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Neuropsychiatric Manifestations
of HIV
Thomas Newton, MD
UCLA/Pacific AIDS Education and Training Center
[email protected]
AIDS Education & Training Centers’
National Resources
Warmline: (800) 933 - 3413
PEPline: (888) 448 – 4911
(888) HIV - 4911
Perinatal Hotline: (888) 448 - 8765
www.aids-etc.org
Neuropsychiatric Manifestations
of HIV: Educational Objectives
At the end of presentation, participants will
be able to:
• Identify risk factors for impairment
• Discuss treatment options
• Identify potential drug interactions
Neuropsychiatric Manifestations
of HIV
Biologic
Psychologic
Social
KEY POINTS
1. HIV has global impact
2. Effects can be understood on variety of
dimensions
3. Biologic effects related to host/virus
interaction
4. Psychologic effects related to
neuropsychiatric impacts and preexisting vulnerabilities
5. Social effects vary by time and place
Biologic
Complications depend on severity of
immunosuppression
Differential diagnosis changes
Early, middle and late stages of illness
Early
definition:
Above 400-500 CD4+, asymptomatic
Non HIV-related psychiatric syndromes more
likely
Be wary of off, early presentations of HIV-related
syndromes
KEY POINTS
1. High CD4 usually found early in infection,
but…
2. Rate of progression extremely variable
Case of Multidrug-Resistant HIV and
Rapid Progression to AIDS in New
York City Background
On February 11th 2005, New York City
health officials reported that a local gay
man in his mid-40s had recently been
infected with multidrug-resistant HIV and
progressed rapidly to AIDS. He also has a
history of unprotected sex while using
methamphetamine.
The man was first diagnosed with HIV
between four and twenty months before
steep drop in CD4 cells and a high viral
load.
Middle
definition:
Roughly between 200 and 500 CD4+
Mild symptoms
Before AIDS-defining O.I.
(symptoms more
important)
KEY POINTS
1. Lower CD4 levels generally found later in
the disease, but…
HIV-1 Evolution and Chemokine
Receptor Genotypes-Implication for
AIDS Progression
Genetic polymorphysms of chemokine receptor
genes (CCR5, CCR2, CXCR4) are closely
associated with AIDS. These chemokine
receptors are coreceptors with CD4 for HIV-1,
mutations in which confer protection against
HIV-1 infection and/or slow progression of the
disease.
The absence of CCR5 in ~1% of Caucasians
very strongly protects against HIV-1
transmission. It is estimated that 25-30% of
patients who remain AIDS-free for >16 years
attribute their survival to mutations in these
receptors. The protective mutation (delta32CCR5) is not present in Africans or Asians who
bear the burden of most of the world's HIV
infection.
Late
definition:
Below 200 CD4+
After AIDS-defining O.I.
Very late: below 50 CD4+
(symptoms predict symptoms)
KEY POINTS
1. What about patients who once had CD4
< 200, but now …
2. …have CD4 > 500
3. …continue with CD4 < 200, but virally
suppressed?
Neuropsychiatric complications
Minimal early course of illness
Develop after other symptoms, usually
By death, probably more than 50% prevalence
(really unknown)
KEY POINTS
1. …Early in illness, psychological
symptoms are psychological until proven
otherwise
2. …Late in illness, psychological
symptoms are due to HIV until proven
otherwise
KEY POINTS
1. …Difficult to determine if any symptom is
due to HIV or other process
2. …Diagnosis and treatment guided by risk
factors and probabilities
Neuropsyiatric complications
cont.
“Personality change” frequent, with
increased lability
Memory, praxis, “cortical” abilities spared
A subcortical dementia, more like
Parkinson’s than Alzheimer’s
Infrequent psychosis or mania
(poorly defined)
KEY POINTS
1. What about patients who once had CD4
< 200, but now …
…have CD4 > 500
…continue with CD4 < 200, but virally
suppressed
Patient with CD4 > 500, but continued
cognitive impairment
Patient with CD4 < 200, but normal with
methylphenidate (dependent on
methamphetamine 15 years ago, now low
risk for relapse)
Clinical Manifestations of HIVrelated dementia
Cognitive impairments
--Short-term memory deficit; “forgetfulness” rather than amnesia
--Decreased concentration and attention
--Confusion and disorientation
--Overall intellectual ability generally well preserved until late Visuospatial
perception deficits
Changes in personality or behavior
--Apathy, decreased interest
--Impaired judgment, erratic behavior
--Social withdrawal
--Rigidity of thought
--Speech impairment: slow, dysarthria, hyphonia; difficulty in following
other speakers
KEY POINTS
1. …Mini Mental State not helpful; detects
delirium or “cortical” impairments
2. …Best screen is history + assessment of
psychomotor speed
Early Entry
Confirmed by intrathecal antibody synthesis
Virus often retrieved from CSF
Probably ubiquitous
Indirect pathogenesis
Infection of non-neuronal cells important
Infection activates CNS macrophages
Activated macrophages produce toxic products
Viral products may be neurotoxic
KEY POINTS
1.
