Disclosures No conflicts of interests · 2018. 8. 1. · Cuba, Spanish speaking Central and South America countries, and other Spanish cultures. » Origin can be considered as the

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HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO

Neurocognitive Impairment in HIV-infected Hispanics/Latinos: Risk and Mechanisms

María J. Marquine, Ph.D. Assistant Professor

Department of Psychiatry University of California San Diego

February 17th, 2018


Disclosures

! No conflicts of interests


Objectives

!  Gain a deeper understanding of rates and pattern of neurocognitive impairment among diverse groups of HIV-infected Hispanics.

!  Identify sociocultural and biomedical factors underlying ethnic disparities in HIV-associated NCI.

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Outline

!  Hispanics in the United States !  Basics of HIV/AIDS !  HIV-associated Neurocognitive Impairment !  Hispanics and HIV !  HIV-associated Neurocognitive Impairment among

Hispanics !  Summary !  Implications for Neuropsychological Research among

Hispanics


Hispanics in the U.S.


Understanding the terms Hispanic, Latino/a, Latinx

!  Hispanic is a person who traces his/her roots to Spanish-speaking nations from Latin America and Spain itself (but not Portuguese-speaking Brazil).

!  Latino/a is a person from Latin America (includes Brazil).

!  Latinx is a gender neutral word for persons of Latin American descent (related term: Latin@)

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Who is Hispanic or Latino/a?

Hispanic

Latino/a


Who is Hispanic or Latino in the U.S.?

!  Who is Hispanic/Latino according to the U.S. Office of Management and Budget? »  Persons who trace their origin or descent to Mexico, Puerto Rico,

Cuba, Spanish speaking Central and South America countries, and other Spanish cultures.

»  Origin can be considered as the heritage, nationality group, lineage, or country of birth of the person or the person's parents or ancestors before their arrival in the U.S.

»  People who identify their origin as Hispanic or Latino may be of any race.


Hispanics in the U.S. by the Numbers

!  57.5 million Hispanics in the U.S., largest ethnic/racial minority group (17.8% of the population)

!  Hispanics by country of origin/descent »  63% Mexican; 9% Puerto Rican; 4% Cuban

!  States with largest numbers of Hispanics: »  California (15.3 million), Texas (10.9 million), Florida (5.1 million) »  Other states with over 1 million: New York, Illinois, Colorado, New

Jersey, New Mexico, Arizona

!  Language use: »  72% of Hispanics (age 5 and older) speak Spanish at home (58% of

those also speak English very well)

!  Place of Birth »  34% of Hispanics are foreign born

U.S. Census Bureau (2017)

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Basics of HIV/AIDS


HIV/AIDS: Basic Definitions

!  HIV = Human Immunodeficiency Virus »  Retrovirus that destroys white blood cells (i.e., CD4 cells)

!  AIDS = Acquired Immune Deficiency Syndrome »  Decline in CD4 cell count (<200) and/or opportunistic infection

!  Viral loads = HIV RNA »  measure of viral replication in plasma and/or cerebrospinal fluid

!  ARV = antiretroviral »  A medication that is designed to treat a retrovirus

!  HAART = Highly Active Antiretroviral Therapy »  A combination of multiple drugs that work via different mechanisms

•  Now referred to as combination antiretroviral therapy (CART)


Annual Rates of Death among Persons 25−44 Years in the US (1987−2010)

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Adults Living with AIDS in the US

HIV Surveillance Report (2016). CDC.


HIV/AIDS Today

!  The development of HAART for HIV infection is one of modern medicine’s most dramatic success stories.

!  HIV/AIDS continues to be prevalent and has been transformed into a chronic disease.


HIV-Associated Neurocognitive Impairment (NCI)

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HIV-Associated Neurocognitive Disorders (HAND) Criteria

Asymptomatic Neurocognitive

Impairment (ANI)

Mild Neurocognitive Disorder (MND)

HIV-Associated Dementia (HAD)

NCI Mild Mild ≥ Moderate Functional Impairment

None Mild ≥ Moderate

•  NCI must be attributed to HIV (at least in part)

•  Neurocognitive impairment required in 2 domains in at least 2 tests (DSM-V criteria for neurocognitive disorders – 1 domain required)

Antinori, et al (2007). Neurology.


70%

25%

5%

Asymptomaptic Neurocognitive Impairment

Mild Neurocognitive Disorder

HIV-associated Dementia

HIV-Associated Neurocognitive Disorders (HAND)

Antinori, et al (2007). Neurology.


