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AntiretroviralTherapyforHIVInfection
Updated:Apr06,2016
Author:RChrisRathbun,PharmD,BCPS,AQID,AAHIVPChiefEditor:JohnBartlett,MDmore...
OVERVIEW
Overview
Background
Anestimated33millionpeopleareinfectedwithHIVworldwide.[1]IntheUnitedStates,morethan1.2
millionpeoplehaveHIVinfection,andalmost1in7(14%)areunawareoftheirinfection.The
estimatedincidenceofHIVintheUnitedStateshasremainedstableinrecentyears,atabout50,000
newinfectionsoccurringeachyear.[2]
Significantadvancesinantiretroviraltherapyhavebeenmadesincetheintroductionofzidovudine
(AZT)in1987.
Withtheadventofhighlyactiveantiretroviraltherapy(HAART),HIV1infectionisnowmanageableas
achronicdiseaseinpatientswhohaveaccesstomedicationandwhoachievedurablevirologic
suppression.[3]
ExcessmortalityamongpatientswithAIDSwasnearlyhalvedintheHAARTera(seetheimage
below),butitremainsapproximately5timeshigherinpatientswithAIDSthaninHIVinfectedpatients
withoutAIDS.Thestrongestriskfactorsforexcessmortalitywereviralloadgreaterthan400
copies/mL(comparedwith<400copies/mL),CD4+countlessthan200cells/mL(comparedwith>200
cells/mL),andcytomegalovirusretinitis.[4]
ChangesinsurvivalofpeopleinfectedwithHIV.Astherapieshavebecomemoreaggressive,theyhavebeen
moreeffective,althoughsurvivalwithHIVinfectionisnotyetequivalenttothatinuninfectedpeople.Modifiedfrom
anoriginalpublishedbyLohseetal(2007),"SurvivalofpersonswithandwithoutHIVinfectioninDenmark,1995
2005."
TheCD4+cellcountthresholdsforHAARTinitiationwererecentlyraisedfrom350to500cells/mLin
theUnitedStatesandfrom200to350cells/mLinmidandlowincomecountries.Datasuggestthat
theserecommendationsmeanasubstantialincreaseinthenumberofpatientswhowillrequire
treatmentandneedearlyHIVtesting.[5]
HAARTprovideseffectivetreatmentoptionsfortreatmentnaiveandtreatmentexperiencedpatients.
Sixclassesofantiretroviralagentscurrentlyexist,asfollows:
Nucleosidereversetranscriptaseinhibitors(NRTIs)
Nonnucleosidereversetranscriptaseinhibitors(NNRTIs)
Proteaseinhibitors(PIs)
Integraseinhibitors(INSTIs)
Fusioninhibitors(FIs)
Chemokinereceptorantagonists(CCR5antagonists)
EachclasstargetsadifferentstepinthevirallifecycleasthevirusinfectsaCD4+Tlymphocyteor
othertargetcell.Theuseoftheseagentsinclinicalpracticeislargelydictatedbytheireaseor
complexityofuse,sideeffectprofile,efficacybasedonclinicalevidence,practiceguidelines,and
clinicianpreference.
Resistance,adverseeffects,pregnancy,andcoinfectionwithhepatitisBvirus,orhepatitisCvirus
presentimportantchallengestoclinicianswhenselectingandmaintainingtherapy.
Thisarticlereviewsthemechanismofaction,resistance,pharmacokinetics,andadverseeffectsof
eachoftheseclasses,aswellascurrenttreatmentguidelinesfortheiruseinadultsandadolescents
withHIVinfection.Alsodiscussedaretheimportantchallengesinvolvedinselectingandmaintaining
antiretroviraltherapyforpregnantwomenandpatientswithacuteHIVinfection,hepatitisBorC
coinfection,orMycobacteriumtuberculosiscoinfection.
ForadditionalinformationonHIVdisease,seetheMedscapeReferencearticlesHIVDiseaseand
PediatricHIV.
TableofFDAApprovedAntiviralsandRegimens
IndividualantiretroviraldrugsaredescribedinTable1,below.
Table1.ClassificationandSummaryofUSFDAApprovedAntiretroviralAgents[6](OpenTableina
newwindow)
Name
Dosage
Form(s)
AdultDose
AdverseEvents
Nucleosidereverse
transcriptaseinhibitors
(NRTIs)
300mg
tablet
Abacavir(Ziagen)
20mg/mL
600mgPOqdor
Hypersensitivityreaction
(mayincludefever,rash,
nausea,vomiting,
diarrhea,malaise,
shortnessofbreath,
cough,pharyngitis)
oral
solution
300mgPObid
patientspositiveforHLA
B*5701areathighestrisk
forhypersensitivity
(performHLAscreening
beforeinitiating)
>60kg:400mgPOqd
125mg,
200mg,
250mg,
400mg
enteric
coated
capsule
<60kg:250mgPOqd
Take30minacor2hr
pc
Didanosine(Videx,Videx
EC)
Peripheralneuropathy,
pancreatitis,nausea,
lacticacidosis
10mg/mL
suspension
Oralsolution:Divide
dailydosebid
200mg
capsule
Emtricitabine(Emtriva)
10mg/mL
oral
solution
150mg,
300mg
tablet
Lamivudine(Epivir)
10mg/mL
oral
solution
15mg,20
mg,30mg,
200mgPOqdor
240mg(24mL)oral
solutionPOqd
Minimaltoxicity,
hyperpigmentation
300mgPOqdor
150mgPObid
Minimaltoxicity,severe
acuteexacerbationof
hepatitismayoccurwith
HBVcoinfectionupon
discontinuation
40mg
capsule
>60kg:40mgPObid
Stavudine(Zerit)
1mg/mL
oral
solution
Tenofovir(Viread)
300mg
tablet
Peripheralneuropathy,
pancreatitis,lactic
acidosis,lipoatrophy,
hyperlipidemia
<60kg:30mgPObid
300mgPOqd
Nausea,vomiting,
diarrhea,headache,
asthenia,renal
insufficiency[7]
0.75mgPOtid
Peripheralneuropathy,
pancreatitis,lactic
acidosis,stomatitis
Zalcitabine(Hivid)
Productdiscontinued
0.375mg,
0.75mg
tablet
300mg
tablet100
mg
capsule
300mgPObidor
Zidovudine(Retrovir)
10mg/mL
oral
solution
200mgPOtid
Nausea,vomiting,
headache,asthenia,
anemia,neutropenia
10mg/mL
intravenous
solution
Nonnucleosidereverse
transcriptaseinhibitors
(NNRTIs)
Delavirdine(Rescriptor)
100mg,
200mg
400mgPOtid
Rash,headache
tablets
600mg
tablet
Efavirenz(Sustiva)
50mg,
200mg
capsule
600mgPOqd
Takeonempty
stomachtodecrease
adverseeffects
Rash,CNS(eg,
somnolence,vivid
dreams,confusion,visual
hallucinations),
hyperlipidemia
100mg,
200mg
Etravirine(Intelence)d
200mgPObid
200mg
tablet400
mgXR
tablet
Nevirapine(Viramune,
ViramuneXR)
10mg/mL
suspension
Rilpivirine(Edurant)
Rash,nausea
tablets
25mg
tablet
200mgPObida
XR:400mgPOqd
25mgPOqdwitha
meal
Rash,hepatitis
Depressivedisorders,
insomnia,headache,rash
Proteaseinhibitors(PIs)
400mgPOqdor
Atazanavir(Reyataz)
100mg,
150mg,
200mg,
300mg
capsules
300mg+ritonavir100
mgPOqd
Indirect
hyperbilirubinemia,
prolongedPRinterval,
hyperglycemia,skinrash
(20%),hyperlipidemia
Darunavir(Prezista)
75mg,
150mg,
300mg,
400mg,
600mg
tablets
700mg
tablet
Fosamprenavir(Lexiva)
50mg/mL
oral
suspension
800mgqd+ritonavir
100mgPOqdbor600
mgbid+ritonavir100
mgPObid
Rash,nausea,diarrhea,
hyperlipidemia,
hyperglycemia
700mgbid+ritonavir
100mgPObidor1400
mgPObidor1400mg
+ritonavir100200mg
POqdb
Suspension:Take
withoutfood
Rash,nausea,vomiting,
diarrhea,hyperlipidemia,
hyperglycemia
BoostedwithRTV:
Takewithfood
800mgPOq8h
Indinavir(Crixivan)
100mg,
200mg,
400mg
capsules
100mg/25
mg,200
mg/50mg
tablets
Lopinavir/ritonavir
(Kaletra)
80mg/20
mgpermL
800mgPObid+
ritonavir100200mg
PObid
Take1hacor2hpc
maytakewithskim
milkorlowfatmeal
Nephrolithiasis,nausea,
indirect
hyperbilirubinemia,
hyperlipidemia,
hyperglycemia
400mg/100mgPObid
or
800mg/200mgPO
qdb
Nausea,vomiting,
diarrhea,asthenia,
hyperlipidemia,
hyperglycemia
oral
solution
Oralsolution:Takewith
meals
1250mgPObidor
250mg,
625mg
tablets,
Nelfinavir(Viracept)
50mg/g
oral
powder
750mgPOtid
(Nelfinavircannotbe
boosted)
Diarrhea,hyperlipidemia,
hyperglycemia
Takewithfood
100mg
tablet100
mgsoft
gelatin
capsule
Boostingdoseforother
proteaseinhibitors:
100400mg/d(referto
otherprotease
inhibitorsforspecific
dose)
Ritonavir(Norvir)
80mg/mL
oral
solution
Nonboostingdose
(Ritonavirusedassole
proteaseinhibitor):600
mgbidc
Nausea,vomiting,
diarrhea,asthenia,
hyperlipidemia,oral
paresthesias,
hyperglycemia
1000mg+ritonavir
100mgPObid
500mg
tablet
Unboostedsaquinavir
isnotrecommended
Saquinavir(Invirase)
200mg
hard
gelatin
capsule
Takewithfood,or
Nausea,diarrhea,
headache,
hyperlipidemia,
hyperglycemia,PRand
QTintervalprolongation
within2hpc
250mg
softgelatin
capsule
Tipranavir(Aptivus)d
100mg/mL
oral
solution
500mg+ritonavir200
mgPObid
Unboostedtipranaviris
notrecommended
Hepatotoxicity,rash,
hyperlipidemia,
hyperglycemia,
intracranialhemorrhage
(rarecasesreported)
Integraseinhibitors(II)
400mgPObid
Raltegravir(Isentress)
400mg
tablet
Withrifampin:800mg
PObid
Nausea,diarrhea,
headache,CKelevations,
myopathy/rhabdomyolysis
(rare)
50mgPOoncedaily
Dolutegravir(Tivicay)
50mg
tablet
WithUGT1A/CY3A
inducers(eg,efavirenz,
fosamprenavir/ritonavir,
tipranavir/ritonavir,
rifampin):50mgPO
BID
CholesterolandTG
elevations,CKelevations,
liverenzymeelevations,
hyperglycemia
85mgPOoncedaily
plusatazanaviror
lopinavirplusritonavir
85mg,
or
Immunereconstitution
Elvitegravir(Vitekta)f
150mg
tablet
syndrome
150mgPOoncedaily
plusdarunaviror
fosamprenaviror
tipranavirplusritonavir
Chemokinereceptor
antagonist(CCR5
antagonist)
300mgPObid
Maraviroc(Selzentry)
150mg,
300mg
tablets
150mgPObid
(CYP3A4inhibitors
inducers)
Constipation,dizziness,
infection,rash
600mgPObid
(CYP3A4inducers)
Fusioninhibitor(FI)
Enfuvirtide(Fuzeon)d
Combination
formulations
Stribildelvitegravir(150
mg)+cobicistate(150mg)
+emtricitabine(200mg)+
tenofovirDF(300mg)qd
thisisacompleteonce
dailyregimen
Genvoyaelvitegravir
(150mg)+cobicistat(150
mg)+emtricitabine(200
90mg/mL
powderfor
injection
90mgSCbid
Injectionsitereactions
(eg,pain,erythema,
induration,nodules)
mg)+tenofovirAFg(10
mg)qdthisisacomplete
oncedailyregimen
Odefseyemtricitabine
(200mg)+rilpivirine(25
mg)+tenofovirAF(25
mg)qdthisisacomplete
oncedailyregimen
Descovyemtricitabine
(200mg)+tenofovirAF
(25mg)qd
EpzicomAbacavir(600
mg)+lamivudine(300
mg)qd
TriumeqAbacavir(300
mg)+dolutegravir(50
mg)+lamivudine(300
mg)qd
TrizivirAbacavir(300
mg)+lamivudine(150
mg)+zidovudine(300
mg)bid
TruvadaTenofovirDF
(300mg)+emtricitabine
(200mg)qd
AtriplaTenofovirDF(300
mg)+emtricitabine(200
mg)+efavirenz(600mg)
qd
CompleraTenofovirDF
(300mg)+emtricitabine
(200mg)+rilpivirine(25
mg)qd
CombivirZidovudine
(300mg)+lamivudine
(150mg)bid
EvotazAtazanavir(300
mg)+cobicistat(150mg)
qd
PrezcobixDarunavir
ethanolate(800mg)+
cobicistat(150mg)qd
*Dosingguidesassume
anabsenceofdrugdrug
interactions(except
ritonavir)andnormalrenal
andhepaticfunction.
