hiv associated neurocognitive disorders (hand) 4-14-12.pdf · hiv‐associated neurocognitive...

4/12/2012

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HIVHIV‐‐Associated Neurocognitive Associated Neurocognitive DisordersDisorders (HAND)Disorders Disorders (HAND)

David B. Clifford, MDWashington University in St. Louis

Disclaimers

• Funding: NIH: NIAID, NINDS, NIMH, NIA, F tFogarty

• Consulting: Biogen, Cytheris, Genzyme, Pfizer, Genentech, Jannsen, Millennium, Novartis, BMS, Roche

• Clinical study support: Biogen Glaxo PfizerClinical study support: Biogen, Glaxo, Pfizer, BMS, Neurogesx, Genentech

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HIV‐1 Associated Neurologic Problems

HIV‐1 Associated Neurologic Problems

• Primary HIV‐associated conditions

– HIV‐associated neurocognitive disorder and dementia

M l h– Myelopathy

– Peripheral neuropathy

– Myopathy

Slide 4

HIV Associated Dementia (HAD)

• Decreased concentration

• Motor slowing

• Behavioral changes• Behavioral changes

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Slide 5

HIV-Associated Dementia (HAD)Formerly AIDS Dementia Complex

• Occurs with low CD4• Occurs with low CD4

• Progressive – untreated death in 6 months

• Correlates at least moderately to active viral replication (in CNS)– CSF VL high

• Correlates to immune activation markers

• Pathology: Multinucleated giant cells

Slide 6

Approved Antiretroviral Agents 1987 - 2012

DLVDDC 3TC

3TC/ZDV

ABC TDF

3TC/ABC

FTC/TDFETR

7 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12

T-20SQV NFV LPV/r

SQV.sgc APV ATV

TPV

DRV

NVP EFV

DLV

ZDV DDI d4T ABC/3TC/ZDVTDF/FTC/EFV

Nucleoside RTI

Non-Nucleoside RTI

Protease InhibitorFusion InhibitorCCR Inhibitor

Integrase Inhibitor

RTG

MVC

Q g

RTV

IDV

RFV

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Slide 7

Slide 8

20

Probable dementia Probable or possible dementia

Toxoplasmosis Cryptococcal meningitis

Progressive multifocal leukoencephalopathy CNS lymphoma

Successful HIV Therapy Helps ( A Lot)

6

8

10

12

14

16

18

20

Inci

de

nce

ra

tes

er

1,0

00

pe

rso

n-y

ea

rs)

Multicenter AIDS Cohort

0

2

4

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Calendar Year

(p

e

Sacktor, personal comm 200HAART

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Slide 9

Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras

Grant 1987 HNRC-500 1995 CHARTER 2008

50%

75%

100%

rcen

t Im

pair

ed

0%

25%

HIV- CDC-A CDC-B CDC-C

Per

Frascati Classification of HIV‐Associated Neurocognitive Disorders (HAND)

• ANI = AsymptomaticANI = Asymptomatic neurocognitiveimpairment

• MND = Mild neurocognitivedisorderdisorder

• HAD = HIV‐1 associated dementia

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HIV Associated Neurocognitive Disorders (HAND): Frascati Criteria

Asymptomatic Neuropsychological

Impairmentabnormality in twoor more cognitive

Mild NeurocognitiveDisordercognitive

impairment with mild functional

HIV-associatedDementia

marked cognitive impairment with

marked functional

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO

gabilitiesimpairmentimpairment

Antinori, et al., Neurology 2007

HIV Associated Neurocognitive Disorders (HAND): Frascati Criteria

Asymptomatic Neuropsychological

Impairmentabnormality in twoor more cognitive

Mild NeurocognitiveDisordercognitive

impairment with mild functional

HIV-associatedDementia

marked cognitive impairment with

marked functional


gabilitiesimpairmentimpairment

Antinori, et al., Neurology 2007

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Asymptomatic HIV-associated Neurocognitive Disorder (ANI) Increases Risk for Future Symptomatic Decline: A Risk for Future Symptomatic Decline: A

