Download Crystal Methamphetamine and HIV Infection

Crystal Methamphetamine and HIV
Infection: Medical and Psychiatric
Aspects of a New Epidemic
Antonio E. Urbina, MD
St. Vincent Catholic Medical Center-Manhattan
Kristina Jones, MD
New York Presbyterian Hospital
Center for Special Studies (HIV)
Methamphetamine
• What is Crystal
Methamphetamine?
– Crystal Methamphetamine is
a chemical that has stimulant
properties.
Spread of Methamphetamine Use
Epidemiology
• High prevalence of HIV in patients who use
crystal MA
• Shoptaw, et al, J Addict Dis 2002 showed in a CA study that
61% of men seeking tx for MA had HIV infection
–
–
–
–
77% of men were white, 17% were Latino
All were in their mid 30’s and had some college education
Reported a mean of 66 different partners in 6 months
Persons with HIV were more likely to have injected MA,
contracted an STD and had more UAI
• Klitzman, et al Am J Psychiatry 2000 reported strong
association between MDMA use and high-risk sexual
behavior
• 2001 report in MMWR found that in an outbreak of 130 cases
of syphilis in CA, 51% were MSM and 18% reported use of
MA
Epidemiology
• Study of 25 HIV+ gay men using MA
(Semple et al., J Subst Abuse Treat 2002)
– “provided temporary escape from being HIV+”
– “helps manage negative self-perception and
social rejection associated with being HIV+
– “method of coping with the specter of death”
Medical Complications
• Short term effects are similar to those of cocaine
– Mediated through release of DA and NE
– Tachycardia, HTN, tachypnea, hyperthermia, CNS
excitation
– Rhabdomyolysis and cardiovascular events
• Retrospective review of ER admissions for rhabdo reported
that 43% used MA ( Richards, J., Am J Emer Med 1999)
• CV responses include vasoconstriction, vasculitis and focal
myocyte necrosis
• Intersection between aging HIV population, metabolic
complications and HIV
Medical Complications
• Cardiopulmonary events associated with long-term use
include MI and stroke
– 4 cases of stroke in pts aged 29-45 have been documented
(Perez, et al. J Emer Med 1999)
• Smoking of MA is associated with acute pulmonary HTN
and dilated CM
• Immunomodulatory activity
– Impairs CD8 mediated T cell function (House, et al
Immunopharmacol Immunotoxicol 1994)
– CD8 cell activity is responsible for early suppression of lentiviral
replication and viral set point
• Leads to significant bruxism and periodontal disease
Metabolism
• MA and related compounds including
MDMA (“Ecstasy”) are metabolized by the
CYP 2D6 isoform of the P450 enzyme
system
• Genetic polymorphism
– 3-10% of white population is deficient in CYP
2D6
Drug Interactions with HIV Meds
• Fatal interactions between amphetamines,
their analogues (MDMA) and PIs
– Ritonavir has greater affinity for enzyme than
amphetamines and results in 3-10 fold
increases in level of MA
• Includes all boosted PIs (i.e. lopinavir/ritonavir,
atazanavir/ritonavir, invirase/ritonavir)
– Delavirdine is partially metabolized and may
have similar pharmacokinetic interactions
Case Reports
• One case of HIV patient receiving a
combination of stavudine, saquinavir, and
ritonavir who died after injecting MA
(Hales,G, et al. Antivir Ther 2000)
– Toxicology consistent with overdose
• Two case reports document fatalities after
ingestion of ritonavir-containing regimens
and MDMA (Henry J., Hill IR, Lancet 1999;
Baker et al, BETA 1997)
Neurotoxicity
• MAs neurotoxic effects are the most
devastating and potentially permanent
sequelae
• Studies in rats indicate MA accumulates in
the brain with a brain to plasma [ ] of 10:1
(Melega et al, J Pharmacol Exp Ther
1995)
• Long plasma half life of ~12 hours
Neurotransmitter Toxicity
• MA use leads to a reduction in dopamine
transporter levels (DAT)
• Study of 15 HIV negative MA abusers using PET
scans found reductions in DAT levels (Volkow
and Chang Am J Psychiatry 2001)
– Neuropsychiatric evidence of impaired motor fx and
verbal learning
– 3 subjects’ DAT levels had ↓ within range seen for
low-severity Parkinson disease
• Extrapyramidal sxs were not seen possibly due to young age
of subjects
Neurotransmitter Toxicity
• Not known whether ↓ DAT levels reflect
irreversible dopamine terminal damage or
neuroadaptive changes
– Another study by Volkow and Chang (J.
