Update on Recommended Antiretroviral Therapy for HIV

Home , Elvitegravir, Integrase inhibitor, Raltegravir

UpdateonRecommended AntiretroviralTherapyforHIV Infection

MichelleLiedtke,Pharm.D.,BCPS,AAHIVP April13,2018

Objective

• Discussguidelinerecommendedinitial antiretroviralagentsandimplicationsfor theiruse

2 PreferredregimensforthetreatmentofHIVin adolescentsandadultsincludewhichofthe followingantiretroviralclasses?(perDHHS guidelines) A. NonͲnucleosidereversetranscriptase inhibitors(NNRTI) B. Proteaseinhibitors(PI) C. Integraseinhibitors(INSTI) D. Alloftheabove

Whototreat?

4 Evolution

1998 CD4<500orVL>20,000

2001 CD4<350orVL>55,000

2004 CD4<350(somewouldwaituntil<200)

2009 CD4<500

2012 AllpatientswithHIVinfection efavirenz,atazanavir/ritonavir, darunavir/ritonavir,raltegravir

Whattotreatwith?

6 2017– PreferredRegimens Nucleoside reverse transcriptase inh Integrase inhibitor abacavir + lamivudine dolutegravir Triumeq® tenofovir disoproxil + emtricitabine elvitegravir (cobicistat) Stribild® tenofovir alafenamide + emtricitabine elvitegravir (cobicistat) Genvoya® dolutegravir tenofovir disoproxil + emtricitabine Tivicay® Truvada® Or tenofovir alafenamide + emtricitabine raltegravir Descovy® Isentress®

2017– PreferredRegimens Nucleoside reverse transcriptase inh Integrase inhibitor abacavir + lamivudine dolutegravir Triumeq® tenofovir disoproxil + emtricitabine elvitegravir (cobicistat) Stribild® tenofovir alafenamide + emtricitabine elvitegravir (cobicistat) Genvoya® dolutegravir tenofovir disoproxil + emtricitabine Tivicay® Truvada® Or tenofovir alafenamide + emtricitabine raltegravir Descovy® Isentress®

PanelonAntiretroviralGuidelinesforAdultsandAdolescents.Guidelinesfortheuseofantiretroviralagentsin HIVͲ1Ͳinfectedadultsandadolescents.DepartmentofHealthandHumanServices.Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf 8 2017– PreferredRegimens Nucleoside reverse transcriptase inh Integrase inhibitor abacavir + lamivudine dolutegravir Triumeq® tenofovir disoproxil + emtricitabine elvitegravir (cobicistat) Stribild® tenofovir alafenamide + emtricitabine elvitegravir (cobicistat) Genvoya® dolutegravir tenofovir disoproxil + emtricitabine Tivicay® Truvada® Or tenofovir alafenamide + emtricitabine raltegravir Descovy® Isentress®

Abacavir

• Onlyrecommendedasapreferredcomponent whenusingthefixedͲdosecombinationof dolutegravir/abacavir/lamivudine(Triumeq®) • Hypersensitivityreactioninupto8%ofpatients • Immunologicbasis • AntigenͲspecificHLAͲB*5701restrictedCD8TͲcell response • OnlyforuseinpatientswhotestHLAͲB*5701 negative

PanelonAntiretroviralGuidelinesforAdultsandAdolescents.GuidelinesfortheuseofantiretroviralagentsinHIVͲ 1Ͳinfectedadultsandadolescents.DepartmentofHealthandHumanServices. 12 TenofovirAlafenamide

ZolopaA.CROI2016:Atlanta,GA 13

TenofovirAlafenamide

• Lowerparenttenofovirconcentrationsin plasma • Lessrenaltoxicity–canbeuseddowntoCrCl 15ml/min • љSerumcreaƟnineincrease • љProteinuria • Significantlysmallerdecreasesinbone mineraldensity

