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11/6/2010
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HIV Brain Injury
Victor Valcour MD
Associate ProfessorDivision of Geriatric Medicine and Department of
Neurology/UCSF
Overview
• The neuropathology of HIV
• HIV Dementia – a current snapshot
• Scenarios of rapid progression
– Immune Reconstitution Inflammatory Syndrome
(IRIS)
– CNS escape
– Acute infection
HIV Dementia
Recommended ReadingEllis, Langford, and Masliah. HIV and antiretroviral therapy in the
brain: neuronal injury and repair. Nature Reviews 2007
HIV characteristics
– Primate lentiviruses recognize CD4 as a receptor protein
• Immunosepression due to depletion of t-helper cells
– Regulatory genes - neurotoxicity
• vif, vpr, vpu, tat, rev, nef, env
– Env polymorphisms resulting
in clade specificity
• Implications for international setting
• Unclear neuropathogenesis by clade
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Critical role of inflammation
• Histopathological
hallmarks
– Perivascular monocytes
• Identified with CD14 and
CD45 markers
• Consistently the most
highly infected cells
– Multinucleated Giant
Cell
Brew et al 1998
Blood Brain Barrier
Capillary lumen
(5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ
(3) Impacts brain cells leading to cognitive dysfunction
(2) Transfer of HIV into the brain - infection establishment in perivascular macrophages
(4) Neuronal dysfunction and death
(1) HIV-infected monocytes, some activated
Cellular co-receptors required for infection (e.g. CD4) – thus, neurons not thought to have substantial infection
CD4
cells
Plasma
HIV
RNA
Time
weeks months years
viral set-
point
HIV in human hosts(aseptic) meningitis,
radiculitis, myelitisdementia,
myelopathy,
neuropathy
opportunistic
infections
Clinical Features
Cognition
Memory loss
Concentration
Mental slowing
Comprehension
Behavior
Apathy
Depression
Agitation, mania
Motor
Unsteady gait
Poor coordination
Tremor
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Clinical CharacteristicsPresenting symptoms
0
10
20
30
40
50
60
70
Memory Gait MentalSlow ing
Depression Tremors Behavioralchanges
Apathy OtherNormal MC/MD HAD
0
5
10
Uni
fied
Par
kins
on D
isea
se R
atin
g S
cale
M
otor
Exa
m M
ean
(95%
CI)
Older
All
Younger
Valcour 2008 J Neurovirology
Neuropsychological deficit
Prominent motor part of advanced disease
Advanced disease
Clinical Features of HAD MRI findings
• Absence of opportunistic
infection
• Periventricular white matter
hyperintensities
• Atrophy
A 79 year old male with HIV
Dementia
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Dementia among HIV patients1996 - Post-HAART realities
1980
40
30
20
10
0
50
35
25
15
5
45
1985 1990 1995 2000 2005
survival
Cognitive Impairment despite HAART
0
0.25
0.5
0.75
1
HIV- CDC-A CDC-B CDC-C
Pro
po
rtio
n Im
pai
red
(1987)Grant
(1995)HNRC-500
(2007)CHARTER
Pre- ARV
Pre-HAART
HAART
Grant et al. 2009
Conference on Retroviruses and Opportunistic Infections
17%
Moderately
Impaired
22% Mildly
Impaired
21% Developed
impairment after 48
weeks of HAART
Brain Impairment and HIV
Robertson K, et al. AIDS. 2007
39% Impaired
HIV infectionHIV Asymptomatic
Neurocognitive
Impairment
Mild
Neurocognitive
Disorder (NMD)
HIV-associated
Dementia
(HAD)
Cognitive Impairment in HIV
Neurology 2007
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Functional consequences of cognitive
impairment in HIV
Heaton et al JINS 2004
Diagnostic Transitions from Baseline to Year 1
• There is considerable movement in the MCMD and HAD arms
• Approximately one-third of HAD patients improve and 18% of MCMD patients decline at one year
60.98%
21.95%
17.07%
17.65%
38.24%
41.18%
2.94%
10.71%
17.86%
53.57%
17.86%
3.57%
28.57%
67.86%
0%
100%
Normal(N=37)
NP Abnormal(N=53)
MC/MD(N=39)
HAD(N=30)
Baseline Diagnosis
Normal NP Abnormal MC/MD HAD
Year 1 Diagnosis as a % of Baseline
Diagnosis
CD68 expression in hippocampusElevated despite viral control with HAART
Anthony, Bell, et al. J Neuropath Exp Neurol 2005
VAMC ID Rounds Feb 2009 Gonzalez-Scrano et al. 2005