Neurosci 2001) of former users showed that
although DAT levels recovered with 12-17
months of abstinence, neuropsychological fx
did not
• Neither gross nor fine motor speed improved
• No improvement in Rey auditory verbal learning
Synergy of MA and HIV
• Clinical features of HIV-related dementia (HAD)
are those of a subcortical type
– Psychomotor slowing, apathy and memory deficits
– Advanced HAD sxs include bradykinesia, altered
posture and gait and incontinence
• HAD is a metabolic encephalopathy that
involves brain cell loss and neuronal dysfunction
– Supporting neuronal cells (microglial cells,
macrophages, astrocytes) induce damage by
secreting inflammatory cytokines that damage brain
cells
• Neurons themselves are not directly infected with HIV
Synergy of MA and HIV
• Experimental evidence suggests that HIV-1
proteins gp120 and Tat are toxic to dopamine
neurons
• There is overlap in that both MA and HIV target
dopamine neurons
– HIV affects the dopamine neurons in subcortical
structures, particularly the basal ganglia
– MA targets dopamine in many regions of the brain
including orbitofrontal cortex, dorsolateral prefontal
cortices and amygdala
Synergy of MA and HIV
• Some researchers suggest that dopaminergic
systems are most vulnerable to such combined
neurotoxicity
• Researchers (Gravilin et al, J Neurovirol 2002)
found that exposing feline astrocytes infected
with FIV to MA increased FIV’s ability to replicate
and mutate by 15-fold.
• Findings imply that MA use in HIV patients could
increase prevalence of HIV-related dementia in
patients who are not receiving ARVs
– Awaits verification in human studies
MA Use and Adherence
• Adherence to HIV meds slips during acute
intoxication
• “Weekend warrior” approach to using Club
Drugs
– Potential increase for transmission of drug
resistant HIV
CDC Survey: Drug-Resistant HIV
Among Recently Diagnosed Patients
Prevalence of MAR (%)
1998
(n=257)
1999
(n=239)
2000
(n=299)
Any drug
5.5
8.8
10.7
NRTI
5.1
7.1
7.7
NNRTI
0.4
2.1
1.7
PI
0
0.8
3.0
>2 drug class
0
1.3
1.3
Resistance to:
MAR=mutations associated with resistance.
Bennett D, et al. 9th CROI, Seattle, 2002. Abstract 372.
Amphetamines and ED Drugs
• ED drugs such as sildenafil (Viagra®), vardenafil
(Levitra®) and tadalafil (Cialis®) are metabolized
via CYP3A4
– Dose reduction recommended with concurrent use of
PIs
• No significant pharmacokinetic interaction
between amphetamines and ED drugs
• Increased prevalence of ED drugs with
amphetamine intoxication
nPEP and MA
• PEP for consensual sexual exposures
• May reduce risk by 80%
• Timing and facilitating rapid access access to
meds (72 hours) are ESSENTIAL
• Barrier from HCP in administering PEP based on
context of behavior in which risk occurred
• MA use/abuse provides counseling opportunity for
PEP
Crystal Meth Effects
•
•
•
•
•
•
Euphoria,
alertness,
well-being,
confidence,
sexual confidence,
sexual enhancement (despite transient
impotence in many users) +/= Viagra
www.erowid.com
Psychiatric Effects/Crystal Meth
•
•
•
•
•
•
•
At higher doses: hypomania, grandiosity,
Extreme insomnia, irritability,
24-72+hrs without sleep,
Appetite suppression, weight loss, skin picking
~10% : frank psychosis,
Identical to paranoid schizophrenia
Violent behavior (physical and sexual)
•
Nordahl et al J Neuropsychiatry & Clinical Neuroscience 15:3 317-324
Crystal Meth Withdrawal
•
•
•
•
•
•
•
“terrible Tuesday” withdrawal:
depression, irritability,
suicidal ideation,
carbohydrate craving
Long-term use (1-2 yrs?)
= chronic depression
62% remain depressed 2-5 yrs after abstinence
Rawson et al J Addictive Diseases 2002; 21:107-19
HIV and Crystal Meth
•
•
•
•
•
•
Class: Amphetamine/stimulant/”speed”
How does it work?
