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35.

HIVAntiretroviralAgents
Dr.GailSkowron,4/1/2013
OBJECTIVES
1. HIVSTRUCTUREANDDRUGTARGETS
a. 2singlestrandedRNAmolecules
b. ReverseTranscriptaseenzyme
c. GP120envelopeprotein
d. Allaretargetsofantiretrovirals
2. HIVLIFECYCLEANDDRUGTARGETS
Eachstepinthelifecycleislistedandanydrugstargetingthatsteparelistedbeloweachstep.
Boldedstepshaveunderlineddrugtargets,withexistingtherapynamesandtheyeartheywere
introducedifitwasmentioned.
Iammaintaininghercolorcodingfromlecture,asfollows:
DHHSPREFERREDuseinTreatmentNavePatients
DHHSALTERNATIVEuseinTreatmentNavePatients
DHHSACCEPTABLEuseinTreatmentNavePatients
RARELYusedorofhistoricalimportance
PMTCT=PreventionofMotherToChildTransmission
Treatmentnaive=neverbeentreatedbefore
SheemphasizedthatweshouldknowallthedetailsaboutalldrugsHIGHLIGHTEDINAQUAfirst,andalsotry
andlearnasmuchaspossibleaboutthoseHIGHLIGHTEDINYELLOW.
CD4binding
CoreceptorbindingCCR5orCXCR4=CCR5antagonist
Maraviroc(20072008)
Fusion=Fusioninhibitor
Enfuvirtide
Onlyinjectableandused2xday
Notoftenused
Reversetranscription(vRNAtovDNA)=Reversetranscriptaseinhibitor
NucleoSideAnalogues
Emtricitabine
Lamivudine
Abacavir
Zidovudine(AZT)
NucleoTideAnalogues
Tenofovir
Nonnucleosidereversetranscriptaseinhibitors(NNRTI)
Efavirenz
Rilpivirine
Nevirapine
Etravirine
FormationofDSvDNA(DNADNA)
IntegrationofDSvDNAintohostcellDNA=Integraseinhibitors
Raltegravir(20072008)
Elvitegravir(2012)
Transcription(vRNAgenomeandmRNA)
Translationofviralproteins
Proteinprocessing=Proteaseinhibitors
Amprenavir
Lopinavir
Atazanavir
FosAmprenavir
Tipranavir
Darunavir
Assembly
Release
3. CLINICALGUIDELINESFORANTIRETROVIRALTHERAPY
a. Use3drugsactiveagainstthepatientsvirus
Becausereversetranscriptaseiserrorprone,1/10,000BPshaveamutation...whichis
thetotalamountofBPsinHIV
ThismeansthatvirtuallyeverytimeHIVreplicatesithasatleast1mutation
Theincidenceofmutationmeansthatrandompointmutationseasilyformwhichcan
conferresistanceontheHIV,somonotherapyDOESNOTWORKforHIV
Monotherapywasonlyeffectivefor6monthsatfirstusedjustAZT
Bitherapyisalsonotapermanentsolution
b. Startandstopallatonce
c. Evaluaterisk:benefitratio
d. Simplerregimenspromotesbetteradherenceandimprovedvirologicresponse
Betteradherence=betterresponse
Ifyoudonotkeeptoyourregimen,HIVquicklybecomesresistanttooneorallofthe
drugsyouaretakingtheseareNOTdrugsyoucanforgettotakeforafewdays
Thereareonly27potentialdrugs,andonceyouhaveresistancetoadrug,youcanno
longerusethisdrugandthatiseliminatedasapossibility
e. Thebestregimenistheonethepatientwilltake
Somedrugsworkforsomepeopleandnotothersyouhavetoplayaroundwiththe
drugsthatworkbestforeachpatient
Forexample,somepatientsendupontheir6thor7thregimenbecause15werent
working
4. PHARMACOLOGICPRINCIPLESOFANTIRETROVIRALUSE
a. Mechanismofaction
b. Pharmacokinetics
Dosageforms:intravenous,subcutaneous,oral,inhalation,topical
Bioavailability:drugsandprodrugs
Tissuedistribution
Metabolismanddoseadjustment
ManyagentsaremetabolizedbythehepaticcytochromeP450systemandmay
