Street Drugs and the Immune System

1
Street Drugs and the Immune System

• Ronald D. Wilcox MD FAAP
• Principal Investigator / Medical Director
• Delta AETC
• Asst Professor Internal Medicine and Pediatrics,
  LSUHSC
• 27 February 2007

2
Speaker Disclosure

• Speakers Bureau Pfizer
• Research Support Tibotec, GlaxoSmithKline,
  Bristol-Myers-Squibb
• No other financial relationship

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
3
Objectives

• To review a few common street drugs
• To review the effects some street drugs may have
  on the immune system
• To review potential interactions between HAART
  and street drugs

4
Definitions

• Chemokine a glycoprotein which activates
  leukocytes or chemotactic activity
• Examples CXCR4, CCR5
• Cytokine a small protein released by cells that
  has a specific effect on the interactions between
  cells, on communications between cells, or on the
  behavior of cells
• Examples interleukins, lymphokines

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Dendritic cells

• Potent antigen presenting cells
• Initial line of defense against HIV-1 infection
• Act as reservoirs for HIV-1
• Function at the interface between adaptive and
  innate immune systems which recognize and
  internalize pathogens, leading to activation of T
  cells.

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Case

• 21 year old white MSM male presents with thrush
• HIV test is positive
• Patient frequently smokes marijuana throughout
  the week and on weekends drinks with his friends,
  occasionally uses crystal meth
• CD4 count 212 (15) with viral load 41,000

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Case

• What effects with his drug use have on his
  ability to take HAART?
• What effects will his drug use have on his immune
  system?
• Will his drug use influence the choice of HAART?

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Effects on Sexual Behavior
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High Risk Behaviors

• Beckett M et al. AIDS Behav 2003 Jun7(2)209-19
• Compared MSM to IDUs to heterosexual men and
  women
• Substance use most prevalent among MSM
• No differences seen between the three groups
  all seen to have increased risk behavior when
  using illicit substances

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Marijuana and Sexual Activity

• Stephens TT, Sprauve NE. Int J STD AIDS 2006
  Jul17(7)463-6
• Collected data from male prisoners from 2000-2003
• No variance in feeling like they would be less
  likely to use precautions after using marijuana
• Those that had anal sex felt they were better
  lovers while using marijuana
• More likely to have anal sex if under the
  influence of marijuana than those who were sober
  (p

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Meth Use and Unprotected Anal Sex

• Mansergh G et al. Sex Transm Inf 2006
  Apr82(2)131-4
• Cross sectional community based survey of MSM in
  SF regarding sexual behavior during most recent
  anal sex encounter
• N 388 - Diverse in race, ethnicity, age,
  income, education, HIV status, and
  homosexual/bisexual identification
• 29 reported unprotected insertive AS and 37
  reported unprotected receptive AS
• Methamphetamine use reported by 15 and
  sildenafil use reported by 6 2 both
• Multivariate analysis
• Meth use with unprotected receptive (OR 2.03, CI
  1.09 3.76)
• Sildenafil use with unprotected insertive (OR
  6.51, CI 2.46 17.24)

12 insertive and 17 receptive with discordant
or unknown status partner
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Meth Use Among Heterosexual Men and HIV Risk
Behaviors

• MMWR 2006 Mar 1755(10)273-7
• CA Dept of Health Services, Office of AIDS,
  analyzed population-based data from 5 northern CA
  counties in the HEY-Men (Health Evaluation in
  Young Men) Study
• Recent meth use among heterosexual men was
  associated with increased incidence of
• Sex with casual or anonymous female partners
• Anal intercourse
• Sex with an IVDU

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Alcohol

• Increases cytokine activity and levels, esp with
  chronic use
• Lung increased expression of transforming
  growth factor beta (TGF-beta) leading to
  respiratory distress syndrome
• Liver increases T-helper 1 (pro-inflammatory)
  activity leading to increases in tumor necrosis
  factor alpha (TNF-alpha), increasing fibrosis
• Brain cytokines felt to likely contribute to
  long-term changes in behavior and
  neurodegeneration
• Augments intracellular survival of MAC

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Alcohol and HIV

• Poonia B, Nelson S et al. JAIDS 2006 Apr
  1541(5)537-47
• SIV viral loads significantly elevated in rhesus
  monkeys consuming alcohol
• Central memory CD4 counts found to be
  significantly depleted in the intestines and
  mesenteric lymph nodes in the alcoholic monkeys 8
  weeks after infection with SIV

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MJ and Immunity

• Heavy use suppresses lymphocyte proliferation in
  culture
• Serum IgG levels decreased, IgE levels increased
• Alveolar macrophages from MJ smokers shown to be
  deficient in phagocytosis and bactericidal
  activity