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HIV DNA in CD14+ cellsCorrelation to HAD HAART naïve Thais
Valcour J Leukocyte Biol 2010
Aging with HIV infection
The New York Times, 2007
The Honolulu Advertiser, 2003
Tau expression in hippocampus
Elevated despite viral control with HAART
Anthony, Bell, et al. J Neuropath Exp Neurol 2006
Prevalence of Dementia
0
10
20
30
40
50
60
70
80
55 60 65 70 75 80 85 90
Age
% of population
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Immune Reconstitution
Inflammatory Syndrome (IRIS)
Recommended reading:Johnson and Nath Neurological complications of immune
reconstitution in HIV-infected populations. Annals of the New York
Academy of Sciences 2010
IRIS – Clinical Presentation
• Profound immune response - often to previously
unrecognized or subclinical pathogens
• Two main categories:
– Simultaneous (“Unmasking”): inflammatory immune
response against an opportunistic pathogen previously
uncontrolled or untreated
– Delayed (“Paradoxical”): inflammatory immune response
against an antigen previously controlled or treated
IRIS – Clinical Presentation
• Some speculation that autoimmune phenomenon
can underlie some IRIS
– Emergence of clear autoimmune phenomenon have been
described (Guillain-Barre, Graves Disease)*
– Independent t-cell mediated encephalitis without
identified pathogen
• Descriptions of paradoxical worsening with
treatment of other infections prior to HAART
– can occur with TB, MAI leprosy treatment - confirms that
the response is due to immune reconstitution – not HAART
*Chen et al, Medicine 2005
CNS-IRISDefining Features
1. Worsening of neurological status after HAART
2. Deterioration of or new radiological findings
suggestive of inflammation
3. Occurring in the context of HIV control
– decrease in plasma HIV viral load of > 1 log appears to be
a better marker than CD4 count recovery
4. Symptoms not explained by: (1) newly acquired disease;
(2) ARV side effects; (3) usual course of other illnesses
5. If biopsy - histopathology confirms T cell
lymphocytic infiltration
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CD4
cells
Plasma
HIV
RNA
Time
weeks months years
viral set-
point
HIV in human hosts
HAART
CD4
cells
Plasma
HIV
RNA
Time
weeks months
viral set-
point
Timing of IRIS
Viral load
CD4
CD8
4 -20 weeks, increasing freq.
Most cases occur within the first 3 months of therapy
Risk Factors
• Severe immune suppression - low CD4 count at
HAART initiation (nadir)
– Implications for populations with delayed diagnosis (aged,
women, international settings)
• Known presence opportunistic infections
• High initial viral load and rapid decline in viral load
(likely a better predictor than rate of CD4 rise)
• Possibly genetic risks
– polymorphisms in cytokine and MHC genes
• Unclear association: timing of HAART c/t OI treatment
Epidemiology of IRIS
• Systemic IRIS
– 15-35% of individuals initiating HAART
• CNS-IRIS
– 0.9% of adults (1.5% if CD4 T cell count <200)
– Most common CNS-IRIS is caused by the JC virus (PML- IRIS)
– Other pathogens
• Viruses: Herpes Viruses [VZV, CMV (retinitis), EBV, HSV 1 and 2], parvovirus,
BK virus, HTLV 2,
• Fungal pathogens: Cryptococcus neoformans, Candida
• Bacterial pathogens: Mycobacterium (M. tuberculosis, M. leprae, M. avium)
• Parasitic pathogens: Toxoplasma gondii
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Clinical Course of CNS IRIS
• Varies greatly based on severity and underlying
pathogen
• Severity
– Asymptomatic – only radiological changes are noted
– Symptomatic, with recovery – clinical deterioration and
imaging confirmation
– Catastrophic – severe neurological deficits can lead to
coma, herniation, death
• PML IRIS associated with high rate of mortality
(>40%) and long-term morbidity
Radiology of PML-IRIS
• Confluent, bilateral, asymmetric, white matter changes
• Similar to chronic PML
– Key differentiation = presence of inflammation: additional peripheral enhancement and/or mass effect
Johnson and Nath, Ann NY Acad Sci 2010
Histopathology and biomarkers
• Biomarkers needed
– Cytokines? (IL-6); Genetic?