3 main neurotransmitters:
Serotonin
Dopamine
Norepinephrine
Neurotransmitter Functions
• Dopamine:
“reward pathway”
“addiction pathway”
• Serotonin: mood, sleep, sex, appetite
• Norepinephrine: increases blood pressure,
gives energy, related to adrenalin
American Psychiatric Association Textbook of Substance Abuse Treatment 2002
Neurotransmitters and Club
Drugs
•
•
•
•
•
•
Crystal Meth:
Dopamine and Norepinephrine
Ecstasy:
Dopamine and Serotonin
Cocaine:
Dopamine, Norepinephrine, Serotonin
American Psychiatric Association Textbook of Substance Abuse Treatment 2002
Methamphetamine Causes
Release of Dopamine
Dopaminergic Neuron
Ecstasy MDMA Intoxication
• Euphoria
• “sensual not sexual”
• but still associated w. unsafe sex
odds ratio 2.77 Klitzman et al Am J Psychiatry 2000;21:91-105
• Danger of seizure esp w. Ritonavir
•
Henry, JA Lancet 1998: 352:1751-2
• No paranoia, no violence
• Long-term : depression
Localizing Drug Effects
NIDA.gov
PET studies of drug addiction
Amphetamine-induced dopamine release
T stat
7.0
3.5
Alcohol-induced dopamine release
7.0
T-value
4.5
Neurons that make dopamine:
“pleasure-reward” system highlighted.
Most drugs of abuse affect this system
Nestler Figure 8-6
BRAIN METABOLISM IN
METHAMPHETAMINE ABUSE
Inf. Temporal
Gyrus
Middle Temporal
Gyrus
Middle Frontal
Gyrus
Human Brain Areas Corresponding to the Mouse
Brain Areas Damaged by Methamphetamine
Methamphetamine-induced damage to nerve terminals of dopamine-producing cells occurs
primarily in a brain region called the striatum. Methamphetamine-induced apoptosis killed off
different types of nerve cells in the frontal cortex, the hippocampus, and the striatum in mice.
Crystal and HIV
• Animal research:
• Crystal may increase viral replication in the
brain by 5-15 fold
Gavrilin J Neurovirol 2002;8:240-9
• Human research:
• Crystal depletes dopamine in the nigrostriatal tract: Parkinson’s disease risk
Volkow Am J Psychiatry 2001;158:377-82
Long term Psychiatric Effects
• In ~10% persons, long-term abuse = psychoses
that mimic schizophrenia
– Cocaine-induced psychosis has a brief duration whereas
MA may last for several days or weeks
Jackson NEJM 1989;321:907
• Chronic use=Major Depression
– California study of 170 former MA abusers, found that
62% of subjects reported having depressive sx s at
baseline and follow-up, while only 7.2% reported
paranoia at followup
Rawson et al J Addict Dis 2002;21:107-19
Long term cognitive effects
• Neuropsychiatric effects problems w.
manipulating information, set shifting,
divided attention and perseveration (like
HIV dementia) Simon et al J Addictive Diseases 2002;21(1):61-73
• Problems with psychomotor speed,
concentration, learning and memory
• n=28 many addicts had Attention Deficit as
children Sim et al J Addictive Diseases 2002;21(1):75-89
Treatment
Psychosis: Neuroleptics (Zyprexa, Risperdal)
RCT of dopamine agonists Bromocriptine and
Pergolide (D1/D2 agonist) show no efficacy
Moscovitz, J Gen Intern med 1993;8:1-4
Malcolm et al Drug Alcohol Depend 2000;60:161-8
D1 receptors may reduce drug cravings
D2 receptors may increase drug cravings
Methylphenidate = not useful for treatment
Treatment of Addiction
• Treat Substance-Induced psychiatric
disorders
• Wellbutrin (Bupropion) 150mg
• Celexa 20 mg po od
• Ambien (Zolpidem) 10mg
• Depakote for mood stabilization
• Zyprexa, Risperdal for psychosis/anxiety
Treatment of Addiction
•
•
•
•
•
•
‘Motivational Interviewing’
Harm Reduction
Adherence Strategies while using
Decreasing other STD transmission
Decreasing spread of resistant HIV
Gay/Lesbian Centered treatment
Crystal and HIV
•
•
•
•
•
Loss of judgement re: safe sex
Loss of judgement re: safe partners
(emotionally, physically)
Overconfidence about other STD risk
Syphillis outbreak in California
•
MMWR 2001;50:117-20
• Adherence to HIV meds slips!
Websites for HIV/Club Drugs
•
•
•
•
•
•
www.nida.gov
(National Institute for Drug Abuse)
www.erowid.org
(pro-drug website w/ pictures)
www.hiv-druginteractions.org
(drug/herb/club-drug interaction charts)