eitherinhibitorinducemetabolismofotherP450metabolizeddrugs(bothforHIV
andforotherdiseases)
Thissomeunpredicteddruginteractions
ALWAYSLOOKUPDRUGINTERACTIONSandknowthattheremaybe
UNPREDICTEDreactionsbecausethereisnotalwaysgooddataforeachdrug
combination
c. Sideeffects:HIVAssociatedLipodystrophySyndrome
Changesinfatdistribution
SubcutaneousfatwastingDDrugsAZT
Lipoatrophy:sunkencheeks,sunkentemples
FataccumulationProteaseInhibitors
IntraabdominalfatLocalized
BreastenlargementBuffalohump
Metaboliccomplications
Dyslipidemia
Insulinresistance
Diabetesmellitus
d. Druginteractions,includingboosting***
ExploitationofdruginteractionstoincreaseefficacyormetabolismofHIVdrugs
UsemedscapetoLOOKUPDRUGINTERACTIONS
Forexample:simvastatiniscontraindicatedforritonavirtherearecertaindrugsyou
NEVERusewithantiretroviralregimens
e. Combinationstrategies(fixeddosecombinations)***
***TheseareasareuniquetoHIVdrugs,andshedidnottalkabouttheseinreferencetoantiviralsfor
otherviruses.
f. Referto:GuidelinesfortheUseofAntiretroviralAgentsinHIV1InfectedAdults&
Adolescents
Lastupdate12Feb2013
276pages
Thereare3categoriesfordrugs:
Preferredregimens:regimenswithoptimalanddurableefficacy,favorable
tolerabilityandtoxicityprofileandeaseofusethesearefornonpregnantpatients
Alternativeregimens:regimensthatareeffectiveandtolerable,buthavepotential
disadvantageswhencomparedwithpreferredregimensanalternateregimen
maybethepreferredregimenforsomepatients
Here,tomakethingseasy,sheisONLYFOCUSINGonthosedrugsusedforINITIALtherapy,notthoseused
specificallyfordrugexperiencedpeoplewhohavedevelopedresistances.
NotethatweareNOTresponsibleforthe3letterabbreviationsforthenames,justthenamesthemselves.As
mentionedabove,thefocusisonPREFERREDdrugsandlesssoonALTERNATIVE/ACCEPTABLEdrugs.
Wealsodonotneedtoknowthespecificnamesofmutationsthatconferresistance.
Shehasaverydetailedhandoutandsuggestedtouseitifithelps,butnotifitdoesnt.
5. NUCLEOSIDEANALOGUEANDNUCLEOTIDEANALOGUE
a. MechanismofAction
Reversetranscriptaseinhibitors
Twomechanismsofaction:
Competitiveinhibition:e.g.azidothymidine(asAZTTP)competeswithdTTP
Chaintermination:onceAZTTPisincorporatedintothegrowingDNAchain,
naturaldNTPcannotbeadded
b. Pharmacokinetics
Target=viralreversetranscriptase
Plasmahalflifeofparentcompoundmaybeshort,intracellulartriphosphate(activedrug)
haslongerhalflifethanparentcompound
TheparentcompoundisNOTtheactivecompoundtheactivecompoundhasa
longerhalflifethantheparentaround12hours
Whentheyoriginallymeasuredtheplasmahalflife,theyusedtheparent
compoundandendedupoverdosingpeoplewithAZTandhorriblesideeffects
NonehavesignificanteffectonCYP450metabolism
c. Mechanismofresistance
Singleormultiplebasepairmutationsinreversetranscriptase
d. DHHSGuidelinesfortheUseofAntiretroviralAgentsinHIV1infectedAdultsand
Adolescents
Twonucleosideanaloguesformthecornerstoneoftriplecombinationtherapy
PreferredforInitialTherapy
Tenofovir+emtricitabine=Truvada
Formulatedinasinglepill
Alternative
Abacavir+lamivudine=Epzicom
Formulatedinasinglepill
