ahigherproportionofparticipantsinthesame day ARTgroupwereretainedincare(80%versus72%),andahigherproportionwere retainedincarewithviralload<50copies/ml(53%versus44%)andviralload<1,000 copies/ml(61%versus52%).Whatdothesefindingsmean? ThisstudydemonstratesthatitisfeasibletoinitiateARTonthedayofHIVdiagnosis forpatientswithearlyHIVclinicaldiseaseandthatsame daytreatmentleadsto increasedARTuptake,retentionincare,andviralsuppression. Thoughsame dayARTinitiationimprovesoutcomes,retentionincareandviralsup pressionremainsuboptimal,sofurtherinterventionstomaximizelong termoutcomes willbeessential. Thestudyislimitedbybeingconductedat1clinicinurbanHaiti.Furtherstudywillbe necessarytodetermineifthisstrategywillbeeffectiveinothersettings.IntroductionTheJointUnitedNationsProgrammeonHIV/AIDS(UNAIDS)90 90 90targetsstatethat 90%ofHIV infectedpersonsknowtheirstatus,90%initiateantiretroviraltherapy(ART),and 90%achievevirologicsuppressionbytheyear2020tocurbtheAIDSepidemic.In2015, theWorldHealthOrganization(WHO)updatedtheirguidelinestorecommendARTforall personslivingwithHIVbasedonevidencethatearliertreatmentimprovesoutcomesand decreasestransmission.Toachievethesegoals,patientsmustbepromptlylinkedtoHIV services,initiatedonART,andretainedinlifelongcare. AttritionratesareparticularlyhighduringtheperiodfromHIVtestingtoARTinitiation, withone quartertoone thirdofpatientslostintheprocessofstartingART.Evenif manyofthesepatientsre engageincareatalaterdate,theywillreturnwithmoreadvanced disease.Thoughtherearemanyfactorsthatcontributetopretreatmentattrition,thecurrent standardofcareinmostsettings,whichrequiresmultiplesequentialvisitsforHIVtestingand counseling,laboratorytesting,andadherencecounselingpriortoARTinitiation,createsbarri erstotreatmentinitiation.AsofJune2016,WHOguidelinesnoteinadequateevidencetosup portarecommendationofsame dayHIVtestingandARTinitiation.However,the availabilityofpoint of caretests,thefactthatCD4cellcountsarenolongernecessarypriorto ARTinitiation,andtheprovisionofsame daycounselingcanacceleratetreatmentinitiation, potentiallyreducingattrition.WeconductedarandomizedtrialinHaititodetermine whethersame dayHIVtestingandARTinitiation,ascomparedwithstandardARTinitiation, improvesretentionincarewithviralsuppression.Methods StudydesignandsettingWeconductedanunblinded,randomizedcontrolledtrialofstandardARTinitiationversus same dayHIVtestingandARTinitiationamongHIV infectedadultsattheHaitianGroupfor Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,20173/

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theStudyofKaposi'sSarcomaandOpportunisticinfections(GHESKIO)inPort au Prince, Haiti.HaitiisthepoorestcountryintheWesternHemisphere,withadultHIVprevalenceof 1.7%.GHESKIOisaHaitiannongovernmentalorganizationandthelargestprovider ofHIVcareintheCaribbean,treatingupto700patientsperdayforHIVand/ortuberculosis (TB).Allcareisprovidedfreeofcharge.Thestudywasapprovedbytheinstitutionalreview boardsatPartnersHealthcare,GHESKIO,WeillCornellMedicalCollege,andFloridaInterna tionalUniversity.SeesupportinginformationfilesS1TextforthestudyprotocolandS2Text fortheCONSORTchecklist.ParticipantsParticipantswererecruitedfromtheHIVvoluntarycounselingandtestingcenteratGHES KIOfromAugust2013toOctober2015.TheyreceivedHIVtestingandposttestcounseling; thosewithapositiveHIVtestwerereferredforsame