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OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorJohnGBartlett,MD

SectionEditorMartinSHirsch,MD

DeputyEditorJenniferMitty,MD,MPH

WhentoinitiateantiretroviraltherapyinHIVinfectedpatients

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Dec2014.|Thistopiclastupdated:Oct23,2014.

INTRODUCTIONAtthetimeoftheintroductionofpotentcombinationantiretroviraltherapy(ART)in1996,therewasa"hithardandhitearly"approachtotreatment[1].However,whenthetoxicitiesandresistanceofchronicARTbecameapparentandcomplicateddosingregimensthwartedadherence,thependulumswungbacktowithholdingtherapyinpatientswithrelativelypreservedCD4Tcellcounts.

AdvancesinHIVtherapyinthelastdecadehaveshiftedtheriskbenefitratiotoearliertreatment.HIVtreatmentguidelinesfromtheUnitedStatesDepartmentofHealthandHumanServices(DHHS)andtheInternationalAntiviralSocietyUSAPanelnowrecommendantiretroviraltreatmentinallpatientswithHIVinfection,regardlessofCD4cellcounts[2,3].Thistopicwilldiscussthestrengthoftheevidencesupportingthesetreatmentguidelines.

Theselectionofspecificmedications,patientevaluation,counselingregardingsideeffects,andlaboratorymonitoringarediscussedelsewhere.(See"CounselingHIVinfectedpatientsregardingpotentialsideeffectsofantiretroviraltherapy"and"PatientmonitoringduringHIVantiretroviraltherapy"and"SelectingantiretroviralregimensforthetreatmentnaveHIVinfectedpatient"and"Considerationspriortoinitiatingantiretroviraltherapy".)

GOALSOFTHERAPYTheprimarygoalsofcombinationantiretroviraltherapyaretoincreasediseasefreesurvivalthroughsuppressionofHIVreplicationandimprovementinimmunologicfunction[2,3].ViralsuppressionalsodecreasestheriskofHIVtransmissiontoanuninfectedsexualpartner[46].

INDICATORSOFIMMUNEFUNCTIONTheCD4cellcountisthemainindicatorofimmunefunctioninpatientswhoareHIVinfectedandisthestrongestpredictorofdiseaseprogressionandsurvival[2,7,8].Itisalsooneofthekeyfactorsindecidingwhethertoinitiatechemoprophylaxisforopportunisticinfectionsandtoevaluateclinicalcomplications.(See"OverviewofprimarypreventionofopportunisticinfectionsinHIVinfectedpatients".)

RATIONALEFORTREATMENTOFALLHIVINFECTEDPATIENTSThebenefitsofantiretroviraltherapy(ART)indecreasingmorbidityandmortalityinpatientswithCD4cellcounts200cells/microLwereheavilyinfluencedbyreportedtoxicities,drugresistance,andlimitedtreatmentoptions[3].ThesupportiveargumentsfortreatmentofallHIVinfectedpatientsaremany,andinclude[917]:

Therapeuticoptionshaveexpanded

Thedrugsaremorepotentthanearlieragents

Drugtoxicityhasdeclinedanddrugtolerabilityhasimproved

Simplifiedregimenshaveledtoimprovedadherence

UntreatedHIVinfectionhasnegativeconsequencesonothercomorbidities,suchascoronaryarterydisease,liverandkidneydisease,neurologicdisease,andmalignancy,whichmaybepartlymediatedbyinflammationandproinflammatorycytokines

Earliertherapyappearstoleadtoamorerobustimmunologicrecoverycomparedwithdeferredtherapy

SuppressiveARTprovidesanimportantpotentialpublichealthbenefitbydecreasingtheriskofsexual

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Argumentsfordelayedtherapyincludethefollowing:

CONSEQUENCESOFDEFERREDTREATMENTDelayedtreatmentcanleadtosubtherapeuticresponsestotreatmentandimmunologicdecline.

RiskofvirologicfailureOneobservationalcohortstudyin7916HIVinfectedpatientswhoinitiatedantiretroviraltherapy(ART)demonstratedthattheriskofvirologicfailuretothreedrugclassesovera10yearperiodwasincreasedinthosepatientswhohadabaselineCD4cellcount200cells/microL(12versus6percent)[18].

