Cognitive impairment in well-treated cohorts

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IntroductiontodiffusionweightedMRI

•  ‘tune’MRIscannertothediffusionofwater

•  Imageinmul:pledirec:ons

Methods Cogni2veba6ery

(tes2nga6en2on,execu2vefunc2on,language,memory,motorfunc2onand

processingspeed)

T1data(n=212)

64direc2ondiffusionweighted

data(n=208)

Biascorrec:onandsegmenta:on(SPM12)

Eddycurrentcorrec:onanddiffusiontensor

fiDed(FSL)

SPM12(DARTEL) DTITK

Dataacquisi2onandpre-processing

Neuroimaging(3T)Volumetric Diffusion

Spa2alnormalisa2on

Radialdiffusivity

Frac2onalanisotropy

Meandiffusivity

Axialdiffusivity

Greyma6er Whitema6erSegmented

Baseline characteristics HIV+(n=134) HIV-(n=79) p-valueAge(years),median(IQR) 55(51-62) 57(52-64) 0.24Gender,n(%) 0.79Female 9(7%) 6(7%) Male 125(93%) 73(92%)

Ethnicity,n(%) 0.03Black-African 16(12%) 2(3%) White 117(88%) 76(97%)

Sexuality,n(%) 0.45MSM 104(77%) 59(75%) Bisexual 10(8%) 4(5%) Heterosexual 18(13%) 16(20%)

Yearsofeduca2on,median(IQR) 14(13-16) 16(14-17) 0.23Smokingstatus,n(%) 0.24Currentsmoker 40(30%) 20(25%) Ex-smoker 58(43%) 29(37%) Neversmoked 36(27%) 30(38%)

Alcoholconsump2on,n(%)CurrentdrinkerPreviousdrinkerNeverdrunk

104(78%)18(13%)12(9%)

71(90%)3(5%)4(5%)

0.04

Useofrecrea2onaldrugsinpast6months,n(%) 44(33%) 18(23%) 0.16

Baseline characteristics: HIV+ group

n=134LikelyrouteofHIVtransmission,n(%)MSM 115(86%)Heterosexualsex 15(11%)IVDU/Bloodproduct 1(1%)Unknown 3(2%)

YearssinceHIVdiagnosis,median(IQR) 15.0(9.1-20.0)

Dura2onofcART(years),median(IQR) 12.5(7.4-16.9)

HIVRNAviralload<200copies/mL,n(%) 134(100%)

CD4count(cells/µL),median(IQR) 629(472-806)

NadirCD4count(cells/µL),median(IQR) 180(90-250)

CD4+:CD8+cellcountra2o,median(IQR) 0.84(0.60-1.12)

p < 0.001 p = 0.01

p < 0.01 p < 0.001

p < 0.001

p = 0.4 p = 0.4

20

30

40

50

60

70

80

Attention Executivefunction

Language Memory Motorfunction

Processingspeed

Global

Cog

nitiv

e do

mai

n T

scor

e

HIV-status

HIV-

HIV+

Boxplotsofdemographicallyadjustedcogni2vedomainT-scoresbyHIV-serostatus.PvaluescalculatedusingWilcoxonranksumtest.

Cognitive function by domain

Globaldeficitscore:• 18%vs.4%• OR5.6(1.9-24.1)Frasca2criteria:• 18%vs.4%• OR5.6(1.7-24.1)

Mul2variatenorma2vecomparison:• 20%vs.3%• OR9.4(2.7-59.2)

5

0

t-sta:s:c

L R

Greyma6ervoxelbasedmorphometrygroupcomparison.Areaswithsignificantly(p<0.05)lowergreymaDervolumecolouredbythet-sta:s:c-correctedformul:plecomparisons(TFCE)andadjustedforage,intracranialvolumeandscanner.Sta:s:calimageoverlaidonMNI152T1

Grey matter volumes

Whitema6ertractbasedspa2alsta2s2csgroupcomparison.Areasofsignificantly(p<0.05)lowerfrac:onalanisotropy(FA),highermeandiffusivity(MD)andhigherradialdiffusivity(RD)arecolouredbyt-sta:s:cred-yellow,lightblueanddarkbluerespec:vely-correctedformul:plecomparisons(TFCE)andadjustedforage,intracranialvolume,sexandscanner.OverlaidonthewhitemaDerskeleton(green)andthemeanFAimage(greyscale).

