AIDS EPI

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Assessment of NeuroAIDS in Africa Ngurdato
Mountain Lodge Tanzania July 17-19
Ethiopian NeuroAIDS Assessment David B. Clifford
and Scott Evans
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Thanks!
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Participants

• Dr. Dawit Wolday
• Dr. Tsehaynesh Messele
• Dr. Yared Mekonnen
• Dr. Guta Zenebe

• Dr. Zenebe Melaku
• Dr. Mesfin Teshome
• Dr. Ayele Zewde
• Dr. Scott Evans
• Dr. Jiameng Zhang

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HIV Epidemic in Ethiopia

• 4-5 of population affected, urbangtrural
• 2 million HIV in Ethiopia
• ARV only now being introduced
• neuroAIDS not previously evaluated

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ENARC Project Objectives

• To evaluate the neuropsychological profile
  untreated African HIV patients
• To measure the prevalence of HIV associated
  neurologic disease in a cohort
• To test a rapid screening test, the International
  HIV Dementia Scale
• To determine prevalence of HIV associated
  neuropathy in untreated Ethiopian HIV patients

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Ethio Netherlands AIDS Research Project

• Established 1994
• Capacity building
• Laboratory
• Training
• Science
• Built with development funds, discontinued
  funding 2004

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Ethiopain Netherlands AIDSResarch Project (ENARP)

• ENARP Cohort studied
• Longitudinal natural hx study of HIV in two
  communities where gen health care available
• All available HIV studied
• Controls from same community, known HIV neg
• HIV and controls participants in longitudinal
  study, selected in general screening of community
  gt5 years prior to study

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Team Structure

• Ethiopia
• Neurologist trained 4 Ethiopian neurologists and
  2 internists
• Physicians perform all exams
• Examiners blind to HIV status (interspersed at
  same sites)

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ENARC Demographics

• Intent to study
• All available HIV
• Match for site, gender, age

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Disease Status
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ENARC Study

• Demographics relevant to neurology
• Functional status history
• Neurological Exam
• Quantitative motor performance exam
• International Dementia Score
• Peripheral neuropathy exam
• More than 12,000 observations

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International Neuro Screening

• International HIV Dementia Scale (Sacktor, et al)
• Naming four objects
• Fingertapping
• Luria psychomotor learning task
• Recall of names

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International HIV Dementia Scale
Memory-Registration Give four words to recall
(dog, hat, bean, red) (in Luganda,
kopo,engatto,doodo,myufo) 1 second to say each.
Then ask the patient all four words after you
have said them. Repeat words if the patient does
not recall them all immediately. Tell the patient
you will ask for recall of the words again a bit
later. 1. Motor Speed Have the patient tap the
first two fingers of the non-dominant hand as
widely and as quickly as possible. 4 ? 15 in 5
seconds 3 11-14 in 5 seconds 2 7-10 in 5
seconds 1 3-6 in 5 seconds 0 0-2 in 5
seconds 2. Psychomotor Speed Have the patient
perform the following movements with the
non-dominant hand as quickly as possible 1)
Clench hand in fist on flat surface. 2) Put hand
flat on surface with palm down. 3) Put hand
perpendicular to flat surface on the side of the
5th digit. Demonstrate and have patient perform
twice for practice. 4 4 sequences in 10
seconds 3 3 sequences in 10 seconds 2 2
sequences in 10 seconds 1 1 sequence in 10
seconds 0 unable to perform 3.
Memory-Recall Ask the patient to recall the four
words. For words not recalled, prompt with a
semantic clue as follows animal (dog) piece of
clothing (hat) vegetable (bean) color
(red). Give 1 point for each word spontaneously
recalled. Give 0.5 points for each correct
answer after prompting Maximum 4
points. Total International HIV Dementia Scale
Score This is the sum of the scores on items 1-3.
The maximum possible score is 12 points. A
patient with a score of lt10 should be evaluated
further for possible dementia. (Sacktor et al.
Neurology 2003 601A186-187)
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IHDS Ethiopia
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ENARC Quantiative Neurologic Performance Testing
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Peripheral Neuropathy Scores
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ENARC Conclusions

• Less HIV associated disability found than
  anticipated
• Performance of controls and HIV impaired by
  Western norms
• IHDS did not demonstrate difference between HIV
  and neg consistent with clinical impression
• Neuropathy was found in 15 of both HIV
  negative and positives populations

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Comparisons to Ugandan Project

• Untreated population in Uganda from clinic (not
  community) showed more cognitive impairment
• CD4/Karnofsky status more advanced in Kampala
• Projects different

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Why the Difference in Our Studies?

