Understanding and Evaluating the Neuropsychological Functioning of HIV-infected Persons

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

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO

Neuropsychology of HIV for Non-Neuropsychologists

David J. Moore, Ph.D. Associate Professor, Department of Psychiatry

University of California, San Diego HIV Neurobehavioral Research Program

[email protected]

mailto:[email protected]


This training is sponsored in part by the American Psychological Association’s HIV Office for Psychology Education (HOPE) Program

funded by the Center for Mental Health Services (CMHS) of the Substance Abuse and Mental Health Services Administration (SAMHSA) under contract number HHSS280200900004C.

Views expressed do not necessarily reflect the official policies of the

Department of Health and Human Services.


Brief Outline

HIV-Associated Neurocognitive Disorders (HAND)

HIV Disease Indicators

Impact of Comorbidities

Daily Functioning

Emerging Treatments for Neurocognitive Complications

Summary & Recommendations


Meet Joe

43 y.o., African American male, one yr of college education, man who has sex with men, HIV+

Dr. Smith is treating Joe with Cognitive Behavioral Therapy (CBT) for depression

Progress in therapy has been slow

Dr. Smith, having heard that some HIV+ may have neurocognitive difficulties, wonders if this is impacting their progress

She’s observed: 1) slow processing of instructions, 2) difficulty learning new strategies, and 3) ineffective problem solving


NEUROCOGNITIVE (NC)

Primary Asymptomatic NC Impairment Mild Neurocognitive Disorder HIV-associated Dementia Secondary Infection Neoplasia Cerebrovascular Nutritional Treatment Related

EMOTIONAL & OTHER BEHAVIORAL

New Onset Depression Anxiety Adjustment Disorders HIV Mania HIV Psychosis Recurrent/Comorbid Mood Disorders Substance Use Disorders Other Mental Disorders

HIV NEUROBEHAVIORAL DISTURBANCES


HIV Associated Neurocognitive Disorders (HAND) Criteria

ASYMPTOMATIC NEUROCOGNITIVE

IMPAIRMENT (ANI)

MILD NEUROCOGNITIVE

DISORDER (MND)

HIV-ASSOCIATED

DEMENTIA (HAD)

NEUROCOGNITIVE IMPAIRMENT > Mild > Mild > Moderate

FUNCTIONAL IMPAIRMENT None > Mild > Moderate

• Impairment must be attributed to HIV, at least in part • Neurocognitive impairment required in 2 domains to receive overall

impairment

Antinori, et al., Neurology 2007, 69 (18):1789-99


COMORBID CONDITIONS

MINIMAL: may have minor effects on NP test results, but unlikely to cause even mild global impairment, e.g., hypertension

MODERATE: likely to have at least mild effects on NP results but unlikely to cause clinically significant global NP impairment by itself, e.g., current Hepatitis C infection (HCV)

SEVERE: likely to have major effects on NP test results, with significant neurocognitive impairment and functional disability, or NP results invalid due to poor effort, e.g., mental retardation, severe TBI

HAND Diagnosis Possible

Precludes HAND

Diagnosis


0%

10%

20%

30%

40%

50%

HIV- Non-AIDS AIDS

19%

29%

46%

16%

36%

43%

Perc

ent I

mpa

ired

Pre-CART CART

Despite ART Benefits on Morbidity and Mortality HAND remains prevalent

N=179 N=507 N=162 N=336 N=516 N=94

p=.03

Heaton et al, Journal of Neurovirology, 2011


Neurocognitive Impairment (NCI) by Domain in HIV+ from Pre-ART and Post-ART Eras

0%

10%

20%

30%

40%

50%

60%

70%

Verbal SIP Learn Recall Attn/WM Exec Motor

Per

cent

Impa

ired

Pre-CART Post-CART

** *** ***

* **

* p<.05; ** p<.01; ***p<.001 Heaton et al, Journal of Neurovirology, 2011


How Do HIV Disease Factors Impact HAND?