IncompleteimmunologicrecoverySomeresearchershaveadvocatedearliertherapeuticinterventionbecauseofconcernsthatimmunologicrecoverymaynotbecompleteiftreatmentisinitiatedlateininfection[1923].

TheseobservationaldatasuggestthatimmunologicrecoveryismorerobustifARTisinitiatedathigherCD4cellcounts.

ProgressionofimmunologicdeclineOnelargecohortstudyof3631patientswhohadabaselineCD4cellcount>500cells/microLfoundthatthemediantimetoprogresstoaCD4countof

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HIVassociatednephropathyHIVassociatednephropathyisthemostcommoncauseofkidneydiseaseinHIVinfectedpatientsandcanoccuratanyCD4cellcount[31,32].SincetheintroductionofpotentART,theincidenceofHIVrelatedendstagerenaldiseasehasdeclined,andthisdiseaseisnowuncommonamongpatientswithviralsuppressiononART[33,34].AnecdotalobservationsofimprovedrenalfunctionwithHIVRNAsuppressiononARTamongthosewithbaselinerenalinsufficiencyalsosupporttheseobservations[2,3538].(See"HIVassociatednephropathy(HIVAN)".)

HIVassociatedneurocognitivedeficitsTheincidenceofHIVassociateddementiahasdeclinedsincetheintroductionofpotentART.Inonecohort,patientswithviralsuppressiononARThadalowerriskofHIVassociateddementiathanpatientswithdetectableplasmaHIVRNA[39].ObservationaldataalsosuggestthatpatientswithHIVdementiaimproveclinicallyaftertheinitiationofHIVtherapy.(See"HIVassociatedneurocognitivedisorders".)

MalignancyLargecohortstudieshavereportedalinkbetweenCD4count350to500cells/microLanduncontrolledHIVviremiaandtheriskofAIDSand/ornonAIDSdefiningmalignancies[4043].ThepotentialeffectofHIVassociatedimmunodeficiencyisparticularlystrikingforcancersassociatedwithotherviralinfections,suchashepatitisB,hepatitisC,humanpapillomavirus,andEpsteinBarrvirus[40,44].(See"HIVinfectionandmalignancy:Epidemiologyandpathogenesis".)

Inaddition,severalpopulationbasedanalysessuggestthattheincidenceofAIDSandnonAIDSassociatedmalignancieshasdeclinedwiththeeraofpotentART[45,46].

CardiovasculardiseaseMarkersofinflammation(eg,interleukin6)andcoagulation(eg,Ddimer)appeartostronglycorrelatewithHIVreplicationandanincreasedriskofcoronaryarterydisease[10].IntheSMARTstudy,theriskofcardiovasculareventswasgreaterinthoserandomlyassignedtotreatmentinterruptionratherthancontinuoustherapy[29].Observationaldataalsosuggestthatimmunosuppressionmaybeassociatedwithanincreasedriskofcardiovasculardisease[47].(See"EpidemiologyofcardiovasculardiseaseandriskfactorsinHIVinfectedpatients".)

Sincesomeantiretroviralagentsarealsoassociatedwithinsulinresistanceandcardiovascularevents,carefulselectionofinitialagentsisneeded.(See"EpidemiologyofcardiovasculardiseaseandriskfactorsinHIVinfectedpatients"and"Epidemiology,clinicalmanifestations,anddiagnosisofHIVassociatedlipodystrophy".)

HepatitisBinfectionVarioustreatmentguidelinessuggestusingantiviralagentswithdualactivityagainstbothHIVandhepatitisBvirus(HBV)intheHIVinfectedpatientwhorequiresHBVtherapy,regardlessofCD4cellcount[2,3].ThetreatmentofhepatitisBintheHIVinfectedpatientisdiscussedelsewhere.(See"Epidemiology,clinicalmanifestations,anddiagnosisofhepatitisBintheHIVinfectedpatient"and"TreatmentofchronichepatitisBintheHIVinfectedpatient".)

