1

“Stateoftheart”ofART

MedicalManagementofAIDSDecember8,2016

MonicaGandhiMD,MPHProfessorofMedicine,DivisionofHIV,InfectiousDiseasesandGlobalMedicine,UCSF

Medicaldirector,“Ward86”,SanFranciscoGeneralHospital

Outline

StateofARTcoveragegloballyThevirallifecycleAscentoftheintegraseinhibitor(descentofATVandEFV)SinglepillcombinationsTAFvsTDF2-drugtherapy(monotherapynotsomuch)Newdrugs

Adults and children estimated to be living with HIV | 2015

Total: 36.7 million [34.0 million – 39.8 million]

People with HIV on antiretroviral therapy| 2010-2015

Total: 17 million (46%)

2

HIV viral lifecycle

1) Virus Entry

5) Translation

6) Cleavage

4) Transcription

7) Packaging

8) Maturation

9) Re-infection

Entry(CD4, CCR5)

2) Reverse transcriptase

RNA

DNA3) Integration

RT

Protease

Integrase

Attachment

Single Tablet Regimens• EFV/FTC/TDF (Atripla) • RPV/FTC/TDF (Complera)• RPV/FTC/TAF (Odefsey)• EVG/cobi/FTC/TDF (Stribild)• EVG/cobi/FTC/TAF (Genvoya)• DTG/ABC/3TC (Triumeq)

u Nucleos(t)ide RTIs• Zidovudine, AZT (Retrovir)• Abacavir, ABC (Ziagen)• Lamivudine, 3TC (Epivir)• Didanosine, ddI (Videx)• Stavudine, d4T (Zerit)• Tenofovir, TDF (Viread)• Emtricitabine, FTC

(Emtriva)• Tenofovir Alafenamide• AZT/3TC (Combivir)• AZT/3TC/ABC (Trizivir)• ABC/3TC (Epzicom)• TDF/FTC (Truvada)• TAF/FTC (Descovy)

u CCR5 receptor blockers• Maroviroc (Selzentry)

u Integrase inhibitors• Raltegravir (Isentress)• Elvitegravir (EVG)• Dolutegravir (DTG) (Tivicay)

u NNRTIs:• Delavirdine (DLV)• Nevirapine,NVP

(Viramune)• Efavirenz,EFV

(Sustiva)• Etravirine

(Intelence)• Rilpivirine(Edurant)

u Fusion inhibitors:• Enfuvirtide,

ENForT20(Fuzeon)

u Protease inhibitors:• 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)

Violet-combinationagentsAntiretroviral Drugs and Combinations

DolutegravirElvitegravir

The history of ARV approvals- let’s talk about the ascent of the integrase inhibitor and the descent of EFV/Atazanavir

2012 2013

Golconda

CumulativeproblemsforEFV(CNSsideeffects)- EFVasInitialTherapy:

IncreasedRiskforSuicidalIdeationReviewof4ACTGstudiesinART-naïvepatientsCompared3241patientsstartingEFVvs2091patientsstartingnon-EFV-basedARTMediandurationf/u96weeksFirstsuicidalideationORattemptedORcompletedsuicideineachgroup• 8.08eventsper1000PYinEFVgroupvs3.66eventsper1000PYinEFV-freegroup(HR:2.28;95%CI,1.27-4.0;P=.006)

Mollan KR, et al. Ann Intern Med. 2014;161:1-10.

3

RAL superior to both PI/r regimens for combined tolerability and virologic efficacy; DRV/r superior to ATV/r;

ATV/r lost due to tolerability issues

RAL + FTC/TDF DRV/r + FTC/TDFATV/r + FTC/TDF

Randomized 1:1:1. Open Label Therapy

HIV+ adults, no previous ART (n=1809)

Lennox J et al, Ann Int Med, 2014

CumulativeproblemsforATV:ACTGA5257 Ascentoftheintegraseinhibitor

Threeandoneproceedingindevelopment

DavidLazar- TheAscent

ARS:WhatisthemeanincreaseofCrseenwithCobicistat inGilead102,103trials?

