Valerio Tozzi National Institute for Infectious Diseases L. Spallanzani. Rome, Italy

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Prevalence and risk factors for HIV associated neurococognitive

disorders (HAND), 1996 to 2010: results from an observational

cohort

Balestra P, Tozzi V, Zaccarelli M, Libertone R, Cataldo G, Liuzzi G, Menichetti S, Giulianelli M, Narciso P, Lorenzini P, Antinori A.

Valerio TozziNational Institute for Infectious Diseases

L. Spallanzani. Rome, Italy

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Rationale

HAND 2011• Still frequent• Often not diagnosed• Increased risk of death (poster TUPE 204)

• Reduced adherence • Poor QoL

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Objectives

• Assess HAND prevalence changes over the past 15 years

• Assess HAND risk factors• Assess changes in HAND severity• Assess qualitative changes in HAND

neuropsychological profile

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Design and Methods

• Single site observational study• Inclusion criteria

– Indication for starting / being on HAART • Exclusion criteria

– confounding neurological, psychiatric, and medical disorders

– active drug use

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Clinical Methods

• Demographics• Medical assessments• Neurological assessments • Standard brain MRI• Routine laboratory, CD4, plasma HIV RNA• Neuropsychological (NP) assessment on 5

domains• Exclusion of confounding conditions

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NP Battery and Domains• Concentration and Speed of Mental

Processing– Trail Making A– WAIS-R Digit Span (forward)– WAIS-R Digit Span (backward) – Digit Symbol– Stroop Word and Colour– Corsi Cube Test

• Mental Flexibility– Trail Making B– Stroop Colour-Word – Controlled Oral Word

• Memory– Rey Auditory Verbal Learning

(immediate)– Rey Auditory Verbal Learning

(immediate)– Rey Complex Figure (after 45’)

• Fine Motor Functioning– Lafayette Grooved Pegboard

(dominant hand)– Lafayette Grooved Pegboard (non

dominant hand)• Visuospatial and Constructional Abilities

– Rey Complex Figure (copy)

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NP Assessment (I)

• Exclusion of confounders (clinical, lab, MRI)• All NP evaluations administered by one of us

(P Balestra) to ensure little variability• NP scores adjusted for age, gender, years of

education • Compared to population based norms

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NP Assessment (II) • Cognitive Impairment:

– 1 SD below the normative mean in 2 tests – or 2 SD below the normative mean in 1 test

• Z-Scores (neg values performance below the mean)

– Z-Scores for each NP test – Z-Scores for each Cognitive Domain– Global NPZ-8 Deficit Score

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Diagnostic Criteria

• Severity of impairment at NP testing

• Declines in everyday functioning by clinical assessment – HAD (HIV Associated Dementia)*

– MND (Mild Neurocognitive Disorder)* – ANI (Asymptomatic Neurocognitive Impairment)*

* AAN 2007 criteria

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• Comparisons between impaired and unimpaired subjects – t-student test for continue variables – chi-squared for categorical variables

• Factors associated with HAND and with HAND severity– logistic regression model

Statistics

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Source Studies and Sample Selection

Studies (1996-2010)

• ISS, 1° Ntl AIDS Program• ISS, 2° Ntl AIDS Program• ISS, 3° Ntl AIDS Program• ISS, 4° Ntl AIDS Progfam• ISS, 5° Ntl AIDS Program

• Ricerca Corrente IRCCS

Sample

1.888 cases

469 confounding conditions (excluded)

44 invalid NP test results (excluded)

1.375 cases

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Patient’s characteristics (I)N=1375 TotalMale gender, % 74.8%Education in years, %<1010-15>15

36.7%47.7%15.6%

Education in years, median (IQR) 13 (8-13)Age in years, median (IQR) 42 (36-49)Age in years, %<3030-3940-55>55

7.7%36.2%44.6%11.5%

Age at 1° HIV, median (IQR) 33 (27-42)Years of exposure to HIV, median (IQR) 6 (1.6-12.2)CDC stage C, % 34.5%

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Patient’s characteristics (II)N=1375 Total

