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NewDirectionsinthe2015ConsolidatedARVGuidelinesUpdate
MegDoherty,MD,PhD,MPH19July2015WHOSatellite
Vancouver – IAS2015
WHOSatellite Treatment,July1920152 |
ObjectivesofPresentation
• 2015ARVGuidelinesupdate- whynow?
• OverviewofEvidenceBase
• Newdirectionsinguidance
90/90/90Vancouver- Saturday18July20153 |
Whydoweneed2015ARVguidelines?
NewScience• Earlytreatment trialsstartingtoreport (TEMPRANO, START)• DataonsafetyofkeyARVs inspecificpopulations
NewCommodities• NewARVsatnewdoses&formulations (INI,lowdoseEFV,DVR/rFDC)• Treatment optimisation forchildrenandadolescents (pellets,newstrategies)
NewTechnologies• BalanceofPOCversus standardCD4,VLandEIDplatforms
RethinkServiceDeliveryModels• Preparation forgreater numbersonARV;improve linkage,referral, adherence
approaches; Enhanceefficiencyandmaintainquality
WHOSatellite Treatment,July1920154 |
2015ARV:Timeline
LaunchFullUpdated2015
ConsolidatedARVGuidelinesDec12015
SupplementlaunchWADDec12014
Evidence retrieval:Systematic reviewsValuesandpreferencesCommunityconsultationsModellingDec2014– May2015 Coregroup
July23-242015
CoregroupOct20-212014
GDGClinical/
OperationalJune1-52015June16-192015
Keyrecommendationspreview
July192015
Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan
LaunchInterimGuidelinesonwhentostartandpre-
exposureprophylaxisSept-Oct2015
Clinical
Programmatic Prioritization
HOWTODOITWELL?• CarePackages
(Differentiated/AdaptiveCare)
• Linkages,Retention,Adherence
• Quality ofcare• Diagnostics• Supplychain
HOWTODECIDE?• Approaches toprioritization &
sequencing• Toolkitsforcountry
adaptation andimplementation
WHATTODO?• Whentostart• Whattousefor
children,adolescents,pregnantwomen
• Howtomonitor• Co-infections• HIVandMH&
NCDs• PrEP
Operational & Service Delivery
WHOConsolidatedARVGuidelines
VALUES&
PREFERENCES
FEASIBILITY&
COST
COMMUNITY&HCW
CONSULTATIONS
GREYLITERATURE
MODELLING(HIVMC,IeDEA)
SURVEYOFARV&LABUSE
(AMDS,GARPr)
DRUGCOSTING(GPRM,AMDS)
2015ARVGuidelines Process
QUALITATIVEDATA
REVIEWS
PROGRAMMEMANAGERSSURVEY(KIT)
SYSTEMATICREVIEWS
2013RECOMMENDATIONS
QUALITYOF
EVIDENCE
QUALITY(GNP+FORUM)
90/90/90Vancouver- Saturday18July20157 |
OverviewofwhentostartARTstudies
Several ACTG and CPCRA studies (early Post HAART Era): ART initiation CD4 < 200cells/mm3 - Impact on AIDS mortality and major OIs incidence
CIPRA and SMART studies (ART initiation at CD4 ≤ 350 cells/mm3) Impact on HIV mortality, dz progression, & co-morbidities (TB)
Observational studies (ART initiation at CD4 > 350 cells/mm3 ) impact on mortality, dz progression & non-AIDS events
HPTN 052: reduction of HIV transmission among HIV serodiscordant couples and risk of TB in adults (impact on HIV incidence)
TEMPRANO and START studies: (ART initiation at CD4 > 500 cells/mm3) impact on severe HIV morbidity &disease progression, without increase in severe adverse events
1995-2005 2005-2010 20152010-2013
90/90/90Vancouver- Saturday18July20158 |
ARTeligibility:5policyscenarios
CD4≤200 CD4≤ 350 CD4≤ 350+TasP
CD4≤500 AllHIV+
1 2 3 4 5
Estimated millions of people eligible for ART (2014)
30m. 36.9m.
Recommendedsince 2003
Recommendedsince 2010
Incremental approach 2012
Treat ALL+ indications for ART at any CD4
2013 guidelines
2015 guidelines
DIRE
CTIONSINW
HENTOSTA
RT
Targetpopulation WHATISEXPECTED IN2015 ARTGUIDELINES?