aAdminister200mgqd
for2weeks,thenincrease
to200mgbid.
bApprovedonlyfor
antiretroviraltreatment
navepatients(orwith
darunavir,treatment
experiencedpatients
withoutdarunavirresistant
mutations).
cTitratedoseover14
days,beginningwith300
mgbidondays12,400
mgbidondays35,and
500mgbidondays613.
dApprovedonlyfor
antiretroviraltreatment
experiencedpatientswith
drugresistance.
eCYP3A4inhibitor
enhancesthesystemic
exposureofCYP3A
substrates,suchas
elvitegravir,where
bioavailabilityislimited
andhalflifeisshortened
byCYP3Adependent
metabolism.
f Seeprescribing
informationformore
details
gE/C/F/tenofovir
alafenamide(TAF)
NucleosideReverseTranscriptaseInhibitors
Thenucleoside/nucleotidereversetranscriptaseinhibitors(NRTIs)werethefirstagentsavailablefor
thetreatmentofHIVInfection.AlthoughlesspotentagainstHIVthannonnucleosidereverse
transcriptaseinhibitors(NNRTIs),proteaseinhibitors(PIs),andintegrasestrandtransferinhibitors
(INSTIs),theNRTIshavehadacentralroleinantiretroviraltreatmentandremainpartofthecurrent
standardofcare.[8,6]TheyexhibitactivityagainstHIV1andHIV2.[9]
Atotalof9drugsmakeuptheNRTIclass8arecurrentlycommerciallyavailableintheUnitedStates,
asfollows:
Abacavir(ABC,Ziagen)
Didanosine(ddI,Videx)
Emtricitabine(FTC,Emtriva)
Lamivudine(3TC,Epivir)
Stavudine(d4T,Zerit)
TenofovirDF(TDF,Viread,partofthecombinationproductStribild)
TenofovirAF(TAF,partofthecombinationproductGenvoya)
Zalcitabine(ddC,HividnolongeravailableintheUnitedStates)
Zidovudine(ZDV,Retrovirformerlyazidothymidine[AZT])
Mechanismofaction
NRTIsinterrupttheHIVreplicationcycleviacompetitiveinhibitionofHIVreversetranscriptaseand
terminationoftheDNAchain.[10]ReversetranscriptaseisanHIVspecificDNApolymerasethat
allowsHIVRNAtobetranscribedintosinglestrandandultimatelydoublestrandproviralDNAand
incorporatedintothehostcellgenome.ProviralDNAchainelongationisnecessarybeforegenome
incorporationcanoccurandisaccomplishedbytheadditionofpurineandpyrimidinenucleosidesto
the3endofthegrowingchain.
NRTIsarestructurallysimilartotheDNAnucleosidebasesandbecomeincorporatedintotheproviral
DNAchain,resultinginterminationofproviralDNAformation.[11]Tenofovir,lamivudine,and
emtricitabineexhibitactivityagainsthepatitisBvirus(HBV)inadditiontoHIVandarefrequently
incorporatedintoantiretroviralregimensforpatientswithHIVandHBVcoinfection.[6]
Resistance
ResistancetoNRTIsoccursbyoneoftwomechanisms:(1)impairedincorporationintotheproviral
DNAchainor(2)removalfromtheproviralDNAchain.[12]Mutationstypicallyoccurgradually,with
accumulationofseveralmutationsrequiredbeforeclinicallysignificantlyresistancedevelops.An
exceptionistheM184Vmutation,whichconfershighlevelresistancetolamivudineandemtricitabine
inasinglestep.MutationsthatselectivelyimpairincorporationintotheproviralDNAchaininclude
M184V,Q151M,andK65R.
Thymidineanalogmutations(mutationsassociatedwithzidovudineresistance[M41L,D67N,K70R,
L210W,T215Y,T215F,K219Q,K219E])removeNRTIsfromtheDNAchainbyfosteringa
conformationalchangeinthereversetranscriptasedomainthatallowstheadditionofATPor
pyrophosphatetotheend.ThisplacementcausesabreakintheproviralDNAandNRTIbond,
enablingcontinuedelongationoftheproviralDNAstrand.[11,12]
Pharmacokinetics
NRTIsareprodrugsandmustundergophosphorylationbyintracellularkinasestoexerttheiractivity.
Collectively,theoralbioavailabilityofNRTIsrangesfrom25%93%,withtenofoviranddidanosineon
thelowerendofthespectrum.FooddoesnotsignificantlyaffectabsorptionofanyoftheNRTIs
exceptdidanosine,whichmustbetakenonanemptystomachtoachieveoptimalabsorptionanddrug
levels.
AlthoughserumhalflivesofNRTIsarerelativelyshort,intracellulardruglevelsarethebestindicator
fordrugactivityanddeterminethedoseadministeredforeachNRTI.[13]MostNRTIsarerenally
eliminatedandrequiredoseadjustmentsinpatientswithrenalinsufficiencytheexceptionisabacavir,
whichisgivenatthenormaldoseregardlessofcreatinineclearance.
NRTIsarenotmetabolizedbythecytochromeP450systemtherefore,minimaldrugdruginteractions
occur.Interactionsthathavebeenfoundtobeclinicallysignificantinvolvedidanosine.Whengivenin
combinationwithtenofovir,didanosinelevelsarehigherthanexpected,andlowerdosesmustbe
giventoavoidpotentiallyseriousadverseeffects.Asimilarscenariohasbeendemonstratedwhen
didanosineiscombinedwithribavirininthetreatmentofpatientswithHIVandhepatitisCvirus(HCV)
coinfection.Thiscombinationshouldbeavoided.[6]
Tenofoviralafenamide(TAF)isaprodrugoftenofovirthathashighantiviralefficacysimilaratadose
lessthanonetenththatoftheoriginalformulationoftenofovirprodrug(ie,tenofovirdisoproxil
fumarate[TDF]).TAFprovideslowerbloodlevels,buthigherintracellularlevelscomparedwithTDF.
[14,15]
Adverseevents
AdverseeffectsoftheNRTIclassincludemitochondrialtoxicities(eg,lacticacidosis,pancreatitis,
peripheralneuropathy,hepaticsteatosis,lipoatrophy).[6]MitochondrialtoxicitiesareduetoNRTI
bindingtohumanmitochondrialDNApolymeraseenzyme,impairingcellularrespiration.Under
theseconditions,normalaerobicmetabolismshiftstoananaerobicprocess,resultingintheabove
manifestations.
AntiretroviraltherapyreducestheriskofchronickidneydiseasealongwithCD4cellrestorationand
suppressionofplasmaviralload,despiteanincreasedriskthatisassociatedwithinitialtreatment
regimensthatincludetenofovirplusaritonavirboostedproteaseinhibitor.[16]
BindingaffinityformitochondrialDNApolymerasebyeachNRTIispredictiveofadverseeffect
potentialandvariesasfollows(indecreasingorderofaffinity):zalcitabine,didanosine,stavudine,
lamivudine/emtricitabine,zidovudine,abacavir,andtenofovir.[17,18]
Individualdrugspecificadverseeffectsincludebonemarrowsuppression,myopathy,andheadache
withzidovudineandasystemichypersensitivityreactionwithabacavir.[6]Abacaviranddidanosine
havebeenassociatedwithanincreasedriskforadversecardiovascularevents.[19]
InitiationofARTisassociatedwithincreasedboneturnoverandbonelossfromthespineandhip,
withanumberofsubjectslosingabout6%bonemassdensitywithin1yearafterstartingtreatment.
[20] AdverseeffectswiththeremainingNRTIsareincludedinTable1.[6]
Althoughnotrecommendedforpatientswithsevererenalimpairment,thosewithmoderaterenal
impairmentcantakeTAF.TenofovirAFappearstobeassociatedwithlesskidneytoxicityandless
decreasesinbonedensitythanpreviouslyapprovedtenofovircontainingregimens.[14,21]Patients
givenE/C/F/tenofoviralafenamidehadsignificantlysmallermeanserumcreatinineincreasesthan
thosegivenE/C/F/tenofovirdisoproxilfumarate(0.08vs0.12mg/dLP<0.0001),significantlyless
proteinuria(median%change3vs20P<0.0001),andasignificantlysmallerdecreaseinbone
mineraldensityatspine(mean%change130vs286P<00001)andhip(.066vs295
P<0.0001)at48weeks.[14]
Inclinicaltrials,patientsreceivingelvitegravir/cobicistat/emtricitabine/tenofovirAF(Genvoya)showed
greaterincreasesinserumlipids(totalcholesterolandlowdensitylipoprotein)thanthosereceiving
otherARTregimens,butthetotalcholesterol/highdensitylipoproteinratiowasunchangedforboth.
[14]
NonnucleosideReverseTranscriptaseInhibitors
Nonnucleosidereversetranscriptaseinhibitors(NNRTIs)wereintroducedin1996withtheapprovalof
nevirapine.NNRTIsexhibitpotentactivityagainstHIV1andarepartofpreferredinitialregimens.[8,6]
Efavirenz,inparticular,confersthemostsignificantinhibitionofviralinfectivityamongtheNNRTIs.[8]
FirstgenerationNNRTIsincludedelavirdine(Rescriptor),efavirenz(Sustiva),andnevirapine
(Viramune).SecondgenerationNNRTIscurrentlyincludeetravirine(Intelence),approvedforusein
theUnitedStatesin2008,andrilpivirine(Edurant)[22]approvedin2011.
AllNNRTIsexhibitthesamemechanismofaction.FirstgenerationNNRTIssharesimilarresistance
patterns,whereasetravirineandrilpivirinedisplayamoreuniqueresistanceprofile.[23]Their
pharmacokineticpropertiesandadverseeffectprofileshaveimportantdifferences.
Mechanismofaction
HIVreversetranscriptaseisaheterodimercomposedof2subunits(p66andp51).[24]NNRTIsbind
thep66subunitatahydrophobicpocketdistantfromtheactivesiteoftheenzyme.This
noncompetitivebindinginducesaconformationalchangeintheenzymethatalterstheactivesiteand
limitsitsactivity.[24]
EtravirinediffersfromfirstgenerationNNRTIsinitsabilitytobindatthissitedespitethepresenceof
somemutationsthatlimittheefficacyoffirstgenerationagents.Itisahighlyflexiblemoleculethatis
abletorotatewithinthebindingsitetoallowmultiplebindingconformations.[25]
AllfourNNRTIsexhibitactivityagainstHIV1isolates.Invitrostudieshaveshownthatetravirinealso
hasactivityagainstHIV2.[26]
Resistance
MutationswithinthereversetranscriptasegenedomainaltertheabilityoftheNNRTIstobindthe
enzyme.FirstgenerationNNRTIshavealowgeneticbarriertoresistance,wherebyasinglemutation
inthebindingsitecandecreasetheabilityofthedrugtobind,significantlydiminishingactivity.[27]
FirstgenerationNNRTIresistancehasbeenassociatedwithmutationsatmultiplecodonshowever,
thepresenceofeitheraK103NorY181Cmutationissufficienttocauseclinicalfailureofdelavirdine,
efavirenz,andnevirapine.[27]
Associatedmutationsincludethefollowing[27]:
DelavirdineA98G,L100I,K101E,K103N,K103T,V179D,Y181C,Y188L,M230L,P236L,
Y318F
EfavirenzL100I,K101E,K103N,V108I,V179D,Y181C,Y188L,G190S,M230L
NevirapineA98G,L100I,K101E,K103N,V106A,V106I,V108I,Y181C,Y191I,Y188C,Y188H,
G190A,P225H,M230L,P236L,Y318W
EtravirinehasahighergeneticbarriertoresistancethanothercurrentlyavailableNNRTIs.Asingle
mutationat103or181isinsufficienttocauseclinicalfailureofetravirine.[28]Clinicaltrialshave
identified17resistancemutationsassociatedwithdecreasedresponsetoetravirine:V90I,A98G,
L100I,K101E,K101H,K101P,V106I,E138A,V179D,V179F,V179T,Y181C,Y181I,Y181V,G190A,
G190S,andM230L.[29]
A2008studyfoundthatdifferentmutationsaffectviralsusceptibilitytoetravirinetovaryingdegrees.
