OverviewofAn,retroviralMedica,ons

Cris%naGruta,PharmDPharmacistSpecialist/Asst.ClinicalProfessor(WOS)

ClinicianConsulta,onCenter

360:ThePosi,veCareCenteratUCSF

Objec,ves•  Describethemechanismofac,onofentryinhibitors,NRTIs,NNRTIs,INSTIs,andPIs

•  Discusstheimportanceofadheringtofoodrequirementsforsomean,retrovirals

•  Associatecommonadverseeffectswiththeirclassesandfromthatbeabletoorderappropriatelabstomonitorfortoxici,es

•  Discussadvantagesanddisadvantagestotheavailablesingle-tabletformula,ons

HIVLifeCycle&An%retroviralTreatment

Step 1: Entry (FI and CCR5*I Target)

Step 2: Transcription (NRTI & NNRTI Target)

Step 3: Integration INSTI Target

Step 4: Cleavage (PI Target)

Step 5: Packaging & Budding

EntryInhibitors

CCR5InhibitorsFusionsInhibitors

Maraviroc(Selzentry®orMVC)•  WorksbyblockingCCR5co-receptoroncellsurface

•  Approvedfortreatment-experiencedpa,entsandnowalsofornaives

•  Virusmustbe“R5tropic”forthisagenttobeeffec,ve– Pa,entmustbescreenedwithtropismassay

•  Dosedependsonotheragentsinregimen– 150mg,300mg,or600mgBID– +/-food

•  CYP3A4substrate!pronetonumerousdrug-druginterac,ons

AdverseEffects:Maraviroc

•  Abdominalpain•  Cough•  Dizziness•  Fever•  Rash•  Hepatotoxicity,whichmaybeprecededbysevererashorothersignsofsystemicallergicreac,ons

•  Joint-relatedsymptoms•  Orthosta,chypotension,especiallyinpa,entswithsevererenalinsufficiency

NucleosideReverseTranscriptaseInhibitors(NRTI)

NRTIscanbetakenwithorwithoutfood,exceptddI!emptystomach

Chemical Acronym

Trade Name Strength (mg)/tab

Sig

AZT/3TC (CBV)

Combivir® 300/150 One BID

AZT/3TC/ ABC

(TZV) Trizivir® 300/150/300 One BID

ABC/3TC (EPZ)

Epzicom® 600/300 One QD

TDF/FTC (TRV)

Truvada® 300/200 One QD

TAF/FTC Descovy® 25/200 One QD

NRTICo-Formula,ons

•  AZT:HA,N/V,fa,gue,bonemarrowsuppression

•  ddI,d4T:peripheralneuropathy,pancrea,,s

•  3TC,FTC:HA,nausea(generallywell-tolerated);FTChandrash

•  tenofovir(TDF,TAF):N/V,bloa,ng,flatulence,renaltoxicity(TDF),decreasedbonemineraldensity(TDF)

•  abacavir(ABC):N/V/D,perioralparesthesias,hypersensi,vityreac,on(HSR),increasedMIrisk?

Class-wide:lac,cacidosis,lipoatrophy(moresowithd4T)

AbacavirHypersensi%vityReac%on(HSR)

•  Occursinupto8%ofpa,entsusuallywithinfirst6weeksofstar,ngABC–  Morecommoninwhites5-8%vsblacks2-3%

•  Mostcommonsymptoms:–  Fever,rash,nausea,malaise/fa,gue,GIsymptoms–  Respiratorysymptomsmayoccur–  Symptomstendtoworsenwitheachdose

•  Canbefatalifcon,nuedorrestarted–  NEVERre-challenge

•  HLA-B*5701screening–  Highlysignificantassocia,onbetweenABCHSRandthe

presenceoftheMHCclassIalleleHLA-B*5701–  HLA-B*5701-posi,vepa,entsshouldnotreceiveABC–  Posi,vestatusshouldberecordedasanABCallergy–  Ptsshoulds,llbeeducatedaboutHSRbecauseimperfecttest