2.
3.
4.
…Other viruses infect neurons
…Herpes, rabies
…These produce irreversible deficits
…HIV produces combination of
reversible and irreversible deficits
HIV and Brain
Fig. 1. Cortical thinning on the lateral brain
surface in HIV/AIDS. (a) Average
profile of cortical thickness in AIDS
patients. Right hemisphere is on the
left. (b) Mean cortical thickness for
matched healthy controls. (c)
Average percentage thinning of the
cortex in AIDS relative to healthy
controls. (d) Color-coded map that
shows the significance of the group
difference, at each cortical point
(reds indicate significant cortical
thinning). The band of thinner cortex
encompasses the primary
sensorimotor, premotor, and parietal
cortices.
Thompson PM, Dutton RA, Hayashi KM, et
al (2005): Thinning of the cerebral cortex
visualized in HIV/AIDS reflects CD4+ T
lymphocyte decline. PNAS
102:15647-52.
KEY POINTS
1. …Affects mood as well as cognition
2. …Unknown if pre-existing mood disorder
risk factor
3. …Unknown roll of alcohol, cocaine,
methamphetamine
Neuropsychiatric manifestations of
HIV
dimensions:
Biologic
Psychologic
Social
Depression
diagnosis:
Differential diagnosis of “DUO”
Adjustment response
“Organic”---secondary to HIV-related disease
Medication complication (antiretroviral)
Psychiatric disorder
Psychologic
background:
Illness occurs in context of numerous losses
Friends and loved may also be ill
Psychologic
depression:
May be more common in gay men regardless
of HIV
Lifetime prevalence* in gay man of
Major depression: 33% vs 3%
Substance abuse: 45% vs 15%
(ECA estimates
for straight
men)
* Williams et al. Arch Gen. Psychiatry, 1991
Depression
diagnosis:
Important considerations:
Onset and course
Symptoms and severity
Previous episodes and treatment response
(remember, treatment is easy,
diagnosis is hard)
Depression
After correct diagnosis:
Controlled trials suggest standard
antidepressants have usual efficacy
Anecdotal evidence for “replacement”
therapies (testosterone)
Psychotherapy helpful for dealing with loss,
etc.
Stimulants useful in advanced illness
Psychologic
anxiety:
Situational anxiety expected, responds to
benzodiazepines
Sleep disturbance expected, responds to
standard treatment
Cognitive/behavioral treatments helpful when
anxiety is reality based
Stressful Life Events and HIV
Coping in Health and Illness Project
(CHIP at UNC)
9 year longitudinal study
Life events and difficulties
 Interviewer based
 Severity, duration, and context important
 Excludes events due to HIV
Leserman et al., CNS Spectrums 8:25-30 2003
CHIPS
At baseline, severe life events in
previous 6 months:
Low NK cells (CD16+ and CD56+)
Fewer CD8+
CHIPS
For each severe stressor:
– Risk of AIDS-defining condition tripled
– For those above median in stress:
• AIDS progression rate was 74%,
• compared to 40% for those below median in
stress
Leserman et al., Psychol Med 32:1059-1073 (2002)
KEY POINTS
1. Stressor depends on individual
2. Best assessed using personal impact,
duration of impact, and change needed
to accommodate
3. Lists of stressors (Holmes and Rahe) fair
but can be missleading
CHIPS
Limitations:
– Small sample (99)
– Geographically limited (N.C.)
– Lack of control for duration of HIV
infection
– Completed prior to HAART
CHIPS
Convergence of
• AIDS diagnosis
• HIV stage progression
• Cellular indices of progression
Suggest validity
KEY POINTS
Unknown:
 Would treatment alter impact of stressor?