dayphysicianevaluation,CD4count (FACSCount,Becton Dickinson,FranklinLakes,NewJersey),WHOstaging,andchestradio graph.PatientswereeligibleforstudyinclusioniftheywereinfectedwithHIV 1, 18yearsof age,andhadWHOStage1or2diseaseandCD4count 500cells/mm3.Initially,enrollment waslimitedtopatientswithCD4count 350cells/mm3,butinFebruary2014,thecutoff wasincreasedto 500cells/mm3inresponsetorevisedWHOandHaitianguidelines. PatientswereexcludediftheywerealreadyawareoftheirHIVdiagnosis,hadreceivedART previously,werepregnantorbreastfeeding,livedoutsideofthegreaterPort au Princemetro politanarea,plannedtotransfercareduringthestudyperiod,orfailedtodemonstratepre parednessonanARTreadinesssurvey,whichwasadministeredbyasocialworkerpriorto studyenrollment.Thesurveyincludesa5 pointscale,withrespondentsrankingtheirpre parednessfrom notatallready to completelyready inresponseto7questions.Studyinclu sionrequiredaresponseof somewhatready or completelyready forall7questions(S3 Text ).RandomizationandmaskingAfterthepatientshadprovidedwritteninformedconsent,thestudyteamperformeda screeningevaluationforstudyexclusioncriteria,andeligibleparticipantswereenrolled andrandomizedonthedayofHIVtesting.Participantswererandomlyassignedwiththe useofacomputer generatedrandom numberlisttoeitherstandardARTorsame day ARTinitiationina1:1ratio,withallocationconcealment.Therandomizationsequence wasgeneratedbyacomputerintheGHESKIOdatamanagementunitbyadatamanager whohadnootherinvolvementinstudyprocedures.Participantswereenrolledinthestudy andassignedtogroupsbyastudyphysician.Participants,sitepersonnel,andstudystatisti cianswerenotmaskedtogroupassignment.ProceduresAfterrandomization,thestandardgroupparticipantsreceivedARTinitiationproceduresthat mirrornationalguidelines.ParticipantswerereferredtoreturnonDay7forbaselinelabora torytests(creatinine,alanineaminotransferase,aspartateaminotransferase,completeblood count,purifiedproteinderivative),physicianevaluation,andcounselingwithasocial worker.OnDay10,theyreceivedinterpretationofPPDresults,andonDays14and21,they wereseenbyaphysicianandsocialworkerforadditionalcounseling,testresults,andongoing evaluationsforopportunisticinfections.ParticipantsstartedARTonDay21andhadanaddi tionalsocialworkerandphysicianvisitatWeek5(Fig1).TheARTregimenwasthesameas Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,20174/

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andcounselingsessionswereprovidedtoeachgroupsothattheonlydifferenceincarewasin thescheduleofvisitsduringthefirst5weeksofthestudyandthetimingofARTinitiation. AllcarewasdeliveredbyGHESKIOclinicstaff,andthesameproviders(physicians,nurses, socialworkers,pharmacists,andfieldworkers)caredforbothgroups.Acounselingmanual wasfollowedwithanoutlineforthesocialworkerstofollowateachscheduledcounseling visit;thesewereidenticalbetweengroups,exceptforthetimingofARTinitiation,andeach sessiontookabout30minutes.Allcounselingwasprovidedforindividualpatients,rather thanforgroups.Thecounselingsessionswereaudiotapedandsystematicallyevaluatedfor qualitycontrolpurposes.Ifaparticipantineithergroupmissedastudyvisitthatincludeda scheduledsocialworkercounselingsession,thecounselingwasprovidedatthenextvisit. Participantsinbothgroupshadmonthlyphysicianvisitsthroughoutthefollow upperiod andreceivedthesamepackageofservicesprovidedtoallHIV