Sax,P,etal.Lancet2015;385:2606Ͳ2615 14 IntegraseInhibitor(INSTI)Pearls

Raltegravir

Dosing Metabolism/Interactions •Isentress®HD(600mg) • UGT1A1glucuronidation 2tabsoncedaily • Limitedinteractions,no •Isentress®(400mg) effectonothersystems 1tabtwicedaily • Ind/Inh ofUGT1A1may poseproblems AdverseEffects • Rifampin • Insomnia,HA,nausea, • Anticonvulsants fatigue,dizziness • Polyvalentcations • Creatine kinaseelevations: myopathy,rabdomyolysis

Raltegravir®PrescribingInformation,revisedNov2017 16 Elvitegravir

Dosing Interactions •Stribild®/Genvoya®* • Cobicistat isaninhibitorof 1taboncedaily(food) CYP3A,CYP2D6,PͲgp, BCRP,OATPs,OCT1and AdverseEffects MATE1 • Nausea,diarrhea,fatigue, • Ind/Inh/Sub:interactions HA • Inh MATE1:decreasing renalsecretionof Metabolism creatinine • Cytochrome3A • Polyvalentcations

*Elvitegravir/cobicistat/tenofovir(disoproxiloralafenamide)/emtricitabine Genvoya®PrescribingInformation,revisedDec2016 17

Dolutegravir

Dosing Metabolism/Interactions •Tivicay®(50mg) • UGT1A1(major)and 1taboncedaily cytochrome3A(minor) 1tabtwicedaily(with • Ind/Inh ofUGT1A1and/or INSTIresistancemutations) CYP3Amayposeproblems •Triumeq®* (possibledoseadjustment 1taboncedaily totwicedaily) • Inh OCT2andMATE1: AdverseEffects decreasingrenalsecretion • Insomnia,HA,nausea, • Metformin fatigue • Creatinine • Polyvalentcations

*Dolutegravir/abacavir/lamivudine Dolutegravir®PrescribingInformation,revisedNov2017 18 PolyvalentCations

• Allintegraseinhibitorshavepotentialfor chelationwhenadministeredwithcations (magnesium,aluminum,calcium,iron) Dolutegravir (DTG) Elvitegravir Raltegravir(RAL) • GiveDTG2hrs • Separate • Coadministration is beforeor6hrs after administrationbyat notrecommended • Withfood,can least2hrs (including • Calciumcanbe coadminister Caand multivitamins) coadministered with Fesupplements RALtwicedaily,but • Noissuewith notrecommended multivitamins withoncedaily

Tivicay®,Genvoya®,Isentress®PrescribingInformation 19

RenalAdjustment

Dolutegravir Elvitegravir Raltegravir • Triumeq®not • Genvoya®not • Noadjustment recommendedfor recommendedfor neededbasedon CrCl<50ml/min CrCl<30ml/min renalfunction • Basedonlamivudine • Stribild®initiationis adjustment notrecommended • Noadjustmentfor forCrCl <70ml/min dolutegravir alone • Stribild® discontinuation recommendedfor CrCl<50ml/min *Note–DTGandcobicistatartificiallyincreaseserumcreatinine duetoinhibitingrenalsecretion

Tivicay®,Genvoya®,Isentress®PrescribingInformation 20 Biktarvy®(Feb2018)

• Bictegravir/tenofoviralafenamide/ emtricitabine • Bictegravir– newestintegraseinhibitor • Verysimilarpk/pdparametersas dolutegravir • Notavailableinindividualcomponents • Notcurrentlyaddressedinguidelines,butwill likelybeadded

Biktarvy®PrescribingInformation,revisedFeb2018 21

PreferredregimensforthetreatmentofHIVin adolescentsandadultsincludewhichofthe followingantiretroviralclasses?(perDHHS guidelines) A. NonͲnucleosidereversetranscriptase inhibitors(NNRTI) B. Proteaseinhibitors(PI) C. Integraseinhibitors(INSTI) D. Alloftheabove

22 Juluca®(Nov2017)

• Dualcombinationdolutegravir/rilpivirine • Indicatedforswitchtherapyinvirologically suppressedpatients • Nothirdantiretroviralrequired

Juluca®PrescribingInformation,revisedDec2017 23

ThankYou