HepatitisCinfectionHepaticfibrosisprogressionratesmaybeslowerinduallyinfectedpatientstakingART.ThetreatmentofhepatitisCvirusintheHIVinfectedpatientisdiscussedindetailelsewhere.(See"TreatmentofhepatitisCvirusinfectionintheHIVinfectedpatient".)

AgingHIVinfectionisassociatedwithimmunosenescence.StudiesduringtheearlyAIDSepidemicdemonstratedthatpatientsovertheageof50haveamorerapidprogressiontoAIDSandpooreroverallsurvivalfollowingHIVseroconversioncomparedwithyoungerpatients[48].IntheeraofpotentART,studieshavealsosuggestedthatolderpatientsmayhavedelayedimmunerecovery.

Whentherapyisinitiated,patientsshouldbecarefullycounseledaboutpotentialsideeffects,sincepharmacokineticdatainthispatientpopulationarescant.(See"HIVandtheolderpatient".)

IMPACTOFARTONHIVTRANSMISSION

DiscordantcouplesAnotherrationaleforearlyantiretroviraltherapy(ART)initiationistopreventHIVtransmissionfromanHIVseropositivepersontoanHIVseronegativesexualpartner[49].

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Ametaanalysiswasperformedin5021heterosexualdiscordantcoupleswith461HIVtransmissioneventstodeterminetheroleofARTinpreventionoftransmission.TherewerenotransmissioneventstoaseronegativepartneramongthoseHIVseropositiveindividualswhohadachievedviralsuppressiononART[4].Asubsequentclinicaltrialamong1763HIVserodiscordantcouples(HIVPreventionTrialsNetworkHPTN052)demonstratedthatimmediateARTinitiationwasassociatedwitha96percentreductioninHIVtransmissioncomparedwithdelayedtherapy[5,6].Adetaileddiscussionontreatmentaspreventionisfoundelsewhere.(See"HIVtreatmentasprevention".)

PregnancyARTisrecommendedinpregnantwomenbyvariousguidelinepanels,regardlessofCD4cellcount,todecreaseratesofperinatalHIVtransmissionaswellastotreatthemother[50].Theevidenceforthisrecommendation,thetimingofARTrelativetostageofpregnancy,andthechoiceofagentsthataresafeinpregnancy,arefoundelsewhere.(See"PrenatalevaluationandintrapartummanagementoftheHIVinfectedpatientinresourcerichsettings"and"UseofantiretroviralmedicationsinpregnantHIVinfectedpatientsandtheirinfantsinresourcerichsettings".)

InjectiondrugusersModelssuggestthatacombinationofARTforHIVinfectedpersonswhoinjectdrugs,combinedwithopioidsubstitutionprogramsandneedleexchangeprograms,havethepotentialtoreduceHIVtransmissiontoHIVuninfectedinjectiondrugusersby50percent[51].

IMPACTOFARTONRISKOFMORTALITYFROMOPPORTUNISTICINFECTIONSAntiretroviraltherapy(ART)isalsoeffectiveinreducingmortalityamongpatientswithadvancedimmunosuppressionwhopresentwithacuteopportunisticinfections(OIs):

THECLINICALBENEFITOFARTVARIESBYBASELINECD4CELLCOUNT

GeneralbackgroundEpidemiologicdatahavedemonstratedthattheintroductionofpotentthreedrugcombinationregimensofantiretroviraltherapy(ART)in1996ledtoremarkabledeclinesinmorbidityandmortalityamongHIVinfectedpatients[5456].ThestrengthoftheevidenceforimprovedsurvivalincreasesastheCD4countdeclines.

TheimpactofthepatientsbaselineCD4cellcountontreatmentoutcomeswaswellillustratedinacollaborativestudy(HIVCAUSALCollaboration)of62,760treatmentnaivepatientsinEuropeandtheUnitedStates[57].Overameanfollowupof3.3years,2039patientsdied.Theoverallriskofmortalitywasreducedbyapproximately50percentamongthosewhoinitiatedARTcomparedwiththosewhodidnot.However,theabsolutesurvivalbenefitdependedonthepatientslevelofimmunocompromisebeforetreatment.InanalysesstratifiedbyCD4cellcount,thecorrespondinghazardratiosformortalityfortreatedversusuntreatedpatientswere:

RepresentativestudiesthatsupporttheinitiationofARTwithinvariousCD4cellcountstrataarediscussedbelow.