Tenofovir(TDF)renaltoxicity•  Maypresentas

–  decreasedGFR(↑serumcrea,nine)–  Tubulardamage!proteinuria,hypophosphatemia,urinaryphosphatewas,ng,glycosuria,hypokalemia,non-aniongapmetabolicacidosis

–  Fanconi’sSyndrome

•  FollowScrandUAonptstreatedwithTDF-containingregimens

Lymphoid Cells

TFV

Plasma

TFV-MP

TFV-DP

TAF

TDF TFV

Gut

TDF

Cathepsin A

TFV

TAF TAF

13

"  TAFismorestableinplasmacomparedwithTDF.1

"  IntactTAFtransitsdirectlyintotargetcellswhereitisintracellularlyac,vatedtotenofovirdiphosphate(TFV-DP).1-3

"  TAFatanequivalentdoseof25mg(10mginboostedregimens)has~90%lowercircula,ngplasmaTFVlevelscomparedtoTDF300mg.4-6

1.  LeeWet.An,micrAgentsChemo2005;49(5):1898-1906. 4.RuaneP,etal.JAcquirImmuneDeficSyndr2013;63:449-5. 2.  BirkusGetal.An,micrAgentsChemo2007;51(2):543-550. 5.SaxP,etal.JAIDS2014.2014Sep1;67(1):52-8.3.  BabusisD,etal.MolPharm2013;10(2):459-66. 6.SaxP,etal.CROI2015.Seasle,WA.#143LB

Tenofoviralafenamide

(TAF)

Tenofovirdisoproxilfumarate

(TDF)

Tenofovir

(TFV)

TenofovirAlafenamide(TAF)

TAFisaTargetedProdrugofTFV-ImprovesIntracellularTFV-DPDelivery&ReducesCircula,ngTFV

PlasmaTFVConcentra,onsStudies104and111:ART-NaïveAdults,Week48CombinedAnalysis

91%reduc%oninTFVplasmaexposureswithE/C/F/TAF

WohlD,etal.CROI2015.Seasle,WA.Oral#113LB

MeanPlasmaTFVCon

centra%on

,ng

/mL(SD)

Time(h)

ECF/TAFScien%ficPointsTAFdevelopedtoimprovethesafetyprofileofTDFandmaintainpotency

•  ECF/TAFconsistentlyshowshighestrateseverreportedofestablishingvirologicsuppressionthrough48weeks

–  92-93%inTreatment-naïveAdults–  91%inTreatment-naïveAdolescents–  92%inRenallyImpairedTreatmentExperiencedPa,ents(eGFR30-69mL/min)–  EfficacyrateconsistentacrossbaselineVL,CD4count,sex,age,race–  Raredevelopmentofresistance:<1%

•  ECF/TAFwelltoleratedthrough48weekswithanimprovedsafetyprofile:–  Discon%nua%onduetoadverseevents<1%intreatmentnaivepa%ents–  Significantimprovementsinmarkersofrenalandbonesafety

•  InARVnaïvepa%ents:–  Nocasesofproximalrenaltubulopathy–  Significantlylessimpactonmul,plemeasuresofrenalfunc,onincluding

proteinuria–  SignificantlylessimpactoneGFR–  SignificantlylessimpactonspineandhipBMD–  IncreaseinBMDinadolescentpopula,onconsistentwithage-adjustedexpected

norms•  InARVtreatedpa%entswithrenalimpairment,aswitchtoECF/TAFresultedin

–  SignificantincreaseinspineandhipBMD–  Significant,rapid,anddurableimprovementinmul,plemeasuresofproteinuria

–  Similarlipidimpactvs.otherNRTIbackbones•  SimilarchangeinTC:HDLra,ovs.TDFbasedregimen

15

NRTIToxi,c,es:Lac,cAcidemia/Acidosis

•  Rarebutpoten,allyfatalsyndrome•  LinkedtoprolongeduseofNRTIs(d4T,ddI>AZT)•  Insidiousonset!abdominalpain,lethargy,fa,gue•  Mayberapidlyprogressivewithtachycardia,

tachypnea,jaundice,muscularweakness,mentalstatuschanges,respiratorydistress,pancrea,,s,andorganfailure

•  Mortalityupto50%insomecaseseries,especiallyinpa,entswithserumlactate>10mmol/L

•  Labfindings:lactate>5mmol/L;increasedaniongap,#LFTs,$arterialpH

•  E,ology:?mitochondrialdysfunc,on

PtMB

•  PtMBhasdecidedwithhisprovidertostartaregimenthatcontainsABC

•  Whatlabmustbedrawnpriortostar,ngABC?

