Neuropsychological Outcomes in PLWHA Initiating HAART: Thoughts from the

EpicentreColumbia University, HIV Center, Grand Rounds

03 March 2011

John A. JoskaDirector, GSH-HIV Mental Health GroupDepartment of Psychiatry and Mental HealthUniversity of Cape Town

Summary of talk

• HIV is highly prevalent in South Africa• HAND is documented to be highly prevalent in

HIV• Both *epidemics* may be different in SA• The effects of HAART may be different• In what ways can we

– Understand HAND better– Improve screening for HAND / raise awareness– Provide support to *many* PLWHA with HAND

HIV/AIDS South Africa Progress Report 2010• “ HIV in South Africa is transmitted predominantly heterosexually

between couples, with mother-to-child transmission being the other main infection route. Drivers of the epidemic in South Africa are intergenerational sex, multiple concurrent partners, low condom use, excessive use of alcohol and low rates of male circumcision.” Dr Aaron Motsoaledi, Minister of Health, South Africa

Antenatal data 2008

Prevalence of HIV-Associated Neurocognitive Disorders (HAND) by Stage of HIV Disease

15.1%

26.5%

4.8%

0.5%

25.4%

18.3%

1.9%

17.7%

28.3%

1.8%

0%

10%

20%

30%

40%

50%

60%

% withDisorder

HIV- CDC A CDC B CDC C

ANI MND HAD

(n=212) (n=437) (n=213) (n=113)

The problem of HIV-D

• HIV seroprevalence in SA adults 18%• >20 000 in Wcape entering stage 4 per year• 50% will get HAART

• >25% of ALL will have diagnosable HAND• 5-10% will be HIV-D• Untreated HIV-D: mean time to death 6/12• Treated HIV-D: mean time to death 44/12• HAND exerts many other deleterious effects

Although HAART improves health and prolongs survival, NeuroAIDS remains prevalent

Adherence to Antiretrovirals Related to Neurocognitive Impairment

0

20

40

60

80

100

NP Unimpaired NP Impaired0

20

40

60

80

100

NP Unimpaired NP Impaired

% That Followed Schedule “Most of the Time”

% That Followed Specific InstructionsRe Meds “Most of the Time”

Slide courtesy of Igor Grant

Differences between global HIV and SA

• Prevalence: 10.5%... 18%... 29%...• Mode of transmission (recombinants?)• Gender (70:30)• Poverty, malnutrition

• Viral factors: clade (B vs C)

A B C D F G 01 02 06 07/08 11 12 19 33

Subtypes/CRF

Thomson et al. 2009

Global distribution of HIV subtypes

Viral factors: Clade C

• Clade C may differ from B in terms of :– Protein binding sites, binding characteristics, replicative capacity– Functional relevance:

• The mutation associated with reduced monocyte chemokine migration

• CNS relevance:– Tat is involved in the migration of monocytes into the brain via

upregulation of inflammatory cytokines and adhesion molecules.– Tat also disrupts the tight-junctions in the BBB– Tat may exert direct or indirect neurotoxic effects on glia/neurons

– Possibly in neurotoxicity and risk for cognitive impairment

HI Viral Genome: Cape Town: South Africa: Viral Sequencing in 65 PLWH Attending

Primary Care Facilities

gag pol Tat 1 vif_vpr Tat 2 Rev Subtype

C 49 33 44 41 36 49

A 4 1 1 0 1 1

B 0 1 0 1 0 0

Other 0 1 0 1 0 0

Recombinant 0 0 0 0 0 8

Joska, Engelbrecht- unpublished data

Questions: A Pilot Study of HAND in Cape Town, South Africa

• How prevalent is HAND in clade C• What are the demographic and clinical

associations• Does apolipoprotein E confer vulnerability• Is it possible to screen for HIV-D using an

existing brief tool• How do PLWH respond to HAART

Updated Nosology for HAND: American Academy / HNRC (Antinori et al 2007)

Normal Asymptomatic Neuropsychological Impairment (ANI)

Mild Neurocognitive Disorder

HIV-Associated Dementia (HIV-D)

Neuropsychology*

No worse than 1.0 SD on one domain

≥ 1.0 SD below mean on ≥ 2 domains

≥ 1.0 SD below mean on ≥ 2 domains

≥ 2.0 SD below mean on ≥ 2 domains

Function No impairment on self-report of knowledgable others

No impairment on self-report or from knowledgeable others

*Mild*impairment on self-report or from knowledgeable others

*Marked*impairment on self-report or from knowledgeable others

Exclusion No other condition, esp delirium, MDD or substances

No other condition, esp delirium, MDD or substances

No other condition, esp delirium, MDD or substances

No other condition, esp delirium, MDD or substances “MDD+HIV-D= HIV-D”

