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MMAHDebatePanelThursday,December8,2016

Case1

HPI• 55yo manwithnewlydiagnosedHIVinitiatescareinyourclinic.HisCD4+cellcountis600,withHIVVL=90,000copies/mL. Heisasymptomaticattoday’svisit,butanxiousabouthisnewHIVdiagnosis.

PMH• Hewaspreviouslynotengagedinmedicalcare.• AtthetimeofHIVdiagnosis,heisalsodiagnosedwith:– Pre-diabetes(a1c=5.9)– Hyperlipidemia

Case1continuedMedications• Hetakesnoothermedications(yet).• HeisARVnaïve,andisreadytostartARVsattoday’svisit.

Allergies• NKDA• HeisHLAB5701 negative

SocialHistory• Heishoused,andlivesalone.Heidentifiesasawhitegay

man.Hesmokescigarettes,butdeniesotherdruguse.Occasionalalcoholuse,butnottoexcess.

Case1(cont)

• HisbaselineCBCandchem7isnormal,withaserumcreatinine of1.0(eGFR >60).

• Hep BandCnegative• HehasanormalUAwithoutproteinuria.• Hetellsyouthatheiswaryofsideeffectsandofpharmaceuticalcompanies.

• HeasksyouwhatyourecommendforhisinitialARVs.

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ARS:Shouldeveryonestartedontenofovir-basedARTstartonTAFinsteadofTDF(initialtherapy)?

1. Yes2. No

TAFvsTDFParameter TAF

BetterTAF≈TDF

TDFBetter

Comments

Efficacy(HIVRNA)

Sax. Lancet.2015;385(9987):2606-2615Gallant.LancetHIV.2016;3:e158-e165

Orkin. 2016InternationalCongressofDrugTherapyinHIVInfection.AbstractO124.

RenalSafetyMarkers

Sax. Lancet.2015;385(9987):2606-2615DeJesus.ASM M icrobe 2016.AbstractLB-087

BoneSafetyMarkers

Sax. Lancet.2015;385(9987):2606-2615Orkin. 2016InternationalCongressofDrugTherapyinHIV

Infection.AbstractO124.WohlD ,etal.EACS2015.Abstract1091

Cost$(topatient)

Mustcheck individualpatient’splan

Cost$(tosystem)

BasedonWACcosts

EfficacyinHepatitisB

Gallant.IAS2015.AbstractWELBPE13

Convenience(singletablet)

Drug-druginteractions

ShouldTAFreplaceTDF?

• TAFisvirologicallyaseffectiveasTDF.

• Compared with TDF,TAFhasmore favorableeffects onrenaland bonemarkers.

− Don’thaveenoughevidenceonwhethertousewithexistingrenalorbonedisease,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:Shouldeveryonestartedontenofovir-basedARTstartonTAFinsteadofTDF(initialtherapy)?

1. Yes2. No

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Case1(cont)

• HetolerateshisnewARVregimenwell(TAF/FTC/DTG)andhisviralloadisundetectabletwomonthslater.

• Hehasnoadversereactionstohisnewregimeninitially,andfollowsupwithyouinclinicregularly.Heishappywithhisregimen,andrelievedatthelackofsideeffects.

Case1(cont)

• However,overthenexttwoyears,hedevelopschronickidneydisease(eGFR=45)thoughtduetoworseningdiabetesandhypertension.

• Discussionquestion:– ShouldthispatientbecontinuedonTAF?

ShouldthispatientbecontinuedonTAFgivenhisCKD?

1. Yes2. No

Point 1: CrCl Cutoffs for ARVs

ARV FDA Approved CrCl cutoff, mL/min

EVG/COBI/FTC/TDF ≥ 70DRV/COBI + FTC/TDF ≥ 70

EFV/FTC/TDF ≥ 50RPV/FTC/TDF ≥ 50DTG/ABC/3TC ≥ 50DRV/RTV, DTG, or RAL + FTC/TDF ≥ 50

EVG/COBI/FTC/TAF ≥ 30RPV/FTC/TAF ≥ 30DRV/COBI, DRV/RTV, DTG, or RAL + FTC/TAF ≥ 30

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Point 1: CrCl Cutoffs for ARVs

