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Crystal Methamphetamine and HIV Infection: Medical and Psychiatric Aspects of a New Epidemic

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Title: Crystal Methamphetamine and HIV Infection: Medical and Psychiatric Aspects of a New Epidemic


1
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)

2
Methamphetamine
  • What is Crystal Methamphetamine?
  • Crystal Methamphetamine is a chemical that has
    stimulant properties.

3
Spread of Methamphetamine Use
4
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 30s 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

5
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

6
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

7
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

8
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

9
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10
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

11
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)

12
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 101 (Melega
    et al, J Pharmacol Exp Ther 1995)
  • Long plasma half life of 12 hours

13
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

14
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

15
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

16
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

17
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 FIVs 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

18
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

19
CDC Survey Drug-Resistant HIV Among Recently
Diagnosed Patients
Prevalence of MAR () Prevalence of MAR () Prevalence of MAR ()
1998 (n257) 1999 (n239) 2000 (n299)
Resistance to 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
gt2 drug class 0 1.3 1.3
MARmutations associated with resistance.
Bennett D, et al. 9th CROI, Seattle, 2002.
Abstract 372.
20
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

21
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

22
Crystal Meth Effects
  • Euphoria,
  • alertness,
  • well-being,
  • confidence,
  • sexual confidence,
  • sexual enhancement (despite transient impotence
    in many users) / Viagra www.erowid.com

23
Psychiatric Effects/Crystal Meth
  • At higher doses hypomania, grandiosity,
  • Extreme insomnia, irritability,
  • 24-72hrs 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 153 317-324

24
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
    21107-19

25
HIV and Crystal Meth
  • Class Amphetamine/stimulant/speed
  • How does it work?
  • 3 main neurotransmitters
  • Serotonin
  • Dopamine
  • Norepinephrine

26
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

27
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

28
Methamphetamine Causes Release of Dopamine
29
Dopaminergic Neuron
30
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31
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32
Ecstasy MDMA Intoxication
  • Euphoria
  • sensual not sexual
  • but still associated w. unsafe sex
    odds ratio 2.77 Klitzman et al Am J Psychiatry
    20002191-105
  • Danger of seizure esp w. Ritonavir
  • Henry, JA Lancet 1998 3521751-2
  • No paranoia, no violence
  • Long-term depression

33
Localizing Drug Effects NIDA.gov
34
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35
PET studies of drug addiction
Amphetamine-induced dopamine release
Alcohol-induced dopamine release
36
Neurons that make dopamine pleasure-reward
system highlighted. Most drugs of abuse affect
this system
Nestler Figure 8-6
37
BRAIN METABOLISM IN METHAMPHETAMINE ABUSE
Middle Frontal Gyrus
Inf. Temporal Gyrus
Middle Temporal Gyrus
38
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.
39
Crystal and HIV
  • Animal research
  • Crystal may increase viral replication in the
    brain by 5-15 fold
  • Gavrilin J Neurovirol 20028240-9
  • Human research
  • Crystal depletes dopamine in the nigro-striatal
    tract Parkinsons disease risk
  • Volkow Am J Psychiatry 2001158377-82

40
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 1989321907
  • Chronic useMajor 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 200221107-19

41
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 200221(1)61-73
  • Problems with psychomotor speed, concentration,
    learning and memory
  • n28 many addicts had Attention Deficit as
    children Sim et al J Addictive Diseases
    200221(1)75-89

42
Treatment
  • Psychosis Neuroleptics (Zyprexa, Risperdal)
  • RCT of dopamine agonists Bromocriptine and
    Pergolide (D1/D2 agonist) show no efficacy
  • Moscovitz, J Gen Intern med 199381-4
  • Malcolm et al Drug Alcohol Depend 200060161-8
  • D1 receptors may reduce drug cravings
  • D2 receptors may increase drug cravings
  • Methylphenidate not useful for treatment

43
Crystal and HIV Meds
  • Reported fatality with Crystal
  • 3Tc, Saquinavir, and Ritonavir
  • Hales Antivir Ther 2000519
  • Two reported fatalities with Ecstasy Ritonavir
  • Henry Lancet 1998352 1751-2

44
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

45
Treatment of Addiction
  • Motivational Interviewing
  • Harm Reduction
  • Adherence Strategies while using
  • Decreasing other STD transmission
  • Decreasing spread of resistant HIV
  • Gay/Lesbian Centered treatment

46
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 200150117-20
  • Adherence to HIV meds slips!

47
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)
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