AdultsARTinitiation atanyCD4
Asapriority, ARTinitiationifWHO clinicalstageIII/IVorCD4≤350
Pregnant/BFwomen
ARVinitiationat any CD4andcontinued lifelong(OptionB+)
Adolescents(10-19yearold)
ARTinitiationatanyCD4
Asapriority,ARTinitiationifWHO clinicalstageIII/IVorCD4≤350
Children
ARTinitiationatanyCD4 if1-10 years-old
ARTinitiationatanyCD4if<1year-old
Asapriority, ARTinitiationif<2years-oldorWHOclinicalstageIII/IVorCD4<25%(<5years)or≤350(>5years)
EvidenceSummary:WhentoStartinAdults
• SystematicReviewof18eligiblestudies(1RCTand17observationalcohorts)
• Someobservationalstudiesreportedresultsfromasinglecohort (6studies)
• Outcomesreported:
ü Mortality
ü SevereHIVdisease
ü HIVdiseaseprogression
ü AIDSevents
ü Non-AIDSevents
ü Malignancy (AIDSandnonAIDS)
ü Tuberculosis
ü HIVtransmission
ü SAEandlababnormalities
ü SevereHIVdiseaseormalignancy or
mortality (combinedoutcome)
WHE
NTOSTA
RT-EV
IDEN
CE
EvidenceSummary:Riskofdeath,severeHIVdiseaseorHIVdiseaseprogression
WHE
NTOSTA
RT-EV
IDEN
CE
ClinicaltrialsEvidenceforlowerriskofdeath,severeHIVdiseaseormalignancycomparedtothosedeferringtreatment (1studyTEMPRANO)
ObservationalstudiesEvidenceforlowerriskofdeathorprogressiontoAIDScomparedtothose deferringtreatment (2studies)
CIconfidenceinterval;df,degreesoffreedom;IV,inversevariance;RCT,randomised controlledtrial
EvidenceSummary:RiskofHIVtransmission
WHE
NTOSTA
RT-EV
IDEN
CE ClinicalTrial(1RCT)EvidenceforlowerriskofHIVtransmission comparedtothosedeferringtreatment
ObservationalstudiesEvidence fornosignificantdifference intheriskofHIVtransmission between earlyvsdeferredtreatment (2studies)
CIconfidenceinterval;IV,inversevariance;RCT,randomised controlledtrial
EvidenceSummary:RiskofHepatic&RenalSAEoranygradeIII/IVSAE
WHE
NTOSTA
RTEVIDE
NCE
ClinicaltrialnoincreasedriskofhepaticandrenalSAEbetweenearlyvsdeferredtreatment (1study)
Observationalstudiesincreased riskofhepaticSAEcomparedtothose deferringtreatment butnoincreasedriskforrenalSAE(1study)
CIconfidenceinterval;IV,inversevariance;RCT,randomised controlledtrial
HepaticSAE
RenalSAE
CombinedNoincreased riskofanygrade3/4SAEbetween earlyanddeferring treatment(2studies)
Grade3/4SAEs
WhentoStartinAdults:EvidenceSummary
• SystematicreviewonwhentostartARTinasymptomaticPLHIVfound1RCTand17cohortsormeta-analysesofcohortsreportingon8separateoutcomesinpatientswith<500CD4and≥500CD4cells/µL
• ClinicalbenefitsofARTinitiationover500CD4toallPLHIVcomparedwith<500CD4initiation,– withreductionofsevereHIVmorbidity,HIVdiseaseprogressionandHIVtransmission,
– withoutincreaseingradeIII/IVadverseevents.WHE
NTOSTA
RT-EV
IDEN
CE
EvidenceforChildren&Adolescents• Lackofdirectevidenceinsupportofearlier
initiation (particularly forhorizontallyinfectedadolescents)1
• Indirectevidence suggestsreduction inmortalityandimprovementingrowth(particularly inchildren5-10yearswithCD4>500)2
• Agrowingbodyofevidence demonstratesthepositiveimpactofARTongrowth3,neurodevelopment4, immunologicalrecovery5 andinpreventingpubertaldelays6
• Gainsappear tobelimited forverticallyinfectedadolescents2,5
References:1.Sigfried etal20142.IeDea network2015
3.McGrathetal20114.Laughtonetal2012
5.Picat etal20136.Szubert etal2015
WHE
NTOSTA
RT-EV
IDEN
CE
ProgrammaticRationaleChildrenandAdolescents
• Eliminatestheneed fordetermining CD4counttoinitiateART
• AvoidsdelayingARTinsettingswithoutaccesstoCD4testing.