ARV FDA Approved CrCl cutoff, mL/min

EVG/COBI/FTC/TDF ≥ 70DRV/COBI + FTC/TDF ≥ 70

EFV/FTC/TDF ≥ 50RPV/FTC/TDF ≥ 50DTG/ABC/3TC ≥ 50DRV/RTV, DTG, or RAL + FTC/TDF ≥ 50

EVG/COBI/FTC/TAF ≥ 30RPV/FTC/TAF ≥ 30DRV/COBI, DRV/RTV, DTG, or RAL + FTC/TAF ≥ 30

Point 1: CrCl Cutoffs for ARVs

ARV FDA Approved CrCl cutoff, mL/min

EVG/COBI/FTC/TDF ≥ 70DRV/COBI + FTC/TDF ≥ 70

EFV/FTC/TDF ≥ 50RPV/FTC/TDF ≥ 50DTG/ABC/3TC ≥ 50DRV/RTV, DTG, or RAL + FTC/TDF ≥ 50

EVG/COBI/FTC/TAF ≥ 30RPV/FTC/TAF ≥ 30DRV/COBI, DRV/RTV, DTG, or RAL + FTC/TAF ≥ 30

§ Multicenter,open-labelphaseIIItrial

§ Outcomes:

– Virologic suppression:Maintained(92%)

– CrCl:Stablethrough96weeks

– Proteinuria,albuminuria,BMD(hip&spine):Improved

GS-112:SwitchingtoaTAF-BasedRegimeninPtsWithRenalImpairment

Posniak,. JAIDS. 2016 Apr 15; 71(5): 530–537.Post FA, et al. CROI 2016. Abstract 680.

Virologically suppressed, HIV-positive pts with mild-moderate renal impairment (stable

eGFRCG [30-69 mL/min])(N = 242)

TDF-Based ART(n = 158)

Non-TDF–Based ART(n = 84)

EVG/COBI/FTC/TAF (N = 242)

Wk96Wk48Wk24

D:A:DRiskScoreforCKDinHIV-InfectedPatients

– Lowrisk:<0– Mediumrisk:0-4– Highrisk:≥5

Mocroft A, et al. PLoS Med. 2015;12:e1001809.

Characteristic Addition to D:A:D Score

Diabetes +2

IDU +2

HCV coinfection +1

Aged 35-50 yrs +4

Aged 51-60 yrs +7

Aged > 60 yrs +10

BL eGFR > 60 to ≤ 70* +6

BL eGFR > 90* -6

Female +1

Nadir CD4+ cell count > 200 cells/mm3 -1

Hypertension +1

Prior CVD +1*mL/min/1.73 m2

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GS-104/111:RenalOutcomesWithTDFvsTAFbyD:A:DRiskScore

• OverallincidentCKD:1(0.1%)E/C/F/TAFvs14(1.6%)E/C/F/TDF

Renal OutcomeHigh Risk for CKD Medium Risk for CKD Low Risk for CKD

E/C/F/TAF(n = 56)

E/C/F/TDF(n = 84)

E/C/F/TAF(n = 107)

E/C/F/TDF(n = 129)

E/C/F/TAF(n = 697)

E/C/F/TDF(n = 648)

Incident CKD, n (%) 0 4 (4.8) 0 3 (2.3) 1 (0.1) 7 (1.1)Renal AE d/c, n (%) 0 3 (2.4) 0 3 (0.8) 0 0

Wohl D, et al. CROI 2016. Abstract 681.Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64.

• Unclearsignificanceofrenalbiomarkers• Betterrushouttomeasuremyretinolbindingproteinandbeta2microglobulin inurine

TDFoutsince2001;TAFsince2015Whatarelong-termclinicalimplicationsofthechangesinrenalmarkers?TAFgives4-7xhigherintracellularTFV-DPconcentrationsthanTDF– whatdoesthatmeanforkidney?25mgofTAFisbeinggivenwithboostedPIsv FDAonlyapproved25mg/200mgTAF/FTCtabletv Weknowthat25mgTAFgivessameexposuretoTFV-DPas10mg

TAF+cobicistat

Wedon’thavetheclinicalexperiencewithTAF GUT PLASMA CELL

Case2

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Case2• CBisa38yowomanwithHIVdiagnosed4yearsago• Baselinelabs:

– CD4267(27%)– HIVRNA18,000– HIVGenotype:wildtype– HepatitisBandCnegative– Cr0.89– HLA-B57*01negative

• Initialregimen:TDF/FTC/EFV• Hadrelapseofheroinandwaspoorlycompliantfor4

months• Nowinresidentialtreatmentandreturningtocare

CASE2(continued)

• Currentlabresults– CD4312(32%)– HIVRNA1400– HIVGenotype:RT:M184V,K103N;PR:Nomutations

• Strongpreferenceforsingle-tabletregimen

ARS:Whatwouldyoustartnow?

