Assessment of NeuroAIDS in AfricaNgurdato Mountain LodgeTanzaniaJuly 17-19

Ethiopian NeuroAIDS AssessmentDavid B. Clifford and Scott Evans

Thanks!

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

HIV Epidemic in Ethiopia

• ~4-5 % of population affected, urban>rural

• ~2 million HIV + in Ethiopia

• ARV only now being introduced

• neuroAIDS not previously evaluated

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

Ethio Netherlands AIDS Research Project

• Established 1994• Capacity building

– Laboratory– Training– Science

• Built with development funds, discontinued funding 2004

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 >5 years prior to study

Team Structure

• Ethiopia– Neurologist trained 4

Ethiopian neurologists and 2 internists

– Physicians perform all exams

– Examiners blind to HIV status (interspersed at same sites)

TotalN = 160

HIV NegativeN = 87

HIV PositiveN = 73

P-Valuea

Age (Median) 38 38 39 NS

Gender (Male) 104(65%) 55(63%) 49 (67%) NS

Marital StatusMarried Ever 147(92%) 82(94%) 65(89%) NS

Read or writeYes 126(80%) 69(80%) 56(79%) NS

Education(Median Yr) 8 8 7 NS

IncomeMean birr/Mo 642 552 NS

Working statusFull time 144(91%) 83(95%) 61(86%)

0.0823d

Diabetes 4(3%) 3(3%) 1(1%) NS

Hypertension 7(5%) 5(6%) 2(3%) NS

Syphilis 12(9%) 6(8%) 6(10%) NS

ENARCDemographics

Intent to study

•All available HIV +

•Match for site, gender, age

Disease StatusHIV Negative

EthiopiaHIV Positive

EthiopiaP-Value

CD4 CountMedian 737 260 <0.0001c

HIV Viral Load

Mean log 10 copies/ml

--------- 4.3

KarnofskyMeanMedian

97.2100

95.7100 NS

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

International Neuro Screening

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

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 seconds3 = 11-14 in 5 seconds2 = 7-10 in 5 seconds1 = 3-6 in 5 seconds0 = 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 seconds3 = 3 sequences in 10 seconds2 = 2 sequences in 10 seconds1 = 1 sequence in 10 seconds0 = 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 promptingMaximum – 4 points.

Total International HIV Dementia Scale ScoreThis is the sum of the scores on items 1-3. The maximum possible score is 12 points. A patient with a score of <10 shouldbe evaluated further for possible dementia.

(Sacktor et al. Neurology 2003 60;1:A186-187)

International HIV Dementia Scale

IHDS – Ethiopia

Total HIV Negative HIV Positive P-Valuea

FingertappingMedianMean(S.d.)

42.342.1(8.4)

4443.6(8.2)

39.840.3(8.3)

0.008c

Timed GaitMedian Avg sec

11.5 11.5 11.3 0.704c

Grooved PegboardMedian sec 111.0 111.5 108.0 0.848c

Verbal FluencyMedian Avg 16 16 15 0.442c

Motor Speed<15 in 5 sec≥ 15 in 5 sec

45(29%)115(71%)

23(26%)64(74%)

22(30%)51(70%)

0.1761d

PsychomotorSpeed< 3 seq/10 sec3 seq/10 sec4 seq/10 sec

27(16%)39(24%)93(58%)

13(15%)23(26%)51(59%)

14(19%)16(22%)42(58%)

0.6197d

Tuning ForkRt toe Median 6.5 6.3 6.5 0.508c

Any CNS or PNS Abnormality

NoYes

113(71%)44(28%)

66(77%)20(23%)

47(66%)24(34%)

0.1431b

HIV+ HIV- Significance

Motor speed ( % not normal)* 30.1 26.4 NS

Finger tapping (mean/median)* 40.3/39.8 43.7/44 P=0.01

Luria motor task (% <4)* 41.1 41.4 NS

Luria motor task (% <3) 19.2 15 NS

Timed gait (Mean sec)* 11.9 12.5 NS

Grooved pegboard (mean sec)* 129.2 131.2 NS

Verbal Fluency (Total words)* 16.9 17.1 NS

Tuning Fork (right toe mean sec)* 14.9 15.7 NS

Tuning Fork (left toe mean sec) 15.1 15.8 NS

ENARCQuantiativeNeurologic PerformanceTesting

Peripheral Neuropathy Scores

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

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

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)

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

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

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

HIV Subtype n AIDS Death Years of Follow-up

Subtype A 21 5 0 5.6Subtype D 89 40 12 5.7Multiple 7 5 0 6.1Recombinant 40 10 11 4.7

• 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.

HIV Subtype Distribution in Uganda and Ethiopia

A/A D/D Other

AIDS Cases

Uganda

C C' Other

Ethiopia

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

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

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

Future Projects - Minocycline

• Neuroprotective strategy using minocycline in Uganda– Population with

cognitive impairment but CD4 250

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?

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 Alzheimer’s (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.

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 seconds3 = 11-14 in 5 seconds2 = 7-10 in 5 seconds1 = 3-6 in 5 seconds0 = 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 seconds3 = 3 sequences in 10 seconds2 = 2 sequences in 10 seconds1 = 1 sequence in 10 seconds0 = 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 promptingMaximum – 4 points.

Total International HIV Dementia Scale ScoreThis is the sum of the scores on items 1-3. The maximum possible score is 12 points. A patient with a score of <10 shouldbe evaluated further for possible dementia.

(Sacktor et al. Neurology 2003 60;1:A186-187)

International HIV Dementia Scale