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Thissiteisintendedforhealthcareprofessionals

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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