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 HospiceAssociate Professor, University of Toronto

Associate Scientist, Centre for Research on Inner City Health, The Keenan Research Centre in the Li Ka Shing Knowledge Institute

Cognitive disorders in HIV + patientsCognitive disorders in HIV + patients

““My brain is not working properly”My brain is not working properly”

HIV brain infectionHIV brain infection CNS brain opportunistic infection/conditionsCNS brain opportunistic infection/conditions

– Toxoplasmosis, PML, cryptococcal meningitis, CMV, lymphoma, Toxoplasmosis, PML, cryptococcal meningitis, CMV, lymphoma, syphilis, malaria, TBsyphilis, malaria, TB

Other medical conditions affecting brainOther medical conditions affecting brain– Including aging related concernsIncluding aging related concerns

Depression & anxietyDepression & anxiety Substance misuseSubstance misuse

Common neurocognitive symptoms Common neurocognitive symptoms MemoryMemory: I’m forgetful; my short-term memory is not as good; I keep : I’m forgetful; my short-term memory is not as good; I keep

misplacing thingsmisplacing things Word finding/retrieval difficultiesWord finding/retrieval difficulties: I have trouble remembering people’s : I have trouble remembering people’s

names; the word is on the tip of my tonguenames; the word is on the tip of my tongue ConcentrationConcentration: I am easily distracted; I have trouble focusing; I can’t do : I am easily distracted; I have trouble focusing; I can’t do

several things at once anymoreseveral things at once anymore SlowingSlowing: I am a lot slower, both mentally and physically, apathy : I am a lot slower, both mentally and physically, apathy Motor concerns:Motor concerns: dyscoordination, fine motor difficulties, psychomotor dyscoordination, fine motor difficulties, psychomotor

inefficiency, gait disturbance/ataxiainefficiency, gait disturbance/ataxia

Problems noted by others:Problems noted by others: my boss is concerned that my productivity is my boss is concerned that my productivity is down and that I am making more errors at workdown and that I am making more errors at work

HIV Associated Neurocognitive DisordersHIV Associated Neurocognitive DisordersEtiologyEtiology 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 HIV associated neurocognitive disorders are presumably due to

the toxic effects on brain parenchyma of virus and viral the toxic effects on brain parenchyma of virus and viral proteins and the neurotoxic effects of inflammatory products proteins and the neurotoxic effects of inflammatory products released in response to brain HIV replication and sequestration. released in response to brain HIV replication and sequestration.

Because of the blood brain barrier and drug efflux transport Because of the blood brain barrier and drug efflux transport mechanisms, the brain may act as separate reservoir of HIV mechanisms, the brain may act as separate reservoir of HIV infection. ART may not have as much impact on brain infection. ART may not have as much impact on brain parenchymal infection as it does on systemic infection. parenchymal infection as it does on systemic infection.

Proposed Updated Case Definitions: HIV Associated Proposed Updated Case Definitions: HIV Associated Neurocognitive Disorders Neurocognitive Disorders (Antinori et al, Neurology 2007)(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 performanceIncreased focus on cognitive performance

– ANI & MND defined by performance < 1 SD below mean of ANI & MND defined by performance < 1 SD below mean of demographically adjusted normative scores in two cognitive areasdemographically adjusted normative scores in two cognitive areas

– HAD performance < 2 SD below mean of demographically adjusted HAD performance < 2 SD below mean of demographically adjusted normative scores in two cognitive areasnormative scores in two cognitive areas

Locating neurocognitive impairment with Locating neurocognitive impairment with respect to respect to clinical state.clinical state. (Reger 2002, JINS)(Reger 2002, JINS)

Compared with HIV- controls:Compared with HIV- controls:– Small Effect size (ES) in asymptomatic HIV+: retrieval, Small Effect size (ES) in asymptomatic HIV+: retrieval,

namingnaming– Small - moderate ES in symptomatic HIV+: information Small - moderate ES in symptomatic HIV+: information

processing speed, problem solving/executive function, processing speed, problem solving/executive function, language language

– Moderate - large ES for AIDS: motor function, problem Moderate - large ES for AIDS: motor function, problem solving/executive function, information processing speed, solving/executive function, information processing speed, immediate visual memory, language, visual constructionimmediate visual memory, language, visual construction

Locating neurocognitive impairment with respect to Locating neurocognitive impairment with respect to ART treatment ART treatment

