Transcript Key Slides - IAS-USA

Neurologic Complications
of HIV
Victor G. Valcour, MD
Professor of Medicine
University of California San Francisco
San Francisco, California
AU Edited: 12/09/15
New Orleans, Louisiana: December 15-17, 2015
Learning Objectives
After attending this presentation, participants will be
able to:
 Describe the frequency, severity, and burden of cognitive
impairment in HIV in the era of combination antiretroviral therapy
 Recognize multiple likes of evidence supporting ongoing HIVrelated brain injury despite suppression of plasma HIV RNA to
undetectable levels
 Describe the role of comorbidity as contributors to cognitive
symptoms in the current era
Slide 2 of 49
Slide 3 of 49
Clinical Features of Impairment
Cognition
Memory loss
Concentration
Mental slowing
Behavior
Motor
Apathy
Depression
Agitation, Mania
Unsteady gait
Poor coordination
Tremor
Slide 4 of 49
HIV-Associated Neurocognitive Disorders
(HAND)
HAND
HIV-associated
Dementia
(HAD)
Mild
Neurocognitive
Disorder (MND)
No HAND
HIV Asymptomatic
Neurocognitive
Impairment
HIV infection
HAND terminology implies that the etiology is HIV; but, likely multifaceted
Neurology 2007
Slide 5 of 49
ARS Question 1
Slide 6 of 49
Prevalence of Cognitive Diagnoses
Pre-cART
Post-cART
HAD
MND
ANI
NL
• Lower incidence, but, no change in prevalence
• Lesser severity
• Most HAND cases are asymptomatic
Modified from Nat Rev Neurosci 2007
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SHOULD WE WORRY ABOUT
“ASYMPTOMATIC”
NEUROCOGNITIVE IMPAIRMENT?
Stephanie Chiao & Lauren Wendelken
Slide 8 of 49
Cognitive Performance
CO
HIV-NL
ANI
HAD
NPZComp Scores
2
1
0
-1
-2
-2
-3
-4
HIV neg.
CO
Controls
HIV+ NL
HIV-NL
Cognition
ANI
SNI
asymptomatic
symptomatic
No difference in summary neuropsychological testing scores between those who were asymptomatic
(ANI) and those who were symptomatic (MND/HAD)
Slide 9 of 49
Everyday Function
1. Memory
Total NAB Score
2. Judgment
4. Bill Pay (Language and calculations)
80
Percentile
3. Driving (Attention/Executive)
100
60
40
20
5. Map (Spatial ability)
0
Control
NL
ANI
MND
NAB = Neuropsychological Assessment
Battery, a series of everyday function
testing
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Is the Cognitive Impairment Real?
DTI measures in HIV vs. controls
Human Brain Mapping 2012
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Asymptomatic Case
79 year old male, brain
MRI with broad
atrophy including
central atrophy and
large areas of
confluent white matter
injury
Slide 12 of 49
Conversion to symptomatic
Conversion to Symptomatic Impairment
From CROI 2012 – Igor Grant - Asymptomatic HIV-associated
Neurocognitive Disorder (ANI) Increases Risk for Future
Symptomatic Decline: A CHARTER Longitudinal Study
347 subjects, 90 months of follow-up
Neurology 2014
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ARS Question 2
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The Role of Confounding Factors
Slide 17
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(a) ARV toxicity
(b) poor CPE
CPE = CNS PenetrationEffectiveness
Slide 18
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5
4
3
2
(a) ARV toxicity
(b) poor CPE
5
1
CPE = CNS PenetrationEffectiveness
Slide 19
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(a) ARV toxicity
(b) poor CPE
1
CPE = CNS PenetrationEffectiveness
Slide 18 of 49
Evidence of Ongoing Neuronal Injury Despite
cART
• Neurofilament (NFL) is a
major structural element of
myelinated fibers
• NFL is elevated in cART vs.
