The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission. AIDS CLINICAL ROUNDS
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Update on Neurocognitive Complications of HIV Disease
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The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS
Update on Neurocognitive Complications of HIV Disease
Scott Letendre, M.D. University of California, San Diego
Acknowledgements & Disclosures
UC San Diego • Ronald J. Ellis • J. Allen McCutchan • Igor Grant • Robert Heaton • Donald Franklin • Florin Vaida • Edmund Capparelli • Brookie Best China CDC, Hospitals, & NSFC • Zhang Fujie • Yu Xin • Wu Hao • Zhao Hongxin • Wu Weiwei
National Institutes of Health
! …Mental Health ! …Drug Abuse ! …Allergy and
Infectious Diseases Industry ! ViiV Healthcare ! Abbvie ! Merck, Inc. ! Gilead Sciences
• Davey Smith • David Moore • Tom Marcotte • Cris Achim • Eliezer Masliah • Mariana Cherner • Melanie Crescini • Debra Rosario
• Shi Chuan • Zhang Hongwei • Han Ning • Zeng Hui • Liu Xia
Study Volunteers
Toward a Biological Classification of HAND
Definition of HAND
Acquired Impairment in ≥ 2 Cognitive
Abilities
Interferes with Daily
Functioning
No Cause Prior to HIV
No Current Strongly
Confounding Condition
Asymptomatic Neurocognitive
Impairment (ANI) ✔ No ✔ ✔
Mild Neurocognitive Disorder (MND)
✔ Mild ✔ ✔
HIV-Associated Dementia (HAD) Marked Marked ✔ ✔
Antinori et al, Neurology 2007, 69: 1789-99
Grant et al, Neurology 2014;82:1–8
• 347 adults who were either unimpaired (n = 226) or had ANI (n = 121) • Assessed every 6 months with median follow-up of 45.2 months • Symptomatic decline was based on self-report or objective, performance-based
problems in everyday functioning • Current CD4 and depression were significant time-dependent covariates
• Not ART regimen, virologic suppression, or substance abuse or dependence
Challenges to the Implementation of the Current Approach to HAND Diagnosis • Screening instruments are not consistently
sensitive between sites • We do not routinely perform comprehensive
neurocognitive testing in clinic • Many of our patients are unemployed or have
below average socioeconomic status, complicating assessment of daily functioning
• Confidently deciding that a condition confounds attribution of the cause of impairment to HIV can be difficult
Soluble Biomarkers Identify a Preclinical Stage in Alzheimer’s
Sperling et al, Alzheimer’s & Dementia 7 (2011) 280–292
ANI and MND are Associated with Higher Neopterin but not NFL
C S F N e o p te r in (n m o l/L )
CS
F N
FL
(n
g/L
)
A N I/M N D
N PN
3 .2 10 32010
100
1 000
1 00 00 r = 0 .2 1
p < 0 .0 5
A .
CS
F N
eo
pte
rin
(n
om
l/L
)
N P N A N I/M N D1
1 0
1 0 0* *
B .
CS
F N
eo
pte
rin
(n
om
l/L
)
N P N A N I/M N D1
1 0
1 0 0* *
B .
Edén et al, CROI 2014, Abstract 490
• Cross-sectional analysis of 100 HIV+ subjects taking suppressive ART without significant neuropsychiatric confounds
• Subjects were classified as NP-normal (NPN, n=79) or NP-impaired (ANI, n = 38; MND, n=33)
p < 0.01
Higher Soluble CD163 in Plasma in MND but not ANI
Burdo et al, AIDS 2013, 27:1387–1395
Higher HIV DNA Content is Associated with Worse Neurocognitive Performance
Additional challenges: • Clinical standardization of assays • Identification of clinically relevant cutpoints
CSF/Plasma Albumin Ratio is Elevated in HAND
Neuroasymptomatic, off ART
On ART
Anesten et al, CROI 2015. Abstract 59
p < 0.001
BBB Permeability During ART May Define Different HAND Phenotypes
CHARTER Data, Manuscript in Preparation
Update on HAND Management (you knew I’d have to talk about CPE, didn’t you?)
N NP Duration Principal Finding Notes
Ciccarelli1 C-S 101 C - Beneficial 2010 version stronger than 2008 version
Ciccarelli2 C-S 215 C - Beneficial Adjusted CPE using GSS
Casado3 C-S 69 B - Trend toward benefit Beneficial when CD4 < 200
Vassallo4 L 96 C 22 months Beneficial ~25% were not virologically suppressed
Cross6 L 69 C ~1 year No association Binary transformation only
Ellis5 RCT 49 C 16 weeks No association Beneficial in subgroup
Wilson7 C-S 118 B - Detrimental on 2 tests Binary transformation only Substance users only
Kahouadji8 C-S 93 B - Detrimental on 1 test Methodological flaws
Caniglia9 L 61,938 N - Detrimental Absolute risk 1.1% vs. 0.9%
Recent CPE Reports Have Mixed Findings
1Ciccarelli et al, Antiviral Therapy 2013, 18: 153-160; 2Ciccarelli et al, 20th CROI 2013, Abstract 405; 3Casado et al, J Neurovirol 2014, 20: 54-61; 4Vassallo et al, AIDS 2014, 28(4):493-501; 5Ellis et al, Clin
Infect Dis. 2014;58(7):1015-22; 6Cross et al, S Afr Med J 2013;103(10):758-762; 7Wilson et al, J Clin Experim Neuropsych 2013, 35:915-25, 8Kahouadji et al, HIV Medicine 2013, 14: 311-5.
