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REVIEWOpenAccess Antiretroviralregimenssparingagentsfromthe class:areviewoftherecentliterature AmitCAchhra * andMarkABoyd Abstract Thenucleoside(tide)reversetranscriptaseinhibitors(NRTIs)havetraditionallybeenanimportant ‘ back-bone ’ ofan antiretroviraltherapy(ART)regimen.Howeverallagentshavebeenassociatedwithbothshort-andlong-termtoxicity. Therehavealsobeenconcernsregardingtheefficacyandsafetyofatreatmentsequencingstrategyinwhichthose withpastexposureand/orresistancetooneormoreNRTIsarere-exposedto ‘ recycled ’ NRTIsinsubsequent ARTregimens.Newer,potentandpossiblesafer,agentsfromvariousARTclassescontinuetobecomeavailable. TherehasthereforebeengrowinginterestinevaluatingNRTI-sparingregimens.Inthisreview,weexaminedstudiesof NRTI-sparingregimensinadultHIV-positivepatientswithvaryingdegreesofARTexperience.Wefoundthatin treatmentexperiencedpatientscurrentlyonafailing regimenwithdetectableviralload,therenowexistsa robustevidencefortheuseofNRTI-sparingregimensincludingraltegravirwithaboosted-proteaseinhibitor withorwithoutathirdagent.InthoseonavirologicallysuppressiveregimenswitchingtoaNRTI-sparing comesfromsmallexploratorytrialsorobservationalstudies.Overall,thesestudiessuggestthatcautionneedstobe exercisedincarefullyselectingtherightcandidateandagents,especiallyinthecontextofadual-therapyregimen,to minimisetherisksofvirologicalfailure.Thereisresidualtoxicityconferredbytheritonavirboostinprotease-inhibitor containingNRTI-sparingregimens.Fully-poweredstudiesareneededtoexploretheplaceofN(t)RTI-sparingregimens inthesequencingofART.Additionallyresearchisrequiredtoexplorehowtominimisetheadverseeffectsassociated withritonavir-basedpharmacoenhancement. Keywords: HAART,Toxicity,NRTI,NNRTI,NRTI-sparing,Class-sparing,HIV,Dualtherapy,Raltegravir,Maraviroc Introduction Thenucleoside(tide)reversetranscriptaseinhibitor(NRTI) classhasformedthe ‘ back-bone ’ ofantiretroviraltherapy (ART)regimenssincetheearlyARTera.Allmajortreat- mentguidelinescurrentlyrecommendtheselectionof 2NRTIsandathirdagentfromaseparateclassin theinitialmanagementofARTnaïveHIV-positivepa- tients;someguidelinessuggestrecyclingNRTIagents tientsexperiencingvirologicalfailure[1-4].However,con- cernsaboutlong-termtoxicitiesandcross – resistance withintheNRTIclasscombinedwiththecontinuingde- velopmentofnewer,seeminglysaferagentsinseveral independentclassesofdrugshasledtoagrowinginterest inthepotentialuseoffeasible,innovativeandappealing NRTI-sparingoptions. Themainpurposeofthisreviewistoexplorethe currentstateofourknowledgeontheefficacyandsafety ofNRTIclass-sparingantiretroviralregimensusedin themanagementofadultHIV-positivepatients.The reviewisrestrictedtostudiesconductedonadultHIV-1 mono-infectedindividualspublishedintheEnglishlan- guage.Thereviewhasagreaterfocusonstudiespublished since2006(soastoensurerelevancetocontemporary practice).Weincludedclinicaltrialsaswellasnon- randomisedsmallclinicalst udies,bothpublishedand unpublished(conferencepresentations). *Correspondence: aachhra@kirby.unsw.edu.au TheKirbyInstitute,UniversityofNewSouthWales,Sydney,Australia ©2013AchhraandBoyd;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsofthe CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse, distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.TheCreativeCommonsPublic DomainDedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthis article,unlessotherwisestated. AchhraandBoyd AIDSResearchandTherapy 2013, 10 :33 http://www.aidsrestherapy.com/content/10/1/33 