Overview of An,retroviral Medicaonsbayareaaetc.org/wp-content/uploads/2016/05/Gruta...Overview of...
Transcript of Overview of An,retroviral Medicaonsbayareaaetc.org/wp-content/uploads/2016/05/Gruta...Overview of...
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OverviewofAn,retroviralMedica,ons
Cris%naGruta,PharmDPharmacistSpecialist/Asst.ClinicalProfessor(WOS)
ClinicianConsulta,onCenter
360:ThePosi,veCareCenteratUCSF
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Objec,ves• Describethemechanismofac,onofentryinhibitors,NRTIs,NNRTIs,INSTIs,andPIs
• Discusstheimportanceofadheringtofoodrequirementsforsomean,retrovirals
• Associatecommonadverseeffectswiththeirclassesandfromthatbeabletoorderappropriatelabstomonitorfortoxici,es
• Discussadvantagesanddisadvantagestotheavailablesingle-tabletformula,ons
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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
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EntryInhibitors
CCR5InhibitorsFusionsInhibitors
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Maraviroc(Selzentry®orMVC)• WorksbyblockingCCR5co-receptoroncellsurface
• Approvedfortreatment-experiencedpa,entsandnowalsofornaives
• Virusmustbe“R5tropic”forthisagenttobeeffec,ve– Pa,entmustbescreenedwithtropismassay
• Dosedependsonotheragentsinregimen– 150mg,300mg,or600mgBID– +/-food
• CYP3A4substrate!pronetonumerousdrug-druginterac,ons
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AdverseEffects:Maraviroc
• Abdominalpain• Cough• Dizziness• Fever• Rash• Hepatotoxicity,whichmaybeprecededbysevererashorothersignsofsystemicallergicreac,ons
• Joint-relatedsymptoms• Orthosta,chypotension,especiallyinpa,entswithsevererenalinsufficiency
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NucleosideReverseTranscriptaseInhibitors(NRTI)
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NRTIscanbetakenwithorwithoutfood,exceptddI!emptystomach
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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
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• 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)
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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
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Tenofovir(TDF)renaltoxicity• Maypresentas
– decreasedGFR(↑serumcrea,nine)– Tubulardamage!proteinuria,hypophosphatemia,urinaryphosphatewas,ng,glycosuria,hypokalemia,non-aniongapmetabolicacidosis
– Fanconi’sSyndrome
• FollowScrandUAonptstreatedwithTDF-containingregimens
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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
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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)
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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
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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
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PtMB
• PtMBhasdecidedwithhisprovidertostartaregimenthatcontainsABC
• Whatlabmustbedrawnpriortostar,ngABC?
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• DRis21yomalewhopresentstoyouinyourPrEPclinic.HeisHIV-uninfectedandreportsheisnotaconsistentcondomuser.AzerappropriatescreeninglabsandcounselingheisstartedonTDF/FTC(Truvada)forPrEP.
• Whattoxicitylabsdoyouneedtofollowonaregularbasis?
PtDR(PrEP)
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Non-NucleosideReverseTranscriptaseInhibitors(NNRTI)
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NNRTI-basedsingle-tabletregimens(STRs)
• TDF300mg/FTC200mg/EFV600mg(Atripla®)– onetabletQHSonempty
stomach
• TDF300mg/FTC200mg/RPV25mg(Complera®)
• TAF25mg/FTC200mg/RPV25mg(Odefsey®)– onetabletdailywithfull
meal(≥400calories)
Atripla®Complera®
Odefsey®
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• RASH– Seenin10-30%ofptswhostartNNRTIs
• SJSanderythemamul,formereportedbutverylowincidence• Allrashesshouldbeevaluatedbymedicalprovider
• Hepatotoxicity– Increasedtransaminases– MaybepartofHSRthatincludesrashandcons,tu,onalsxs
– AppearstobemorecommonwithNVPaspartofHSR• SeenmoreinwomenwithCD4>250orinmenwithCD4>400
– Co-infec,onwithHBVorHCVnotconsistentlyposeshigherriskforincreasedlivertoxicity
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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
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PtJF• JFisnewlydiagnosedandwantsasingle-tabletregimen.HeisstartedonTDF/FTC/rilpivirine(Complera®).
• Whatlabsshouldbedrawnnowandrou,nelyfortoxicityfollow-up?
• HowshouldJFbecounseledabouttakinghisregimenwithrespecttomeals?