infectedpatientsatGHESKIO, includingprophylactictreatmentwithtrimethoprim sulfamethoxazoleandisoniazid.Field workersphonedpatientswhomissedavisitandattemptedahomevisitforthosenotreachable byphone.Participantsreceivedatransportationsubsidyof100Haitiangourdes(US$1.70)per visit.OutcomesTheprimaryendpointwasretentionincarewithHIV 1RNA<50copies/mlat12months afterHIVtesting.Retentionwasdefinedasattendingthe12 monthvisit(1clinicvisitbetween 12and15monthsafterHIVtesting).Losttofollow up(LTFU)wasdefinedasfailuretoattend the12 monthvisit.Deathswereascertainedbyreviewofmedicalrecordsorreportfromfam ilymembers.ANationalInstitutesofHealthDivisionofAIDSExpeditedAdverseEventForm wasfilledoutwithin48hoursafterthestudyteambecameawareofanydeath.Transferswere ascertainedbyconfirmationthattheparticipantwasreceivingcareatadifferentsite.Second aryoutcomesincludesurvival,ARTinitiation,retentionincarewithHIV 1RNA<1,000cop ies/mlat12monthsafterHIVtesting,adherenceasmeasuredbypharmacyrefillrecordsand self report,andcostandcost effectivenessofstandardandsame dayART;theadherenceand cost effectivenessevaluationswillbereportedinseparatemanuscripts.StatisticalanalysisDemographic,clinical,andlaboratorydatafromtheelectronicmedicalrecordandstudy formswerede identified,enteredintoanExcelspreadsheet,andexportedintoStatav14soft ware(StataCorp,2011,CollegeStation,Texas)foranalysis.Afterstudycompletion,allpartici pantswhowereLTFUwererecontactedtodeterminetheirvitalstatus. Thestudywaspoweredtodetecta10%absolutedifferenceintherateofretentionwith virologicsuppressionbetweenthe2groupsat12monthsafterenrollment(65%inthestan dardand75%inthesame dayARTgroup).Atthe=0.05significancelevel,weestimated thatwewouldneedtoenroll349participantspergroup(698intotal)toachieve80%powerto detectthisdifference.Becausepatientswhotransferredduringthestudyperiodwereexcluded, weincreasedthetotalsamplesizeto762participants.Forallanalyses,amodifiedintention to treatapproachwasused,inwhichallpatientswereanalyzedaccordingtotheirassignment group,excludingpatientswhotransferredtoanotherfacilityduringthefollow upperiod, accordingtoprotocol. Baselinecharacteristicsweresummarizedusingsimplefrequenciesandproportionsand medianswithinterquartileranges(IQRs)stratifiedbytreatmentarm.Amongparticipants whodied,baselineCD4countwascomparedusingtheWilcoxonrank sumtest.Wecompared theproportionofparticipantswhowereretainedincarewithHIV 1RNA<50copies/ml Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,20176/

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(primaryendpoint),retainedwithHIV 1RNA<1,000copies/ml,retainedregardlessofHIV 1RNA,initiatedART,anddied(secondaryendpoints)at12monthsafterenrollmentusinga chi squaretest.Weconductedmultivariablelogisticregressionincludingallcovariateslisted inTable1tocontrolforanyresidualconfounding.Wepresentunadjustedandadjustedrisk ratios(RR)with95%confidenceintervals.Becauseofthechangeinenrollmentcriteriamid study,weconductedasensitivityanalysisthatincludedonlytheparticipantswhomettheorig inalenrollmentcriteriaofCD4count 350cells/mm3.Inresponsetoareviewer'srequest,we alsoplottedretentionincare,regardlessofviralload,forbothgroupsandcomparedthedistri butionswiththelog ranktest.ThestudyisregisteredwithClinicalTrials.govnumber NCT01900080 .ResultsAtotalof821patientswerescreened,and762wereenrolledinthestudyandunderwentran