Neuropsychiatric Aspects of HIV

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Neuropsychiatric Aspects of HIV

• University of Hawaii
• James Dilley, MD and Emily Leavitt, LCSW

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Prevalence of MH Disorders among People with
HIV/AIDSn 1489

• Vitiello et al. AJPsych 2003, 160547-54
• from HIV Cost and Services Utilization
  Study1996

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Depression in HIV

• Most common dx in outpt settings
• Concern re diagnosis in medically ill
• Emphasize cognitive/affective vs. neurovegatative
  signs/sxs
• Assoc with ?CD4, soc support and ? phys
  limitations and HIV sx
• Excellent pharmacologic response
• Give benefit of the doubt

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Pharmacotherapy of Depression in HIV
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Depression Testosterone

• 50 of men with Sx HIV/AIDS have deficiency and
  sx of hypogonadism
• Fatigue
• Decreased libido
• Decreased appetite
• Decreased mood

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Screening Tests

• Total Serum Testosterone lt300-400ng/dl
• Serum Free testosterone lt5-7 pcg/ml
• Tx depot IM injections q ii wks (100-200mg IM
  max 400 mg/wk)
• Patch (5-10mg 1-2 times daily)
• Gel (25-100 mg to skin daily)
• Can see mood improvement

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CNS HIVs Most Important Sanctuary Site

• May result in peripheral success (pVL) but
  central failure

• HIV produces at diff rates in CNS vs. plsma
• Diff phen/genotypes esp later in disease
• All ARVs not in treating CNS cx

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HIV Neuropathogenesis

• Early and continuous seeding
• Importance of Blood Brain Barrier

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HAD A Diagnosisof Exclusion

• HIV antibody positive
• No other treatable disorder known to be
  associated with mental status changes (e.g., no
  other CNS OIs, trauma, metabolic disorders, etc.

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Diagnosis Requires (continued)

• Clinical findings of disabling cognitive and /or
  motor dysfunction interfering with occupation or
  activities of daily living
• Neuropsychological testing often needed,
  especially in early cases--
• (1 SD below age/education adjusted norms on 2/8
  tests) AND
• Either impairment in lower ext or fine motor
  skills or selfreported depression interfering
  with function

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Pseudo-Dementia

• Depression in dementias clothing
• Index of suspicion high if
• unremitting and detailed c/o memory pblms
• I dont know responses to cog questions
  communicates distress/emphasizes disability
• Behavior often incongruent w/level of complaint
• In early stages of HIV disease
• Frequently has past hx of psychiatric pblms

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Cognitive Functions

• A. Memory
• Short-term vs. delayed
• B. Concentration, Calculation and
• Constructional Ability
• C. Personality Change alteration or
  accentuation of pre-morbid traits
• D. Language
• E. Judgement
• Reasonable plans

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Early Manifestations of HAD

• Cognitive
• Memory Loss (names, historical details, etc.)
• Impaired Concentration (difficulty reading,
  loses track of conversation)
• Mental slowing (not as quick, less verbal)
• Confusion (time, especially)

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Early Manifestations of HAD (continued)

• Behavioral
• Apathy, withdrawal, depression
• Agitation, hallucination
• Motor
• Unsteady gait
• Bilateral leg weakness
• Tremor
• Loss of fine motor coordination

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Late Manifestations

• Cognitive
• global dementia in all spheres
• confusion and distractability
• slow verbal responsiveness
• Behavioral
• vacant stare
• disinhibition and restlessness
• organic psychosis

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Late Manifestations (cont.)

• Motor
• general slowing
• truncal ataxia
• weakness legs gt arms
• pyramidal tract signs spasticity, hyperreflexia

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Effect of HAART

• Significant changes in the epidemiology of CNS
  disorders since HAART
• In Sx illness
• Studies are more consistent with subcortical
  dementia
• In asx illness, NP findings are inconsistent
• gt Length of battery?gtNP deficits
• Significance clinically is unclear

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Pathological Findings in CNS of AIDS Patients at
Autopsy N 1597

• 1984-1987
• (No therapy)
• 1988-1994
• (monotherapy)
• 1995-1996
• (dual comb. therapy)
• 1997-2000
• (triple comb. therapy)

Vago L., et al. AIDS 2002, 161925-28
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Risk Factors for Cognitive Impairment in HIVCase
Control 90 HIV- 88 ASX 94 SXCI Scores of
2SD below the means of the control on 2 or more
standard neuropsychological tests
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HAART Use NP FunctionN 130 Avg Age 41
42 NW 82 AIDS

• HAART
• N 69
• CD 4 254
• UVL 42
• NPI 22

• Non-HAART
• 61
• 342
• 20 plt0.01
• 54 plt0.0001

Ferrando et al., AIDS, 1998, 12F 65-70
NOTE IMP ? 25D in the impaired direction of
age-matched population-based norms HAART ?
NRTI Ritanavir, Indinavir or Nelfinavir
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Median HIV RNA levels for brain (for all
available brain regions) and peripheral tissues
stratified by neurologic status non-demented,
mild, and moderate/severe
McClernon D.R, et al. Neurology 2001,
571396-1401
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Correlation of Plasma VL to CSF VL

