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ACTHIV 2019: A State-of-the-Science Conference for Frontline Health Professionals

InitialTreatmentofHIV

ThankyoutoDelaneyTaylorforassistancewiththeseslides

RajeshT.Gandhi,M.D.MassachusettsGeneralHospital

HarvardMedicalSchool

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LearningObjectives

• IndividualizeinitialantiretroviraltherapyforapersonwithHIVinfection

• EvaluatenewoptionsfortreatingHIV

FacultyandPlanningCommitteeDisclosures

• PleaseconsultyourprogrambookortheconferenceApp

• Anyoff-labelorinvestigationaluseswillbeindicatedinthepresentation

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Outline

• WhentoStart

• WhattoStart– InmostpeoplewithHIV– Inpersonsinwhomintegraseinhibitorsarenotoptimal

– Inawomanofchild-bearingpotentialconsideringpregnancy

– Twodrugtherapy– FutureART

ARSQuestion:WhentoStart• 40yo MSMwithfeverandsorethroatfor1week.Recentnew

sexualpartner.• Noothermedicalconditions.Examnormal.• HIVAb/Agpositive;HIVdifferentiationAbnegative;HIVRNA10

million.• CD4cellcountpending;creatininepending;genotypepending;

HLA-B5701pending.• Hesayshe’swillingtostarttreatment• WhenwouldyoustartART?

1) Sameday2) Within2-3days3) Whenallhislabsreturn(7-10dayslater)4) Nextavailableclinicslot(4weekslater)

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LundgrenJ,etal.8th IASConference.Vancouver,2015.AbstractMOSY0301.TheINSIGHTSTARTStudyGroup.NEnglJMed.2015;July20.Lifson Aetal,CROI2016,#475;Borgesetal,CROI2016,#160

0

20

40

60

80

100

Num

ber o

f Eve

nts

AIDS-Related

Non-AIDS Related

Components(Serious Events)

CompositeEndpoint

96Deferred ART (n=2359)Immediate ART (n=2326)

4250

14

47

29

NumberofSeriousEvents

57%Reduction(P<0.001)

72%Reduction(P<0.001)

39%Reduction(P=0.04)

• HIV-infectedadultswithCD4>500

• RandomizedtoimmediateordeferredART

• TB,KS,lymphoma—mostcommonAIDS-relatedevents— alllessfrequentinimmediate-ARTgroup

• Cancerrates(combiningAIDS/non-AIDS)lowerinimmediate-ARTgroup

HIVTherapyRecommendedRegardlessofCD4:START

WhentoStartARTinPatientswithAcuteOI:ACTG5164

ZolopaAetal,PLoS One.2009

• 282HIVptswithacuteOI

• ~2/3PCP.TBexcluded

• Randomized to:- EarlyART:~2wks afterOItherapy

- DeferredART:~6wks afterOItherapy

• RateofAIDSprogression/deathlowerin“early”ARTgroup

0

20

40

60

80

100

14.2

24.1

p=0.035

Patie

ntsp

rogressing

toAIDSorDeath

atW

k48

(%)

Early Deferred

5

WhentoStartARTinPatientwithOI

OI WhentostartCryptosporidiosis,

microsporidiosis,PMLAspartofinitialtherapyofOI

PCP,MAC,Toxoplasma,mostotherOIs

Within2weeks

Tuberculosis IfCD4<50:within2wkIfCD4>50:within8-12wks

(TBmeningitis:closemonitoring/consultation)

Cryptococcalmeningitis 4-5wks afteranti-fungalRx

Zolopa Aetal,PLoS One.2009;GuidelinesforPreventionandTreatmentofOpportunisticInfectionsinHIV-InfectedAdultsandAdolescents,2013,WHOConsolidatedARVGuidelines,2013.ZanoniandGandhi,Inf Dis Clin NAm,2014

WhenpatientpresentswithOIorlowCD4count,ARTshouldbestartedinhospitalorsoonafterdischarge

ShouldARTbestartedondayofdiagnosis?