1. Meancreatinineincreasesof0.05mg/dL2. Creatinineincreasesof0.08mg/dL3. Creatinineincreasesof0.14mg/dL4. Creatinineincreasesof0.25mg/dL5. Creatinineincreasesof0.5mg/dL

• Welltolerated• Fewestdrug-druginteractions• OKinhepaticandrenalfailure• Nofoodrequirements• CanuseRALwithcations

exceptAlandMg(donotco-administer)

PROS• Lowgeneticbarrierto

resistance• BIDdosing(butemerging

dataforhigherdoseoncedaily)

• Nosinglepillcombination• CKelevations;

rhabdomyolysis

CONS

• Twosinglepillcombinations• Gilead102,103showed

similarefficacycomparedtoEFVorATV/r,respectively

PROS• Lowgeneticbarrierandcross

resistancewithRAL• Cobicistat increasesCr(0.1-0.4

mg/dL (mean0.14)• Mostdrug-druginteractionsdue

tocobicistat (statins,rifamycins,anticonvulsants..)

• Foodrequirements(373kcal)• Stribild- GFR>70mL/min• Spaceallcationsoutby2hours

CONS

Raltegravir

Elvitegravir

4

ONCEMRKSTUDY

Cahn P et al. IAS, 18-22 July 2016, Durban, South Africa. Abstract FRAB0103LB

• 802ptsrandomized(2:1)– RAL1200mgQD+TDF/FTC

– RAL400mgBID+TDF/FTC

• RALQDnon-inferiortoRALBID– VL<40:88.9%vs.88.3%

• RALQD(600x2)likelyavailablenextyear

Wk 48 VL<40 (Snapshot)

Pivotal phase III trials of dolutegravir – TREATMENT NAIVEStudy Patient

population Main outcome Dose Reference

SINGLE Treatment naïve (ABC/3TC + DTG vs TDF/FTC/EFV)

DTG regimen superior to EFV, driven mainly by more discontinuations with EFV

50mg once daily

Walmsley S. NEJM 201328

SPRING-2 Treatment-naïve (TDF/FTC or ABC/3TC with either DTG or RAL)

DTG regimen non-inferior to RAL-based regimens

50mg once daily

Raffi F. Lancet 2013 (48 wks) and Lancet ID (96)

FLAMINGO Treatment naïve (TDF/FTC or ABC/3TC with either DTG or DRV/r)

DTG regimen superior to DRV/r, driven by more d/c with DRV/r and more virologic response with DTG with vl >100,000 copies/mL

50mg once daily

Clotet. Lancet 2014; Molina Lancet HIV 2015

Pivotal phase III/IIb trials DTG - TREATMENT EXPERIENCED PATIENTSStudy Patient population Main outcome Dose ReferenceSAILING ART-experienced,

INSTI-naïve patients with at least 2-class resistance: DTG vs RAL with OBR

DTG regimen superior to RAL, driven by more d/c, virologic failures and treatment-emergent resistance with RAL

50mg once daily

Cahn P. Lancet 2013 (48 wks)32

VIKING-3, 4 Patients with resistance to 2 or more ART classes, including INSTI. DTG vs optimized

DTG regimen superior to optimized regimen with failures most prominent (76%) in patients with the Q148H/R +2 other mutations

50mg po twice daily

Eron JJ. JID 201333

and Nichols G. JID 2014; Castagna JID 2014

BottomlinewithDTGresistance• HigherbarriertoresistancetoDTGthanRAL/EVG• MajorpathwaysINSTIresistance:N155,Q148,Y143,E92(EVG)• BaselineINSTImutationofQ148H(especially+G140S)reducesDTGsusceptibility(e.g.don’tuse)

• Treatmentemergentresistancecanoccurinhighly-experiencedpatients(HardyAAC2015)

ARS:WhatisthemeanincreaseofdolutegravirAUCseenwithamoderate-

fatmeal?