domization(Fig2).Afterrandomization,59participants(28inthestandardARTand31in same dayARTgroup)transferredtoanotherclinicandwereexcludedfromallanalyses,asper protocol.Themedianagewas37yearsold(IQR:30 45years),347(49%)werewomen,and themedianCD4countwas248cells/mm3(IQR:148,345). Ofthe356participantsinthestandardgroup,256(72%)wereretainedincare,20(6%) died,and80(23%)wereLTFU(Table2).Amongthe256participantsretainedinthestandard ARTgroup,156(61%ofretainedand44%overall)hadHIV 1RNA<50copies/ml.Ofthe347 participantsinthesame dayARTgroup,277(80%)wereretainedincare,10(3%)died,and 60(17%)wereLTFU.Amongthe277participantsretainedinthesame dayARTgroup,184Table1.Baselinecharacteristicsofstudyparticipantsbygroup. CharacteristicStandardGroup(n=356)Same DayARTGroup(n=347) Age(years) Median(IQR)37(30,45)37(29,46) Femalesex no.(%)181(51)166(48) Education no.(%) Noschool90(25)93(27) Primaryschool110(31)111(32) Secondaryschoolormore156(44)143(41) Income no.(%) Noincome92(26)90(26) $0to$1/day176(49)159(46) $1to$2/day67(19)76(22) $2/day21(6)22(6) Maritalstatus no.(%) Single71(20)71(20) Currentlymarried/livingwithpartner222(62)211(61) Formerlymarried63(18)65(19) WHOStage no.(%) WHOStage1117(33)101(29) WHOStage2239(67)246(71) CD4count(cells/mm3) Median(IQR)247(150,349)249(143,336) Bodymassindex Median(IQR)*21.6(19.7,23.9)20.9(19.3,23.5) *Bodymassindexdifferedsignificantlybetweenthe2groups(p=0.025). ART,antiretroviraltherapy;IQR,interquartilerange,WHO,WorldHealthOrganization. https://doi.org/10.1371/journal.pmed.1002357.t001 Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,20177/

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InthestandardARTgroup,184(72%ofretainedand52%overall)participantswhowere retainedincarehadHIV 1RNA<1,000copies/ml.Inthesame dayARTgroup,212(77%of retainedand61%overall)participantswhowereretainedincarehadHIV 1RNA<1,000cop ies/ml.TheunadjustedRRofbeingretainedincareat12monthsandachievingHIV 1RNA < 1,000copies/mlwas1.18(95%CI:1.04,1.31;p=0.012)forthesame dayARTgroupcom paredtothestandardARTgroup(Table3);theadjustedRRforthiscomparisonwas1.20 (95%CI:1.05,1.33;p=0.008).Inthesensitivityanalysisthatincludedonlyparticipantswho mettheoriginalenrollmentcriteria(CD4count 350cells/mm3),theadjustedRRofbeing retainedincareat12monthsandachievingHIV 1RNA<50copies/mlwas1.19(95%CI: 0.99,1.38;p=0.060),andtheadjustedRRofbeingretainedincareat12monthsandachieving HIV 1RNA<1,000copies/mlwas1.18(95%CI:1.01,1.34;p=0.035). Vitalstatusattheendofthestudywasknownfor328(92%)participantsinthestandard ARTgroupand329(95%)inthesame dayARTgroup.TheunadjustedRRformortalitywas 0.51(95%CI:0.24,1.08;p=0.073)forthesame daygroupcomparedtothestandardgroup; theadjustedRRforthiscomparisonwas0.43(95%CI:0.19,0.94;p=0.033).InthesensitivityTable2.Studyoutcomesbygroup. OutcomeStandardARTGroup ( n=356)Same DayARTGroup ( n=347)UnadjustedRiskDifference (95%CI)p value PrimaryOutcome Retainedincareat12monthswithVL50 copies/ml156(43.8%)184(53.0%)9.2%(1.8%,16.6%)0.015 SecondaryOutcomes Retainedincareat12monthswithVL1,000 copies/ml184(51.7%)212(61.1%)9.4%(2.1%,16.7%)0.012 Retainedincareat12months,regardlessof VLresults256(71.9%)277(79.8%)7.9%(1.6%,14.2%)0.014 Died20(5.6%)10(2.9%) Losttofollow up80(22.5%)60(17.3%) p valuecomparingtheproportionofallpatientswhowereretainedincarewithviralload50copies/mlbetweenthe2arms. p