the rationale for 2 drug art - acthiv

ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

TheRationalefor2DrugART

Babafemi Taiwo,MBBSGeneStollerman ProfessorofMedicine,InfectiousDisease

Chief,DivisionofInfectiousDiseasesNorthwesternUniversityFeinbergSchoolofMedicine


Disclosure• Dr.TaiwohasservedasapaidconsultanttoViiV Healthcare/GlaxoSmithKline,GileadandJanssen,andreceivedresearchfundingthroughNorthwesternUniversityfromViiV/GlaxoSmithKline.


EvolvingARTGoals

�SaveLives

�Immunerestoration�Durableviralsuppression�End-organoutcomes

�Long-termsuccess�Healthyaging�Qualityoflife


WHATISSUCCESFULART?S=sminusc

S=Successs=suppressionwithoutresistancec=costs(e.g.,toxicity/adverseevents,QOL,andfinancial)

Ø HIVisproneto“overtreatment”Ø AnyunnecessaryARVaddstothe“cost”


Cantwo-drugdual-siteregimensprovidesimilarefficacybutbetterlong-termsafety,costand

druginteractionprofile?


DHHSGuidelinesforARTalreadyincludedualregimens

VIROLOGICALLYSUPPRESSEDINDIVIDUALS


2018DHHSGuidelines

“ThePanelalsonotesthat,traditionally,theGuidelineshaverecommendedstartingART-naivepatientsonaregimenconsistingofatleastthreeactivedrugs,severalstudieshavenownotedthatpersonswithHIVwhohavesustainedviralsuppressionwithnodrugresistancemaybemaintainedonregimensincludingonlytwoactivedrugs”

Panel on Antiretroviral Guidelines for Adults and Adolescents. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March

2018

BT:Eventhisconservativescopecouldcover>50%ofPLWH


2018DHHSTreatmentExperiencedGuidelinesTreatmentMaintenance

DualTherapy

PI/r+3TC(B1)DTG+RPV(A1)

PanelonAntiretroviralGuidelinesforAdultsandAdolescents.GuidelinesfortheUseofAntiretroviralAgentsinAdultsandAdolescentsLivingwithHIV.DepartmentofHealthandHumanServices.Availableathttp://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.AccessedMarch31,2018.


Somerecentcomparativetrialsof2versus3drugARTintreatmentnaïveandsuppressedPLWH

89% 88.3% 91.5%

84% 89.5% 89%

93%

83.7% 90.9%

78% 79.7%

93%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DRV/RTV+RAL LPV/RTV+3TC LPV/RTV+3TC ATV/RTV+3TC ATV/RTV+3TC DRV/RTV+3TC

NEAT GARDEL OLE SALT ATLAS DUAL-GESIDA

NAÏVE TREATMENTEXPERIENCED

2DR3DR

1 2

1

53 4 6

See slide notes for references


MaintenanceDolutegravir +Rilpivirine (SWORD)SnapshotoutcomesatWeek48(pooled)

• Dolutegravir+rilpivirine wasnon-inferiortostandardART

• NoINSTItreatment-emergentresistanceineitherarm

• Aparticipantondolutegravir +rilpivirinehadvirologic reboundwithK101K/E,andre-suppressedwithimprovedadherence

0

20

40

60

80

100

Virologicsuccess

Virologicnon-response

Novirologicdata

HIV

-1 R

NA

<50

c/m

L, %

DTG+RPV(n=513)CAR(n=511)

95 95

<1 15 4

Llibre JM, et al. 24th CROI. Seattle, 2017. Abstract 44LB.

Adjusted Treatment difference: -0.2% (95% CI:-3.0%-2.5%


LATTE2(LACABOTEGRAVIR+RPV)Wk 96

Ø ATLAS, FLAIR, ATLAS 2M

94

4 2

87

0

13

84

2

14

0

20

40

60

80

100

Virologicsuccess

Virologicnonresponse

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

CAB+RPVLAQ8W(n=115)

CAB+RPVLAQ4W(n=115)

CAB+NRTIsPO(n=56)

Margolis DA, et al. Lancet.2017;390(10101):1499-1510


CD4 BINDING

CO-RECEPTOR BINDING

FUSIONBUDDING

HIVViron

gp120

CD4

Assembly

Translation

Viral RNAs

Transcription

Proviral DNA

Reverse transcriptionof viral RNA genome

Integration

ChemokineCo-receptor(CCR5 orCXCR4)

ssRN

MATURATION

NEW HIV VIRON

BothTripleandDualRegimensTargetTwoSteps

Figure adapted from: Reyskens K et al.

Biochimica et Biophysica Acta

2014;1842:256-268.

Ø Doweneedtoblockreversetranscriptionwith2drugs?

EXAMPLE:DTG+TAF/FTCVERSUS

DTG+RPVDTG+3TC


*ThisstudydoesnotyethaveanNCTidentifiernumber.a. JolyV,etal.CROI2017.Poster458;b. Taiwo BO,etal. ClinInfectDis.2017Dec26;.