• Internationalstudies– SouthAfrica(RosenSetalPLoS Med2016)

– Haiti(KoenigSetal,PLoS Med2017)

– Lesotho (LabhardtNDetal. JAMA 2018)

• US– SanFrancisco(PilcherCDetal,JAIDS2016;

CoffeySetal,AIDS,2019)

– Atlanta (Colasanti Jetal,OFID,2018)

• Mytake:– Eachcaresettingshoulddevelop

sustainableprogramstodeliverARTasquicklyaspossible:same-dayorsoonthereafter

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ARSQuestion:WhattoStart• 40yo MSMwithfeverandsorethroatfor1week.Recentnew

sexualpartner.• HIVAb/Agpositive;HIVdifferentiationAbnegative;HIVRNA10

million.• CD4cellcountpending;creatininepending;genotypepending;

HLA-B5701pending.• Hesayshe’swillingtostarttreatment.Whatdoyoustart?

1)Dolutegravir+FTC/tenofovirAF2)Bictegravir/emtricitabine/tenofovirAF3)Dolutegravir/abacavir/lamivudine4)Dolutegravir+lamivudine5)Doravirine/lamivudine/tenofovirDF6)Darunavir/cobi/FTC/tenofovirAF7)Somethingelse

ChoosingAnInitialRegimen

EFV

RPVEVG/cobi

EVG/cobi

EFV

ATV/r

DRV/r

ATV/r

DTG

RALDTG

DTG

EFV

DRV/r

RAL

ATV/r

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ART2019:>30optionsNucleoside/nucleotideRTIs(NRTI)• Zidovudine,AZT(Retrovir)• Abacavir,ABC(Ziagen)• Lamivudine,3TC(Epivir)• Didanosine,ddI (Videx)• Stavudine,d4T(Zerit)• TenofovirDF,TDF(Viread)• Emtricitabine,FTC(Emtriva)• AZT/3TC(Combivir)• AZT/3TC/ABC(Trizivir)• ABC/3TC(Epzicom)• TDF/FTC(Truvada)• TAF/FTC(Descovy)• TDF/3TC(Cimduo) Non-nucleosideRTIs(NNRTIs)

•Delavirdine (DLV)•Nevirapine,NVP(Viramune)•Efavirenz,EFV(Sustiva)•Etravirine,ETR(Intelence)•Rilpivirine,RPV(Edurant)•Doravirine,DOR(Pifeltro)

Proteaseinhibitors(PI):•Indinavir,IDV(Crixivan)•Saquinavir,SQV(Invirase)•Nelfinavir,NFV(Viracept)•Amprenavir,APV(Agenerase)•Atazanavir,ATV (Reyataz)•Fosamprenavir,FPV (Lexiva)•Lopinavir/ritonavir (Kaletra)•Tipranavir (Aptivus)•Darunavir (Prezista)•Darunavir/cobicistat(Prexcobix)

•Atazanavir/cobicistat (Evotaz)

Red– combinationagents

Integrasestrandtransferinhibitors(INSTIs)•Raltegravir,RAL(Isentress)•Elvitegravir,EVG•Dolutegravir,DTG(Tivicay)•Bictegravir,BIC

Singlepillcombinations(n=10)

• EFV/FTC/TDF(Atripla)• EFV/3TC/TDF (Symfi)• EFV400/3TC/TDF(Symfi-lo)• RPV/FTC/TDF(Complera)• RPV/FTC/TAF(Odefsey)• EVG/cobi/FTC/TDF

(Stribild)• EVG/cobi/FTC/TAF

(Genvoya)• DTG/ABC/3TC(Triumeq)• BIC/FTC/TAF(Biktarvy)• DOR/TDF/3TC(Delstrigo)

CCR5receptorblocker•Maroviroc (Selzentry)Fusioninhibitors•Enfuvirtide,ENF,T20(Fuzeon)CD4Post-attachmentinhibitor•Ibalizumab(Trogarzo)

WhattoStartinMostPeoplewithHIV:IntegraseInhibitor+2NRTI

IAS-USA(7/2018)RecommendedInitialRegimens

• Bictegravir/TAF/FTC

• Dolutegravir/abacavir/3TC

• Dolutegravir+TAF/FTC

DHHS(10/2018)RecommendedforMostPeoplewithHIV

• Bictegravir/TAF/FTC

• Dolutegravir/abacavir/3TC

• Dolutegravir+TAF/FTCorTDF/FTC

• Raltegravir +TAF/FTCorTDF/FTC

References:DHHS.http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.RevisionOctober25,2018.