RationaleforNRTI-sparingregimensThethymidineanalogueNRTIs,suchaszidovudineandinparticularstavudine(d4T)havebeenassociatedwithseriousmitochondrialtoxicitywhichhasbeenlinkedtolipoatrophy.Inaddition,zidovudinehasbeenassociatedwithanaemiaanddidanosinewithperipheralneuropathy.Asaconsequencetheseagentsarenolongerrecom-mendedaspreferredcomponentsoftherapy;inthecaseofstavudineithasbeenrecommendedthatitsusebephasedout,eveninlow-andmiddle-incomecountries[2].However,oneofthemostimportantpushfactorsfortheassessmentofNRTI-sparingregimenshasbeenagrowingunderstandingofthelong-termtoxicityprofileofeventhenewer,relativelysafeNRTIsincommonusesuchastenofovirandabacavir.Tenofovirhasbeenassociatedwithnephrotoxicity,includingacuteandchronicrenalfailure,proximaltubulardysfunction,nephrogenicdia-betesinsipidusandnephroticsyndrome[1,4,5].InalargeEuroSIDAcohortstudy,tenofovirusewasassociatedwitha20%increasedriskofchronickidneydisease[6].Further,clinicaltrialsandobservationalstudieshaveconsistentlydemonstrateddeclineinbone-mineraldensity(BMD)ofabout2-10%intheshort-termattributabletotheuseoftenofovir[7,8].Cumulativeuseoftenofovirhasbeenasso-ciatedwithahigherriskofosteoporoticfracture[9].Fi-nally,oneobservationalstudyattributedincreasedriskofheartfailuretothetenofoviruse,althoughthisobserva-tionhasnotbeenreplicated[10].Abacavir,anothercom-monlyusedNRTIhasbeenimplicatedintheriskofmyocardialinfarctionbysomelargecohortstudiesandaclinicaltrial[10-12].However,theevidenceisnotdefini-tiveasthisassociationhasnotbeenseeninotherstudies[13].Nevertheless,ithasgeneratedconsiderableanxietyintheprovidercommunity,especiallyforitsuseinpatientswithahighcardiovascularrisk.Further,abacavirisassoci-atedwiththeriskofseverehypersensitivityreactionswhichcanonlybeeliminatedbyscreeningoutthosecar-ryingtheHLA-B57*01allele[1,14].OneofthemainconcernspromptingstudiesonNRTI-sparingregimensinfailingpatientshasbeenthatofpossiblereducedpotencyofNRTIagentsduetocurrentorarchivednucleosidemutationssuchasthymidineanalogueassociatedmutations(TAMs).Asaresult,ifNRTIsarebeingrecycledinsuchpatients,theycouldpo-tentiallybeexposedtoaregimenwithor3fully-activeagents.ThisisespeciallyofconcerninresourcelimitedsettingswhereNRTIsarerecommendedforrecyclingfollowingtreatmentfailureidentifiedthroughimmuno-logicalorvirologicalfailure.Thissurrogatemeansofiden-tifyingvirologicalfailureisassociatedwithsubstantialdegreesofresistancewhichmaysignificantlycompromisetheactionofrecycledNRTIsinfutureARTregimens[15].Moreover,accesstoagentsbeyondNRTIsandtheritonavir-boostedproteaseinhibitorsatazanavir,lopinaviranddarunavirislimited[2].Switchingaspecificanchoragenttoonewithalowergeneticbarrier(e.g.LPV/rre-placedbyraltegravir[16]orPIreplacedwithanotherNRTI[17])withacompromisedNRTIbackbonecouldre-sultinhigherratesoftreatmentfailure.Finally,recyclingNRTIsmightmeanexposingpatientstolongtermNRTIagentswhichmayresultinunanticipated,cumulativead-verseeffects.Severalneweragentsfromvariousclasseswithagoodsafetyprofiletodatecontinuetobecomeavailable.Theseincludenewintegraseinhibitors,newernon-nucleosidereversetranscriptaseinhibotors(NNRTIs,e.g.etravirineandrilpivirine),theCCR5attachmentinhibitormaravirocandthePIslopinavir,darunavirandatazanavir.Itisthere-forepossibletoconstructregimenscontaining2-3fully-activeagentswhichareNRTI-sparing.WenextdiscussNRTI-sparingregimensthathavebeenevaluatedineachofthethreemaintypesofpatientpopu-lations:treatment-experiencedfailingpatientswheremostoftheevidenceisconcentrated;virologicallysuppressedpatients;andART-naïvepatients.NRTI-sparingregimensintreatment-experiencedfailingRecentlargeclinicaltrialshaveevaluatedNRTI-sparingregimensintreatmentexperiencedpatientsexperiencingvirologicalfailure(keystudiessummarisedinTable1[18-25]).