1. HIV Neuropsychiatric Issues Warren Y.K. Ng, M.D. NYPH/ Harlem Hospital HIV Mental Health Training Project Columbia University

2. 28 th Year of AIDS World AIDS Day Dec 1, 2009

3. Twenty-Five year trends in HIV and AIDS cases 1984-2007

4. Good News and Bad News Steven Deeks MD IAS-USA May 2009 Poor life expectancy 10-30 years less “Patients receiving long term antiretroviral therapy are at increased risk of age associated non-AIDS related morbidity/mortality…” Higher rates of non-AIDS dx Cardiovascular disease Cancers Osteopenia LV Dysfunction Liver Failure Kidney Failure Cognitive Decline Accelerated aging/chronic inflammation

5. New York Magazine 11-9-09 The New HIV Scare

6. Article: Another Kind of AIDS Crisis “Brain impairments are the unexpected new minefield among HIV positive people who have been on protease inhibitors. According to research presented this summer … in Capetown, 52 % of all Americans infected with HIV (mean age 43) suffer from some type of cognitive impairment- mostly mild or moderate dementias, … impeding one’s ability to function on a day-to-day basis.”

7. Another Kind of AIDS Crisis CHARTER (CNS HIV antiretroviral therapy effects research) Igor Grant UCSD Started in 2002 $38 million in NIH grants Follows 1500 patients living with HIV Scott Letendre UCSD viral replication in CNS Manhattan HIV Brain Bank 250 volunteers Persistent inflammation, little viral replication High rates of psychiatric/substance abuse disorders

8. Overview of Psychiatric issues Psychiatric disorders are common with Individual living with HIV/AIDS ( Bing 2001, Mellins 2002, McKinnon 2008) 50% Mood and Anxiety disorder 25% current Substance abuse or dependence 26% Personality Disorder Psychiatric dx are linked to slower rates of virologic suppression and treatment (Pence et al 2007) Treatment of Psychiatric disorders is associated Slower disease progression and mortality (Belanoff 2005) Improved treatment adherence (Wyatt 2004) Decrease in HIV transmission risk behavior (Sikkema 2008, Wyatt 2004) Improved quality of life (Sikkema 2005)

9. Assessing Neuropsychiatric issues Look for underlying biological cause 1.Medications: HIV, psychiatric, other 2.Substances: Alcohol, drugs, herbal, other 3.Non-HIV medical problems 4.HIV-related illnesses: CNS lesions, infections Non-CNS medical problems Psychiatric Syndromes HIV-neuropsychiatric manifestations: MCMD HAD and/or

10. Initial Approach to Management  Exclude other treatable causes ▪ MRI to exclude OIs; Labs: thyroid, B12, hematology/chemistry; CSF for OI or VL ▪ Rule out substance abuse issues- crystal meth, ETOH  Self-reports of cognitive problems and bedside cognitive status tests may be insensitive, particularly to subtler forms of impairment  Neuropsychological screeners  Family and collateral history

11. HIV-Neuropsychiatric Manifestations

12. HIV Associated Neurocognitive Disorders (HAND) Asymptomatic neurocognitive impairment (ANI) Minor Cognitive Motor Disorder/ Mild Neurocognitive Disorder HIV Associated Dementia/ Moderate Neurocognitive Disorder

13. Prevalence of HIV Associated Neurocognitive Disorders - HAND NP Normal “Sub-clinical” NP Test Impairment 30-50% MCMD 20% HAD 2-4%  Functional Impairment  NP – Neuro-Psychological Minor Cognitive Motor Disorder – MCMD/Mild Neurocognitive Disorder HIV Associated Dementia – HAD/Moderate-Severe ND) ≠

14. Neuroimaging studies Pre ARV- subcortical & Periventricular White Matter Changes Post ARV- mixed cortical and subcortical features

15. HIV and the CNS HIV enters the central nervous system (CNS) soon after initial infection and is responsible for a range of neuropsychiatric complications HIV enters the central nervous system (CNS) soon after initial infection and is responsible for a range of neuropsychiatric complications Although HIV is neuroinvasive, it does not directly infect neurons Although HIV is neuroinvasive, it does not directly infect neurons The major brain reservoirs for HIV infection and replication are microglia and macrophages. Astrocytes can be infected but are not a site of active HIV replication The major brain reservoirs for HIV infection and replication are microglia and macrophages. Astrocytes can be infected but are not a site of active HIV replication HIV-associated neurological complications are indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxins HIV-associated neurological complications are indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxins

