taege two as good as three update 9.13.18 · (95% ci: -12.6% to 16.5%) dtg + 3tc (n = 44) continued...
TRANSCRIPT
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Two as Good as Three? Dual Therapy
AlanJ.Taege,MD
AssistantProfessorofMedicineDepartmentofInfectiousDisease
ClevelandClinic
Cleveland,OH
September14,2018
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BenefitsofCoffee!!
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Outline
• WhyConsider• StudiesofDualTherapy–InitialvsMaintenance,combinations• Cautions• FutureDirection
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Why? (The Holy Grail of Medical Care)
• Simplification• Avoidtoxicity• Improvetolerability,convenienceandadherence• Managepotentialdrug–drugordrug–foodinteractions• Pregnancy• BMD• Renal• CV-lipids• Resistance• Costsavings:
• $ 500millionover5years*
DHHS Guidelines. *CID2016;62(6):784-91
NotanewConcept(“nucsparing”)
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Class DHHS[1] IAS-USA[2]
INSTI § BIC/TAF/FTC§ DTG/ABC/3TC§ DTG+(TAForTDF)/FTC§ EVG/COBI/(TAForTDF)/FTC§ RAL+(TAForTDF)/FTC
§ BIC/TAF/FTC§ DTG/ABC/3TC§ DTG+TAF/FTC
DHHS, IAS-USA Guidelines: Recommended Regimens for First-line ART
• RecommendationsmaydifferbasedonbaselineHIV-1RNA,CD4+cellcount,CrCl,eGFR,HLA-B*5701status,HBsAgstatus,osteoporosisstatus,andpregnancystatus
• Dataarelackingforwomenofchild-bearingagenotusingcontraception• IAS-USAnowlistsEVG/COBI/TAF/FTCandRAL+TAF/FTCasalternativeregimens(lowerresistancebarriersand,moredruginteractionsandhigherpillburden[2]
BoldtextidentifiesSTR.
1.DHHSGuidelines.May2018.2.SaagMS,etal.JAMA.2018;320:379-396.
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DHHS Guidelines: Initial ART Recommendations “Certain Clinical Situations”
DHHS guidelines. March 27, 2018.
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DHHS: Key Concerns With Selected Triple-Therapy Regimens Containing ABC, TAF, or
TDF
• DTG+RPVreasonableoptionwhenNRTIsnotdesirable/whennoexpectedresistancecomponents
• PI/RTV+3TCmaybereasonableoptionwhenTDF,TAF,orABCiscontraindicatedornotdesirable
DHHS Guidelines.
Component Key DDIs May Be Suboptimal for Pts With: Use Standard Dose When
CrCl: Hyperlipidemia CVD Osteoporosis NRTI Backbone ABC/3TC X ≥ 50 mL/min
FTC/TAF ≥ 30 mL/min
FTC/TDF X ≥ 50 mL/min
Additional Agents
Boosted PIs Lipid-lowering agents, PPIs, steroids X
DTG Antacids
EVG/COBI Lipid-lowering agents, steroids X
RAL Antacids
RPV PPIs, dexamethasone
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Dual Therapy: Potential Boosted PI Regimens for Initial/Maintenance Therapy
Study Treatment Setting N Regimen Results
NEAT001[1] Initial 805 DRV/RTV + RAL Similar efficacy as DRV/RTV + FTC/TDF; poor efficacy in pts with high HIV-1 RNA, low CD4+ cell counts
GARDEL[2] Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs MODERN[3] Initial 813 DRV/RTV + MVC Inferior efficacy vs DRV/RTV + FTC/TDF
SPARTAN[4] Initial 94 ATV + RAL Similar virologic suppression, higher VF and hyperbilirubinemia rates vs ATV/RTV + FTC/TDF
ANDES[5] Initial 145 DRV/RTV + 3TC Similar efficacy as DRV/RTV + 3TC/TDF OLE[6] Switch 250 LPV/RTV + 3TC Similar efficacy as continued standard ART KITE[7] Switch 60 LPV/RTV + RAL Small study; encouraging efficacy SALT[8] Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs ATLAS-M[9] Switch 266 ATV/RTV + 3TC Improved efficacy vs ATV/RTV + 2 NRTIs DUAL-GESIDA[10] Switch 257 DRV/RTV + 3TC Similar efficacy as DRV/RTV + 2 NRTIs
Slide credit: clinicaloptions.com
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Selected Studies of Boosted PI–Based Initial Dual Therapy
Study N Regimen Results
NEAT001[1] 805 DRV/RTV + RAL § Similar efficacy vs DRV/RTV + FTC/TDF § Poor efficacy in pts with high HIV-1 RNA, low
CD4+ cell counts GARDEL[2] 426 LPV/RTV + 3TC § Similar efficacy vs LPV/RTV + 2 NRTIs
SPARTAN[3] 94 ATV + RAL § Similar virologic suppression, higher VF and
hyperbilirubinemia rates vs ATV/RTV + FTC/TDF
ANDES[4] 145 DRV/RTV + 3TC § Similar efficacy vs DRV/RTV + 3TC/TDF* § Efficacy maintained when BL HIV-1 RNA
> 100,000 copies/mL
1. Raffi F, et al. Lancet. 2014;384:1942-1951. 2. Cahn P, et al. EACS 2015. Abstract PS10/4. 3. Kozal MJ, et al. HIV Clin Trials. 2012;13:119-130. 4. Sued O, et al. IAS 2017. Abstract MOAB0106LB.