CHARTER Longitudinal Study

Robert Heaton, PhD1, Donald Franklin, BS1, Steven Woods, PsyD1, Christina Marra, MD2, David Clifford, MD3,

Benjamin Gelman, MD,PhD4, Justin McArthur, MBBS5, Susan Morgello MD6 Allen McCutchan MD1 and


Susan Morgello, MD6, Allen McCutchan, MD1, and Igor Grant, MD1 for the CHARTER Group

1 University of California, San Diego; 2 University of Washington, Seattle; 3 Washington University, St. Louis;4 University of Texas Medical Branch, Galveston; 5 Johns Hopkins University, 6 Mount Sinai School of Medicine

DiagnosisCHARTER Neurocognitive Test Battery

Verbal Fluency Motor» Letter Fluency» Category Fluency

Speed of Information Proc.» WAIS-III Symbol Search» WAIS-III Digit Symbol» Trail Making Test Part A

Attention/Working Memory

» Grooved Pegboard

Abstraction/Executive» Wisconsin Card Sorting Test 64» Trail Making Test Part B

Learning and Memory» Hopkins Verbal Learning Test-R» Brief Visuospatial Memory Test R


» Paced Auditory Serial Addition Test -50

» WAIS-III Letter-Number Sequencing

» Brief Visuospatial Memory Test-R» Story Memory Test » Figure Memory Test

Everyday Functioning: Patient’s Assessment of Own Functioning InventoryActivities of Daily Living Scale

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Participants

347 longitudinal CHARTER participants with up to 90 months of follow-up (median 45.2 months)months of follow up (median 45.2 months)» 226 NML cases: No neurocognitve impairment and no self-

reported or observed declines in everyday functioning

» 121 ANI cases: Neurocognitvely impaired, but no self-reported or observed declines in everyday functioning

Participants completed neuromedical, laboratory,


neurocognitive, and both self-report and performance-based measures of everyday functioning approximately every 6 months

Self-Report Functional Impairment Measures

Patients Assessment of Own Functioning Inventory (PAOFI): Measures cognitive complaints over 5 domains (eg Measures cognitive complaints over 5 domains (eg., memory, language, cognition)» Symptomatic = 3 or more complaints

Activities of Daily Living (ADL): Measures increased dependence in completing basic activities of daily living (eg., housekeeping, cooking, managing finances)


( g , p g, g, g g )» Symptomatic = declines in 2 or more areas at least partially

attributed to cognitive problems

Self-report symptomatic HAND requires both PAOFI and ADL to be symptomatic

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Performance-based Functional Impairment Measures

Medication Management Test-Revised (MMT-R): Assesses ability to perform tasks related to medication management» Tasks include ability to correctly place pills in a pill organizer according

to prescription schedule and ability to infer answers from prescription labels

» Symptomatic = Score 1SD below the mean of cognitively normal sample

Valpar System 3000 Work Samples and Computerized Assessment: Assesses abilities considered important for


Assessment: Assesses abilities considered important for performing work-related tasks» Symptomatic = Score 1SD below the mean of cognitively normal

sample

Baseline Comparison of ANI and NML:Background Characteristics

NML (n=226) ANI (n=121) P-value

A 43 0 (8 6) 44 8 (8 0)Age 43.0 (8.6) 44.8 (8.0)

Education 12.9 (2.4) 13.5 (2.2) .04

% Male 81.9% 81.8%

% Caucasian 45.6% 46.3%

% Lifetime Substance Dx 71.2% 69.4%

% with Comorbidity 22.6% 44.6% <.0001


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Baseline Comparison of ANI and NML:Disease Characteristics

NML (n=226) ANI (n=121) P-value

% AIDS 56.2% 62.8%

Current CD4 459 [290-669] 425 [286-578]

Nadir CD4 201 [61-370] 162 [38-273] .03

% on ART 66.2% 72.7%

Est. Duration HIV+ (months) 117.7 (75.0) 120.7 (81.6)