16. Nomenclature of HIV-1 CNS Disorders 1 Mild Manifestations HIV-Associated Mild Cognitive/Motor Disorder (MCMD) HIV-Associated Mild Cognitive/Motor Disorder (MCMD) Mild Neurocognitive Disorder (MND) Mild Neurocognitive Disorder (MND) Diagnostic Criteria 1 At least 2 symptoms: impaired attention, concentration, memory, mental and psychomotor slowing, impaired coordination, personality change. 2 >1 month

17. Minor Cognitive-Motor Disorder/ Mild Neurocognitive Disorder (MND) Minor Cognitive-Motor Disorder/ Mild Neurocognitive Disorder (MND) Clinical Features Mild impairment in functioning Mild impairment in functioning Impaired attention or concentration Impaired attention or concentration Memory/concentratio n problems Memory/concentratio n problems Low energy/slowed movements Low energy/slowed movements Impaired coordination Impaired coordination Personality change, irritability or emotional lability Personality change, irritability or emotional lability Patient Complaints/Symptoms Patients may not recognize the problem since their is mild functional impairment Patients may not recognize the problem since their is mild functional impairment Has difficulty with complex tasks Has difficulty with complex tasks Mild memory problems Mild memory problems Distractibility/confusion Distractibility/confusion Needs to make lists Needs to make lists Adherence problems Adherence problems May make excuses for forgetting May make excuses for forgetting

18. Minor Cognitive-Motor Disorder / Mild Neurocognitive Disorder (MND) Overview Prevalence pre ARV 20-30% for asymptomatic clients 20-30% for asymptomatic clients 60%-90% for late stage clients 60%-90% for late stage clients Prevalence post ARV 5%, 15% & 25% in asymptomatic, early or late stage 5%, 15% & 25% in asymptomatic, early or late stage Possible Risk Factors Age, late stage disease, viral load Age, late stage disease, viral load

19. Minor Motor-Cognitive Disorder / Mild Neurocognitive Disorder (MND) Often does not present for any treatment and not recognized nor diagnosed Differential Diagnosis: Diagnosis of Exclusion Treatment Antiretroviral medications Antiretroviral medications Neurotransmitter manipulation Neurotransmitter manipulation Non-pharmacological treatments and issues Non-pharmacological treatments and issues

20. Nomenclature of HIV-1 CNS Disorders 2 Severe Manifestations HIV-Associated Dementia (HAD) HIV-Associated Dementia (HAD) Moderate to severe neurocognitive disorder Moderate to severe neurocognitive disorder Diagnostic Criteria 1 Acquired cognitive abnormality in 2 or more domains, causing functional impairment 2 Acquired abnormality in motor performance or behavior 3 No clouding of consciousness or other confounding etiology (e.g. other CNS OIs, psychopathology, drug abuse)

21. HIV-Associated Dementia (HAD)/ Moderate to Severe Neurocognitive Disorder Clinical Features Cognitive, motor, and behavioral problems Attention/concentrati on problems Slowed decision- making Abstraction/reasonin g problems Visuospatial skill problems Memory/learning impairment Speech/language problems Patient Complaints, Symptoms Memory problems/“I’m very forgetful” Memory problems/“I’m very forgetful” Distractibility/“I lose track of conversations” Distractibility/“I lose track of conversations” “I can’t keep up with work” “I can’t keep up with work” Anger/irritability Anger/irritability Fatigued/slow Fatigued/slow “I am depressed”/sadness “I am depressed”/sadness Complains of poor balance, clumsiness Complains of poor balance, clumsiness

22. HIV-Associated Dementia (HAD)/ Moderate to Severe Neurocognitive Disorder Overview Prevalence pre ARV Early studies estimated 15-20% Early studies estimated 15-20% Current studies estimate 5-10% Current studies estimate 5-10% Prevalence post ARV Prevalence post ARV 50% reduction; not as prominent as other CNS OIs 50% reduction; not as prominent as other CNS OIs Possible Risk Factors Older age, low CD4 count, high viral load, drug interactions, co-infections, gender, previous delirium Older age, low CD4 count, high viral load, drug interactions, co-infections, gender, previous delirium

