Page 70 - HIV/AIDS Guidelines

studiessuggestedthatLPV/r,IDV,fosamprenavir(FPV),orritonavir-boostedfosamprenavir(FPV/r)maybe
associatedwithincreasedratesofmyocardialinfarction(MI)orstroke. 40-41 Bothstudieshadtoofewpatients
receivingATV/rorritonavir-boosteddarunavir(DRV/r)tobeincludedintheanalysis.Ritonavir-boosted
saquinavir(SQV/r)canprolongthePRandQTintervalsonelectrocardiogram(ECG).ThedegreeofQT
prolongationseenwithSQV/risgreaterthanthatseenwithsomeotherboostedPIs.Therefore,SQV/rshould
beusedwithcautioninpatientsatriskoforwhouseconcomitantdrugsthatmaypotentiatetheseECG
abnormalities. 42

ThepotentinhibitoryeffectofRTVonthecytochromeP(CYP)4503A4isoenzymeallowstheadditionof
low-doseRTVtootherPIsasaPKboostertoincreasedrugexposureandprolongtheplasmahalf-lifeofthe
activePI.BoostingwithRTVallowsforreduceddosingfrequencyand/orpillburden,whichmayimprove
overalladherencetotheregimen.Theincreasedtroughconcentration(C min )mayimprovetheARVactivity
oftheprimaryPI,whichcanbebeneficialwhenthepatientharborsHIVstrainswithreducedsusceptibility
tothePI 43-45 andalsomaycontributetothelowerriskofresistanceatvirologicfailurewithboostedPIsthan
withunboostedPIs.Thedrawbacksassociatedwiththisstrategyarethepotentialforincreasedriskof
hyperlipidemiaandagreaterpotentialofdrug-druginteractionsfromtheadditionofRTV.Inpatientswithout
pre-existingPIresistance,supportfortheuseofonce-dailyboostedPIregimensthatuseonly100mgper
dayofRTVisgrowing.ThisisbecausetheseregimenstendtocausefewerGIsideeffectsandlessmetabolic
toxicitythanregimensthatuseRTVatadoseof200mgperday.

ThePanelusesthefollowingcriteriatodistinguishbetweenpreferredandalternativePIsinART-naive
patients:(1)demonstratedsuperiorornoninferiorvirologicefficacywhencomparedwithatleastoneother
PI-basedregimen,withatleastpublished48-weekdata;(2)RTV-boostedPIwithnomorethan100mgof
RTVperday;(3)once-dailydosing;(4)lowpillcount;and(5)goodtolerability.Usingthesecriteria,the
PanelrecommendsATV/r(oncedaily)andDRV/r(oncedaily)aspreferredPIs.

Preferred Protease Inhibitor (in alphabetical order, by active protease inhibitor
component)
Ritonavir-Boosted Atazanavir. RTVboostingofATV,givenastwopillsoncedaily,enhancesthe
concentrationsofATVandimprovesvirologicactivitycomparedwithunboostedATVinaclinicaltrial. 46
TheCASTLEstudycomparedonce-dailyATV/rwithtwice-dailyLPV/r,eachincombinationwith
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TDF/FTC,in883ARV-naiveparticipants.Inthisopen-label,noninferioritystudy,analysisat48weeks and
48
at96weeks showedsimilarvirologicandCD4responsesofthetworegimens.Morehyperbilirubinemia
andlessGItoxicitywereseenintheATV/rarmthanintheLPV/rarm.Thisstudysupportsthedesignation
ofATV/r+TDF/FTCasapreferredPI-basedregimen(AI).

ThemainadverseeffectassociatedwithATV/risindirecthyperbilirubinemia,withorwithoutjaundiceor
scleralicterus,butwithoutconcomitanthepatictransaminaseelevations.Nephrolithiasisalsohasbeen
reportedinpatientswhoreceivedRTV-boostedorunboostedATV. ATV/rrequiresacidicgastricpHfor
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dissolution.Thus,concomitantuseofdrugsthatraisegastricpH,suchasantacids,H2antagonists,and
particularlyPPIs,mayimpairabsorptionofATV.Table15a providesrecommendationsforuseofATV/rwith
theseagents.
Ritonavir-Boosted Darunavir. TheARTEMISstudycomparedDRV/r(800/100mgoncedaily)withLPV/r
(onceortwicedaily),bothincombinationwithTDF/FTC,inarandomized,open-label,noninferioritytrial.
Thestudyenrolled689ART-naiveparticipants.At48weeks,DRV/rwasnoninferiortoLPV/r.Amongthose
participantswhosebaselineHIVRNAlevelswere>100,000copies/mL,thevirologicresponserateswere
lowerintheLPV/rarmthanintheDRV/rarm.Grades2to4adverseevents,primarilydiarrhea,wereseen
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morefrequentlyinLPV/rrecipientsthaninDRV/rrecipients. Atvirologicfailure,nomajorPImutations
38
weredetectedinparticipantsrandomizedtoeitherarm. At96weeks,virologicresponsetoDRV/rwas
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents F-9

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