SaagMS,etal.JAMA.2018;320:379-396.

• Fewerlong-termsafetyandefficacydatawithBICthanwithDTG

• Ifsubstantialcostdifference,TDF(withFTCor3TC)iseffectiveandgenerallywell-tolerated,esp.ifpt notathighriskforbone,renaldisease

• DifferencesbetweenTAFandTDFaccentuatedwhenTDFisusedwithritonavir orcobicistat

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Regimen PROS CONS

ABC/3TC/DTG• Notnephrotoxic• Singlepillcombination

• Must confirmHLA-B5701negative• Some studies, butnotall,show

associationwithcardiacevents

TDF/FTC+DTG

• TDFlowerslipids• GoodoptionforHIV/HBV

• GreaternephrotoxicitythanABCandTAF(avoidifCrCl <60)

• LargerdeclineinbonemineraldensitythanwithABCorTAF(avoidinpeoplewithosteoporosis)

TAF/FTC+DTG

• TAFhasmorefavorableeffectsonrenalandbonemarkersthanTDF

• GoodoptionforHIV/HBV

• Twopillsperday• DonotuseTAFifCrCL <30

TAF/FTC/BIC • Singlepillcombination• GoodoptionforHIV/HBV

• Less long-termdata• DonotuseTAFifCrCl <30

Expertopinion

CustomizingART:DrugInteractions

Scenario CommentHCVTherapyAnticipated

Oftenuseraltegravir,dolutegravir,bictegravir:fewerdruginteractions

Acid-lowering therapy Avoidorcaution: rilpivirine, atazanavir

CYP3A4 metabolizedmedications,includingmany

inhaledandinjectedsteroids1

AvoidorcautionwithPIs, cobi(Amonginhaledsteroids,

beclomethasoneOKtousewithPIs,cobi2)

Usefulsite:http://www.hiv-druginteractions.org

1HyleEetal,JAIDS,2013;2BoydSetal,JAIDS,2013

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AreintegraseinhibitorsperfectforeveryonewithHIV?

Scenario CommentPolyvalent Cations Stagger dosingofintegraseinhibitors

Metformin DTGdoubles metforminexposure;don’texceed>1000mgdaily

http://www.hiv-druginteractions.org

IntegraseInhibitorDrugInteractions

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WeightGainandIntegraseInhibitors

• NA-ACCORD:observationalstudyof24,001participantsinitiatingART– INSTIs,PIsassociatedwithgreaterweightincreasethanNNRTI–DTGandRALassociatedwithgreaterweightgainthanEVG

Bourgi Ketal,CROI2019,#670

78

80

82

84

86

0.0 0.5 1.0 1.5 2.0

Pre

dic

ted

we

igh

tYears since ART initiation

+6.0

+3.8

NNRTI

PI

EVG

RAL

DTG

Year 2

+4.9

ART class/INSTI drug NNRTI-based PI-based RAL DTG EVG

ART group INSTI-based NNRTI-based PI-based

Year 5

Year 2

0 1 2 3 4 5

+6.0

+5.1

+4.3

+4.9

+4.4

+3.3NNR

TI

PI

INSTI

78

80

82

84

86

Pre

dic

ted

we

igh

t

Years since ART initiation

WeightGainandIntegraseInhibitors

• SwitchstudiesshowingassociationbetweenINSTIsandweightgain:–ACTG(n=972):increasedweightafterswitchingtoINSTI;DTGassociatedwithgreatestgain