Theregimenmostofinteresthasbeenthatofaboosted-PIwithraltegravir,and/ormaravirocand/orTheSECOND-LINEstudy(n=541)[18]evaluatedritonavir-boostedlopinavir(LPV/r)withraltegravirvs.LPV/r+NRTIs(theWHOstandardofcareofrecyclingNRTIsinHIV-positivepatientswithdemonstrableviro-logicalfailureoffirst-lineNNRTI-basedART),withnopreviousPIorintegraseinhibitorexposure.Theuseofresistancetestingatrandomizationwasoptional.Ofthe492patientswithresistancetestsavailable,89%hadNRTImutationsand60%hadM184VwithNRTImu-tationsatbaseline.Patientswererandomised(stratifiedbybaselineHIVRNAor-29;.39;馓退100,000copies/mL)toreceiveLPV/rwithraltegravirorLPV/rwithphysician-chosenNRTIs.At48weeks,theNRTI-sparingraltegravirarmwasnon-inferiortotheNRTI-containingcontrolarmfortheprimaryendpointofvirologicalcontrol00copies/mLwithanoverall81.7%virologicalresponserate.TheNRTIcontrol-armresultedina2-4%greaterdeclineinBMDcomparedtotheNRTI-sparingarm(likelyduetopatientsswitchingtotenofovir)[25].Ontheotherhandtheraltegravirarmwasassociatedwithagreaterdegreeofhypercholesterolaemia.Despitethistherewasnodiffer-enceintheresultanttotal:HDLcholesterolratio.Finally,emergenceofPImutationswasnegligibleinthoseexperi-encingvirologicalfailure,attestingtothehighgeneticAchhraandBoydAIDSResearchandTherapy:33Page2of9http://www.aidsrestherapy.com/content/10/1/33 barrierofLPV/runderconditionsoffrequent(3monthly)virologicalmonitoring.TheEARNESTstudy[19]wassimilarlydesignedtoSECOND-LINEandperformedinanidenticalpatientpopulation(withanadditionalarmofLPV/rmono-therapyaftera12weekinductioncombinedwithral-tegravir).After96weeksoffollow-uptheinvestigatorsfoundnodifferencebetweentheraltegravirandNRTI-armsinthestudysprimarycompositeendpointofgooddiseasecontrol(i.e.alivewithnoWHOstage4disease,CD4�250/mmandviralload0,000orᅰ10,000copies/mLwithnoPImutations),aswellasvirologicaloutcome(viralload00or0copies/mL).Theinvestigatorsalsofoundnodifferenceingrade3/4eventsat96-weeksfollow-up.Ofnote,themonotherapyarmwasfoundtobevirologicallyinferiortothecontrolandLPV/rplusralte-gravirarms.TheOPTIONSstudy[20]wasconductedonasetoftreatmentexperiencedpatientsfailingaPI-basedregi-menandwithpastexposuretoNRTIsandNNRTIs(n=360).PatientswererandomisedtoeitherNRTI-includingorNRTI-excludingoptimisedregimenarmscontaining兰2fullyactiveagents(notincludingNRTIs).IntheNRTI-sparingarm,themostcommonregimenswereraltegravirwithboosted-darunavir(DRV/r)andei-theretravirine(56%),maraviroc(14%)orboth(9%).At1yearoffollow-up,virologicalsuppressionratesweresimilarinbotharms.Ofnote,thestudyonlyhadthepowertofindanon-inferioritymarginof15%.Finally,thoughtherewerenomajordifferencesinthegrade3/4safetyoutcomestheNRTI-armexperiencedgreatermor-tality.ItisunclearifcausesofdeathswereNRTI-related.Afewsmallerobservationalstudiesconfirmthesefind-ingsinroutineclinicsettings(Table1).Inonestudyof122patientswithpriortriple-classfailure,theregimenofraltegravirwithDRV/randmaravirocoretravirinedem-onstratedsimilarvirologicalefficacy(兰75%)comparedtothoseusingNRTIagentsat48weeks[21].Collectively,thesestudiesconfirmthatinvirologicallyfailingpatients,thestrategyofselecting2or3fully-active Table1KeyrecentstudiesofNRTI-sparingregimensintreatmentexperiencedpatientsAuthor,nameofthetrial,ifany/year/published?DesignComparisonNFollow-up(weeks)Boydetal.[],SECOND-LINE/2013/YesPhase-3/4RCT,non-inferiority(i)LPV/r+RALvs.(ii)LPV/r+recycledNRTIsinthosefailinglineNNRTI-basedART541(271vs.48-Arm(i)non-inferiortoarm(ii)forvirologicaloutcome-Nomajordifferencesinseriousadverseevents-GreaterdeclineinBMDinarm(ii)[Patonetal.