•  DRis21yomalewhopresentstoyouinyourPrEPclinic.HeisHIV-uninfectedandreportsheisnotaconsistentcondomuser.AzerappropriatescreeninglabsandcounselingheisstartedonTDF/FTC(Truvada)forPrEP.

•  Whattoxicitylabsdoyouneedtofollowonaregularbasis?

PtDR(PrEP)

Non-NucleosideReverseTranscriptaseInhibitors(NNRTI)

NNRTI-basedsingle-tabletregimens(STRs)

•  TDF300mg/FTC200mg/EFV600mg(Atripla®)–  onetabletQHSonempty

stomach

•  TDF300mg/FTC200mg/RPV25mg(Complera®)

•  TAF25mg/FTC200mg/RPV25mg(Odefsey®)–  onetabletdailywithfull

meal(≥400calories)

Atripla®Complera®

Odefsey®

•  RASH–  Seenin10-30%ofptswhostartNNRTIs

•  SJSanderythemamul,formereportedbutverylowincidence•  Allrashesshouldbeevaluatedbymedicalprovider

•  Hepatotoxicity–  Increasedtransaminases– MaybepartofHSRthatincludesrashandcons,tu,onalsxs

–  AppearstobemorecommonwithNVPaspartofHSR•  SeenmoreinwomenwithCD4>250orinmenwithCD4>400

–  Co-infec,onwithHBVorHCVnotconsistentlyposeshigherriskforincreasedlivertoxicity

NNRTIs:AdverseEffects•  CNSeffects

–  EFV!seda,on,insomnia,vividdreams,dizziness,confusion,feelingof“disengagement”

–  RPV!insomnia,depression,HA•  EFVteratogenicity–categoryDdrug

–  Rarereportsofneuraltubedefects–  Currenttakeofteratogenicityrisk!birthdefectratenohigheronEFVvsbaselinerateingeneralpopula,on

– AvoidifintendingtogetpregnantbutEFVactuallyapreferredcomponentintrea,ngHIVpregnantwomen>8weeksofpregnancy

PtJF•  JFisnewlydiagnosedandwantsasingle-tabletregimen.HeisstartedonTDF/FTC/rilpivirine(Complera®).

•  Whatlabsshouldbedrawnnowandrou,nelyfortoxicityfollow-up?

•  HowshouldJFbecounseledabouttakinghisregimenwithrespecttomeals?

IntegraseStrandTransferInhibitor(INSTI)

hsp://www.pnas.org/content/100/19/10581/F1.expansion

INSTIspreventintegra,onofproviralDNAintohostgenome

IntegraseStrandTransferInhibitor(INSTI)INSTI Formula%ons(adult) Dosing STR(YesorNo)

Raltegravir(RAL,Isentress®)

•  400mgtablet •  OnetabBID No

Elvitegravir(EVG,Vitekta®,inStribild®,inGenvoya®)

•  85mg,150mg(Vitekta)

•  150mginStribildorGenvoya(with150mgcobicistat/200mgFTC)/300mgTDForTAF10mg

•  85mgQD*or150mgQD#

•  OnetabQD

Yes(Stribild,Genvoya)

Dolutegravir(DTG,Tivicay®,inTriumeq®)

•  50mg•  50mginTriumeq

(with600mgABC/300mg3TC)

•  OnetabQD•  OnetabQD

Yes(Triumeq)

*#-co-administeredwithRTV-boostedPI

Raltegravir(Isentress®orRAL)

•  FirstdruginINSTIclass•  Verypotentdrugiftakenwithotherac,veARVagents

•  Approvedfortreatment-naïveandtreatment-experiencedpts

•  Dose400mgBID(+/-food)•  AEs–nausea,rash(includingSJS,TEN),diarrhea,HA,fevers,myopathy,CPKeleva,ons