• P ? CSF
• lt 200 gt200
• No No
• No Yes
• No Yes
• No Yes
• No No

• CSF ? NP Status
• lt 200 gt200
• Yes No
• Yes No
• Yes No
• Yes No
• Yes No

Brew (Aus) Ellis (US) MacArthur (US) Dore
(US) DiStephano (Italy)
___________________________ Correlation exists
in ASX state
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Favorable CNS Characteristics of ARVs

• protein binding (? better)
• lipid solubility (? better)
• molecular weight (? better)
• inhibitory concentration (? better)

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Medical Rx of HAD

• 1. Aggressive ARV neuroprotective
• 2. Use combinations of 3, 4 or more
• Should include
• AZT, D4T, 3TC, Abac-NRTI
• Nevirapine, Efavirenz-NNRTI
• Indinavir - PI
• (best BBB penetrance)

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Factors Influencing Efficacy of ARV Rx

• Stage of HIV disease
• Degree of CNS replication/resistance
• Integrity of BBB
• Specific treatment strategy/ARV choice

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Some Neuroprotective Disappointments

• Nimodipene ? interaction with CAH
• Peptide T block gp-120
• Memantine NMDA antagonist/showing efficacy
  for ADV
• Deprenyl Anti-oxidant/anti-poptotic
• Lexipafant PAF antagonist
• some benefits

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Case History - JC
ID 42 y/o GWM architect admitted for
agitation, irritability, decreased sleep, and
grandiose delusions. Brought in by lover of 7
yrs. HPI Two mos intermittent confusion/
hypomania (rapid speech, disorganized thinking
over last 3 days focus on spiritual issues.
Felt friends were trying to harm him, stated he
had been cured of AIDS claimed he was a
millionaire. PMH HIV infected x 10 years
current CD4 count 70. No OIs. No previous
psych hx.
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Case History - JC (cont.)
MS Alert, mildly agitated, unable to sit
still. Speech mildly pressured, loud, but
interruptable. Thought process overly
inclusive, loose assns. Content grandiose,
richest family in California, had cured
himself of AIDS. Some paranoia. Cognitive 0
x 2. Memory Imm 4/4 2/4 _at_ 5 mins. 3/4
with prompts. Attention Serial 7s mult.
Errors WORLD backwards,
d-l-o-w. Abstraction Some
concreteness. Construction OK Insight
none Judgement impaired
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Case History - JC (cont.)
Diff Dx Axis 1 Delirium due to HIV
disease (293.0). Dementia due to HIV disease
(294.1) R/O BAD R/O Toxic Psychosis Axis
II Deferred Axis III AIDS
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Hospital Course
LAB MRI Extensive cortical atrophy. LP
unremarkable Rx Trilafon 2mg p.o. BID
and 4 mg _at_ HS Valproic acid 250mg p.o. BID and
500 mg _at_ HS Ativan 0.5 mg p.o. BID and prn
agitation
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Psychotropic Medication Use

• NOTE Use among Af-Am was significantly lower
  than White or Hispanic.
• Vitiello et al. AJPsych 2003, 160547-54
• from HIV Cost and Services Utilization
  Study1996

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Psychopharmacology in HIV Disease
? Consider geriatric dosing - start low and
go slow ? Look for low-anticholinergic
meds ? ConsiderPay special attention to
Ritonavir (NORVIR - strong CYP3A4 inhibitor) ?
Overall, anti-HIV meds are not problematic
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Pharmacotherapy of Anxiety Disorders
1. Reactive Anxiety - Lorazepam 0.5 mg
B/TID Max 4 mg q 4 hrs 2. Panic Disorders
with or without Agoraphobia Paroxetine
(Paxil) 10-40 mg/D Lorazepam for
breakthrough 3. GAD - Paroxetine Buspirone
(Buspar) 5-10 mg BID - 20 mg TID Note
Buspirone is the does not drug cause
tolerance, physical dependence or a withdrawal
syndrome, have abuse potential (hypnotic, muscle
relaxant activity), work right away
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Ritonavir (Norvir)(Potent inhibitor of CP450,
esp. 2D6 and 3A4)
1. Adjust Anti-depressants SSRIs
- initially ? by 1/2 TCAs - initially ? by 1/2
to 1/3 Nefazodone and St. Johns Wort 2.
Avoid Benzodiazepines Anti-psychotics Clonazepam
(Klonopin) Clozapine Alprazolam
(Xanax) Pimozide Diazepam (Valium) Flurazepam
(Dalmane) Triazolam (Halcion) Zolpidem
(Ambien) 2. Allow Temazepam (Restoril) Oxazepam
(Serax) Lorazepam (Ativan) Bupropion
(Wellbutrin)
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Methadone

• Ritonavir and Nevirapine (and likely Efavirenz)
  has been shown to lead to significant withdrawal
  symptoms in stable methadone users
• Should follow serum meth levels before after
  initiation may need to increase by 25-30

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Other Pharm Issues

• Sildenafil levels may be significantly raised by
  Ritonavir, Saquinavir and Indinavir--potentially
  serious CV effects (DNE 25mg)
• Fatal case reports have been filed suggesting
  Ritonavir in combination with methamphetamine and
  Ecstasy (MDMA) was the cause of death
• St. Johns Wort may decrease PIs

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ARV Classes