1. 0%increase2. 33%increase3. 41%increase4. 66%increase5. 100%increase

Low-fat(300kcal,7%fat),moderate-fat(600kcal,30%fat),orhigh-fat(870kcal,53%fat)meal

5

ARS:WhatisthemeanchangeindolutegravirAUCwithrenalinsufficiency

(CrCl<30ml/min)?

1. 0%2. 10%increaseinAUC3. 10%decreaseinAUC4. 40%increaseinAUC5. 40%decreaseinAUC

Dolutegravirnotappreciablyremovedbyhemodialysis(BollenAIDS2016;MoltoAAC2016)

Pros and cons of dolutegravir

• Potentandhighgeneticbarrier

• AvailableinsinglepillcombinationwithABC/3TC,

• Welltolerated(thoughinsomnia,psychiatriceffectsreal-worldpopulations1,esp.women,olderpts2)

• Nofoodrequirements(although33%,41%,66%increaseinAUCwithlow,moderate,high-fatmeal,respectively3)

• CanuseDTGwithcationsofCaandFeifadministerwithmeal4

PROS• Inhibitscreatininesecretion

(meanriseCr0.11mg/dL)• AbacavirinSPCneedsHLA-

B5701testing• SeparatefromMg,Al

containingantacidsby2hours

• Increasedosewithconcomitantrifampin,EFV,CBZ;don'tgivewithetravirine unlessboostedPIspresent;nodoseadjustmentswithRPV

• Increasesmetforminlevels• LargestpillsizeofSPCs• Notcoformulated with

tenofovir• DecreasedAUCwithCrCl

<305

CONS

1DeBoerAIDS2016;2HoffmanHIVMed2017;3Song.AAC2012;4Song.JClin.Pharm2015;5Weller.Eur JClinPK2014

Outline

StateofARTcoveragegloballyThevirallifecycleHistoryofART andascentoftheintegraseinhibitor(descentofATVandEFV)SinglepillcombinationsTAFvsTDF2-drugtherapy(monotherapynotsomuch)Newdrugs,long-actingART

Singlepillcombinationsmayaidinadherence

WorldHealthOrganization.AdherencetoLong-TermTherapy.EvidencetoAction.2003;NationalCouncilonPatientInformationandEducation.EnhancingPrescriptionMedicationAdherence:ANationalActionPlan2007.Chobanian AV.JAMA2003;CohenJD.JClinicalLipid2012;Osterberg &Blaschke.NEJM2005;Blaschke.AnnRevPharmTox ‘12

TheWorldHealthOrganizationhasdeclaredthatmorepeopleworldwidewouldbenefitfromeffortstoimprovemedicationadherencethanfromthedevelopmentofnewmedicaltreatments

NonadherencehasbeenlabeledAmerica’s“otherdrugproblem”NationalCouncilonPatientInformationandEducation

Only51%ofAmericanstreatedforhypertensionareadherenttotheirlong-termtherapy

About25-50%ofpatientsdiscontinuestatinswithinoneyearoftreatmentinitiation

Costtosociety$290billion(rivalingcancertreatment)

“Drugsdon’tworkinpatientswhodon’ttakethem”

C.EverettKoop

6

ARS:HowmanysinglepillcombinationsdowehaveforthetreatmentofHIVin

2016?

1. 32. 43. 54. 65. 7

Picture of SPC Drugs in SPC Approval date

Food effects

TDF/FTC/efavirenz(Atripla®)

2006 Foodh levels

TDF/FTC/rilpivirine(Complera®)

2011 Take withsolidmeal(390kcal)

TDF/FTC/elvitegravir/cobicistat (Stribild®)

2012 Takewithfood(373kcal)

ABC/3TC/dolutegravir(Triumeq®)

2014 Foodh levels

TAF/FTC/elvitegravir/cobicistat (Genvoya®)

2015 Takewithfood(373kcal)

TAF/FTC/rilpivirine(Odefsey®)

2016 Take withsolidmeal(390kcal)

Currently available SPCs

ARS:Inyourpractice,areyouswitchingeveryoneonTDFtoTAF?