*Interim analysis.
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Selected Dual-Therapy Regimens Under Investigation for Initial/Maintenance Therapy
Regimen Treatment Setting Studies
DTG + 3TC
Maintenance § ASPIRE* (randomized phase III)[1]
§ ANRS 167 LAMIDOL* (single-arm phase II)[2]
Initial § GEMINI 1 & 2 (randomized phase III)[3,4]
§ PADDLE* (single-arm phase IV)[5,6]
§ ACTG A5353* (single-arm phase II)[7]
DTG + DRV/RTV Maintenance § DUALIS (randomized phase III)[8]
DRV/RTV + 3TC Maintenance § DUAL-GESIDA* (randomized phase IV)[9]
Initial § ANDES* (randomized phase IV)[10]
ATV/RTV + 3TC Maintenance § SALT* (randomized phase IV)[11] § ATLAS-M* (randomized phase IV)[12]
LA CAB + RPV Maintenance § ATLAS, FLAIR, ATLAS-2M (randomized phase III)[13-15] § LATTE-2* (randomized phase IIb)[16]
*Available data. Slide credit: clinicaloptions.com
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ANDES: DRV/RTV + 3TC vs DRV/RTV + 3TC/TDF in Treatment-Naive Patients at Wk 48
• Randomized,open-labelphaseIVstudyinArgentina
Slide credit: clinicaloptions.com Figueroa MI, et al. CROI 2018. Abstract 489.
DRV/RTV + 3TC QD (n = 75)
DRV/RTV+3TC/TDFQD(n=70)
ART-naive patients with HIV-1 RNA > 1000 c/mL,
no NRTI or PI resistance,
and HBsAg negative (N = 145)
Primary Endpoint Wk 48
Dosing: DRV/RTV, 800/100 mg; 3TC, 300 mg; 3TC/TDF, 300/300 mg.
93 9194 92
0
20
40
60
80
100
AllPts PtsWithBLHIV-1RNA>100,000c/mL(n=35)
Patie
nts
(%)
HIV-1 RNA < 50 copies/mL at Wk 48 (ITT) DRV/RTV + 3TC DRV/RTV + 3TC/TDF
n/N = 70/75 66/70
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Selected Studies of Boosted PI Maintenance Dual Therapy
Study N Regimen Results
SALT[1] 286 ATV/RTV + 3TC § Similar efficacy, less frequent d/c for AEs vs ATV/RTV + 2 NRTIs
ATLAS-M[2] 266 ATV/RTV + 3TC § Improved efficacy, similar safety profile vs ATV/RTV + 2 NRTIs
DUAL-GESIDA[3] 257 DRV/RTV + 3TC § Similar efficacy and tolerability vs DRV/RTV + 2 NRTIs
1. Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784. 2. Di Giambenedetto S, et al. J Antimicrob Chemother. 2017;72:1163-1171. 3. Pulido F, et al. HIV Glasgow 2016. Abstract O331.