% HCV+ 20.4% 27.3


ANI Increases Risk for Symptomatic HAND: Based on Self-Report of Functional Impairment

p=.003

(Asy

mp

tom

atic

)

NML: n=226ANI: n=121

Relative Risk: 2.30CI: 1.38, 3.86


Su

rviv

ing

(

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ANI Increases Risk for Symptomatic HAND: Performance-based Functional Impairment

NML: n=226

p<.0001

g (

As

ymp

tom

ati

c)




Su

rviv

ing

ANI Increases Risk for Symptomatic HAND: Self-report or Performance-based


p< 0001g (

As

ymp

tom

ati

c)



p<.0001

Su

rviv

ing

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Asymptomatic Neurologic Impairment May Predict Functional Decline

Mechanism remains uncertain

Cannot “write off” this substantial portion of successfully treated HIV patients

Tracking change in this population is challenging

Measures of cognitive function that can be


Measures of cognitive function that can be repeated and tracked might be of value

International HIV Dementia Scale

•International HIV Dementia Scale •Naming four objects•Fingertapping•“Luria” psychomotor learning task•Recall of names


Sacktor et al. Neurology 2003 60;1:A186-187

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CogState

Executive Function


http://library.cogstate.com/public/Brochures/12_Minute%20Brochure%20REV6_LowRes.pdf

CROI 2010, Winston, et al

DiagnosisNPZ -4 used in ACTG

Trail making A and B Robertson et al ALLRT Trail making A and B

Symbol digit test

Hopkins Verbal Learning test

Robertson, et al, ALLRT


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Cognitive ScreeningMontreal Cognitive Assessment (MoCA)

Broad balanced test

O li d f Online and free

Bedside scoring

Being assessed in comparison with tools currently used that

i li d


require licenses, and norming

http://www.mocatest.org/

Cognitive Dysfunction in HIV

AIDS Dementia (now HAD)Pre‐HAART

HAND (ANI/MND)Post‐HAART

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Slide 29

To develop effective treatment we need to know causes HAND now…

• Evidence for direct• Evidence for direct viral mechanism poor

• Cytokines that formerly were most closely associated no longer provide reliablelonger provide reliable signal

…by the way, I’m from Missouri where famously you have to “Show me….”

• “Noninfectious pathologies and minimalNoninfectious pathologies and minimal changes correlated with HIV‐associated neurocognitive disorder, suggesting a shift in pathogenesis from florid HIV replication to other, diverse mechanisms”

• 88% of sample had HAND88% of sample had HAND

• 17.5 % has parenchymal HIV brain pathology which was associated to nadir CD4 and plasma viral load

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Slide 31

To develop effective treatment we need to know causes HAND now?

• Co-morbidities• Co-morbidities

• Virus

• Inflammation

• Drugs

• Perfusion/Vascular

Slide 32

Is this all due to non-HIV-associated co-morbidities?

• Contribution of other factors to cognitive performance– ?trauma

– ?drugs

– ?hepatitis

– ?CMV

– ?psychiatric dx/rx

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Slide 33

Neurocognitive Impairment by Co-Morbidity Status

30

40

50

60

70

80

impa

irm

ent

0

10

20

Total Minimal Moderate Severe

%

Slide 34

Co-morbidity

• Large effect of co morbid associated• Large effect of co-morbid associated impairment masks HIV associated findings

• Only in the “clean” group can one see impact of HIV viral load, CD4 nadir

• Co-morbidity may set up environment for C y y pongoing pathologic interaction with HIV and/or its consequences like inflammation

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Slide 35



• Virus

• Inflammation

• Drugs


Slide 36

Viral Escape• CNS is functional

compartment• Untreated HIV

– CSF generally one log – Viral isolates may be

unique

– Cells infected in CNS are monocytes/macrophages with unique viral

lower VL than periphery

– During HAD CSF VL rises with autonomous CNS isolates

– Most often when requirements

– Rx may differperipheral virus controlled so is CSF

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Slide 37

Symptomatic Viral Escape

Peluso, Spudich et al, Poster 489

• Controlled plasma viral pload

• Subacute onset of new neurologic symptoms

• CSF demonstrated independent replicationp p

• Drug selection based on virus in CSF improved clinical condition

Implications of Viral Escape

• HIV therapy is not perfect

• Viral replication sometimes occurs in CNS and generates important resistance mutations

