Out of sight out of mind:
Brain Impairment and HIV
Victor Valcour MD
Associate Professor
Memory and Aging Center
University of California – San Francisco/ USA
The Double-Edged Sword: Long-Term Complications of ART and HIV
Brain Impairment and HIV
•
•
Cognitive impairment remain frequent despite
HAART
Causes of brain:
1) Current treatment approaches do not clear reservoirs
2) Co-existing factors (treatment complications/side
effects, other diseases, non-HIV related issues)
•
Aging with HIV
– Should we be worried about neurological
degenerative disorders (Alzheimer’s? Parkinson's?)
The Double-Edged Sword: Long-Term Complications of ART and HIV
Brain Impairment and HIV
22% Mildly
Impaired
17%
Moderately
Impaired
39% Impaired
21% Developed
impairment after 48
weeks of HAART
Robertson K, et al. AIDS. 2007
The Double-Edged Sword: Long-Term Complications of ART and HIV
Cognitive Impairment despite
HAART
Proportion Impaired
1
0.75
Pre- ARV
)Grant
(1987
)HNRC-500
Pre-HAART(1995
0.5
)CHARTER
HAART (2007
0.25
0
HIV-
CDC-A
CDC-B
CDC-C
Grant et al. 2009
Conference on Retroviruses and Opportunistic
Infections
The Double-Edged Sword: Long-Term Complications of ART and HIV
Neuropsychological Impairment in
the era of HAART (2007)
HIVassociated
Dementia
Mild
Neurocognitive
Disorder
HIV
Asymptomatic
Neurocognitive
Impairment
HIV infection
without cognitive
impairment
Consensus Working Group, Neurology 2007
The Double-Edged Sword: Long-Term Complications of ART and HIV
Clinical Features
Cognition
Memory loss
Concentration
Mental slowing
Comprehension
Behavior
Apathy
Depression
Agitation, mania
Motor
Unsteady gait
Poor coordination
Tremor
The Double-Edged Sword: Long-Term Complications of ART and HIV
Functional consequences of
cognitive impairment in HIV
Heaton et al JINS 2004
The Double-Edged Sword: Long-Term Complications of ART and HIV
The Case of Mr. B
• 79 year old male, high school degree, held
miscellaneous jobs
• Referred for research project studying
aging
– “would be a good control subject…has no
cognitive problems”
• Participant -asymptomatic
– “I like opera and I used to be able to name all
the singers…a lot of it escapes me now”
The Double-Edged Sword: Long-Term Complications of ART and HIV
Mr. B’s HIV history
• HIV+ since 1985
• Asymptomatic for decades but eventually started
HAART in 2001 with CD4~200
• No opportunistic infections; mild neuropathy
• Currently plasma HIV RNA level – undetectable
• Current CD4 ~ 250
• Has not had detectable viral load or CD4 less
than 200 since 2001
The Double-Edged Sword: Long-Term Complications of ART and HIV
Mr. B’s other medical issues
• Past Medical History
– hepatitis A (1960); occasional vertigo,
intermittent illicit drug use including
methamphetamine (last use at 75 years old)
• Neurological exam abnormal
– Increased reflexes, slowed finger tapping,
distal symmetric neuropathy, abnormal eye
movements
– Neuropsychological deficits broadly and
severe
The Double-Edged Sword: Long-Term Complications of ART and HIV
Mr. B’s Brain Imaging
The Double-Edged Sword: Long-Term Complications of ART and HIV
Why is this occurring?
(1) Is HAART sufficient?
(2) What is the role of coexisting morbidity?