•  Interac,onpoten,al–minimalwithdrugsmetabolizedthroughp450isoenzymes

Elvitegravir150mg/Cobicistat150mg/TDF300mg/FTC200mg(Stribild®)

•  FirstINSTISTFapproved2012fortreatment-naïvepts•  Dose:onetabletdailywithfood•  EVGmetabolizedthroughCYP3A•  Containscobicistat–pharmacologicenhancerNOTac,ve

againstHIV•  CobicistatcanincreaseScrby0.2-0.4!compe,,ve

secre,on•  CannotbestartedifCLcr<70mL/min;mustbe

discon,nuedifCLcrdrops50mL/min•  MostcommonAEs

–  Nausea16%,diarrhea12%–  Proteinuria39%(vs29%withAtripla)

•  ApprovedNovember2015•  Onetabletdailywithfood•  CanbegivensolongasCLcr>30mL/min

Elvitegravir150mg/Cobicistat150mg/TAF10mg/FTC200mg(Genvoya®)

VirologicandImmunologicOutcomesatWeek48

•  E/C/F/TAFwasnon-inferiortoStribildatWeek48ineachstudy–  93%E/C/F/TAFvs92%Stribild(Study104)–  92%E/C/F/TAFvs89%Stribild(Study111)

•  IncreaseinCD4count(cells/μL)atWeek48–  E/C/F/TAF:+211vsStribild:+181(P=0.024)

Studies104and111:ART-NaïveAdults,Week48CombinedAnalysis

FavorsE/C/F/TAF

0

4.7% ‒0.7%

2.0%

HIV-1RNA<50c/m

L,%

92

4 4

90

4 6

0

20

40

60

80

100

VirologicSuccess

VirologicFailure

NoVirologicData

E/C/F/TAF(n=866)Stribild(n=867)

TreatmentDifference(95%CI)VirologicOutcome

‒12% +12%

FavorsStribild

WohlD,etal.CROI2015.Seasle,WA.Oral#113LB

CommonAdverseEvents(≥5%)ThroughWeek48

Adverse event (all grades), % E/C/F/TAFn=866

Stribildn=867

Diarrhea 17 19 Nausea 15 17 Headache 14 13 Upper respiratory tract infection 11 13 Nasopharyngitis 9 9 Fatigue 8 8 Cough 8 7 Vomiting 7 6 Arthralgia 7 5 Back pain 7 7 Insomnia 7 6 Rash 6 5 Pyrexia 5 5 Dizziness 5 4

Studies104and111:ART-NaïveAdults,Week48CombinedAnalysis

RatesandtypesofAEsweresimilarbetweenbotharms.Nonewsafetyfindings.

WohlD,etal.CROI2015.Seasle,WA.Oral#113LB

Dolutegravir(DTG,Tivicay®,inTriumeq®)•  ThirdINSTIinmarketapprovedAugust2013•  50mgoncedailywithorwithoutfood•  Co-formulatedwithABC600mg/3TC300mgas2ndINSTI-basedSTR--onetabletoncedaily

•  ApprovedforART-naïveand–experiencedpa,ents•  AEs–insomnia,HA,rareHSRs(rash,liverinjury)•  NeedHLAB*5701testifconsideringSTR•  MetabolizedthroughUGT1A1(major),CYP3A4

–  DoseincreasetoBIDifco-administeredwithpotentliverenzymeinducers(EFV,rifampin)

ProteaseInhibitors

hsp://www.pnas.org/content/100/19/10581/F1.expansion

Proteasepreventsprocessingoflongpolypep,deprotein

ProteaseInhibitors(PIs)

•  Exploitstheenzymeinhibi,onproper,esofPIs,especiallyRTV!enhancinglevelsofmainPI

•  Cobicistatisapurepharmacoenhancerwithnoan,viralac,vity– AvailableunbundledasTybost®at150mgQD–  Co-formulatedinStribild®,Prezcobix®,andEvotaz®

•  Pharmacoenhancementallowsfor–  Lessenspillburden,#dosesperday–  ⇑drugexposure,efficacy