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Dual Therapy: bPI Naïve Studies Meta-analysis
InfectionJune2018onlinehttps://doi.org/10.1007/s15010-018-1171-z
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Dual Therapy: bPI Switch Studies Meta-analysis
InfectionJune2018onlinehttps://doi.org/10.1007/s15010-018-1171-z
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Dual Therapy: bPI Naïve Studies Meta-analysis Results
InfectionJune2018online https://doi.org/10.1007/s15010-018-1171-z
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Dual Therapy: bPI Switch Studies Meta-analysis Results
InfectionJune2018onlinehttps://doi.org/10.1007/s15010-018-1171-z
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Dual Therapy: bPI Dual and Switch Studies Meta-analysis
InfectionJune2018onlinehttps://doi.org/10.1007/s15010-018-1171-z
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ANRS 167 LAMIDOL: Switch to DTG + 3TC in Virologically Suppressed Pts on Triple ART
• Open-label,single-arm,multicentertrial
Joly V, et al. CROI 2017. Abstract 458.
DTG 50 mg QD + 2 NRTI†
Pts with HIV-1 RNA ≤ 50 copies/mL
for ≥ 2 yrs on first-line ART; ≤ 2 ART modifications
allowed, except within 6 mos of study start; CD4+ cell count
> 200 cells/mm3
(N = 110)
Wk 8* Wk 56
Primary Endpoint
*Pts with HIV-1 RNA ≤ 50 copies/mL proceeded to phase II. †In phase I, third agent (NNRTI, boosted PI, or INSTI) in regimen replaced with DTG; baseline NRTI backbone maintained.
DTG50mgQD+3TC300mgQD
(n=104)
Phase I Phase II
§ 97%(n/N=101/104)ofptsmaintainedtherapeuticsuccessthrough40wks(studyWk48)
§ 7seriousAEs,only2relatedtodualtherapySlide credit: clinicaloptions.com
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ASPIRE: Switch to DTG + 3TC in Virologically Suppressed Pts on Triple ART
• Randomized,open-label,multicenterphaseIIItrialinwhichptswhowerevirologicallysuppressedon3-drugARTregimenwithnohistoryofVFwererandomizedtoDTG+3TCQDorcontinued3-drugART(N=90)
Taiwo BO, et al. EACS 2017. Abstract PE8/5. Slide credit: clinicaloptions.com
Wk 48 Efficacy
HIV-1 RNA < 50 c/mL
No Data
100
80
60
40
20
0
Pts
(%)
90.9 88.9
2.3 2.2 6.8 8.9
Treatment difference: 2.0% (95% CI: -12.6% to 16.5%)
DTG + 3TC (n = 44) Continued ART (n = 45)
HIV-1 RNA > 50 c/mL
§ Similarlipidchangesbetweenregimens
§ CrClchangesfrombaseline,DTG+3TCvscontinuedART:
– Wk24:–6vs3.6(P<.001)
– Wk48:–3.8vs0(P=.07)
§ SimilarratesofSAEs;1d/cforAEs(DTG+3TCarm,grade2constipation)
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ACTG A5353: DTG + 3TC for ART-Naive Pts • Single-armphaseIIstudy
Slide credit: clinicaloptions.com Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB.
Virologic Outcome at Wk 24, n (%)
Baseline HIV-1 RNA, copies/mL Total
(N = 120) > 100,000 (n = 37)
≤ 100,000 (n = 83)
Success* 33 (89) 75 (90) 108 (90) Nonsuccess 3 (8) 2 (2) 5 (4) Nodata 1 (3) 6 (7) 7 (6)
§ n = 3 with PDVF; n = 1 with emergent M184V and R263R/K mixture – All 3 pts had DTG levels
reflective of suboptimal adherence
*HIV-1 RNA < 50 copies/mL.
ART-naive pts with HIV-1 RNA ≥ 1000 and < 500,000 copies/mL; no RT, INSTI, major PI resistance mutations
(N = 120)
DTG 50 mg + 3TC 300 mg
Primary Endpoint Wk 24
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GEMINI 1 & 2: DTG + 3TC for Treatment-Naive Pts
• Ongoingmulticenter,randomized,double-blind,active-comparatorphaseIIIstudies
Slide credit: clinicaloptions.com ClinicalTrials.gov. NCT02831673. ClinicalTrials.gov. NCT02831764.