• Simplifies paediatric treatmentandfacilitateexpansion ofpaediatric ART(task-shifting anddecentralization)
• Improves retention incarecompared topre-ART
Source:UgandaNationalprogramme- RapidassessmentMay2015
Only~20%arenoteligiblebasedonexistingcriteria
Needadherencesupport(particularlyinadolescents),carefulplanning,strengtheninglaboratoryservicesandimprovementofprocurementsandsupplyofkeycommodities
WHE
NTOSTA
RT-EV
IDEN
CE
ACCE
PTAB
ILITY
Community– ledGlobalConsultation:
• 24workshops,8countries,8subpopulations,206people livingwithHIV,74service providers.
• Earlier initiationwasdeemed acceptable, specific considerationswerehighlighted
• Collaborative decision-making withtheultimatedecision toinitiateARTbeingclient-driven
• Therequirement forcomprehensive andaccurate information toensureaninformed decisionaswellasreadiness
• InitiatingART isrelativelyeasyhowevermaintaining adherence ischallenging
• Stigmaanddiscrimination wereuniformlyraisedasfundamentalconcernsbyallandseentoconstrain treatment accessandadherence
AFROCAB
AcceptabilityofEarlierInitiationofART
90/90/90Vancouver- Saturday18July201518 |
2012GuidanceforMSM&SerodiscordantCouplesinthecontextofdemonstrationprojectstoencouragecountriestoconductsuchdemonstrationprojects
2014ConsolidatedKeyPopulationsGuidelines- RecommendationforMSMAmongmenwhohavesexwithmen,PrEPisrecommended as anadditional HIVpreventionchoicewithinacomprehensiveHIVpreventionpackage
2015OralPrEP(containingTDF)shouldbeofferedasanadditionalpreventionchoiceforpeopleatsubstantialrisk ofHIVinfectionaspartofcombinationpreventionapproaches• Notpopulationspecific• SignificantHIVriskmeansHIVincidence>3per100py
WHOguidanceonPrEP:2012─2015
Effectiveness (%)
Study
-130
-60 -40 -20 0 20 40 60 80 100
Effect size (CI)
MTN003/VOICE – daily Tenofovir gel(Women – South Africa, Uganda, Zimbabwe) 15% (-21; 40)
CAPRISA 004 – coital Tenofovir gel(Women – South Africa) 39% (6; 60)
FEMPrEP – daily Truvada(Women – Kenya, South Africa, Tanzania) 6% (-52; 41)
MTN003/VOICE – daily Truvada(Women – South Africa, Uganda, Zimbabwe) -4% (-49; 27)
MTN003/VOICE – daily Viread(Women - South Africa, Uganda, Zimbabwe) -49% (-129; 3)
iPrEx – daily Truvada(MSM - America’s, Thailand, South Africa) 44% (15; 63)
TDF2 – daily Truvada(Heterosexuals men and women- Botswana) 62% (22; 84)
Partners PrEP – daily Truvada(Discordant couples – Kenya, Uganda) 75% (55; 87)
Partners PrEP – daily oral Tenofovir(Discordant couples – Kenya, Uganda) 67% (44; 81)
Ora
l PrE
PTo
pica
l PrE
P
IPERGAY – on demand Truvada(MSM – France & Canada) 86% (39; 99)
PROUD – daily oral Truvada(MSM – United Kingdom) 86% (62; 96)
Overall evidence for PrEP: July 2015
FACTS 001– coital Tenofovir gel(Women – South Africa) 0% (-40, 30)
90/90/90Vancouver- Saturday18July201520 |
WhattouseinfirstlineARVTherapy
20
Edward Mills, Steve Kanters, M. Eugenia Socias, For WHO ARV GDG, June 1-5 2015
• systematic reviewusinga comparativepairwiseandnetworkmeta-analysisevaluated 76trialsfordirectandindirectevidence• 35,270patients randomized to171
treatment arms
• Directevidenceforcomparative efficacyandsafetyofINSTIscompared toEFVwasobtained from6RCTs• SINGLE,PROTOCOL004,GS102
study,GS104study,SPRING-1andSTARTMRK.
• Theevidence onlowdoseEFV(EFV400)camefromENCORE1.
90/90/90Vancouver- Saturday18July201521 |
• AlltreatmentregimensarecomparablewithrespecttomortalityorAIDSdefiningillnesses.
• EvidencethatDTGandEFV400superiorwithrespectCD4recoveryat24,48and96weeks
• INSTIs(DTG>RAL)aremoreeffectivethanEFVandotherregimensforviralsuppressionat24,48and96weeks.