Acceptable
Zidovudine+lamivudine=Combivir
e. AdverseSideEffects
Lacticacidosis,hepaticfatdeposition
Veryrarenow
Stillhaveablackboxwarning,however
Peripheralneuropathy
Canbepermanent
Lipoatrophy,increaselipids
Pancreatitis
MostlyattributabletotheddrugsddC(zalcitabine),ddI(didanosine)andd4T
(stavudine):
Usedextensivelyinthepast
Allhavefallenoutoffavorduetothesesideeffects
Nowweusebettertolerateddrugs
f. ListofDrugs
Tenofovir(TDF)WESHOULDKNOWEVERYTHINGLISTEDBELOWFORTHIS
DRUG
MOA:AnucleoTideanalogue
Tenofovirdisoproxilfumarateistheprodrugoftenofovir
DOSING:1050hourintracellularhalflife
Donthavetorememberthisnumber,butknowitsLONG
Dosed1xday
METABOLISM:Renalexcretion
SIDEEFFECTS:inccreatinine,proteinuria,decbonedensity
Thesewerediscountedearlyon
RESISTANCE:K65R(locationofcodonthatconfersresistance)
OTHER:ActivevsHepatitisB.
MonitorHBV/HIVcoinfectedptsafterstoppingTDFforposttreatment
exacerbationofhepatitis
IfyouhaveapatientwithbothHBVandHIV,choseanagentactive
against,bothbutbecarefulifyoustopyourHIVtherapybecausethenHBV
mightflare
COMBODRUGS:
Truvada(Emtricitabine+Tenofovir)
Atripla(Emtricitabine+Tenofovir+Efavirenz)
Emtricitabine(FTC)ANDLamivudine(3TC)
Thesetwodrugsareanalogues
MOA:AnucleoSideanalogue
DOSING:Dosed1xday
METABOLISM:Renalexcretion
SIDEEFFECTS:Few,extremelywelltolerated
RESISTANCE:M184V,RAPIDLYDEVELOPS
Ifyouskipthispillatall,youwillgetresistance
Bothdrugsshareasinglecodonthatconfersresistance
OTHER:ActivevsHepatitisB
MonitorHBV/HIVcoinfectedptsafterstoppingTDFforposttreatment
exacerbationofhepatitis
COMBODRUGS:
Truvada(Emtricitabine+Tenofovir)
Atripla(Emtricitabine+Tenofovir+Efavirenz)
Abacavir(ABC)
MOA:AnucleoSideanalogue
DOSING:Dosed1xday
METABOLISM:Metabolizedbyalcoholdehydrogenaseintheliver
SIDEEFFECTS:Hypersensitivityreactionin5%
Fever,rash,fatigue,GIorrespiratorysymptoms
Usuallyoccurswithinfirst6weeksoftherapy
DANGER!Rechallenging(i.e.stoppingthemedbecauseofthe
hypersensitivityreactionandthenrestartingitlater)severe
hypotensionanddeath
WecanscreenforthiswithHLAB*5701testingifyouarenegative,you
wontgetthissyndromeweonlygivethedrugtothosenegativefor
HLAB*5701
COMBODRUG:Epzicome(Abacavir+lamivudine)
Zidovudine(AZT)firstdrugevertestedforHIV
MOA:AnucleoSideanalogue
DOSING:Dosed2xday
Thisistheachillesheelofthedrug
METABOLISM:glucuronidatedintheliver
SIDEEFFECTS:anemia,granulocytopenia,nausea
Usedgive2500mgwithseveresideeffects,someofwhicharepermanent
Now,give600mg/daywithlesssideeffects
OTHER:
ExcellentCNSpenetration60%ofplasmathisisimportantbecauseit
canbeusedtotreatpatientswithHIVdementiaorcognitivesymptoms
ImportantcomponentofPMTCT
AvailableforIVuseduringlaboranddelivery(theonlyantiretroviral
thathasanIVform)
Giventoinfantafterbirth
COMBODRUG:Combivir(Zidovudine+lamivudine)
Fixeddosecombinationsmostcommonlygivenasacombinationpill
Truvada
Emtricitabine+Tenofovir
1pill/day
Epzicom
Abacivir+lamivudine
1pill/day
Combivir
Zidovudine+lamivudine
1pill/day
6. NONNUCLEOSIDEREVERSETRANSCRIPTASEINHIBITORS(NNRTIs)
UseNNRTIsbecausenooneeverusesthefullname.