*Must sample: verbal/language; attention/working memory; abstraction/executive;memory (learning; recall); speed of information processing; sensory-perceptual, motor skills

Issues: Neuropsychology

• Norms– Age, education, gender, and ethnicity– May affect rates of impairment by up to 50%– CT studies: 50-100 controls… norms

• Test administration– Language of testing– Competency of tester– Approx 30 of first participants tested in… English

• Domains– IHDS= memory and motor– 2 tests across at least 3 domains desirable

Language of Testing: Tests Used to Quantify HAND

Issues: Functional Assessment• Should be assessed using either/and

– Self-report– Report of “knowledgable” person– Objective measure

• Functional data should be obtained using “standardized instruments” and ideally with “norms”

• Needs to measure cognitive abilities and iADLs– Meds, finances, shopping, cooking, housekeeping, driving,

working• We used PAOFI and CT ADL

– Pts under-rate impairment; most unemployed; most have limited access to “instruments”; “knowledgeable others” not readily available.

Meaning of NP Impairment: Employment

7.9%

17.5%

0

2

4

6

8

10

12

14

16

18

20

NP Normal (N=152) NP Impaired (N=80)

% U

NE

MP

LO

YE

D

Domain Self-report Collateral report Objective assessment

Memory Cell-phone number, shopping list

Communication Listening to cell-phone instructions

Use of hands/fingers

Dialling a number

Financial/money Making change from a taxi

Towards a Valid Brief Functional Assessment Tool for South Africa (or the

developing world?)

Issues: Exclusion

• HIV-related OI’s and tumours• Developmental e.g. ADHD/ ID• Neuropsychiatric e.g. depression and substance

– Wait a month; although if HIV-D present= HIV-D• Unrelated neurological e.g. epilepsy, TBI

• What to do: MINI / scales, self-report, neuromedical examination, ?which special investigations- Hep C*, RPR*, CTB*, LP*, nutritional parameters– Resources, based on level of suspicion.

Approach: Cape Town

*Neuropsychological Assessment*

Neuropsychiatric Assessment

Functional Assessment

PAOFI / CTADL / QLESQ

NeurologicalMINI / AUDIT / CES-

D / SAMISS

Domains: Attention/Concentration, Memory (verbal and visual),

Psychomotor/ speed of processing, Executive, Language, Intelligence

Clinical staging of neurocognitive status: Marder et al 2008

MSK stageNEAD

modificationFeatures

New AAN criterion

Grooved pegboard (non-dom)

IHDS score

IHDS category

Stage 0 (normal) NP normal Normal N/A 0.35 (0.5) 11,120. No

impairment

             

Stage 0.5 (sub-clinical)

NP normal with CNS/ADL problem OR NP=1 with no

CNS/ADL

Mild features, no impairment

Asymptomatic neuropsycholgical impairment (ANI)

-1.1 (1.2) 100. No

impairment

             

Stage 1 (mild HIV-D)

NP=1 with CNS/ADL problems OR NP=2 with no CNS/ADL

problems

Clear NP problem, mild ADL problem,

walking

Mild neurocognitive disorder (MND) -2.2 (2.8) 9 1. Mild NCD

             

Stage 2 (moderate HIV-D)

NP=2 with CNS/ADL problems, but not

severe

Basic ADLs fine, others impaired, walking

perhaps cane

HIV-associated dementia (HAD or

HIV-D)-3.8 (3.1) 8

2. HIV-D (moderate)

             

Stage 3 (severe HIV-D)

NP=2 or 3 and moderate to severe problems CNS/ADL

Severe cognitive OR psychomotor

problems, walks with assistance

HIV-associated dementia (HAD or

HIV-D)-18.1 6,7

2. HIV-D (severe)

             

Stage 4 (v severe/end stage

HIV-D)

Unable to test, unable to walk

Nearly vegetative,

paretic, incontinent

HIV-associated dementia (HAD or

HIV-D)  <6

2. HIV-D (severe)

Test Performance HIV+ vs HIV- : Tests included in analyses

 HIV negative controls

(n=93)HIV positive participants

(n=96) P value

Age 25.16 (5.15) 29.75 (3.67) 0.000

Education 10.88 (1.28) 10.05 (1.77) 0.000

Gender female (%) 58 (62.4) 76 (79.2) 0.790

CD4 cell count 218.09 (150.57)

Years since diagnosis 3.35 (2.04)

