management of neurocognitive impairment in hiv+...
TRANSCRIPT
Management of Neurocognitive
Impairment in HIV+ Adults
Scott Letendre MDProfessor of Medicine and Psychiatry
University of California San Diego
Disclosures
Research funds were
paid to UC San Diego on
behalf of Dr Letendre
bull National Institutes of
Health
bull Gilead Sciences
bull Merck amp Co Inc
bull ViiV Healthcare
Dr Letendre was paid
for an advisory board
bull Merck amp Co Inc
bull ViiV Healthcare
Dr Letendre was paid
for a lecture
bull Gilead Sciences
bull Janssen
And Now for Something
Completely Differenthellip
Modified from Valcour et al
Neurology 200463822ndash827
Heaton et al J Neurovirology
2012 18(Suppl 1) S46
HIV x Age Interaction p = 0004
HIV May Accelerate
Neurocognitive Decline
HIV May Accelerate
White Matter Injury in the Brain
Unpublished CHARTER Data
HIV x Age Interaction p = 0003
Seider et al J Neurovirol (2016)
22201ndash212
Wh
ite M
att
er
Hyp
eri
nte
nsit
ies
HIV x Age Interaction p = 001
HIV May Accelerate
Subcortical Gray Matter Changes
Kuhn et al Human Brain Mapping 2016 DOI 101002hbm23436
HIV x Age Interaction p lt 0001
(bilateral nucleus accumbens amygdala caudate and thalamus)
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Disclosures
Research funds were
paid to UC San Diego on
behalf of Dr Letendre
bull National Institutes of
Health
bull Gilead Sciences
bull Merck amp Co Inc
bull ViiV Healthcare
Dr Letendre was paid
for an advisory board
bull Merck amp Co Inc
bull ViiV Healthcare
Dr Letendre was paid
for a lecture
bull Gilead Sciences
bull Janssen
And Now for Something
Completely Differenthellip
Modified from Valcour et al
Neurology 200463822ndash827
Heaton et al J Neurovirology
2012 18(Suppl 1) S46
HIV x Age Interaction p = 0004
HIV May Accelerate
Neurocognitive Decline
HIV May Accelerate
White Matter Injury in the Brain
Unpublished CHARTER Data
HIV x Age Interaction p = 0003
Seider et al J Neurovirol (2016)
22201ndash212
Wh
ite M
att
er
Hyp
eri
nte
nsit
ies
HIV x Age Interaction p = 001
HIV May Accelerate
Subcortical Gray Matter Changes
Kuhn et al Human Brain Mapping 2016 DOI 101002hbm23436
HIV x Age Interaction p lt 0001
(bilateral nucleus accumbens amygdala caudate and thalamus)
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
And Now for Something
Completely Differenthellip
Modified from Valcour et al
Neurology 200463822ndash827
Heaton et al J Neurovirology
2012 18(Suppl 1) S46
HIV x Age Interaction p = 0004
HIV May Accelerate
Neurocognitive Decline
HIV May Accelerate
White Matter Injury in the Brain
Unpublished CHARTER Data
HIV x Age Interaction p = 0003
Seider et al J Neurovirol (2016)
22201ndash212
Wh
ite M
att
er
Hyp
eri
nte
nsit
ies
HIV x Age Interaction p = 001
HIV May Accelerate
Subcortical Gray Matter Changes
Kuhn et al Human Brain Mapping 2016 DOI 101002hbm23436
HIV x Age Interaction p lt 0001
(bilateral nucleus accumbens amygdala caudate and thalamus)
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Modified from Valcour et al
Neurology 200463822ndash827
Heaton et al J Neurovirology
2012 18(Suppl 1) S46
HIV x Age Interaction p = 0004
HIV May Accelerate
Neurocognitive Decline
HIV May Accelerate
White Matter Injury in the Brain
Unpublished CHARTER Data
HIV x Age Interaction p = 0003
Seider et al J Neurovirol (2016)
22201ndash212
Wh
ite M
att
er
Hyp
eri
nte
nsit
ies
HIV x Age Interaction p = 001
HIV May Accelerate
Subcortical Gray Matter Changes
Kuhn et al Human Brain Mapping 2016 DOI 101002hbm23436
HIV x Age Interaction p lt 0001
(bilateral nucleus accumbens amygdala caudate and thalamus)
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
HIV May Accelerate
White Matter Injury in the Brain
Unpublished CHARTER Data
HIV x Age Interaction p = 0003
Seider et al J Neurovirol (2016)
22201ndash212
Wh
ite M
att
er
Hyp
eri
nte
nsit
ies
HIV x Age Interaction p = 001
HIV May Accelerate
Subcortical Gray Matter Changes
Kuhn et al Human Brain Mapping 2016 DOI 101002hbm23436
HIV x Age Interaction p lt 0001
(bilateral nucleus accumbens amygdala caudate and thalamus)
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
HIV May Accelerate
Subcortical Gray Matter Changes
Kuhn et al Human Brain Mapping 2016 DOI 101002hbm23436
HIV x Age Interaction p lt 0001
(bilateral nucleus accumbens amygdala caudate and thalamus)
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
HIV May Accelerate
Neuronal Injury in the Frontal Lobe
Chang et al Neurology 2014