Higher nadir CD4 Lower Risk of Impairment

Ellis et al., AIDS, 2011


CHARTER: Neurocognitive Impairment Related to HIV Disease Factors only in Minimal

Comorbidity Group

NC Impaired n = 339

NC Normal n = 504

% AIDS * 64.6% 57.1%

% Nadir (lowest ever) CD4 < 200 * 59.6% 50.6%

* P < 0.05


Joe’s HIV Disease Characteristics

Current CD4: 420 cells/µL Nadir CD4: 174 cells/µL Plasma Viral Load: Undetectable Duration of HIV infection: 10 years ART on/off: On Meets Criteria for AIDS


Risk and Protective Factors for Joe’s Neurocognitive (NC) Functioning

Joe’s NC Fxn

HIV Disease Factors Con: AIDS, Nadir CD4 <200, Chronic HIV Pro: On ART, VL Undetectable


How Do Comorbidities Influence HAND?


Minimal

Moderate

Severe

N+/VL+ N=111

N-/VL+ N=210 N+/VL-

N=68 N-/VL- N=111

N+/VL+ N=60

N-/VL+ N=129

N+/VL- N=36

N-/VL- N=98

N+/VL+ N=27 N-/VL+

N=62 N+/VL- N=14

N-/VL- N=65

1.0

0.0

0.8

0.6

0.4

0.2 N+: Nadir CD4 ≥ 200 N-: Nadir CD4 < 200 VL+: Undet Plasma VL VL-: Det Plasma VL

% Impairment is Related to Disease Factors only with Minimal Comorbidity (Pts on ART)

Heaton et al., Neurology, 2010

Pro

babi

lity

of Im

pairm

ent


Rates of NP Impairment by Number of Risk Factors HIV, HCV, Meth

% G

LOB

AL

NP

Impa

irmen

t

n=80

n=186 n=99 n=35 Cherner et al., Neurology, 2005


Incident Depression Does Not NCI in HIV

0

2

4

6

8

10

12

14

16

18

20

Baseline Follow-up

Incident Depression

No Incident Depression

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Baseline Follow-up

Incident Depression

No Incident Depression

BDI T

otal

Sco

re

Glo

bal D

efic

it Sc

ore

Cysique et al., JINS, 2007


Joe’s Comorbidities

Substance Use Diagnoses: » Lifetime Hx. of Methamphetamine dependence » Lifetime Hx. of Cannabis abuse » No current substance use disorder » Last used Methamphetamine 8 years ago

Mood Disorders: » Lifetime Major Depressive Disorder (MDD) » Current MDD » Beck Depression Inventory–II Total = 19

Medical Comorbidities » Hypertension » Remote mild Traumatic Brain Injury (mTBI)



Joe’s NC Fxn

Comorbidities Con: LT Hx. Meth Dep, Past mTBI Pro: No current Sub Use dep; no HCV



Does Joe Have Neurocognitive Complaints?


Joe’s Neurocognitive Complaints

Dr. Smith asks him about his cognitive abilities

Joe has some recent cognitive complaints that are a change from his normal functioning: » Loses track of time » Forgets to do things he’s agreed to do » Has some difficulty coming up with correct words » Difficulty planning and organizing activities



Cognitive Complaints Con: Loses track of time, forgetting some things, problems planning Pro: Only four complaints where many more possible

Joe’s NC Fxn




How is Joe Performing Neurocognitively?


Example Neuropsychological (NP) Test Battery

Verbal Fluency » Animals » Letter

Attn/Working Memory » PASAT-50 » Letter-Number Sequencing

Processing Speed » WAIS-III Digit Symbol » WAIS-III Symbol Search » Trail Making Test A

Executive Functioning » WCST-64 PR » Trail Making Test B

Learning » Verbal (HVLT-R) Total » Visual (BVMT-R) Total

Recall » Verbal (HVLT-R) Recall » Visual (BVMT-R) Recall

Motor » Grooved Pegboard DH » Grooved Pegboard NDH

= 15 individual NP measures


Joe’s Objective Neurocognitive Performance

Impaired: » Learning » Executive Functioning

Within Normal Limits: » Verbal functioning » Speed of Information Processing » Recall » Motor » Attention/Working Memory

His global neuropsychological performance is mildly impaired (impairment ≥ 2 Domains)




Joe’s Mild NCI




Do Joe’s Neurocognitive Impairments Impact His Daily

Functioning?