Progressive neurocognitive decline in the previously untreatedProgressive neurocognitive decline in the previously untreated

Chronic active neurocognitive impairment in those treated with Chronic active neurocognitive impairment in those treated with ART, with variable viral load control ART, with variable viral load control

Chronic active neurocognitive impairment in those treated with Chronic active neurocognitive impairment in those treated with ART and sustained systemic viral load control (presumed lack of ART and sustained systemic viral load control (presumed lack of impact of ART on brain parenchyma)impact of ART on brain parenchyma)

Chronic Inactive neurocognitive impairment in those with prior Chronic Inactive neurocognitive impairment in those with prior dementia and stable deficits post-ART (head injury model)dementia and stable deficits post-ART (head injury model)

HIVAssociated Dementia: Incidence 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 AIDS1991: 3.71 per 100 persons living with AIDS– 2003: 0.24 per 100 persons living with AIDS2003: 0.24 per 100 persons living with AIDS

– (Dilley 2005, AIDS)(Dilley 2005, AIDS)

Patients who are marginalized and unable to actively Patients who are marginalized and unable to actively access preventative health care or maintain ART access preventative health care or maintain ART adherenceadherence

Patients who have survived with HIV disease for Patients who have survived with HIV disease for many years but have not achieved adequate viral load many years but have not achieved adequate viral load control and have developed multi class drug resistancecontrol and have developed multi class drug resistance

HIV associated neurocognitive impairment:HIV associated neurocognitive impairment:

prevalence prevalence (Robertson: AIDS, 2007)  

ALLRT observational cohortALLRT observational cohort– 14 ACTG linked ART studies14 ACTG linked ART studies– 3 naïve, 9 experienced, 2 both (50% of subjects were ART naïve, 3 naïve, 9 experienced, 2 both (50% of subjects were ART naïve,

47% nadir CD4 < 200)47% nadir CD4 < 200) Neuroscreen Neuroscreen

– Baseline at least 20 weeks after parent study entry, follow up at 48 Baseline at least 20 weeks after parent study entry, follow up at 48 weeksweeks

– Trails A & B, WAIS R digit symbol subtestTrails A & B, WAIS R digit symbol subtest– Impaired = < 2 SD on one test or < 1 (1.5) SD on two testsImpaired = < 2 SD on one test or < 1 (1.5) SD on two tests– Sustained NCI = impaired at baseline and follow up neuroscreenSustained NCI = impaired at baseline and follow up neuroscreen

Lower nadir CD4 count significantly associated with NCILower nadir CD4 count significantly associated with NCI

                                                                                                                     

                                 

Robertson: AIDS, Volume 21(14).September 2007.1915–1921

Prevalent and incident neurocognitive impairment in ALLRT study subjects

HIV Associated Neurocognitive Disorders (HAND)HIV Associated Neurocognitive Disorders (HAND)

TreatmentTreatment Antiretroviral therapy, which achieves full viral suppression, Antiretroviral therapy, which achieves full viral suppression,

is necessary for the treatment of HANDis necessary for the treatment of HAND Prevention of progression with early intervention with ART Prevention of progression with early intervention with ART

decreases the risk of HAND and attenuates the symptom decreases the risk of HAND and attenuates the symptom severityseverity– Timing of ART initiation remains unclearTiming of ART initiation remains unclear

Theoretical benefit of using ART that penetrates into the Theoretical benefit of using ART that penetrates into the central nervous systemcentral nervous system– Evidence to guide clinical situation for both treatment and Evidence to guide clinical situation for both treatment and

prevention is limitedprevention is limited

Persistent neurocognitive impairement Persistent neurocognitive impairement despite ART despite ART (Tozzi JAIDS 2007)(Tozzi JAIDS 2007)

Italian cohort of HIV+ NCI+ studied over 5 years Italian cohort of HIV+ NCI+ studied over 5 years of HAART exposureof HAART exposure

63% had persistent NCI at follow up as compared 63% had persistent NCI at follow up as compared to 37% who showed normalizationto 37% who showed normalization

Not related to ART choice/CNS penetrationNot related to ART choice/CNS penetration Most associated with degree of deficit at baselineMost associated with degree of deficit at baseline

ART treatment of HIV associated ART treatment of HIV associated neurocognitive disordersneurocognitive disorders

Observational/Cross sectional studiesObservational/Cross sectional studies

Patients on HAART, as compared to those on no treatment show: 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 improved performance on verbal memory, executive function, psychomotor speed (Ferrando