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Marijuana and HIV

• Cristiani SA et al. J Neuropsychiatry Clin
  Neurosci 2004 Summer16(3)330-5
• Examined interaction of HIV disease-stage and
  marijuana use in 282 subjects
• After controlling for effects of depression,
  anxiety, and alcohol use
• Significant decrease in ability to perform memory
  tasks, esp in those with symptomatic HIV NOT
  seen previously in those without HIV

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Marijuana and HIV

• Abrams DI et al. Ann Intern Med 2003 Aug
  19139(4)258-66
• Randomized placebo-controlled 21 day trial in San
  Francisco n 67
• Assigned to smoke a marijuana cigarette or take a
  dronabinol 2.5 mg or a placebo three times daily
  before meals
• Measured HIV RNA, CD4 cells, CD8 cells, and
  pharmacokinetics of PIs
• No effects seen by the groups who smoked MJ or
  those that took dronabinol

20
THC and HIV

• Roth MD et al. Life Sci 2005 Aug
  1977(14)1711-22
• Human peripheral blood leukocytes were implanted
  in mice with SCID and infected with an HIV
  reporter construct in presence and absence of THC
• Administration of THC alone decreased CD4 counts
  and the CD4CD8 ratio
• Administration of THC with HIV did not reduce CD4
  counts further but increased of cells infected
  by HIV as compared to saline-treated animals
• Viral load increased 50 fold in those with THC
• THC increased CCR5 and CXCR4 presentation early
  but lost this effect by 10 days
• Both THC and HIV decreased the number of
  IFN-gamma producing cells with additive effects
  seen

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Methamphetamine

• Types white, yellow, orange, pink or light
  brown crystalline powder or clear chunks
  resembling ice
• Common names Chalk, Crystal, Ice, Meth, Rock
  Candy, Speed, Tina, Tweek, Quartz
• Class of drug CNS stimulant, sympathomimetic,
  appetite stimulant
• Routes of administration
• Snorted effects in 3-5 minutes
• Ingested effects in 20-30 minutes
• Smoked effects in 7-10 seconds
• Injected effects in 15-30 seconds
• Booty bumped effects in 15-30 seconds

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Methamphetamine
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Methamphetamine

• Pharmacology
• Increases synaptic levels of dopamine, serotonin,
  and norepinephrine
• Alpha and beta agonist effects
• Stimulant effects similar to cocaine but slower
  and longer acting
• Peak concentrations after oral ingestion 2.6
  3.6 hours with mean half-life 10 hours

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Methamphetamine

• Physical effects
• Increases heart rate, BP, perspiration
• Urinary retention, dry mouth, dilated pupils,
  decreased appetite
• Addiction occurs quickly
• Morbidity irritability, hypothermia, insomnia,
  aggressiveness, paranoia, anxiety, strokes, heart
  attacks, Parkinson-like syndrome with chronic
  use, crystal dick
• Psychological effects
• rush or flash very pleasurable but short
  lived
• Oral or nasal use produces high but not rush
• Hypersexuality, euphoria, lowering of sexual
  inhibitions, boredom, loneliness, increased
  self-esteem and confidence

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Meth Mouth
Shetty K. Med J Aust 2006 Sep 4
Shaner JW et al. AIDS Pat Care 2006
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Methylenedioxymethamphetamine (MDMA)

• Types white, tan, or brown powder. Mainly
  available as tablets
• Common names Ecstasy, Adam, Candy Canes, Disco
  Biscuit, Doves, E, Eckie, Essence, Hug Drug, Love
  Drug, MM, Rolls, White Doves, X, XTC
• Class of Drugs Mild CNS Stimulant,
  hallucinogenic, psychedelic
• Routes administered
• Usually orally but may be dissolved and injected
  or crushed and snorted

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Methylenedioxymethamphetamine (MDMA)

• Pharmacology
• Causes marked depletion of serotonin
• Suicide Tuesday
• Rapidly absorbed with half-life 7 hours

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Methylenedioxymethamphetamine (MDMA)

• Physical Effects
• High doses hyperthermia, possibly liver or
  kidney or cardiovascular failure
• Low to moderate doses muscle tension,
  involuntary jaw clenching, nausea, blurred
  vision, dilated pupils, faintness, chills,
  sweating, tachycardia, hypertension
• Psychological effects
• High doses agitation, panic, depression,
  confusion, sleep problems, hallucinations
• Low to moderate doses increased relaxation,
  euphoria, feelings of well-being, heightened
  sensitivity, changes in perception, empathy,
  dis-inhibition