Comorbidity Group Comparisons for Daily Functioning

Minimal 843 (54%)

Moderate 473 (31%)

Severe 239 (15%)

% Impaired 41% 59% 84% Min<Mod<Sev

% Employed 33.0% 19.7% 13.0% Min>Mod,Sev

Cognitive Symptoms 4.9 (6.3) 7.4 (8.0) 9.3 (9.0) Min<Mod<Sev

IADL Declines 1.3 (1.8) 1.9 (2.1) 2.1 (2.3) Min<Mod, Sev

Heaton et al., Neurology, 2010

Unemployment, increased cognitive symptoms, and increased Instrumental Activities of Daily Living (IADL) Declines significantly correlated with worse levels of neurocognitive impairment (p <0.01)


Methamphetamine Increases Risk of Unemployment in HIV

Blackstone et al., JAM, 2013

0

10

20

30

40

50

60

70

80

90

HIV-/MA- HIV-/MA+ HIV+/MA- HIV+/MA+

% U

nem

ploy

ed

* p < .01

n=217 N=155 n=237 n=189


Agreement between self report (SR) and performance based (PB) functional measures

0%

10%

20%

30%

40%

50%

60%

70%

80%

Agre

emen

t rat

e (%

)

Agree: No FunctionalImpairment (n=156)

Agree: FunctionalImpairment (n=20)

Disagree: Impaired bySelf-report Only (n=37)

Disagree: Impaired byPerformance-based Only(n=20)

Blackstone, et al., JINS, 2012, 18: 79-88


How is Joe doing in everyday life?

Joe is unemployed Previously worked as a manager of an

apartment complex but stopped about 6 years ago

He has some declines from his baseline (pre-HIV) with managing his medications and finances



Daily Functioning Con: Unemployed, Med and Financial mgmt problems Pro: Still maintains social relationships


Joe’s Mild NCI




What’s Joe’s HAND Diagnosis

NP: Definite mild impairment Daily functioning:

» Unemployed » Declines from baseline with managing

medications and finances » Some cognitive complaints (although have to be

careful of these in context of depression)

Diagnosis is: » Mild Neurocognitive Disorder (MND)



HAND Dx. MND

Daily Functioning Con: Unemployed, Med and Financial mgmt problems Pro: Still maintains social relationships


Joe’s Mild NCI




How Might You Screen for NP Impairment If Joe Was In Your Office?


Classification Accuracy of the HIV Dementia Scale (HDS)

Sakamoto et al., JAIDS, 2013

27%

69%

92%

57%

0%10%20%30%40%50%60%70%80%90%

100%

Raw cutpoint (≤ 10) Norms

Sensitivity

Specificity

*Overall Accuracy: Raw = 57% Norms = 63% CHARTER study, N = 1580


Brief Screening Predicts Larger NP Battery

Minutes Sensitivity Specificity

• Action Fluency • Stroop Color • PASAT • HVLT-R Learning

18 86.5 (71.1–95.0 87.1 (80.8–91.7)

• Trail Making Test A • PASAT • Grooved Pegs Nondominant

9 76.3 (60.0–88.2) 80.1 (73.5–85.9)

Moore et al., PLoS ONE, 2012

Less intensive NP assessment can provide a screen Requires some expertise; when in doubt refer


Can We Improve Joe’s HAND?


Neurocognitive Rehabilitation of Real-World Problems in HIV: A Call To Action

HAND persists despite effective ART » Non-ARV pharmacological approaches have not held up in trials

Few studies to date examined NC Rehab in HIV » Large literature in other conditions

Slide Courtesy of S.P. Woods


Neurocognitive Rehabilitation of HAND: Memory

Neurocognitive remediation rooted in models of changing specific neuropsychological deficits

Interventions often NC domain specific

Few studies using these NC rehabilitation techniques in HIV but growing interest/demand

Weber et al., 2012

Slide Courtesy of S.P. Woods


Executive Functioning Training

Executive Dysfunction (planning,

monitoring, set-shifting)

Compensatory Strategy

Application (e.g., alarm)

Antiretroviral Adherence

Impaired Metacognition

Metacognitive deficits Poorer rehabilitation outcomes and motivation and poorer vocational attainment

Antiretroviral Non-adherence

Blackstone Dissertation


Computerized Speed of Processing Training

0100200300400500600700800900

1000

Pre Training Post Training

Intervention

Control

Control Δ = 115.21 ms

Intervention Δ = 212.41 ms

All participants HIV+ Intervention group

significantly increased their speed of processing compared to control (p <.05)