DTG + 3TC QD
DTG+FTC/TDFQD
ART-naive pts with HIV-1 RNA > 1000 to ≤ 500,000 copies/mL,
no HBV infection, CrCl ≥ 50 mL/min/1.73 m2
(planned N = 700 for each trial)
Wk 48
Dosing: DTG 50 mg, 3TC 300 mg, FTC/TDF 200/300 mg.
§ Primaryendpoint:proportionwithHIV-1RNA<50copies/mLatWk48
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GEMINI-1 and -2: Virologic Response at Wk 48
CahnP,etal.AIDS2018.AbstractTUAB0106LB.
*ITT-Epopulationexcludingsignificantprotocolviolations.†AdjustedforHIV-1RNA(≤vs>100,000copies/mL),CD4+cellcount(≤vs>200cells/mm3),andstudy(GEMINI-1vsGEMINI-2).
Slidecredit:clinicaloptions.com
VirologicOutcomesbyFDASnapshotAnalysis
DTG+3TC(n=716)DTG+TDF/FTC(n=717)
VirologicSuccess
VirologicNonresponse
NoVirologicData
HIV-1RN
A
<50cop
ies/mL(%
)
ITT-E
DTG+3TC(n=694)DTG+TDF/FTC(n=693)PP*
DTG+TDF/FTC DTG+3TC
-4.4 1.1
-1.7
PercentageDifference
-1.3
-3.9 1.2
ITT-E
PP*
AdjustedTreatmentDifference,†%(95%CI)
100
80
60
40
20
0
9193 9394
3 2 2 1 6 5 5 4
-10 -8 -6 -4 -2 2 108640
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GEMINI-1 and -2: Virologic Response at Wk 48 by Baseline HIV-1 RNA and CD4+ Cell
Count
• TRDFincludesconfirmedvirologicwithdrawal,withdrawalforlackofefficacyortreatment-relatedAEs,andparticipantsmeetingprotocol-definedstoppingcriteria
CahnP,etal.AIDS2018.AbstractTUAB0106LB. Slidecredit:clinicaloptions.com
VirologicOutcomesbyTRDFAnalysisDTG+3TC DTG+TDF/FTC
Patie
ntsW
ithou
tTRD
F(%
)BaselineCD4+
CellCount,cells/mm3
100
80
60
40
20
98 98 99 97 98 100
≤100,000>100,000BaselineHIV-1RNA,c/mL
>200 ≤200
566/576
553/564
138/140
149/153
642/653
647/662
62/63
55/55
98 98
VirologicOutcomesbyFDASnapshotAnalysis
BaselineCD4+CellCount,cells/mm3
100
80
60
40
20
91 94 92 90 93 93
79
93
≤100,000>100,000BaselineHIV-1RNA,c/mL
>200 ≤200
526/576
531/564
129/140
138/153
605/653
618/662
50/63
51/55
Patie
ntsW
ith
HIV-1RN
A<50c/m
L(%
)
n/N=n/N=00
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SWORD-1 and -2: Switch to DTG + RPV vs Continuation in Virologically Suppressed
Adults • Parallel,randomized,open-label,multicenterphaseIIInoninferioritystudies[1,2]
• Primaryendpoint:HIV-1RNA<50copies/mLmaintainedin95%ofpatientsineacharmatWk48;adjustedtreatmentdifference:-0.2%(95%CI:-3.0to2.5)[2]
SwitchtoDTG+RPV(n=513)
ContinueBaselineART(n=511) SwitchtoDTG+RPV
ContinueDTG+RPV
EarlySwitchPhase
1.AboudM,etal.AIDS2018.AbstractTHPEB047.2.LlibreJM,etal.Lancet.2018;391:839-849. Slidecredit:clinicaloptions.com
AdultsonstableART(INSTI,NNRTI,orPI+
2NRTIs)withHIV-1RNA<50copies/mLfor≥6mosatscreening;nopreviousVForcurrentHBVinfection
(N=1024)
LateSwitchPhase
Wk148Wk52CurrentAnalysis
Wk100
DTGdosed50mgPOQD;RPVdosed25mgPOQD.
PrimaryEndpointWk48
*70%to73%ofpatientsreceivingTDFatbaseline.