PatientswithCD4counts200cells/microLClinicaltrials,cohortanalysesandmetaanalyseshavedefinitivelyshownthatpotentARTimprovessurvivalandreducesAIDSrelatedcomplicationsinpatientswithadvanceddisease[50,5860]:

Inarandomizedtrialof282patientspresentingwithvariousOIs,"earlyART"(initiatedwithin14daysofpresentation)ledtoa50percentreductioninAIDSrelatedmortalitycomparedwith"lateART"(initiatedwhenOItreatmentwascompleted)withoutanyincreaseintreatmentrelatedadverseevents[52].AsurvivalbenefitofearlyARThasbeenshownbyothergroupsaswell[53].

0.29forpatientswith500cells/microL(95%CI0.581.01)

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PatientswithCD4counts200350cells/microLMultiplelargeobservationalstudiesandarandomizedcontrolledtrialsuggestthatpatientswithCD4cellcountsbetween200and350cells/microLalsobenefitfromART[24,6165]:

PatientswithCD4counts350to500cells/microLObservationaldataandonecontrolledtrialsuggestthatinitiationofARTinpatientswithCD4countsbetween350and500cells/microLdecreasesAIDSrelatedeventsandimprovessurvival[14,57,66,67].

TheclinicalbenefitofARTwasdemonstratedintheHIVPreventionNetworkTrial052,whichenrolled1763HIVserodiscordantcouplestoassesstheefficacyofARTinpreventingHIVtransmission[5].Thepreventionaspectsofthetrialarediscussedabove.(See'ImpactofARTonHIVtransmission'above.)

Inthistrial,HIVinfectedtreatmentnavepartnerswereeligibleforARTiftheirCD4countwasbetween350and550cells/microL.Serodiscordantcoupleswererandomlyassignedtothe"earlyART"arm(initiationofHIVtreatmentatenrollment)orthe"delayedART"arm(initiationofHIVtreatmentwhentheCD4countdroppedbelow250cells/microLorafteranAIDSrelatedillness).PatientsintheearlytherapyarmhadalowerriskofanHIVrelatedclinicaleventthanthoseinthedelayedtherapyarmoverthe1.7yearperiodoffollowup(HR0.5995%CI0.400.88).Thedifferenceintherateofclinicaleventswasmostcloselyassociatedwiththeincidenceofextrapulmonarytuberculosis,whichoccurredmainlyamongpatientsfromendemicareas(3versus17casesintheearlyanddelayedgroups,respectively).Nodifferencesinmortalityrateswereseenbetweenthearms.(See"HIVtreatmentasprevention".)

OneoftheobservationalstudiesthatsupportsinitiationofARTamongpatientswithinthe350to500CD4cellcountstratum(NAACCORD)isdiscussedbelow.

PatientswithCD4counts>500cells/microLTherearefewerobservationaldataontheuseofARTinpatientswithCD4cellcounts>500cells/microLcomparedwithpatientswithlowerCD4cellcountsandtherearenorandomizedcontrolledtrialsthathaveexaminedtheefficacyofthisapproach[67].

NAACCORDstudyTwoparallelanalysesinvolvingatotalof17,517asymptomaticHIVinfectedpatientswhohadnotreceivedpriorARTwereanalyzedbasedonoutcomedatafromcohortstudiesconductedfrom1996

Arandomizedtrial(ACTG320)in1156patientswithCD4cellcounts350/microLwererandomlyassignedtoaCD4cellcountguidedstrategyofresumingtherapyonlywhentheCD4countwas

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through2005intheUnitedStatesandCanada(ie,theNAACCORDstudy)[67].PatientswerestratifiedintotwogroupsaccordingtotheirCD4cellcountatbaseline(351to500cellsor>500cells/microL).Ineachgroup,comparisonsweremadeintherelativeriskofdeathforpatientswhoinitiatedtherapywhentheCD4cellcountwasaboveeachofthetwothresholds(earlytherapygroup)withthatofpatientswhostartedtherapyaftertheirCD4cellcountshadfallenbelowthesethresholds(deferredtherapygroup).

