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

Rationale HAND 2011 Still frequent Often not diagnosed Increased risk of death (poster TUPE 204) Reduced adherence Poor QoL

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

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

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

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 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)

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

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

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

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

Source Studies and Sample Selection Studies ( ) 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 cases 469 confounding conditions (excluded) 44 invalid NP test results (excluded) cases

Patient’s characteristics (I) N=1375Total Male gender, %74.8% Education in years, % < > % 47.7% 15.6% Education in years, median (IQR)13 (8-13) Age in years, median (IQR)42 (36-49) Age in years, % < >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 ( ) CDC stage C, %34.5%

Patient’s characteristics (II) N=1375Total Current CD4, median (IQR)381 ( ) 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%)

HAART exposure HAART exposure >52 weeks; p< % 73.2% 48.1% 61.3% 75.3%

Proportion Impaired (HAND) HAND (3 yrs incr): OR 0.92 (95% CI ); p= % 44.4% 39.4% 38.2%

Proportion with HAND by CDC stage

HAND predictors, unajusted FactorImpaired (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%0.049 Previous intavenous drug use, %33.9%18.6%<0.001 CDC stage C, %49.4%23.9%<0.001 HCV infection, %50.7%31.0%<0.001 Years of HIV exposure, mean (  SD)8.3 (6.8)6.9 (6.2)<0.001 Current CD4/mm 3, mean (  SD)349 (277)478 (309)<0.001 Nadir CD4/mm 3, mean (  SD)158 (155)231 (193)<0.001 Detectable plasma viral load, %71.3%69.5%0.721 Log10 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

HAND predictors by HAART era, unajusted FactorPre-HAART Early HAART Late HAART OR (95% CI) Age, 10 years incr1.72 ( )1.58 ( )1.56 ( ) Age at 1° HIV test, 10 years incr1.24 ( )1.26 ( )1.23 ( ) Male gender1.95 ( )1.24 ( )1.10 ( ) Previous IDV1.76 ( )2.36 ( )2.45 ( ) CDC stage C2.61 ( )3.66 ( )2.86 ( ) HCV infection1.87 ( )2.41 ( )2.49 ( ) Years of HIV exposure,1 year incr1.11 ( )1.04 ( )1.03 ( ) Current CD4, 100 cells incr0.82 ( )0.78 ( )0.92 ( ) Nadir CD4, 100 cells incr0.79 ( )0.74 ( )0.79 ( ) Log10 HIV-RNA, 1 log incr1.55 ( )1.26 ( )0.76 ( ) Years of ART exposure, 1 year incr0.85 ( )0.94 ( )1.02 ( ) Years of education, 1 year incr0.85 ( )0.83 ( )0.80 ( ) Any cardiovascular risk factor0.58 ( )1.33 ( )1.39 ( ) Delta CD4 (current-nadir), 100 cells incr0.83 ( )0.82 ( )1.01 ( )

HAND predictors, multivariable (n=1.375) FactorOR95% CIp-value Age (10 years increase) <0.001 CDC stage C <0.001 Education (1 year increase) Years of HIV exposure (1 year increase) Previous IVDU HCV infection Current CD4 (100 cells increase) Calendar year, (3 years increase) Years of HAART exposure, (1 year increase) <0.001

Proportion of HAD-MND-ANI HAD + MND (3 yrs incr): OR 0.89 (95% CI ); p= % 27.2% 29.2% 25.4% 19.4% 29.9% 27.2% 29.2% 25.4% 18.4%

Symptomatic (HAD/MND) vs asymptomatic (ANI) predictors, unajusted FactorHAD/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%)0.936 Previous intavenous drug use, %129 (36.0)62 (30.1)0.151 CDC stage C, n. (%)208 (62.7)72 (36.7)<0.001 HCV infection, n. (%)149 (53.6)67 (45.3)0.102 Years of HIV exposure, mean (  SD)8.1 (6.6)8.6 (7.1)0.537 Current CD4/mm 3, mean (  SD)326 (275)390 (278)0.003 Nadir CD4/mm 3, mean (  SD)140 (122)190 (196)0.017 Log10 HIV-RNA, mean (  SD)4.2 (0.04) Calendar year < 2004, n. (%)202 (56.4)107 (51.9)0.303 Years 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)<0.001 Any cardiovascular risk factor*, n. (%)132 (54.5)64 (39.8)0.004 * i.e. diabetes, hypertension, hyperlipedemia, prior myocardial infarction, obesity

Symptomatic (HAD/MND) vs asymptomatic (ANI) predictors, multivariable (n=569) FactorOR95% CIp-value Age (10 years increase) CDC stage C Any cardiovascular risk factor Current CD4 (100 cells increase) Years of education (1 year increase)

NPZ-8, HAND (n=569) β= -0.05; p=0.646 Mean (±SD) Global z-score NP test  p Trail Making A WAIS-R Digit Span (forward) Digit Symbol Trail Making B Rey Auditory Verbal Learning (immediate) Rey Auditory Verbal Learning (after 15 min) Lafayette Grooved Pegboard (dom. hand) Lafayette Grooved Pegboard (non dom. hand)

Concentration and Speed of Mental Processing z-scores, HAND (n=569) Β= -0.08; p=0.263 NP test  p Trail Making A WAIS-R Digit Span (forward) WAIS-R Digit Span (bakward) Digit Symbol Stroop Word and Colour Corsi Cube Mean (±SD) Global z-score

Mental Flexibility z-scores, HAND (n=569)  = -0.01; p=0.861 NP test  p Trail Making B Stroop Colour- Word Controlled Oral Word Mean (±SD) Global z-score

Memory Z-scores, HAND (n=569)  =-0.05; p=0.234 NP test  p Rey Auditory Verbal Learning (immediate) Rey Auditory Verbal Learning (after 15 min) Rey Complex Figure (after 45’)* Mean (±SD) Global z-score * visual memory and spatial perception

NP test  p Rey Auditory Verbal Learning (immediate) Rey Auditory Verbal Learning (after 15 min) Rey Complex Figure (after 45’)* * visual memory and spatial perception Rey Complex Figure Test

NP test  p Rey Auditory Verbal Learning (immediate) Rey Auditory Verbal Learning (after 15 min) Rey Complex Figure (after 45’)* * visual memory and spatial perception Rey Complex Figure Test Rey Complex Figure Test (after 45’): Score 18.5 (n.v. >16)

NP test  p Rey Auditory Verbal Learning (immediate) Rey Auditory Verbal Learning (after 15 min) Rey Complex Figure (after 45’)* * visual memory and spatial perception Rey Complex Figure Test Rey Complex Figure Test (after 45’): Score 18.5 (n.v. >16) Rey Complex Figure Test (after 45’): Score 3.5 (n.v. >16)

Fine Motor Functioning Z-scores, HAND (n=569)  = 0.01; p=0.758 NP test  p Lafayette Grooved Pegboard (dominant hand) Lafayette Grooved Pegboard (non dominant hand) Mean (±SD) Global z-score

Visuospatial and Constructional Abilities Z-scores, HAND (n=569)  = 0.02; p=0.620 NP test  p Rey Complex Figure (copy) Mean (±SD) Global z-score

Study limitations Based exclusively on NP evaluations (i.e.: no CSF, no advanced MRI) Diagnostic Nomenclature changed in 2007 –HAD = HAD –MND  retrospectively*, yrs –ANI  retrospectively*, yrs 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

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

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

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

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