• Histopathology
– Inflammatory cells:
• Predominantly CD8 t cells, typically in the perivascular
spaces
• macrophages, CD4+ t cells also present
– Brain biopsy sensitivity and specificity: 64-96%
and 100% in PML-IRIS
IRIS Treatment
• No published randomized trials to direct
recommendations
• Exclude non-IRIS possible explanations
– Drug toxicities, interactions, poor HAART
adherence, other diseases with progression
• Continue HAART
– No guarantee that the condition will not recur
once HAART is resumed
– Likely and increased risk of HIV and OI progression
if HAART is stopped
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IRIS Treatment – use of steroids
• Catastrophic cases
– Despite lack of published data, likely needed, high
doses
• Symptomatic cases - Use of steroids is
controversial
– Inflammatory response likely beneficial to
controlling pathogen
– In non-HIV diseases, use of adjuvant steroids
accepted
CSF Escape
Case
• 45 year old male from Dublin with chronic
well-controlled HIV infection
• Presents with acute exacerbation of
depression requiring hospitalization
• Psychomotor slowing, depressed affects,
markedly decreased response times
Blood Brain Barrier
Capillary lumen
(5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ
(3) Impacts brain cells leading to cognitive dysfunction
(2) Transfer of HIV into the brain - infection establishment in perivascular macrophages
(4) Neuronal dysfunction and death
(1) HIV-infected monocytes, some activated
HAART
?
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CompartmentsAntiretrovirals: CNS Penetration-Effectiveness
Courtesy: S. Letendre, UCSD
poor better
NRTI didanosine emtricitabine abacavir
tenofovir lamivudine zidovudine
zalcitabine stauvudine
NNRTI efavirenz delavirdine
nevirapine
PI nelfinavir amprenavir amprenavir-r
ritonavir atazanavir indinavir-r
saquinavir atazanavir-r lopinavir-r
tipranavir-r indinavir
enfuviride
CPE and CSF viral load
Letendre et al 2008 Arch Neurol
Proportion with detectable virus in CSF
HAART with higher BBB penetration
CompartmentsCSF viral load and cognition
Improved control of CSF HIV RNA relates to greater
improvements in cognitive performance
Ellis et al Ann Neurol 2004
Acute meningoencephalitis
Case Series
• Case series – 3 cases
– Suppressed plasma HIV
RNA presenting with acute
meningoencephalitis
– All had detectable virus in
CSF ( 7059, 180,692, and
11,227 copies/ml)
– All had MRI changes
– All responded to change in
ARVs
Representative T2 image
Wendel and McArthur CID 2003
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Subacute Neurological SyndromesCase Series
Age CD4 Months
VL<50
Neurological symptoms ARVs CSF HIV
RNA
Plasma
HIV RNA
50 592 36 Persistent headache TDF/FTC/ATZr 12,885 147
49 190 11 Memory disorder, cerebellar ataxia AZT/3TC/IDVr/T20 845 <50
43 400 18 Cerebellar dysarthria, cerebellar ataxia 3TC/ABC/ATV/IDVr 1190 <50
50 432 68 Tactile allodynia TDF/FTC/fAPRr 870 78
36 107 75 Glasgow Coma Score of 3 3TC/ABC/TDF/DRVr 5035 <50
47 631 64 Persistent Headache DRVr 580 <50
44 544 14 Memory d/o, cerebellar ataxia, pyramidal
syndrome
FTC/ABC/ATVr 558 <50
53 360 12 Lower limb dysesthesia and hypoesthesia 3TC/AZT/ABC/EFV 1023 <50
68 147 12 Memory d/o, left lower limb dysesthesia 3TC/DDI/TDF/NVP 586 <50
68 534 18 Temporospatial disorientation, cerebellar
ataxia
3TC/AZT/ATV 880 <50
56 593 10 Memory d/o, cerebellar dysarthria LPVr 6099 483
Canestri et al CID 2010
Subacute Neurological SyndromesCase Series
• All but one had CSF pleocytosis and/or
elevated protein levels
• resistance-associated mutations seen in 7 of 8
CSF strains that were genotyped
• Optimization of HAART in response to
resistance mutations identified or to increase
CSN penetration effectiveness resulted in
suppression of HIV RNA in CSF and clinical
improvement for all
Canestri et al CID 2010
Practical implications
• All cases presented with sub-acute symptom
progression - ? Approach for the 50% of
subjects with chronic impairment