1. Yes,switchingallpatientsfromTDFtoTAF2. No,Iamevaluatingonacase-by-casebasis

Tenofoviralafenamide

TAFisprodrugoftenofovir(asisTDF). BothrequireconversiontoTFV-DPforactivityPlasmalevelsofTFV4-7xlowerwithTAF(25mgdaily)thanwithTDF(300mgdaily). TFV-DPlevelsmuchhigher(4-7x)withinlymphocyteswithTAF

7

Onlyonephase3trialofTAFheadtoheadwithTDF;restbioequivalenceorswitchstudies

Typeofstudy ARVs Dose ofTAF

Numbers /Reference

Results

Initialtherapy(phase3)

TDF/FTC/ELV/cobi VSTAF/FTC/EFV/cobi

10mg Noninferior (Gilead 104,111),

Switchstudy TDF/FTC-containingregimensTOTAF/FTC/EFV/cobi

10mg 1443pts,96wks

• Maintainedvirologicsuppression

• ImprovedeGFR,proteinuria

• Improvedbonemineraldensity

• Increasedlipids

Switchstudy TDF/FTC TOTAF/FTCwith3rd agent

10 or25mg

663pts,48wks

Switch study TDF/FTC/RPV TOTAF/FTC/RPV

25mg 630pts,48wks

Switch study TDF/FTC/EFVTOTAF/FTC/RPV

25mg 875 pts,48wks

Initialtherapy(phase2,safety)

DRV/Cobi/TDF/FTCVSDRV/Cobi/TAF/FTC

10mg 153 pts, 48weeks

SaxLancet2015;Pozniak JAIDS2016;Gallant.LancetHIV2016;MillsJAIDS2015;Raffietal,HIVtalIDWeek,2016;DeJesus etal,IDWeek,2016;Orkin etal,HIVGlasgow,2016;MillsLancetID2016

TAFvs.TDFinTreatment-NaïvePts(104,111)

HIV-1RNA<5

0%at4

8wee

ks

92

4 4

90

4 60

20

40

60

80

100

Success Failure No Data

• 1733treatmentnaiveadults(eGFR>50):866E/C/F/TAFvs866E/C/F/TDF1

• TAFassociatedwith:− SmallerdecreaseineGFR(-6.4vs.-11mL/min)

− Less proteinuria− Smallerdecreaseinbonemineraldensity(BMD)

− Butgreaterincreaseincholesterol,LDL,HDL,TGs§ D TC:+29mg/dL§ D LDL:+14mg/dL§ D TC:HDL:same

E/C/F/TAF

E/C/F/TDF

1SaxPetal,Lancet,2015;2PozniakAetal,JAIDS,2016;Wardetal,7th

InternationalWorkshoponHIV&Aging,September26-27,2016,WashingtonDC

• EVG/c/FTC/TAFapprovedforpatientswithCrCLdownto302

• 144weekdatepresentedSept2016(84%TAFvs80%TDF;12renaleventswithTDF)

• 663patientswithvirologicsuppressiononTDF/FTC+3rd agentrandomizedtocontinueTDF/FTCorswitchtoTAF/FTC(plus3rd agent)

• TAFusedas25mgifnon-boosted3rdagentand10mgifboosted(becauseTAF10mg+cobigivessamelevelsasTAF25mgwithoutcobi2)

• 93%/94%stayedsuppressed• TAFgroup:

– increasedeGFR(+8.4vs.2.8ml/min)– improvedproteinuria– increasedBMD(1.1-1.5%)– But:increasedcholesterol,LDL,TG

TAF/FTCSwitchStudy

GallantJetal,LancetHIV,2016;2ZackJ.EAC2015

94.3

0.35.4

93.0

1.5 5.5

0

20

40

60

80

100

Success Failure NoData

F/TAF(n=333) F/TDF(n=330)

HIVRNA<50atwk48

94 93

SomeremainingquestionsonTAF

Whatarelong-termclinicalimplicationsofthechangesinrenalandbonemarkers?Islackofsystemicexposuregood?• Whatisimpactoflackofexposureinextrapyramidaltissuesandgenitalmucosaforpreventionandcure?