The Double-Edged Sword: Long-Term Complications of ART and HIV
HIV
(1) HIV-infected
monocytes, some
activated
HAART
Capillary lumen
Blood Brain Barrier
(3) Impacts
brain cells
leading to
cognitive
dysfunction
(2) Transfer of HIV into
the brain - infection
establishment in
perivascular
macrophages
(5) Altered integrity of the BBB
facilitating further transmigration
of infected M/MФ
(4) Neuronal
dysfunction and
death
Pathology demonstrates multinucleated
infected cells (perivascular monocytes), little
neuronal infection, but dysfunctional neurons
with decreased arborization and damaged
synaptic function
The Double-Edged Sword: Long-Term Complications of ART and HIV
Peripheral monocyte infection
correlates to HIV dementia
1
performance
Poorer cognitive
NPZcomp
Dementia
Non-dementia
0.5
0
-0.5
-1
-1.5
-2
0
1
2
3
4
5
6
Monocyte HIV DNA (log10)
Valcour Neurology 2009
The Double-Edged Sword: Long-Term Complications of ART and HIV
Failure of HAART to eradicate virus
in circulating monocytes
Valcour et al, J Leukocyte Biology 2010
The Double-Edged Sword: Long-Term Complications of ART and HIV
Correlation between HIV DNA and
cognition in treated subjects
All Individuals
Not Impaired
Individuals with
undetectable
plasma HIV RNA
Impaired
Not Impaired
Impaired
Shiramizu, et al 2005 AIDS
The Double-Edged Sword: Long-Term Complications of ART and HIV
CD68 expression in hippocampus
Elevated despite viral control with HAART
Anthony, Bell, et al. J Neuropath Exp Neurol 2005
The Double-Edged Sword: Long-Term Complications of ART and HIV
(1) HIV-infected
monocytes, some
activated
HAART
Capillary lumen
Blood Brain Barrier
(3) Impacts
brain cells
leading to
cognitive
dysfunction
(2) Transfer of HIV into
the brain - infection
establishment in
perivascular
macrophages
(5) Altered integrity of the BBB
facilitating further transmigration
of infected M/MФ
?
(4) Neuronal
dysfunction and
death
The Double-Edged Sword: Long-Term Complications of ART and HIV
CPE and CSF viral load
Proportion
with
detectable
virus in CSF
HAART with higher BBB penetration
Letendre et al 2008 Arch Neurol
The Double-Edged Sword: Long-Term Complications of ART and HIV
Non-HIV specific Contributors to Cognitive
Impairment in HIV
The Double-Edged Sword: Long-Term Complications of ART and HIV
Cerebrovascular risks
Smoking
Hypertension
Younger
43%
12%
2%
Younger
21%
Older
47%
26%
7%
Older
42%
Diabetes
Younger
FG 100-125
15%
FG > 125 or DM 3%
Deaths in the
Hawaii Aging
with HIV Cohort
Undetermined
21.05%
Older
25%
22%
Cardiovascular
21.05%
Drug overdose
10.53%
Cancer
21.05%
Liver failure
5.26%
HAART related lactic
acidosis
10.53%
AIDS-related
10.53%
The Double-Edged Sword: Long-Term Complications of ART and HIV
JNC7
Cognitive performance worse with
greater number of cerebrovascular
risk factors
The Double-Edged Sword: Long-Term Complications of ART and HIV
The role of Co-existing Morbidity
• Cerebrovascular disease
– Carotid Intimal Medial Thickness correlates to
cognitive performance in the Multicenter AIDS
Cohort Study (MACS)
• Other non-HIV specific factors
– Illicit drug use
– Co-infections, particularly Hepatitis C
– Depression and other psychiatric conditions
Becker 2010 Neurology and Valcour 2005 JAIDS
The Double-Edged Sword: Long-Term Complications of ART and HIV
Aging with HIV infection
The Honolulu Advertiser
2003
The New York Times
January 2007
The Double-Edged Sword: Long-Term Complications of ART and HIV
Prevalence of Dementia
80
70
60
50
% of
40
population
30
20
10
0
55
60
65
70
75
80
85
90
Age
The Double-Edged Sword: Long-Term Complications of ART and HIV
Prevalence of Dementia
80
70
60
50
% of
40
population
30
20
10
0
55
60
65
70
75
80
85
90
Age
The Double-Edged Sword: Long-Term Complications of ART and HIV
Amyloid deposition in HIV
• Amyloid accumulation
• Amyloid degradation
The Double-Edged Sword: Long-Term Complications of ART and HIV
Amyloid deposition in HIV
• Amyloid accumulation