1. StartDTG/3TC/ABC(Triumeq)2. StartEVG/Cobi/TAF/FTCorTDF/FTC

(Genvoya®orStribild®)3. StartDRV/c-r+TDF-TAF/FTC4. StartDTG+TDF-TAF/FTC5. StartDRV/c-r+DTG+TDF-TAF/FTC

CASE2StartDRV/c-r+TDF-TAF/FTC

VFduetonon-adherenceonAtriplaàM184V,K103N– Patientwantsasingletabletoption.Whataretheoptions?

• RPV/TAForTDF/FTC• c/EVG/TAForTDF/FTC• DTG/3TC/ABC

– 3activedrugs(DRV/r/DTG/TDF/FTC) =mostconservative– Whatabout2drugs:DRV/c-r vs. DTG +TDF-TAF/FTC

DTG≠DRV/rBoostedDRV:• 1.Strongerevidence(thanDTG)forefficacyofdualtherapywithboostedPIs(e.g.GARDEL:LPV/r/3TCnon-inferiortoLPV/r/3TC+NRTI);andswitchtoDRV/rmonotherapy (e.g.MONET)

• 2.Longerclinicalexperience

Sub-optimalbecause:- LowbarriertoresistanceofRPV

- Samelowbarrierw/EVG

- 184Vcauseslow-levelABCResist

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96weekresultsofFLAMINGOtrial

DTG80%

DRV/r68%Difference12·4,95%CI4·7–20·2;p=0·002)

DTG/TDFvsDRV/r/TDF• Rememberthatneitherofthesehavebeenstudiedas“dualtherapy”(“NOT-1and2”)

• ButnotasinglecaseoftreatmentemergentresistanceinthenaïveDTGtrials(SINGLE,SAILING,FLAMINGO)

• (4inARTEMIS-DRV/rnaïvetrial,butnotmajor1)• RareemergenceofresistancewithDTGinexperiencedpatients;morecommonwithDRV(POWER1,22)

• IncreasingdataonINSTI+2nd drug

1Orkin.HIVMed2013;2ClotetLancet2007

Case3

Case3

• 56yo manwithHIVdiagnosedin2015naïvetotherapy

• HTN(BP145/95)• DM(HbA1c9.8)• Coronaryarterydisease• Chronickidneydisease• Osteoporosis

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Case3(continued)

• Labs– CD4count580cells/mm3;viralload140,000cp/ml

– HIVgenotypewildtype– HLA-B5701negative– EstimatedCrCl45ml/min

ARS:Whatwouldyoudonow?

1. OptforNRTI-includingregimen2. OptforNRTI-sparingregimen

Case3OptforNRTI-includingregimen

• NRTI-sparingregimensasinitialRx?Notyet…– SeveraltrialsofNuc-sparing(+/- 3TC)Rx– Almostallhavebeenproblematic*:

• Failuretomeetnon-inferiorityinvirologicsuppression– SPARTAN (ATV/RALvs.ATV/r/RAL/TDF/FTC)>RxfailureinATV/RAL– ACTG5262:singlearmstudyofDRV/r+RAL->unexpectedlyhighratesofvirologic failurew/resistance(esp baselineHIVVL>100K)

• Metnon-inferiorityforvirologicfailure...but,– ACTG5142:Greaterratesoffailurewithresistance– NEAT001:Concerningsub-groups(CD4<200inferior;VL>100,000)– PROGRESS:LPV/r/3TC(2M184Vmutations)vs.LPV/r/3TC+NRTI(nomutations)

• PADDLE=smallstudy;toosoontosay…*EspeciallyNRTI-freevs.NRTI-sparing(3TC)

• Inthiscase:• TAF/FTCvs.ABC/3TCasNRTIbackbonebothoptions• TAF:CrCl =45(ie.>30)• ABC:

– CanreduceMI/CVriskbyaddressingmodifiableriskfactors– Virologic suppressionimportantforreducingCVrisk– Mostlybasedonobservational(cohort)data;FDAmeta-analysisofRCTs:noe/oassociationw/MI

– AbsoluteriskofMIassociatedwithABCuseislow

Case3OptforNRTI-includingregimen

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SummaryofKeyAnalysesShowingABCAssociatedWithRiskofMI

Study StudyDesign

Age, Yrs(Range)

Event(n)

Pts,N

ABC CV Effect

Time on ABC, Mos

Risk of MI (95% CI)

D:A:D Cohort 40 (35-47)

MI, validated(387)