ReduceddoseofTAF:Concernwithconcomitanthumancellularmetabolicenzymesoreffluxtransporterse.g.rifampin(inducesp-gp)Will25mgofTAFgivetoohighofintracellularTFV-DPwithboostedPIs(whichinhibitp-gp)?• FDAonlyapproved25mg/200mgTAF/FTCtablet

LingeringquestionsonTAF

8

ShouldTAFreplaceTDF?

• TAFisvirologicallyaseffectiveasTDF.

• Compared with TDF,TAFhasmore favorableeffects onrenaland bonemarkers.

− Don’thaveenoughevidenceonwhethertousewithexistingenal orbonedisease,butmaybethosewithhighriskofthesecomplications.

• CostofTAF- andTDF-regimenscurrentlysimilar.

Reasons to choose TAF• ComparedwithTAF,moreandlonger-termdatawithTDF,particularlyintreatmentnaïve

• Morefavorablelipideffects.• RenalandbonemarkeradvantagesofTAFnotyetknowntotranslateintobetterclinicaloutcomes.

• TDF-regimenslikelytobecheaperthanTAFwhenTDFgoesgeneric

• Patientonrifamycins (TB)• ForPrEP• Nodatainpregnantwomen• WithboostedPIs(nodataon25mgTAFandboostedPIs)

Reasons to choose TDFARS:WhatdoyouthinkaboutTAF/FTC

forPrEP?

a. TheyshouldberoughlyequivalentandIamusingTAF/FTCforPrEP

b. Don’tknowimplicationsofplasmaandintracellularconcentrationdiscrepanciesbetweenTDFandTAFonpreventionefficacy

c. TAFmaygivelowerTFV-DPconcentrationsincervicovaginal andrectaltissuesthanTDF

d. Understudybutinmen/TGWonlye. b,candd

Need more data for TAF/FTC and PrEP

§ TFV-DPwasundetectablein75%offemalegenitaltissueswithTAF25mg(25%undetectablewithTDF)

§ TFV-DPwasundetectablein63%ofrectaltissueswithTAF25mg(0%undetectablewithTDF),butFTCsame

§ Discovertrial(TAF/FTCvsTDF/FTCforPrEP)onlyenrollingmen/TGwomen

Femalegenitaltracttissue

GarrettK.CROI2016LB

Outline

StateofARTcoveragegloballyThevirallifecycleHistoryofART andascentoftheintegraseinhibitor(descentofATVandEFV)SinglepillcombinationsTAFvsTDF2-drugtherapy(monotherapynotsomuch)Newdrugs

9

Whydualtherapyasopposedto3-drug?

NRTIintolerance(HLA-B5701andrenalfailure)orNRTImutationsMinimizepillburdenMinimizetoxicitiesMinimizecostPreservetreatmentoptionsforfutureINSTIs(e.g.dolutegravir,cabotegravir)potentandhighgeneticbarriertoresistance– willthisallowthepossibility?Allowforlong-actingtherapy(just2availablerightnow)

Monotherapy

SomeevidenceforPI/rmonotherapy,butinferiorto3-drugtherapy(GirardHIVMed2017)

Dolutegravirmonotherapyofinterest(notreatmentemergentresistanceinnaïvetrials)“Meta-analysis”of4tinystudies(one5patients),87patients(Moreira,JAC2016)

• 6%virologicfailurerateoverall(4outof5whofailedhadINSTIexperience)

• 4whofaileddevelopedINSTIRAMsonDTGmonotherapy• UnacceptablerateofINSTIresistance– thisisnotreadyforprimetime,9ptsinItaly(Lanzafame JAIDS 2016),othertinystudies

ARS:ManyNRTI-sparingtrialsfailed.Forwhichcombobelowdowehavesome

evidenceofsuccess?