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Methamphetamine and HIV in MSM A
time-to-Response Association?
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Cerebral Morphology

• HIV
• damages cerebral white matter and striatal gray
  matter
• Also seen to decrease volume of thalamus,
  hippocampus, and cerebral cortex (frontal,
  temporal)
• MDMA
• temporal lobe shrinkage as well as decreases in
  gray matter of the cingulate and other limbic
  cortices lateralized to the right hemisphere
  also have seen volume reduction in the
  hippocampal volume bilaterally.
• Hypertrophy of cerebral white matter

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Hippocampus
Caudate
Frontal
Parietal
Thalamus
Lenticular nucleus
Temporal
Amygdala
Nucleus accumbens
Occipital
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Yellow MA Red HIV Orange MA
HIV
Jernigan et al. Am J Psychiatry 1628, August
2005, pp. 1461-72
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Methamphetamine

• Chronic use modulates the dendritic cellular
  expression of several genes
• Chemokine regulation
• Cytokinesis
• Signal transduction mechanisms
• Apoptosis
• Cell cycle regulation

Mahajan SD et al. Mol Diagn Ther
200610(4)257-69
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Methamphetamine

• MSM
• 39 used MA within past 12 months
• usually snorted or rectally inserted
• Heterosexual men and women
• 30 of men and 19 of women used MA within past
  12 months
• More likely to inject than MSM
• More likely to have increased number of sexual
  partners

Mitchell SJ et al. AIDS Patient Care
200620(7)502-10
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Methamphetamine

• HIV-1 people who abuse meth are known to develop
  more severe encephalitis and neuronal damage
• Interacts with HIV-1 protein tat to enhance
  dopaminergic neurotoxicity
• In rats tat has been shown to elevate levels of
  striatal TNF-alpha which may predispose the
  dopaminergic terminals to subsequent damage by
  methamphetamine
• Also found levels of monocyte chemotactic protein
  (MCP-1), IL-1alpha, and tissue inhibitor of
  metalloproteinase-1 (TIMP-1) noted to be
  increased 4 hours after use for those with tat
  MA compared to saline, tat, or MA
• Interaction prevented in mice deficient in MCP-1
  with consequent attenuation of neurotoxicity

Theodore S et al. Neurobiol Dis 2006 Jul 5
e-Pub and Exp Neurol 2006 Jun199(2)490-8
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Sex Risk Reduced with TxUARI Past 30 Days
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Cocaine and Crack

• Types
• Cocaine white to light brown powder
• Crack white to beige flaky solid chunks
• Common names for cocaine Coke, Snow, Flake,
  Blow, Cane, Dust, Shake, Toot, Nose Candy, White
  Lady
• Common Names for crack Rock, Freebase
• Class of Drugs CNS stimulant, local anesthetic
• Routes of administration Injected, snorted,
  smoked

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Cocaine
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Cocaine and Crack

• Pharmacology
• Rapidly absorbed
• Blocks uptake of dopamine, norepinephrine, and
  serotonin, resulting in euphoric rush
• Rush lasts 5-10 minutes from smoking, 15-30
  minutes from snorting

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Cocaine and Crack

• Physical and Psychological Effects
• Increased BP, temperature, heart rate
• Dilated pupils
• Euphoric effects hyperstimulation, reduced
  fatigue, mental clarity
• May cause restlessness, irritability, anxiety
• Major complications arrhythmias, acute coronary
  spasm, chest pain, stroke, seizure

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Cocaine

• Decreases mitogen-induced T-lymphocyte
  proliferation in rats following IV administration
• Increases HIV infection of human PBMCs in vitro
• Human PBMCs implanted in SCID mice showed cocaine
  treatment increased number of HIV-infected PBMC
  and viral load as well as decreased the CD4/CD8
  ratio

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Cocaine and Alcohol

• Compared EtOH and cocaine using HIV-1 AA women
  to drug-free HIV AA women.
• Monitored cellular immune parameters
• Findings
• Significant inverse correlation between
  CD8/CD38 cells and subpopulations of CD4 cells
  with CD45RA expression for users with the
  CD4/CD45RA cells being significantly higher
  (p
• Importance CD45RA cells have decreased
  production of IL-2 in vitro by TH1 and TH2
  cytokines advancing progression to AIDS

Chiappelli F et al. Front Biosci 2006 Sep
1112434-41
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Heroin

• Three types
• China White
• Black Tar
• Synthetic
• Common Names Smack, H, Skag, Silk, Horse, Junk,
  Bags, Blue-Steel, China White, P-Dope
• Class of Drugs opiate
• Routes administered
• Injected (IV / mainlining or SQ / skin popping)
• Smoked
• Snorted