Current CD4, median (IQR) 381 (198-599)

Nadir CD4, median (IQR) 165 (60-294)

HAART duration < 2 wks, % 24.1%

HAART duration 2-52 wks, % 20.0%

HAART duration >52 wks, % 55.9%

Log10 vir load, mean (SD) 4.16 (1.12)

Undetect viral load, % 30.6%

Any cardiovascular risk factor, % 45.4%

Previous IVDU, % 25.0%

HCV infection, % 29.2%

NP test result, n. (%)- NP Unmpaired (normal cognition)- NP Impaired (HAND)

806 (58.6%)569 (41.4%)

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HAART exposureHAART exposure >52 weeks; p<0.001

23.2%

73.2%

48.1%

61.3%

75.3%

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Proportion Impaired (HAND)HAND (3 yrs incr): OR 0.92 (95% CI 0.85-0.99); p=0.031

45.6% 44.4% 39.4% 39.4% 38.2%

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Proportion with HAND by CDC stage

0102030405060708090

100

1996-1998 1999-2001 2002-2004 2005-2007 2008-2010

CDC A CDC B CDC C

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HAND predictors, unajustedFactor Impaired

(n=569)Unimpaired

(n=806)p-value

Age, mean (SD) 45.0 (10.1) 41.3 (10.0) <0.001

Age at 1° HIV test, mean (SD) 36.8 (12.1) 34.5 (10.3) <0.001

Male gender, % 77.5% 72.8% 0.049Previous intavenous drug use, % 33.9% 18.6% <0.001CDC stage C, % 49.4% 23.9% <0.001HCV infection, % 50.7% 31.0% <0.001Years of HIV exposure, mean (SD) 8.3 (6.8) 6.9 (6.2) <0.001

Current CD4/mm3, mean (SD) 349 (277) 478 (309) <0.001

Nadir CD4/mm3, mean (SD) 158 (155) 231 (193) <0.001

Detectable plasma viral load, % 71.3% 69.5% 0.721Log10 HIV-RNA, mean (SD) 4.25 (1.16) 4.10 (1.10) 0.094

Calendar year < 2004, % 49.4% 55.2% 0.034

Years of HAART exposure, mean (SD) 3.1 (3.8) 3.2 (3.9) 0.550

Years of education, mean (SD) 10.1 (3.7) 12.5 (3.4) <0.001

Any cardiovascular risk factor, % 48.4% 43.6% 0.124

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HAND predictors by HAART era, unajusted

Factor Pre-HAART1996-1998

Early HAART1999-2004

Late HAART2005-2010

OR (95% CI) OR (95%CI) OR (95%CI)

Age, 10 years incr 1.72 (1.21-2.44) 1.58 (1.28-1.93) 1.56 (1.32-1.84)

Age at 1° HIV test, 10 years incr 1.24 (0.93-1.65) 1.26 (1.05-1.51) 1.23 (1.07-1.41)

Male gender 1.95 (1.13-3.38) 1.24 (0.82-1.86) 1.10 (0.74-1.63)

Previous IDV 1.76 (1.07-2.89) 2.36 (1.60-3.48) 2.45 (1.54-3.89)

CDC stage C 2.61 (1.58-4.32) 3.66 (2.50-5.36) 2.86 (1.99-4.09)

HCV infection 1.87 (1.12-3.12) 2.41 (1.65-3.53) 2.49 (1.53-4.05)

Years of HIV exposure ,1 year incr 1.11 (1.04-1.19) 1.04 (1.01-1.07) 1.03 (1.01-1.05)

Current CD4, 100 cells incr 0.82 (0.71-0.95) 0.78 (0.73-0.84) 0.92 (0.87-0.98)

Nadir CD4, 100 cells incr 0.79 (0.63-1.01) 0.74 (0.66-0.82) 0.79 (0.71-0.88)

Log10 HIV-RNA, 1 log incr 1.55 (1.09-2.21) 1.26 (1.03-1.53) 0.76 (0.59-0.97)