• Attention to virus in CNS remains critical

• Justify CSF analysis when new neurologic problems occur in HIV patient even with goodproblems occur in HIV patient, even with good control in plasma

• Rarity suggest it doesn’t explain common HAND

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Slide 39

Does viral subtype matter?

• Work in Uganda with dementia suggests• Work in Uganda with dementia suggests difference in risk between Subtype A and D

• Work in Ethiopia suggests Subtype C might have less neurovirulence

• Projects in Cape Town and in Brazil are j C paddressing potential differences, to date seems less likely to be important

HIV infection in the brain may not be fully reflected in blood studies and therapies not as effective in brain….

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Slide 41

CNS Penetration-Effectiveness Ranks2010

4 3 2 1NRTIs Zidovudine Abacavir Lamivudine Didanosine

Emtricitabine Stavudine TenofovirZalcitabine

NNRTIs Nevirapine Delavirdine EtravirineEfavirenz

PIs Indinavir-r Darunavir-r Atazanavir NelfinavirFosamprenavir-

rAtazanavir-r Ritonavir

Indinavir Fosamprenavir SaquinavirLopinavir-r Saquinavir-r

Tipranavir-rEntry Inhs Vicriviroc Maraviroc Enfuvirtide

Integrase Inhs Raltegravir

Slide 42

CNS Penetration-Effectiveness Ranks

CPE 2010 RanksCross-Sectional Analysis

Letendre S, et al. Arch Neurol 2008; 65:65-70

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Slide 43

CNS Penetration Effectiveness

• Unproven • More potent delivery• Unproven

• CIT2 – a randomized trial of rx based on CPE has been stopped

• Lack of proof by underpowered study

• More potent delivery of drugs contemplated, eg nanoparticles

• Drug entry might be double edged sword

• Toxicity of drugs is anunderpowered study doesn’t completely discredit this idea

• Toxicity of drugs is an increasing concern

Slide 44

Damaged brain may heal poorlyCD4 Nadir

• Legacy of prior damageg

• Nadir CD4 count– CHARTER analysis

suggest significant impact of nadir <350

– Data too limited to test hi h dihigher nadirs

• Treating a scar? Tough target

• Implies earlier rxcould be helpful

CROI 2010, Poster 429,Ellis, et al

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0.7 Nadir CD4 > 200/ Detectable VL

Reduced Risk of NCI in those with Absent History of Severe Immunosuppression and Good Virologic Control

lity

of I

mpa

irmen

t

0.6

0.5

0.4

0.3

Detectable VLNadir CD4 < 200/ Detectable VL

Nadir CD4 < 200/ Undetectable VL

Pro

babi

0.0

0.1

0.2Nadir CD4 > 200/ Undetectable VL

45

Changes in Brain Cortex: Damage to the computer

Vacuolar Changes

Synaptophysin

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Slide 47

To develop effective treatment we need to know causes HAND now…


• Virus

• Inflammation

• Drugs


Slide 48

Inflammation – Ongoing Chronic Inflammation

• Biology of HIV i l d h iincludes chronic immune activation

• Microbial translocation/LPS associated withassociated with dementia Brenchley et al, Nature Med, 2006

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~60% still have elevated neopterin and IgG Index after 4 yrs HIV rx

Slide 50

CSF Viral Escape Can Drive Ongoing CNS Immune Activation

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Detection of microglial cell activation in patients on suppressive ART

Garvey et l

Garvey L et al. CROI #78LB

al, CROI2012

Accrual of inflammation in brain attenuated with ART in early infection

Young et al. Abstract #79CROI 2012

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CMV Might Drive Inflammation and Neurocognitive Change