–HOPS:BMItrajectoryslopes:DTG>RALorEVG–WIHS:observationalswitchstudyinwomen

• Studiesshowingmixedresultornoassociation:– TRIOstudy:associatedinbivariateanalysis,notmultivariablemodel

–HPTN077:CabotegravirinpeoplewithoutHIV

LakeJetal,CROI2019,#669;Kerchberger Aetal,CROI2019,#672;PallelaFJetal,CROI2019,#674;McComsey Getal,CROI2019,#671;LandovitzRetal,CROI2019,#34

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MyTake:AreINSTI-BasedRegimensassociatedwithweightgain?

• AccumulatingdatathatINSTI-basedregimensmaybeassociatedwithgreaterweightgainthansomeotherregimens;randomizeddatafrominitialtherapytrialsneeded

• WhethertherearedifferencesbetweenINSTIsandtheroleoftheNRTIintheregimenareuncertain

• Mechanismofweightgainanddistributionoffatafterinitiationofmodernregimens,includingINSTI-basedtherapies,shouldbeevaluated

• Inpatientswithsignificantweightgain,theimpactofchangingtoanon-INSTIbasedregimenneedstobestudied

OtherTreatmentOptionsWhenYouDon’tThinkanIntegraseInhibitorisOptimal

• GenericEFV/TDF/3TC

• Rilpivirine/FTC/TDForRilpivirine/FTC/TAF– Foodrequirement(about400caloriemeal)–Donotusewithproton-pumpinhibitor;staggerdosingifonH2blocker

• Doravirine/3TC/TDForDoravirine +FTC/TAF

• Darunavir/cobi/FTC/TAF–DruginteractionswithCYP3A4metabolizedmedications

Expertopinion

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NON-NUCS?

Doravirine:ANewNNRTI

• ActiveinvitroagainstHIVresistanttofirst-generationNNRTI(K103N,Y181C,G190A,E101K,E138K)1

• Oncedaily.Lowpotentialfordruginteractions

• Inphase3randomizedtrials(DRIVE-FORWARD2,DRIVE-AHEAD3,4),non-inferiortodarunavir/ritonavirandefavirenzinvirologicsuppression– DOR:betterlipideffectsthanDRV/r;fewerneuropsychiatric

effectsthanEFV

• Inswitchstudy(DRIVE-SHIFT)5,changingtoDOR/3TC/TDFnon-inferiortocontinuingbaselineART

• DORavailablealoneandcoformulated withTDF/3TC1LaiAAC2014;58:1652-1663. 2MolinaJM,22nd IAC,AbstractLBPEB017.3Orkin.IDWeek2018.AbstrLB1.

4Orkin.ClinInfectDis.2018;[Epub].5KumarP.IDWeek 2018.Abstr LB2.

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Doravirine (DOR)Resistance

• 7/747(0.9%)inphase3DORtrialsdevelopedresistance

–V106IandF227C

–F227C:hypersusceptibletosomeNRTI,includingtheinvestigationalagent,MK-8591(NRTTI)(inphase2withDORand3TC)

• MostisolateswithDORmutationsremainsusceptibletoETR

• MostEFV-resistantvirusesremainsusceptibletoDOR

LaiMTetal,22nd IAC,abstractTHPDB01

Darunavir/cobi/FTC/TAF

• Highvirologicsuppressionrate

• Highbarriertoresistance:noparticipantinphase3AMBERstudydevelopedtenofovirorDRVresistance

• PromisingresultsinsinglearmDIAMONDstudyofrapidinitiation(n=109):~90%virologicsuppressionrate

Huhn GDetal,CROI2019,abstract500;Huhn GDetal,22nd InternationalAIDSConference,WEPEC200

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ARSQuestion32yo FwithHIV.Sheandherboyfriend(whoisnotinfectedwithHIV)arehopingtohavechildrensoon.Whichregimendoyoustart?