Years of ART exposure, 1 year incr 0.85 (0.60-1.23) 0.94 (0.87-1.01) 1.02 (0.98-1.06)

Years of education, 1 year incr 0.85 (0.79-0.92) 0.83 (0.79-0.88) 0.80 (0.76-0.84)

Any cardiovascular risk factor 0.58 (0.30-1.12) 1.33 (0.89-2.00) 1.39 (0.98-1.98)

Delta CD4 (current-nadir), 100 cells incr 0.83 (0.69-1.00) 0.82 (0.76-0.90) 1.01 (0.94-1.07)

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HAND predictors, multivariable(n=1.375)

Factor OR 95% CI p-value

Age (10 years increase) 1.51 1.26-1.79 <0.001

CDC stage C 2.39 1.76-3.25 <0.001

Education (1 year increase) 0.92 0.86-0.99 0.016

Years of HIV exposure (1 year increase) 1.03 1.00-1.06 0.090

Previous IVDU 1.19 0.78-1.81 0.422

HCV infection 1.47 1.00-2.18 0.052

Current CD4 (100 cells increase) 0.92 0.87-0.97 0.002

Calendar year, (3 years increase) 1.03 0.89-1.20 0.657

Years of HAART exposure, (1 year increase) 0.87 0.83-0.91 <0.001

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Proportion of HAD-MND-ANIHAD + MND (3 yrs incr): OR 0.89 (95% CI 0.82-0.97); p=0.008

29.9% 27.2% 29.2%25.4%

19.4%29.9% 27.2% 29.2%

25.4% 18.4%

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Symptomatic (HAD/MND) vs asymptomatic (ANI) predictors, unajusted

Factor HAD/MND (n=360)

ANI (n=209)

p-value

Age, mean (SD) 45.9 (10.6) 43.5 (9.0) 0.052

Age at 1° HIV test, mean (SD) 37.9 (13.0) 35.1 (10.3) 0.056

Male gender, n. (%) 277 (77.4%) 160 (77.7%) 0.936Previous intavenous drug use, % 129 (36.0) 62 (30.1) 0.151CDC stage C, n. (%) 208 (62.7) 72 (36.7) <0.001HCV infection, n. (%) 149 (53.6) 67 (45.3) 0.102Years of HIV exposure, mean (SD) 8.1 (6.6) 8.6 (7.1) 0.537

Current CD4/mm3, mean (SD) 326 (275) 390 (278) 0.003Nadir CD4/mm3, mean (SD) 140 (122) 190 (196) 0.017Log10 HIV-RNA, mean (SD) 4.2 (0.04) 4.2 (0.04) 0.225

Calendar year < 2004, n. (%) 202 (56.4) 107 (51.9) 0.303Years of HAART exposure, mean (SD) 3.0 (3.6) 3.3 (4.1) 0.873

Years of education, mean (SD) 9.6 (3.6) 10.9 (3.6) <0.001Any cardiovascular risk factor*, n. (%) 132 (54.5) 64 (39.8) 0.004

* i.e. diabetes, hypertension, hyperlipedemia, prior myocardial infarction, obesity

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Symptomatic (HAD/MND) vs asymptomatic (ANI) predictors, multivariable

(n=569)

Factor OR 95% CI p-valueAge (10 years increase) 1.03 1.00-1.05 0.028CDC stage C 2.06 1.31-3.23 0.002Any cardiovascular risk factor 1.71 1.08-2.72 0.023Current CD4 (100 cells increase) 0.92 0.85-0.99 0.029Years of education (1 year increase) 0.92 0.87-0.97 0.005

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NPZ-8, HAND (n=569)

β= -0.05; p=0.646

Mean (±SD) Global z-score

NP test b p

Trail Making A -0.01 0.176

WAIS-R Digit Span (forward)

0.06 0.245

Digit Symbol 0.02 0.712

Trail Making B -0.02 0.298

Rey Auditory Verbal Learning (immediate)

-0.05 0.188

Rey Auditory Verbal Learning (after 15 min)

-0.03 0.410

Lafayette Grooved Pegboard (dom. hand)