• Alltreatmentstendtobecomparableintermsofemergentseriousadverseevents,withexceptionofNVP(elevatedrisk)
• Limitation:MinimaldataonDTG+TDF+XTC(SPRING-2)
21
DirectionsoftheSystematicReviewEdward Mills, Steve Kanters, M. Eugenia Socias, For WHO ARV GDG, June 1-5 2015
90/90/90Vancouver- Saturday18July201522 |
Whatwillbenewinthe2015ARVguidelines?• Treatall(atanyCD4)- peoplelivingwithHIVacrossallages
• Thesickestremainapriority(symptomaticdiseaseandCD4<350)
• NewagebandforAdolescents(age10-19)
• OptionBnottakenforward;OptionB+asthenewstandard
• PlacementofINSTIs(DTG)anddosereductionoptionsin1st and2nd linetherapy
• PrEP recommendedasanadditionalpreventionchoiceforallpeopleatsubstantialriskofHIVinfection(>3%incidence)
90/90/90Vancouver- Saturday18July201523 |
CountriesareleadingthewayExamplesfromfivecountriesimplementingTreatAllorTreatingAllinspecificpopulations:
• Brazil has been treating all for one year • Leading to increase in median CD4 at
ART initiation (265 to 419)• Similar retention and VLS at 12 months
(81% for CD4 > 500)
• Uganda started to treat all children < 15 years in 2014
• Seen increase in overall number children on ART
• Retention at 12 m similar; VLS = 84%
Acknowledgements
CoreGroupCo-ChairsWafaa El-Sadr (ICAPandColumbiaUniversity;USA)YoganPillay(SAMoH)
GuidelineDevelopmentGroupCo-ChairsElaineAbrams(ICAP,andColumbiaUniversity,USA)SergeEholie(ANEPA/TreichvilleHospital,Abidjan,Côted’Ivoire)AnthonyHarries(theUnion;UK)FabioMesquita (BrazilMOH)
Special thanks to all the external experts who contributed as members of the Guideline DevelopmentGroups, and to those who contributed to the GRADE systematic reviews and supporting evidence whichinformed the guidelines process.
WHODepartmentGottfriedHirnschallAndrewBallRachelBaggaleyRachelBeanlandMarcoVitoriaMartinaPenazzatoShaffiq EssajeeNathanFordEyerusalemKebedeNegussieAliceArmstrongFrancoiseRenaudBobGrant(consultant)MichelleRodolphAnnabelBaddeley,AlbertoMattelli,HaileGetahun
OtherContributorsTemprano,STARTresearchteamsTheUniversityofCalifornia, SanFranciscoUniversityofBaselGlobalEvaluationService(GES)TheHIVModellingConsortiumAFROCAB,APN+,AHFUkraine,ICW,Vialibre,PangaeaTheGlobalNetworkofPeoplelivingwithHIV/AIDSAvenir HealthCDCPEPFARBillandMelindaGatesFoundation
WHOARVGuidelinesEvolution2002to2015
Topic 2002 2003 2006 2010 2013 2015Whentostart
CD4≤200 CD4≤200 CD4≤200- Consider350- CD4≤350forTB
CD4≤350-RegardlessCD4forTBandHBV
CD4≤500- RegardlessCD4forTB,HBVPWandSDC- CD4≤350aspriority
Towards Treat AllAdolescents age band
1st LineART 8options- AZTpreferred
4options- AZTpreferred
8options- AZTorTDFpreferred- d4Tdosereduction
6options&FDCs- AZTorTDFpreferred- d4Tphaseout
1preferredoption&FDCs- TDFandEFV
preferredacrossallpops
Continue with FDC and harmonization across age bands
2nd LineART Boostedandnon-boostedPIs
BoostedPIs-IDV/rLPV/r,SQV/r
BoostedPI- ATV/r,DRV/r,FPV/rLPV/r,SQV/r
BoostedPI- HeatstableFDC:ATV/r,LPV/r
BoostedPIs- HeatstableFDC:ATV/r,LPV/r
Greater number of options
3rd LineART None None None DRV/r,RAL,ETV DRV/r,RAL,ETV Encourage HIV DR to guide
ViralLoadTesting
No No(Desirable)
Yes(Tertiarycenters)
Yes(Phaseinapproach)
Yes(preferredformonitoring,useofPoC,DBS)
Support for scale up of VL using all technologies
Earlier initiation
Simplertreatment
Lesstoxic,morerobustregimens
Betterandsimplermonitoringz