Pattern of HIV-Associated NCI

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 (2011). Journal of NeuroVirology

•  NCI is observed in approximately half of HIV+ persons

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Hispanics and HIV


Adults/Adolescents Living with Diagnosed HIV Infection by Race/Ethnicity (2015—United States)

1017.8

379.4

160.3 150.9 122.6 74.8

0

200

400

600

800

1000

1200

Black Hispanic Pacific Islander

White American Indian

Asian

Rat

e pe

r 100

,000

HIV Surveillance Report (2016). CDC.


HIV Disease Worse among Hispanics

!  Hispanics tend to present with reduced healthcare use and access, and higher HIV disease burden.

»  HIV+ Hispanics less access to care1.

»  HIV+ Hispanics are at greater risk for delayed care and diagnosis than Whites2, 3.

»  HIV+ Hispanics lower CD4 counts, higher plasma viral loads, more opportunistic infections4.

»  Differences among subgroups of Latinos by country/region of birth5.

1 Shapiro et al. (1999) JAMA; 3Dennis et al (2011) CID; 3 Chen et al. (2012) J Immigrant and Minority Health; 4 Swindells et al (2002) AIDS; 5 Sheehan et al (2015) Int J STD AIDS.

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HIV-Associated Neurocognitive Impairment (NCI) among

Hispanics



NCI in HIV+ Puerto Rican Women

!  Participants: 49 HIV+ women living in Puerto Rico with nadir CD4 counts <500 cells/mm3

(Age M=36.7, SD=6.3; Educ M=12.0, SD=2.0)

!  Neurocognitive Battery

!  Reference group: 34 HIV-uninfected women matched on age, education & SES

!  NCI < 1 SD from based on reference group Wojna et al. (2006). Journal of NeuroVirology

Cognitive Domain Test

Psychomotor Speed Digit Symbol Modality Test

Verbal Memory Rey Auditory Verbal Learning Test

Frontal Executive Stroop; Trail Making Test B

Motor Speed Trail Making Test A

Visuoconstruction Cube

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22.4

32.7

16.3

28.6

0

5

10

15

20

25

30

35

NP Normal ANI MCMD HAD

Perc

ent

Note. 77.6% NCI ; ANI = asymptomatic neurocognitive impairment; MCMD = minor cognitive motor disturbances; HAD = HIV associated dementia NCI not significantly associated with age, education, CD4 cell count, plasma RNA, mode of transmission nor treatment modality.

Wojna et al. (2006). Journal of NeuroVirology



Deficits across domains; most prominent in verbal memory and psychomotor speed.

Wojna et al. (2006). Journal of NeuroVirology


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NCI in HIV+ (Caribbean) English-Speaking Hispanics

!  Participants: »  HIV+ from Manhattan HIV Brain Bank (advanced stage of disease) »  51 (Caribbean) English-Speaking Hispanics and 49 non-Hispanic Whites »  Age: M=44.5, SD=7.4; Education=12.9, SD=2.4; 78% men


Rivera-Mindt et al. (2008). Cultur Divers Ethnic Minor Psychol

Cognitive domain Tests

Verbal Functioning FAS

Speed of Information Processing

WAIS-III Digit Symbol, WAIS-III Symbol Search, TMT-A

Learning HVLT & BVMT Total Correct

Delayed Recall HVLT & BVMT Delayed Recall

Attention/Working Memory WAIS-III Letter-Number; PASAT

Abstraction/Executive Function

WCST – 64, TMT-B

Motor Grooved Pegboard


NCI in HIV+ (Caribbean) English-Speaking Hispanics

!  Results »  Among HIV+ Hispanics: 70% impaired (TS<40)

•  28% mild, 36% mild to moderate, 31% moderate, 6% severe

Variable Global TS Β (p)

Learning TS Β (p)

Att/WM TS Β (p)

Abstraction/EF TS Β (p)

Ethnicity -.12 (.30) -.06 (.59) -.11 (.34) -.33 (.01) SES -.18 (.11) -.06 (.54) -.08 (.47) -.21 (.08) WRAT-3 .43 (<.001) .49 (<.001) .43 (<.001) .15 (.18) CD4 count .08 (.41) .08 (.38) .05 (.58) .03 (.78)

Predictors of NP performance in HIV+

Rivera-Mindt et al. (2008). Cultur Divers Ethnic Minor Psychol


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HIV/aging: NCI in HIV+ (Caribbean) English-Speaking Hispanics