 Who’s at greatest risk?
 What factors are protective?
UCLA Study
• Bereavement associated with more
rapid decline in CD4 cells
• Not accounted for by differences in
health habits, drug use, age
• Finding meaning in bereavement
mitigated against decline
Bower et al., J Consult Clin Psychol 66:979-986 (1998)
KEY POINTS
 “Stress” can be toxic or beneficial
 Mechanism unknown
 What aspects of immune function
impacted not always clear
Pharmacokinetic Mechanisms of
Drug Interactions
Altered drug absorption
Inhibition of metabolism
Induction of metabolism
First Pass Metabolism
Systemic
Circulation
Oral
Medication
Hepatic
Artery
Hepatic
Vein
Intestine
Portal Vein
-P450
Directly metabolized
here before reaching
systemic circulation
-P450 Enzymes present in
intestinal cells
-PGP
Altered Drug Absorption:
Food Requirements
Didanosine (ddI, Videx)
Tenofovir (TDF, Viread)
Efavirenz (EFV, Sustiva)
Kaletra (lopinavir/ritonavir)
Amprenavir (Agenerase)
Indinavir (Crixivan)
Saquinavir (Fortovase)
Nelfinavir (Viracept)
empty stomach
w/ food
empty stomach
w/ food
avoid high fat
light snack
w/ food
w/ food
Pharmacodynamic Mechanisms of
Drug Interactions
Synergism
Antagonism
D4T and AZT
IDV and SQV
Can effect drug activity or toxicity
 Ritonavir + saquinavir
 in liver enzymes or cholesterol
 AZT + ganciclovir
enhanced bone marrow suppression
 d4T + ddI
worsened neuropathy
Beneficial Drug Interactions
• Improve bioavailability
–
•
drug dose; pill burden; eliminate food requirements
CL
– less frequent administration
• Concentration of active metabolites
• Displace highly protein bound drugs
–
active drug
• Improve drug exposure
– overcome resistant virus
KEY POINTS
1. Drug interactions common
2. May be beneficial or dangerous
3. Identification of the existence of an
interaction not always helpful
Cytochrome P450 Enzyme Classes
A
A
B
C
D
E
F
A
IA1 IIA3 IIB6 IIC8 IID6 IIE1 IIF1 IIIA3
IA2
IV
III
II
I
IIB7 IIC9 IID7
IIIA4
IIB8 IIC10 IID8
IIIA5
A
B
IVB1
KEY POINTS
1. Many CYP exist
2. Only three relevant to human drug
metabolism
3. 2D6 and 3A4 most important
P450 Substrates
 >50% of all metabolized drugs are substrates for
the CYP450 3A4 enzyme
 Major player in the metabolism of most HIV
antiretrovirals
 Not the only available pathway of metabolism (I.e.
NFV and RTV
2D6, 2C9)
Contributes to the complexity of HIV
polypharmacy
P450 Inhibitors
• Any drug that inhibits the metabolism of a
P450 substrate
• Results in levels of coadministered drug
• Competitive and reversible
• All PI’s are 3A4 inhibitors
• RTV and SQV are 2D6 inhibitors
Model of CYP50 Inhibition
Drug Concentration
Inhibitor added
Time
P450 CYP3A4
Degree of inhibition of liver CL
ritonavir
NFV, IDV, LOP/r
EFV, DLV
SQV, AMP
+
0
RED FLAG List - P450 3A4 Inhibitors
These Agents will  Concentrations of Co-Administered Drug
DRUG
CLASS
HIV
Protease
Inhibitors
Macrolides
RANK LIKLIHOOD of Drug
Interaction
ALTERNATIVES /
Comments
Ritonavir> Indinavir= lopinavir>
nelfinavir>amprenavir>
saquinavir
Saquinavir has less
potential to cause
interactions
Erythromycin > Clarithromycin
Azithromycin – not
metabolized by P450
Antifungals
Ketoconazole> Itraconazole>
Fluconazole
HIV NNRTI’s
Delavirdine
Efavirenz (mixed)
H2
Antagonists
SSRIs
Cimetidine (high propensity)
Fluconazole assoc w/ less
drug i/a with doses <200mg.