[EARNEST/2013/NoPhase-3/4RCT,non-inferiority(i)LPV/r+RAL(i)433;(ii)418;(iii)42696-Arm(i)non-inferiortoarm(iii)foracompositeofvirologicalandclinical(ii)LPV/rmonotherapyafterinductionwithLPV/r+RAL(iii)LPV/r+recycledNRTIs(control)inthosefailing1NNRTI-basedART-Arm(ii)inferiortootherarmsforvirologicaloutcomeandhigherLPV/rresistance-Nodifferencesingrade3/4eventsTashimaetal.[OPTIONS/2013/NoPhase-3/4RCT,non-inferiority(i)NRTI-omittingoptimised(i)179;(ii)18148-Similarvirlogicaloutcomesinboth(ii)NRTI-includingoptimisedregimenintriple-classexperiencedfailingpatients-Nodifferencesingrade3/4events-Highermortalityinarm(ii).Ruaneetal.[INROADS/2013/NoSingle-armexploratoryphase-2btrialDRV/r+ETVinfailingpatients(78%)orARTnaïvepatientswithtransmittedresistance(22%)54(75%completedthestudy)48-100%ofARTnaïveand87%offailingpatientsachievedvirological-2patientsdevelopedETVmutationsandnonehadDRVmutations.Imazetal.[]/2011/YesObservationalSalvageregimenofatleastthreeactiveagentsfromDRV,ETV,RALandMVC,withorwithoutNRTIs12248-78%virologicallysuppressed(equalinbotharms)-Higherbaselineviralloadassociatedwithworseoutcomes.Nozzaetal.[]/2011/YesObservationalSalvageregimenofRAL+MVC+2896-96%virologicallysuppressed(copies/ml)Florenceetal.[]/2010/YesObservationalSalvageregimenofETV+optimisedregimen,40%withoutNRTIs94124-70%and90%hadviralloadand400copies/mLrespectively.AchhraandBoydAIDSResearchandTherapy:33Page3of9http://www.aidsrestherapy.com/content/10/1/33 pharmacologicallycompatibleagentsisafeasiblestrategy.Ofnote,allofthesestudieshaveincludedaboosted-PI,andbecauseoftheirhighgeneticbarriertoresistance,thedatashouldnotbeextrapolatedtoother2-classregimens.Also,recycledNRTIagentsseemtoretaineffi-cacy(i.e.non-inferiortothecomparatorarms),whichisreassuringinsettingswhereneweragentsarenotyetwidelyavailable.NRTI-sparingregimensinpatientsreceivingsuppressiveSwitchingtoaNRTI-sparingregimeninavirologicallysuppressedpatientneedsconsiderationofseveralfactors.Theseincludethetreatmenthistory,archivedmutations,durationofviralsuppression,expectedlevelofadherence,thechoiceofagentsaswellasthepatientmotivationtoswitchfromastableregimen.Large,wellpoweredtrialsinsuchpatientsarefewanddifficulttorecruit,althoughseveralsmallerstudieshaveidentifiedpromisingregimens.KeystudiesonthispatientpopulationaresummarisedinTable2[26-36].IntheACTG5116trial[34],virologicallysuppressedpatientsreceivingastandardPI-orNNRTI-basedARTregimenwererandomisedtoefavirenzwithLPV/rorefavirenzwithNRTIs(standardARTarm).Thoughnotafullypoweredtrial,theNRTI-sparingarmperformedpoorlyduelargelytohigherratesofdiscontinuationandtoxicityaswellasdyslipidemia.Thisstudysuggeststhatthechoiceofagentswillbeimportantinconstructingsuchregimensastheywillneedtoprovideclearevi-denceofgreatersafetybeforeconvincingARTprovidersand/orpatientstoconsideraswitch.Inamorerecentsmallexploratorystudy(theKITEtrial[31]),virologicallysuppressedpatientswithnohis-toryoffailuretoPI-basedregimenswererandomisedtostandardART(n=20)orLPV/rwithraltegravir(n=40).At42weeks,therewerenodifferencesinvirologicalsup-pressionrates(90-92%)andnotreatmentlimitingsideeffects,althoughtherewasatrendforhighertriglyceridesintheNRTI-sparingarm.Anothersimilarexploratorysingle-armtrial[33](n=29)reportedsimilarresultswithraltegravirplusaboosted-PI(mainlydarunavir)regimenwithnoseriousdyslipidaemiaat24weeks.SincemoststudiesonNRTI-sparingregimenshavein-cludedaboosted-PIregimen,residualtoxicityconcernswithritonavirasthebooster(suchasgastrointestinalupsetanddyslipidemia)havebeenseenasarelativedis-advantage.Withseveralnewagentsnowavailable,itisnowpossibletoconceiveregimenswhichexcludenotonlyNRTIsbutalsoritonavir,aswellasfirst-generationNNRTIssuchasefavirenz(alsoassociatedwithdyslipidae-miaandneurotoxicity)ornevirapine.