VirologicResponseWithDTG+RPVbyFDASnapshot
89%
93%
(HIV-1RNA<50copies/mLatWk100)
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SWORD-1 and -2: Bone and Lipid Markers
• AllboneturnovermarkerssignificantlyloweratWk100vsBLexceptprocollagen1N-terminalpropeptideinearlyswitcharm
• Nochangesinlipidlevels(totalcholesterol,LDL-C,HDL-C,triglycerides,totalcholesterol:HDL-Cratio)oratherogenesisandinflammationbiomarkersatWk100vsBLineithergroup
• Earlyswitchgroupmaintainedimprovementsinmarkersofrenaltubularfunction(urineretinol-bindingprotein/creatinineratioandurineβ2-microglobulin/creatinineratio)observedfromBLtoWk48throughWk100
AboudM,etal.AIDS2018.AbstractTHPEB047. Slidecredit:clinicaloptions.com
PValueforChangeFromBLinMeanSerumConcentration
EarlySwitch LateSwitch
Wk48 Wk100 Wk100
Osteocalcin <.001 <.001 <.001
Bone-specificalkalinephosphatase <.001 <.001 <.001
Procollagen1N-terminalpropeptide <.001 - .05
Type1collagen-Ctelopeptide <.001 <.001 .05
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SWORD-1 and -2: Resistance
• 10/990(1%)confirmedvirologicwithdrawalsthroughWk100• Treatment-emergentNNRTIresistancemutationsdocumentedin3/10,allfromearlyswitcharm*
TimeofFailure
PreviousRegimen
MutationsatBaseline
MutationsatConfirmedVirologicWithdrawal
NNRTI INSTI NNRTI INSTIWk36 EFV/TDF/FTC None None K101K/E NoneWk88 DTG/ABC/3TC None None E138E/A None
EFV/TDF/FTC K101E,E138A G193E K101E,E138A,M230M/L Wk100
AboudM,etal.AIDS2018.AbstractTHPEB047. Slidecredit:clinicaloptions.com
*Forthese3patients,HIV-1RNAatlastmeasurement:<50copies/mL,55copies/mL,300copies/mL,respectively.
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DTG/RPV FDA Approved for Maintenance Therapy
• Once-dailysingle-tabletregimenofDTGandRPV• First2-drugSTRFDAapprovedforuseasacompleteregimenintheUS
KeyUSLabelInformation
Indication § For pts who have been virologically suppressed for ≥ 6 mos
§ Pts must have no history of treatment failure and no resistance to DTG or RPV Administration requirements § Must be taken with a meal
Key DDIs § Separate dose of DTG/RPV and antacid/polyvalent cation–containing
medications
§ Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone
Dose adjustments
§ None required for pts with mild/moderate renal impairment; in pts with CrCl < 30 mL/min, increase monitoring for AEs
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LATTE-2: Cabotegravir IM + Rilpivirine IM: Long-Acting Maintenance ART
• Multicenter,open-label,randomizedphaseIIbstudy• Cabotegravir:INSTIformulatedasoraltabletandforlong-actingIMinjection
Margolis DA, et al. IAC 2016. Abstract THAB0206LB. ClinicalTrials.gov. NCT02120352.
CAB 400 mg + RPV 600 mg IM Q4W†
(n = 115)
CAB 600 mg + RPV 900 mg IM Q8W‡
(n = 115)
*Pts with HIV-1 RNA < 50 copies/mL from Wks 16-20 continued to maintenance phase. †CAB loading dose at Day 1. ‡CAB loading doses at Day 1 and Wk 4.
ART-naive HIV-infected pts
> 18 yrs of age with CD4+ cell count > 200 cells/mm3
(N = 309) CAB 30 mg + ABC/3TC 600/300 mg PO QD (n = 56)
CAB 30 mg + ABC/3TC 600/
300 mg PO QD
Wk 32
Wk 20
Induction Phase* Maintenance Phase
Day 1 Wk 96 Wk 16: RPV 25 mg PO QD added Wk 48
Slide credit: clinicaloptions.com
§ Injections were 2-3 mL, IM (gluteal region), provider administered
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LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance
ART • At96wks,~30%ptsreceivingIMinjectionexperiencedISR
• 99%ofISRsmild/moderate• AEsleadingtowithdrawal:pooledQ4W/Q8WIMarms,4%;POarm,2%
• PDVF,n=3(n=1POarm;n=2Q8Warm)• 1ptinQ8WgroupwithK103N,E138G,K238T(NNRTI)andQ148R(INSTI)resistancemutations
• NoadditionalPDVFsafterWk48inanyarm
• PhaseIIImaintenancetrialsongoing:ATLASandFLAIRassessingQ4Wdose;ATLAS-2McomparingQ4WandQ8Wdoses[3-5]
Slide credit: clinicaloptions.com
*HIV-1 RNA < 50 copies/mL.
