Cognitive impairment in well-treated cohorts

Dr Jonathan Underwood Imperial College London July 2016

What am I going to talk about?

•  Background

•  POPPYstudy

•  COBRAstudy(POPPYneurologicalsub-study)

•  Conclusions

Data: Public health England 2014 report

About 108,000 people living with HIV in the UK

The cohort is ageing

PHEHIVintheUK;2014report

We all age… … some quicker than others

✔ ✖

What do we know about co-morbidities in well-treated patients?

Clin Infect Dis. 2014 Dec 15;59(12):1787-97

Significantly more hypertension, angina, MI, liver disease, renal failure and cancer in HIV-infected subjects

Number of comorbidities per patient

Mean number of age-associated non-communicable comorbidities0.68 0.80 1.03 1.15 1.47 0.89 1.35 1.52 1.65 2.04

Number of participants166 108 70 53 34 159 111 86 62 52

HIV negative HIV positive100

Num

ber,

%

80

60

40

20

0

3+210

How do we age?

Cognitive impairment

Cerebrovascular disease

Osteoporosis

Kidney dysfunction

Cardiovascular disease

Liver dysfunction

Severe

Mild

AsymptomaAc

0%

5%

10%

15%

20%

25%

30%

35%

Pre-1997

AnAretroviraleraAdaptedfromMcArthuretal.,AnnNeurol67,699-714,2010.

What’s the prevalence of cognitive impairment?

Key questions

Whatistheprevalenceinwell-treatedcohorts?WhatarethecharacterisJcsofimpairmentinwell-treatedcohorts?WhatarethemechanismsofcogniJveimpairmentinwell-treatedindividuals?

POPPY – preliminary findings

387subjectsaged>50enrolled:–  290HIV+–  97demographicallycomparableHIV-controls

AllparJcipantsansweredthe3EACScogniJvecomplaintsscreeningquesJonsandcompletedquesJonnairesdetailing:

•  Physical&mentalhealth(SF-36)•  AcJviJesofdailyliving(LawtonIADL)•  Depression(PHQ-9,CES-D)•  Falls•  SexualfuncJon

Methods cont…

AllweretestedwiththeCogStatecogniJveba\ery(seetable):RawscoresconvertedtodemographicallyadjustedTscoresusingtheHIV-groupasthereferencepopulaJon.CogniJveimpairmentdefinedusingpublishedmethods(seetable):

CogniAvedomain Testadministered

ANenAon/WorkingMemory OnebacktaskTwobacktask

ExecuAveFuncAon GrotonMazeLearningtestSetshieingtask

Processingspeed DetecJontaskVisualANenAon IdenJficaJontask

VerbalLearning/Memory InternaJonalShoppinglisttaskInternaJonalShoppinglisttask–delayedrecall

VisualLearning/MemoryConJnuouspairedassociatelearningtestGrotonMazeLearningtest–delayedrecallOnecardlearningtask

DefiniAon DefiniAonofabnormaltestresult

DefiniAonofabnormalcogniAvedomain

Affecteddomains

FrascaAcriteria1 1SDbelownormaJvemean

meandomainperformanceabnormal

≥2

Globaldeficitscore(GDS)2

GDSscore≥0.5(theGDSscoreisobtainedbyconverJngdomainTscoresintodeficitscorerangingfrom0to5andthenaveragingthem)

MulAvariatenormaAvecomparison(MNC)3

Hotelling’sT2staJsJc(analogoustoamulJvariatet-testperformedonallcogniJvetestssimultaneously)exceedsacriJcalvalue

1AnJnoriAetal,Neurology(2007);2CareyCLetal.JClinExpNeuropsyc(2004);3HuizengaHMetal,Neurospychologia(2007)

Baseline characteristics

HIV+(n=290) HIV-(n=97) p-value Gender,n(%) <0.001 Female 34(11.7%) 33(34.0%) Male 256(88.3%) 57(66.0%)

