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Neuropsychiatric Aspects of HIV. University of Hawaii James Dilley, MD and Emily Leavitt, LCSW. Prevalence of MH Disorders among People with HIV/AIDS n = 1489. Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”. Depression in HIV.

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neuropsychiatric aspects of hiv

Neuropsychiatric Aspects of HIV

University of Hawaii

James Dilley, MD and Emily Leavitt, LCSW

prevalence of mh disorders among people with hiv aids n 1489
Prevalence of MH Disorders among People with HIV/AIDSn = 1489

Vitiello et al. AJPsych 2003, 160:547-54

from “HIV Cost and Services Utilization Study—1996”

depression in hiv
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
depression testosterone
Depression & Testosterone
  • 50% of men with Sx HIV/AIDS have deficiency and sx of hypogonadism:
    • Fatigue
    • Decreased libido
    • Decreased appetite
    • Decreased mood
screening tests
Screening Tests
  • Total Serum Testosterone: <300-400ng/dl
  • Serum Free testosterone: <5-7 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
cns hiv s most important sanctuary site
HIV produces at diff rates in CNS vs. plsma

Diff phen/genotypes: esp later in disease

All ARV’s not = in treating CNS cx

May result in peripheral success (pVL) but central failure

CNS: HIV’s Most Important Sanctuary Site
hiv neuropathogenesis

HIV Neuropathogenesis

Early and continuous seeding

Importance of Blood Brain Barrier

had a diagnosis of exclusion
HAD: A Diagnosisof Exclusion
  • HIV antibody positive
  • No other treatable disorder known to be associated with mental status changes (e.g., no other CNS OI’s, trauma, metabolic disorders, etc.
diagnosis requires continued
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
pseudo dementia
  • Depression in “dementia’s clothing”
  • Index of suspicion high if:
    • unremitting and detailed c/o memory pblms
    • “I don’t 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
cognitive functions
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”

early manifestations of had
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)

early manifestations of had continued
Early Manifestations of HAD (continued)
  • Behavioral

Apathy, withdrawal, “depression”

Agitation, hallucination

  • Motor

Unsteady gait

Bilateral leg weakness


Loss of fine motor coordination

late manifestations
Late Manifestations
  • Cognitive

global dementia in all spheres

confusion and distractability

slow verbal responsiveness

  • Behavioral

vacant stare

disinhibition and restlessness

organic psychosis


Late Manifestations (cont.)

  • Motor

general slowing

truncal ataxia

weakness: legs > arms

pyramidal tract signs: spasticity, hyperreflexia

effect of haart
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
    • > Length of battery>NP deficits
    • Significance clinically is unclear
pathological findings in cns of aids patients at autopsy n 1597
Pathological Findings in CNS of AIDS Patients at Autopsy N = 1597


(No therapy)




(dual comb. therapy)


(triple comb. therapy)

Vago L., et al. AIDS 2002, 16:1925-28


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

haart use np function n 130 avg age 41 42 nw 82 aids

N 69

CD 4 254

UVL 42%

NPI 22%




20% p<0.01

54% p<0.0001

HAART Use & NP FunctionN = 130; Avg Age = 41; 42% NW; 82% AIDS

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


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, 57:1396-1401

correlation of plasma vl to csf vl

< 200 >200

No No

No Yes*

No Yes

No Yes*

No No

CSF  NP Status

< 200 >200

Yes No

Yes No

Yes No

Yes No

Yes No

Correlation of Plasma VL to CSF VL

Brew (Aus)

Ellis (US)

MacArthur (US)

Dore (US)

DiStephano (Italy)


* Correlation exists in ASX state

favorable cns characteristics of arvs
Favorable CNS Characteristics of ARVs
  • % protein binding ( = better)
  • lipid solubility ( = better)
  • molecular weight ( = better)
  • inhibitory concentration ( = better)
medical rx of had

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)

factors influencing efficacy of arv rx
Factors Influencing Efficacy of ARV Rx:
  • Stage of HIV disease
  • Degree of CNS replication/resistance
  • Integrity of BBB
  • Specific treatment strategy/ARV choice
some neuroprotective disappointments
Some NeuroprotectiveDisappointments

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


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 OI’s. No previous psych hx.


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 @ 5 mins. 3/4 with prompts.

Attention: Serial 7’s = mult. Errors;

WORLD backwards, “d-l-o-w.”

Abstraction: Some concreteness.

Construction: OK

Insight: none

Judgement: impaired


Case History - “JC” (cont.)

Diff Dx:

Axis 1: Delirium due to HIV disease (293.0).

Dementia due to HIV disease (294.1)


R/O Toxic Psychosis

Axis II: Deferred



Hospital Course


MRI: Extensive cortical atrophy.

LP: unremarkable

Rx: Trilafon 2mg p.o. BID and 4 mg @ HS

Valproic acid 250mg p.o. BID and 500 mg @ HS

Ativan 0.5 mg p.o. BID and prn agitation

psychotropic medication use
Psychotropic Medication Use

NOTE: Use among Af-Am was significantly lower than White or Hispanic.

Vitiello et al. AJPsych 2003, 160:547-54

from “HIV Cost and Services Utilization Study—1996”


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


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


Ritonavir (Norvir)(Potent inhibitor of CP450, esp. 2D6 and 3A4)

1. AdjustAnti-depressants SSRI’s - initially  by 1/2 TCA’s - initially  by 1/2 to 1/3

Nefazodone and St. John’s 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)

  • 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%
other pharm issues
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. John’s Wort: may decrease PI’s