a. Mechanismofaction:Inhibitreversetranscriptaseatadifferentsite
b. Use:PotentinhibitorsofHIV1NOTHIV2(rememberthis!)
c. AdverseSideEffects
Rashisasideeffectcommontotheclass,maybesevere
d. Resistance
Lowgeneticbarriertoresistance=singlepointmutationcausesresistance(efavirenz
&nevirapine)
e. ListofDrugs
EfavirenzKNOWEVERYTHINGBELOWFORTHISItisaverypopulardrug!
MOA:Inhibitreversetranscriptase
DOSING:1xday
METABOLISM:inducessomeP450enzymes,inhibitsothers
SIDEEFFECTS:
CNSorpsychiatricsymptomsin50%(dizziness,impaired
concentration,somnolence,abnormaldreams,insomnia)
Generallyresolvein24weeks.
Mayimprovewithdosingatbedtime(QHS)
Fattyfoodsincabsorption(sodonteatwithfattyfoods)
Rashin27%,generallymildtomoderate
RESISTANCE:K103N(singlemutation)
OTHER:Donotgiveduring1sttrimesterofpregnancy
Now,werecommendNOTtostartthisduringthefirsttrimesterof
pregnancyortogetpregnantifyouareonit
However,ifyougetpregnantwhiletakingit,mostdoctorswillnothaveyou
stopthedrug,becauseusuallybythetimeyoufindoutyouarepregnant
thewindowofopportunityforseriousbirthdefectshaspassedanditstoo
late
COMBODRUG:Atripla
Tritherapyin1pill
Emtricitabine+tenofovir+efavirenz
PREFERREDDHHSregimenfornaivepatients
Onepill,onceaday!
Rilpivirine
MOA:Inhibitreversetranscriptase,activeagainstmutationscausedbyfirst
generationpills
DOSING:1xday
Takewitha500caloriemealthismakesithardforpeoplewithcertain
eatinghabits
Avoidacidreducingagents
SIDEEFFECTS:comparedtoEFV(ATRIPLA),fewerdiscontinuationsforCNS
adverseeffects,fewerlipideffects,fewerrashes
OTHER:NotrecommendedinpatientswithpreRxHIVRNA>100,000copies/mL
COMBODRUG:Complera(Tenofovir+Emtricitabine+Rilpirvirine),1xday
Nevirapine
MOA:Inhibitreversetranscriptase
DOSING
2xdayforgeneric
1xdayforforViramune
METABOLISM:InducesP450metabolism
SIDEEFFECTS:
Rash:greaterseveritythanothersinthecategoryrelatedtoCD4countat
timeofdruginitiation
Elevatedtransaminases
OTHER:
AvoidinwomenwithCD4>250,menwithCD4>400
ImportantcomponentofPMTCT
Give3dosestonewborn
COMBODRUG:2NRTI+Nevirapine
Etravirine(TreatmentExperiencedONLY)
MOA:Inhibitreversetranscriptase
DOSING:2xday
METABOLISM:Hepatic,manydruginteractions
SIDEEFFECTS:Rash,nausea,noCNSsideeffects
RESISTANCE:
2ndgenerationNNRTI,fullyactivevs.K103Nvirus(whichisresistantto
EFV,NVP)
ResistancerequiresmultipleNNRTImutations,Y181Cisakeymutation
MutationinY181Cconfersresistancetotheentireclassofdrugs
OTHER:
AvoidinwomenwithCD4>250,menwithCD4>400
ImportantcomponentofPMTCT
Give3dosestonewborn
Approvedfortreatmentexperiencedpatientsonly
COMBODRUG:Incombinationwithproteaseinhibitor
7. PROTEASEINHIBITORS
