1. Neuropsychological Outcomes in PLWHA Initiating HAART: Thoughts from the Epicentre Columbia University, HIV Center, Grand Rounds 03 March 2011 John A. Joska Director, GSH-HIV Mental Health Group Department of Psychiatry and Mental Health University of Cape Town

2. Summary of talk HIV is highly prevalent in South Africa HAND is documented to be highly prevalent in HIV Both *epidemics* may be different in SA The effects of HAART may be different In what ways can we – Understand HAND better – Improve screening for HAND / raise awareness – Provide support to *many* PLWHA with HAND

4. HIV/AIDS South Africa Progress Report 2010 “ HIV in South Africa is transmitted predominantly heterosexually between couples, with mother-to-child transmission being the other main infection route. Drivers of the epidemic in South Africa are intergenerational sex, multiple concurrent partners, low condom use, excessive use of alcohol and low rates of male circumcision.” Dr Aaron Motsoaledi, Minister of Health, South Africa Antenatal data 2008

5. Prevalence of HIV-Associated Neurocognitive Disorders (HAND) by Stage of HIV Disease

6. The problem of HIV-D HIV seroprevalence in SA adults 18% >20 000 in Wcape entering stage 4 per year 50% will get HAART >25% of ALL will have diagnosable HAND 5-10% will be HIV-D Untreated HIV-D: mean time to death 6/12 Treated HIV-D: mean time to death 44/12 HAND exerts many other deleterious effects

7. Although HAART improves health and prolongs survival, NeuroAIDS remains prevalent

8. Adherence to Antiretrovirals Related to Neurocognitive Impairment % That Followed Schedule “Most of the Time” % That Followed Specific Instructions Re Meds “Most of the Time” Slide courtesy of Igor Grant

9. Differences between global HIV and SA Prevalence: 10.5%... 18%... 29%... Mode of transmission (recombinants?) Gender (70:30) Poverty, malnutrition Viral factors: clade (B vs C)

10. ABC D F G01 020607/08111219 33 Subtypes/CRF Thomson et al. 2009 Global distribution of HIV subtypes

11. Viral factors: Clade C Clade C may differ from B in terms of : – Protein binding sites, binding characteristics, replicative capacity – Functional relevance: The mutation associated with reduced monocyte chemokine migration CNS relevance: – Tat is involved in the migration of monocytes into the brain via upregulation of inflammatory cytokines and adhesion molecules. – Tat also disrupts the tight-junctions in the BBB – Tat may exert direct or indirect neurotoxic effects on glia/neurons – Possibly in neurotoxicity and risk for cognitive impairment

12. HI Viral Genome: Cape Town: South Africa: Viral Sequencing in 65 PLWH Attending Primary Care Facilities gagpolTat 1 vif_vprTat 2 RevSubtype C493344413649 A411011 B010100 Other010100 Recombinant000008 Joska, Engelbrecht- unpublished data

14. Questions: A Pilot Study of HAND in Cape Town, South Africa How prevalent is HAND in clade C What are the demographic and clinical associations Does apolipoprotein E confer vulnerability Is it possible to screen for HIV-D using an existing brief tool How do PLWH respond to HAART

16. Updated Nosology for HAND: American Academy / HNRC (Antinori et al 2007) NormalAsymptomatic Neuropsychological Impairment (ANI) Mild Neurocognitive Disorder HIV- Associated Dementia (HIV-D) Neuropsychology * No worse than 1.0 SD on one domain ≥ 1.0 SD below mean on ≥ 2 domains ≥ 2.0 SD below mean on ≥ 2 domains Function No impairment on self-report of knowledgable others No impairment on self-report or from knowledgeable others *Mild*impairment on self- report or from knowledgeable others *Marked*impairment on self-report or from knowledgeable others Exclusion No other condition, esp delirium, MDD or substances No other condition, esp delirium, MDD or substances “MDD+HIV-D= HIV-D” *Must sample: verbal/language; attention/working memory; abstraction/executive; memory (learning; recall); speed of information processing; sensory-perceptual, motor skills

17. Issues: Neuropsychology Norms – Age, education, gender, and ethnicity – May affect rates of impairment by up to 50% – CT studies: 50-100 controls… norms Test administration – Language of testing – Competency of tester – Approx 30 of first participants tested in… English Domains – IHDS= memory and motor – 2 tests across at least 3 domains desirable

18. Language of Testing: Tests Used to Quantify HAND

19. Issues: Functional Assessment Should be assessed using either/and – Self-report – Report of “knowledgable” person – Objective measure Functional data should be obtained using “standardized instruments” and ideally with “norms” Needs to measure cognitive abilities and iADLs – Meds, finances, shopping, cooking, housekeeping, driving, working We used PAOFI and CT ADL – Pts under-rate impairment; most unemployed; most have limited access to “instruments”; “knowledgeable others” not readily available.