22,625 Yes ≥ 6 2.04 (1.66-2.51)

D:A:D 2015 Cohort 39(33-46)

MI(493)

32,663 Yes Current 1.47(1.26-1.71)

SMART RCT 45(39-51)

MI, validated(19)

2752 Yes Current 4.3 (1.4-13.0)

STEAL RCT 45.7±8.8

MI(4)

357 Yes 96 2.79*(1.76-4.43)

QPHID CC 47 (22-67)

MI(125)

7053 Yes Any 1.79 (1.16-2.76)

Danish Cohort 39(33-47)

MI(67)

2952 Yes > 6 2.00 (1.07-3.76)

VA (Choi) Cohort 46 CVD event(501)

10,931 Yes Recent 1.64(0.88-3.08)

Swiss Cohort Not given CVD event(365)

11,856 Yes Recent 4.06†

(2.24-7.34)MAGNIFICENT CC 50

(22-85.5)CVD event

(571)1875 Yes Current 1.56

(1.17-2.07)NA-ACCORD Cohort MI, validated

(301)16,733 Yes Recent 1.33

*Risk for serious non-AIDS events (most common was CVD, including MI); HR for CVD with TDF vs ABC: 0.12 (95% CI: 0.02-0.98; P = .048).†Risk for CVD event, including MI, invasive CV procedure, or CV-related death.

SummaryofKeyAnalysesShowingABCNOTAssociatedWithRiskofMI

Study StudyDesign

Age, Yrs (Range)

Event(n)

Pts,N

ABC CV

Effect

Time on ABC, Mos

Adj Risk of MI

(95% CI)

FHDH CC 47(41-54)

MI(289) 74,958 No < 12/

recent1.27*

(0.64-2.49)

ALLRT/ACTG Cohort 37

(26-51)MI

(36) 5056 No 72 0.6 (0.3 -1.4)

VA Cohort 46 MI(278) 19,424 No Per 12 1.18

(0.92-1.50)

FDAMeta-

analysis of RCTs

36-42 MI(46) 9868 No 19 1.02

(0.56-1.84)

NA-ACCORD Cohort

MI, validated

(301)16,733 No Recent 1.33

*Without adjustment for cocaine use OR: 2.01 (1.11-3.64).

NovelTDF- andABC-SparingARTStrategies

1. Cahn P, et al. EACS 2015. Abstract 961. 2. Raffi F, et al. Lancet. 2014;384:1942-1951. 3. Figueroa MI, et al. EACS 2015. Abstract 1066. 4. Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784. 5. Di Giambenedetto S, et al. EACS 2015. Abstract 867. 6. Arribas JR, et al. Lancet Infect Dis. 2015;15:785-792. 7. Casado JL, et al. J Antimicrob Chemother. 2015;70:630-632. 8. Margolis DA, et al. Lancet Infect Dis. 2015;15:1145-1155. 9. Margolis DA, et al. CROI 2016. Abstract 31LB.

Study InitialorSwitchFromSuppr.ART

N Regimen Results

GARDEL[1] Initial 426 LPV/RTV+3TC SimilarefficacyasLPV/RTV+2NRTIsPADDLE[2] Initial 20 DTG+3TC Smallstudy;encouragingefficacyNEAT001/ANRS143[3]

Initial 805 DRV/RTV+RAL SimilarefficacyasDRV/RTV+TDF/FTC

SALT[4] Switch 286 ATV/RTV +3TC SimilarefficacyasATV/RTV+2NRTIsATLAS-M[5] Switch 266 ATV/RTV+3TC Similar(improvedinposthocanalysis)

efficacyvsATV/RTV+2NRTIsOLE[6] Switch 250 LPV/RTV+3TC Similarefficacyascont.standardARTNA[7] Switch 48 DRV/RTV+3TC Smallstudy;encouragingefficacyLATTE[8] Switch 243 CAB+RPV Similarefficacyascont.standardARTLATTE-2[9] Induction-

Maintenance309 Induct:CAB+ABC/3TCPO;

Mainten:LACAB+LARPVIMQ4WorQ8W

Similarefficacyascont.oralCAB+ABC/3TC;injection-siterxns frequentbuthighpt satisfaction

NEAT-001/ANRS143:DRV/RTV+RALvsDRV/RTV+TDF/FTCinNaivePts

• Randomized,open-labelphaseIIIstudy

Raffi F, et al. CROI 2014. Abstract 84LB.