822213ndash2222
Cysique et al PLoS ONE 8(4) e61738
doi101371journalpone0061738
APOE ε4- APOE ε4+
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Not All Neurocognitive and Imaging
Studies Support Accelerated Aging
Age
Ciccarelli et al JAGS 2012 602048ndash2055
Cysique et al J Neuropsych Clin Neurosci
2011 23(1) 83-9
Ances et al J Acquir Immune Defic Syndr
2012 59 469-77
Ances et al J Infect Dis 2010 201336ndash40
Caud
ate
Volu
me (
log
10)
HIV x Age Interaction
p lt 006
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Biomarker Correlates of HAND May
Differ in Older amp Younger HIV+ Adults
bull Stronger association in
older adultsndash HIV DNA
ndash Telomere length and other
aging biomarkers
ndash IL-6 MCP-1 sCD40L
ndash Amyloid β1-42 p-Tau
bull Similar in older and
younger adultsndash HIV RNA (SCA)
ndash Neurofilament light
ndash sCD163
ndash Neopterin
ndash D-dimer hsCRP
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
A B
00 05 10 150
10
20
30
40
50
GDS
HIV
DN
A(s
qrt[c
psm
illio
ncells
])
( )
- ( )
( )
Younger
Older
00 02 04 06 08 10 12 14
14
16
18
20
22
24
26
28
GDS
MC
P-
1-
CS
F(s
qrt
[pg
mL
])
( )
- ( )
- ( )
Younger
Older
0 10 20 30 40 50 601
10
100
1000
10000
Age (years)
HIV
inte
grat
ed
DN
A in
10
6C
D4
ce
lls
p = 0006r = 045
Boulassel Routy et al J Clin Virol 2012 53 29ndash 32
Graph Courtesy Jean-Pierre Routy McGill University
Shiramizu et al Int J Med Sci 2006 64(1)13-8
Higher HIV DNA Levels are
Associated with Older Age and HAND
Oliveira et al Sci Rep 2015 5 17094
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
NCI BDI Apathy ImpulsSens
Seek
HIV
Transm
Immune Response
CXCL10 CSF
sCD14 Plasma
IL-16 CSF
IL-6 Plasma
CXCL10 Plasma
MCP-1 Plasma
IL-6 CSF
sTNFR-II Plasma
Aging
Telomere Length
mtDNA
Vascular
ICAM-1 Plasma
uPAR Plasma
MMP-7 Plasma
MMP-7 CSF
MMP-2 CSF
uPAR CSF
VCAM-1 Plasma
Claudin-1 Plasma
Claudin-1 CSF
VCAM-1 CSF
PECAM-1 Plasma
PECAM-1 CSF
ZO-1 CSF
Occludin Plasma
TIMP-1 CSF
TIMP-2 Plasma
VEGF CSF
Oxidative Stress
Malondialdehyde CSF
8-OHdG CSF
Protein Carbonyls Plasma
8-isoprostane CSF
Neuronal
NFL CSF
Glutamate CSF
Composites
ge Prefrail
BMI ge 25
Karnofsky lt 90
Negative Positive
NCI=Neurocognitive Impairment BDI=Beck Depression
Inventory Impuls=Impulsivity Sens Seek=Sensation Seeking
HIV Transm=HIV Transmission Behavior
bull HIV Effect p=00032
bull HIV by Age Interaction p=013Unpublished Interim Data
Copyright S Letendre 2016
Leeansyah et al JID
2013 2071157
Reynoso et al J Virol
2012 86(19)10327
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Accelerated Aging in Brain Tissue
by DNA Methylation Array
Horvath amp Levine J Infect Dis
2015 2121563ndash73
Levine et al J Neurovirol
2016 22(3)366-75
Blood Brain
HIV+HIV-
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Gianella amp Letendre J Inf Dis 2016 214 Suppl 2S67-74
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Anti-CMV IgG is Associated with
Neurocognitive Performance
Correlation for Entire Group
r = -020 p = 002Letendre et al J Infect Dis 2016 Submitted
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Poly
pharmacy
Stimulant amp
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Other
Organism
Related
Viral
Hepatitis
Gut
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Chronic
Inflammation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Oxidative
Stress
Unsuccessful
CNS Aging
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Management of HAND in Aging HIV+
Adultsbull Earlier initiation of ART
ndash Consider changing ART based on symptoms
bull Treat mood sleep amp substance use disorders
bull Manage vascularmetabolic risk amp diseasendash Healthy diet regular exercise smoking cessation
ndash Treat dyslipidemia and insulin resistancediabetes
bull Treat co-infections (HCV Syphilis CMV)
bull Limit polypharmacy drug-drug interactions
bull Role of other interventions is unclearndash Anti-inflammatories neurotrophinsgrowth factors
ndash AChE inhibitors NMDA-R antagonists
ndash Probiotics hormone replacement
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Aerobic Fitness amp Exercise are Associated
with Better Neurocognitive Performance
Dufour et al J Neurovirol
2013 19(5)410-7
bull 335 HIV+ adults with self-reported
activity within 72 hours
bull Exercisers were less likely to have
global neurocognitive impairment
(odds ratio = 038 p lt 005)
Mapstone et al Aging and Disease
2013 4(6) 311-9
bull Assessed 37 HIV+ adults older than