Thisstrategyises-peciallyattractiveinvirologicallysuppressedpatientswithminimaltreatmentexperience,wheregoodadherencecanbepresumedandthepossibleadverseimpactofhighviralloadonregimenefficacyislessofaconcern.Inonerecentcohortstudyontreatmentexperienced,virologicallysuppressedpatientsswitchingtodualtherapyofetravirinewithraltegravir,91%maintainedvirologicalsuppressionat48weeks[36].Inanotherexploratoryob-servationalstudyof62patients(themajoritywithHIVRNA400copies/mL)switchingtoNRTI-sparingregi-mens,92%hadundetectableviralloadsat42months[26].Themostcommonregimensusedwere:raltegra-vir,unboostedatazanavir,andmaraviroc(33%);raltegravirandunboostedatazanavir(22%);raltegravir,maraviroc,andetravirine(13%).Ofnote,3outof15peoplere-ceivingatwodrugregimendemonstratedlow-levelviremia(i.e.�50but200copies/mL),theclinicalmeaningofwhichisdebated.Inanotherstudy,calledNoNucNoBoost[29],ART-naïveR5tropicpatientswithhighCD4countsandbaselineviralload10logcopies/mLwerefirsttreatedwithtenofovir/emtricitabine,raltegravirandmaravirocforsixmonthsafterwhichthosewithplasmaviralload50copies/mLat24weekswerecontinuedonatwo-drugcombinationofraltegravirandmaravirocforafurther24weeks.Allpatientsretainedviralload50cop-ies/mLondualtherapy.However,inanothersimilarstudy(RocNRaL)onmoretreatmentexperiencedpatients,thisdualregimendemonstratedlowerefficacy[28].Collect-ively,thesestudiessuggestthatwhilesuchunconventionalregimensarepromisingincarefullyselectedpatients,cau-tionmustbeexercisedwhenusingdualtherapyregimenswithoutthesupportofahighgeneticbarriertotheselec-tionofresistancelikeLPV/rorDRV/r.Boosted-PImonotherapyGiventhehighgeneticbarrierofboostedPIs,severallargestudieshaveevaluatedthissimplificationstrategy.Boosted-PImonotherapytrialshavebeenextensivelyreviewedpreviously[37,38]andarethereforenotcov-eredindetailhere.Inthe96-weektrialofLPV/rmono-therapyinvirologicallysuppressedpatientsreceivingaboosted-PI+NRTIregimenwithnohistoryoffailure(OKtrial),althoughthevirologicalsuccessratewassimilar,themonotherapyarmhadasignificantlyhigherrateoflow-levelviremia(12%)necessitatingreinductionwithNRTIs[39].AsimilartrialwithDRV/rmonother-apy(MONET)[40]alsodemonstratedahighvirologicalsuccessratewithDRV/rhoweverthemonotherapyarmhadahigherrateoflow-levelviremia.Overall,althoughthevirologicalresponseratesinLPV/rorDRV/rmono-therapyarmsarehighandPImutationsarerareinthesettingofregularvirologicalmonitoring,thereappearstobeagreaterriskofconsistentlow-levelviremiawhichmayheraldvirologicalfailureinthemonotherapyarms.InthefullypoweredEARNESTstudy[19]describedabove,thePImonotherapyarm(combinedforthefirstAchhraandBoydAIDSResearchandTherapy:33Page4of9http://www.aidsrestherapy.com/content/10/1/33 12weeksoftreatmentwithRAL400mgbid)wasfoundtobesignificantlyinferiortothestandardARTarm.Theauthorsconcludedthatsuchastrategyisunsuitableforapublichealthapproach.Presently,noneofthemajortreatmentguidelinesrecommendPImonotherapybe-causeofconcernsregardingefficacy[1-4].NRTI-sparingregimensinARTnaïvepatientsLarge,fullypoweredtrialsevaluatingNRTIsparingregimensinARTnaïvepatientsarefewandmostsmallerstudieshavesuggestedthatcaremustbeexer-cisedinselectingbothsuitableagentsandcandidatesforsuchregimens.KeystudiesaresummarisedinTable3[41-48].TheACTG5142trialrandomisedART-naïvepatientstostandardARTarmswithLPV/rorefavirenz,bothgivenwithinvestigatorselected2NRTIsandaNRTI-sparingarmofLPV/randefavirenz[46].ThoughtheNRTI-sparingarmshowedcomparablevirologicaleffi-cacyoverallat96weeks,itperformedpoorlyinthosewithbaselineviralload�100,000copies/mLandtherateofdiscontinuationduetoadverseeventswassignificantlyhigherthanothertwoarms.Ofnote,thedoseofLPV/rwasincreasedduetoitsinteractionwithefavirenz,whichmayhavecontributedtotheadditionaltoxicityinthisarm.Morerecentpilotstudieshaveexploredadualtherapyregimenofraltegravirwithaboosted-PI.Thesestudies Table2KeyrecentstudiesofswitchtoNRTI-sparingregimensinvirologicallysuppressedpatientsonstandardARTAuthor,nameofthetrial,ifany/year/published?DesignComparisonNFollow-up(weeks)Monteiroetal.