NeuroAIDS in Pune

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NeuroAIDS in Pune

• Thomas D. Marcotte, PhD
• HIV Neurobehavioral Research Center
• University of California, San Diego
• San Diego, CA USA

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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

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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 gt 55 in
  participants with advanced disease (Yepthomi et
  al., 2006) and across disease stages (Das Gupta,
  2007)

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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)

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NeuroAIDS in IndiaNIMH R01-078748

• United States India
• Thomas D. Marcotte, PhD, PI Sanjay Mehendale, MD,
  MPH, PI
• Robert K. Heaton, PhD Manisha Ghate, MBBS, DCH,
  Co-PI
• Scott Letendre, MD Jayanta Bhattacharya, PhD
• Davey Smith, MD Sheela Godbole, MBBS, MD
• Doug Richman, MD Smita Kulkarni, PhD
• Igor Grant, MD Arun Risbud, MD, MPH
• Sunil Ahuja, MD Seema Sahay, PhD
• Madhuri Thakar, PhD
• Srikanth Tripathy, MBBS, MD
• HIV Neurobehavioral Research Center National
  AIDS Research Institute
• University of California, San Diego Pune,
  Maharashtra, India
• University of Texas, San Antonio

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Pune, Maharashtra, India
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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?

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Study Design
BASELINE
350 lt CD4 lt 500 (n 200) (from HPTN 052)
CD4 lt 200 (n 100) (from Govt. program)
HIV- (n 300)
(n 300)
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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

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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)

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Pattern of Deficits Among 320 NP-Impaired HIV
Participants
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Impairment Patterns in HIV NP Impaired
SubjectsFirst 19 patterns (320 Subjects, 164
Patterns)

• 36 impaired in learning and attention/working
  memory

Marcotte et al., 2005
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InternationalNeurobehavioral Test Battery

• Verbal Fluency
• Phonemic
• Animals
• Action
• Attn/Working Memory
• PASAT-50
• WMS-III Spatial Span
• Processing Speed
• WAIS-III Digit Symbol
• WAIS-III Symbol Search
• Trails A

• Executive Functioning
• WCST-64
• Color Trails II
• Category Test
• Learning/Memory
• Verbal (Hopkins Verbal Learning Test - Revised)
• Visual (Brief Visuospatial Memory Test - Revised)
• Motor
• Grooved Pegboard

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InternationalNeurobehavioral Test Battery

• Cognitive ScreenInternational HIV Dementia
  ScaleSubset of NP test battery
• Everyday Functioning
• Patients Assessment of Own Functioning (PAOFI)
• Activities of Daily Living
• Psychiatric Measures
• Beck Depression Inventory - II
• Mini-International Neuropsychiatric Interview
• Substance Use Questionnaire

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Preliminary Work

• Translation/backtranslation
• Test modifications
• Letter-Number Sequencing (auditory attention)
  -gt Spatial Span (visual attention)
• Words on Hopkins Verbal Learning Test
• Trailmaking Test Part B -gt Color Trails (no
  reliance on alphabet)

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

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Participant Characteristics

• HIV- 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 3 C 9CD4 cells/mm3 156
  (89,245) 200-300 10 (31) 100-199 13
  (41) lt100 9 (28)
• AIDS 25 (78)
• ARV History 1 with prior tx

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Neuropsychological Test Results
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Effect Sizes for Neurocognitive Domains(HIV
performance vs. HIV- Performance)
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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

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Depressive Symptomatology
HIV- HIV p BDI Total 3.9 (4.2) 16.8
(10.3) lt.001 BDI Cognitive 3.1 (3.4) 11.7
(7.0) lt.001 Thoughts of killing
self 0 47 lt.001 Major Depression 0 16 .02
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NP Impairment Predicts Cognitive Complaints in
Non-Depressed HIV Participants (BDI lt 17)
p .05
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Neuropsychological Test Battery

• No floor effects for participants with low
  education (lt 3 years)
• Excellent test-retest reliability (r .91 for
  summary measure most individual measures gt .80)

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Neuropsychological Impairment Rates (GDS) in
India and the U.S.
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Neuropsychological Impairment Rates (GDS) in
India and the U.S.
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Neuropsychological Impairment Rates (GDS) in
India and the U.S.
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HNRC International Neuropsychological Battery
Standardized Administration, Structured Training,
On-going QA
Country Clade Principal Investigators India Pune C
Marcotte/Mehendale/Ghate Chandigarh C Kumar/Prab
hakar Chennai 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
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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

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NeuroAIDS in India