ConferenceCallMeetingMinutes

ImprovingHealthOutcomesinHIVImmunologicNon-Responders(INRs)

OrphanDrugDesignationPossibilities

ACommunityInitiatedProposaltotheFDA

June10,2016

Participants

JeffreyMurray,M.D.,M.P.H.,DeputyDirector-CDER

CarolWeiss-SectionChief,CBER,OfficeofVaccinesResearchandReview

IlanIrony-SupervisoryMedicalOfficer,CBER,OfficeofCellularTissuesandGeneTherapies

RichardJefferys-TreatmentActionGroup

JeffSheehy-CaliforniaInstituteofRegenerativeMedicine

JeffTaylor-AIDSTreatmentActivistsCoalition

MattSharp-TreatmentAdvocate

LyndaDee-AIDSActionBaltimore

NelsonVergel-ProgramforWellnessRestoration

NOTE:NomembersfromtheFDAOfficeofOrphanProductsDevelopment(OOPD)wereinattendance.

AconferencecallmeetinginitiatedbyHIVcommunityadvocateswasheldwithFDAmembersonJune10,2016todiscusswaystoadvancetheevaluationanddevelopmentofproducts(drugsorbiologics)thatdemonstratepromiseinimprovinghealthoutcomesinHIV-positivepatientswithinadequateimmuneresponseafterlongtermsuccessfulHIVtreatment.Thereisnotcurrentresearchspecificallyaimedatthispopulationduetorealandperceivedconcernsbyindustry.Duetotherelativelysmallsizeofthisat-riskpopulationandcomplexitiesinprovingclinicalbenefitofpotentialimmune-enhancingtherapies,theadvocacycommunityinitiatedeffortstocreatively

stimulateindustry’sinterestbyreviewingwiththeFDAspecificapproachestocurrentdrugdevelopmentpathsforindicationsaimedatthispopulation.

Toestimatethesizeandspecialneedsofthispatientpopulation,NelsonVergelgaveaslidepresentationthatcontainedthefollowingfactsandestimates.

PoorCD4TCellRecoveryDespiteHIVSuppressionLinkedtoIncreasedMorbidityandMortality

• AsubsetofHIV-positivepeoplewhoinitiateantiretroviraltherapy(ART)andachievesuppressionofHIVreplicationexperiencepoorrecoveryofCD4Tcellnumbers.

• Termsusedtodescribethissubsetofindividualsinclude“immuno-virologicaldiscordants(ID)”and“immunologicalnon-responders”(INRs).

• Asyet,thereisnouniversallyaccepteddefinitionofINRs(e.g.persistentlybelow200,250or350cellsdespiteHIVsuppression).

• Dependingonthedefinition,estimatesoftheproportionofpeoplestartingARTwhocanbecategorizedasINRsaretypicallyaround5-20%.

• Instudiesconductedtodate,themostconsistentlyreportedriskfactorsforthisoutcomearelowCD4TcellcountsatthetimeofARTinitiationandolderage.

• SeveralpublishedstudieshavealsoreportedthatINRshaveagreaterriskofmorbidityandmortalitycomparedtoHIV-positiveindividualswithmorerobustCD4Tcellgains.

FunctionalCD4BoostingisEssentialforImprovedINRSurvivalandHealthOutcomes:StatementbyINRResearcher

“…todate,strategiestodirectlyinfluenceimmunereconstitutionbyaddinginterleukin-2orbymodifyingcARTregimenshavefailedtoshowbenefitoverviralsuppressionalone;thereforenewstrategiesperhapsaimingatothermechanismstoboostfunctionalCD4cellsordecreasingthelevelsofimmune-activation(e.g.interleukin-7,probiotics)needtobetestedinpeoplewhoshowincompleteimmunereconstitutiondespitesustainedviralsuppression.”

AlexanderZoufalyetal,EuroSIDAinEuroCoord.Immuno-VirologicalDiscordanceandtheRiskofNon-AIDSandAIDSEventsinaLargeObservationalCohortofHIV-PatientsinEurope.January31,2014DOI:10.1371/journal.pone.0087160

INRPatientPopulationEstimate

FromCDC.gov/vitalsigns

TotalHIVPopulationintheUS:1.3Million

30%VirallySuppressed=390,000people

20%of390,000maybeINR=78,000patients

INRandNewInfections:TheCDCsurveillancereportfromJuly2015states:

"AmongpersonswithanHIVdiagnosisduring2013,23.6%ofinfectionswereclassifiedasstage3(AIDS)atthetimeofdiagnosis…Theoverallpercentagesweresimilarforeachyearduring2009–2013."