valuecomparingtheproportionofallpatientswhowereretainedincarewithviralload1,000copies/mlbetweenthe2arms. p valuecomparingtheproportionofallpatientswhowereretainedincarebetweenthe2arms. ART,antiretroviraltherapy;VL,viralload. https://doi.org/10.1371/journal.pmed.1002357.t002Table3.Unadjustedandadjustedriskratiosofstudyoutcomes. UnadjustedAdjustedforAllBaselineCo variates RR95%CIp valueRR95%CIp value Retainedincarewithviralload50copies/ml StandardARTGroup1.01.0 Same DayARTGroup1.21(1.04,1.38)0.0151.24(1.06,1.41)0.008 Retainedincarewithviralload1,000copies/ml StandardARTGroup1.01.0 Same DayARTGroup1.18(1.04,1.31)0.0121.20(1.05,1.33)0.008 Mortalityduringstudyperiod StandardARTGroup1.01.0 Same DayARTGroup0.51(0.24,1.08)0.0730.43(0.19,0.94)0.033 ART,antiretroviraltherapy;RR,riskratio. https://doi.org/10.1371/journal.pmed.1002357.t003 Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,20179/

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analysisthatincludedonlyparticipantswithCD4count 350cells/mm3,theadjustedRRfor mortalitywas0.41(95%CI:0.18,0.93;p=0.033).Amongtheparticipantswhodied,the medianbaselineCD4countwas100cells/mm3(IQR:45,192)inthestandardand207cells/ mm3(IQR:112,291)inthesame dayARTgroup(p=0.078).Eightof20(40%)deathsinthe standardARTgroupoccurredinparticipantswhowereLTFUpriortoART,8(40%)deaths occurredinthoseLTFUafterstartingART,and4(20%)occurredwhileincare;thecausesof deathforthoseincarewerestroke,trauma,andcancerin3,andthefourthhadpainanddied afterseeingatraditionalhealer.Threeofthe10(30%)deathsinthesame dayARTgroup occurredinparticipantswhowereLTFUafterstartingART;amongthe7(70%)participants whodiedwhileincare,1ofeachdiedofstroke,pneumonia,malaria,renalfailure,andsudden death,and2diedofgastroenteritis.Nodeathsforthoseincarewereattributedtoimmune reconstitutionsyndromeoranopportunisticinfectionthatwasmissedatARTinitiation.In Fig3,theKaplan Meiercurveplotstheretentionincare,regardlessofviralload,forboth groups.Thelog ranktestcomparingthecurvesbetweenthestandardandsame dayART groupindicatesasignificantdifference(p=0.028). Inthesame dayARTgroup,344of347(99%)participantsstartedARTonthedayofHIV testing,andtheremaining3patientsstartedARTwithinthesubsequentweek.DuringtheDay 3follow upvisit,13patients(4%)inthesame dayARTgrouphadadjustmentsintheirART regimens(replacementoftenofovirwithzidovudineorabacavir)becausetheyhadcreatinine clearance<50mL/minuteonbaselinetesting.Inthestandardgroup,281(79%)participants initiatedARTbyDay28,theendofthetimewindowforthe3 weekARTinitiationvisit. Thirty six(10%)standardgroupparticipantsinitiatedARTfromDay29toDay90,and12 (3%)initiatedARTafterDay90duetolateormissedvisits.Twenty seven(8%)standard groupparticipantsneverstartedARTduringthestudyperiodbecausetheywereLTFUordied priortoinitiatingtreatment.Isoniazidprophylaxiswasinitiatedfor337(95%)participantsin thestandardgroupand340(98%)inthesame daygroup.EightcasesofTBwerediagnosed duringthefirst3monthsafterARTinitiation;6oftheseoccurredinthestandardgroupand2 inthesame dayARTgroup. Fig3.Retentionincarebystudygroup. https://doi.org/10.1371/journal.pmed.1002357.g003 Same dayHIVtestingandantiretroviraltherapyinitiationPLOSMedicine|https://doi.org/10.1371/journal.pmed.1002357July25,201710/

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