NeuroAIDS in Pune - UNC School of Medicine NEUROBEHAVIORAL RESEARCH CENTER NeuroAIDS in Pune ... HIV NEUROBEHAVIORAL RESEARCH CENTER Pune, ... Chennai C Letendre/Kumarasamy/Bharti

HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER

NeuroAIDS in Pune

Thomas D. Marcotte, PhD

HIV Neurobehavioral Research CenterUniversity of California, San Diego

San Diego, CA USA


HIV in India 2.5 - 5 million HIV-infected individuals in India

90% have clade C virus (A, B, E and recombinant AC can be found in the northeast)

Access to antiretroviral treatment has been limited; the Government of India has initiated a program to provide treatment to individuals with advanced disease

Approximately 35% of the Indian population is illiterate


HIV-Associated Neurocognitive Disorders in India

Prevalence of HIV-Associated Dementia (HAD) estimated at less than 6% (Deshpande et al., 2005; Satischandra et al., 2000; Wadia et al., 2001)

35% of HIV+ individuals scored in the impaired range on the International HIV Dementia Scale, vs. 15% of controls (Riedel et al., 2006)

Neurocognitive impairment rates > 55% in participants with advanced disease (Yepthomi et al., 2006) and across disease stages (Das Gupta, 2007)


Why Might the Relationship Between HIV and Cognition Be Different with HIV Clade C?

A variation in clade C Tat may result in reduced migration of monocytes across the blood-brain barrier, leading to less HIV in the CNS and less HIV associated dementia (Ranga et al.,2004)

Positions in and near the V3 loop in env may be important in defining a neurotropic genotype in Clade B. Clade C env has less variability in this region and thus may be less neurotropic (Pillai et al., 2006)


NeuroAIDS in IndiaNIMH R01-078748

United States IndiaThomas D. Marcotte, PhD, PI Sanjay Mehendale, MD, MPH, PIRobert K. Heaton, PhD Manisha Ghate, MBBS, DCH, Co-PIScott Letendre, MD Jayanta Bhattacharya, PhDDavey Smith, MD Sheela Godbole, MBBS, MDDoug Richman, MD Smita Kulkarni, PhDIgor Grant, MD Arun Risbud, MD, MPHSunil Ahuja, MD* Seema Sahay, PhD

Madhuri Thakar, PhDSrikanth Tripathy, MBBS, MD

HIV Neurobehavioral Research Center National AIDS Research InstituteUniversity of California, San Diego Pune, Maharashtra, India* University of Texas, San Antonio


Pune, Maharashtra, India


Research Questions What is the prevalence and nature of HIV associated

neurocognitive disorders (HAND) in individuals with clade C virus in India?

What is the impact of antiretroviral treatment on HAND?

How do viral genetics influence the development of HAND in individuals infected with clade C?

What is the relationship between host factors (host genetics, chemokines) and HAND in individuals with clade C virus?


Study Design

Treatment(n = 100)

No Treatment(n = 100)

Treatment(n = 100)

HIV-(n = 300)

(n = 300)

ANNUAL FOLLOW-UPS

(n = 150)

BASELINE

350 < CD4 < 500(n = 200)

(from HPTN 052)

CD4 < 200(n = 100)

(from Govt. program)

HIV+(n = 300)


Study Design All participants complete:

• Neurobehavioral assessment

• Neuromedical evaluation

• Blood draw

• 40 participants will receive a lumbar puncture

Neuropsychological test norms will be developed for literate and illiterate groups (using structured literacy evaluation)

Recruitment, assessments, and all assays but host genetics assays will performed by NARI

Neurobehavioral, neuromedical, viral genetics and biomarker training and quality assurance provided by HNRC


Neuropsychological Test Battery

Assess multiple domains

• HIV results in “spotty” neuropsychological impairments (Heaton et al., 1995)

• Subtle, spotty impairments are more likely to be detected by a battery assessing multiple domains (White et al., 1995)


Pattern of Deficits Among 320 NP-Impaired HIV+ Participants

6259

44 43 41 4035

26

0

10

20

30

40

50

60

70

Learning Attn/WorkingMemory

Abstraction Verbal Sens-Perc Motor Perc. MotorSpeed

MemoryRetention

Perc

ent I

mpa

ired


Impairment Patterns in HIV+ NP Impaired SubjectsFirst 19 patterns (320 Subjects, 164 Patterns)

LearnAttn/Wrk

Mem Abst Verb Motor SensP-MotorSpeed Mem Cases

111197665555554444444

Marcotte et al., 200536% impaired in learning and attention/working memory


InternationalNeurobehavioral Test Battery

Verbal FluencyPhonemicAnimalsAction

Attn/Working MemoryPASAT-50WMS-III Spatial Span

Processing SpeedWAIS-III Digit SymbolWAIS-III Symbol SearchTrails A

Executive FunctioningWCST-64Color Trails IICategory Test

Learning/MemoryVerbal (Hopkins Verbal

Learning Test - Revised)Visual (Brief Visuospatial

Memory Test - Revised)

MotorGrooved Pegboard


InternationalNeurobehavioral Test Battery

Cognitive ScreenInternational HIV Dementia ScaleSubset of NP test battery

Everyday FunctioningPatient’s Assessment of Own Functioning (PAOFI)Activities of Daily Living

Psychiatric MeasuresBeck Depression Inventory - IIMini-International Neuropsychiatric Interview

Substance Use Questionnaire


Preliminary Work Translation/backtranslation Test modifications:

• Letter-Number Sequencing (auditoryattention) -> Spatial Span (visual attention)

•Words on Hopkins Verbal Learning Test•Trailmaking Test Part B -> Color Trails (no reliance on alphabet)

Permission from test publishers Training of NARI personnel Bi-weekly conference calls Feasibility study


Participant CharacteristicsHIV- HIV+

(n = 28) (n = 32)Age 32.7 (6.1) 33.2 (6.0)Education 8.6 (3.6) 7.7 (3.6)Gender (% male) 68% 72%CDC Stage A 20

B 3C 9

CD4 cells/mm3 156 (89,245)200-300 10 (31%)100-199 13 (41%)<100 9 (28%)

% AIDS 25 (78%)ARV History 1 with prior tx


Domain NP Test HIV-(n = 28)

HIV+(n = 32) Effect size

Fluency Sound Fluency (PAS) 30.8 (14.4) 15.8 (6.7) -1.06 Animal Fluency 19.6 (5.4) 15.1 (3.8) -0.94 Action Fluency 13.5 (4.5) 9.0 (3.9) -1.06 Processing Speed Digit Symbol 52.4 (15.9) 41.0 (14.6) -0.74 Symbol Search 21.7 (9.2) 17.4 (9.3) -0.46 Trails A seconds 49.8 (17.8) 64.8 (20.0) -0.78 Color Trails 1 54.2 (22.9) 70.8 (24.7) 0.69 Stroop Word 82.1(19.1) 77.5 (19.7) Stroop Color 54.0 (11.3) 46.4 (12.7) -0.62 Attention/Working Memory PASAT-50 26.3 (7.5) 22.1 (6.7) -0.59 Spatial Span 14.2 (3.9) 12.7 (4.1) -0.37 Executive Functioning Category Test 59.6 (22.9) 70.6 (29.3) 0.41 WCST-64 12.2 (6.4) 16.4 (10.4) 0.47 Color Trails 2 115.6 (40.0) 128.3 (42.8) 0.30 Stroop Incongruent 31.3 (7.7) 26.8 (8.3) -0.55 Learning BVMT-R Total Learning 22.0 (5.5) 16.7 (7.9) -0.76 HVLT-R Total Learning 26.9 (4.5) 23.5 (4.3) -0.76 Memory (recall) BVMT-R Delay 8.1 (2.5) 6.8 (3.0) -0.46 HVLT-R Delay 9.8 (1.7) 8.7 (1.9) -0.60 Motor Pegs Dominant 69.6 (17.4) 78.4 (18.6) 0.48 Pegs Non-Dominant 80.6 (20.5) 84.6 (15.9) 0.22

Neuropsychological Test Results


Effect Sizes for Neurocognitive Domains(HIV+ performance vs. HIV- Performance)

0

0.2

0.4

0.6

0.8

1

1.2

Effe

ct S

ize

Fluency Learning ProcessingSpeed

Executive Memory Attn/Wmem Motor

Cognitive Domain


Neurocognitive Diagnosis

• 33% of impaired were unemployed, vs. 7% of cognitive normal HIV+ individuals

• 10/15 impaired individuals reported significant cognitive problems in their daily life

• 7 of these 10 reported a decline in at least 1 ADL; 3 had declines in 2 or more ADLs


Depressive SymptomatologyHIV- HIV+ p

BDI Total 3.9 (4.2) 16.8 (10.3) <.001

BDI Cognitive 3.1 (3.4) 11.7 (7.0) <.001

Thoughts of killing self 0% 47% <.001

Major Depression 0% 16% .02


NP Impairment Predicts Cognitive Complaints in Non-Depressed HIV+ Participants (BDI < 17)

6.57

2.5

0

1

2

3

4

5

6

7

NP Normal (n = 10) NP Impaired (n = 7)

Num

ber o

f Com

plai

nts

p = .05


Neuropsychological Test Battery

• No floor effects for participants with low education (< 3 years)

• Excellent test-retest reliability (r = .91 for summary measure; most individual measures > .80)


Neuropsychological Impairment Rates (GDS) in India and the U.S.

13

60

36

87

0102030405060708090

100

U.S. India India Recalibrated

% Im

paire

d

HIV-HIV+



13

60

15

36

87

0102030405060708090

100


% Im

paire

d

-HIV+HIV



13

60

15

36

87

48

0102030405060708090

100


% Im

paire

d

-HIV+HIV


HNRC International Neuropsychological Battery

Country Clade Principal InvestigatorsIndia Pune C Marcotte/Mehendale/Ghate

Chandigarh C Kumar/PrabhakarChennai C Letendre/Kumarasamy/Bharti

China B/C/AE Heaton/Wu

Brazil B/C Ellis/de Almeida

Romania F Achim/Duiculescu

Cameroon CRF02-AG, A Kanmogne

United States B HNRC/CHARTER/NNTC

Standardized Administration, Structured Training, On-going QA


Summary

Potentially identify the inter-individual differences that • Put one at risk for HIV-associated neurocognitive

disorders• Affect CNS benefit from treatment

Build neuroAIDS research capacity in India• Neurocognitive assessment• Viral and host genomics• Biomarker techniques


NeuroAIDS in India

Documents

NeuroAIDS in Pune - UNC School of Medicine NEUROBEHAVIORAL RESEARCH CENTER NeuroAIDS in Pune ... HIV NEUROBEHAVIORAL RESEARCH CENTER Pune, ... Chennai C Letendre/Kumarasamy/Bharti