1. Dolutegravir+FTC/tenofovirDF

2. Bictegravir/FTC/tenofovirAF

3. Elvitegravir/cobi/FTC/tenofovirAF

4. Raltegravir +FTC/tenofovirDF

5. Raltegravir +FTC/tenofovirAF

6. Atazanavir/r+3TC/tenofovirDF

7. Somethingelse

PregnancyandART

• Approximately5000womenwithHIVgivebirtheachyearintheUS

• Comprehensivecare,includingARTduringpregnancy,improvesmaternaloutcomesandpreventsHIVtransmissiontotheinfant

• RegardlessofCD4cellcount,ARTshouldbestartedasearlyaspossibleduringpregnancyor,evenbetter,beforeconception

DHHS. http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf. Revision December 7, 2018.

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BirthOutcomesWhenEFVorDTGStartedDuringPregnancy

0%

2.3%

6.1%

17.4%

3.8%

18.0%

10.7%

33.2%

1.3%

2.3%

6.7%

18.5%

3.5%

18.5%

11.3%

35.0%

0% 5% 10% 15% 20% 25% 30% 35% 40%

Neonatal death

Stillbirth

Very SGA 3%ile wt for GA

SGA 10%ile wt for GA

Very preterm <32 wk GA

Preterm <37 wk GA

Any severe adverse outcome

Any adverse outcome

EFV/TDF/FTC (N=4,593)DTG/TDF/FTC (N=1,729)

Zash Retal.LancetGlobalHealth2018;6:e804-10

Tsepamo:BirthOutcomesSurveillanceStudyinBotswana

• Dolutegraviratconceptionandneuraltubedefects(NTD)– May1,2018:4infantswithNTDbornamong426women

– July15,2018:1additionalinfantwithNTDexposedtoDTGduringpregnancy[8wksgestationalage]

• Updatedprevalence:4/596(0.67%,95%CI0.26%,1.7%)

• Nextformalanalysis:after3/19 ZashR,etal.NEnglJMed.2018;379:979-981.

Zash R,etal.JInt AIDSSoc.2018;21(suppl6).AbstractTUSY15.

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WhattoStartinPregnancy:DHHSGuidelinesDec7,2018

Integrase inhibitor:Raltegravir (twicedaily)orDolutegravir(after 1st trimester)or

Proteaseinhibitor:Darunavir/ritonavir(twicedaily)orAtazanavir/ritonavir

TwoNRTIsAbacavir/3TCorTDF/FTCorTDF/3TC

Plus

DONOTUSE:TAF(insufficientdata)Bictegravir (insufficientdata)Elvitegravir/cobi (PKconcerns)DRV/cobi (PKconcerns)ATV/cobi (PKconcerns)DOR(insufficientdata)

Whatistheroleoftwo-drugtherapyforHIV?

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Case

•50yo HIV+Mwithdiabetes,hypertension,chronicrenalinsufficiency(creatinineclearanceof25)

•HIVRNA30,000,CD4cellcount450

•HLA-B5701positive

•YouwanttochoosearegimenthatavoidsTAF,TDF,ABC

1.Darunavir/cobicistat +FTC2.Darunavir/ritonavir+raltegravir

3.Darunavir/ritonavir+dolutegravir

4.Darunavir/ritonavir+3TC5.Dolutegravir +3TC

6.Dolutegravir+rilpivirine7.Atazanavir+elvitegravir/cobicistat

ARSQuestion

NRTI-limiting Regimens for Initial Therapy

•DRV/r+RAL(NEAT001)1,2

–Non-inferiortoDRV/r+TDF/FTC–CD4<200:DRV/r+RALinferiortoDRV/r+2NRTI–VL>100K:morefailureswithDRV/r+RAL

•DRV/r+3TC3 (ANDES)–Non-inferiortoDRV/r+FTC/TDF(n=145)

1RaffiFetal,Lancet,2014;2Lambert-NiclotSetal,JAntimicrob Chemother,2016;3Figueroaetal,CROI2018,Abstract489

NRTI-limitingRegimensforInitialTherapy

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GEMINI-1and-2Studies:Dolutegravir+LamivudineinTreatment-NaïvePatients

CahnP,etal.Lancet.2019;393:143-155.