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IntegraseStrandTransferInhibitor(INSTI)
hsp://www.pnas.org/content/100/19/10581/F1.expansion
INSTIspreventintegra,onofproviralDNAintohostgenome
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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
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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
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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)
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• ApprovedNovember2015• Onetabletdailywithfood• CanbegivensolongasCLcr>30mL/min
Elvitegravir150mg/Cobicistat150mg/TAF10mg/FTC200mg(Genvoya®)
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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
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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
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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)
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ProteaseInhibitors
hsp://www.pnas.org/content/100/19/10581/F1.expansion
Proteasepreventsprocessingoflongpolypep,deprotein
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ProteaseInhibitors(PIs)
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• Exploitstheenzymeinhibi,onproper,esofPIs,especiallyRTV!enhancinglevelsofmainPI
• Cobicistatisapurepharmacoenhancerwithnoan,viralac,vity– AvailableunbundledasTybost®at150mgQD– Co-formulatedinStribild®,Prezcobix®,andEvotaz®
• Pharmacoenhancementallowsfor– Lessenspillburden,#dosesperday– ⇑drugexposure,efficacy
• Theore,calabilitytosuppressresistantHIVstrainsbyenhancementofARVplasmalevels
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• PIsbestiftakenwithfood– Excep,on:IDV800mgq8needsemptystomachorlightmeals
• Foodenhancesabsorp,onofNFV,LPVrsolu,on,ATV,SQV,DRV
• AvoidfasymealswithFPV
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PIAdverseEffects:Class-wide• GIintolerance(n/v/d)
– DiarrheacommonwithNFV>LPVr>>ATVrorDRVr
• Hepatotoxicity• Lipodystrophy• Dyslipidemias• Insulinresistance/hyperglycemia• $BMD,osteopenia/osteoporosis• Possibleincreasedbleedinginhemophiliacs
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PIAdverseEffectsPI Rash EKGchanges Kidney
stonesHighbilirubin
SQV ✔
IDV ✔ ✔
FPV ✔
LPVr ✔
ATV ✔ ✔ ✔ ✔
TPV ✔
DRV ✔
QT,PR
QT,PR
PR
10%
20%
12-19%
3-21%
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PIsandHepatotoxicity
• RTVuselinkedtoincreasedriskofseverehepatotoxicity– Sulkowski,JAMA2000;283:74
• Drug-inducedhepa,,sandhepa,cdecompensa,onobservedwithallPIsatvaryingdegrees–TPVrhashighestrateofevents
• Morecommoninptswithchronicviralhepa,,s(HBV,HCV)– DatadonotsupportwithholdingPIsfromptsco-infectedwithHBVorHCV
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HAARTToxici,es:Lipodystrophy
• Bodyhabituschanges– Centralfataccumula,on(PIsandEFV?)– Peripheralfatwas,ng–associatedwithNRTIs(d4T>ddI>AZT)
• Riskfactors– Femalegender(maybegetitworse)– Olderage– HAART– Proteaseinhibitoruse
• Somesuccessoftrea,nglipoatrophywithpioglitazone
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Dorsocervical fat pad (“buffalo hump’) in HAART-treated patient
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Lipoatrophy
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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
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PIsandInsulinResistance
• ReportedforsomePIs(IDV,LPVr)• Progressiontofrankdiabetesmellituspossible
• Monitorwithfas,ngglucosevalues• ImprovementozenseenwithswitchingoutofPI-basedregimens,butnotalways
• Somesuccessw/me�ormin(Glucophage)
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ART&LowBoneMineralDensity(BMD)
• ObservedinbothART-untreatedaswellasART-treatedindividuals– Likelymul,factoriale,ology!HIVinfec,on,highETOHandtobaccouse,lowvitaminD,ARTuse
• ARTini,a,onhasledtoclinicallysignificantlossinBMD– EarlystudiesasributedbonelosstoPIs– Morerecentstudiespossiblyshowstrongerrela,onshiptoTDFuse
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MBnewregimen• MBhadanega,veHLAB*5701sowasstartedonABC/3TC/DTG(Triumeq)
• Azerhisfirst2weeksontreatment,hedevelopedanall-overbodyrashandMBinsistedonchanginghisregimen.
• TheproviderchangedhistoTAF/FTC+DRVcwiththethinkingthatDTGwastherashculprit.
• Whatshort-termandlong-termtoxici,esdoyoueducateMBaboutonthisnewregimen?
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Thank you!!
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JEOPARDY!!PLEASEBREAKINTOGROUPSFOR