• Theactualnumberin2013was9,846.

• Aconservativeestimatewouldbethataround20%oftheselate-diagnosedindividualsmightbecomeINRs(2,000patients/year).Thistrendmaydeclineinthefuturedependingonoutreach/educationeffortsfortreatmentandprevention.

• FromFDA.gov:

“TheOrphanDrugDesignationprogramprovidesorphanstatustodrugsandbiologicswhicharedefinedasthoseintendedforthesafeandeffectivetreatment,diagnosisorpreventionofrarediseases/disordersthataffectfewerthan200,000peopleintheU.S.,orthataffectmorethan200,000personsbutarenotexpectedtorecoverthecostsofdevelopingandmarketingatreatmentdrug”.

• Consideringcurrentestimateandnewinfectionsperyear(andexcludingdeathrateofINRs),itwouldtake61yearstoreach200,000INRpatientsintheU.S.(orphandrugdesignationpatientpopulationmax)

ThefollowingtablesshowthehistoryofHIV/AIDSrelatedorphandrugdesignationsandapprovalssincethebeginningoftheepidemic(Source:FDA.gov).Thirtydesignationsandfiveapprovalshavetakenplace.Mostapprovedonesalsohavemoreexpansiveindications.Thelastorphandrugdesignationtookplaceon10/20/2014foraCD4monoclonalantibody(ibalizumab)forthetreatmentofmultidrugresistantHIV.

ImmunotherapyinHIVinfection:PastandCurrentChallenges

• IL-2

• IL-2wasextensivelystudiedinseveralphaseIIandtwolargephaseIIIstudies.ResultsfromthesestudiesshowedthatIL-2significantlyincreasesCD4countsinthelongterm.However,thisbiologicaleffectdidnottranslateintoclinicalbenefit.

• IL-7

• CytherishadambitiousplanstoconductaphaseIIIclinicalendpointtrialinINRs,butwentoutofbusinessin2015.TherightstopursueIL-7asatherapyforHIV-relatedimmuneimpairmentarereportedlynowbeingdirectedbyacollaborationinvolvingtheFrenchNationalAgencyforResearchonAIDSandViralHepatitis(ANRS)andCognateBioServices.Atbest,thiswillcertainlydelayevaluationoftheabilityofIL-7toreducemorbidityandmortalityinINRs.

• SB-728-T(ZFN-CCR5-genemodification)

• ResearchcontinuesintotheuseoftheSangamoBioSciencestechnologytogeneticallymodifyCD4+Tcellsexvivo.Likeothersmallcompanies,SangamohasnotbeenabletomoveaproductnearFDAapprovalandhasshownnointerestinpursuinganINRindicationafterreceivingletterfromcommunitymembersadvocatingforit.

MattSharp:ClinicalTrialParticipantTestimonial

MattSharpdescribedhisexperienceasaparticipantintheclinicaltrialofSB-728-TthatrecruitedINRs.SharpwasdiagnosedHIV-positiveinthe1980sandhadanextensiveantiretroviraltreatment

history.Hewasunabletoachieveanundetectableviralloaduntiltheadventofintegraseinhibitors.Despiteviralloadsuppression,CD4Tcelllevelsremainedbelow200.ReceiptofasingleinfusionofSB-728-Tmorethandoubledthesenumbersforaperiodofyears.SharpalsonotedthisCD4increasewasassociatedwithimprovedhealth,specificallyanabsenceofupperrespiratorytractinfections(URIs)thathadpreviouslyoccurredseveraltimesperyear.OnlyrecentlywhenCD4Tcelllevelsclosetobaselinehasheexperiencedarecurrenceofupperrespiratorysymptoms.Sharpgaveapresentationdescribinghisexperienceatthe2012InternationalAIDSConference,whichcanbedownloadedat:http://pag.aids2012.org/PAGMaterial/PPT/30_40/finaldccureworkshop.pptx

BrainstormingonPotentialEndpoints

RichardJefferysbrieflyoutlinedseveralofthekeybiomarkersthathavebeenassociatedwithmorbidityandmortalityinHIVinfection,particularlyintreatedindividualsandINRs.AlthoughCD4TcellcountsprovedtobeaninadequatesurrogatemarkerofefficacyintwolargetrialsofthecytokineIL-2,subsequentresearchsuggeststhatabroadersuiteofbiomarkersmightprovidemorecompellingevidencethataninterventionishavingadisease-modifyingeffect.Researchershavenotedthatassessmentsofimmuneresponsefunctionalitymighthaveaparticularlyimportantroletoplay.