Eachetravirineresistanceassociatedmutationwasassignedarelativeweight.Thevirologic
responsewasfoundtobeafunctionofthenumberandweightofresistancemutations.Witha
cumulativescoreof02,aresponserateof74%wasreported.Withascoreof2.53.5or4ormore,
responseratesof52%and38%,respectively,werereported.[29]
Theetravirinemutationweightingschemeisasfollows[29]:
3Y181I,Y181V
2.5L100I,K101P,Y181C,M230L
1.5V106I,E138A,V179F,G190S
1V90I,A98G,K101E,K101H,V179D,V179T,G190A
Pharmacokinetics
NNRTIsdisplayconsiderableinterindividualvariabilityintheirpharmacokineticproperties.Allcurrently
approvedNNRTIsutilizethecytochromeP450systemformetabolismandexertvaryinginductionand
inhibitioneffectsonspecificisoenzymes(eg,CYP3A4,CYP2C9).Thisresultsinasignificantpotential
fordrugdruginteractions(seeTable2andTable3,underTablesofAntiretroviralDrugInteractions,
below).[25,30]
Delavirdineprimarilyusesthe3A4isoenzymeformetabolism.Nevirapineismetabolizedmainlyby
3A4withsomesecondarymetabolismthrough2B6.Efavirenzisprimarilymetabolizedthrough2B6
andsecondarilythrough3A4.Etravirineisasubstrateof3A4,2C9,and2C19.
Withtheexceptionofnevirapine,theNNRTIsarehighlyproteinbound(9899%),primarilytoalbumin
andalpha1acidglycoprotein.TheserumhalflivesoftheNNRTIsarefairlyextended,rangingfrom25
55hours,exceptfordelavirdine,whichhasashorterhalflife(211h).[25,30]
Adverseevents
Rash,whichisthemostcommonadverseeffectassociatedwithallNNRTIs,[6]usuallydevelops
withinthefirstfewweeksoftherapyandresolveswithcontinuedtreatment.[6,25,31]AllNNRTIs
exceptetravirinehavetheabilitytocausesomedegreeofhepatotoxicity.[25,32]Delavirdineand
efavirenzcanincreasetransaminaselevels,whilenevirapinecancauseseveretoxicity,including
hepaticnecrosisinpatientswithCD4countsthatexceed250cells/L.[6,33]
EfavirenzisuniqueamongNNRTIs,causingCNSeffectssuchasinsomnia,vividdreaming,dizziness,
confusion,andhallucinations.
TolerancetoefavirenzrelatedCNSadverseeffectscommonlyoccursafterseveralweeksoftherapy.
Bedtimeadministrationandavoidanceoffoodatthetimeofadministrationcanminimizetheintensity
ofadverseeffects.CNSeffectsmaypersistinasmallnumberofpatients,requiringdrug
discontinuation.[6]
GutirrezValenciaetalfoundthatgradualupwardtitrationofefavirenzover2weeksreduced
neuropsychiatricsymptomsandinsomnia.Inarandomized,doubleblind,controlledtrialthatincluded
114patients,thosepatientswhoreceivedafulldoseof600mgdailyfromday1hadahigher
incidenceandseverityofdizziness(66%vs32.8%),hangover(45.8%vs20.7%),impaired
concentration(22.9%vs8.9%),andhallucinations(6.1%vs0%)duringthefirstweek,comparedwith
patientswhohadgradualefavirenztitrationto600mgdailybyday14.[34]
Duringweek2,theincidenceoftheseaforementionedadverseeventswassimilarineachgroup
however,severitywasgreaterinthefulldosegroup.Virologicandimmunologicefficacywassimilarin
bothgroups.[34]
ProteaseInhibitors
HIVproteaseinhibitors(PIs)werefirstintroducedin1995andareanintegralpartoftreatmentofHIV
infection.[6]Atotalof8compoundsareapprovedforuse,asfollows:
Atazanavir(Reyataz)
Darunavir(Prezista)
Fosamprenavir(Lexiva)
Indinavir(Crixivan)
Lopinavir/ritonavir(Kaletra)
Nelfinavir(Viracept)
Saquinavir(Invirase)
Tipranavir(Aptivus)
Althoughallproteaseinhibitorsexhibitthesamemechanismofaction,theyhaveimportantdifferences
inpharmacokinetics,efficacy,andadverseeventprofiles.
Mechanismofaction
HIVproteaseisa99aminoacid,asparticacidproteinandisresponsibleformaturationofvirus
particleslateinthevirallifecycle.HIVproteasesystematicallycleavesindividualproteinsfromthe
gagandgagpolpolypeptideprecursorsintofunctionalsubunitsforviralcapsidformationduringor
shortlyafterviralbuddingfromaninfectedcell.
HIVproteaseinhibitorsfunctionascompetitiveinhibitorsthatdirectlybindtoHIVproteaseand
preventsubsequentcleavageofpolypeptides.[35]Theyexhibitactivityagainstclinicalisolatesofboth
HIV1andHIV2.[35]
Resistance
ResistancetoHIVproteaseresultsfrommutationsbothinsideandoutsidetheactiveprotease
domain.[36]Resistancetypicallyoccursthroughthedevelopmentofoneormoremajormutations,
whichproduceconformationalchangesintheproteasebindingsite,followedbysecondary
compensatorymutationsthatimproveenzymaticactivityand,insomecases,viralfitness.[36]
Resistancetofirstgenerationproteaseinhibitors(indinavir,ritonavir,nelfinavir,saquinavir)occurswith
thedevelopmentofoneormoreofthefollowingprimarymutations[36]:
G48V,L90M(saquinavir)
M46I,V82A/L/F,I84V(indinavir)
V82A/L/F,I84V(ritonavir)
D30N,L90M(nelfinavir)
I50L,I84V,N88S(atazanavir)
I50V,I84V(fosamprenavir)
Multiplemutationsaretypicallynecessarytocausehighlevelresistancetoritonavirboosted(ie,
coadministeredwithlowdoseritonavirtodecreaseintestinalandhepatic3Ametabolism,thereby
increasingproteaseinhibitorserumconcentrationlevels)proteaseinhibitors,whichexhibitahigher
geneticthresholdforresistancethanunboosted(ie,notcoadministeredwithlowdoseritonavir)
proteaseinhibitors.[37]Crossresistancetootherproteaseinhibitorsdevelopsasthenumberof
mutationsincreases.
Thesecondgenerationproteaseinhibitorslopinavir/ritonavir,darunavir,andtipranavirmayretain
activityinthepresenceofresistancetofirstgenerationagents.Lopinavir/ritonavirrequiresthe
accumulationof7ormoremutationsbeforehighlevelresistancedevelops.[36]Darunavirand
tipranavirtypicallyretainactivityagainstlopinavir/ritonavirandfirstgenerationproteaseinhibitor
resistantstrains.[36]
Elevenresistancemutationshavebeendescribedfordarunaviraccumulationof3ormoreis
associatedwithvirologicfailure.Tipranaviralsorequiresaccumulationofmultiplenonoverlapping
mutationsbeforehighlevelresistancedevelops.[36]
Areviewof2725HIVisolatesforproteaseinhibitorsusceptibilityrevealedthatcertainmutationscould
resultinincreasedsusceptibilitytoaparticulardrug,andthatsomeeffectsonresistancehadbeen
underestimated.[38]Thestudyconcludedthatcrossresistancebetweenthevariousprotease
inhibitorsnowandinthefuturemaybemissedwithoutsystematicanalysisoftheeffectsofspecific
mutations.
Pharmacokinetics
Proteaseinhibitorsexhibitsubstantialinterpatientandintrapatientvariabilityinpharmacokinetics.[39]
SignificantfirstpassmetabolismbycytochromeP450(CYP)3A4and3A5andintestinaleffluxbyp
glycoproteinisobserved.[39]Withtheexceptionofindinavir,proteaseinhibitorsarehighlyprotein
bound(9799%),primarilytoalbuminandalpha1acidglycoprotein.[6]DistributionintotheCNSis
limited.Proteaseinhibitorshaverelativelyshortserumhalflives,rangingfrom1.52hoursforindinavir
and7hoursforatazanavir.[6]
RelianceonmetabolismthroughCYP3A4resultsinsignificantpotentialfordrugdruginteractionswith
othermedicationsclearedthroughthispathway(seeTable2andTable3).Interactionswith
medicationsclearedthroughotherCYP450isoenzymesandphaseIIpathways(eg,glucuronidation)
arepossible,dependingontheindividualproteaseinhibitor.[6]
Lowdoseritonavir(100200mg)isfrequentlycoadministeredwithotherproteaseinhibitorstoblock
intestinalandhepatic3Ametabolism.Theadditionoflowdoseritonavirimprovespharmacokinetic
variability,resultinginmoreconsistentserumconcentrationsthroughoutthedosingintervaland
improvedtreatmentresponse.[39]Cobicistatisaneweragentthatalsoblocks3Ametabolismandis
usedtoenhancethepharmacokineticprofileofproteaseinhibitors.
Adverseevents
Commonadverseeventsassociatedwithproteaseinhibitorsincludegastrointestinalsideeffects
(diarrhea,nausea,vomiting)andmetaboliccomplications(dyslipidemia,insulinresistance,
lipodystrophy).
Metaboliccomplicationsarecommoninpatientsreceivingproteaseinhibitortherapyandrepresentan
importantconsiderationinselectingantiretroviraltherapy.Dyslipidemiadevelopsinupto70%of
patientsreceivingproteaseinhibitorsandcommonlyrequiresinstitutionoflipidloweringtherapy(ie,
statins,fibrates,omega3fattyacids).
Druginteractionscanprecludetheuseofsomelipidloweringagents(seeTable2).Lifestyleand
geneticpredispositionareimportantcontributingfactorstothetypeandseverityoflipidabnormalities.
[40]
In1997,theFDArequiredthatallproteaseinhibitorsincludelabelingregardingthepotentialfor
hyperglycemiaanddiabetesmellituswiththerapyhowever,thedifferentproteaseinhibitorshave
significantlydifferentpropensitiesforaffectingglucosemetabolism.Indinavirexhibitsthegreatest
potentialforalteringglucosemetabolism.
Modesteffectshavebeenobservedwithnelfinavir,lopinavir/ritonavir,fosamprenavir,andtipranavir.
Atazanavir(boostedorunboosted),darunavir,andsaquinavirappeartohavelimitedeffectoninsulin
sensitivityandglucosehomeostasis.[41]
Alteredfatdistribution(fatredistribution)occursin4050%ofpatientsreceivingproteaseinhibitorsin
combinationwithnucleosidereversetranscriptaseinhibitors(NRTIs).[42]Commonmanifestations
includefataccumulation(increasedanteriorcervicalanddorsocervicalfat,increasedbreastfat,
centripetalobesity)orfatloss(sunkencheeks,wastedbuttocksandextremities).Althoughboth
abnormalitiesmaydevelopinthesamepatient,theyareconsideredindependententities.
Fataccumulationhasbeenprimarilyassociatedwithproteaseinhibitortherapyhowever,morerecent
datademonstratethatitoccurswithbothproteaseinhibitorandnonnucleosidereversetranscriptase
inhibitors(NNRTI)basedregimens.
Numerousmanagementstrategieshavebeenexplored(eg,metformin,recombinanthumangrowth
hormone,dietandexercise),withmixedresults.Conversionfromproteaseinhibitorbasedtherapyto
aproteaseinhibitorsparingregimendoesnotresultinsignificantimprovementandisnot
recommended.[43]
Adverseeffectsthatoccurwithindividualproteaseinhibitorsneedtobeconsideredwhenselecting
therapyforpatientswithothercomorbidities.
Asymptomatichyperbilirubinemiaiscommoninpatientswhoreceiveatazanavirandindinavirbutdoes
notrequirediscontinuationoftherapyintheabsenceofconcomitantelevationinlevelsofliver
transaminases.[6]Nephrolithiasisoccurswithindinavirand,lesscommonly,atazanavir.[6]
Cardiacconductionabnormalities(atrioventricularblock,bundlebranchblock)developin5%of
patientsreceivingatazanavirandhavebeenreportedwithotherproteaseinhibitors(ritonavir,
lopinavir/ritonavir,nelfinavir).[44]
TipranavirmayelevatelevelsoflivertransaminasesandshouldbeavoidedinpatientswithhepatitisB
orhepatitisCcoinfection.Intracranialbleedingeventshavebeenreportedduringtipranavirtherapy.[6]
IntegraseStrandTransferInhibitors
ThecrystalstructureofHIVintegrasewasfirstdescribedin1994andledtotheidentificationofnovel
inhibitors.[45]NohomologforHIVintegraseexistsinhumanstherefore,identificationofselective
inhibitorsisexpectedtoresultinalowfrequencyofadverseeffects.[46,47]TheFDAapproved
raltegravir(Isentress)in2007asthefirstintegrasestrandtransferinhibitor(INSTI)availableforuse.
[48]
Elvitegravir(Vitekta)isanotheragentintegraseinhibitorthatisusedincombinationwithanHIV
proteaseinhibitor(ie,atazanavir,lopinavir,darunavir,fosamprenavir,ortipranavir)andcoadministered
withritonavirplusotherantiretroviraldrug(s)asindicatedforthetreatmentofHIV1infectionin
antiretroviraltreatmentexperiencedadults.