 dose  potential
Delavirdine may be used to
 conc of other drugs
Any other H2 Antagonist
(ranitidine, nizatidine,etc)
Led to serotonin syndrome;
mirtazapine, venlafixine
have least P450
Grapefruit
juice
Daily intake
Fluoxetine
P450 3A4 Substrates
 Macrolide antibiotics:
clarithromycin
erythromycin (not 3A5)
NOT azithromycin
 Anti-arrhythmics:
quinidine=>3-OH (not
3A5)
 Benzodiazepines:
alprazolam
diazepam=>3OH
midazolam
triazolam
 Immune Modulators:
cyclosporine
HIV Antivirals:
indinavir
nelfinavir
ritonavir
saquinavir
 Calcium Channel
Blockers:
HMG CoA Reductase
Inhibitors:
NOT pravastatin
simvastatin
RED FLAG List - P450 2D6 Inhibitors
These Agents will  Concentrations of Co-Administered Drug
DRUG
CLASS
HIV
Protease
Inhibitors
Macrolides
RANK LIKLIHOOD of Drug
Interaction
ALTERNATIVES /
Comments
Ritonavir
Antifungals
HIV NNRTI’s
H2
Antagonists
Fluoxetine, paroxetine
SSRIs
Grapefruit
juice
N/A
Citalopram, venlafaxine, etc
P450 2D6 Substrates
Beta Blockers:
carvedilol
S-metoprolol
propafenone
timolol
Antidepressants:
amitriptyline
clomipramine
desipramine
imipramine
paroxetine
 Antipsychotics:
haloperidol
perphenazine
risperidone=>9OH
thioridazine
 Other:
alprenolol
amphetamine
bufuralol
chlorpheniramine
chlorpromazine
codeine (=>O-desMe)
encainide
flecainide
P450 Inducers
Increases the production of P450 enzyme
More enzymes
more rapid CL of drugs that
are substrates
exposure to coadministered
drugs
blood levels
Occurs after 7-10 days & effects persist for
several days
Can turn on multiple genes at once
(I.e 3A4, 2D6, conjugation, etc)
Model of CYP450 induction
Drug Concentration
Inducer added
Time
P450 CYP3A4
Degree of Liver Enzyme Induction
rifampin, phenobarbital
RTV*, NFV*, LOP/r*, AMP
EFV*, NVP, phenytoin
+
* mixed effects on enzymes- not exclusively metabolized by 3A4
0
RED FLAG List - P450 Inducers
These Agents will Concentrations of Co-Administered Drug
DRUG
CLASS
Rifamycins:
Rifampin,
Rifabutin
HIV Protease
Inhibitors
HIV NNRTI’s
Anticonvulsants
St. Johns
Wort
RANK LIKLIHOOD
of INTERACTION
Both are POTENT
Inducers; use rifabutin
over rifampin for TB if
pt on a PI
Ritonavir = Nelfinavir
ALTERNATIVE /
COMMENTS
Avoid rifampin while on PI’s; Use
½ Rifabutin dose w/ IDV, APV,
NFV; Use ½ dose qMWF with
RTV; EFV ok (rifabutin 450mg )
All other PI’s
Efavirenz = Nevirapine
Phenobarbital >
Phenytoin =
Carbamazepine
If clinically indicated: Valproic
Acid, Gabapentin, Lamotrigene,
Topiramate; Bidirectional;
documented virologic failure when
combined with PI’s
RED FLAG List - Metabolized Drugs with
Narrow Therapeutic Indices
Use EXTREME Caution with P450 inhibitors/inducers as serious side effects
may occur if their concentrations are altered
CATEGORY
Antiarrythmics
Opiate
Analgesics
Benzo’s
Ergotamines
Ergot Derivs
Anticoagualants
OC’s
DRUGS
Flecainide,
Quinidine
Fentanyl
(duragesic)
Midazolam,
Triazolam,
alprazolam
Cafergot,
Hydergine, DHE
Warfarin
Ethinyl Estradiol;
norethindrone
ALTERNATIVES / COMMETNS
Monitor closely with P450 inhibitors
Hydromorphone, codeine, NSAIDS (esp
in pts on RTV)
Oversedation;
use temazepam; lorazepam
Monitor INR when initiating or changing
therapy
Efficacy 45%;Use alternative methods
when pts receive P450 inducing PI’s
RED FLAG Lists:
http://medicine.iupui.edu/flockhart/