– Inflammation (Alisky 2007)
– Metabolic syndrome (Giunta
2008)
– IFNg, TNFa (Liao 2004, Cu 2008)
– Ubiquitin proteosome dysfunction
due to HAART (Clifford 2007)
– Gamma secretase impairment
due to immune activation (Brew
2005)
– Increased APP as an acute phase
reactant (Xu 2008)
– GP41 inhibitions of protein kinase
C ((Ikezu 2008)
• Amyloid degradation
– Tat inhibition of micoglial uptake of
amyloid beta (Giunta 2008)
– Tat interactions with low density
lipoprotein receptor inhibiting
uptake of amyloid (Liu 2000)
– Protease inhibitor down-regulation
of insulin degradation enzyme
which degrades amyloid
– Tat interactions with neprolysin,
inhibiting amyloid degradation
(Rempel & Pulliam, 2005)
– TNFa stimulated BACE1
suppressing amyloid beta
degradation in microglia (Xu 2008)
– Sub-lethal HIV mediated NMDA
excitations leading to alpha
secretase inhibition (Xu 2008)
The Double-Edged Sword: Long-Term Complications of ART and HIV
Clifford et al, Neurology 2009
The Double-Edged Sword: Long-Term Complications of ART and HIV
Good news
• No evidence for increased fibrillary
amyloid plaque in well-controlled HIV Ances,
Clifford 2010
• Damage to neuron synapses and
decreased arborization of neurons
appears to be reversible Ellis, Masliah, 2008
The Double-Edged Sword: Long-Term Complications of ART and HIV
UCSF HIV Over 60 Cohort
5%
23%
53%
19%
Normal Cognition
Asymptomatic Neurocognitive Impairment
Mild Neurocognitive Disorder
HIV-associated Dementia
Abstract # 11302, IAS 2010
The Double-Edged Sword: Long-Term Complications of ART and HIV
Where do we go from here?
• HIV cognitive impairment remains a silent
epidemic
– Although dementia is rare, milder levels of
impairment are frequent and impact function
– Many patients adopt compensatory means of
getting by
• Work is needed to detect and treat these
issues
The Double-Edged Sword: Long-Term Complications of ART and HIV
Where do we go from here?
• HIV appears to be inadequately treated
within current treatment approaches
– Sequestered reservoirs are inadequately
treated – monocytes
– Not all antiretroviral medications adequately
get into the brain
• More information is needed, but early data suggest
this is a problem for some patients
• Work is needed to address treatment of
reservoirs
The Double-Edged Sword: Long-Term Complications of ART and HIV
Where do we go from here?
• Confounding factors are likely to emerge as
important treatable aspects of cognitive
impairment
– Illicit drug use, cerebrovascular risk factors, hepatitis
C, medication effects, sleep apnea, others
• Patients and doctors should address these
issues aggressively
• Patients should remain physically and socially
engaged
The Double-Edged Sword: Long-Term Complications of ART and HIV
Where do we go from here?
• There are theoretical concerns for the
emergence of increased risk for
neurodegenerative disorders in older HIV
patients
• It is too early to make firm conclusions at
this time
• More research is needed
The Double-Edged Sword: Long-Term Complications of ART and HIV
Thank you
Research support
R01 NS061696 (Monocyte HIV DNA and HIV
Dementia)
K23AG032872 (Brain Impact of Aging with
HIV)
Special Thanks:
Bruce Miller and the Memory and Aging Center
Cecilia Shikuma, Bruce Shiramizu and the
Hawaii Center for AIDS
Jintanat Ananworanich and the Southeast Asia
Research Collaboration with Hawaii (SEARCH,
www.SEARCHThailand.org)
Our research subjects in California, Hawaii and
Thailand
R21-MH086341 (Neurological Complications
of Acute HIV Infection)
UCSF AIDS Research Institute
(NeuroImaging Correlates to Dementia in HIV
over 60)
UCSF-Gladstone Center for AIDS Research
(NeuroImaging Correlates to Dementia
in HIV over 60)
Hillblom Foundation (Cognitive Impact of
Insulin Resistance in Aging HIV Patients)
Disclosures: Dr. Valcour has provided consultative services to GlaxoSmithKline, Merck, and Abbott
The Double-Edged Sword: Long-Term Complications of ART and HIV