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12/8/16
1
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
12/8/16
7
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
12/8/16
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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