ElvitegravirwasinitiallyapprovedasacomponentoftheFDAapprovedquadpill,
elvitegravir/cobicistat/emtricitabine/tenofovir(Stribild).The4componenttabletcontainsacomplete
oncedailyregimenfortreatmentnaveadultsandincludeselvitegravir,cobicistat(aCYP3A4inhibitor
withoutantiviralactivity),emtricitabine,andtenofovir.[49]ApprovaloftheARTfixeddosecombination
productwasbasedonanalysesof48weekdatafrom2randomized,doubleblind,activecontrolled
trialsintreatmentnave,HIV1infectedindividuals(n=1408).Resultsshowedasingletabletregimen
ofStribildmetitsprimaryobjectiveofnoninferioritycomparedto(efavirenz/emtricitabine/tenofovir)
fixeddosecombination(Atripla)andtoaregimencontainingritonavirboostedatazanavirplus
emtricitabine/tenofovir(Truvada).[50,51]
Dolutegravir(Tivicay)wasapprovedbytheFDAinAugust2013.Anintegrasestrandtransferinhibitor
(INSTI),dolutegravirwasapprovedbytheFDAfortreatmentofHIV1infectionincombinationwith
otherantiretroviralagentsinadultsandchildrenaged12yearsorolderwhoweighatleast40kg.
AwiderangingphaseIIItrialprogramincluded2trialsintreatmentnavepatients.Thefirsttrial
included822HIVinfected,treatmentnavepatientsrandomizedtoreceiveeitherdolutegravir(50mg
oncedaily)orraltegravir(400mgtwicedaily)incombinationwithafixeddosedualNRTItreatment.
Atweek48,virologicsuppressionwassimilarbetweenthe2groups88%fordolutegravirand86%for
raltegravir.[52]
Thesecondtrialalsoincludedtreatmentnavepatients(n=833)andcomparedaoncedaily
dolutegravirregimenplusabacavir/lamivudinetooncedailyefavirenz/emtricitabine/tenofovirdisoproxil
fumarate(Atripla).Astatisticallysignificantimprovementinvirologicsuppressionwasobservedwith
dolutegravir(88%)comparedwithAtripla(81%).[53]
AthirdphaseIIItrialstudied719treatmentexperiencedpatientswhowerefailingoncurrenttherapy,
butwhohadnotpreviouslybeentreatedwithanintegraseinhibitor.Participantswererandomizedto
oncedailydolutegravir50mgortwicedailyraltegravir400mg.Atweek24,79%ofpatientsonthe
regimencontainingdolutegravirwerevirologicallysuppressedcomparedwith70%ofpatientsonthe
regimencontainingraltegravir.[54]
TheVIKING3trialstudied183treatmentexperiencedpatientswithresistancetomultipleclassesof
HIVmedicines,includingresistancetointegraseinhibitors.Researchersevaluatedtheeffectiveness
oftwicedailydolutegravironviralloadinthesepatientsandfoundtheregimenimprovedvirologic
suppressionat24weeks(63%).However,poorresponsewasobservedwithINSTIresistance
involvingQ148plus2ormoreINSTIresistancesubstitutions.[55]
Approvalofdolutegravirfortheindicationinchildrenaged12yearsorolderwasbasedondatain
integrasenavepatients.
Mechanismofaction
HIVintegraseisresponsibleforthetransportandattachmentofproviralDNAtohostcell
chromosomes,allowingtranscriptionofviralproteinsandsubsequentassemblyofvirusparticles.[56]
Proviralintegrationinvolves2catalyticreactions,asfollows:
3'processinginthehostcellcytoplasmtoprepareproviralstrandsforattachment
StrandtransferwherebyproviralDNAiscovalentlylinkedtocellularDNA
Theseagentscompetitivelyinhibitthestrandtransferreactionbybindingmetallicionsintheactive
site.[57,58]
Resistance
Mutationsintheintegrasegeneareassociatedwithresistancetoraltegravirandelvitegravir.[59,60,61]
TwoprimaryresistancepathwaysassociatedwithraltegravirtreatmentfailuresintheBENCHMRK1
andBENCHMRK2studieshavebeendescribed,asfollows[62]:
Q148K/R/H(25folddecreaseinsusceptibility)
N155H(10folddecreaseinsusceptibility)
Themostcommonmutationalsequence(Q148H/G140S)resultsinagreaterthan100folddecrease
insusceptibilitytoraltegravir.[37]AthirdresistancepathwayinvolvingmutationsatY143C/H/Rhas
alsobeendescribedforraltegravirbutisuncommon.[63]Secondarymutations(L74M/R,E92Q,T97A,
E138A/K,G140S/A,V151I,G163R,H183P,Y226D/F/H,S230R,D232N)conferadditionalresistance.
[63]
Preliminaryfindingsfromclinicalstudiesshowthathighlevelresistancetoelvitegravirisassociated
withmutationsatE92QincombinationwithE138K,Q148K/R/H,orN155H,leadingtoa150foldloss
ofsusceptibility.ResistancepatternsinvolvingQ148H/G140SandQ148R/G140Sdemonstrate
resistancetobothelvitegravirandraltegravir,suggestingcrossresistanceislikely.[64]
Pharmacokinetics
Raltegravirexhibitsrapidabsorptionandmaybetakenwithorwithoutfood.Itsterminalhalflifeof10
12hourssupportstwicedailyadministration(400mgtwicedaily).Sexrelateddifferencesin
pharmacokinetics(longerhalflifeinwomen,lowerCmininmen)havebeenobservedbutarenot
thoughttobeclinicallysignificant.Raltegraviris83%boundtoplasmaproteinsandisasubstratefor
PglycoproteintheextentofpenetrationintotheCNSremainstobedetermined.
Metabolismoccursthroughuridinediphosphateglucuronyltransferase1A1(UGT1A1).Dosage
adjustmentisnotrequiredinpatientswithrenalinsufficiencyormildtomoderatehepaticimpairment.
Raltegravirexhibitslowpotentialtoaffectthemetabolismofotherdrugshowever,otherantiretroviral
agentsmayalterthemetabolismofraltegravir.
Antacidsmaydecreaseabsorptionbydivalentcationbinding,butnointeractionwithgastricacid
suppressants(protonpumpinhibitors,H2antagonists)isexpected.Arelationshipbetweenraltegravir
serumconcentrationsandviralsuppressionhasnotbeenestablished.[65,66,67]
Elvitegravirisadministeredwithlowdoseritonavir(100mg)toreduceitsfirstpassmetabolismand
systemicclearance.Ritonavircoadministrationresultsina20foldincreaseinsystemicexposureand
aterminalhalflifeof1013hours.ElvitegravirismetabolizedthroughCYP3A4andUGT1A1/UGT1A3.
Lessthan7%iseliminatedrenallytherefore,thelikelihoodthatdosingadjustmentswillbenecessary
inpatientswithrenalinsufficiencywhoreceiveelvitegravirislow.
Drugdruginteractionswithothermedicationsarelikelybecauseofritonavircoadministration.Aswith
raltegravir,antacidsmaydecreaseabsorptionbydivalentcationbinding,butnointeractionwith
gastricacidsuppressantsisexpected.Indoserangingstudies,lowelvitegravirtroughconcentrations
havebeenassociatedwithvirologicfailureinsomepatients.[67,68,69]
Adverseevents
Commonadverseeffectsobservedinclinicalstudiesofraltegravirincludegastrointestinaleffects
(nausea,diarrhea)andheadache.Laboratoryabnormalitiesoccurredatafrequencysimilartoother
therapyinphaseIIIstudiesandincludegrade34elevationsinlevelsofalanineaminotransferaseand
aspartateaminotransferase,serumcholesterolandtriglycerides,andamylaseandlipase.
Elevationsincreatinekinaselevels(grade24)wereobservedwithraltegravirinphaseIIIstudies,
alongwithrarecasesofmyopathyandrhabdomyolysis.[70,71]Raltegravirshouldbeusedwith
cautioninpatientsreceivingothermedicationsthatmayincreasetheriskformyopathyand
rhabdomyolysis.[71]
Arelativeriskofmalignancyof1.2casesper100patientyears(95%CI,0.44.1)hasbeenreported
inphaseIIandphaseIIIclinicalstudiesofraltegravirandrequirescontinuedsurveillance.[70]
Gastrointestinaleffects(nausea,diarrhea),fatigue,andheadachehavebeenmostcommonly
observedwithelvitegravirinlimitedclinicalstudiestodate.[68]
FusionInhibitors
Fusioninhibitors(FIs)werethefirstclassofantiretroviralmedicationstotargettheHIVreplication
cycleextracellularlyandreceivedacceleratedFDAapprovalin2003.Theiruniquemechanismof
actionprovidesadditionaloptionsfortherapyinpatientswhoarehighlytreatmentresistant.
Theuseoffusioninhibitorshasbeenlimited,however,becauseoftheproductiontimeandcosts,
limitedcoveragefrominsurancecompaniesandHIVdrugassistanceprograms(HDAPs),
inconvenientadministration(subcutaneousinjection),andadverseeffectprofile.Thediscoveryof
additionalantiretroviralclassesandmedicationswithactivityagainsthighlyresistantviralstrainshas
furtherlimitedtheutilityofthefusioninhibitors.Currently,enfuvirtide(Fuzeon)istheonlyproduct
marketedinthisclass.
Mechanismofaction
FusioninhibitorsactextracellularlytopreventthefusionofHIVtotheCD4orothertargetcell.
EnfuvirtideblocksthesecondstepinthefusionpathwaybybindingtotheHR1regionofglycoprotein
41(gp41).ThismechanismdoesnotallowHR1andHR2tofoldproperly,therebypreventingthe
conformationalchangeofgp41requiredtocompletethefinalstepinthefusionprocess.[72,73]
Resistance
ResistancetoenfuvirtidehasbeenwelldescribedandoccursintheHR1domainofgp41.Aminoacid
substitutionsoccurinthe3645regionsandresultinsignificantlossofenfuvirtideactivity.[74]
Theriskofresistancecanbeminimizedbycombiningenfuvirtidewithotherantiretroviralagentsthat
displaygenotypicorphenotypicactivity,whichisnowmoreeasilyachievedwiththeavailabilityof
secondgenerationnonnucleosidereversetranscriptaseinhibitors(NNRTIs)andproteaseinhibitors
(PIs)andnewantiretroviralclasses(eg,integrasestrandtransferinhibitors[INSTIs]andCCR5
inhibitors).[75,76]Crossresistancewithotherantiretroviralagentshasnotbeendemonstratedtodate.
Pharmacokinetics
Enfuvirtidetherapyrequirestwicedailysubcutaneousinjection.Ithasnotbeenshowntoinfluencethe
metabolismofconcomitantmedicationsthroughthecytochromeP450system.
Doseadjustmentsarenotrequiredinpatientswithrenalinsufficiencyormildtomoderatehepatic
insufficiency.Limiteddosingdataexistforpatientswithadvancedliverdiseasetherefore,enfuvirtide
shouldbeusedwithcautioninpatientswithhepaticdecompensation.[6,77]
Adverseevents
Mostpatientsreceivingenfuvirtideexperienceinjectionsitereactions,increasingdrugdiscontinuation
rates.Manifestationsincludesubcutaneousnodules,erythema,pruritus,pain,andecchymoses.Other
adverseeffectsthatoccurtoalesserextentincludediarrhea,nausea,andfatigue.Hypersensitivity
reactionshavebeendescribedbutarerare.Enfuvirtidehasbeenassociatedwithanincreasedriskfor
bacterialpneumonia,butcausalityhasnotbeenestablished.[75,76]
ChemokineReceptorAntagonists
InAugust2007,maraviroc(Selzentry)wasapprovedbytheFDAandwasthefirstmedicationina
novelclassofantiretroviralagentstermedchemokinereceptor5(CCR5)antagonists.Itjoinsthe
fusioninhibitors(FIs)asanothertypeofagentunderthegeneralantiretroviraltreatmentclassofHIV
entryinhibitors.
Mechanismofaction
ThemethodbywhichHIVbindstoCD4cellsandultimatelyfuseswiththehostcellisacomplex
multistepprocess,whichbeginswithbindingofthegp120HIVsurfaceproteintotheCD4receptor.
ThisbindinginducesastructuralchangethatrevealstheV3loopoftheprotein.TheV3loopthen
bindswithachemokinecoreceptor(principallyeitherCCR5orCXCR4),allowinggp41toinsertitself
intothehostcellandleadingtofusionofthecellmembranes.
MaravirocisasmallmoleculethatselectivelyandreversiblybindstheCCR5coreceptor,blockingthe
V3loopinteractionandinhibitingfusionofthecellularmembranes.MaravirocisactiveagainstHIV1
CCR5tropicviruses.IthasnoactivityagainstCXCR4tropicordual/mixedtropicvirus.[78]
Resistance
Althoughexperiencewithmaravirocislimited,treatmentfailureduetoresistancehasbeenobserved.