– Current published studies are mixed
• Provides no basis for using neuro-HAART in
asymptomatic patients
An approach to impairment in HIV
Lancet Neurology 2005
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Acute HIVCD4
cells
Plasma
HIV
RNA
Time
weeks months years
viral set-
point
HIV in human hosts(aseptic) meningitis,
radiculitis, myelitis
Laboratory Staging of Acute HIVLaboratory Staging of Acute HIVLaboratory Staging of Acute HIVLaboratory Staging of Acute HIV----1 Infection1 Infection1 Infection1 Infection
Fiebig et al., AIDS 2003
Fiebig 1 (5 days)Fiebig 2 (10 daysFiebig 3 (14 days)
Acute HIV InfectionImpact on the brain
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Procedures
Main
Clinical PhlebotomyQuestionnairesLeukopheresis
Gut
Colon biopsySemen, anal,cervical
Days 0, 2, 3, 5, 7, 10Wks 2, 4, 8, 12, 16, 20, 24 then every 24 wks till 96 wks
Wks 0, 24, 96 D 0, 3, 7, wks 2, 4, 12, 24, 48, 72, 96
Genital
Compartment (optional)
MRI/MRSLPNP test
Wks 0, 6, 12, 24, 48, 96LP wks 0, 24, 96
Neuro
Acute Retroviral Syndrome (ARS)
Symptoms N(%)Fever 8(72.7)Oral ulcer 5(45.4)Sore throat 5(45.4)
Headache 4(36.4)Myalgia 4(36.4)Anorexia 4(36.4)Diarrhea 4(36.4)Skin rash 4(36.4)Adenopathy 2(18.2)Arthalgia 2(18.2)Genital ulcer 1(9.1)Oral candidiasis 1(9.1)Vaginal candidiasis 1(9.1)
Of 11 subjects, 9 subjects (82%) had ARS
Characteristics and neurological profile
of acute HIV infected subjects at enrollment
ID Age/ge
nder
Risk Fiebig HIV RNA CD4/CD8 Subtype ARS
symptoms
Headache
(yes or no)
CSF cell count
1 28yr/F Hetero III 794,947 341/264 CRF01_AE Yes No RBC=0,WBC=02 28yr/M MSM III 1,069,278 426/238 NT Yes Yes RBC=0,WBC=103 30yr/M MSM III 302,722 740/917 NT Yes
No RBC=10,WBC=304 30yr/F Hetero IV 571,082 463/1227 CRF01_AE Yes No RBC=10,WBC=505 46yr/M Hetero III 258,559 525/245 CRF01_AE Yes Yes RBC=8,WBC=06 25yr/M MSM II 150,633 269/203 NT No No Not done7 23yr/M MSM II 285,651 218/191 CRF01_AE Yes No RBC=1,WBC=08 24yr/M MSM III 81,978 428/500 B No Yes RBC=2,WBC=19 25yr/M MSM III 48,421 381/998 NDY Yes No RBC=0,WBC=0
10 25yr/M MSM III >750,000 298/426 NDY Yes No RBC=1,WBC=011 25yr/M MSM II 276,124 311/271 NDY Yes Yes RBC=10,WBC=0
All had normal CSF protein and sugar
HIV CNS penetration during acute
Infection
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Early inflammation in Acute HIV
Cho/Cr
Feib
ig 1
&2 : B
G
Feib
ig 3
&4 : B
G
Contro
l : B
G
0.15
0.20
0.25
0.30
0.35
MRS Feibig
MRS – Basal Ganglia CSF Cytokines before and after megaHAART
Major unanswered Questions
• Our there founder viruses in CSF that may
uncover aspects of neurotropism
• Do CNS outcomes depend on early immune
responses
• Is there a CNS impact of treatment within the
first weeks of infection
Conclusions
• HIV-related brain injury remains frequent
despite HAART
• There is evidence that on-going brain
inflammation may be occurring
– Infiltration of macrophages at autopsy
– Circulating HIV DNA
Conclusions
• HIV can present as a rapidly progressive
dementia syndrome
– Immune Reconstitution Inflammatory Syndrome
• In association with opportunistic infection
• Autoimmune phenomenon
– CNS escape syndromes
– Acute HIV
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A B
C D
Top
Thank you
Research support
R01 NS061696 (Monocyte HIV DNA and HIV
Dementia)
K23AG032872 (Brain Impact of Aging with HIV)
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)
P50 AG023501 (UCSF Alzheimer’s Disease
Research Center)
Disclosures: Dr. Valcour has provided consultative services to GlaxoSmithKline, Merck, and Abbott
Special Thanks:
Krista Nicolas
Edgar Busovaca
Stephanie Chaio
Lauren Wendelken
Howard Rosen, Bruce Miller and the Memory and
Aging Center Staff
Cecilia Shikuma, Bruce Shiramizu and the Hawaii
Center for AIDS
Jintanat Ananworanich and the Southeast Asia
Research Collaboration with Hawaii (SEARCH,
www.SEARCHThailand.org)
Jerome Kim and the US Army HIV Research team
Our research subjects in California, Hawaii and
Thailand