20. Meaning of NP Impairment: Employment

22. DomainSelf-reportCollateral reportObjective assessment MemoryCell-phone number, shopping list CommunicationListening to cell- phone instructions Use of hands/fingers Dialling a number Financial/moneyMaking change from a taxi Towards a Valid Brief Functional Assessment Tool for South Africa (or the developing world?)

23. Issues: Exclusion HIV-related OI’s and tumours Developmental e.g. ADHD/ ID Neuropsychiatric e.g. depression and substance – Wait a month; although if HIV-D present= HIV-D Unrelated neurological e.g. epilepsy, TBI What to do: MINI / scales, self-report, neuromedical examination, ?which special investigations- Hep C*, RPR*, CTB*, LP*, nutritional parameters – Resources, based on level of suspicion.

24. Approach: Cape Town *Neuropsychological Assessment* Neuropsychiatric Assessment Functional Assessment PAOFI / CTADL / QLESQ Neurological MINI / AUDIT / CES-D / SAMISS Domains: Attention/Concentration, Memory (verbal and visual), Psychomotor/ speed of processing, Executive, Language, Intelligence

25. Clinical staging of neurocognitive status : Marder et al 2008 MSK stageNEAD modificationFeaturesNew AAN criterion Grooved pegboard (non- dom) IHDS scoreIHDS category Stage 0 (normal) NP normalNormalN/A0.35 (0.5) 11,12 0. No impairment Stage 0.5 (sub- clinical) NP normal with CNS/ADL problem OR NP=1 with no CNS/ADL Mild features, no impairment Asymptomatic neuropsycholgical impairment (ANI) -1.1 (1.2) 10 0. No impairment Stage 1 (mild HIV- D) NP=1 with CNS/ADL problems OR NP=2 with no CNS/ADL problems Clear NP problem, mild ADL problem, walking Mild neurocognitive disorder (MND) -2.2 (2.8) 91. Mild NCD Stage 2 (moderate HIV-D) NP=2 with CNS/ADL problems, but not severe Basic ADLs fine, others impaired, walking perhaps cane HIV-associated dementia (HAD or HIV- D) -3.8 (3.1) 8 2. HIV-D (moderate) Stage 3 (severe HIV- D) NP=2 or 3 and moderate to severe problems CNS/ADL Severe cognitive OR psychomotor problems, walks with assistance HIV-associated dementia (HAD or HIV- D) -18.1 6,7 2. HIV-D (severe) Stage 4 (v severe/end stage HIV-D) Unable to test, unable to walk Nearly vegetative, paretic, incontinent HIV-associated dementia (HAD or HIV- D) <6 2. HIV-D (severe)

27. Test Performance HIV+ vs HIV- : Tests included in analyses HIV negative controls (n=93) HIV positive participants (n=96)P value Age25.16 (5.15)29.75 (3.67)0.000 Education10.88 (1.28)10.05 (1.77)0.000 Gender female (%)58 (62.4)76 (79.2)0.790 CD4 cell count218.09 (150.57) Years since diagnosis3.35 (2.04) Screener IHDS total10.89 (1.10)10.29 (1.55)0.005 IHDS FT subscore3.88 (0.36)3.52 (0.79)0.000 IHDS hand sequence subscore3.21 (0.88)3.22 (0.92)0.937 IHDS 4-word recall3.78 (0.59)3.35 (0.91)0.000 Motor FT non-dom 6.77 (1.71)8.87 (2.08) 0.000 GP non-dom 78.36 (12.54)87.05 (25.46) 0.004 Memory HVLT recall 8.07 (2.07)7.03 (2.09) 0.001 BVMT recall 8.97 (2.92)6.52 (3.50) 0.000 Attention MAT 16.47 (6.43)16.76 (5.20) 0.747 Mental control 23.67 (5.93)19.48 (5.62) 0.000 Psychomotor processing Digit symbol 46.83 (14.62)40.72 (13.18) 0.003 TMTA 40.18 (16.31)60.56 (32.41) 0.000 Colour I 54.66 (21.10)53.21 (16.93) 0.605 Executive Colour II 115.48 (50.98)122.27 (48.47) 0.350 RCF copy 32.82 (3.87)29.26 (6.34) 0.000 Stroop C/W 33.66 (9.57)27.91 (9.24) 0.000 WCST per errors 31.92 (19.68)45.34 (25.41) 0.000 Language animal 15.80 (4.64)13.27 (4.67) 0.000 fruit & veg 15.11 (3.61)13.70 (4.07) 0.013