Resistanceappearstooccurviaoneoftwomechanisms.Thefirstmechanismismostlikelythrough
aminoacidsubstitutionsintheV3loopofgp120.Althoughthespecificmutationsassociatedwith
resistancehavenotyetbeendescribed,theyappeartoallowHIVbindingtothecoreceptordespite
thepresenceofmaraviroc.
Thesecondmechanismisnotacquiredresistancebutrathertheinabilityofphenotypictropism
assaystodetectsmallquantitiesofCXCR4virusthatmaybepresent,leadingtoovergrowthof
CXCR4virusinthepresenceofmaravirocandlossofviralcontrol.Thedevelopmentofanenhanced
tropismassaywithhighersensitivityshouldminimizethefrequencyofthisoccurrence.[78,79]
GenotypicassayscanalsobeusedtopredictCCR5andCXCR4coreceptortropismbysequencing
thegp120V3loop.Theseassayshaveshowngoodtoexcellentconcordancewithphenotypic
assays.[80,81]
Pharmacokinetics
Maravirocisapproximately75%proteinbound,primarilytoalbuminandalpha1acidglycoprotein.Its
terminalhalflifeis1530hours.MaravirocismetabolizedthroughCYP3A4andisasubstrateforthe
effluxpumppglycoprotein.Dosageadjustmentisrequiredwhenmaravirocisadministeredin
combinationwithpotentinhibitorsorinducersofCYP3A4.[78]SeeTable1.[6]
Adverseevents
Adverseeventsreportedatahigherfrequencythanplaceboinclinicalstudiesincludethefollowing:
Cough
Pyrexia
Upperrespiratorytractinfections
Rash
Musculoskeletalsymptoms
Abdominalpain
Dizziness
Therateofdiscontinuationduetoadverseeffectswassimilartothatfoundwithplacebo(4.9%and
5.3%,respectively).Posturalhypotensionisadoselimitingeffectthatwasdiscoveredearlyinthe
developmentofmaraviroc.Inpooledanalysis,posturalhypotensionoccurredonlyinpatientswho
receivedmaravirocatdosesthatexceeded600mg/day.Themanufacturerwarnsthatsevere
hepatotoxicityhasbeenreportedwithmaraviroccautionshouldbeusedwhenmaravirocis
administeredtoanypatientpredisposedtohepaticimpairment.[78]
DHHSTreatmentGuidelines
Goalsoftherapy
TheUSDepartmentofHealthandHumanServicesPanelonAntiretroviralGuidelinesforAdultsand
Adolescents(DHHSARTGuidelines)issuesrecommendationsfortheadministrationofantiretroviral
therapy.[6]Guidelinesarebasedonresultsofclinicalstudiesandexpertopinionandareupdatedon
anongoingbasis.
Separateguidelinesaddressantiretroviraltreatmentforpregnantwomen,children,andindividuals
withpotentialoccupational(eg,healthcareindustry)andnonoccupational(eg,highrisksexual
encounters)exposuretoHIV.Guidelinesforantiretroviraltreatmentinitiationinadultsarealso
availablefromtheInternationalAIDSSocietyandtheWorldHealthOrganization(WHO).
Thediscussionofantiretroviraltreatmentstrategiesinthisarticlefocusesonrecommendationsfrom
theDHHSPanel.
TheDHHSARTGuidelinespresentthefollowing5overarchinggoalsfortherapy:
ReduceHIVinfectionrelatedmorbidityandprolongsurvival
Improvequalityoflife
Restoreandpreserveimmunologicfunction
Maximallyanddurablysuppressviralload
PreventverticalHIVtransmission
Suppressionofviremiaalsohasthepotentialtoreducecardiovascular,renal,andhepaticevents
thoughttoberelatedtoongoinginflammationandimmuneactivationfromuncontrolledviremia.The
riskforbothAIDSrelatedandnonAIDSassociatedmalignancymayalsobereducedbyimproved
immunity.[6]
Treatmentnaivepatients
Indicationsforinitiatingantiretroviraltherapy
TheDHHSARTGuidelinesrecommendthattherapyshouldbeinitiatedinallpatientsirrespectiveof
CD4counttodecreasetheriskforHIVdiseaseprogression,nonHIVrelatedmorbidityandmortality,
andtopreventtransmissionofHIVinfection.Thedecisiontobeginantiretroviraltherapy,aswellas
theselectionoftheindividualantiretroviralcomponents,shouldbetailoredtoeachpatient,takinginto
accountpatientspecificvariablesandpreferences.Thepatientsreadinessandcommitmentto
lifelongtherapyshouldsimilarlybeevaluated.DatafromtheSTARTandTEMPRANOrandomized
trialshaveshowncompellingevidenceregardingthebenefitofinitiatingARTinHIVinfected
individualswithhighCD4cellcounts(>500cells/mL),ratherthandefertreatmentuntilCD4cell
countsdecline.[82,83]FindingsfromthesestudiesshowedalowerrateofdeathorsevereHIVrelated
illness(eg,tuberculosis,Kaposisarcoma,malignantlymphomas)inthosewhoweretreatedearlywith
ARTscomparedtothosethatweredeferredtreatmentuntilalowerCD4cellcountwasobserved.
Therapyoptions
Currently,26antiretroviralagentsin6antiretroviralclassesplusfixeddosecombinationproductsare
approvedforuseintheUnitedStates.Theseagentsvaryintheirantiviralpotencyandadministration
requirements.Itiscurrentlyrecommendedthatantiretroviraltherapybeinitiatedwith2NRTIsin
combinationwithanNNRTI,PI,orintegraseinhibitor.[6]
Inanattempttosimplifytheselectionofaninitialregimen,theDHHSARTGuidelineshaveoutlined
preferredandalternativeregimensforinitiationinantiretroviralnavepatients.Therearenow5
recommendedregimensforantiretroviraltherapy(ART)naivepatients4integrasestrandtransfer
inhibitor(INSTI)basedregimensand1ritonavirboostedproteaseinhibitor(PI/r)basedregimen.The
fivepreferredregimenshaveevidenceratingsofAI(ie,strongrecommendationwithdatafrom
randomizedcontrolledtrials).Theserecommendationsarebasedonefficacyandsafetyofthese
combinations,aswellasotherfactors,includingeaseofadministration.[6]
PreferredregimensforARTnavepatientsincludethefollowing:
INSTIbasedregimens
Seethelistbelow:
Dolutegravir/abacavir/lamivudine(TriumeqDTG/ABC/3TC)aonlyforpatientswhoareHLA
B*5701negative
Dolutegravir(DTG)+tenofovirDF/emtricitabine(TruvadaTDF/FTC)a
Elvitegravir/cobicistat/tenofovirDF/emtricitabine(StribildEVG/c/TDF/FTC)onlyforpatients
withpreARTCrCl>70mL/min
Raltegravir(RAL)+tenofovirDF/emtricitabine(TruvadaTDF/FTC)a
PI/rBasedRegimen
Seethelistbelow:
Darunavir/ritonavir(DRV/r)+tenofovir/emtricitabine(TruvadaTDF/FTC)a
alamivudine(3TC)maybesubstitutedforemtricitabine(FTC)orviceversa
AlternativeregimensforARTnavepatientsincludethefollowing:
NNRTIbasedRegimens
Seethelistbelow:
Efavirenz/tenofovirDF/emtricitabine(AtriplaEFV/TDF/FTC)a
Rilpivirine/tenofovirDF/emtricitabine(CompleraRPV/TDF/FTC)aonlyforpatientswithpre
treatmentHIVRNA<100,000copies/mLandCD4cellcount>200cells/mm3
PIbasedRegimens
Seethelistbelow:
Atazanavir/cobicistat(EvotazATV/c)+tenofovir/emtricitabine(TruvadaTDF/FTC)aonlyfor
patientswithpretreatmentestimatedCrCl70mL/min
Atazanavir/ritonavir(ATV/r)+tenofovirDF/emtricitabine(TruvadaTDF/FTC)a
Darunavir/cobicistatordarunavir/ritonavir(PrezcobixDRV/corDRV/r)+abacavir/lamivudine
(EpzicomABC/3TC)aonlyforpatientswhoareHLAB*5701negative
Darunavir/cobicistat(PrezcobixDRV/c)+tenofovirDF/emtricitabine(TruvadaTDF/FTC)a
onlyforpatientswithpretreatmentestimatedCrCl70mL/min
alamivudine(3TC)maybesubstitutedforemtricitabine(FTC)orviceversa
Inalongtermstudyoftreatmentnavepatients,raltegravircombinedwithtenofovir/emtricitabine
delivereddurableviralsuppressionandimmunerestorationthatwasatleastequivalenttothe
combinationofefavirenzandtenofovir/emtricitabine.Inaddition,fewerdrugrelatedclinicaladverse
eventsandsmallerelevationsinlipidlevelsoccurredinpatientsintheraltegravircombinationgroup.
[84]
Resistance
Onestudyhasreportedthatantiretroviralresistancecanbedetectedin616%oftreatmentnaive
individuals.[6]Basedonthispossibility,DHHSguidelinesrecommendthatresistancetestingbe
performedinallpatientswithHIVinfectionattheonsetofcare.
Genotypesaregenerallythetestofchoice,asdenovoresistancetoNRTIsorNNRTIsismost
commonlyobserved.Genotypesarealsolesscostlyandexhibitashorterturnaroundtime.Ifthe
intervalbetweenenteringcareandbeginningantiretroviraltherapyissignificant,itisgenerally
recommendedthatthepatientundergotestingwithanothergenotypetoassessanyresistance
acquiredintheinterim.[6]
Therapyselection
Theantiretroviralregimenselectedshouldbebasedonpatientspecificfactorsandpreferences.
Factorstoconsiderincludeassociatedcomorbidities,theadverseeffectprofilesofthemedications
beingconsidered,thepotentialforpregnancy,adherencebarriers,regimenconvenience,and
potentialdrugfoodanddrugdruginteractions.Resistancetestingfindingsshouldalsobeconsidered
intheinitialregimenselection.
Certainagentsrequireconsiderationofotherfactors(eg,HLAB*5701testingforabacavir
hypersensitivity,pretreatmentCD4countfornevirapine)beforetheiruse.[6]
Treatmentendpoints
Virologicendpointsfortherapyincludethefollowing:
Onelog10declineinHIV1RNAby28weeks
Fewerthan50HIV1RNAcopies/mLby1624weeks
Ifoneoftheseendpointsisnotmet,thepatientshouldbeevaluatedtodeterminewhether
nonadherence,drugintolerance,orresistanceisafactor.Alterationoftherapymaybenecessary
basedonthespecificcircumstances.[6]
Treatmentexperiencedpatients
Definitionoftreatmentfailure
Althoughsuccesswithantiretroviraltherapyhasgreatlyimprovedwiththeintroductionofmorepotent
andwelltoleratedmedications,treatmentfailureremainsanimportantchallengeforclinicians.Failure
ofantiretroviraltherapyisdefinedunderthefollowingcircumstances[6]:
Virologicfailure(suboptimalviralsuppressionorlossofsuppression[>50HIV1RNA
copies/mL])
Immunologicfailure(failuretoachieveormaintainCD4cellcountrecoverydespiteeffectiveviral
suppression)
Clinicaldiseaseprogression(developmentofnewopportunisticinfectionsorneoplasmsdespite
apparentCD4countrecovery)
Treatmentfailureisoftenduetomultiplefactors.Theidentificationofpotentialcontributingfactorsis
importantsothatcorrectivemeasurescanbeinstitutedtoimprovethelikelihoodofsuccesswithnew
therapy.Commonfactorsthatcontributetotreatmentfailureincludethefollowing:
Nonadherence
Drugtoxicity
Potencyoftheantiretroviralregimen
Drugdruginteractionsleadingtosuboptimaldrugconcentrations
Preexistingdrugresistancepriortoinstitutionofantiretroviraltherapy
Developmentofresistance
Virologicfailureisthemostcommonreasonfortreatmentfailure.VirologicfailureintheDHHSART
Guidelinesisdefinedasincompletevirologicsuppressionorviralrebound,leadingtoinabilityto
maintainviralsuppression.[6]Differentdefinitionsofvirologicfailureareapplieddependingonwhen
theantiretroviralregimenwasinitiated,asfollows:
Morethan400HIV1RNAcopies/mLafter24weeks
Morethan50HIV1RNAcopies/mLafter48weeks
Repeatedlydetectableviremiaafterpriorviralsuppression(ie,<50HIV1RNAcopies/mL)
Noconsensusonthemanagementofvirologicfailureexists.Oneapproachistochangeantiretroviral
therapywhenHIV1RNAisrepeatedlydetectable(>50copies/mLon2consecutivemeasurements).