Ethnicity,n(%) 0.46 Black-African 37(12.8%) 9(9.3%) White 253(81.2%) 88(90.7%)

Age(years),median(Q1,Q3) 57(53,62) 58(54,62) 0.22 CD4count(cells/mm3),median(Q1,Q3) 610(479-780) N/A LikelyrouteofHIVtransmission,n(%) N/A MSM 229(79.0%) Heterosexualsex 61(21.0%)

ReceivinganAretrovirals,n(%) 238(82.1%) N/A

Prevalence of cognitive impairment

30.0% 34.5% 22.1%16.5% 14.4% 7.2%0%10%20%30%40%

FRASCATI GDS MNC0%5%10%15%20%

25 35 45 55

GlobalT-score

≥50HIV- ≥50HIV+ p-valueMedian(IQR): 50.8(47.5,54.1) 48.6(43.5,52.3) <0.001

Prevalence

OR(95%CI): 2.17(1.20,3.92) 3.12(1.69,5.78) 3.64(1.61,8.24)p-value: 0.011 <0.001 0.001

30.0%34.5%

22.1%16.5% 14.4%

7.2%

0%

10%

20%

30%

40%

FRASCATI GDS MNC

≥50HIV+ ≥50HIV-

Cognitive scores by domain

BoxplotsofdemographicallyadjustedcogniAvedomainT-scoresbyHIV-serostatus.PvaluescalculatedusingWilcoxonranksumtest.

Association with symptoms

62% 75%38% 25%CI NOTCI

p=0.02

Memoryloss Reasoning ANenAon

59% 75%41% 25%CI NOTCI

p=0.02

60% 77%40% 23%CI NOTCI

p<0.01

60% 62%40% 38%CI NOTCI

p=0.77

57% 63%43% 37%CI NOTCI

p=0.42

57% 64%43% 36%CI NOTCI

p=0.24

69% 72%31% 28%CI NOTCI

p=0.59

66% 73%34% 27%CI NOTCI

p=0.28

64% 75%36% 25%CI NOTCI

p=0.0761.8% 38.2%

Neverorhardlynever Yes,definitely

FRASCATI GDS MNC FRASCATI GDS MNC FRASCATI GDS MNC

Associations with summary health scores

Ji\erplotsofSF-36summaryscoresformentalandphysicalhealthforthosewith(triangles)vs.without(circles)cogniJveimpairmentforthethreediagnosJccriteria.Blacklinesindicatemedians.PvaluescalculatedusingWilcoxonranksumtest.

Conclusions from POPPY

CogniAveimpairmentismorecommoninHIV-posiAveindividualsBUT:• It’sgenerallymild• CorrelatespoorlywithsymptomsThismaybedueto:• over-reporJngofsymptoms• subjecJvityofcogniJvescreeningquesJonsandotherpaJentreportedmeasures• lackofaclearrelaJonshipbetweensubjecJveexperienceandobjecJvemeasuresofcogniJvefuncJon

Understanding cognitive impairment

Neurologicalsub-study

Asautopsydataisrarenowweneedtouseothertoolstostudydiseasemechanisms•  Neuroimaging•  CSFbiomarkers

InclusioncriteriaHIV+group(n=134)•  documentedHIVinfecJon•  age≥45yearsatstudyentry•  documentedplasmaHIVRNA<50

copies/mL>12monthsoncART

HIV-group(n=79)•  documentednegaJveHIVtestinpast6

monthsoratscreening•  age≥45yearsatstudyentry

Exclusioncriteria•  currentmajordepression(PHQ-9≥15)•  chronicneurologicaldiseases•  historyofsevereheadinjury•  historyofcerebralinfecJons(including

AIDSdefiningillnesses)•  severepsychiatricdisease

COBRA (neurological sub-study)

Allunderwent:cogniAvetesAng,MRIscanning(severalmodaliJes)andCSFexaminaJon

CogniAvebaNery(tesAngaNenAon,execuAvefuncAon,language,memory,motorfuncAonand

processingspeed)

Methods