!  Participants »  HIV+ from NYC »  84 Hispanic and 42 non-Hispanic »  Exclusion criteria: Notable psychiatric or medical comorbidity



Verbal Functioning FAS; Animal Fluency


WCST – 64, TMT-B, Iowa Gambling Task







Rivera-Mindt et al. (2014). Behavioral Medicine


42.93

46.83

41.48 40.49

30 32 34 36 38 40 42 44 46 48 50

Younger Older

Glo

bal N

euro

cogn

ition

(TS)

NH White Hispanic


*

n=20 n=62 n=22 n=22


*p=.054



0

0.2

0.4

0.6

0.8

1

1.2

1.4

Verbal Fluency

Processing Speed

Learning Memory Working Memory

Executive Fx

Motor

Coh

en’s

d E

ffect

Siz

e

Younger Older

*p<.05

Within older group: No significant association with acculturation or HIV disease characteristics

*

* (*)


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NCI in HIV+ English-speaking Hispanics in the US

!  Participants »  HIV+ from CHARTER study (academic medical centers across U.S.) »  194 English-Speaking Hispanics; 600 NH Whites



Verbal Functioning FAS; Animal Fluency







WCST – 64, TMT-B


Marquine et al (2017). JINS


Study Cohort by Ethnic Group Variable Whites (n=600) Hispanics (n=194)

Demographics

Age, M(SD) 43.07 (9.14) 41.33 (8.14)

Education, M(SD)*** 13.39 (2.69) 12.50 (2.77)

Gender (% Male)** 87.83% 78.35%

Major Genetic Ancestry (%)a ***

Europe 100% 64.57%

Africa 0% 11.81%

American Indian 0% 3.94%

East Asian 0% 0.79%

No Single Major Ancestry 0% 18.90%

a Major genetic ancestry = genetic ancestry proportion of ≥.5 for a given region (Africa, Europe, America, East Asia, Central Asia, and Oceania), all frequencies <.5 = “no single major ancestry”; Whites: n=419; Latinos: n=127 *p<.05; **p<.01; ***p<.001

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HIV Disease Characteristics by Ethnic Group

Variable! Whites (n=600)! Hispanics (n=194)!

% AIDS*! 51.84%! 60.53%! Estimated duration of infection (years), M(SD)!

9.44 (6.72)! 9.99 (6.57)!

Current CD4, Median (IQR)**! 471 (315, 647)! 402 (258, 585)! Nadir CD4, Median (IQR)*! 192 (60, 317)! 150 (40, 281)! On ART! 69.28%! 76.09%! % detectable plasma **! 39.15%! 53.62%! % detectable CSF *! 9.12%! 18.02%! Months exposure to ART, Median (IQR)! 48.59 (6.67, 96.98)! 59.33 (8.53, 97.05)!

*p<.05; **p<.01; ***p<.001



Comorbidities by Ethnic Group Variable! Whites (n=600)! Hispanics (n=194)!

VACS Index, Median (IQR)! 15 (7, 24)! 16 (10, 27)!Comorbidity Status (%)! ! ! Incidental! 61.27%! 52.63%! Contributing! 26.21%! 32.11%! Confounding! 12.52%! 15.26%!Psychiatric Characteristics! ! ! Beck Depression Inventory, M(SD)! 14.93 (11.19)! 14.10 (9.88)! Current Major Depressive Disorder! 16.78%! 16.23%! Lifetime Major Depressive Disorder *! 59.30%! 50.79%! Current Any Substance Use Disorder! 4.19%! 3.66%! Lifetime Any Substance Use Disorder! 72.53%! 67.02%! Intravenous drug use ever! 26.67%! 25.26%! Urine toxicology positive 12.75% 16.67%


NCI by Ethnic Group

42

21

40

23

44 40

26

32

54

24

51

30

54 49

40

31

0

10

20

30

40

50

60

Global Verbal Fluency

Executive Dysfunction


Learning Recall Working Memory

Fine Motor Skills

Neu

roco

gniti

ve Im

pairm

ent (

%)

NH White (n=600) Hispanic (n=194) ** **

*

* *

**


•  Ethnic differences in NCI (global and most domains) remained significant after adjusting for significant covariates (HIV disease characteristics and comorbidities).

•  Nadir CD4 was the only significant partial mediator of differences in global NCI.