Screener

IHDS total 10.89 (1.10) 10.29 (1.55) 0.005

IHDS FT subscore 3.88 (0.36) 3.52 (0.79) 0.000

IHDS hand sequence subscore 3.21 (0.88) 3.22 (0.92) 0.937

IHDS 4-word recall 3.78 (0.59) 3.35 (0.91) 0.000

Motor FT non-dom 6.77 (1.71) 8.87 (2.08) 0.000

GP non-dom 78.36 (12.54) 87.05 (25.46) 0.004

Memory HVLT recall 8.07 (2.07) 7.03 (2.09) 0.001

BVMT recall 8.97 (2.92) 6.52 (3.50) 0.000

Attention MAT 16.47 (6.43) 16.76 (5.20) 0.747

Mental control 23.67 (5.93) 19.48 (5.62) 0.000

Psychomotor processingDigit symbol 46.83 (14.62) 40.72 (13.18) 0.003

TMTA 40.18 (16.31) 60.56 (32.41) 0.000

Colour I 54.66 (21.10) 53.21 (16.93) 0.605

Executive

Colour II 115.48 (50.98) 122.27 (48.47) 0.350

RCF copy 32.82 (3.87) 29.26 (6.34) 0.000

Stroop C/W 33.66 (9.57) 27.91 (9.24) 0.000

WCST per errors 31.92 (19.68) 45.34 (25.41) 0.000

Language animal 15.80 (4.64) 13.27 (4.67) 0.000

fruit & veg 15.11 (3.61) 13.70 (4.07) 0.013

HIV-associated neurocognitive disorders in primary care, Cape Town

Neurocognitive disorder category (n=170) (%)

  Normal ANI MND HIV-D statistical value

No (%) 40 (23.5) 15 (8.8) 72 (42.4) 43 (25.3)

Demographics          

Women, no (%) 33 (82.5) 11 (73.3) 53 (73.6) 29 (69.1) Fisher's exact= 0.551

Left handed, No (%) 35 (87.5) 14 (93.3) 66 (91.7) 39 (90.7) Fisher’s exact= 0.903

Language isiXhosa, no (%) 34 (85) 14 (93.3) 63 (87.5) 40 (93) Fisher’s exact= 0.203

Age, median (IQR) 30.5 (27.5-32) 28 (25-31) 28.5 (26-32) 31 (28-33) chi-sq=8.420, p=0.038

Education, median (IQR) 11 (11-12) 9 (9-11) 10 (9-11) 10 (8-11) chi-sq=18.215, p=0.0003

Medical          

CD4, median (IQR) 172 (126-190) 205 (148-235)174.5 (116.5-

236.5)139 (97-182) chi sq=7.76, p=0.0512

Peripheral neuropathy, no

(%)37 (64.86) 15 (26.67) 69 (60.87) 39 (61.54) Fisher’s exact= 0.072

AUDIT 0 (0) 1 (0) 2 (0) 3 (0) chi sq=0.925, p=0.815

CES-D 0 (0) 1 (0) 2 (0) 3 (0) chi sq=1.000, p=0.815

Joska et al, Aids and Behaviour Epub

Newborns from the same community have higher frequency of E2,2

Joska et al, J. Neurovirol 2010

Apoliprotein E4 is not associated with the development of HIV-D in South Africa

Characteristics of Participants: Retained vs Non-retained

Individual Neuropsychological Tests all NS except: CT1, Stroop, Animals

Non-HAART: 15 high CD4, 6 erratic attenders, 1 used HAART for 1/12

Characteristics of Retained group: HAART vs non-HAART

Characteristics of Retained group: HAART vs non-HAART cont.

HAART initiators improved *more*

Predictors of NP Change

Patterns of HIV-D in HAART era

McArthur 2004

Explaining NP Improvement• Whole group (HAART and non-HAART)• Non-HAART group small• Practice/ test-experience effect

– Language of testing– Experienced technicians (IRR?)

• HAART does not appear to produce deterioration in our population

• LTFU’s remove the ?non-improvers (ITT analysis)• HAART: suppresses peripheral VL, reduces HIV entry into

CNS, reduces frank inflammatory processes in a severely immuno-compromised group (?but not micro-inflammation)

Towards a model of Neurocognitive Outcomes

Neuro-psychological Impairment

Age

Duration of Infection

Testing methodology

Comorbidity: depression

Pre-morbidity: ETOH, Meth, TBI

Education IntelligenceGenes: APOE, MCP-1, et al

Inflammatory response

HIV sub-type / viral factors

HAART:CPE/ Metabolic/

Neurotoxic effects

Age-related decline:Metabolic/ vascular/

SDAT

Screening for neurocognitive disorders: The IHDS

Cut-off score <10: Sensitivity 80%, Specificity 55%

Sacktor et al 2005

Performance of the IHDS in Cape Town

Cut-off points of the IHDS: is 11 better than 10?

Joska et al, Aids Patient Care and STDs 2011

Conclusions

• HAART appears to result in significant NP improvement in PLWH infected with predominantly clade C HIV.

• Technical problems with study potential cloud findings

• Future study:– Matching group with similar disease characteristics– Careful immunological profiling at visits– NP technical issues/ testing environment/ norms– Imaging (MRS) plus …CSF

Thank you!

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