• CMV powerful antigenic stimthat may reactivate and drivethat may reactivate and drive chronic inflammation

• Increases with aging and severity of nadir CD4

• In 138 CHARTER patients serum CMV IgG correlated with neurocognitivewith neurocognitive impairment

• Fits model of “co‐morbidity” driving impairment

Letendre, et al, Abstract 466, CROI 2012

Adjunctive Studies for HAND

• CPI – 1189 (TNF‐alpha antagonist)• Lexipafant (Platelet activating factor antagonist)

M i (NMDA i )• Memantine (NMDA antagonist)• Minocycline (Anti‐inflammatory and p38 MAP kinase inhibitor)• Nimodipine (Calcium channel antagonist)• Nitroglycerin (Vasodilator)• OPC 14117 (antioxidant)• Pentoxifylline (Platelet activating factor antagonist, TNAa antagonist)• Peptide T (possible chemokine receptor blocker)• Prednisone (Macrophage suppression)Prednisone (Macrophage suppression)• Selegiline (deprenyl) (Monoamine oxidase‐B inhibitor)• Thioctic acid (antioxidant)• Valproic acid – unknown• Lithium – GSK‐3β inhibtion

Cochrane Review, 2008

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Minocycline for HAND• SIV model data

• Potential mechanisms– Anti‐inflammatory/ y

neuroprotective via suppression of p38 MAP kinase

– Anti‐oxidant via iNOS inhibition

– Anti‐apoptotic

– Inhibits matrix metalloproteinasesthat may damage BBB

– ?Anti‐viral effect in SIV

• A5235 is open placebo t ll d t i l f i li fcontrolled trial of minocycline for

HIV patients with cognitive impairment

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A5235: Minocycline vs Placebo x 24 wks

Pre-post NPZ8 Plot for A5235

-2-1

01

24

We

ek

NP

Z8

MinocyclinePlacebo

-5 -4 -3 -2 -1 0 1

-5-4

-3

Baseline NPZ8

2

Slide 58



• Virus

• Inflammation

• Drugs


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ARV Interruption Improves NP Performance

Does CPE have a downside?

• A5170 found stopping A B

MAP‐2

pp gARV resulted in cognitive improvement

• ACTG 736 results suggested poorer performance in better penetrating regimens

A B

C D• Elevated penetration

could cause increased toxicity

CROI 2010, Liner et al,Poster 435

A=Control, B=ATV, C=EFV (dendrites), D=EFV(neuron loss)

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Aging/HAART/HAND

• Does HIV or its therapy accelerate aging?accelerate aging?

• Path evidence of premature p‐tau and amyloid

• Driving force could be chronic inflammatory or toxicor toxic

• Findings were subclinical but evident at post mortem

Anthony et al, Acta Neuropathol , 2006

• NNTC evaluation in HIV subjects 50‐76 yo

• Neuritic α‐synuclein in 12/73 HIV+ and not controls

• β‐amyloid deposits in 35/36 HIV brains

• Not found in association with HIV brain pathologypathology

• Suggest accelerated degenerative disease not directly HIV virus driven

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Potential Mechanisms

• Chronic inflammatoryinflammatory state may lead to amyloiddeposition

• TAT inhibition of neprilysnneprilysn

• Ubiquitin‐proteosomedysfunction

Neurology, Dec 2009

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CSF Amyloid β 1‐42 Is Low in Cognitively Impaired HIV+ Patients

CSF Tau Not Elevated

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Better Biomarkers: CSF Amyloid and PET PIB

• Biology of low CSF AB42• Biology of low CSF AB42 appears different in HIV and AD

• PIB binding correlates to low CSF AB42 in AD

• In HIV, low CSF AB42 is NOT i t d ith

A. HIV +, Low Aβ1‐42, cog NB. Community, Low Aβ 1‐42, cog NAnces and Clifford, Archives of Neurology,

2012

NOT associated with extracellular amyloiddeposits

Alzheimer’s Disease in HIV

• AD is common and will likely occur in HIV

• HAND may be distinguished by:likely occur in HIV

patients as they age

• Rx for AD advancing, and specific dx will be important

– Anticholinesterase rx

distinguished by:

– Lack of tau elevations in CSF

– Lack of PIB binding amyloid on PET scanning of brain

– Anticholinesterase rx

– NMDA antagonist (memantine)

• More data needed on biology of amyloid in HIV (as well as AD!)