controls; 85 subjects on
cART for > 1 year with
plasma HIV RNA < 50
copies
Krut et al PlosOne 2014
Abnormalities in Diffusion Tensor Imaging
Slide 19 of 49
• n=56, all but 6 with
suppressed plasma HIV
RNA, age > 60
• Broad abnormalities in DTI
in HIV vs. controls; +:
Exacerbated by APOE4
Fractional Anisotropy
Nir et al. Human Brain Mapping 2013
Slide 20 of 49
Elevated sCD163 Associated with Impairment
34 CHARTER (US) participants with suppressed plasma HIV RNA, on cART > 1 year; CD4 > 500
CD163 = scavenger receptor involved in inflammation and secreted from monocytes as sCD163
Burdo et al AIDS 2013
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Effect of cART on HIV Reservoir Size
Before cART
6 months
12 months
Differing response in those with dementia vs. those without
Valcour et al J Leukocyte Biol 2010
Slide 22 of 49
Increased Macrophage Staining Despite cART
n=10 cART vs. 9 NL
Anthony et al J Neuropath Exp Neuro 2005
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• 7 asymptomatic subjects, mean 9 years of HIV
– on cART > 3 years, undetectable plasma HIV RNA
• PET Scan with 11c-PK1116 PET ligand
• Microglial activation noted
– signal in corpus callosum, anterior cingulate, posterior cingulate, temporal
and frontal lobes
– Correlated to poorer executive function
Garvey et al AIDS 2014
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Maraviroc Intensification for HAND
• Reduction of inflammation
• Reduction of HIV DNA
reservoir
• Cognitive improvement
J Neurovirology 2014
Slide 28
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(a) ARV toxicity
(b) poor CPE
CPE = CNS PenetrationEffectiveness
Slide 26 of 49
Neuronal Injury linked to Antiretroviral
Therapy
Schinburg et al JNV 2005
Slide 30
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Healthy neurons
Neurons treated for
7 days with ARV
Slide 28 of 49
Cognitive Performance During Treatment
Interruption
167 subjects, mean CD4 > 400 before interruption; had been on cART > 4 years
Robertson et al, Neurology 2010
Slide 32
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(a) ARV toxicity
(b) poor CPE
CPE = CNS PenetrationEffectiveness
Slide 30 of 49
Increasing Frequency of Ischemic Stroke in
HIV
Ovbiagele and Nath 2011 Neurology & Chow et al 2011 JAIDS
Metabolic Disorders and Cerebrovascular
Disease
# CVD risk factors
Number of cerebrovascular risk factors and cognitive performance
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White Matter Injury
Subjects over the age of 60 in the US
who are living with HIV as a chronic
illness
Slide 33 of 49
ARS Question 3
Slide 34 of 49
Mild
Moderate
• Autopsy series in the US between
1999 to 2011
• Associated with PI use; ? Legacy
effect
Severe
50 % of cases
Soontornniyomkij et al AIDS 2014
Slide 38
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(a) ARV toxicity
(b) poor CPE
CPE = CNS PenetrationEffectiveness
CNS Escape: Sub-Acute or Acute Neurological
Syndromes (Case Series)
Slide 36 of 49
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
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Projected Proportion of HIV Over 50+ Years Old
Projected based on 2008 CDC data
50%
47%
Projections as of 2008
•San Francisco
•NY City
44%
45%
41%
37%
39%
35%
33%
27%
27%
2006
2007
29%
25%
17%
2001
19%
2002
21%
22%
2003
2004
2005
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Adapted from JAMA 2013
Aging with HIV – An International Issue
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Mills et al NEJM 2012
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Prevalence of Dementia
80
70
60
Prevalence
50
Theoretical increased risk
associated with
comorbidity*
40
30
20
Age associated population risk
for dementia
10
0
55
60
65
70
75
80
85
Age
* Comorbidities: HIV infection, Hepatitis C, Cerebrovascular disease, lifestyle factors
90
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Considerations
• Age and HIV impact cognition, but not synergistically
(additive)
– Nevertheless, older individuals are more likely to meet a threshold of
important amounts of decline
• Older patients tend to be more symptomatic
• Age is not the most important determinant of cognition in
HIV
– The variation in age is as great as the variation across ages
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Where do we go from here?
Treatment options
•
•
•
•
•
•
Antiretroviral treatment considerations
Treatments for neurodegenerative disorders?
Exercise
Cognitive stimulation
Treatment of morbidities
Safety in the home/ advanced planning
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Summary
• Cognitive impairment remains frequent despite cART
• cART does not control HIV-related contributions
• Antiretroviral therapy may contribute to cognitive
impairment
• Suppression of plasma HIV RNA is essential in the
treatment of cognitive impairment
– Attention to CNS penetration effectiveness of ARVs is
important in select (uncommon) circumstances
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Summary
• The etiology of cognitive impairment is likely
heterogeneous
– Contributions from cerebrovascular disease
– With age, possibly neurodegenerative disorders
– Background comorbidity may play a role in the
frequency of poor neuropsychological performance in
some