[]/2013/YesObservationalRAL+ETV2548-91%virologicallysuppressedinper-protocolanalysis-LipidsimprovedWardetal.[]/2013/NoObservationalSwitchingfortoxicityconcernstoaRAL+1or2agents,mostcommonlyonRAL+ATV/rwithorwithoutETVorMVC62168-92%virologicallysuppressed;-3of15ondualtherapyhadtoaddthirdagentforlow-levelviremiaCalinetal.[]/2013/NoObservationalSwitchingtoRAL+ETVregimen9148-93%hadviralloadcopies/mL-4/5withvirologicalfailureshadpastNNRTImutations-3patientshadRALmutationsKatlamaetal.[ROCnRAL/2013/NoSingle-armexploratorytrialR5-trophicsuppressedpatientsswitchedtoMVC+RAL4148-Failurein11.4%-RALmutationsin3/5patientswho-1/5hadR5to×4virusswitchCotteetal.[],NoNucNoBoost/2013/NoSingle-armexploratorytrialMVC+RAL1048-Novirologicalfailures(P-2;˜.6;�愀50copies/mL)-NoseriousadverseeventBurgosetal.[]/2012/NoObservationalSwitchingfortoxicityconcernstoaPI/r+2agent,manywithnoNRTI13156-P-2;˜.6;�愀90%virologicallysuppressed.Ofotokunetal.[KITE/2012/NoExploratorypilot(i)LPV/r+RAL;(ii)standardART6048-92%inarm(i)and88%inarm(ii)withviralloadcopies/mL;-Highertriglyceridesinarm(i)-NodifferenceinBMDorbodyCareyetal.[SPARTA/2012/YesPilotcross-overPatientsreceivingATV/rrandomizedto:(i)ATV/r(300/100mgrespectivelyoncedaily)+RAL(800mgoncedaily)2576%infollow-upfor48weeks-Bothagentspharmacologically(ii)ATV(300mgtwicedaily)+RAL(400mgtwicedaily)-AllpatientsremainedvirologicallyCorderyetal.[]/2010/YesObservationalRAL+ATV(unboosted)2072-Only1(5%)failureAllavenaetal.[]/2009/YesObservationalSwitchingfortoxicityconcernstoaPI/r+RAL.2948-100%virologicallysuppressedFischletal.[]/2007/YesRCT,notfully(i)LPV/r+EFV;23696-Arm(i):shortertimetofailureordiscontinuation;(ii)EFV+NRTIs-Arm(i):greaterincreaseinAchhraandBoydAIDSResearchandTherapy:33Page5of9http://www.aidsrestherapy.com/content/10/1/33 suggestthatahighbaselineplasmaviralloadcouldad-verselyimpactthesuccessoftheregimeninsuchpa-tients.Inasinglearmstudyof112patientsreceivingraltegravirandDRV/r,virologicalfailure�(50copies/mL)was26%at48weeks[45].Most(21/28)ofthepatientswithvirologicalfailureandallofthosewithintegrasemu-tationshadabaselineplasmaviralload�100,000copies/mL.Almost50%offailureswerethatoflowlevelviremia�(50but200or400copies/mL).NoPImutationsweredetected.However,thesimilarfully-poweredtrialofDRV/r+RAL(NEATprotocol001,seebelow)isongoingandhasnotbeenstoppedbyDataSafetyMonitoringBoard.IntheRADARstudy(smallrandomisedstudyofDRV/rwitheitherraltegravirorNRTIs),responserateswerepoorerintheraltegravirarmwhichalsoexperiencedhigherratesofdyslipidemia[44].IntheSPARTANpilotstudyevaluatingexperimentalunboostedatazanavir(300mg)withraltegravir(vs.NRTIwithboosted-atazanavir),mostraltegravirresistancemutationsoc-curredinthosewithbaselineviralload�100,000copies/mL[47].Also,therateofhyperbilirubinemiaintheraltegravirarmwashigher(possiblyduetothehigherdoseofatazanavirusedinthatarm(300mgbid)andtheknownpharmacoenhancementeffectofRALonATV)[47].InarandomisedstudyofLPV/rwithraltegravirorwithNRTIs(PROGRESStrial),virologicalresponsedidnotdifferbybaselineviralloadalthoughtherewereonlyafewpatientswithhighviralloadatbaseline[42].Ofnote,inthisstudy,surrogaterenalandboneoutcomesweresignificantlymorefavourableintheNRTI-sparingarm.Overall,thesestudiessuggestthatwhileNRTI-sparingregimensarepromising,cautionneedstobeexercisedintheselectionofpatients.Inparticular,theimpactofthe Table3KeyrecentstudiesofswitchtoNRTI-sparingfirst-lineARTregimensinARTnaïvepatientsAuthor,nameofthetrial,ifany/year/published?DesignComparisonNFollow-up(weeks)Millsetal.