5

0

5

0

5

0

t-sta:s:cFA

MD

RD

L R

White matter microstructure

Conclusions from COBRA Cogni2veimpairmentismorecommoninHIV-posi2veindividualsdespitefullysuppressiveART• Againit’sgenerallymild• AssociatedwithmodestgreymaDerlossandwhitemaDermicrostructuralinjuryImportantlythecogni2veandMRIchangesaremoremodestthanthosereportedinpreviousstudies• Moreappropriatecontrolgroup• An:retroviraltherapyprobablypreventssignificantfurtherinjury–awai:nglongitudinaldatatoconfirmthis

Dr Jasmini Alagaratnam and Dr Alan Winston Clinical Trials Centre,

St Mary’s Hospital, Imperial College London

AVICCI TRIAL

What is the AVICCI trial?

• A phase II open label feasibility study to assess the effects of:

• AntiretroViral Intensification with Cenicriviroc for the management of HIV-associated Cognitive Impairment.

• Aim: 10 participants

What is Cenicriviroc? • Orally active, CCR2 and CCR5 receptor inhibitor

• Phase II studies confirm antiretroviral activity and suggest anti-inflammatory activity

• Pilot data suggests that targeting CCR5 receptors has beneficial CNS effects. •  - at present, there are no proven interventions for cognitive impairment in HIV disease

• Cenicriviroc likely to achieve active drug exposure in the CNS (similar to maraviroc)

• We hypothesise that blockade of both CCR5 and CCR2 may be a suitable intervention for the management of HIV-associated cognitive disorders.

Location

• Study visits take place at St Mary’s Hospital

• 6 visits over 4 mth period

• Will be seen by research Dr & nurse

• MRI scans take place at Hammersmith Hospital

• Research Dr will also attend

• Lasts about 1hr – 1hr 30min, with tasks during MRI scan

What taking part will entail

•  Patient review •  Blood tests •  Paper questionnaires •  Neurocognitive testing on computer •  2/12 CVC once daily (dose depends on ARV) •  LP and cerebral MRI at baseline and week 8 visit

Safety

•  Generally safe & well tolerated •  Avoid direct sunlight •  Common side effects:

–  Fatigue – Headache – Nausea – Diarrhoea – Rash

•  579 subjects (159 HIV-1 infected subjects) have received at least 1 dose of CVC in completed studies.

Questions? •  Research Fellow •  Dr Jasmini Alagaratnam •  Tel: 0203 312 1670 •  E-mail: j.alagaratnam@imperial.ac.uk

•  Research Nurse •  Claire Petersen •  Tel: 0203 312 6738 •  E-mail: claire.petersen@imperial.nhs.uk

Acknowledgments Thepa2entsforpar2cipa2ngPOPPYManagementTeamMartaBoffito,PaddyMallon,FrankPost,CarolineSabin,MemorySachikonye,AlanWinstonScien2ficSteeringCommi6eeJaneAnderson,DavidAsboe,MartaBoffito,LucyGarvey,PaddyMallon,FrankPost,AntonPozniak,CarolineSabin,MemorySachikonye,JaimeVera,IanWilliams,AlanWinstonPOPPYSitesandTrialsUnit• EltonJohnCentre,BrightonandSussexUniversityHospital(Mar:nFisher,AmandaClarke,JaimeVera,AndrewBexley,CeliaRichardson)• StStephen'sCentre,ChelseaandWestminsterHospital(MartaBoffito,DavidAsboe,AntonPozniak,ChrisHiggs,ElishaSeah,StephenFletcher,MichelleAnthonipillai,AshleyMoyes,Ka:eDeats)• HomertonSexualHealthServices,HomertonUniversityHospital(JaneAnderson,SifisoMguni,RebeccaClark,RhiannonNevin-Dolan)• CaldecotCentre,King’sCollegeHospital(FrankPost,LucyCampbell,SelinYurdakul,SaraOkumu,LouisePollard)• HIVMolecularResearchGroup,MaterMisericordiaeUniversityHospital(PaddyMallon,AlanMacken,BijanGhavani-Kia,JoanneMaher,MariaByrne,AilbheFlaherty)• DepartmentofInfec:onandPopula:onHealth,UniversityCollegeLondon(IanWilliams,DamilolaO:ko,LauraPhillips)• St.Mary’sHospitalLondon,ImperialCollegeHealthcareNHSTrust(AlanWinston,LucyGarvey,MaDhewScoD,LindaMcDonald)• ImperialClinicalTrialsUnit,ImperialCollegeLondon(AndrewWhitehouse,LauraBurgess,DaphneBabalis)FundersThePOPPYstudyisfundedfrominves:gatorini:atedgrantsfromBMS,GileadSciences,Janssen,MerckandViiVHealthcare.