Amoreconservativeapproachwouldbetochangetherapyonceviremiaexceedssomepredefined
level(eg,1,0005,000copies/mL).Apotentialdisadvantagetothisapproachisthatadditional
resistancemutationsmaybeselectedduringthisperiodofviremia.Theavailabilityofother
antiretroviraltherapyoptionsoftendictateswhichapproachshouldbetaken.[6]
Theidentificationandmanagementoftreatmentfailureduetoimmunologicfailureislessclear.No
standarddefinitionforimmunologicfailureexists.Insomeinstances,theinabilitytosurpass
predefinedthresholds(CD4count>350cells/L)overaspecifiedperiodwhenCD4countsare
expectedtoplateau(47y)hasbeenlabeledimmunologicfailure.Inotherinstances,alackofCD4
cellcountincreasefrombaseline(eg,100cells/L)overadefinedperiodhasalsobeenconsidereda
failure.[6]
Riskfactorsassociatedwithimmunologicfailureincludethefollowing:
LowCD4count(<200cells/L)
Comorbidities(eg,malignancy,viralcoinfection)
Olderage
NRTIs(zidovudine,tenofovirdidanosine)
Othermedications(eg,corticosteroids,chemotherapy,pegylatedinterferon)
Ongoingimmuneactivation
Lossofimmunesystemregenerativepotential
TheimplicationsforpersistentlyimpairedCD4recoveryintheindividualpatientneedtobebalanced
withexistingtreatmentoptions.Considerationsincludethefollowing[6]:
PatientswithCD4cellcountsthatexceed350500cells/LareatalowriskfornonAIDS
relatedclinicalevents
PatientswithCD4cellcountsoflessthan200cells/LareatgreatestriskforbothAIDSrelated
andnonAIDSrelatedevents
Replacementofindividualantiretroviralcomponents(eg,NNRTItoproteaseinhibitor)canbe
attemptedprovidedthatcompleteviralsuppressionispresent,butthisstrategyremains
unproven
Additionofasingleantiretroviralagenttotheexistingregimenhasnotbeenshowntobe
effective
Theuseofimmunestimulants(eg,interleukin2,growthhormone)ispresentlyrecommended
onlyinthecontextofaclinicaltrial
Likewise,decisionstoalterantiretroviraltherapyinpatientswithdiseaseprogressionaredetermined
basedonclinicalseverityandexistingtreatmentoptions.
Therapyselection
Antiretroviralactivityanddurabilityimproveswiththeadditionofatleast2or,optimally,3fullyactive
agentstoanoptimizedbackgroundregimen.Theselectionofindividualagentsforanoptimized
backgroundregimenshouldbebasedontheantiretroviraltreatmenthistory,genotypicand/or
phenotypicresistanceresults,drugdruginteractionpotential,andmedicationintolerance,withthe
goalofmaximizingantiviralactivityandadherence.
Divergencefromthestrategyofusing2NRTIswitheitheranNNRTIoraproteaseinhibitoristypically
necessaryastheextentofdrugresistanceincreases.Fourtosixdrugregimensarecommonlyused
inpatientswithextensivedrugresistanceinordertoincreasethedegreeofactivity.[6]
Theintroductionofnewantiretroviralagentshasbroadenedthenumberofactiveagentsavailablefor
treatmentofpatientswithinfectionduetoresistantHIVandhasimprovedthesuccessrateoftherapy.
Raltegravir,tipranavir,darunavir,enfuvirtide,maraviroc,andetravirinearefrequentlyconsideredfor
use.Limitedinformationexistsregardingoptimalcombinationsoftheseagentsfortreatment,as
selectionisoftenbasedonresistancetestingresults,priortreatmenthistory,andintolerance.[6]
Enfuvirtideishighlyeffectiveinthetreatmentofantiretroviraltherapyexperiencedpatientsbut
requiressubcutaneousinjectiontwicedailyandisassociatedwithinjectionsitereactions.
Darunavirandtipranavirtypicallyretainactivityinthepresenceofmultipleproteaseinhibitor
mutations.
Theuseoftipranavirhasbeenhinderedbythepotentialforinteractionwithotherantiretroviralagents,
hepatotoxicity,andreportsofintracranialbleedingevents.
Raltegravirhasbeendemonstratedtobehighlyactiveinpatientswithextensivedrugresistancein
shorttermstudies(48weeks)andiswelltolerated.
Etravirineismosteffectivewhencombinedwithotheractiveagentsbutmaycausedrugdrug
interactionswithotherantiretroviralagents.
Theroleofmaravirocinthissettinghasbeenlimitedbecauseofthehighfrequencyofdual/mixed
tropicorCXCR4tropicvirusinpatientswithmorelongstandingHIVinfectionandthenecessityfor
expensivetropismassaypretesting.
Goalsoftherapy
Thegoalsoftherapyintreatmentexperiencedpatientsarethesameasintreatmentnaivepatients.
[6] Withtheintroductionofneweragents,suppressionofviremiatobelowthelimitofassaydetection
(<48copies/mL)isnowachievableinmanypatientswhoharbordrugresistantviralstrains.
Genotypicorphenotypicresistancetestingshouldbeusedtoassistwithselectionofappropriate
therapyandshouldbeobtainedwhilepatientsremainontheirprevioustherapyorwithin4weeksof
discontinuationtoimprovethesensitivityofresults.Phenotypictestingisgenerallyaddedtogenotypic
testingwhencomplexdrugresistancemutationpatterns,especiallytoproteaseinhibitors,are
confirmedorsuspected.[6]
Virologicendpointsfortherapyincludethefollowing:
Onelog10declineinHIV1RNAby8weeks
Fewerthan400HIV1RNAcopies/mLby24weeks
Fewerthan50HIV1RNAcopies/mLby48weeks
Ifoneoftheseendpointsisnotmet,thepatientshouldbeevaluatedtodeterminewhether
nonadherence,drugintolerance,orresistanceisafactor.
Specialpopulations
Pregnancy
AntiretroviraltherapyisrecommendedinallpregnantwomenwithHIVinfectionregardlessofviral
loadorCD4count.Independentofviralload,antiretroviraltherapyhasbeenshowntodecreasethe
likelihoodofmothertochildtransmission.Thegoaloftherapyistoachievemaximalvirologic
suppressiontominimizethetransmissionrisk.Itisrecommendedthatallwomeninitiatingtherapyfor
thefirsttimeorthosereceivingtherapywhohaveadetectableviralloadundergogenotypicresistance
testingtoguidetherapyselection.
Preferredagentsincludethefollowing:
NRTIZidovudine,lamivudine
NNRTINevirapine
Proteaseinhibitor(PI)Lopinavir/ritonavir
AntiretroviraltherapyshouldconsistoftwoNRTIswitheitheranNNRTIorPI,guidedbyresistance
testing.Lopinavir/ritonavirincombinationwithzidovudine/lamivudineispreferredinmostcases.
Efavirenzisnotrecommendedduringthefirsttrimesterbecauseofsignificantteratogenicityinprimate
studiesandshouldbeusedduringthesecondandthirdtrimestersonlyifitoffersclearbenefitover
otheralternatives.
Aretrospectivecohortstudyreviewedtherecordsof3,273HIVpositivewomenreceivingprenatal
careinMalawiandMozambiquefromJuly2005toDecember2009.Patientsweretreatedwithtriple
antiviraltherapyduringpregnancyuntil6monthspostpartumforpreventionofverticaltransmission.
RegardlessofCD4count,ARTprovidedaprotectiveeffectagainstmortality,fetaldemise,and
prematurebirth.[85]
PIbasedHAARTisassociatedwithincreasedpretermdelivery(21.4%versus11.8%withNRTI
therapy)butnotwithincreasedinfanthospitalizationsormortality.[86]
Cautionshouldbeusedwithnevirapineregimensowingtoobservedhepaticfailureanddeathina
smallnumberofpatients.TheriskfornevirapinerelatedtoxicityisincreasedwithCD4countsabove
250/Linwomentherefore,nevirapineshouldbeusedonlyinwomenwithhigherCD4countsifthe
benefitoutweighstherisk.
TheOCTANEstudyshowedthatritonavirboostedlopinavirplustenofoviremtricitabinewassuperior
tonevirapineplustenofoviremtricitabineforinitialantiretroviraltherapyinwomenwithpriorexposure
toperipartumsingledosenevirapine(butnotinthosewithoutpriorexposure).[87]Zidovudineshould
beincludedinallregimensunlessitsuseisprecludedbyseveretoxicityordocumentedresistance.
Regardlessoftheantenatalregimen,zidovudineshouldbeadministeredbyintravenousinfusionto
themotherduringlaborandorallytotheneonatefor6weeksfollowingbirth.Moredetailed
informationregardingtreatmentofpregnantwomenwithHIVinfectionisincludedinguidelinesfrom
theU.S.PublicHealthServiceforpreventionofperinatalHIVtransmission.[88]Providersare
encouragedtoreportallcasesofperinatalantiretroviralexposuretotheAntiretroviralPregnancy
Registry.
PostexposureprophylaxisfollowingoccupationalHIVexposures
Postexposureprophylaxis(PEP)hasbeendemonstratedtoreducetheriskofHIVinfectionwhen
administeredsoonafterexposure.TheriskforHIVinfectionisdeterminedbasedontheexposure
type(percutaneous,mucousmembrane,intactskin),severityofexposure(smallorlargevolume,
superficialordeepinjury),andsourcestatus(knownorunknownHIVstatus).Postexposure
prophylaxisisrecommendedforexposuresfromadocumentedHIVsourceandisconsideredoptional
whentheHIVstatusofthesourceindividualisunknown.
Forlowriskexposures(eg,mucousmembrane),a2drug(basic)regimenisrecommended.Forhigh
riskexposures(eg,percutaneousneedlestick),a3drug(expanded)regimenisrecommended.
Ideally,therapyshouldbestartedassoonaspossibleafterexposure(withinhours)andcontinuedfor
28days.
Thefollowingarethepreferredbasicregimens:
Zidovudinepluslamivudine
Zidovudineplusemtricitabine
Tenofovirpluslamivudine
Tenofovirplusemtricitabine
Thepreferredexpandedregimenisthebasicregimenpluslopinavir/ritonavir.
Aconsultationwithanexpertshouldbesoughtwhenantiretroviraltherapyforpostexposure
prophylaxisisconsidered,especiallywhentheantiretroviraltreatmenthistoryofthesourceindividual
isknown.AdditionalinformationontreatmentselectionandmanagementcanbefoundintheUS
PublicHealthguidelinesforoccupationalHIVexposure.[89]
PostexposureprophylaxisfollowingnonoccupationalHIVexposures
NonoccupationalexposuretoHIVincludesanyexposuretopotentiallyinfectiousbodilyfluidsand
tissuesnotsecondarytojobduties.Theseexposuresincludebutarenotlimitedtosexualcontactand
thesharingofinjectiondrugequipment.
Datafromanimalstudies,perinataltransmissionstudies,experiencewithoccupationalpostexposure
prophylaxis,andobservationalstudiessupportthepremisethatinitiationofabriefcourseof
antiretroviraltherapyafternonoccupationalexposuremaydecreasethelikelihoodofHIV
transmission.[90]
Itisrecommendedthatpatientswhopresent72hoursorsoonerafterasubstantialriskHIVexposure
involvinganHIVinfectedsourcebeofferedpostexposureprophylaxisconsistingof3antiretroviral
agents.Theriskisbasedonthetypeofexposure.IftheHIVstatusofthesourceisunknown,each
caseshouldbedeterminedindividuallybasedonrisk.[90]
Substantialriskcriteriaincludethefollowing:
SiteofexposureVagina,rectum,eye,mouth,orothermucousmembrane,nonintactskin,or
percutaneouscontact
InfectiousmaterialBlood,semen,vaginalsecretions,rectalsecretions,breastmilk,oranybody
fluidthatisvisiblycontaminatedwithblood
SourcestatusKnownHIVinfectioninthesource
Negligibleriskcriteriaincludethefollowing:
SiteofexposureVagina,rectum,eye,mouth,orothermucousmembrane,intactornonintact
skin,orpercutaneouscontact
InfectiousmaterialUrine,nasalsecretions,saliva,sweat,ortearsifnotvisiblycontaminated
withblood
SourcestatusRegardlessoftheknownorsuspectedHIVstatusofthesource
Postexposureprophylaxisisnotrecommendedinpatientswhopresentmorethan72hoursafter
exposureorwhohaveexposuresdeemedtorepresentanegligiblerisk.Ifantiretroviraltherapyis
initiated,itshouldbecontinuedfor28days.[90]
Thepreferredregimensareasfollows:
Efavirenzpluslamivudineoremtricitabinepluszidovudineortenofovir
Lopinavir/ritonavirpluslamivudineoremtricitabinepluszidovudine
Adolescents
AdolescentswithHIVinfectionrepresentaheterogenouspatientpopulation.Thispopulationincludes
newlyinfectedpatientsandlongtermsurvivorswhowereinfectedperinatallyorthroughblood
products.Adulttreatmentguidelinesareusuallyappropriateinpostpubertaladolescents.Similarly,
patientsinfectedwithHIVviaintravenousdruguseorsexualencountersshouldbemanaged
accordingtoadultguidelines.
