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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
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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