Virologic Success*
94 87 84
4 0 2 2 13 14
Virologic Nonresponse
No Virologic Data
Pts
(%)
100
80
60
40
20
0
IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) PO CAB + ABC/3TC (n = 56)
Wk 96 Virologic Efficacy
Treatment difference (vs CAB PO): CAB IM Q4W: 3.0% (95% CI: -8.4% to 14.4%)
CAB IM Q8W: 10.0% (95% CI: -0.6% to 20.5%)
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DHHS: Principles of Regimen Switching in Virologically Suppressed Pts
• ReviewARThistoryforintoleranceorpossiblevirologicfailure• Reviewallavailabledrugresistancetestingresults• Ifpriorresistanceuncertain,onlyconsiderswitchifnewregimenlikelytomaintainsuppressionofresistantvirus
• CareneededwhenswitchingfromPI/RTVtoanotherclassiffulltreatmentorresistancehistoryisnotknown
• Consultanexpertwhenswitchingaptwithresistanceto≥1class• Withinclassswitchesusuallymaintainvirologicsuppressionifnoresistancetodrugsinthatclassarepresent
• Increasemonitoringduringfirst3mosafterswitch
DHHS Guidelines.
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DHHS: Guidance for Switching to Dual Therapy in Virologically Suppressed Pts
• DTG+RPVareasonableoptionwhenuseofNRTIsnotdesirableandwhennoexpectedresistancetoregimencomponents
• PI/RTV+3TCmaybeareasonableoptionwhenuseofTDF,TAF,orABCiscontraindicatedornotdesirable
• Insufficientevidencetorecommend:DTG+3TC,DRV/RTV+RAL
• Notrecommended:DTGorPI/RTVmonotherapy,ATV/RTV+RAL• bPI+MVCorNNRTInotnoninferiororsignificantincreasesideeffects
DHHS guidelines. October 2017.
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Summary
• DTG/RPVQDSTRapprovedformaintenancetherapyinvirologicallysuppressedpts
• MaybeparticularlyrelevantforptsforwhomNRTI-containingregimensaresuboptimalduetocomorbiditiesorDDIs
• Additionalregimensunderinvestigation:• DTG+3TC(first-line/maintenance)• BoostedPIs+3TC(first-line/maintenance)• DTG+boostedPIs(maintenance)• LACAB+RPV(maintenance)
Slide credit: clinicaloptions.com
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Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
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Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors (cont’d)
Nonnucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)
Etravirine
Efavirenz
Nevirapine
Rilpivirine
***
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Mutations in the Protease Gene Associated With Resistance to Protease Inhibitors
Atazanavir +/-ritonavir
Darunavir/ ritonavir
Fosamprenavir/ ritonavir
Indinavir/ ritonavir
Lopinavir/ ritonavir
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Mutations in the Integrase Gene Associated With Resistance to Integrase Strand Transfer Inhibitors
Dolutegravir
Elvitegravir
Raltegravir
Bictegravir?
* * *
**
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37
63y/oHIV~1997,psychogenicswallowingdisorder.Previousregimens:3TC,FTC,D4T,TDF,tAF,EVT,RTV,DRV,NVP,ETR.Oftenmissedatleast2-3doses/week.PresentedtoourpracticeforcaretakingEVTc/FTC/tAF.VL67000,CD4141/9%.Genotypeobtainedanddisplayed.