a. Mechanismofaction:Targetviralprotease
TheHIVmakesabigpolyproteinstrandwhenittranscribesfromRNA
Thispolyproteinmustbecleavedintoactiveproteins/enzymes
Inhibitsproteolysisofgagandgagpolproteins
Rendersprogenyvirionsnoninfectious
b. Metabolism:allproteaseinhibitorsinhibitP450metabolism
c. Boosting:Ritonavir
SmalldosesofritonavirinhibitP450metabolism,whichincreasesthetroughandAUCof
asecondPI
Becauseallthesedrugshaveshorthalflives,theyusedtohavetobedosedevery812
hoursaddingtinydosesofritonavirprolongsthehalflifeofthesedrugsandallowsthem
tobetakenlessoften
Whenyouaddritonavir,yougetahigherCmaxandCmin(trough)andthisextendsthe
halflife
d. Resistance
BoostedPIshavealowrateofresistanceinbreakthroughvirionsduetohightrough
concentrations
e. DHHSGuidelinesforInitialTherapy
2NRTI(orNRTI+NtRTI)plus:
Preferred
Atazanavir/rtv:2pillsoncedaily
Darunavir/rtv:2pillsoncedaily
Alternative
Fosamprenavir/rtv:onceandtwicedailyregimens
Lopinavir/rtv:2pillstwiceaday
f. ResistanceMutations
Mutationsthatconferresistancetothesedrugsisverycomplex
Thesegenescanaccumulatemanydifferentmutations
g. ListofDrugs
Atazanavir
MOA:Targetviralprotease
DOSING:Dosed1xday
Takewithfood
Protonpumpinhibitors(PPIs),H2blockers(H2B)andantacidsreduce
absorptioncomplexguidelinesforacidreducingagents
METABOLISM:IfgivenwithTDF,mustuseboostedATV/rtv
SIDEEFFECT:Indirect(unconjugated)hyperbilirubinemia
DuetoinhibitionofUDPglucuronosyltransferase(UGT)
Doserelated,higherratewithRTVboosting
Nomedicalconsequence
OTHER:PartofpreferredregimenforPMTCT(justadded)
COMBODRUGS:Atazanavir/rtv:2pillsoncedaily
Darunavir
MOA:Targetviralprotease
SIDEEFFECT:Nausea,diarrhea,headache,skinrash
RESISTANCE:Activeagainstvirusesthatareresistanttomultipleother
proteaseinhibitors(2ndgenerationPI)
OTHER:Containssulfamoietyusewithcautioninpatientswithseveresulfa
allergy
COMBODRUGS:Darunavir/rtv:2pillsoncedaily
FosAmprenavir
MOA:Targetviralprotease
Prodrugofamprenavirwithgreaterbioavailability
DOSING:Usedtobemanypillsaday,nowthereisaformulationthatis2pills,2x
day
OTHER:Containssulfamoietyusewithcautioninpatientswithseveresulfa
allergy
COMBODRUGS:Fosamprenavir/rtv:2pills,2xdaily
Lopinavir/Ritonavir(alwayscoformulated!)=Kaletra
MOA:Targetviralprotease
DOSING:400mglopinavir+100mgritonavir,2xday
Fixeddosecombinationpill(tablet)
200mgplus50mg=2pillstwiceaday
Maybegivenas4pillsonceaday(butthismayworsenside
effects)
The200mgritonavir/dayishigherthanotherboostedPIs(which
are100mg/day)thisworsesideeffects
SIDEEFFECTS:diarrhea,nausea,hyperlipidemia
OTHER:PartofpreferredregimenforPMTCTmostimportantdrug!