*p<.01; **p<.001

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Predictors of NCI by Ethnic Group

!  Hispanics »  Lower nadir CD4 »  On ART * »  Comorbidity status *

!  NH Whites »  AIDS »  Lower nadir CD4 »  More months on ART »  Comorbidity status * »  Depressed mood



Characteristics of Hispanics by Country of Origin/Descent

Mexican (n=79)

Puerto Rican (n=60)

Demographics

Age, M(SD) ** 40.15 (8.48) 43.87 (6.95)

Education, M(SD) 12.27 (2.55) 11.98 (2.68)

Gender (% Male) *** 87.34% 61.67%

Major Genetic Ancestry (%) *

Europe 66.13% 69.70%

Africa 3.23% 18.18%

American Indian 4.84% 0%

East Asian 1.61% 0%

No Single Major Ancestry 24.19% 12.12%

*p<.05; **p<.01; ***p<.001



HIV Disease Characteristics by Hispanic Subgroup

HIV Disease Characteristics! Mexican (n=79)!

Puerto Rican (n=60)!

AIDS, n (%)! 47 (59)! 38 (63)! Estimated duration of infection (years), M(SD) ***!

8.56 (6.53)! 12.57 (4.99)!

Current CD4, Median (IQR)! 416 (274, 588)! 394 (254, 506)! Nadir CD4, Median (IQR)! 171 (47, 279)! 145 (25, 258)! On ART! 55 (71)! 48 (84)! n (%) detectable plasma! 26 (48)! 26 (54)! n (%) detectable CSF* 6 (12) 11 (34)

*p<.05; **p<.01; ***p<.001


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Comorbidities by Hispanic Subgroup Mexican (n=79)

Puerto Rican (n=60)

VACS Index, Median (IQR)** 13 (7, 22) 22 (12, 37)

Comorbidity Status (%)**

Incidental 60.76 36.67

Contributing 31.65 40.00

Confounding 7.59 23.33

Psychiatric Characteristics

Beck Depression Inventory, M(SD) 14.00 (9.62) 13.93 (9.45)

Current Major Depressive Disorder 16.67% 16.95%

Lifetime Major Depressive Disorder 53.85% 49.15%

Current Any Substance Use Disorder 6.41% 3.39%

Lifetime Any Substance Use Disorder 72.15% 64.41%

Intravenous drug use ever 31.65% 18.33%

Urine toxicology positive** 6.58% 27.12%


NCI by Hispanic Subgroup

0

10

20

30

40

50

60

70

80

Global Cognition

Verbal Fluency

Executive Function

Speed of Information

Learning Memory Working Memory

Fine Motor Skills

Neu

roco

gniti

ve Im

pairm

ent (

%)

Mexican (n=79) Puerto Rican (n=60)

** ** *

•  Differences in domain and global NCI remained significant after adjusting for significant covariates.

•  Comorbidity status was the only significant partial mediator of differences associated with country of origin. Marquine et al (2017). JINS


Predictors of NCI by Hispanic Subgroup

!  Mexican origin/descent »  Lower nadir CD4 * »  Comorbidity status *

!  Puerto Rican origin/descent »  On ART * »  Comorbidity status *


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Characteristics of Hispanics by Country of Origin/Descent

Study Site, n (%) ***

Mexican (n=79)

Puerto Rican (n=60)

New York (NY) 2 (3) 47 (78)

San Diego (CA) 36 (46) 5 (8)

Galveston (TX) 26 (33) 1 (2)

Seattle (WA) 10 (13) 3 (5)

St Louis (MO) 4 (5) 2 (3)

Baltimore (MD) 1 (1) 2 (3)



NCI By Hispanic Subgroup and Site

33

54 47

79

0 10 20 30 40 50 60 70 80 90

San Diego New York

Perc

ent G

loba

l NC

I

Study Site

NH White Hispanic

Mex

ican

Pue

rto R

ican

Logistic regression on global NCI showed: •  Significant main effects of Hispanic ethnicity (OR = 2.31, p<.001) and NY

site (OR = 2.83, p<.001), and no significant interaction (p=.35).


Global HIV-Associated NCI: Ethnicity and Genetic Ancestry

!  Analyses in overall sample »  Main effect of ethnicity and no significant effect of major genetic

ancestry on global NCI

!  Within Hispanics »  Main effect of country of origin and major genetic ancestry on

global NCI •  No Major ancestry > European > African/East Asian

!  Stratified analyses by ethnicity and Hispanic subgroup showed no significant effect of proportion of genetic ancestry (European, African or American Indian) in any of the groups.


17



Longitudinal Neurocognitive Change in HIV

0%

10%

20%

30%

40%

50%

60%

70%

Decline (n=99) Stable (n=265) Improve (n=72)

23%

61%

17%

50Heaton et al. (2015). CID.

