Neuropsychiatric Manifestations of HIV

Thomas Newton, MDUCLA/Pacific AIDS Education and Training Center

tnewton@mednet.ucla.edu

AIDS Education & Training Centers’ National Resources

Warmline: (800) 933 - 3413PEPline: (888) 448 – 4911 (888) HIV - 4911

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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

dimensions3. Biologic effects related to host/virus

interaction4. Psychologic effects related to

neuropsychiatric impacts and pre-existing 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

Earlydefinition:

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 andRapid 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.

Middledefinition:

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 (delta32-CCR5) is not present in Africans or Asians who bear the burden of most of the world's HIV infection.

Latedefinition:

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 complicationscont.

“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 HIV-related 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. …Other viruses infect neurons

2. …Herpes, rabies

3. …These produce irreversible deficits

4. …HIV produces combination of reversible and irreversible deficits

HIV and BrainFig. 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. PNAS102:15647-52.

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 HIVdimensions:

Biologic

Psychologic

Social

Depressiondiagnosis:

Differential diagnosis of “DUO”

Adjustment response

“Organic”---secondary to HIV-related disease

Medication complication (antiretroviral)

Psychiatric disorder

Psychologicbackground:

Illness occurs in context of numerous losses

Friends and loved may also be ill

Psychologicdepression:

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

Depressiondiagnosis:

Important considerations:

Onset and course

Symptoms and severity

Previous episodes and treatment response

(remember, treatment is easy, diagnosis is hard)

DepressionAfter 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

Psychologicanxiety:

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 studyLife 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

Portal Vein

-P450 Enzymes present in intestinal cells

Directly metabolized here before reaching systemic circulation

Hepatic Vein

Systemic Circulation

Hepatic Artery

Oral Medication

Intestine

-PGP

-P450

Altered Drug Absorption: Food Requirements

Didanosine (ddI, Videx) empty stomach

Tenofovir (TDF, Viread) w/ food

Efavirenz (EFV, Sustiva) empty stomach

Kaletra (lopinavir/ritonavir)

w/ food

Amprenavir (Agenerase) avoid high fat

Indinavir (Crixivan) light snack

Saquinavir (Fortovase) w/ food

Nelfinavir (Viracept) w/ food

Pharmacodynamic Mechanisms of Drug Interactions

SynergismAntagonism

D4T and AZTIDV 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

I II III IV

A A B C D E F A A B

IA1 IIA3 IIB6 IIC8 IID6 IIE1 IIF1 IIIA3 IVB1

IA2 IIB7 IIC9 IID7 IIIA4

IIB8 IIC10 IID8 IIIA5

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 InhibitionD

rug

Co

nce

ntr

atio

n

Time

Inhibitor added

P450 CYP3A4 Degree of inhibition of liver CL

0+

ritonavir

NFV, IDV, LOP/r

EFV, DLV

SQV, AMP

RED FLAG List - P450 3A4 InhibitorsThese Agents will Concentrations of Co-Administered Drug

DRUG CLASS

RANK LIKLIHOOD of Drug Interaction

ALTERNATIVES / Comments

HIV Protease Inhibitors

Ritonavir> Indinavir= lopinavir> nelfinavir>amprenavir> saquinavir

Saquinavir has less potential to cause interactions

Macrolides Erythromycin > Clarithromycin Azithromycin – not metabolized by P450

Antifungals Ketoconazole> Itraconazole> Fluconazole

Fluconazole assoc w/ less drug i/a with doses <200mg. dose potential

HIV NNRTI’s Delavirdine Efavirenz (mixed)

Delavirdine may be used to conc of other drugs

H2

Antagonists Cimetidine (high propensity) Any other H2 Antagonist

(ranitidine, nizatidine,etc)

SSRIs Fluoxetine Led to serotonin syndrome; mirtazapine, venlafixine have least P450

Grapefruit juice

Daily intake

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: cyclosporineHIV Antivirals: indinavir nelfinavir ritonavir saquinavir

Calcium Channel Blockers:HMG CoA Reductase Inhibitors: NOT pravastatin simvastatin

RED FLAG List - P450 2D6 InhibitorsThese Agents will Concentrations of Co-Administered Drug

DRUG CLASS

RANK LIKLIHOOD of Drug Interaction

ALTERNATIVES / Comments

HIV Protease Inhibitors

Ritonavir

Macrolides

Antifungals

HIV NNRTI’s

H2

Antagonists

SSRIs Fluoxetine, paroxetine Citalopram, venlafaxine, etc

Grapefruit juice

N/A

P450 2D6 Substrates

Beta Blockers:carvedilolS-metoprololpropafenonetimolol

Antidepressants:amitriptyline  clomipramine  desipramineimipramine  paroxetine

Antipsychotics:haloperidolperphenazinerisperidone=>9OHthioridazine

Other:alprenololamphetaminebufuralolchlorpheniraminechlorpromazinecodeine (=>O-desMe)encainideflecainide

P450 Inducers

Increases the production of P450 enzymeMore 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 inductionD

rug

Co

nce

ntr

atio

n

Time

Inducer added

P450 CYP3A4Degree of Liver Enzyme Induction

rifampin, phenobarbital

RTV*, NFV*, LOP/r*, AMP

EFV*, NVP, phenytoin

0+* mixed effects on enzymes- not exclusively metabolized by 3A4

RED FLAG List - P450 InducersThese Agents will Concentrations of Co-Administered Drug

DRUG CLASS

RANK LIKLIHOOD of INTERACTION

ALTERNATIVE / COMMENTS

Rifamycins: Rifampin, Rifabutin

Both are POTENT Inducers; use rifabutin over rifampin for TB if pt on a PI

Avoid rifampin while on PI’s; Use ½ Rifabutin dose w/ IDV, APV, NFV; Use ½ dose qMWF with RTV; EFV ok (rifabutin 450mg )

HIV Protease Inhibitors

Ritonavir = Nelfinavir

All other PI’s

HIV NNRTI’s Efavirenz = Nevirapine

Anti-convulsants

Phenobarbital > Phenytoin = Carbamazepine

If clinically indicated: Valproic Acid, Gabapentin, Lamotrigene, Topiramate; Bidirectional; documented virologic failure when combined with PI’s

St. Johns Wort

RED FLAG List - Metabolized Drugs with Narrow Therapeutic Indices

CATEGORY DRUGS ALTERNATIVES / COMMETNS

Anti-arrythmics

Flecainide, Quinidine

Monitor closely with P450 inhibitors

Opiate Analgesics

Fentanyl (duragesic)

Hydromorphone, codeine, NSAIDS (esp in pts on RTV)

Benzo’s Midazolam, Triazolam, alprazolam

Oversedation; use temazepam; lorazepam

Ergotamines Ergot Derivs

Cafergot, Hydergine, DHE

Anti-coagualants

Warfarin Monitor INR when initiating or changing therapy

OC’s Ethinyl Estradiol; norethindrone

Efficacy 45%;Use alternative methods when pts receive P450 inducing PI’s

Use EXTREME Caution with P450 inhibitors/inducers as serious side effects may occur if their concentrations are altered

RED FLAG Lists:

http://medicine.iupui.edu/flockhart/