TheCo-morBidityinRela2ontoAids(COBRA)Collabora2on

ImperialCollegeofScience,TechnologyandMedicine-DepartmentofMedicine,DivisionofInfec4ousDiseases:A.Winston,J.Underwood,L.McDonald,M.StoD,K.Legg,A.Lovell,O.Erlwein,N.Doyle,C.Kingsley.DepartmentofMedicine,DivisionofBrainSciences,TheComputa4onal,Cogni4ve&ClinicalNeuroimagingLaboratory:D.J.Sharp,R.Leech,J.H.Cole.

GöteborgsUniversitet-M.Gisslén,D.Fuchs,H.ZeDerberg.

AcademischMedischCentrum,UniversiteitvanAmsterdam-DepartmentofGlobalHealthand

AmsterdamIns4tuteforGlobalHealthandDevelopment(AIGHD):P.Reiss,F.W.N.M.Wit,J.Schouten,

K.W.Kooij,R.A.vanZoest,B.C.Elsenga,F.R.Janssen,M.Heidenrijk,W.Zikkenheiner.DivisionofInfec4ous

Diseases:M.vanderValk.DepartmentofExperimentalImmunology:N.A.Kootstra,A.M.Harskamp-Holwerda,I.

Maurer,M.M.MangasRuiz,A.F.Girigorie.

DepartmentofMedicalMicrobiology:J.Villaudy,E.Frankin,A.Pasternak,B.Berkhout,T.vander

Kuyl.DepartmentofNeurology:P.Portegies,B.A.Schmand,G.J.Geurtsen,J.A.terStege,M.Klein

Twennaar.DepartmentofRadiology:C.B.L.M.Majoie,M.W.A.Caan,T.Su.DepartmentofCellBiology:K.Weijer.DivisionofEndocrinologyandMetabolism:

P.H.L.T.Bisschop.DepartmentofExperimentalneuroendocrinology:A.Kalsbeek.Departmentof

Ophthalmology:M.Wezel.DepartmentofPsychiatry:I.Visser,H.G.Ruhé.

AlmaMaterStudiorumUniversitadiBologna-DepartmentofExperimental,Diagnos4candSpecialtyMedicine:C.Franceschi,P.Garagnani,C.Pirazzini,M.Capri,F.Dall’Olio,M.Chiricolo,S.Salvioli.

UniversitätKonstanz-DepartmentofBiology:A.Bürkle,T.Sindlinger,M.Moreno-Villanueva,A.Keller.

GGDAmsterdam/PublicHealthServiceAmsterdam-ClusterofInfec4ousDiseases,researchdepartment:M.Prins,M.Martens,S.Moll,J.Berkel,M.ToDé,S.Kovalev.

S2ch2ngHIVMonitoring-S.Zaheri,M.M.J.Hillebregt,Y.M.C.Ruijs,D.P.Benschop.

VlaamsIns2tuutvoorBiotechnologie-Inflamma4onresearchcenter:C.Libert,S.Dewaele.

UniversitàdeglistudidiModenaeReggioEmilia-DepartmentofMedicalandSurgicalSciencesfor

Children&Adults:G.Guaraldi.

S2ch2ngKatholiekeUniversiteitNijmegen-D.Burger,M.deGraaff-Teulen.

ErasmusUniversitairMedischCentrumRo6erdam-DepartmentofGene4cs:J.Hoeijmakers,J.Pothof.

UniversityCollegeLondon-ResearchDepartmentofInfec4onandPopula4onHealth:C.Sabin,D.deFrancesco.

ThisresearchwasfundedbytheEuropeanUnion’sSeventhFrameworkProgramme(FP7/2007-2013)undergrantagreementn˚305522toCOBRA;theNetherlandsOrganisa:onforHealthResearchandDevelopment(ZonMW)grantnr.300020007&S:ch:ngAIDSFondsgrantnr.2009063,Nuts-OhraFounda:ongrantnr1003-026.andunrestrictedscien:ficgrantsfrom:ViiVHealthcare,GileadSciences,JanssenPharmaceu:caN.V.BristolMyersSquibb,andMerck&CototheAGEhIVcohortstudy,aswellasinves:gatorini:atedgrantsfromBMS,GileadSciences,Janssen,MerckandViiVHealthcaretothePOPPYcohortstudy

Thankyouforlistening.Anyques:ons?

TheCo-morBidityinRela2ontoAids(COBRA)Collabora2on