1998, AIDS; Ferrando 2003, J Neuropsychiatry); 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 studiesLongitudinal studies Open label trial in late stage HIV illness found sustained improvements in NP function with Open label trial in late stage HIV illness found sustained improvements in NP function with

HAART (Tozzi 1999, AIDS)HAART (Tozzi 1999, AIDS) Improves NPI in small group in Uganda treated with AZT, 3TC, Tenofovir (Sacktor 2006, Improves NPI in small group in Uganda treated with AZT, 3TC, Tenofovir (Sacktor 2006,

Neurology)Neurology)

Dementia Treatment RCT TrialsDementia Treatment RCT Trials High dose AZT, Abacavir treatment trial (Brew PLOS 2007) High dose AZT, Abacavir treatment trial (Brew PLOS 2007)

CNS penetrance effectiveness rankCNS penetrance effectiveness rank

Well Well EquivocalEquivocal PoorlyPoorlyAZT AbacavirIDV-rLPV-rAPV-rf-APV-rATV-rNevirapineDelavirdine

ddIddC

TenofovirT20

RTV SQV

SQV-rTPV-r

NFV

D4T3TCFTC

Efavirenz APV

f-APVATVIDV

Limits to the evidence in H-AND treatment Limits to the evidence in H-AND treatment and preventionand prevention

There are no RCT trials of CNS penetrating There are no RCT trials of CNS penetrating agents versus non penetrating agents in agents versus non penetrating agents in treatment of HIV associated neurocognitive treatment of HIV associated neurocognitive impairmentimpairment

There are no RCT trials of CNS penetrating There are no RCT trials of CNS penetrating versus non penetrating agents in the versus non penetrating agents in the prevention of onset of H-ANDprevention of onset of H-AND

Persistent neurocognitive impairment: Persistent neurocognitive impairment: differential diagnosisdifferential diagnosis

Drug misuse disordersDrug misuse disorders DepressionDepression Aging related cognitive disordersAging related cognitive disorders Comorbid medical conditions (hepatitis C Comorbid medical conditions (hepatitis C

coinfection, syphilis, vascular disorders)coinfection, syphilis, vascular disorders)

Treatment approach to HIV Related Brain Treatment approach to HIV Related Brain DiseaseDisease

Initiate Antiretroviral Treatment & Adherence PromotionInitiate Antiretroviral Treatment & Adherence Promotion Symptomatic Treatment of comorbid psychiatric conditions: Symptomatic Treatment of comorbid psychiatric conditions:

depression, substance misuse, psychosis, behavioural disturbancesdepression, substance misuse, psychosis, behavioural disturbances Use sequential neuropsychological testing to monitor for treatment Use sequential neuropsychological testing to monitor for treatment

response. In cases of progression despite ART, consider LP for CSF response. In cases of progression despite ART, consider LP for CSF HIV viral loadHIV viral load

Theoretical interventionsTheoretical interventions– {Intensify ART}{Intensify ART}

– {Neuroprotection}{Neuroprotection}

– {Use of cholinesterase inhibitors}{Use of cholinesterase inhibitors} NonPharmacological Interventions to improve functional outcomesNonPharmacological Interventions to improve functional outcomes

– Cognitive rehabilitationCognitive rehabilitation– Psychosocial SupportPsychosocial Support

ConclusionsConclusions ART has significantly reduced the prevalence of severe HIV ART has significantly reduced the prevalence of severe HIV

associated dementiaassociated dementia Optimum timing of initiation of ART to prevent Optimum timing of initiation of ART to prevent

neurocognitive impairment remains unclear. Intuition and neurocognitive impairment remains unclear. Intuition and theory suggests earlier is better. theory suggests earlier is better.

Optimum regimen for treatment to reverse deficits remains Optimum regimen for treatment to reverse deficits remains unclear. Intuition and theory suggests that it is best to unclear. Intuition and theory suggests that it is best to prevent it. If unable to prevent it, suggests CNS penetrating prevent it. If unable to prevent it, suggests CNS penetrating agents are optimal agents are optimal

These are complex cases requiring thoughtful, These are complex cases requiring thoughtful, comprehensive, biopsychosocial care approaches delivered comprehensive, biopsychosocial care approaches delivered by a solid, collaborative, multidisciplinary teamby a solid, collaborative, multidisciplinary team

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.