23. HIV-Associated Dementia (HAD)/ Moderate to Severe Neurocognitive Disorder Differential Diagnosis: Diagnosis by Exclusion Treatment Antiretroviral medications Antiretroviral medications Neurotransmitter manipulation Neurotransmitter manipulation Non-pharmacological treatments Non-pharmacological treatments Environmental engineering Environmental engineering Education Education Supportive Therapy Supportive Therapy

24. HIV-Associated Dementia (HAD)/ Moderate to Severe Neurocognitive Disorder ARV and HAD: Improvement in Cognitive Status ARV and HAD: Improvement in Cognitive Status Improvement in immune status? Improvement in immune status? Increased CD4 cell count and decrease in plasma viral load and cerebral spinal fluid (CSF) viral load Increased CD4 cell count and decrease in plasma viral load and cerebral spinal fluid (CSF) viral load Some studies, CSF HIV viral load correlates with severity of cognitive dysfunction, particularly if CD4 <200 Some studies, CSF HIV viral load correlates with severity of cognitive dysfunction, particularly if CD4 <200 Measurement of viral load in CSF is a research tool, rather than routine standard of care Measurement of viral load in CSF is a research tool, rather than routine standard of care

25. HIV Dementia Scale Screening Test Score Memory-Registration Give four words to recall (dog, hat, green, peach) - 1 second to say each. Then ask the patient all 4 after you have said them.) 4 Attention Anti-saccadic eye movements 1 : 20 (twenty) commands. ____ errors of 20 trials. (less than or equal to 3 errors = 4; 4 errors = 3; 5 errors = 2; 6 errors = 1; > 6 errors = 0) 6 Psychomotor Speed Ask patient to write the alphabet in upper case letters horizontally across the page (use back of this form) and record time: ___seconds. (less than or equal to 21 sec = 6; 21.1 - 24 sec = 5; 24.1 - 27 sec = 4; 27.1 - 30 sec = 3; 30.1 - 33 sec = 2; 33.1 - 36 sec = 1; > 36 sec = 0) 4 Memory - Recall Ask for 4 words from Registration above. Give 1 point for each correct. For words not recalled, prompt with a "semantic" clue, as follows: animal (dog); piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each correct after prompting. 2Construction Copy the cube; record time: __ seconds. ( 35 sec = 0) 16 (10 or less ~ HIV dementia) (10 or less ~ HIV dementia) 1 Hold both hands up at patient's shoulder width and eye height, and ask patient to look at your nose. Move the index finger of one hand, and instruct patient to look at the finger that moves, then look back to your nose. Practice until patient is familiar with task. Then, instruct patient to look at the finger which is NOT moving. Practice until patient understands task. Perform 20 trials. An error is recorded when the patient looks towards the finger that is moving.

26. HIV Dementia Scale Screening Test (modified) Score Memory-Registration Give four words to recall (dog, hat, green, peach) - 1 second to say each. Then ask the patient all 4 after you have said them.) 6 Psychomotor Speed Ask patient to write the alphabet in upper case letters horizontally across the page (use back of this form) and record time: ___seconds. (less than or equal to 21 sec = 6; 21.1 - 24 sec = 5; 24.1 - 27 sec = 4; 27.1 - 30 sec = 3; 30.1 - 33 sec = 2; 33.1 - 36 sec = 1; > 36 sec = 0) 4 Memory - Recall Ask for 4 words from Registration above. Give 1 point for each correct. For words not recalled, prompt with a "semantic" clue, as follows: animal (dog); piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each correct after prompting. 2Construction Copy the cube; record time: __ seconds. ( 35 sec = 0) 12 (7.5 or less ~ HIV dementia) (7.5 or less ~ HIV dementia)

27. Screening for HIV Associated Neurocognitive Disorders – HAND: MOS HIV Cognitive Functional Status Scale 1. Difficulty reasoning and solving problems? 2. Forget things that happened recently? 3. Trouble keeping your attention on any activity? 4. Difficulty doing activities involving concentration and thinking? Validated against NP overall performance Knippels et al., AIDS 2002