50 on a treadmill
bull Peak VO2 (oxygen consumption)
related to verbal and visual memory
visual perception and language
bull Lower peak VO2 associated with
more HAND (p = 001)
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Smoking Cessation Reduces
Risk of Cardiovascular Events
bull More than 27000 HIV+
adults had a total of 3680
cardiovascular events or
mortality
bull Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 23 within
the first year to 15 after
gt 3 years compared with
those who never smoked
Petoumenos et al HIV Medicine
2011 12412ndash421
Myocardial infarction
Cardiovascular Disease
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Zhang et al CROI 2015 Abstract 56 Ma et al CROI 2015 Abstract 444
ITT-C Analysis N = 233
Cognitive Decline May Be Linked to
Drug Distribution into CSF
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Letendre et al 18th CROI 2011 Abstract 408
Blood-Brain Barrier Permeability
Increases with Age and may Increase
Drug Distribution into the CNS
Croteau et al 19th CROI 2012 Abstract 592
p = 004
p = 05
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Higher Concentrations of ART Drugs
Can Injure Neurons in the Lab
Robertson et al J Neurovirol 2012 18 388-299
Untreated
Neuronal
Injury
Hinckley et al CROI 2016 Abstract 395
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
HAND May Improve with
Maraviroc Intensification
bull Open-label MVC intensification in 12 adults
on suppressive ART
bull MVC reduced circulating CD14+CD16+
monocytes and monocyte HIV DNA content
bull Neurocognitive performance
improved in the 6 subjects who
were impaired at entry
bull 12-month open-label randomized
placebo-controlled trial
bull 14 adults on suppressive ART with recent
progression to HAND
bull Large difference at 6-months and
medium difference at 12-months
ndash Arm x Time interaction p lt 005
Ndhlovu et al J Neurovirol 201420(6)571-82 Gates et al AIDS 2016 30(4) 591-600
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Cell-Targeted Circulation-Stabilized
ART-Loaded Magnetic Nanoparticles
Sagar et al Rev Med Virol
2014 24 103ndash124
Kong et al Journal of Controlled Release
2012 164 49ndash57
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
CNS Immune Response in HIV Can
Result in Life-Threatening Complications
Riedel et al Nat Clin Pract Neurol
2006 2 557-65
Lescure et al Clin Infect Dis
2013 57(1)101ndash8
CNS IRIS CD8+ T-Cell Encephalitis
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Acknowledgements amp Conflicts
UC San Diegobull Igor Grant
bull Bob Heaton
bull Allen McCutchan
bull Ronald J Ellis
bull Cris Achim
bull David Moore
bull Brookie Best
bull Edmund Capparelli
CHARTER or ACTGbull Kevin Robertson
bull David Clifford
bull Justin McArthur
bull Ann Collier
bull David Clifford
National Institutes of Health
hellipMental Health
hellipDrug Abuse
hellipAllergy and
Infectious Diseases
Industry Gilead Sciences
Janssen
Merck Inc
ViiV Healthcare
Davey Smith
Sara Gianella
Connie Benson
Chip Schooley
Cris Achim
Tom Marcotte
Debra Rosario
Serena Spudich
Christina Marra
Susan Morgello
David Simpson
Ben Gelman
Study Volunteers
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
8th International Workshop on HIV amp Aging25-26 September 2017
Washington DC
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
CNS Safety-Focused Summary of
Latency ReversalEpigenetic Drugs
bull Direct TCR Stimulation OKT3 + rhIL-2
ndash Headaches stiff neck seizure reported
bull Histone Deacetylase (HDAC) inhibition
ndash Valproic acid Vorinostat Disulfiram Romidepsin
ndash CNS side effects reported Mood changes headache
concentration changes lethargy nausea
bull Other drugs in development
ndash Panobinostat Entinostat Bryostatin Trichostatin A
Chaetocin BIX-01294 Prostratin PMA JQ1
ndash Immune checkpoint Anti-PD-1 anti-CTLA-4
Spivak amp Planelles Trends Mol Med 2016 22 10-27
Kumar et al Clinical Epigenetics (2015) 7103
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Persistent
Inflammation
Insulin
Resistance
Dyslipidemia
Visceral Fat
Steatohepatitis
Liver Fibrosis
Vascular
Disease
Brain
Disease
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years
Older HIV+ APOE ε4 Carriers May be
at Increased Risk for Brain Injury
Wendelken et al J Acquir Immune Defic Syndr
201673426ndash432
n=76
Median 64 years
Chang et al Neurology 2014822213ndash2222
Morgan et al J Neurovirol (2013)
19150ndash156
n=466
Mean 44 years