ART-naive pts with HIV-1 RNA > 1000 c/mL

CD4+ cell count ≤ 500 cells/mm3

(N = 805)

§DRV/RTV 800/100 mg QD + RAL 400 mg BID(n = 401)

Wk 96

DRV/RTV 800/100mg QD + TDF/FTC 300/200 mg QD(n = 404)

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NEAT:RAL+DRV/RTVNoninferiortoTDF/FTC+DRV/RTVat96Weeks

• Overall,regimensnoninferiorby%reachingcompositeprimaryendpointof6virologicandclinicalendpointsatWk96

– RAL:17.4%;TDF/FTC:13.7%– InferiorresponseinptswithBLCD4<

200andatrendtowardmoreprimaryendpointsinptswithBLVL≥100K

• SimilarnumbersofptswithPDVF(RAL:n=66;TDF/FTC:n=52)

• NoptswithresistanceinTDF/FTCarmvs5withintegrasemutationsand1withK65RinRALarm

Raffi F, et al. CROI 2014. Abstract 84LB. Reproduced with permission.

Overall N=805

BL HIV-1RNA

<100,000c/mL

≥100,000c/mL

n=530

n=275

BLCD4+cellcount

<200/mm3

≥200/mm3

n=123

n=682

PrimaryEndpointatWk96:AdjustedDifferenceEstimate(95%CI)

RAL- TDF/FTC

-10 0 10 20 30

RAL TDF/FTC

17.4 13.7

7

36

7

27

(P=.09)

39.0

13.6

21.3

12.2

(P =.02)

§ Significantly greater mean increases in fasting lipids in RAL arm

LATTE-1:GSK1265744(Cabotegravir)asPartofARTinNaivePts

• GSK1265744(744),DTGanaloguewithlonghalf-life,oralorinjectableformulations• Randomized,dose-rangingphaseIIbstudyoforalformulation• Primaryendpoint:HIV-1RNA<50c/mLatWk48

744 10 mg QD + RPV 25 mg QD

744 30 mg QD + RPV 25 mg QD

*Pts with HIV-1 RNA < 50 c/mL at Wk 24 continued to maintenance phase.�TDF/FTC or ABC/3TC.

ART-naive pts,HIV-1 RNA

> 1000 c/mL(N = 243)

744 60 mg QD + RPV 25 mg QD

EFV 600 mg QD + 2 NRTIs QD (n = 62)

Margolis D, et al. EACS 2013. Abstract PS7/1. Margolis D, et al. CROI 2014. Abstract 91LB; Margolis D Lancet ID 2015.

744 10 mg QD + 2 NRTIs�

(n = 60)

744 30 mg QD + 2 NRTIs�

(n = 60)

744 60 mg QD + 2 NRTIs�

(n = 61)

Wk 48primary analysis

Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL) and NRTI Wk 24

Induction Phase* Maintenance Phase

LATTE-1:Virologic SuccessDuringInductionandMaintenancePhases

• 2ptswithPDVFduringmaintenance;bothwithINSTImutationsatBL

Margolis D, et al. EACS 2013. Abstract PS7/1. Margolis D, et al. CROI 2014. Abstract 91LB; Margolis D Lancet ID 2015.

HIV

-1 R

NA

< 5

0 c/

mL

by

Snap

shot

Alg

orith

m (%

)

100

80

60

40

20

0BL 2 4 8 12 16 24

Wks

92%94%96%

91%

Cabotegravir 10 mg (n = 60)Cabotegravir 30 mg (n = 60)Cabotegravir 60 mg (n = 61)EFV 600 mg (n = 62)

Induction Phase Maintenance Phase

26 28 32 36 40 48

DolutegravirMonotherapyinTreatment-NaivePts

• N=9ptswhorefusedNRTIsandinitiatedDTGmonotherapy– AllptshadbaselineHIV-1RNA<100,000copies/mL– NobaselineNRTI,NNRTI,PI,orINSTIresistance

Lanzafame M, et al. J Acquir Immune Defic Syndr. 2016;72:e12-e14.

PtHIV-1 RNA, copies/mL CD4+ Cell Count, cells/mm3

Mos on DTGBaseline After 4 Wks’ DTG At Last Visit Baseline At Last Visit

1 20,400 Undetectable Undetectable 248 600 102 18,400 Undetectable < 20 335 471 93 90,500 31 Undetectable 356 527 74 39,000 35 Undetectable 350 623 75 43,300 < 20 Undetectable 329 613 76 17,500 45 < 20 229 404 67 18,200 < 20 Undetectable 785 879 68 16,900 Undetectable Undetectable 214 309 89 52,000 < 20 Undetectable 345 484 6