28. Mainstay of Treatment for Neurocognitive Disorders Is ARV

29. NP Improvement with ARV Greater numbers of CSF-penetrating drugs showed greater reduction in CSF viral load. Greater numbers of CSF-penetrating drugs showed greater reduction in CSF viral load. CSF virological suppression demonstrated greater global deficit score (GDS) improvement CSF virological suppression demonstrated greater global deficit score (GDS) improvement NP improvement was greater in ART-naive versus treatment-experienced subjects. NP improvement was greater in ART-naive versus treatment-experienced subjects. Including CSF-penetrating drugs in the ART regimen and monitoring CSF viral load Including CSF-penetrating drugs in the ART regimen and monitoring CSF viral load Letendre et al., Ann Neurol 2004

30. Conceptualization of CNS Treatment Strategies Antiretroviral medications with higher CPE stavudine (D4T) stavudine (D4T) zidovudine (ZDV) zidovudine (ZDV) abacavir (ABV) abacavir (ABV) efavirenz (EFV) efavirenz (EFV) nevirapine (NVP) nevirapine (NVP) indinavir (IDV) indinavir (IDV) lamivudine (3TC) lamivudine (3TC)

31. CNS penetration-effectiveness (CPE) Rank CNS penetration-effectiveness (CPE) Rank CHARTER Study (CNS HIV Antiretroviral Therapy Effects Research) 0Low 0Low 0.5 Intermediate 0.5 Intermediate 1 High 1 High Based on chemical properties (large molecular weight) Based on chemical properties (large molecular weight) concentrations in CSF (measurable animal/human) concentrations in CSF (measurable animal/human) effectiveness in CNS in clinical studies effectiveness in CNS in clinical studies Letendre et al., 2008

32. CNS penetration–effectiveness (CPE) score to estimating HAART ability to improve cognition n = 92 at risk for, and n = 93 with HIV-associated neurocognitive disorders underwent neuropsychological (NP) testing before HAART initiation and at follow-up Higher CPE scores correlated with greater improvements in NP testing Higher CPE scores correlated with greater improvements in NP testing The correlation was stronger among NP-impaired patients. The correlation was stronger among NP-impaired patients. No association was seen between CD4 and plasma viral load changes with both scores. No association was seen between CD4 and plasma viral load changes with both scores. CPE scores 1 high zidovudine, abacavir, delavirdine,nevirapine, amprenavir-ritonavir, fosamprenavir-ritonavir, atazanavir-ritonavir, indinavir-ritonavir, lopinavir-ritonavir 0.5 intermediate stavudine, lamivudine, emtricitabine, efavirenz, amprenavir, fosamprenavir atazanavir, indinavir 0 low remaining antiretrovirals Tozzi et al, J Acquir Immune Defic Syndr 2009;52:56–63

33. Copyright restrictions may apply. Letendre et al., Arch Neurol 2008 Subjects who had lower CNS Penetration-Effectiveness (CPE) ranks were more likely to have detectable cerebrospinal fluid (CSF) viral load when CPE rank was analyzed as a continuous variable (A) or as a categorical variable (B)

34. How important is CPE? In theory, this is an important issue since the use of “neuroactive” HAART regimens appears promising However, standardized CPE ratings and specific clinical guidelines for antiretroviral medications At this time, the selection of antiretroviral regimens must be based on sensitivity/resistance patterns Adherence issues quality of life considerations

35. Conceptualization of CNS Treatment Strategies Adjuvant agents (SSRIs, SNRIs, Stimulants, Modafinil, others) Adjuvant agents (SSRIs, SNRIs, Stimulants, Modafinil, others) Rehabilitative Rehabilitative Supportive therapy and cognitive skills training Supportive therapy and cognitive skills training Anti-inflammatory agents: Vitamin E, Selenium Anti-inflammatory agents: Vitamin E, Selenium If deficient: If deficient: Hormone (replace/supplement): Testosterone, DHEA Hormone (replace/supplement): Testosterone, DHEA Nutritional interventions: Vitamin E, B6, B12, Zinc, Selenium, SAM, Folate, Omega-3 fatty acids Nutritional interventions: Vitamin E, B6, B12, Zinc, Selenium, SAM, Folate, Omega-3 fatty acids

36. Conclusion HIV Neuropsychiatric Manifestations Disease of the immune system and CNS HIV Assoc Neurocognitive Disorders (HAND) and new terms ANI, Mild-severe ND Increasingly prevalent with advancing age CHARTER recommendations regarding HAND Primary focus of treatment is ARVs Neuroactive HAART regimens ARV Adherence is critical Symptomatic improvement is secondary