HIV Associated Neurocognitive Disorders (HAND) 4-14-12.pdf · HIV‐Associated Neurocognitive...
Transcript of 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
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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
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
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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
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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
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» 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,
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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)
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( 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
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
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
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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
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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)
NML: n=226ANI: n=121
Relative Risk: 4.70CI: 2.93, 7.71
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Su
rviv
ing
ANI Increases Risk for Symptomatic HAND: Self-report or Performance-based
NML: n=226ANI: n=121
p< 0001g (
As
ymp
tom
ati
c)
Relative Risk: 3.02CI: 2.08, 4.42
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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
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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
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Sacktor et al. Neurology 2003 60;1:A186-187
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CogState
Executive Function
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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
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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
To develop effective treatment we need to know causes HAND now?
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
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
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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…
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
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
To develop effective treatment we need to know causes HAND now?
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
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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
To develop effective treatment we need to know causes HAND now?
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
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)