• CD4Tcellcount

• CD4:CD8ratio

• Immuneresponsefunctionalityassessedbyvaccination

• Inflammatory&coagulation

• Immuneactivation

• HIVDNA

• Tcellphenotypes

• DecayoftheHIVDNAreservoir

NelsonVergeldescribedadditionaloutcomesthatcouldbeconsideredforuseasendpointsinclinicaltrialsofcandidateinterventionsforINRs:

• PatientReportedOutcomes(PROs).In2004,WillkeandcolleaguesreviewedtheefficacyendpointsreportedinthelabelsofnewdrugsapprovedintheUnitedStatesfrom1997through2002toevaluatetheuseofpatient-reportedoutcome(PRO)endpoints.Ofthelabelsreviewed,30%includedPROs.TheirstudyaimedtobuildonthisworkbydescribingthecurrentstateofPROlabelclaimsgrantedfornewmolecularentities(andbiologiclicenseapplicationssinceFebruary2006afterthereleaseoftheUS

FoodandDrugAdministration(FDA)draftPROguidance.Ofthe116productsidentified,28(24%)weregrantedPROclaims;24(86%)wereforsymptoms,and,ofthese,9(38%)claimswerepainrelated.Ofthe28productswithPROclaims,aPROwasaprimaryendpointfor20(71%),allsymptomrelated.NoHIVrelatedindicationsexceptoneforEgrifta(tesamorelin)hasbeengrantedPROclaims.ImmunereconstitutioncouldpotentialityprovidesignificantimprovementinPROs.

• FrailtyIndex(VACS,MACS,etc).SeveralfrailtyindexesvalidatedinHIVrelatedstudiescouldbeconsideredindeterminingifimprovedfrailtycanbearesultofimmuneenhancementtherapies.However,welackdataabouttheincidenceoffrailtyinINRpatients.

• Decreaseincomorbiditesorclinicalsymptoms(i.e.,diarrhea,fatigue,pain,upperrespiratoryinfections,skindisorders,etc).IfwecanidentifythemostcommoncomorbiditiesandhealthcomplaintsinINRpatients,wecouldspecificallydesignstudiesfocusedonmonitoringspecificsymptomsorcommonillnessesasINRpatientsacquirebetterimmuneresponseand/ormarkers.ThethreeFDAmembersonthecallagreedthatthismaybeanapproachworthexploring.CommunityparticipantswillcontacttheauthorsofstudiesassessingmorbidityandmortalityinINRstorequestinformationonthemostfrequentlyobservedclinicalevents.

RegulatoryProcess-TwoDifferentTracks

FDArepresentativesnotedthattheprocessesforpursuinganorphandrugdesignationandadrugapprovalareseparate,involvingdifferentdepartmentswithintheagency.Howevertheseprocessescanbeundertakensimultaneously,inparallel.CompaniesseekingtodevelopinterventionsforINRsareencouragedtosetuppre-INDmeetingswithFDAtodiscusstheissuesinvolved.FDArepresentativesfeltthatitwasunlikelythatmarketingapproval(whetherprovisionalorfull)couldbeobtainedbasedonlyonbiomarkersorothernon-clinicalendpoints;itwassuggestedthatincludingevaluationsofnon-seriousclinicaleventssuchasupperrespiratorytractinfectionsmightofferameansofdemonstratingclinicalbenefitthatwouldnotrequirethetrialsamplesizesnecessaryforassessingtheimpactofaninterventiononmorbidityandmortality.PROscouldpotentiallybeconsidered-itwashighlightedthattheyhavebeenusedinapprovinginfluenzatreatments.

ActionItems:

1-Circulateconferencecallminutesamongattendantsandinterestedstakeholders.

2-ContactprivateinvestigatorsofpreviouslyreportedINRcohortsabouttheirknowledgeofmostcommonhealth-relatedissuesseeninINRpatients.

3-Entertainthepossibilityofhavingameetingwithindustry,theFDA,advocatesandinvestigatorstodiscussINRresearchandopportunities/challengesinthedevelopmentoftherapeuticsforthispopulation.