0.00 0.864

Lafayette Grooved Pegboard (non dom. hand)

0.01 0.661

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Concentration and Speed of Mental Processing z-scores,

HAND (n=569)

Β= -0.08; p=0.263

NP test b pTrail Making A -0.01 0.176

WAIS-R Digit Span (forward)

0.06 0.245

WAIS-R Digit Span (bakward)

0.02 0.735

Digit Symbol 0.02 0.712

Stroop Word and Colour

-0.04 0.069

Corsi Cube -0.06 0.234


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Mental Flexibility z-scores, HAND (n=569)

b= -0.01; p=0.861NP test b pTrail Making B -0.02 0.298

Stroop Colour-Word

-0.01 0.648

Controlled Oral Word

0.04 0.341


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Memory Z-scores, HAND (n=569)

B =-0.05; p=0.234 NP test b pRey Auditory Verbal Learning (immediate)

-0.05 0.188


-0.03 0.410

Rey Complex Figure (after 45’)*

0.13 0.007


* visual memory and spatial perception

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NP test b pRey Auditory Verbal Learning (immediate)

-0.05 0.188


-0.03 0.410


0.13 0.007


Rey Complex Figure Test

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-0.05 0.188


-0.03 0.410


0.13 0.007



Rey Complex Figure Test (after 45’):

Score 18.5 (n.v. >16)

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-0.05 0.188


-0.03 0.410


0.13 0.007




Score 18.5 (n.v. >16)


Score 3.5 (n.v. >16)

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Fine Motor Functioning Z-scores, HAND (n=569)

b= 0.01; p=0.758NP test b pLafayette Grooved Pegboard (dominant hand)

0.00 0.864

Lafayette Grooved Pegboard (non dominant hand)

0.01 0.661


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Visuospatial and Constructional Abilities Z-scores, HAND (n=569)

b= 0.02; p=0.620

NP test b pRey Complex Figure (copy)

0.02 0.620


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Study limitations• Based exclusively on NP evaluations (i.e.: no

CSF, no advanced MRI) • Diagnostic Nomenclature changed in 2007

– HAD = HAD– MND retrospectively*, yrs 1996-2007– ANI retrospectively*, yrs 1996-2007

• Patients with confounding (i.e.: liver cirrhosis, current i.v.d.u.) conditions excluded. Role of incidental and contributing conditions (i.e.: HCV, previous i.v.d.u.) not evaluated

* Based on data on file and previous classifications, by (AAN, 1991) (Grand and Atkinson, 1995) criteria

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Conclusions (I)

• Cognitive impairment persists• Small, but significant, downtrend in HAND

prevalence HAART protective• Strongest predictors of HAND

– Low HAART exposure HAART protective– Previous AIDS immunodeficiency– Low current CD4 persistent immunodeciciency – Advanced age time-related cofactors– Low education reduced cognitive reserve

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Conclusions (II)• Downtrend in prevalence of symptomatic (HAD/MND)

forms of HAND evidences for milder forms of HAND

• Strongest predictors of symptomatic (HAD/MND) vs asymtomatic (ANI) forms of HAND – Advanced age time-related cofactors– Low education reduced cognitive reserve – Previous AIDS immunodeficiency – Low current CD4 persistent immunodeficiency – Cardiovascular risk factors chronic inflammation

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Conclusions (III)

• Some evidences of less impairment in measures of visual memory and spatial perception

• Overall, almost no changes in qualitative profile of cognitive impairment (“subcortical profile”, core deficits: attention/memory, motor skills, processing speed, and executive functioning) very limited evidences for a change in HAND neurocognitive profile

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Acknowledgments • Istituto Superiore di Sanità• Ministero della Salute• Coauthors

– Zaccarelli M – Libertone R – Cataldo G – Liuzzi G – Menichetti S – Giulianelli M– Sampaolesi A– Giannetti A– Picchi G – Narciso P – Antinori A

• Neuropsychologist– Balestra P

• Statistician– Lorenzini P

• Our patients

Documents

Valerio Tozzi National Institute for Infectious Diseases L. Spallanzani. Rome, Italy