Neuropsychological Outcomes in PLWHA Initiating HAART: Thoughts from the Epicentre

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 InstructionsRe 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. Global distribution of HIV subtypes Thomson et al. 2009 A B C 02 06 07/08 11 12 19 D G 01 33 F Subtypes/CRF

11. Viral factors: Clade C • CladeC may differ from B in terms of : • Protein binding sites, binding characteristics, replicativecapacity • Functional relevance: • The mutation associated with reduced monocytechemokine 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 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) *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. 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 MINI / AUDIT / CES-D / SAMISS Neurological Domains: Attention/Concentration, Memory (verbal and visual), Psychomotor/ speed of processing, Executive, Language, Intelligence

27. Test Performance HIV+ vs HIV- : Tests included in analyses

28. HIV-associated neurocognitive disorders in primary care, Cape Town 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. Characteristics of Retained group: HAART vs non-HAART Non-HAART: 15 high CD4, 6 erratic attenders, 1 used HAART for 1/12 Individual Neuropsychological Tests all NS except: CT1, Stroop, Animals

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

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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