C-S = Cross-sectional, L = Longitudinal, RCT = Randomized clinical trial, C = Comprehensive, B = Brief, N = None, GSS = Genotype Susceptibility Score
Two Uncontrolled Longitudinal Studies Found Similar Effect Sizes but Came to Different
Conclusions South Africa
Cross et al, S Afr Med J 2013;103(10):758-762
France
Vassallo et al, AIDS 2014, 28(4):493-501 Graph is adapted from Table 2
OR = 0.64
Odds ratio is calculated from data in the manuscript
Targeted Pharmacogenetics Inflammation Biomarkers in Blood
Open%Label*
Blinded to Treatment Arm: Investigators from US, China CDC, and Beijing University Mental Health Institute !
Neurocognitive Methods • An 8-test battery that
assessed 5 cognitive abilities was administered at 48 and 96 weeks
• Cross-sectional & longitudinal normative data – Adjust for effects of age, gender,
and education using data from HIV- adults in China
• Summary measures – Primary outcome: Summary
Change Score* – Secondary outcomes: Global
neurocognitive impairment, Global deficit score
Neurocognitive Test Battery • Hopkins Verbal Learning Test-
Revised - Total Learning • Brief Visuospatial Learning
Test-Revised - Total Learning • WAIS-III Digit Symbol Test • Grooved Pegboard Test • WMS-III Spatial Span • Action Fluency Test • Paced Auditory Serial
• 14 adults on suppressive ART with recent progression to HAND completed the trial
• Large effect (d 0.77) at 6-months and moderate effect at 12-months (d 0.55)
– Arm x Time interaction: p < 0.05
• Glutamate concentration in BG was stable in MA arm but increased in control arm at 12-months
Ndhlovu et al, J Neurovirol. 2014;20(6):571-82 Gates et al, CROI 2015. Abstract 441
DHHS Preferred Regimens (ART Naive)
TDF%FTC*
EFV1*
ATV/r1*
DRV/r*
RAL*
• Short- and long-term neurotoxicity
• CSF concentrations do not consistently exceed inhibitory concentrations
• Associated with CSF viral escape
• CSF concentrations exceed 50% inhibitory concentrations in all
• CSF concentrations exceed 50% inhibitory concentrations in all
EVG/c* • No CSF pharmacokinetic data
DTG*• CSF concentrations exceed 50%
inhibitory concentrations in all • Fewer CNS side effects than EFV
DTG*ABC%3TC* • No CSF ABC pharmacokinetic data on daily dosing
RPV2*• CSF concentrations do not consistently
exceed inhibitory concentrations
1May be combined with ABC-3TC when HIV RNA < 100,000 copies/mL; 2In patients with HIV RNA < 100,000 copies/mL; Last updated 1 May 2014; Available at http://www.aidsinfo.nih.gov/guidelines
TDF%FTC*
EFV1*
ATV/r1*
DRV/r*
RAL*
EVG/c*
DTG*
DTG*ABC%3TC*
1May be combined with ABC-3TC when HIV RNA < 100,000 copies/mL; 2In patients with HIV RNA < 100,000 copies/mL; Last updated 1 May 2014; Available at http://www.aidsinfo.nih.gov/guidelines
RPV2*
DHHS* EACS* BHIVA* WHO*
�︎* �︎* �︎* �︎*
�︎* �︎* �︎*
�︎* �︎* �︎*
�︎* �︎* �︎*
�︎* �︎* �︎*
�︎* �︎*
�︎* �︎*
�︎* �︎*
Other Findings of Interest
ART Drug Concentrations in Brain: Regional Variation, CSF Comparability
n Overall Mean
WM (mean)
GP (mean)
CGM (mean)
Concentrations Similar to Historical CSF Concentrations
Atazanavir (ATV) 2 < 25 < 25 < 25 < 25
Efavirenz (EFV) 2 38.6 45.2 34.8 35.9
Emtricitabine (FTC) 4 181.3 230.4 173.2 140.3
Lamivudine (3TC) 3 196.9 205.5 209.8 175.4
Concentrations in White Matter Higher than Historical CSF Concentrations
Lopinavir (LPV) 4 153.3 410.6 < 25 < 25
Concentrations Higher than Historical CSF Concentrations
Tenofovir (TDF) 6 206.0 220.0 212.1 185.8
WM = White Matter; GP = Globus Pallidus (Deep Gray Matter); CGM = Cortical Gray Matter
Bumpus et al, CROI, 2015, Abstract 436
Concentration units are ng/mL
Suppressive ART protects against neurodegeneration in CNTN
Bette
r
W
orse
Co
mbi
ned
Neu
rode
gene
ratio
n Sc
ore
(MAP
2, S
YN)
ARV Naive
cART Failure
cART Success
Bryant et al, AIDS 2015, 29(3):323-30
Protease Inhibitor Use is Associated with Cerebral Small Vessel Disease
• 144 adults with HIV/AIDS who died between 1999 and 2011 and had been evaluated prior to death in CNTN