AppendixAttached

Appendix

SupportingInformationandReferences

Immuno-VirologicalDiscordance(ID)andtheRiskofNon-AIDSandAIDSEventsinaLargeObservationalCohortofHIV-PatientsinEurope(EuroSIDA)

• 2,913patientsinEuroSIDAstartingatleast1newARVwithCD4<350cells/µlandVL>500copies/mLwerefollowed-upfromthefirstdayofVL<=50copies/mluntilanewfatal/non-fatalnon-AIDS/AIDSevent.

• PatientswereclassifiedovertimeaccordingtowhethercurrentCD4count>(non-ID)or<(ID)thanbaselineCD4count.

• TheRRofdevelopingpre-specifiednon-AIDSeventsforIDvs.non-IDwas1.96(95%CI1.37–2.81,p<0.001).IDwasnotassociatedwiththeriskofAIDSevents.

• Long-termmortalityinHIVpositiveindividualsvirallysuppressedformorethanthreeyearswithincompleteCD4recovery.

• Thispurposeofthisstudywastoidentify(1)riskfactorsforfailuretoachieveCD4count>200cells/µLafterthreeyearsofsustainedviralsuppressionand(2)theassociationofachievedCD4countwithsubsequentmortality.

• Of5,550eligibleindividuals,835(15%)didnotreachCD4count>200cells/µLafterthreeyearsofsuppression.

• Increasingage,lowerinitialCD4count,maleheterosexualandinjectiondrugusetransmission,cARTinitiationafter1998andlongertimefrominitiationofcARTtostartofthevirallysuppressedperiodwereriskfactorsfornotachievingCD4count>200cells/µL.

• IndividualswithCD4≤200cells/µLafterthreeyearsofviralsuppressionhadsubstantiallyincreasedmortality(adjustedhazardratio2.60;95%confidenceinterval1.86-3.61)comparedtothosewhoachievedCD4count>200cells/µL.

• Increasedmortalitywasseenacrossdifferentpatientgroupsandforallcausesofdeath.

ClinInfectDis.(2014)doi:10.1093/cid/ciu038

LowerCurrentCD4andFrailtyinHIV

• ExampleofFrailtyRelatedMeasures

• Consideredfrailif3ormoredeficitspresent:

– Weightloss:≥10poundsinpastyear,selfreportedandconfirmedbyphysicalexam

– Exhaustion:basedonresponsestotwoitemsfromtheCES-Dscale

– Lowactivity:AmodifiedversionoftheMinnesotaLeisureTimeActivitiesQuestionnairecapturingintensityanddurationof18activitiesthatrangefromworktochildcare

– Slowness:Timed4mwalk

– Weakness:Gripstrengthmeasuredwithdynamometer

Source:Women'sInteragencyHIVStudy(USA)

SelectedCitationsforCandidateBiomarkers

CD4Tcellcount:

EngsigFN,ZangerleR,KatsarouO,etal.Long-termmortalityinHIV-positiveindividualsvirallysuppressedformorethan3yearswithincompleteCD4recovery.ClinInfectDis.2014May;58(9):1312-21.doi:10.1093/cid/ciu038.Epub2014Jan22.http://cid.oxfordjournals.org/content/58/9/1312.full

ZoufalyA,Cozzi-LepriA,ReekieJ,etal.Immuno-virologicaldiscordanceandtheriskofnon-AIDSandAIDSeventsinalargeobservationalcohortofHIV-patientsinEurope.PLoSOne.2014Jan31;9(1):e87160.doi:10.1371/journal.pone.0087160.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087160

BakerJV1,PengG,RapkinJ,etal.CD4+countandriskofnon-AIDSdiseasesfollowinginitialtreatmentforHIVinfection.AIDS.2008Apr23;22(7):841-8.doi:10.1097/QAD.0b013e3282f7cb76.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618460/

AdditionalcitationsintheGuidelinesfortheUseofAntiretroviralAgentsinHIV-1-InfectedAdultsandAdolescentschapteronpoorCD4recovery:https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/470/poor-cd4-recovery

CD4:CD8ratio:

Serrano-VillarS,SainzT,LeeSA,etal.HIV-infectedindividualswithlowCD4/CD8ratiodespiteeffectiveantiretroviraltherapyexhibitalteredTcellsubsets,heightenedCD8+Tcellactivation,andincreasedriskofnon-AIDSmorbidityandmortality.PLoSPathog.2014May15;10(5):e1004078.doi:10.1371/journal.ppat.1004078.eCollection2014May.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022662/

