New Directions in the 2015 Consolidated ARV Guidelines Update · New Directions in the 2015...

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)


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


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


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)


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.


• 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


Whatwillbenewinthe2015ARVguidelines?• Treatall(atanyCD4)- peoplelivingwithHIVacrossallages

• Thesickestremainapriority(symptomaticdiseaseandCD4<350)

• NewagebandforAdolescents(age10-19)

• OptionBnottakenforward;OptionB+asthenewstandard

• PlacementofINSTIs(DTG)anddosereductionoptionsin1st and2nd linetherapy

• PrEP recommendedasanadditionalpreventionchoiceforallpeopleatsubstantialriskofHIVinfection(>3%incidence)


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

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