• Protease inhibitor use was associated with cerebral small vessel disease – Mild: OR 2.8 (95% CI 1.03–7.9) – Moderate-severe: 2.6 (95% CI 1.03–6.7)
• Mild CSVD was associated with HAND – OR 4.8 (95% CI 1.1–21.2)
Soontornniyomkij et al, AIDS 2014, 28:1297–1306
HIV RNA in CSF May Increase Risk for New Onset Depression
0.1
1
10
Unadjusted Model 1 Final Model
Haz
ard
Rat
ios
for
Dep
ress
ion
CSF Plasma
Model 1: Adjusted for CSF/Plasma HIV RNA and adherence Final model: Adjusted Model 1 for lifetime MDD, lifetime alcohol and substance abuse, duration of ART, CPE, age, sex, race
* * *p < 0.01 20
5
2
Error bars are 95%
confidence intervals
Hammond et al, CROI 2014, Abstract 33
Exercise & Cognitive Rehabilitation May Improve HAND
Dufour et al, J Neurovirol 2013, DOI 10.1007/s13365-013-0184-8
Exercisers had lower odds of having global neurocognitive impairment
(OR= 0.38, p < 0.05)
Weber et al., Neuropsychol Rev 2013, DOI 10.1007 s11065-013-9225-6
Strategic imagery improved prospective memory
Summary & Conclusions • Published reports of the cognitive effects of ART
continue to have inconsistent findings – Substantial variation in methods – Few studies use ideal methods or have sufficient power to address
the questions
• Randomized clinical trial in China supports differences in two ART regimens in preventing HAND – Effect sizes are small to medium – May be due to both ineffectiveness and toxicity in the CNS
• BBB permeability may define different HAND phenotypes that may inform clinical management – Independent confirmation is needed
• Selecting the “right” ART for the CNS should consider effectiveness and toxicity outside the CNS
Please Help Us AVRC: 619-543-8080 • ACTG 5324
– Patients with HAND on suppressive ART
– Randomized to addition of placebo, dolutegravir, or dolutegravir+maraviroc
• CSF Stribild – ART naive patients will
to start ART – No HAND requirement
• CNS HCV DAA – Genotype 1 HCV – HIV- or HIV+ – No active drug use for
3 months – Will provide sofosbuvir
and ledipasvir HNRC: 619-543-5050 • California
NeuroAIDS Tissue Network – Brain bank study for
patients with more advanced disease
Other Characteristics May Influence the ART Efficacy & Safety in the CNS
Shikuma et al, Antiviral Therapy 2012, 17: 1233-42
Combined Characteristics May Alter Estimates of CNS Effectiveness
NVP-ZDV-3TC EFV-TDF-3TC
Summary • EFV-TDF-3TC was associated with greater
neurocognitive decline over 96 weeks than NVP-ZDV-3TC
• These long-term effects were offset by adverse events of other organs that were short-term and reversible but sometimes severe – Power was substantially reduced in as-treated analyses
by greater than projected NVP-ZDV-3TC discontinuations, most prominently at one site
• In a supplemental project, drug concentrations, magnetic resonance imaging, and inflammation biomarkers differed by either neurocognitive decline or treatment arm
Acknowledgements
• Melanie Crescini • Robert Heaton • Hua Jin • Florin Vaida
Beijing University • Chuan Shi • Xin Yu • Psychometrists
Study Volunteers
Ditan Hospital • Hongxin Zhao • Ning Han • Hui Zeng • Xia Liu
China CDC • Fujie Zhang • Weiwei Zhang • Yao Zhang • Weiwei Mu
Youan Hospital • Hao Wu • Hongwei Zhang
• Donald Franklin • Rachel Schrier • Katie Riggs • Yeng Wu
Univ. at Buffalo • Qing Ma
UC San Diego
Data and Safety Monitoring Board
Supplemental Project of 30 Subjects Was Performed
• 15 Neurocognitive Decliners were matched to 15 Non-Decliners for age, education, ethnicity, and baseline NC performance – Decline determined at Week 48
• 23 successfully underwent lumbar puncture – ART drug concentrations were measured in
matched blood and CSF specimens
Cases & Controls were Comparable Non-Decliners Decliners P Value
• ART Brain • Other CNTN findings • HIV DNA, Monocyte,
Maraviroc • China • A5324 • CNTN
TDF%FTC*
EFV1*
ATV/r1*
DRV/r*
RAL*
EVG/c*
DTG*
DTG*ABC%3TC*
1May be combined with ABC-3TC when HIV RNA < 100,000 copies/mL; 2In patients with HIV RNA < 100,000 copies/mL; Last updated 1 May 2014; Available at http://www.aidsinfo.nih.gov/guidelines