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Mental health considerations in the evolving face of HIV/AIDS – focus on neurocognitive disorders Mark Halman MD FRCP(C) Director, HIV Psychiatry Program,

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Presentation on theme: "Mental health considerations in the evolving face of HIV/AIDS – focus on neurocognitive disorders Mark Halman MD FRCP(C) Director, HIV Psychiatry Program,"— Presentation transcript:

1 Mental health considerations in the evolving face of HIV/AIDS – focus on neurocognitive disorders Mark Halman MD FRCP(C) Director, HIV Psychiatry Program, St Michael’s Hospital Consulting Psychiatrist, Casey House Hospice Associate Professor, University of Toronto Associate Scientist, Centre for Research on Inner City Health, The Keenan Research Centre in the Li Ka Shing Knowledge Institute

2 Cognitive disorders in HIV + patients “My brain is not working properly” HIV brain infection HIV brain infection CNS brain opportunistic infection/conditions CNS brain opportunistic infection/conditions –Toxoplasmosis, PML, cryptococcal meningitis, CMV, lymphoma, syphilis, malaria, TB Other medical conditions affecting brain Other medical conditions affecting brain –Including aging related concerns Depression & anxiety Depression & anxiety Substance misuse Substance misuse

3 Common neurocognitive symptoms Memory: I’m forgetful; my short-term memory is not as good; I keep misplacing things Memory: I’m forgetful; my short-term memory is not as good; I keep misplacing things Word finding/retrieval difficulties: I have trouble remembering people’s names; the word is on the tip of my tongue Word finding/retrieval difficulties: I have trouble remembering people’s names; the word is on the tip of my tongue Concentration: I am easily distracted; I have trouble focusing; I can’t do several things at once anymore Concentration: I am easily distracted; I have trouble focusing; I can’t do several things at once anymore Slowing: I am a lot slower, both mentally and physically, apathy Slowing: I am a lot slower, both mentally and physically, apathy Motor concerns: dyscoordination, fine motor difficulties, psychomotor inefficiency, gait disturbance/ataxia Motor concerns: dyscoordination, fine motor difficulties, psychomotor inefficiency, gait disturbance/ataxia Problems noted by others: my boss is concerned that my productivity is down and that I am making more errors at work Problems noted by others: my boss is concerned that my productivity is down and that I am making more errors at work

4 HIV Associated Neurocognitive Disorders Etiology HIV enters the brain early after initial infection. HIV enters the brain early after initial infection. HIV resides in astrocytes and monocyte – macrophage cells. HIV resides in astrocytes and monocyte – macrophage cells. HIV associated neurocognitive disorders are presumably due to the toxic effects on brain parenchyma of virus and viral proteins and the neurotoxic effects of inflammatory products released in response to brain HIV replication and sequestration. HIV associated neurocognitive disorders are presumably due to the toxic effects on brain parenchyma of virus and viral proteins and the neurotoxic effects of inflammatory products released in response to brain HIV replication and sequestration. Because of the blood brain barrier and drug efflux transport mechanisms, the brain may act as separate reservoir of HIV infection. ART may not have as much impact on brain parenchymal infection as it does on systemic infection. Because of the blood brain barrier and drug efflux transport mechanisms, the brain may act as separate reservoir of HIV infection. ART may not have as much impact on brain parenchymal infection as it does on systemic infection.

5 Proposed Updated Case Definitions: HIV Associated Neurocognitive Disorders (Antinori et al, Neurology 2007) HIV Associated Dementia (HAD) HIV Associated Dementia (HAD) HIV Associated Mild Neurocognitive Disorder (MND) HIV Associated Mild Neurocognitive Disorder (MND) Asymptomatic Neurocognitive Impairment (ANI) Asymptomatic Neurocognitive Impairment (ANI) –Increased focus on cognitive performance –ANI & MND defined by performance < 1 SD below mean of demographically adjusted normative scores in two cognitive areas –HAD performance < 2 SD below mean of demographically adjusted normative scores in two cognitive areas

6 Locating neurocognitive impairment with respect to clinical state. (Reger 2002, JINS) Compared with HIV- controls: Compared with HIV- controls: –Small Effect size (ES) in asymptomatic HIV+: retrieval, naming –Small - moderate ES in symptomatic HIV+: information processing speed, problem solving/executive function, language –Moderate - large ES for AIDS: motor function, problem solving/executive function, information processing speed, immediate visual memory, language, visual construction