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Impact of M184V on Virologic Efficacy of Switch to 3TC-Based Dual ART
• Retrospectiveobservationalstudycomparingefficacyof3TC-baseddualARTforpatientswithorwithoutM184VhistoryinAntiretroviralResistanceCohortAnalysisdatabase(N=436)
• Inclusioncriteria:HIVRNA≤50copies/mL,switchingtodualtherapy(3TC+eitherPI/RTVorINSTI),≥1priorgenotyping
• M184Vdeterminedinhistoricgenotypicresistancetestsandlastgenotyping
• Primaryendpoint:timetovirologicfailureinM184V-positivevsM184V-negativepatients
Gagliardini R, et al. CROI 2018. Abstract 498. Slide credit: clinicaloptions.com
Dual Therapy Initiated
LPV/RTV + 3TC ATV/RTV + 3TC
DRV/RTV + 3TC
DTG + 3TC
RAL + 3TC
10%
24%
36%
29%
1%
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M184V and Switch to 3TC-Based Dual ART: More Blips But No Greater Risk of Virologic Failure
• Nodifferencein3-yrprobabilityofremainingfreefromvirologicfailurewithoutvswithM184V(P=.323)
• Significantlyhigher3-yrprobabilityofremainingfreefromviralblip‡withoutvswithM184V(log-rankP=.016)
• M184V:79.8%(95%CI:67.8%to91.8%)• NoM184V:90.1%(95%CI:84.0%to96.2%)
Gagliardini R, et al. CROI 2018. Abstract 498. Reproduced with permission. Slide credit: clinicaloptions.com
*VF: 2 HIV-1 RNA findings > 50 c/mL or 1 finding ≥ 200 c/mL. †No VF in 21 pts on DTG + 3TC over median f/u of 10 mos. ‡Viral blip: single HIV-1 RNA finding 51-199 c/mL, not confirmed.
Estimated Probability of Remaining VF-Free on Dual Therapy*†
Pro
porti
on F
ree
From
VF
Yrs From Dual ART Initiation
1.0
0.8
0.6
0.4
0.2
0 0 0.5 1.0 1.5 2.0 2.5 3.0
M184V+ overall M184V- overall M184V+ with time of viral suppression ≤ 6.6 yrs M184V- with time of viral suppression ≤ 6.6 yrs M184V+ with time of viral suppression ≤ 3 yrs M184V- with time of viral suppression ≤ 3 yrs
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Significance of NNRTI Minority Variants
• Evolutionofunderstandingandnewermedications• Degreeofadherence• Priorexperienceinclass• Primaryinfectionvsexperienced
JAIDS2005;38:371,JID2010;201:672-6802,JAMA2011;305:1327-353;AIDS2012;26:185-924;JClinVir2012;55:107-135,CID2018;66(10):1588-94
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Dolutegravir Resistance S230R
• Oneisnotasgoodastwo!(andfarinferiortothree)• DomonoTrial(andSailing)• Mutationsemergedonmonotherapy
modestdecreasedinRCbutwithincreaseinIC50• Previouslybelievedtorequireassociationwithmajormutation• No“major”mutations
• Muchtolearnbut…………………..
NoMonotherapy!JID2018;218:688-97,673-5,698-706
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Think Carefully! • Strategynotforallpatients• Probablynotrapidstartcombination• Noknownbackgroundresistanceinnaïve(transmitted)orswitchpatients• Switchtodualonlyaftersuccessfulsuppressionontripleorspecialcircumstances–currentrecommendations
• Maravirocshouldbeavoidedindualtherapy• PatientshouldnothaveHBV• WatchforDDIandmealrequirements• Ifbliporconcernofadherence/resistance–followcarefullyandcounsel
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Additional Longer-Acting and mAb Investigational Agents (Phase II/III)
Agent MoA Phase Implications
3BNC117[1,2] Anti-CD4 receptor mAb II § Studiesongoingintreatment-experienced
andnaivepts
TMC278LA[3] LAinjectableRPV(IM) II § Potentialaslong-actinginjectable(Q8W)
UB-421[4] Anti-CD4receptormAb II § StudiedaspossibleARTalternativefor
maintenancetherapyinsuppressedpts
VRC01[5,6] Anti-CD4 receptor mAb II § PhaseIIPrEPandtreatmenttrialsongoing
1. Caskey M, et al. Nature. 2015;522:487-491. 2. ClinicalTrials.gov. NCT03041012. 3. Bekker L-G, et al. CROI 2017. Abstract 421LB. 4. Wang C-Y, et al. CROI 2017. Abstract 450LB. 5. ClinicalTrials.gov. NCT02716675. 6. ClinicalTrials.gov. NCT02568215.
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Future?
• Doravirine–NNRTI–approvedSTRandstandalone• Fostemsavir–AttachmentInhibitor• Newcombinations• MonoclonalAntibodyTherapy-Ibalizumab
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Questions?
ThankyouforattendingWehopethishasbeenaworthwhilelearning
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