COMBODRUGS:Kaletra
8. CCR5ANTAGONIST
a. MechanismofAction:
Thereare2typesofvirus,onethatisCXCR4andonethatisCCR5
ThisdrugonlyblocksthosethatbindCCR5

b. ListofDrugs(only1)
Maraviroc
MOA:CCR5Antagonist
OnlyactiveagainstR5virus
Mustsendtropismtestbeforestarting(Trofiledetects>.3%ofX4
virus)
DOSING:Dosed2xday
RESISTANCE:
Aminoacidsubstitutions/deletionsintheV3loopoftheHIV1envelope
(gp120)allowsvirustocontinuetobindtoCCR5receptor
TropismshiftemergenceofX4ordual/mixedtropicvirusthatisnot
inhibited
Nocrossresistancewithotherclassesbecauseitsabrandnewclass
SIDEEFFECT:generallywelltoleratedorthostatichypotension,especiallyin
patientswithrenalorhepaticdysfunction
COMBODRUGS:
9. HIVINTEGRASEINHIBITORS=INTEGRASESTRANDTRANSFERINHIBITORS(INSTI)
a. MechanismofAction
Thereisapreintegrationcomplexthatforms
Theyblock3processingandstrandtransfer
b. ListofDrugs
Raltegravir
MOA:Bindstopreintegrationcomplex
DOSING:2xday
METABOLISM:notasubstrate,inhibitor,orinducerofCYP3A4primarily
metabolizedbyglucuronidationviaUGT
SIDEEFFECTS:welltolerated,rarelyincreaseCPK,rash(possiblysevere)
RESISTANCE:lowerbarriertoresistancecomparedtoboostedPIsusewith2
otherfullyactiveagents&givetoapatientthatwilltakeitasdirected
COMBODRUG:Usewith2otherfullyactiveagents
Elvitegravir(pluscobicistatakacobi)
MOA:Bindstopreintegrationcomplex
DOSING:1xday
METABOLISM:metabolizedbyCYP3A4,coformulatedwithaCYP3A4
inhibitor,cobicistatwhichboosts
RESISTANCE:crossresistancewithraltegravir
COMBODRUG:Stribild=coformulatedwithtenofovir+emtricitabine+cobicistat
(theQUADpill)LOTSOFdruginteractions
OTHER:DruginteractionsduetoCYP3A4inhibitionbycobicistat
SUMMARY
REVIEWQUIZ
1.WhatisthemechanismofactionforTenofovir?
A.nucleosideanalogue
B.nucleotideanalogue
C.proteaseinhibitor
D.reversetranscriptaseinhibitor
E.CCR5antagonist
2.WhichstrainofHIVisresistanttoTenofovir?
A.K65R
B.K60R
C.K65P
D.M184V
E.K103N
3.WhatisthemechanismofactionforEmtricitabineandLamivudine?
A.nucleosideanalogue
B.nucleotideanalogue
C.proteaseinhibitor
D.reversetranscriptaseinhibitor
E.CCR5antagonist
4.WhatstrainisresistanttoEmtricitabineandLamivudine?
A.K65R
B.K60R
C.K65P
D.M184V
E.K103N
5.WhatisthemechanismofactionforEfavirenz?
A.nucleosideanalogue
B.nucleotideanalogue
C.proteaseinhibitor
D.reversetranscriptaseinhibitor
E.CCR5antagonist
6.WhichstrainisresistanttoEfavirenz?
A.K65R
B.K60R
C.K65P
D.M184V
E.K103N
7.WhatisthemechanismofactionforAtazanavir?
A.nucleosideanalogue
B.nucleotideanalogue
C.proteaseinhibitor
D.reversetranscriptaseinhibitor
E.CCR5antagonist
8.WhatisthemechanismofactionforDarunavir?
A.nucleosideanalogue
B.nucleotideanalogue
C.proteaseinhibitor
D.reversetranscriptaseinhibitor
E.CCR5antagonist
ANSWERS:
1.B.nucleotideanalogue
2.A.K65R
3.A.nucleosideanalogue
4.D.M184V
5.D.reversetranscriptaseinhibitor
6.E.K103N
7.C.proteaseinhibitor
8.C.proteaseinhibitor