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Slide 69



• Virus

• Inflammation

• Drugs


Cardiovascular Risks Associated with Poor Cognitive Performance in SMART

Study• Traditional HIV associated risk factors

CROI 2010

associated risk factors were not associated with baseline NP performance

• CVD risk factors were associated with poorerassociated with poorer baseline performance

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Multicenter AIDS Cohort

Af i f d i• After accounting for education, depression and race

• Carotid intima‐media thickness (IMT) and GFR associated with psychomotor speed

• IMT associated with memory

• HIV serostatus not associated with poorer cognitive performance overall

• In HIV+, HIV detection in plasma associated with poorer memory

Slide 72

HIV Indirectly Contributes to Cognitive Impairment?

HIV Age

Carotid IntimaThickening

HIV gHBPDMLipids

Cognitive Normal

CognitiveImpaired

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Slide 73

Effects of HIV and Aging on rCBF

m/m

in)

ebra

l blo

od f

low

(m

l/10

0gm

Ances et al. , JID, Feb 2010

Cer

e

Age (years old)

Slide 74

Blood Flow May be Biomarker for Blood Flow May be Biomarker for HIV HIV SynaptodendriticSynaptodendritic Injury/InflammationInjury/Inflammation

HIV

DisruptionNormal

Synapto-dendriticDensity

Normal

Disruption or Loss of Synapto-dendriticcommunication

R d d

Masliah et al,Ann Neurol 1997

Masliah et al,Ann Neurol 1997

NormalCerebral

Blood Flow

ReducedCerebral

Blood Flow

HAART

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Slide 75

Modifiable Risk FactorsModifiable Risk Factors

SmokingSmokingSmokingSmoking

DietDiet•• GlucoseGlucose•• LipidsLipids

ExerciseExercisePh i lPh i l•• PhysicalPhysical

•• MentalMental

RestRest

Slide 76

Modifiable Risk FactorsModifiable Risk Factors

SmokingSmokingSmokingSmoking

DietDiet•• GlucoseGlucose•• LipidsLipids

ExerciseExercisePh i lPh i l•• PhysicalPhysical

•• MentalMental

RestRest

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Overall NC Impairment status at baseline and last visit: No major cohort worsening

NP Normal Mild NCI NP Normal

Baseline Last Visit

38%

8%

NP Normal Mild NCI

≥ Moderate NCI

29%

11%

Mild NCI

≥ Moderate NCI

54%38%

60%

29%

77

Slide 78

ConclusionsConclusions

Cognitive functions remain impaired Cognitive functions remain impaired in many optimally treated HIVin many optimally treated HIVin many optimally treated HIV in many optimally treated HIV patientspatients

Optimal therapy should avoid low Optimal therapy should avoid low nadir CD4, optimize HIV control, nadir CD4, optimize HIV control, minimize chronic immune activation,minimize chronic immune activation,minimize chronic immune activation, minimize chronic immune activation, and optimize cerebral perfusionand optimize cerebral perfusion

Healthy lifestyles as well as HIV Healthy lifestyles as well as HIV control should contribute to better control should contribute to better neurologic outcomesneurologic outcomes

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Thanks• Washington U

• Beau Ances• Turner Overton• ACTU and NARC staff

• NARC investigators• Ned Sacktor• Justin McArthur• David Simpson• Christina Marra• Giovanni Schifitto• Scott Evans

• CHARTER investigators• Ron Ellis• Ron Ellis• Scott Letendre• Igor Grant

• NIH: NINDS (NARC and CHARTER)• NIH: NIMH (CHARTER and CIT2)• NIH: NIAID (ACTU)• NIH: Fogarty (West Africa)

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