• Issue with examiners
• Training, stability of team, level of experience
• Different populations importance of norms
• Blinding of HIV status to examiners
• Demographic differences in populations
• Patient differences
• Genetic diversity in Africa
• Passive selection bias (sick patients stay home
  in research studies, motivated, capable people
  volunteer)

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Possible Reasons for Preserved Status

• More impaired subjects did not volunteer for exam
• Examined all available HIV from established
  community cohort
• Most were working (unclear if those disabled
  would be more or less likely to volunteer)
• Early death may have removed impaired in
  population

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Effects of Controls on Results

• Norms for tests must be developed locally and
  require appropriate normal pop
• Exam conditions and examiners should be same
• Demographic influences may be meaningful and
  unrecognized
• Our populations was well matched and exams were
  performed by same examiners in blind (sometimes
  double blind) fashion

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HIV Subtype D Associated With Faster Disease
Progression

• Retrospective study of 140 HIV seroconverters
  followed over 5 years
• Patients with subtype D had faster progression to
  AIDS or death

• In a subgroup of patients, 5/31 seroconverters
  had dual (CXCR4 and CCR5)-tropic infection within
  2 years of infection all type D
• 4/5 died within 3 years of infection

Laeyendecker O, et al. CROI 2006. Abstract 44LB.
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HIV Subtype Distribution in Uganda and Ethiopia
Uganda
Ethiopia

AIDS Cases
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Could the virus explain discordant results?

• Evidence that there are biologically meaningful
  differences in clade biology
• Clade C perinatal transmission
• Clade D has more rapid progression
• ?Predilection for nervous system disease

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Conclusions

• International neuroAIDS studies are challenging
• Questions and populations need to be carefully
  chosen
• Instruments need careful validation in settings
• Team design and stability very important
• Language/culture may have marked effects on
  results

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Future Projects

• NARC is currently supporting the Uganda group to
  evaluate neuro status of 100 subjects starting
  HAART
• Replication of this study planned in Ethiopia
  with close attention to common training and
  administration

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Future Projects - Minocycline

• Neuroprotective strategy using minocycline in
  Uganda
• Population with cognitive impairment but CD4 250

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What are neuroAIDS questions that are most
important to target?Could we link with dynamic
new programs to achieve these goals?How to
assemble teams that can do the work?How do we
design studies that allow clear answers to our
questions?
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Identifying HIV individuals at risk for HIV
dementia

• Screening tests are essential for directing
  limited resources for the diagnosis of dementia.
• Brief instruments have been developed for
  Alzheimers (MMSE) and HIV dementia in the US
  (HDS)
• The HDS includes subtests (antisaccadic-error
  test, alphabet writing, cube-copying,) that are
  difficult to administer by non-neurologists or
  difficult for individuals with a non-Western
  educational background.

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International HIV Dementia Scale
Memory-Registration Give four words to recall
(dog, hat, bean, red) (in Luganda,
kopo,engatto,doodo,myufo) 1 second to say each.
Then ask the patient all four words after you
have said them. Repeat words if the patient does
not recall them all immediately. Tell the patient
you will ask for recall of the words again a bit
later. 1. Motor Speed Have the patient tap the
first two fingers of the non-dominant hand as
widely and as quickly as possible. 4 ? 15 in 5
seconds 3 11-14 in 5 seconds 2 7-10 in 5
seconds 1 3-6 in 5 seconds 0 0-2 in 5
seconds 2. Psychomotor Speed Have the patient
perform the following movements with the
non-dominant hand as quickly as possible 1)
Clench hand in fist on flat surface. 2) Put hand
flat on surface with palm down. 3) Put hand
perpendicular to flat surface on the side of the
5th digit. Demonstrate and have patient perform
twice for practice. 4 4 sequences in 10
seconds 3 3 sequences in 10 seconds 2 2
sequences in 10 seconds 1 1 sequence in 10
seconds 0 unable to perform 3.
Memory-Recall Ask the patient to recall the four
words. For words not recalled, prompt with a
semantic clue as follows animal (dog) piece of
clothing (hat) vegetable (bean) color
(red). Give 1 point for each word spontaneously
recalled. Give 0.5 points for each correct
answer after prompting Maximum 4
points. Total International HIV Dementia Scale
Score This is the sum of the scores on items 1-3.
The maximum possible score is 12 points. A
patient with a score of lt10 should be evaluated
further for possible dementia. (Sacktor et al.
Neurology 2003 601A186-187)