1. www.ias2011.org 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

2. www.ias2011.org Rationale HAND 2011 Still frequent Often not diagnosed Increased risk of death (poster TUPE 204) Reduced adherence Poor QoL

3. www.ias2011.org 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

4. www.ias2011.org 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

5. www.ias2011.org 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

6. www.ias2011.org 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)

7. www.ias2011.org 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

8. www.ias2011.org 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

9. www.ias2011.org 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

10. www.ias2011.org 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

11. www.ias2011.org 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

12. www.ias2011.org Patient’s characteristics (I) N=1375Total Male gender, %74.8% Education in years, % <10 10-15 >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, % <30 30-39 40-55 >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%

13. www.ias2011.org Patient’s characteristics (II) N=1375Total 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%)

14. www.ias2011.org HAART exposure HAART exposure >52 weeks; p<0.001 23.2% 73.2% 48.1% 61.3% 75.3%

15. www.ias2011.org 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% 38.2%

16. www.ias2011.org Proportion with HAND by CDC stage

17. www.ias2011.org 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

18. www.ias2011.org HAND predictors by HAART era, unajusted FactorPre-HAART 1996-1998 Early HAART 1999-2004 Late HAART 2005-2010 OR (95% CI) Age, 10 years incr1.72 (1.21-2.44)1.58 (1.28-1.93)1.56 (1.32-1.84) Age at 1° HIV test, 10 years incr1.24 (0.93-1.65)1.26 (1.05-1.51)1.23 (1.07-1.41) Male gender1.95 (1.13-3.38)1.24 (0.82-1.86)1.10 (0.74-1.63) Previous IDV1.76 (1.07-2.89)2.36 (1.60-3.48)2.45 (1.54-3.89) CDC stage C2.61 (1.58-4.32)3.66 (2.50-5.36)2.86 (1.99-4.09) HCV infection1.87 (1.12-3.12)2.41 (1.65-3.53)2.49 (1.53-4.05) Years of HIV exposure,1 year incr1.11 (1.04-1.19)1.04 (1.01-1.07)1.03 (1.01-1.05) Current CD4, 100 cells incr0.82 (0.71-0.95)0.78 (0.73-0.84)0.92 (0.87-0.98) Nadir CD4, 100 cells incr0.79 (0.63-1.01)0.74 (0.66-0.82)0.79 (0.71-0.88) Log10 HIV-RNA, 1 log incr1.55 (1.09-2.21)1.26 (1.03-1.53)0.76 (0.59-0.97) Years of ART exposure, 1 year incr0.85 (0.60-1.23)0.94 (0.87-1.01)1.02 (0.98-1.06) Years of education, 1 year incr0.85 (0.79-0.92)0.83 (0.79-0.88)0.80 (0.76-0.84) Any cardiovascular risk factor0.58 (0.30-1.12)1.33 (0.89-2.00)1.39 (0.98-1.98) Delta CD4 (current-nadir), 100 cells incr0.83 (0.69-1.00)0.82 (0.76-0.90)1.01 (0.94-1.07)

19. www.ias2011.org HAND predictors, multivariable (n=1.375) FactorOR95% CIp-value Age (10 years increase)1.511.26-1.79<0.001 CDC stage C2.391.76-3.25<0.001 Education (1 year increase)0.920.86-0.990.016 Years of HIV exposure (1 year increase)1.031.00-1.060.090 Previous IVDU1.190.78-1.810.422 HCV infection1.471.00-2.180.052 Current CD4 (100 cells increase)0.920.87-0.970.002 Calendar year, (3 years increase)1.030.89-1.200.657 Years of HAART exposure, (1 year increase)0.870.83-0.91<0.001

20. www.ias2011.org Proportion of HAD-MND-ANI HAD + 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%

21. www.ias2011.org 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) 0.225 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

22. www.ias2011.org Symptomatic (HAD/MND) vs asymptomatic (ANI) predictors, multivariable (n=569) FactorOR95% CIp-value Age (10 years increase)1.031.00-1.050.028 CDC stage C2.061.31-3.230.002 Any cardiovascular risk factor1.711.08-2.720.023 Current CD4 (100 cells increase)0.920.85-0.990.029 Years of education (1 year increase)0.920.87-0.970.005

23. www.ias2011.org NPZ-8, HAND (n=569) β= -0.05; p=0.646 Mean (±SD) Global z-score NP test  p Trail Making A-0.010.176 WAIS-R Digit Span (forward) 0.060.245 Digit Symbol0.020.712 Trail Making B-0.020.298 Rey Auditory Verbal Learning (immediate) -0.050.188 Rey Auditory Verbal Learning (after 15 min) -0.030.410 Lafayette Grooved Pegboard (dom. hand) 0.000.864 Lafayette Grooved Pegboard (non dom. hand) 0.010.661

24. www.ias2011.org Concentration and Speed of Mental Processing z-scores, HAND (n=569) Β= -0.08; p=0.263 NP test  p Trail Making A-0.010.176 WAIS-R Digit Span (forward) 0.060.245 WAIS-R Digit Span (bakward) 0.020.735 Digit Symbol0.020.712 Stroop Word and Colour -0.040.069 Corsi Cube-0.060.234 Mean (±SD) Global z-score

25. www.ias2011.org Mental Flexibility z-scores, HAND (n=569)  = -0.01; p=0.861 NP test  p Trail Making B-0.020.298 Stroop Colour- Word -0.010.648 Controlled Oral Word 0.040.341 Mean (±SD) Global z-score

26. www.ias2011.org Memory Z-scores, HAND (n=569)  =-0.05; p=0.234 NP test  p Rey Auditory Verbal Learning (immediate) -0.050.188 Rey Auditory Verbal Learning (after 15 min) -0.030.410 Rey Complex Figure (after 45’)* 0.130.007 Mean (±SD) Global z-score * visual memory and spatial perception

27. www.ias2011.org NP test  p Rey Auditory Verbal Learning (immediate) -0.050.188 Rey Auditory Verbal Learning (after 15 min) -0.030.410 Rey Complex Figure (after 45’)* 0.130.007 * visual memory and spatial perception Rey Complex Figure Test

28. www.ias2011.org NP test  p Rey Auditory Verbal Learning (immediate) -0.050.188 Rey Auditory Verbal Learning (after 15 min) -0.030.410 Rey Complex Figure (after 45’)* 0.130.007 * visual memory and spatial perception Rey Complex Figure Test Rey Complex Figure Test (after 45’): Score 18.5 (n.v. >16)

29. www.ias2011.org NP test  p Rey Auditory Verbal Learning (immediate) -0.050.188 Rey Auditory Verbal Learning (after 15 min) -0.030.410 Rey Complex Figure (after 45’)* 0.130.007 * 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)

30. www.ias2011.org Fine Motor Functioning Z-scores, HAND (n=569)  = 0.01; p=0.758 NP test  p Lafayette Grooved Pegboard (dominant hand) 0.000.864 Lafayette Grooved Pegboard (non dominant hand) 0.010.661 Mean (±SD) Global z-score

31. www.ias2011.org Visuospatial and Constructional Abilities Z-scores, HAND (n=569)  = 0.02; p=0.620 NP test  p Rey Complex Figure (copy) 0.020.620 Mean (±SD) Global z-score

32. www.ias2011.org 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

33. www.ias2011.org 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

34. www.ias2011.org 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

35. www.ias2011.org 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

36. www.ias2011.org 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