AntiretroviraldosingshouldbebasedontheTannerstagingofpuberty.PatientsinstageIorIIshould
receivemedicationsaccordingtopediatricschedulesthoseinlatepuberty(stageV)shouldundergo
managementaccordingtoadultguidelines.Fewdataprovideguidancefordosinginadolescentswho
fallinstagesIIIandIV.Closemonitoringforefficacyandtoxicityisimperative,regardlessofthe
dosingscheduleusedtoimplementtherapy.[6]
PatientswithacuteHIVinfection
LimiteddataareavailabletodefinetheroleoftreatmentinpatientswithacuteHIVinfection.The
potentialbenefitsofinitiatingtreatmentduringacuteinfectionremaintheoretical.Treatingacute
infectionmaydecreasetheseverityofacutedisease,lowerthelevelofchronicviremiafollowing
symptomresolution,decreaseviralmutation,preserveimmunefunction,andreducetransmission.
Ifthepatientandproviderdecidetoimplementtreatmentbasedonthesepotentialbenefits,
combinationtherapyshouldbeinitiatedsimilartothatadministeredinpatientswithchronicinfection.It
isrecommendedthatproteaseinhibitorbasedregimensbeconsideredowingtothelowerincidence
ofresistancetotheseagentsintreatmentnavepatients.Providersmaywanttoconsiderenrolling
thesepatientsintoaclinicaltrialevaluatingthenaturalhistoryandtheroleofantiretroviraltreatment
inacuteHIVinfection.[6]
Coinfection
AsignificantamountofmorbidityandmortalityinpersonswithHIVinfectionresultsfromcoinfection
withMycobacteriumtuberculosis(MTB),hepatitisBvirus(HBV),orhepatitisCvirus(HCV).Eachof
theseinfectionsismoredifficulttomanageinpatientswithHIVinfectionbecauseoftheaccelerated
rateofdiseaseprogression,lowertreatmentresponserates,drugdruginteractions,andadditive
toxicitiesthatresultfromconcomitanttherapies.Furthermore,HIVtreatmentismoreimperativeinthe
presenceofcoinfection,leadingtoinitiationofantiretroviraltherapyathigherCD4countsthanin
patientswithHIVmonoinfection.
Theantiretroviraltreatmentsequencingstrategyforeachtypeofcoinfectionischallengingandmust
betailoredtoindividualpatientspecificneedstoprovidethebestpossibleoutcomeandtorestore
qualityoflife.
Tuberculosis
TheoverallrateofmorbidityandmortalityassociatedwithMtuberculosiscoinfectioninpatientswith
HIVinfectionissignificant.Worldwide,estimatesofthemortalityrateduetoMtuberculosisinfectionin
thepresenceofHIVinfectionare13%however,suchrateshavesignificantlydecreasedintheUnited
StatesbecauseoftheaggressiveimplementationofpublichealthandhospitalMtuberculosis
programs.[91]
Nonetheless,significantoverlapexistsinthepatientpopulationswhoareexposedtoMtuberculosis
andareatriskforHIVinfection.Diseaseprogressionratesofeachareacceleratedwithcoinfection
andrequireswiftandaggressivemanagementstrategies.However,patientsarenotroutinely
screenedfortuberculosispriortotheinitiationofantiretroviraltherapy.AcohortstudyofHIVinfected
patientsidentifiedriskfactorsfordevelopingtuberculosisafterHAARTinitiationinanefforttofocus
screeningefforts.ResultssuggestpatientswithCD4counts<200cells/LorincreasedHIV1RNA,
personsofnonwhiteraceorHispanicethnicity,andpatientswithahistoryofinjectiondruguseshould
betargetedfortuberculosisscreening.[92]
CurrentrecommendationssuggestthattreatmentforMtuberculosisinfectionandHIVinfectionbe
initiatedseparatelybecauseofadditiveadverseeffectsandoverlappingtoxicitieshowever,theideal
timeframebetweenthetwoislesswelldefined.[93]
FactorstoconsiderwithtreatmentsequencingforHIVandMtuberculosiscoinfectionincludewhento
initiateeachtherapyandhowtomanagedrugdruginteractions,adverseeffects,andadditive
toxicities.Intreatmentnavepatients,thefocusoftherapyshouldbedirectedinitiallytowardM
tuberculosisinfection,buttheimplicationsforsubsequentantiretroviraltherapymustbeconsideredin
ordertoavoidormanagependingdrugdruginteractions.
TreatmentselectionforlatentoractiveMtuberculosisinfectionisgenerallystraightforwardhowever,
significantdrugdruginteractionsarepossiblewithantiretroviralmedicationswhenarifamycinis
includedinthetreatmentplanbecauseoftheirstronginductiveeffectsonthecytochromeP450
system.[94]Rifabutinisusuallyselectedoverrifampinbecauseofitslesspotentmetabolicinduction
whenantiretroviraltherapyisrequired,butdoseadjustmentsarenecessarywhenproteaseinhibitors
andNNRTIsareadministeredconcomitantly.
Delayingantiretroviraltherapyintreatmentnavepatientsiscontroversialbutnecessaryinorderto
assesspotentialsideeffectsandtoxicities(eg,gastrointestinaleffect,hepatotoxicity)thataresimilar
witheachtherapy.Currentguidelinesrecommendadelayinantiretroviraltherapyfor28weeksafter
theinitiationofMtuberculosisinfectiontherapy,withconsiderationgiventothepotential
consequencesofantiretroviraltherapydeferralineachpatient.
SeveralstudiesindicatethatinitiatingHAART2weeksafterthestartoftuberculosistreatment
significantlyimprovessurvivalamongHIVinfectedadultswithCD4+Tcellcountsof200percubic
millimeterorlower.Startingstavudine,lamivudine,andefavirenzafter2weeksoftuberculosis
treatmentinsteadof2monthsimprovedmortalityfrom27%to18%inonestudywith661patients.[95]
Inanotherstudy,earlierHAARTwasassociatedwithalowerrateofnewAIDSdefiningillnessand
death(27%vs16%)in881patientswithCD4+Tcellcountsoflessthan50percubicmillimeter.[96]
Astudywith642ambulatorypatientsshowedadecreasedincidencerateofAIDSordeathwith9and
27casesper100personyearsinpatientswithCD4+Tcellcountsoflessthan50percubicmillimeter
(1monthvs2.5months).[97]However,theriskofimmunereconstitutioninflammatorysyndromewas
significantlyincreasedintheearlierHAARTgroup(2.5%vs3.6%).
Inpatientscurrentlyreceivingantiretroviraltherapy,Mtuberculosisinfectiontherapyshouldbe
initiatedassoonaspossible,withsimilarconsiderationgiventothepotentialfordrugdrug
interactions.AntiretroviraltherapyrecommendationsforpatientsreceivingtreatmentforM
tuberculosisinfectionarediscussedbelow.[6,93]
Fortreatmentnave(antiretroviraltherapyinitiationwithintheMtuberculosisinfectiontreatment
period),recommendationsareasfollows:
ProteaseinhibitorbasedregimenRecommendedtouseritonavirboostedregimen
NNRTIbasedregimenNodoseadjustmentsrequiredforefavirenzornevirapinelimiteddata
foretravirine
MaraviroccontainingregimenPotentialforalteredserumlevels(dosedeterminedby
concomitantantiretroviralagentsinthepresenceofrifabutin)
Fortreatmentexperienced(currentlyreceivingantiretroviraltherapy),recommendationsareasfollows
forproteaseinhibitorcontainingregimens:
UnboostedChangetoritonavirboostedform
CurrentlyboostedNodoseadjustmentrequired
Fortreatmentexperienced(currentlyreceivingantiretroviraltherapy),recommendationsareasfollows
forNNRTIcontainingregimens:
EfavirenzornevirapineNodoseadjustmentsrequired
EtravirineIfnotgivenconcomitantlywithboostedproteaseinhibitor,consideralternative
MaravirocLimiteddata
HepatitisBvirusinfection
Approximately10%ofindividualsinfectedwithHIVhaveHBVcoinfection.[98]Treatmentforeach
diseasecanbechallengingbecauseofaccelerateddiseaseprogressionandlowertreatment
responseratesforHBVinfectionandincreasedratesofhepatotoxicitywithantiretroviraltherapy.
PatientswithHIVandHBVcoinfectionoftenhavehigherHBVDNA,lowerHBeAgseroconversion
rates,andanincreasedriskofliverrelatedmortality.[99,100,101,102]
Additionally,acutehepaticflaresduetoantiretroviraltherapyaremorelikelyinthepresenceofHBV
owingtothecompromisedstateoftheliverandimmunereconstitutionreactionsthatcanoccurwith
treatmentinitiationatlowCD4counts.[100]Nonetheless,overlappingtherapiesexistandare
integratedintoatreatmentregimenthatisoptimalforbothHIVinfectionandHBVinfection.
ThegoalsoftherapyforHIVandHBVcoinfectionreflectthoseofHIVandHBVmonoinfection.The
sequencingoftherapyispatientspecificandisguidedbycriteriaforeachdisease.Treatmentforboth
canbesuccessfullycombinedandshouldincludeNRTIsthatpossessactivityagainstbothviruses
(tenofovir,lamivudine,emtricitabine).
Mostoften,a3drugcombinationisrecommendedinpatientswithHIVandHBVcoinfectionwhen
treatmentisindicatedforeitherdiseaseinordertopreventthedevelopmentofantiretroviraldrug
resistance.BothHIVandHBVcanacquireresistancetotheNRTIs,sotherapymustbetailoredto
retainvirologiccontrol.
Ifeithervirusacquiresresistance,additionalmedicationsshouldbeaddedtothecurrentregimen
ratherthansubstitutedinordertomaintainvirologiccontroloftheremainingdrugsusceptiblevirus.
WhenHBVacquiresresistanceinthepresenceofHIV,otherNRTIsthatlackHIVactivity(adefovir,
telbivudine)canbeaddedtotheexistingHBVregimenhowever,entecavirshouldbeusedonlyin
coinfectedindividualswithlongstandingHIVRNAsuppressionbecauseofitsactivityagainstHIVand
theproposedriskofHIVdrugresistance.
InpatientsreceivingHBVtreatmentwithoutconcomitantHIVtherapy,pegylatedinterferon,adefovir,
ortelbivudineisrecommended.AntiretroviraltherapyrecommendationsinpatientswithHIVandHBV
coinfectionarediscussedbelow.[100]
IfonlyHIVtreatmentisrequired(andnotHBV),recommendationsareasfollows:
NRTIbackboneshouldincludetenofovirplusemtricitabineorlamivudine:Combinationactively
treatsbothHIVandHBV
ThirdagentforHIV(patientorproviderspecificchoicethatminimizeshepatotoxicitypotential)
IfonlyHBVtreatmentisrequired(andnotHIV),recommendationsareasfollows:
HBVDNAgreaterthan2000IU/mL:AntiretroviraltherapymustbeinitiatedtopreventHIV
resistanceandshouldincludetenofovirplusemtricitabineorlamivudinefortheNRTIbackbone
HBVDNAlessthan2000IU/mL:Pegylatedinterferonalpha2a180gonceweeklyfor48
weeks,Adefovir,Telbivudine
HepatitisCvirusinfection
Approximately25%ofpersonswithHIVinfectionarecoinfectedwithHCV.[103,104]HCVinfectionin
thepresenceofHIVinfectionprogressestocirrhosisorendstageliverdiseasetwiceasquicklyasin
HCVmonoinfection.[105]
Treatmentoutcomes,asmeasuredbyendoftreatmentresponseandsustainedvirologicresponse
rates,arealsolowerinpatientswithHCVandHIVcoinfection.[106,107]AlthoughHIVdisease
progressionhasnotbeendirectlylinkedtoHCVcoinfection,itissignificantlyinfluencedbythelower
riseinCD4countsonceantiretroviraltherapyisinitiatedandtheincreasedriskforhepatotoxicitywith
antiretroviraltherapy.
DruginteractionswithantiretroviraltherapyandstandardHCVtherapyhavebeendemonstratedwith
theNRTIsandribavirin.Suchinteractionscanproducesignificanttoxicitiesand/orreducethe
likelihoodofresponsetoHCVtherapy.SequencingoftherapyusuallybeginswithtreatmentofHIV
infectionhowever,whenapatienthasnotmettreatmentcriteriaorisunabletotolerateantiretroviral
therapy,HCVtreatmentshouldbeconsidered.
Ideally,patientswithHCVandHIVcoinfectionshouldhaveaCD4countthatexceeds200/Lpriorto
HCVtreatmentinitiationinordertoimprovetoleranceandresponsetotherapyhowever,sufficient
CD4recoveryisnotwithinreachinsomecases.[6,100]Inthesesituations,HCVtherapyshouldbe
initiatedratherthandelayedfurtherbecauseoftheurgencytoreduceHCVdiseaseprogression.[100]
TreatmentoptionsforHCVtherapyarepresentlylimitedtocombinationtherapywithpegylated
interferonandribavirin.Responseratesarelowerincoinfectedpatients,andextendedtreatment
durations(eg,4872weeks)areoftenrecommended.[106,107,108]
TherapyforHIVconsistsofthestandard3drugregimen,butdruginteractionsbetweenantiretroviral
agentsandribavirinandoverlappingtoxicitiescanfurthercomplicatetreatmentselection.Close
monitoringofserumtransaminasesduringcombinedantiretroviraltherapyandHCVtherapyis
warrantedbecauseoftheincreasedriskofhepatotoxicity.