1. ATV/r+RAL(HARNESS)2. MVC+DRV/r(MODERN)3. LPV/r+EFV(A5142)4. DRV/r+RAL(NEAT)5. DRV/r+TDF(NOT-1)6. DTG+TDF(NOT-2)

Dualtherapyasinitial therapy–emergingevidenceformainly3 oralcombinations

Dualcombination

ParticularARVs,Studyname

Results

1)Boosted PI+3TC

LPV/r+3TCGARDEL1

• Noninferior toLPV/r+2NRTIs(n=426)• Highpillburden,toxicities

2)BoostedPI+INSTI

DRV/r+RALNEAT-0012,3

PROGRESS4LPV/r/RALpilot

• Overallnonnoninferior (n=805)• Didn’tdoaswellasDRV/r +TDF/FTCif

CD4<200orvl >100K• MorefailureswithDRV/r+RALandmore

resistance(5INSTIRAMs,gulp)• PROGRESS(206)vsLPV/2N,2M184Vss

3)INSTI +3TC DTG+3TC(PADDLE4),A5353etc.

• Open-label single-arm,naïvepatients• n=20only• Allmaintainedsuppressionat24wks

EFV/LPV/r6 inA5142hadmoreNNRTIresistance1CahnPetal,LancetID2014;2RaffiFetal,Lancet,2014;3Lambert-NiclotSJAC2016;4ReynesARHR2013;

4FigueroaMIetal,15th EACS,2015;5MargolisLancetID2015;6Riddler.NEJM2008

10

COMPLETED• LPV/r+3TCvs2N(OLE,n=250)1

• ATV/r+3TCvs2N(SALT,n=286)2

• DRV/r+RPVvsstandardcART (PROBE,n=60)3

• CAB+RPVpo vsEFV/2N(LATTE-1,n=243)UNDERSTUDY• DRV/r+3TC(DUAL)• DRV/r+DTG(DUALIS)• DTG+3TC(ASPIRE,A5353,LAMADOL,GEMINI1and2-Viiv)• DTG/RPV(SWORD-1and-2- Viiv,1000pts)• IMCabotegravir+IMRPV(LATTE-2,n=309)4 –Goingto96wks

Two-drug therapy regimens that work AFTER virologic suppression

(maintenance)

1ArribasJRetal,LancetID,2015;2Perez-MolinaJAetal,LancetID,2015;3MaggioloF,JAIDS,2016;4MargolisDAetal,CROI2016,#31LB

All4simplificationsmaintainedgoodvirologicsuppressionrates≥6months

LATTE-2:CabotegravirIM+RilpivirineIMforLong-ActingMaintenanceART

• Multicenter,open-labelphaseIIb study– Primaryendpoints:HIV-1RNA<50c/mLbyFDAsnapshot,PDVF,and

safetyatmaintenanceWk 32

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W(n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W(n = 115)

*Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to maintenance phase. 6 pts discontinued for AEs or death in induction analysis.

ART-naive HIV-infected pts withCD4+ cell count > 200 cells/mm3

(N = 309) CAB 30 mg PO + ABC/3TC PO QD(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32primary analysis; dose selection

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96Wk 16: RPV PO added

MargolisDAetal,CROI2016,Abstract31LB

LATTE-2:MaintenanceWk 32VirologicEfficacy(ITT-MaintenanceExposed)

• VirologicefficacyofQ4WandQ8WIMregimenssimilartooralregimen• 1patientinq8wk armand1pt inoralarmmetprotocoldefinedVF• NoINSTI,NNRTI,orNRTIresistancemutationsdetected

Margolis DA, et al. CROI 2016. Abstract 31LB. Reproduced with permission.