Identicalphase3studiesTreatment-naïveDouble-blind(week0-48)Open-label(week48-144)Non-inferiorityHIVRNA>1K-500Kcopies/mLNomajorIAS-USAresistancemutationsNoHBVorneedforHCVtherapy

Randomization1:1

Dolutegravir+Emtricitabine/TenofovirDF(n=717)

Dolutegravir +Lamivudine(N=716)

Week 0 48 144

PrimaryEndpointHIVRNA<50Copies/mL

(10%non-inferioritymargin)WhowasinGEMINI?Male:85%.Age:32-33years.Black:12%.HIVRNAlevel:Mean:4.4log10 copies/mL>100K copies/mL):20%.

CD4count:Mean:462cells/µL.≤200cells/µL:8%.

DropinVLcomparablebetween2DRand3DR

Eron Jetal,HIVDARTandEmergingViruses,2018,Miami,FL

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GEMINI-1and-2Studies:PooledVirologicOutcomesWithDolutegravir+LamivudineinTreatment-NaïvePatients

Patie

nts

(%)

HIV RNA <50 Copies/mL at Week 48

0

20

40

60

80

100

Overall (ITT)(n=716/717)

91% 93%

≤100K(n=576/564)

Dolutegravir + lamivudine Dolutegravir + FTC/TDFDifference (%):

-1.7 (-4.4, 1.1)

>100K(n=140/153)

Baseline HIV RNA (copies/mL)

>200(n=653/662)

≤200(n=63/52)

Baseline CD4 Count (cells/mm3)

91% 94% 92% 90%79%

93%93% 93%

No treatment-emergent INSTI or NRTI mutations in either arm

CahnP,etal.Lancet.2019;393:143-155.

Mytake:Are2-DrugRegimensOptimalforMostPersonsWithHIV?

• Forinitialtherapy,DTG+3TClookspromising

– Single-tabletformulationofDTG/3TCapprovedbyFDAonApril8,2019forinitialtreatmentofadultswithnoknownorsuspectedresistancetoitscomponents

• Onepilloncedailywithorwithoutfood

• ShouldnotbeusedinpeoplewithHIV/HBV(testforHBV)

– LongertermdataawaitedbeforeguidelinesrecommendDTG/3TCformostpersonswithHIV

– InapatientforwhomABC,TAFandTDFarenotoptimal,DTG/3TCisarecommendedregimen

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FutureART?

• InjectableCabotegravir(CAB),anINSTI,andrilpivirine (RPV),anNNRTI– bothareinvestigational

• Long-actingformulations;half-livesofmonths• Phase3studies

• FLAIR:TreatmentnaïvepeoplewithHIV;suppresswithoralART;thenswitchtomonthlyIMLACAB/RPVorcontinueoralART

• ATLAS:SuppressedpeoplewithHIV;switchtomonthlyIMLACAB/RPVorcontinueoralART

• ATLAS-2M(ongoing):SuppressedpeoplewithHIV;every4weekvs.every8weekIMLACAB/RPV

FLAIR:MonthlyInjectableCAB/RPVNon-inferiortoOralART

OrkinC,etal.CROI2019;#140.Swindells S,etal.CROI2019;#139

SimilarresultsinATLAS:inpeoplewhoarevirologically suppressed,CAB/RPVcomparabletocontinuingoralART

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Summary• WhentoStart?InitiateARTinpeoplewithHIVassoonaspossible

• IntegraseinhibitorbasedregimensarepreferredformostpeoplewithHIV

• OptionswhenintegraseinhibitorsarenotoptimalincludeNNRTI- andPI-basedregimens

• Inwomenconsideringpregnancy,payspecialattentiontosafetyofdifferentregimens

• Accumulatingdatasupporting2-drugtherapy;longer-termfollow-upneeded

• Injectablelong-actingregimensadvancing

ACTHIV 2019: A State-of-the-Science Conference for Frontline Health Professionals