•  Predictors of neurocognitive decline: non-HIV comorbidity, being off ART, lifetime methamphetamine use diagnosis, Hispanic ethnicity

•  Predictors of neurocognitive improvement: No lifetime Major Depressive Disorder, higher premorbid cognitive functioning


In a model adjusting for characteristics that differed significantly between groups: Hispanic - NH White: OR=2.8, CI=1.4-5.6, p<.001 Hispanic - NH Black: OR=3.2, CI=1.6-6.3, p<.001

Neurocognitive Decline by Ethnic/Racial Group

*p<.05

19 20

40

0 5

10 15 20 25 30 35 40 45

Perc

ent N

euro

cogn

itive

D

eclin

e

Ethnic/racial group

NH White (n=185) NH Black (n=184) Hispanic (n=57)

Marquine et al (In preparation)

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Baseline Predictors of Subsequent Neurocognitive Decline by Ethnic/Racial Group

NH White (n=185)

NH Black (n=184)

Hispanic (n=57)

Comorbidity status X X Current Major Depression X Detectable plasma RNA X Baseline Neurocognitive Impairment

X

Marquine et al (In preparation)



The Veterans Aging Cohort Study (VACS) Index and NCI

34.3 35.4

57.3

0 10 20 30 40 50 60 70

Low Mid High

Perc

ent w

ith N

CI

VACS Index

The VACS Index combines1-4: •  Age •  Traditional HIV biomarkers (current

CD4 count and HIV-1 plasma RNA) •  Non-HIV biomarkers (renal and liver

function, anemia and hepatitis C)

Marquine et al (2014). JAIDS. Marquine et al (2016). CID

1Justice (2010). Curr HIV/AIDS; 2Justice et al. (2012). CID; 3Tate et al. (2013). AIDS; 4Justice et al. (2013). JAIDS.

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pred

icte

d Pr

opor

tion

of

Par

ticip

ants

with

out N

CI

VACSLower 25%Middle 50%Upper 25%

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Changes in VACS Index and Neurocognitive T Scores Over Time

Time (years)

●

●

●

●

●

●

●

●

●

●●

●●

0 1 2 3 4 5 6

4344454647484950

35

30

25

20

15

Mea

n T−

scor

e

Mea

n VA

CS

●VACS T−score

Bette

r

Bette

r

Wor

se

Wor

se


VACS Index and NCI by Ethnic/Racial Group

Marquine et al (2015). Journal of NeuroVirology


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Summary

!  There appears to be an effect of Hispanic ethnicity on NCI among HIV+ persons »  Most of the work has been done in English-speaking Hispanics »  Hispanic effect might be more notable among subgroups of

Hispanics (older age, Caribbean descent)

!  The pattern of HIV-associated NCI among Hispanics is similar to that of non-Hispanic Whites »  The pattern of NCI among subgroups of Hispanics might differ


Summary

!  Key factors underlying these ethnic disparities in HIV-associated NCI »  Socio-demographic »  Nadir CD4 »  Others?

!  Key predictors of NCI among HIV+ Hispanics »  Nadir CD4 »  Comorbidities


Implications for Neuropsychology Research among Hispanics

!  When investigating the impact of a disease on NCI among Hispanics, consider potential “pre-existing” ethnic differences.

!  Develop studies from the perspective of Hispanics. »  While some factors might be relevant across ethnic groups, do not assume

that factors that have “consistently” been associated with NCI among other ethnic/racial groups will play similar role among Hispanics

!  Be critical about the meaning of certain well-established predictors of NCI among Hispanics, i.e. years of education, “premorbid” estimates.

!  Consider differences among subgroups of Hispanics that might impact NCI and its predictors

!  Clearly characterize Hispanics (e.g., country of origin/descent, country of birth, years in the US, SES, etc).

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Acknowledgements

!  INS CE Committee

!  Study Volunteers and Staff !  Research Collaborators !  Robert Heaton, PhD !  Mariana Cherner, PhD

!  K23 MH105297 !  R25 MH080663 !  CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER)

»  N01 MH22005, HHSN271201000036C, HHSN271201000030C !  HNRP Group

»  P30MH062512, U24MH100928, U01MH083506, R24MH59745, P01DA12065,


Thank you for your attention

María J. Marquine, PhD [email protected]

Documents

Disclosures No conflicts of interests · 2018. 8. 1. · Cuba, Spanish speaking Central and South America countries, and other Spanish cultures. » Origin can be considered as the