[A4001078/2013/YesRCT,phase-2bpilot(i)MVC+ATV/r12148-75%inarm(i)and84%inarm(ii)hadviralload(ii)TDF+FTC+ATV/r-Morehyperbilirubenmiainarm(i)-Nineinarm(i)and3inarm(ii)hadlow-levelviremiaaftervirologicalsuppressionReynesetal.[PROGRESS/2013/YesRCTpilotstudy(i)LPV/r+RAL(i)101;(ii)10596-66.3%inarm(i)and68.6%inarm(ii)respondedby(ii)LPV/r+TDF+FTC-Betterbodycompinarm(i)-GreaterdeclineineGFRinarm(ii)Kozaletal.[SPARTAN/2012/YesRCTpilotstudy(i)ATV+RAL(i)63;(ii)3124-74.6%inarm(i)and63.3%inarm(ii)hadviralload(ii)ATV/r+TDF+FTC-4/6failuresinarm(i)hadRALmutations.-20%incidenceofgrade-4hyperbilirubenimiainarm(i).Taiwoetal.[MIDAS/2013/YesSingle-armpilotMVC+DRV/r2596-Viralload50copies/mL:8.3%and10%atweek48and96,respectively.-Virologicalfailuresmainlyexplainedbehighbaselineviralload&#x-193;&#x.600;c100000copies/mLBedimoRetal.[RADAR/2011/NoRCTpilot(i)RAL+DRV/r8024-86%inarm(i)and87%inarm(ii)hadviralloadcopies/mL(ii)DRV/r+TDF+FTCTaiwoetal.[ACTG5262/2011/YesSingle-armpilotDRV/r+RAL11248-26%withviralloadP-2;˜.6;�愀50copies/mL,majoritywithlow-levelviremia(copies/mL)-BaselineviralloadȀ-;ʖ.;怀ؐ100000copies/mLstronglyassociatedwithfailureRiddleretal.[ACTG5142/2008/YesRCT(i)EFV+NRTIs(i)25096-89%,77%and83%hadviralloadcopies/mLinarms(i),(ii)and(iii)respectively(ii)LPV/r+NRTIs(ii)253(iii)LPV/r+EFV(iii)250-Nodifferenceintimetotoxiceffects-Atfailure,resistancemutationsmorecommoninarm(iii)NOTEforTables:ATV/r=ritonavirboostedatazanavir,DRV/r=ritonavirboosteddarunavir,LPV/r=ritonavirboostedlopinavir,RAL=raltegravir,ETV=etravirine,MVC=maraviroc,EFV=efavirenz,TDF=tenofovir,FTC=emtricitabine,NRTI=Nucleoside(tide)reversetranscriptaseinhibitors,PI=proteaseinhibitors.AchhraandBoydAIDSResearchandTherapy:33Page6of9http://www.aidsrestherapy.com/content/10/1/33 baselineplasmaviralloadonregimenefficacyandtheriskofbaselineorarchivedresistancemutationsforfail-ureneedfurtherstudy.Dual-therapyregimensingeneralhaveresultedinmixedresults.Welldesigned,appropri-atelypoweredrandomisedcontrolledtrialsarerequiredtoreachdefinitiveconclusions.Inarecentwell-poweredtrialofLPV/rwithlamivudine(arelativelysafeNtRTI)vs.LPV/r+2NRTIs,thedualtherapyarmdemonstratednon-inferiorefficacyof�85%at48weeksregardlessofbaselineviralload,withfewertoxicity-relateddiscontinuations[49].Thisstudyindicatesthatcarefullyselecteddualther-apycouldbeareasonableoptioneveninART-naïvepa-tients.Ofnote,however,dyslipidemiatendedtobemorepronouncedinthedualtherapyarm,whichmaybeduetotheabsenceoftenofovirwhichisknowntobeassociatedwithafavourablelipidprofile[50,51].Ontheotherhand,theMODERNstudyawellpoweredstudyofmara-viroc+DRV/rvs.standardART(n=791)wasprematurelystoppedat48weeksduetoinferiorperformanceofthedual-therapyarm(unpublisheddata)[52].Ongoingstud-iessuchasA4001095(DRV/rwithmaravirocorNRTIs)(TrialIdentifier:NCT01345630)andtheNEATprotocol001/ANRS143(DRV/rwithraltegravirorNRTIs)(TrialIdentifier:NCT01066962)shouldprovideaclearerun-derstandingoftheuseofsuchregimensinART-naïvepatients.Limitations,conclusionsandfuturedirectionsNRTI-sparingregimensappeartobepromisingandifestablished,willbeanimportantsteptowardsopti-misingARTtomaximisepatientsafety.However,thereareafewimportantpointstoconsider.First,trialsevaluatingsuchregimenswillneedtoshowaclearbenefitintermsoflong-termsafetysoastoconvinceclinicianstomoveawayfrommuchmorefamiliarNRTI-basedregimens.Promisingregimenssuchastheuseofaboosted-PIwithraltegravirhaveshownahigherriskofdyslipidemiainsomestudieslikelyat-tributabletoritonavirandpossiblytheabsenceoftenofovir.FuturestudiesconsideringregimenswithoutNRTIs,ritonavirandefavirenz(duetoneuro-psychaitricadverseevents)willbeimportantinidentifyingsafer,bettertoleratedARTregimens.ArecentstudybyourgroupsuggestedthatmostHIV-positivepatientswillhavesuchregimenoptionsavailabletothemregard-lessoftheirtreatmentexperience[53].Inaddition,mostclinicaltrialsfollowparticipantsupfor48to96weeks,which,alongwiththeirenrolmentnumber,isnotofsufficientdurationtodemonstratedif-ferencesinhardclinicalendpointssuchasrenalfailureorfractures.Cohortstudieswillbeinstrumentalinthisregard.Also,mostofthestudiesaresmallandunpub-lished.Betterqualityevidenceisthereforeclearlyneededinthisarea.Second,manyofthestudiesonNRTI-sparingtwodrugregimenssuggestthatinselectedpatients(e.g.thosewithhighbaselineviralloads),theriskofvirologicalfailureandselectionofresistancemutationstothenon-PIcompo-nentarearisk.Thissuggeststhatsuchregimens,espe-ciallyoneswithoutaboosted-PIsupport,shouldideallybefirstevaluatedinvirologicallysuppressedpatients.Finally,manyNRTI-sparingregimensaremayrequiretwicedailydosingfrequencyand1-2pills/day.Thismayimpacttheadherence(exampleselectivelowerad-herencetothe2doseofraltegravirinDRV/r+ralte-gravirregimen).However,bothetravirineandmaravirochavepharmacokineticandclinicaldatasupportingonce-dailydosing[41,54],andRALisbeingstudiedina1200-mgonce-dailyformulation.Therefore,NRTI-sparingonce-dailyregimenscouldbepossibleinfuture.Inconclusion,therehasnowaccumulatedasizeableevidencebasethatsupportstheuseofNRTI-sparingregimensof23fully-activeagentsforHIV-positivepa-tientscurrentlyonafailingARTregimen.Forvirologic-allysuppressedpatients,anNRTI-sparingregimenmaybeanoptionissomepatientsalthoughfurther,morede-finitivestudiesareneeded.Finally,theevidenceissparseforsuchregimensintheARTnaïvepatientpopulationandmoreresearchisrequiredtogeneraterobustevi-dence.FuturestudiessuchasA4001095andNEATprotocol001/ANRS143willbeinstrumentalininform-ingtheevidencebaseforsuchregimens.CompetinginterestsACAhasreceivedGileadAustraliaFellowshipfortheyear2013.MBhasreceivedresearchgrantsupportandhonorariaforservingonadvisoryboardsandeducationalpresentationsfromAbbVie,BoehringerIngelheim,BristolMyersSquibb,GileadSciences,JanssenPharmaceuticals,andMerck.MABconceivedtheidea.ACAandMABbothperformedtheliteraturesearchandplannedthestructureofthereview.ACAconductedthereviewandwrotethefirstdraftandsubsequentchangestothemanuscript.MABprovidedkeyinputtothecontentsandprovidedoverallsupervisionoftheproject.Allauthorsreadandapprovedthefinalmanuscript.Received:4November2013Accepted:30November2013Published:13December20131.ThompsonMA,AbergJA,HoyJF,TelentiA,BensonC,CahnP,EronJJ,GunthardHF,HammerSM,ReissP,etalAntiretroviraltreatmentofadultHIVinfection:2012recommendationsoftheInternationalAntiviralSociety-USApanel.2.WorldHealthOrganisation:ConsolidatedguidelinesontheuseofantiretroviraldrugsfortreatingandpreventingHIVinfection.2013.http://www.who.int/hiv/pub/guidelines/arv2013/en/.AccessedonOctober2013.3.EuropeanAIDSClinicalSociety:EuropeanGuidelinesfortreatmentofHIV-infectedadultsinEurope.Availableathttp://www.eacsociety.org/Guidelines.aspx.AccessedonOctober2013.4.PanelonAntiretroviralGuidelinesforAdultsandAdolescents:GuidelinesfortheuseofantiretroviralagentsinHIV-1-infectedadultsandadolescents.http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.AssesedonOctober2013.5.CalzaL:Renaltoxicityassociatedwithantiretroviraltherapy.HIVClinTrialsAchhraandBoydAIDSResearchandTherapy:33Page7of9http://www.aidsrestherapy.com/content/10/1/33 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