InvestigationalDTG+3TC:Treatment-ExperiencedPLWH

Study Description: MaintenanceTreatment

LAMIDOL[a]Single-arm,multicenterstudy;104initiatedDTG+3TC97%maintainedVL<50c/mLatwk 40ofdualtherapy,noresistanceemergence

ASPIRE[b]Phase2,randomized,pilotstudyofDTG+3TCvsstandard tripletherapy(N=90)No differenceinsuccessratesatweeks24and48,noresistanceemergence

TANGO* DTG+3TCswitchstudyinpatientsreceivingTAF-containingtripletherapy


DHHSGuidelinesforARTalreadyincludedualregimens

TREATMENTNAÏVEINDIVIDUALS


2018DHHSGuidelinesClass First-line ART

DHHS Recommended RecommendedinCertainSituations

INSTI Dolutegravir/ABC/3TCDolutegravir+FTC/TDForFTC/TAFElvitegravir/COBI/FTC/TAFElvitegravir/COBI/FTC/TDFRaltegravir + FTC/TAF or FTC/TDFBictegravir/FTC/TAF

BoostedDRV orATV +2NRTIs withDRVpreferredoverATVNNRTI +2NRTIs(B)DRV/r+RAL BID(C)LPV/r+3TCBID(C)

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 31, 2018

§ 3TC is the only agent also present in 1998 guidelines§ Safety/cost/access consideration between TDF and TAF


a. CahnP,etal,JIntAIDSSoc. 2017;20:216788;b. Taiwo BO,etal.Clin InfectDis.Nov2017.AbstractMOAB0107LB;c. NCT02831673.ClinicalTrials.gov;d. NCT02831764.ClinicalTrials.gov.

InvestigationalDTG+3TC:Treatment-NaivePatients

Study Description: InitialTreatment

PADDLE[a]Single-arm,pilotstudy,DTG+3TC(N=20)ParticipantshadVL<100,000c/mLandCD4cellcount>200ar screeningAtwk48,90%reachedtheprimaryendpointofaplasmaVL<50c/mL

A5353[b]Phase2,single-arm,pilotstudyofDTG+3TC(N=120;31%VL>100,000c/mL)Atweek24,90%hadVL<50c/mLwithnodifferencebybaselineVL3TCandDTGresistancemutationsemergedin1poorlyadherentpatient

GEMINI1andGEMINI2[c.d]

Phase3,randomized trials (ongoing):DTG+3TCor DTG+TDF/FTCParticipantswithVL£500,000c/mL


DRV/r/3TCFDCforHIV-1Treatment-NaivePatients:Week48ResultsoftheANDESStudy

• 145randomized• 1patientVFatw48onTT• NodifferenceinCD4count(~200cells

increase)• LDLandTriglyceridesnon-significanttrendin

favorofTT• AEdiscontinuationsimilarbetweenarms

Endpoint DualTherapy

TripleTherapy

ITT 93% 94%ITTifVL>100K(24%)

91% 92%

Per Protocol 100% 99%Grade2-4AE(28pts)

11 17

María I.Figueroa etal.CROI2018


Whatisthefutureofdualtherapyinguidelinesandinreality?


PLWHAreOlder

Centers for Disease Control and Prevention. HIV Surveillance Report, 2015; vol. 27. http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html. Published November 2016. Accessed [21Dec2017].

17% ≥50 years

≈50% ≥50 years


ARVDrugsMayIncreasetheRiskofComorbiditiesARVAgent Potentialrisk

Tenofovir Disoproxil Fumarate Renal/bone

Tenofovir Alafenamide ?Exemplifies “overtreatment”

Boosted Pis Possible dyslipidemia/cardiovascularrisk/BOOSTER

Atazanavir Treatment-limitingjaundice

Dolutegravir ?Insomnia

Efavirenz CNS adverseeffects

Abacavir Cardiovascularrisk

Ritonavir orCobicistat Drug-drug interactions

NounnecessaryARVmedicationissafe

FinancialandothercostsaccumulateoverdecadesofART


ClinicalInfectiousDiseases®2016;62(6):784–91

• With50%uptakeof2-drugsforART-naïvepatients,costsavingstotaled$800million,within5years

• Savingsreached>$3billionif25%ofcurrentlysuppressedpatientswereswitchedtoDTG+3TCmaintenance.


TopReasonsCitedinSupportofTripleTherapy

1. Hep Bco-infection–contraindicationUNLESSENTECAVIRisadded2. TAFissosafe,it’sanobrainer3. Compartmentsconcerns4. Failure/resistancefear5. Experiencewithtripletherapy Experience:Repeatingthe

samemistakewithincreasedconfidence


FirstDHHSGuidelines(1998)

Recommended Antiretroviral Agents for Treatment of Established HIV Infection

Preferred Strong evidence of clinical benefit and/or sustained suppression of plasma viral load. Once choice each from column A and column B. Drugs are listed in random, not priority, order:

Column AIndinavir (AI)Nelfinavir (AII)Ritonavir (AI)Saquinavir – SGC* (AII)Ritonavir + Saquinavir SGC or HGC** (BII)Efavirenz (AII)

Column BZDV +ddI (AI)d4T + ddI (AII)ZDV + ddC (AI)ZDV + 3TC† (AI)d4T + 3TC† (AII)

DHHS https://aidsinfo.nih.gov/contentfiles/adultandadolescentgl12011998012.pdf Accessed December 21, 2017,

†optional use is in 3-drug antiretroviral combinations that reduce viral load to undetectable levels.

THE HIV FIELD HAS A TRADITION OF EVIDENCE-DRIVEN PROGRESS


Isitpossiblethatthemajorityof patients donotneed3drugsforover95%oftheir

treatmentlife?


Acknowledgments

• ChicagoAIDSClinicalTrialsUnit• VolunteerPLWH• JudithAberg

the rationale for 2 drug art - acthiv

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