7 Locating neurocognitive impairment with respect to ART treatment Progressive neurocognitive decline in the previously untreated Progressive neurocognitive decline in the previously untreated Chronic active neurocognitive impairment in those treated with ART, with variable viral load control Chronic active neurocognitive impairment in those treated with ART, with variable viral load control Chronic active neurocognitive impairment in those treated with ART and sustained systemic viral load control (presumed lack of impact of ART on brain parenchyma) Chronic active neurocognitive impairment in those treated with ART and sustained systemic viral load control (presumed lack of impact of ART on brain parenchyma) Chronic Inactive neurocognitive impairment in those with prior dementia and stable deficits post-ART (head injury model) Chronic Inactive neurocognitive impairment in those with prior dementia and stable deficits post-ART (head injury model)

8 HIVAssociated Dementia: Incidence HIV dementia incident cases are rare HIV dementia incident cases are rare San Francisco AIDS Case suveillance: San Francisco AIDS Case suveillance: –1991: 3.71 per 100 persons living with AIDS –2003: 0.24 per 100 persons living with AIDS –(Dilley 2005, AIDS) Patients who are marginalized and unable to actively access preventative health care or maintain ART adherence Patients who are marginalized and unable to actively access preventative health care or maintain ART adherence Patients who have survived with HIV disease for many years but have not achieved adequate viral load control and have developed multi class drug resistance Patients who have survived with HIV disease for many years but have not achieved adequate viral load control and have developed multi class drug resistance

9 HIV associated neurocognitive impairment: prevalence HIV associated neurocognitive impairment: prevalence (Robertson: AIDS, 2007) ALLRT observational cohort ALLRT observational cohort –14 ACTG linked ART studies –3 naïve, 9 experienced, 2 both (50% of subjects were ART naïve, 47% nadir CD4 < 200) Neuroscreen Neuroscreen –Baseline at least 20 weeks after parent study entry, follow up at 48 weeks –Trails A & B, WAIS R digit symbol subtest –Impaired = < 2 SD on one test or < 1 (1.5) SD on two tests –Sustained NCI = impaired at baseline and follow up neuroscreen Lower nadir CD4 count significantly associated with NCI Lower nadir CD4 count significantly associated with NCI

10 Robertson: AIDS, Volume 21(14).September –1921 Prevalent and incident neurocognitive impairment in ALLRT study subjects

11 HIV Associated Neurocognitive Disorders (HAND) Treatment Antiretroviral therapy, which achieves full viral suppression, is necessary for the treatment of HAND Antiretroviral therapy, which achieves full viral suppression, is necessary for the treatment of HAND Prevention of progression with early intervention with ART decreases the risk of HAND and attenuates the symptom severity Prevention of progression with early intervention with ART decreases the risk of HAND and attenuates the symptom severity –Timing of ART initiation remains unclear Theoretical benefit of using ART that penetrates into the central nervous system Theoretical benefit of using ART that penetrates into the central nervous system –Evidence to guide clinical situation for both treatment and prevention is limited

12 Persistent neurocognitive impairement despite ART (Tozzi JAIDS 2007) Italian cohort of HIV+ NCI+ studied over 5 years of HAART exposure Italian cohort of HIV+ NCI+ studied over 5 years of HAART exposure 63% had persistent NCI at follow up as compared to 37% who showed normalization 63% had persistent NCI at follow up as compared to 37% who showed normalization Not related to ART choice/CNS penetration Not related to ART choice/CNS penetration Most associated with degree of deficit at baseline Most associated with degree of deficit at baseline