Also improved their performance on a timed IADL measure

Self-reported that “games” improved their mental functioning

Vance et al., J Assoc Nurses AIDS Care, 2013


Directly Target Daily Functioning


Time from Target Dose by Group M

ean

Dos

e D

elay

(min

)

N=25 N=25 N=25 N=25

Antiretroviral Psychotropic


Exercise and NP Functioning in HIV

15.66

30.95

0

5

10

15

20

25

30

35

Exercisers Non-Exercisers

Dufour et al., JNV, 2013

% w

ith N

euro

cogn

itive

Impa

irmen

t

n=83 n=252


Text Messaging for Physical Activity

Physical Activity

Quality of life

Neurocognition

Everyday function

Inflammation

Cerebral blood flow

Neurogenesis

Neurobiological Mechanisms

Metabolic function

Outcome Measures


Joe Makes a Nice Story…

but what about others?


John 58 y.o., Caucasian male, one yr of college

education, man who has sex with men, HIV+ Current CD4: 790 cells/µL Nadir CD4: 256 cells/µL Plasma VL: Undetectable ART on/off: On Substance Use Diagnoses: Lifetime Hx. Meth

dependence, No Current Substance Use Dx. Mood Disorders: Lifetime Hx. MDD Medical Comorbidity: HCV+ Global Neurocognitive Impairment

Classification: Within normal limits Neurocognitive Impaired Domains: 0 Daily Functioning and Cognitive Complaints: 0 HAND Dx: None

58 y.o., Caucasian male, one yr of college education, man who has sex with men, HIV+

Substance Use Diagnoses: Lifetime Hx. Meth dependence, No Current Substance Use Dx.

Medical Comorbidity: HCV+ Global Neurocognitive Impairment

Classification: Within normal limits Neurocognitive Impaired Domains: 0 Daily Functioning and Cognitive Complaints: 0 HAND Dx: None


Gabe 29 y.o., Hispanic male, college graduate, man

who has sex with men, HIV+ Current CD4: 360 cells/µL Nadir CD4: 354 cells/µL Plasma VL: Detectable ART on/off: On Substance Use Diagnoses: Lifetime Hx.

Alcohol Abuse Mood Disorders: None Medical Comorbidity: None Global Neurocognitive Impairment

Classification: Mild-to-Moderate Impairment Impaired Neurocognitive Domains: Learning,

Executive Function, Attention/Working Memory

Daily Functioning and Cognitive Complaints: None

HAND Dx: ANI

29 y.o., Hispanic male, college graduate, man who has sex with men, HIV+

Current CD4: 360 cells/µL Nadir CD4: 354 cells/µL Plasma VL: Detectable ART on/off: On Substance Use Diagnoses: Lifetime Hx.

Alcohol Abuse Mood Disorders: None Medical Comorbidity: None Global Neurocognitive Impairment

Classification: Mild-to-Moderate Impairment Impaired Neurocognitive Domains: Learning,

Executive Function, Attention/Working Memory

Daily Functioning and Cognitive Complaints: None

HAND Dx: ANI


Actions to Take with

HIV+ Clients with

Possible NCI

Determine severity of disease » In cases without comorbidities nadir

CD4, off ART, detectable VL, AIDS related to increased NCI

Ask about changes in: » Cognitive Functioning

» Daily Functioning

» Recognize that cognitive complaints may be elevated in persons with MDD

Identify comorbidities

If trained, screen for HAND, if not make referral for screening


Take Away Message

Despite improved HIV survival, neurocognitive complications persist and can impact everyday functioning

Comorbidities can complicate and worsen neurocognitive problems in HIV, but HIV-related neurocognitive problems exist even in those without comorbidities

Need to find effective treatments for HAND


Acknowledgments

SAMHSA Funding Support

» NIMH » NIDA » California HIV/AIDS Research Program » Henry M. Jackson Foundation

HNRP Co-Investigators/Collaborators » J. Hampton Atkinson, M.D. » Mariana Cherner, Ph.D.* » Ronald J. Ellis, M.D. » Igor Grant, M.D. » Robert K. Heaton, Ph.D. » Scott Letendre, M.D. » Thomas Marcotte, Ph.D. » Erin Morgan, Ph.D. » Maiko Sakamoto, Ph.D. » Steven P. Woods, Psy.D.