28. HIV-associated neurocognitive disorders in primary care, Cape Town Neurocognitive disorder category (n=170) (%) Normal ANIMNDHIV-Dstatistical value No (%)40 (23.5)15 (8.8)72 (42.4)43 (25.3) Demographics Women, no (%)33 (82.5)11 (73.3)53 (73.6)29 (69.1)Fisher's exact= 0.551 Left handed, No (%)35 (87.5)14 (93.3)66 (91.7)39 (90.7)Fisher’s exact= 0.903 Language isiXhosa, no (%)34 (85)14 (93.3)63 (87.5)40 (93)Fisher’s exact= 0.203 Age, median (IQR)30.5 (27.5-32)28 (25-31)28.5 (26-32)31 (28-33)chi-sq=8.420, p=0.038 Education, median (IQR)11 (11-12)9 (9-11)10 (9-11)10 (8-11)chi-sq=18.215, p=0.0003 Medical CD4, median (IQR)172 (126-190)205 (148-235) 174.5 (116.5- 236.5) 139 (97-182)chi sq=7.76, p=0.0512 Peripheral neuropathy, no (%) 37 (64.86)15 (26.67)69 (60.87)39 (61.54)Fisher’s exact= 0.072 AUDIT0 (0)1 (0)2 (0)3 (0)chi sq=0.925, p=0.815 CES-D0 (0)1 (0)2 (0)3 (0)chi sq=1.000, p=0.815 Joska et al, Aids and Behaviour Epub

30. Newborns from the same community have higher frequency of E2,2 Joska et al, J. Neurovirol 2010

31. Apoliprotein E4 is not associated with the development of HIV-D in South Africa

33. Characteristics of Participants: Retained vs Non-retained

34. Individual Neuropsychological Tests all NS except: CT1, Stroop, Animals Non-HAART: 15 high CD4, 6 erratic attenders, 1 used HAART for 1/12 Characteristics of Retained group: HAART vs non-HAART

35. Characteristics of Retained group: HAART vs non-HAART cont.

36. HAART initiators improved *more*

37. Predictors of NP Change

38. Patterns of HIV-D in HAART era McArthur 2004

39. Explaining NP Improvement Whole group (HAART and non-HAART) Non-HAART group small Practice/ test-experience effect – Language of testing – Experienced technicians (IRR?) HAART does not appear to produce deterioration in our population LTFU’s remove the ?non-improvers (ITT analysis) HAART: suppresses peripheral VL, reduces HIV entry into CNS, reduces frank inflammatory processes in a severely immuno-compromised group (?but not micro-inflammation)

40. Towards a model of Neurocognitive Outcomes Neuro- psychological Impairment Age Duration of Infection Testing methodology Comorbidity: depression Pre-morbidity: ETOH, Meth, TBI EducationIntelligence Genes: APOE, MCP-1, et al Inflammatory response HIV sub-type / viral factors HAART: CPE/ Metabolic/ Neurotoxic effects Age-related decline: Metabolic/ vascular/ SDAT

41. Screening for neurocognitive disorders: The IHDS Cut-off score <10: Sensitivity 80%, Specificity 55% Sacktor et al 2005

42. Performance of the IHDS in Cape Town

43. Cut-off points of the IHDS: is 11 better than 10? Joska et al, Aids Patient Care and STDs 2011

44. Conclusions HAART appears to result in significant NP improvement in PLWH infected with predominantly clade C HIV. Technical problems with study potential cloud findings Future study: – Matching group with similar disease characteristics – Careful immunological profiling at visits – NP technical issues/ testing environment/ norms – Imaging (MRS) plus …CSF

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