Afteradjustmentsforpotentialconfounders,thetwoanalysesdemonstratedthatdeferredtherapywasassociatedwithincreasedmortalityatbothCD4cellcountthresholds,comparedwithearlytreatment:

Limitationsofthisobservationalstudyincludethesmallnumberofdeathsobserved,thelackofdataconcerningcauseofdeathandthepossibilitythatpatientswhostartedARTathighCD4cellcountsmayalsohaveother"healthseekingbehaviors"thatcontributedtotheoutcomesobserved[68].Furthermore,asubstantialproportionofpatientswhodeferredARTandyetmaintainedstableCD4cellcountswerenotincludedintheanalysis.Itis,thus,unclearifthissubsetofpatientswouldhavealsobenefitedfromearlytreatment[68].Finally,thereisnoinformationondrugtoxicity,andtheexactcauseofdeathwasonlyknownfor16percentofthepatientpopulation.

TheSTARTtrialArandomizedcontrolledtrialisinprogresstoaddressthetimingofARTwithrespecttospecificCD4strata.Someexpertsareconcernedthatbythecompletionofthistrialin2015orlater,theresultswillnolongerberelevanttocontemporaryclinicalpractice[69].

TREATMENTRECOMMENDATIONSWeagreewiththe2014HIVtreatmentguidelinesfromtheUnitedStatesDepartmentofHealthandHumanServices(DHHS)andthe2014InternationalAntiviralSocietyUSAPanelthatrecommendantiretroviraltherapy(ART)beofferedtoallHIVinfectedpatients,includingasymptomaticpatients,regardlessofimmunestatus[2,3].ThestrengthoftheevidencesupportingthisrecommendationvariesbythepretreatmentCD4cellcount,asdiscussedbelow.

PatientswithaCD4count500cells/microLInpatientswithCD4countsgreaterthan500cells/microL,wesuggestinitiationofARTbasedonthefollowingrationale:

Among8362patients,2084(25percent)initiatedARTwithaCD4cellcountof351to500/microL,whiletherestdeferredtherapy.Therewasasignificantincreaseintheriskofdeathinthedeferredversusearlytherapygroup(relativerisk1.69,95%CI1.262.26).Thisanalysiswasbasedonatotalof375deathsinbothgroupscombined.

Among9155patients,2220(24percent)initiatedARTataCD4cellcountofmorethan500cells/microL,whiletherestdeferredtherapy.Therewasasignificantincreaseintheriskofdeathinthedeferredversusearlytherapygroup(relativerisk1.94,95%CI1.372.79).Thisanalysiswasbasedonatotalof311deathsinbothgroupscombined.

InitiationofARTinpatientswithahistoryofanAIDSdefiningillnessoraCD4count

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SomeobservationaldatasuggestasurvivalbenefitwithearlierinitiationoftreatmentatCD4cellcounts>500cells/microLcomparedwithdelayedtreatment[67].However,thepotentialbenefitofARTneedstobebalancedagainstthepossibletoxicitiesassociatedwithlongtermtreatment.Longtermclinicaloutcomesinsuchpatientsarenotavailable.

AnongoinginternationalclinicaltrialisexaminingtheoptimaltimeforasymptomaticHIVinfectedpatientswithCD4cellcounts>500cells/microLtobeginART,althoughtheresultswillnotbeavailableforseveralyears.Thus,patientpreferenceand/or"readiness"shouldplayanimportantroleinthedecisiontoinitiatetherapy,pendingresultsofthedefinitivetrial.Patientsshouldbeadvisedofallthepotentialbenefitsnotedabove,butthattheriskofanAIDSornonAIDSrelatedeventsecondarytountreatedHIVinfectionisgenerallylowamongpatientswithCD4cellcount>500cells/microLcarefulconsiderationissuggestedbeforeafinaldecisionismade[13,67].

OtherpatientsubgroupsWithoutHIVtreatment,asmallsubsetofpatients(2to3percent)areabletomaintainnormalCD4cellcountsformanyyears("longtermnonprogressors")whileanevensmallersubset(0.5to1percent)areabletomaintainviralsuppressionwithviralloads

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Eachpatientmustbeevaluatedfortheir"readiness"tostartdailyantiretroviraltherapy.Theprovidermustdevotetimetoeducatethepatientregardingthenegativeimpactofpooradherenceontheriskofdrugresistance.