Trainees » Kaitlin Blackstone, M.S. » Catherine Dufour » Pariya Fazeli, Ph.D. » Maria Marquine, Ph.D. » Jessica Montoya

Staff » Candy Carson » Matthew Dawson » Ben Gouaux » Alexandra Rooney

Contact Information » David J. Moore, Ph.D. » [email protected] » 619-543-5093


Your feedback is important to us. Please visit http://survey.abtassociates.com/s/APANeuropsych/

to provide an evaluation of this training.

http://survey.abtassociates.com/s/APANeuropsych/

http://survey.abtassociates.com/s/APANeuropsych/


Neuropsychology of HIV for Non-Neuropsychologists

David J. Moore, Ph.D. Associate Professor, Department of Psychiatry

University of California, San Diego HIV Neurobehavioral Research Program

[email protected]

mailto:[email protected]


Chris Age: 56 Education: 7 Sex: Male Ethnicity: Native American Current CD4: 433 Nadir CD4: 184 Plasma VL: Undetectable ART on/off: On Substance Use Diagnoses: Lifetime Alcohol

Dependence, Cannabis Dependence, Inhalant Dependence

Mood Disorders: Major Depressive Disorder, Panic Disorder with Agoraphobia, Generalized Anxiety Disorder

Global Impairment Classification: Mild-to-Moderate Impairment (6)

Impaired Domains: Learning, Working Memory

IADL Complaints: 2 HAND Dx: ANI


Raul Age: 34 Education: 15 Sex: Male Ethnicity: Hispanic Current CD4: 294 Nadir CD4: 255 Plasma VL: 0 ART on/off: On Substance Use Diagnoses: None Mood Disorders: None Global Impairment Classification: Definite

Mild Impairment (5) Impaired Domains: Learning, Memory,

Executive Function IADL Complaints: 0 PAOFI Complaints: 0 HAND Dx. ANI



• Does individualized Texting for Adherence Building (iTAB) improve med adherence and dose timing for HIV-infected persons with bipolar disorder?

David J. Moore et al. (P21)

Improve Overall Adherence? Maybe

Improve Dose Timing? YES!

Mea

n %

MEM

S Ad

here

nce

Mea

n D

ose

Del

ay

(min

.)

CTRL (n = 25) iTAB (n = 25) *

* p < 0.05


Comorbidity Group Comparisons

Minimal 843 (54%)

Moderate 473 (31%)

Severe 239 (15%)

% Impaired 41% 59% 84% Min<Mod<Sev

Depression (BDI) 12.3 (10.0) 15.7 (11.1) 16.5 (11.9) Min<Mod, Sev

Heaton et al., 2010


METH Abuse and HIV Combine to Increase Neurocognitive Impairment

0

10

20

30

40

50

60

70

80

HIV- HIV+ HIV- HIV+

Non-Meth Abusing Group Meth Abusing Group

Per

cent

Neu

roco

gniti

vely

Impa

ired

Rippeth et al., J Int Neuropsychol, Soc, 2004,10(1): 1-14


FUNCTIONAL IMPAIRMENT CRITERIA (NEED 2)

1. IADL dependence, after person became HIV+, attributed to cognitive (not physical) impairment, 2. Unable to work, or significantly reduced work efficiency, attributed to HIV related cognitive changes, 3. Complaints of increased cognitive difficulties in everyday life (cannot use this if person has clinically significant depression), 4. Impaired performance on objective everyday functioning tasks: standardized work samples or medication management (available only for CHARTER longitudinal cohort).


HIV+ with Bipolar Disorder More NP Impaired

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Speed of Info.Processing

Learning** Recall** Executivefunctions*

Verbal Fluency Attn/WorkingMemory

Motor Global DeficitScore**

NP

Def

icit

Scor

es

HIV+/BD+ HIV+/BD-

*p<0.05; **p<0.01

Impairment

Moore et al., in prep


General Association of NC Impairment with Everyday Functioning in CHARTER

p-value

Unemployment .005 IADL Dependence .0002 Cognitive Complaints <.0001

Understanding and Evaluating the Neuropsychological Functioning of HIV-infected Persons

Health & Medicine

neuropsychology of hiv

brief outline hiv

current research

neurocognitive difficulties

mild glo

department of health

overall impairment antinori

mental health services