DrugsthatinteractoraddtoxicitieswithribavirinincludetheNRTIsdidanosine,zidovudine,and
abacavir.Thecombinationofdidanosineandribaviriniscontraindicatedowingtoincreased
intracellularconcentrationsofdidanosinethatsignificantlyincreasetheriskoflifethreateninglactic
acidosisandpancreatitis.[109]
Zidovudineandribavirincancauseadditiveanemiaandshouldbeconsideredonlyinpatientswitha
stablehemoglobinconcentration.LowerHCVtreatmentresponserateshavebeendescribedin
coinfectedpatientsreceivingabacavircontainingantiretroviraltherapyregimensin2clinicaltrials.
[110,111]
Whenearlyvirologicresponseratesandsustainedvirologicresponserateswerecomparedbetween
abacavircontainingregimensandothernucleosideregimens,pooreroutcomesreachingstatistical
significanceweredemonstratedintheabacavirgroup.
Althoughtheribavirinandabacavirinteractionhasnotbeenfullydescribed,bothareguanosine
analogsandhypothesizedtohavecompetitivephosphorylationthatcanresultinlowerribavirin
concentrations.Tenofovir,ontheotherhand,hasbeenshowntoimproveHCVtreatmentresponse
rateswhenincludedintheantiretroviraltherapyregimenandcombinedwithribavirin.[111]
AlthoughguidelinesfortheuseofabacavirandtenofovirincombinationwithHCVtherapyhavenot
beenimplemented,considerationshouldbegiventothesemorerecentfindings.Anabacavir
containingregimenshouldbeavoidedincoinfectedpatientswhoarecandidatesforHCVtherapyuntil
furtherdatabecomeavailable.
Preexposureprophylaxis
Amultinationalstudy,calledthePreexposureProphylaxisInitiative(iPrEx)trial,foundthatoncedaily
emtricitabineplustenofovirdisoproxilfumarate(FTCTDF)reducedtheriskofacquiringHIVby44%
inastudypopulationofhighrisk,HIVnegativemenortransgenderwomenwhohavesexwithmen.
[112]
Currently,nodataareavailableonthebenefitsofFTCTDFinheterosexualsorinjectiondrugusers.
TheCentersforDiseaseControlandPrevention(CDC)willdeterminehowtomosteffectivelyuse
FTCTDFincombinationwithotherpreventionstrategiestoreducenewHIVinfections.TheCDC,
NationalInstitutesofHealth(NIH),andotherinstitutionsarealsoconductingtrialstodeterminethe
safetyandeffectivenessofpreexposureprophylaxis(PrEP)forthesepopulations.[113,114]
Preexposureprophylaxis(PrEP)maybepartofcomprehensiveHIVpreventionservicesinwhichHIV
negativepeoplewhoareathighrisk,takeantiretroviralmedicationdailytotrytolowertheirchances
ofbecominginfectedwithHIViftheyareexposedtoit.PrEPconsistsoftakingthecombinationdrug,
emtricitabine200mgandtenofovir300mg(Truvada),oncedaily.[115,116]
Complianceisessential.Instudies,thelevelofprotectionvariedwidelydependingonhow
consistentlyparticipantsusedPrEP.Amongthosewhosedata(basedonselfreports,bottles
dispensed,andpillcounts)indicateuseon90%ormoredays,HIVriskwasreducedby73%.Among
thosewhoseadherencebythesamemeasurewaslessthan90%,HIVriskwasreducedbyonly21%.
Comprehensivepreventionservicesarealsorequired(ie,monthlyHIVtesting,condomprovision,
counseling,andmanagementofothersexuallytransmittedinfections).
Todate,PrEPhasbeenshowntobeeffectiveonlyinmenwhohavesexwithmen(MSM)and
transgenderedwomenwhohavesexwithmen.StudiesareunderwaytoevaluatewhetherPrEPis
safeandeffectiveinreducingHIVinfectionamongheterosexualmenandwomenaswellasinjection
drugusers,butthoseresultsarenotyetavailable.
HIVdiscordantcouples
ACochraneDatabaseofSystematicReviewsanalysisof7observationalstudiesfoundthatARTis
verypotentforthepreventionofHIVincouplesinwhichonlyonepartnerisinfectedwiththevirus.
Resultsshowthatinserodiscordantcouples,uninfectedpartnersofinfectedindividualsbeingtreated
withantiretroviraldrugshavea5timeslowerriskofcontractingHIVcomparedtouninfectedpartners
ofinfectedindividualsnotreceivingtreatment.
WhethertoinitiateARTinthispopulationatthetimeofdiagnosisorataspecificCD4orplasmaviral
loadlevelisunclear.Alarge,randomizedcontrolledtrialaddressingthisquestionisscheduledto
concludein2015.[117]
Amulticontinent,randomized,controlledtrialbytheHIVPreventionTrialsNetwork(HPTN)in2011
evaluatedearlyversusdelayedantiretroviraltherapyforHIVinfectedpatientswithCD4counts
between350and550/Lwhowereinstablesexualrelationshipswithnoninfectedpartners.Findings
showthatearlyinitiationofantiretroviraltherapyreducedtransmissionratesofthediseaseby96%.
Earlytherapywasalsoassociatedwitha41%reductioninthenumberofHIVrelatedclinicalevents.
[118]
TablesofAntiretroviralDrugInteractions
InteractionsbetweenantiretroviraldrugsaredescribedinTable2,below.Interactionsbetween
antiretroviraldrugsandotherdrugsaredescribedinTable3,below.
Foradditionaldetailedinformation,seeDrugInteractionswithAntiretroviralTherapyorNIHGuidelines
fortheUseofAntiretroviralAgentsinHIV1InfectedAdultsandAdolescents.
Table2.DrugInteractionsBetweenAntiretroviralAgents[6](OpenTableinanewwindow)
AntiretroviralAgent
Interacting
Antiretroviral
Agent
PredictedEffect
Management
Atazanavir(ATV)
Tenofovir
ATV
AdministerATV
300mgwith
ritonavir100mg
Etravirine
ATV,ETV
Donotcoadminister
Nevirapine(NVP)
ATV,NVP
Donotcoadminister
Efavirenz
ATV
AdministerATV400
mgwithritonavir100
mg(treatmentnaive)
donotcoadminister
(treatment
experienced)
Abacavir(ABC)
Tipranavir
ABC
Avoid
coadministration
Darunavir(DRV)
Lopinavir/ritonavir,
saquinavir
DRV
Donot
coadminister
Didanosine(ddI)
Tenofovir
ddI
DecreaseddI
dose(250mg
qd)
Etravirine(ETV)
Tipranavir
ETV
Donot
coadminister
FPV
Donot
coadminister
Lopinavir/ritonavir,
Fosamprenavir(FPV)
tipranavir
Etravirine
FPV
Avoid
coadministration
Indinavir(IDV)
Tipranavir
IDV
Donot
coadminister
LPV/r500/125
mgbid(tablet)
or533/133mg
bid(liquid)
Lopinavir/ritonavir(LPV/r)
Efavirenz,
nevirapine
LPV
Tipranavir
LPV
Donotcoadminister
Maraviroc(MVC)
Efavirenz,
etravirine
MVC
PIs(excepttipranavir)
MVC
DecreaseMVCdose
(150mgbid)
Delavirdine
MVC
DecreaseMVCdose
(150mgbid)
Nelfinavir(NFV)
Tipranavir
NFV
Donot
coadminister
Saquinavir(SQV)
Tipranavir
SQV
Donot
coadminister
Zidovudine(ZDV)
Tipranavir
ZDV
Avoid
coadministration
IncreaseMVC
dose(600mg
bid)
Abbreviations:ART,
antiretroviraltherapyNNRTIs,
nonnucleosidereverse
transcriptaseinhibitorsPIs,
proteaseinhibitors.
Table3.RepresentativeListofDrugInteractionsBetweenAntiretroviralAgentsandOtherMedications
[6,119,120,121] (OpenTableinanewwindow)
Medication
Antiretroviral
Agent
Predicted
Effect
Management
Antacids
Raltegravir(RAL),
elvitegravir(ETG)
RAL,ETG
Avoidconcurrent
administration
Atazanavir(ATV)
Tipranavir/ritonavir
(TPV/RTV)
ATV
TPV
TakeATV2h
beforeor1h
afterantacids
Fluticasone
PIs,delavirdine
Fluticasone
Avoidcoadministration
BoostedATV:Administer
simultaneouslyor>10hafter
H2Adonotexceed40mg
famotidinedoseequivalent
bid(treatmentnaive)or20
mgbid(treatment
experienced)
Atazanavir(ATV)
Fosamprenavir
(FPV)
ATV
APV
H2antagonists(H2A)
Rilpivirine(RPV)
UnboostedATV:Administer
>2hbeforeor>10hafter
H2Adonotexceed20mg
famotidinedoseequivalent
bid(treatmentnaive)
RPV
UnboostedFPV:Administer
FPV>2hbeforeH2A
considerRTVboosting
RPV:AdministerH2Aeither
12hbeforeor4hafterRPV
Methadone
BoostedPIs,
nelfinavir
Methadone
Monitorforwithdrawal
symptoms
PDE5inhibitors
(sildenafil,tadalafil,
vardenafil)
PIs,delavirdine
PDE5
inhibitor
Beginwithsildenafil25mg
q48h
Beginwithtadalafil5
mgdonotexceed10
mgq72h
Beginwithvardenafil
2.5mgdonotexceed
2.5mgq72h
Phenytoin(PHT)
Lopinavir/ritonavir
PHT,LPV/r
MonitorPHTserum
PHT,LPV/r
(LPV/r)
Atazanavir(ATV)
concentrationsandHIVRNA
ATV
PPIsnotrecommendedwith
unboostedATVorinART
experiencedpatients.Donot
exceedomeprazole20mg
doseequivalentseparate
dosingby12h(ARTnave)
Protonpumpinhibitors
Tipranavir/ritonavir
(TPV/RTV)
Omeprazole
(with
TPV/RTV)
(PPIs)
Rilpivirine(RPV)
TPV/RTV:Consider
omeprazoledoseincrease
withTPV/RTV
RPV
RPV:Donotcoadminister
withPPIs
Rifabutin
PIs
Rifabutin
Efavirenz
Rifabutin
Increase
rifabutindose
to450mg
Rilpivirine(RPV),
delavirdine(DLV)
RPV,DLV
Donot
coadminister
Rifampin
PIs
PI
Donot
coadminister
withNVP,DLV,
ETV,RPV
NNRTIs
NNRTI
EFV:Consider
EFVdose
increaseto
800mg/dfor
patients>60
kg
Decreaserifabutindoseto
150mgqdqod
Donotcoadminister
increasedriskfor
hepatotoxicity
Maraviroc(MVC)
Raltegravir(RAL)
MVC
Donot
coadminister
RAL
Rifampinisa
strong
UTG1A1
inducer
increaseRAL
doseto800
mgbid
Salmeterol
PIs
Salmeterol
Avoidcoadministration
increasedriskofQTinterval
prolongation
Statins(simvastatin,
lovastatin,pitavastatin)
PIs,delavirdine
Statin
Donotcoadminister
NNRTIs(except
delavirdine)
Statin
Adjuststatin
dose
accordingto
response
Voriconazole
BoostedPIs
Voriconazole
Voriconazole
Increase
voriconazole
maintenance
doseto400
mgbidand
decreaseEFV
doseto300
mg/d
Efavirenz
Warfarin
BoostedPIs,nevirapine
Abbreviations:INR,
internationalnormalized
ratioPDE5,
phosphodiesterase5
EFV
Efavirenz,
delavirdine,
etravirine
Warfarin
Warfarin
MonitorINR
andadjust
warfarindose
accordingly
Donotcoadminister
MonitorINRandadjust
warfarindoseaccordingly
inhibitorsPIs,protease
inhibitors.
PharmacokineticEnhancers(BoostingAgents)
Cobicistat(Tybost)isaCYP3Ainhibitor.Asasingleagent,itisindicatedtoincreasesystemic
exposureofatazanavirordarunavir(oncedailydosingregimen)incombinationwithother
antiretroviralagents.Itisalsoacomponentofelvitegravir/cobicistat/emtricitabine/tenofovir(Stribild).
Cobicistatmaybeusedfortreatmentnaveorexperiencedpatients(withoutdarunavirresistance
associatedsubstitutions).Thedosageis150mgPOoncedailyplusatazanavir300mgPOoncedaily
ordarunavir800mgPOoncedaily.
RitonavirisalsoapotentCYP3A4inhibitorthatisinmanycombinationproductionsandincludedin
manyHIVtreatmentregimenstoaugmentsystemicexposuretootherantiretroviralagents.
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