•  Theore,calabilitytosuppressresistantHIVstrainsbyenhancementofARVplasmalevels

•  PIsbestiftakenwithfood– Excep,on:IDV800mgq8needsemptystomachorlightmeals

•  Foodenhancesabsorp,onofNFV,LPVrsolu,on,ATV,SQV,DRV

•  AvoidfasymealswithFPV

PIAdverseEffects:Class-wide•  GIintolerance(n/v/d)

– DiarrheacommonwithNFV>LPVr>>ATVrorDRVr

•  Hepatotoxicity•  Lipodystrophy•  Dyslipidemias•  Insulinresistance/hyperglycemia•  $BMD,osteopenia/osteoporosis•  Possibleincreasedbleedinginhemophiliacs

PIAdverseEffectsPI Rash EKGchanges Kidney

stonesHighbilirubin

SQV ✔

IDV ✔ ✔

FPV ✔

LPVr ✔

ATV ✔ ✔ ✔ ✔

TPV ✔

DRV ✔

QT,PR

QT,PR

PR

10%

20%

12-19%

3-21%

PIsandHepatotoxicity

•  RTVuselinkedtoincreasedriskofseverehepatotoxicity–  Sulkowski,JAMA2000;283:74

•  Drug-inducedhepa,,sandhepa,cdecompensa,onobservedwithallPIsatvaryingdegrees–TPVrhashighestrateofevents

•  Morecommoninptswithchronicviralhepa,,s(HBV,HCV)– DatadonotsupportwithholdingPIsfromptsco-infectedwithHBVorHCV

HAARTToxici,es:Lipodystrophy

•  Bodyhabituschanges–  Centralfataccumula,on(PIsandEFV?)–  Peripheralfatwas,ng–associatedwithNRTIs(d4T>ddI>AZT)

•  Riskfactors–  Femalegender(maybegetitworse)–  Olderage–  HAART–  Proteaseinhibitoruse

•  Somesuccessoftrea,nglipoatrophywithpioglitazone

Dorsocervical fat pad (“buffalo hump’) in HAART-treated patient

Lipoatrophy

ARVsandDyslipidemiasandCAD/MIs

•  #TGs,#LDL,#HDL!allRTV-boostedPIs•  Hypertriglyceridemia!riskofpancrea,,s•  Generallytreatedw/fibratesand/orsta,ns•  Inconsistentresultsfromswitchstudies

–  EFValsocan#TGs,LDL,HDL–  d4T>AZT>ABCcanalso#TGsandLDL

•  Bewareofdruginterac,ons,riskofmyosi,s•  Cohortstudiessuggest#CAD/MIs/CVAspoten,allylinkedtoPIuse

•  Conflic,ngresultsregardingABCuseandassocia,onwith#MIrisk

PIsandInsulinResistance

•  ReportedforsomePIs(IDV,LPVr)•  Progressiontofrankdiabetesmellituspossible

•  Monitorwithfas,ngglucosevalues•  ImprovementozenseenwithswitchingoutofPI-basedregimens,butnotalways

•  Somesuccessw/me�ormin(Glucophage)

ART&LowBoneMineralDensity(BMD)

•  ObservedinbothART-untreatedaswellasART-treatedindividuals– Likelymul,factoriale,ology!HIVinfec,on,highETOHandtobaccouse,lowvitaminD,ARTuse

•  ARTini,a,onhasledtoclinicallysignificantlossinBMD– EarlystudiesasributedbonelosstoPIs– Morerecentstudiespossiblyshowstrongerrela,onshiptoTDFuse

MBnewregimen•  MBhadanega,veHLAB*5701sowasstartedonABC/3TC/DTG(Triumeq)

•  Azerhisfirst2weeksontreatment,hedevelopedanall-overbodyrashandMBinsistedonchanginghisregimen.

•  TheproviderchangedhistoTAF/FTC+DRVcwiththethinkingthatDTGwastherashculprit.

•  Whatshort-termandlong-termtoxici,esdoyoueducateMBaboutonthisnewregimen?

Thank you!!

JEOPARDY!!PLEASEBREAKINTOGROUPSFOR