AdelayofARTismuchmoreconsequentialamongpatientswithlowCD4cellcounts,AIDSdefiningconditions,acuteopportunisticinfections,abaselineviralload>100,000c/mLorarapidlydecreasingCD4count(>100cells/microLperyear).Treatmentdelaymayalsohavesignificantconsequencesinpatientswithothercomorbidities,suchasHIVassociatednephropathyorviralhepatitis.Whenconcernspersistabouttreatmentreadinessinapatientwithadvancedimmunosuppression(

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Treatmentrecommendations

AntiretroviraltherapydecreasestheriskofHIVtransmission

'Consequencesofdeferredtreatment'above.)

UntreatedHIVinfectionisalsoariskfactorfordevelopingcoronaryarterydisease,kidneydisease,liverdisease,neurocognitivedeficits,andnonHIVassociatedmalignancy.SomeoftheseobservationsmayberelatedtoHIVinducedproinflammatorycytokines,chronicinflammation,andTcellactivation,leadingtoendorgandamage.Inarandomizedcontrolledstudyofstructuredtreatmentinterruptions,higherratesofmortalityrelatedtocancer,myocardialinfarction,andliverrelateddeathsoccurredinpatientswhostoppedARTcomparedwiththosewhocontinuedART.(See'ImpactofARTonriskofothercomorbidities'above.)

AmajorpublichealthrelatedrationaleforearlyARTinitiationistopreventHIVtransmissionfromanHIVseropositivepersontoanHIVseronegativesexpartnerandfromanHIVinfectedpregnantwomantoanuninfectedinfant.ThesepreventivehealthbenefitsmayalsoapplytoHIVdiscordantinjectiondruguserswhosharedrugparaphernalia.(See'ImpactofARTonHIVtransmission'above.)

Sincetheintroductionofpotentthreedrugcombinationantiretroviralregimens,epidemiologicdatahavedemonstratedremarkabledeclinesinmorbidityandmortalityamongHIVinfectedpatients.ThestrengthoftheevidenceforimprovedclinicaloutcomesincreasesastheCD4countdeclines.(See'TheclinicalbenefitofARTvariesbybaselineCD4cellcount'above.)

GuidelinesfromtheUnitedStatesDepartmentofHealthandHumanServicesandtheInternationalAntiviralSocietyUSAPanelrecommendtreatmentofallpatientswithHIVinfectionregardlessofCD4Tcellcounts.

ForpatientswithaCD4count500/microL,whoaremotivatedtobetreated,wesuggestinitiationofantiretroviraltherapy(Grade2C).PatientsshouldbeadvisedthatthereislessevidenceforthepotentialbenefitsoftreatmentatearlierstagesofHIVinfection,andthedecisiontotreatneedstobebalancedagainstpotentialtoxicitiesoflongtermtherapy.Aclinicaltrial,whichisevaluatingthesafetyandefficacyofARTamongtreatmentnaivepatientswithCD4cellcounts>500cells/microL,isinprogress.(See'PatientswithCD4counts>500cells/microL'aboveand'PatientswithCD4counts>500cells/microL'above.)

CliniciansshouldexplaintodiscordantheterosexualcouplesthatviralsuppressiononARTdecreasestheriskofHIVsexualtransmissiontotheHIVseronegativepartnersubstantially,butdoesnotcompletelyeliminatetherisk,ortheneedfortraditionalpreventivemeasures(eg,condoms).ItisnotknownifviralsuppressiononARTwouldhaveasimilarbeneficialeffectontransmissionratesamongmenwhohavesexwithmen(MSM)andtheirHIVseronegativepartners.HIVtreatmentforpreventionoftransmissionisdiscussedindetailelsewhere.(See"HIVtreatmentasprevention"and'ImpactofARTonriskofothercomorbidities'above.)

ARTisrecommendedinpregnantwomenbyvariousguidelinecommittees,regardlessofCD4cellcount,to

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