9594 91

4< 1 4 < 15 5

VirologicSuccess

VirologicNon-

response

No Virologic

Data

HIV

-1 R

NA

<50

c/m

L (%

) 100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)IM CAB + RPV Q8W (n = 115)Oral CAB + ABC/3TC (n = 56)

Treatment Differences (95% CI)

Q8W

-4.83.7

12.2

IMOral

-12-10 -8 -6 -4 -2 0 2 4 6 8 10 12

Q4W

-5.8

2.811.5

-12-10 -8 -6 -4 -2 0 2 4 6 8 10 12

MargolisDAetal,CROI2016,Abstract31LB

LATTE-2:Safetydatathroughwk 32• MostfrequentISRswerepain(67%),swelling(7%),andnodules(6%)

– ISRevents/injection:0.53– 99%ofISRsgrade1/2;nonegrade4– ProportionofptsreportingISRsdecreasedwithtimefrom86%onDay1

to33%atWk 32;1%ofptswithdrewforISRs• PatientsatisfactionwithLAregimenhighAEs,% PooledCAB+RPVIM

Arms(n=230)OralCAB+ABC/3TC

(n=56)

Drug-relatedgrade3/4AEs(excludingISRs) 3 0

SeriousAEs 6 5

AEsleadingtowithdrawal 3 2

MargolisDAetal,CROI2016,Abstract31LB

11

• Openlabelcohortstudy(n=38),19yrs multidrugtx experienceallvirologically suppressed,previoushistoryofvirologicfailure

• RegimenattimeofswitchtoDTG+RPV(median4.3drugs):– NRTI+NNRTI+PI+INSTI:53%(restNRTI+NNRTI+PI)

• Pre-existingresistancemutations:NRTI:65%;NNRTI37%;PI32%;INSTI:NA

• Virologicsuppressionin35of38(92%)atwk 48• NoVF:1patientstoppedb/oGItoxicity,1b/odrug

interactions,1b/ophysiciandecision• 132ptsinclinicinItaly2 and14ptsinNewarksimilarresults3

• PhaseIIISWORDtrials(DTG/RPV)stillongoing

SwitchingtoDTG+RPVinHeavilypre-TreatedPatientsWhoareVirologically Suppressed

Díaz A,etal.IAC2016July2016.AbstractTUPDB0106;2CapettiPLOSOneOct2016;3Salingetal.IDWeek2016

ARS:Whichnovelanti-HIVdrugindevelopmentseemsmostexciting

toyou?1. Bictegravir,anINSTI2. VRC01,broadlyneutralizingantibody3. Doravirine,anNNRTI4. Fostemsavir,anattachmentinhibitor5. BMS-663068,amaturationinhibitor6. EFDa,anNRTIinhibitor7. None,toomanyvir namestoremember!

Newanti-HIVdrugsDrugclass Name ofdrug Comments

NRTI EFDa (4ʹ-ethynyl-2-fluoro-2ʹ-deoxyadenosine)

Phase Idata;animaldata;weeklyoralandmaybeformulatedtoONCEYEARLY

NNRTI Doravirine Phase IIIinprogress;beingstudiedasSPCwith3TC/TDF;canuseagainstRPV-resistantvirus

INSTI GS-9883 orBictegravir PhaseIII inprogresswithSPCasbictegravir/TAF/FTC;highgeneticbarriertoresistance

Attachmentinhibitor

BMS-663068orfostemsavir

LooksgoodinphaseIIb; nowinPhaseIII;novelclass

Maturationinhibitor

BMS-955176 Promising inphaseI;nowinPhaseII

BroadlyneutralizingAb

VRC01,forprevention ortreatment

Earlyindevelopment;Baretal.NEJMNov9,2016– delaysviralreboundbutresistance

ThankyoutoDrs.DianeHavlir,RajGandhi,MegNewman,VivekJain,GabeChamie,HarryLampiris,AnnieLuetkemeyer