13 ART treatment of HIV associated neurocognitive disorders Observational/Cross sectional studies Patients on HAART, as compared to those on no treatment show: improved psychomotor speed performance (MACS cohort - Sacktor 1999, Neurology); improved psychomotor speed performance (MACS cohort - Sacktor 1999, Neurology); improved performance on verbal memory, executive function, psychomotor speed (Ferrando 1998, AIDS; Ferrando 2003, J Neuropsychiatry); improved performance on verbal memory, executive function, psychomotor speed (Ferrando 1998, AIDS; Ferrando 2003, J Neuropsychiatry); Improved psychomotor and executive function (women) (Cohen 2001, AIDS) Improved psychomotor and executive function (women) (Cohen 2001, AIDS) Longitudinal studies Open label trial in late stage HIV illness found sustained improvements in NP function with HAART (Tozzi 1999, AIDS) Open label trial in late stage HIV illness found sustained improvements in NP function with HAART (Tozzi 1999, AIDS) Improves NPI in small group in Uganda treated with AZT, 3TC, Tenofovir (Sacktor 2006, Neurology) Improves NPI in small group in Uganda treated with AZT, 3TC, Tenofovir (Sacktor 2006, Neurology) Dementia Treatment RCT Trials High dose AZT, Abacavir treatment trial (Brew PLOS 2007) High dose AZT, Abacavir treatment trial (Brew PLOS 2007)

14 CNS penetrance effectiveness rank Well EquivocalPoorly AZT Abacavir IDV-r LPV-r APV-r f-APV-r ATV-r N evirapine Delavirdine ddI ddC Tenofovir T20 RTV SQV SQV-r TPV-r NFV D4T 3TC FTC Efavirenz APV f-APV ATV IDV

15 Limits to the evidence in H-AND treatment and prevention There are no RCT trials of CNS penetrating agents versus non penetrating agents in treatment of HIV associated neurocognitive impairment There are no RCT trials of CNS penetrating agents versus non penetrating agents in treatment of HIV associated neurocognitive impairment There are no RCT trials of CNS penetrating versus non penetrating agents in the prevention of onset of H-AND There are no RCT trials of CNS penetrating versus non penetrating agents in the prevention of onset of H-AND

16 Persistent neurocognitive impairment: differential diagnosis Drug misuse disorders Drug misuse disorders Depression Depression Aging related cognitive disorders Aging related cognitive disorders Comorbid medical conditions (hepatitis C coinfection, syphilis, vascular disorders) Comorbid medical conditions (hepatitis C coinfection, syphilis, vascular disorders)

17 Treatment approach to HIV Related Brain Disease Initiate Antiretroviral Treatment & Adherence Promotion Initiate Antiretroviral Treatment & Adherence Promotion Symptomatic Treatment of comorbid psychiatric conditions: depression, substance misuse, psychosis, behavioural disturbances Symptomatic Treatment of comorbid psychiatric conditions: depression, substance misuse, psychosis, behavioural disturbances Use sequential neuropsychological testing to monitor for treatment response. In cases of progression despite ART, consider LP for CSF HIV viral load Use sequential neuropsychological testing to monitor for treatment response. In cases of progression despite ART, consider LP for CSF HIV viral load Theoretical interventions Theoretical interventions –{Intensify ART} –{Neuroprotection} –{Use of cholinesterase inhibitors} NonPharmacological Interventions to improve functional outcomes NonPharmacological Interventions to improve functional outcomes –Cognitive rehabilitation –Psychosocial Support

18 Conclusions ART has significantly reduced the prevalence of severe HIV associated dementia ART has significantly reduced the prevalence of severe HIV associated dementia Optimum timing of initiation of ART to prevent neurocognitive impairment remains unclear. Intuition and theory suggests earlier is better. Optimum timing of initiation of ART to prevent neurocognitive impairment remains unclear. Intuition and theory suggests earlier is better. Optimum regimen for treatment to reverse deficits remains unclear. Intuition and theory suggests that it is best to prevent it. If unable to prevent it, suggests CNS penetrating agents are optimal Optimum regimen for treatment to reverse deficits remains unclear. Intuition and theory suggests that it is best to prevent it. If unable to prevent it, suggests CNS penetrating agents are optimal These are complex cases requiring thoughtful, comprehensive, biopsychosocial care approaches delivered by a solid, collaborative, multidisciplinary team These are complex cases requiring thoughtful, comprehensive, biopsychosocial care approaches delivered by a solid, collaborative, multidisciplinary team

19 This layout reflects the master slide layout. In order to not use the master slide layout, go to the “Format” menu, then click “Background” And then click “Omit background graphics from master”. This layout reflects the master slide layout. In order to not use the master slide layout, go to the “Format” menu, then click “Background” And then click “Omit background graphics from master”. Acknowledgment I gratefully acknowledge the support of the Ontario Ministry of Health and Long-Term Care The views expressed in this presentation are the views of the authors and do not necessarily reflect the views of the Ontario Ministry of Health and Long-Term Care.


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