Serrano-VillarS,Pérez-ElíasMJ,DrondaF,etal.Increasedriskofseriousnon-AIDS-relatedeventsinHIV-infectedsubjectsonantiretroviraltherapyassociatedwithalowCD4/CD8ratio.PLoSOne.2014Jan30;9(1):e85798.doi:10.1371/journal.pone.0085798.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907380/

LuW,MehrajV,VybohK,CaoW,LiT,RoutyJP.CD4:CD8ratioasafrontiermarkerforclinicaloutcome,immunedysfunctionandviralreservoirsizeinvirologicallysuppressedHIV-positivepatients.JIntAIDSSoc.2015Jun29;18:20052.doi:10.7448/IAS.18.1.20052.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486418/

Immuneresponsefunctionalityassessedbyroutinevaccination:

LandrumML,HullsiekKH,O'ConnellRJ,ChunHM,GanesanA,OkuliczJF,etal.HepatitisBvaccineantibodyresponseandtheriskofclinicalAIDSordeath.PLoSOne.2012;7(3):e33488.doi:10.1371/journal.pone.0033488http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310879/

ValdezH,MitsuyasuR,LandayA,SevinAD,ChanES,SpritzlerJ,KalamsSA,PollardRB,FaheyJ,FoxL,NamkungA,EstepS,MossR,SahnerD,LedermanMM.Interleukin-2IncreasesCD4+lymphocytenumbersbutdoesnotenhanceresponsestoimmunization:resultsofA5046s.JInfectDis.2003Jan15;187(2):320-5.Epub2003Jan6.http://jid.oxfordjournals.org/content/187/2/320.full

ValdezH,SmithKY,LandayA,ConnickE,KuritzkesDR,etal.ResponsetoimmunizationwithrecallandneoantigensafterprolongedadministrationofanHIV-1proteaseinhibitor-containingregimen.AIDS.2000;14:11–21.http://journals.lww.com/aidsonline/Fulltext/2000/01070/Response_to_immunization_with_recall_and.2.aspx

Inflammatory&coagulation:

SandlerNG,WandH,RoqueA,LawM,NasonMC,NixonDE,PedersenC,RuxrungthamK,LewinSR,EmeryS,NeatonJD,BrenchleyJM,DeeksSG,SeretiI,DouekDC;INSIGHTSMARTStudyGroup.PlasmalevelsofsolubleCD14independentlypredictmortalityinHIVinfection.JInfectDis.2011Mar15;203(6):780-90.doi:10.1093/infdis/jiq118.Epub2011Jan20.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071127/

TenorioAR,ZhengY,BoschRJ,etal.SolublemarkersofinflammationandcoagulationbutnotT-cellactivationpredictnon-AIDS-definingmorbideventsduringsuppressiveantiretroviraltreatment.JInfectDis.2014Oct15;210(8):1248-59.doi:10.1093/infdis/jiu254.Epub2014May1.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192039/

RodgerAJ,FoxZ,LundgrenJD,KullerLH,BoeseckeC,GeyD,SkoutelisA,GoetzMB,PhillipsAN;INSIGHTStrategiesforManagementofAntiretroviralTherapy(SMART)StudyGroup.ActivationandcoagulationbiomarkersareindependentpredictorsofthedevelopmentofopportunisticdiseaseinpatientswithHIVinfection.JInfectDis.2009Sep15;200(6):973-83.doi:10.1086/605447.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892757/

KullerLH,TracyR,BellosoW,etal.InflammatoryandcoagulationbiomarkersandmortalityinpatientswithHIVinfection.PLoSMed.2008Oct21;5(10):e203.doi:10.1371/journal.pmed.0050203.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570418

TenorioAR,ZhengY,BoschRJ,etal.SolublemarkersofinflammationandcoagulationbutnotT-cellactivationpredictnon-AIDS-definingmorbideventsduringsuppressiveantiretroviraltreatment.JInfectDis.2014Oct15;210(8):1248-59.doi:10.1093/infdis/jiu254.Epub2014May1.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192039/

HsuDC,MaYF,HurS,etal.PlasmaIL-6levelsareindependentlyassociatedwithatherosclerosisandmortalityinHIV-infectedindividualsonsuppressiveART.AIDS.2016May12.[Epubaheadofprint]http://journals.lww.com/aidsonline/Abstract/publishahead/Plasma_IL_6_levels_are_independently_associated.97760.aspx

GrundB,BakerJV,DeeksSG,etal.RelevanceofInterleukin-6andD-DimerforSeriousNon-AIDSMorbidityandDeathamongHIV-PositiveAdultsonSuppressiveAntiretroviralTherapy.PLoSOne.2016May12;11(5):e0155100.doi:10.1371/journal.pone.0155100.eCollection2016.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865234/

BorgesÁH,O'ConnorJL,PhillipsAN,etal.Interleukin6IsaStrongerPredictorofClinicalEventsThanHigh-SensitivityC-ReactiveProteinorD-DimerDuringHIVInfection.JInfectDis.2016Apr30.pii:jiw173.[Epubaheadofprint]http://jid.oxfordjournals.org/content/early/2016/05/30/infdis.jiw173.abstract

SeretiI,EstesJD,ThompsonWL,etal.DecreasesincolonicandsystemicinflammationinchronicHIVinfectionafterIL-7administration.PLoSPathog.2014Jan30;10(1):e1003890.doi:10.1371/journal.ppat.1003890.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907377/

HIVDNA:

OstrowskiSR,KatzensteinTL,ThimPT,PedersenBK,GerstoftJ,UllumH.Low-levelviremiaandproviralDNAimpedeimmunereconstitutioninHIV-1-infectedpatientsreceivinghighlyactiveantiretroviraltherapy.JInfectDis2005;191:348-57.http://jid.oxfordjournals.org/content/191/3/348.full

ChunTW,ShawnJustementJ,PandyaP,etal.Relationshipbetweenthesizeofthehumanimmunodeficiencyvirustype1(HIV-1)reservoirinperipheralbloodCD4+TcellsandCD4+:CD8+TcellratiosinaviremicHIV-1-infectedindividualsreceivinglong-termhighlyactiveantiretroviraltherapy.JInfectDis2002;185:1672-6.http://jid.oxfordjournals.org/content/185/11/1672.full

TsiaraCG,NikolopoulosGK,BagosPG,GoujardC,KatzensteinTL,MingaAK,RouziouxC,HatzakisA.ImpactofHIVtype1DNAlevelsonspontaneousdiseaseprogression:ameta-analysis.AIDSResHumRetroviruses.2012Apr;28(4):366-73.doi:10.1089/aid.2011.0032.Epub2011Aug30.http://online.liebertpub.com/doi/abs/10.1089/aid.2011.0032

Tcellphenotypes:

WeissL,LetimierFA,CarriereM,etal.InvivoexpansionofnaiveandactivatedCD4+CD25+FOXP3+regulatoryTcellpopulationsininterleukin-2-treatedHIVpatients.ProcNatlAcadSciUSA.2010Jun8;107(23):10632-7.doi:10.1073/pnas.1000027107.Epub2010May24.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890853/

HortaA,NobregaC,Amorim-MachadoP,etal.PoorimmunereconstitutioninHIV-infectedpatientsassociateswithhighpercentageofregulatoryCD4+Tcells.PLoSOne.2013;8(2):e57336.doi:10.1371/journal.pone.0057336.Epub2013Feb20.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057336

SaisonJ,FerryT,DemaretJ,etal.RelationshipbetweendiscordantresponsetoHAART,Tregs,immuneactivationandlow-levelviraemia.JIntAIDSSoc.2014Nov2;17(4Suppl3):19672.doi:10.7448/IAS.17.4.19672.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225367/

SaisonJ1,FerryT,DemaretJ,Metal.Associationbetweendiscordantimmunologicalresponsetohighlyactiveanti-retroviraltherapy,regulatoryTcellpercentage,immunecellactivationandverylow-levelviraemiainHIV-infectedpatients.ClinExpImmunol.2014Jun;176(3):401-9.doi:10.1111/cei.12278.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008985/

Overallreview(from2009):

GazzolaL,TincatiC,BellistrìGM,MonforteAd,MarchettiG..TheabsenceofCD4+Tcellcountrecoverydespitereceiptofvirologicallysuppressivehighlyactiveantiretroviraltherapy:clinicalrisk,immunologicalgaps,andtherapeuticoptions.ClinInfectDis.2009Feb1;48(3):328-37.doi:10.1086/595851.Reviewhttp://cid.oxfordjournals.org/content/48/3/328.full