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Heroin

• Sometimes is cut with inert or toxic adulterants
• Sugars
• Starch
• Powdered milk
• Quinine
• Meat tenderizer
• Ketamine
• Speedball mixture of heroin with either cocaine
  or methamphetamine

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Heroin

• Pharmacology
• Very short half life ( metabolism to active opiate
• Narrow therapeutic index
• High physical and psychological dependence
• Tolerance requires increasing doses

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Heroin

• Physical effects
• Respiratory depression, CNS depression,
  analgesia, reduced GI motility, overdose
• Withdrawal within 6-12 hours, lasting 5-10 days
• Psychological effects
• Rapid, intense feeling of euphoria, alternating
  between wakeful and drowsy states
• Feeling of well-being, relaxation, sedation,
  lethargy, disconnectedness, self-absorption,
  mental clouding, delirium

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Opiate Effects on Immunity

• Opioid receptors have been demonstrated on immune
  cells
• Infectious complications and progression of HIV
  disease decreased in IVDUs who quit use
• In vitro studies have noted decreased
  phagocytosis, chemotaxis, and cytokine and
  chemokine production when opiates present
• Alters hypothalamus-pituitary-adrenal (HPA) axis,
  leading to alteration in glucocorticoid levels.
  Glucocorticoids play an important role in
  decreasing and regulating cellular immune
  responses

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• Does drug use interfere with HAART therapy?
• Are there particular dangers when used when
  someone is on HAART?

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Drug Use and Adherence

• EtOH
• chronic drinkers have not been shown consistently
  to have decreased adherence
• binge drinkers do have problems
• MJ not shown to interfere
• Cocaine strong correlation with inadherence
• Heroin mixed results
• MA, MDMA likely poor adherence while using

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CYP3A4

• Inducers
• Carbamazepine
• Phenytoin
• Rifampin
• Nevirapine
• Tipranavir
• High dose ritonavir
• Efavirenz

• Inhibitors
• Protease inhibitors
• Low-dose Ritonavir
• Delavirdine
• Nefazodone
• Paroxetine
• Fluoxetine

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HAART and EtOH

• Abacavir and EtOH both use alcohol
  dehydrogenase for metabolism increase levels of
  ABC by 41
• Acute EtOH induces CYP2D6 and 2C19, chronic use
  induces CYP2E1 and 3A4
• OCP, PI, NNRTI, statin levels can all be low

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HAART and Benzodiazepines

• Ritonavir acts as both an inducer and inhibitor
  of CYP3A4
• Triazolobenzodiazepines (Versed, Halcion, Xanax)
  dependent on CYP3A4 for metabolism
• Levels initially increased with RTV and then
  decreased with continued use
• Flunitrazepam (Rohypnol) when use with
  ritonavir, paroxetine, or nefazodone may have
  toxicity

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HAART and Cocaine

• N-demethylation results in active, hepatotoxic
  metabolite norcocaine primarily performed at
  CYP 3A4
• Levels may be increased by some ART use, esp
  ritonavir, indinavir, efavirenz
• Potential for overdose when co-administered,
  leading possibly to rhabdomyolysis, arrhythmia,
  cardiovascular collapse

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HAART and GHB (Liquid X)

• Up to 50 of MSM with HIV have history of use
• First pass metabolism is mediated by cytochrome
  P450 system
• Case HIV man recently began HAART including
  RTV SQV took MDMA (Ecstasy) then took a small
  dose of GHB to counteract the extended effects of
  the MDMA within 20 minutes became unresponsive
  with HR 40 and required intubation.

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HAART and Special K

• Ketamine a derivative of PCP
• Metabolized by CYP2B6 primarily but also somewhat
  by CYP3A4 and 2C9
• Animal data suggest ketamine may inhibit CYP3A4,
  leading to increased PI levels and possible
  toxicity

57
HAART and LSD (Acid)

• Metabolism not completely understood
• No known interactions with HAART

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HAART and MDMA (Ecstasy), Methamphetamine, and
Amphetamine

• Metabolized primarily via CYP2D6 but also by 1A2,
  2B6, and 3A4
• Case HIV male recently started on HAART
  regimen including ritonavir took 180 mg MDMA.
  Within hours became tachypneic, tachycardic,
  hyperthermic, had a generalized seizure, and
  died.
• Potent inhibitors of CYP2D6 include ritonavir,
  bupropion, fluoxetine, paroxetine, and quinidine

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HAART and Opiates

• Fentanyl
• may have increased levels when given with RTV,
  EFV, DLV
• Meperidine
• may have increased levels with inhibitors or
  decreased levels with inducers
• Methadone
• Withdrawal may occur with LPV/r, RTV, NVP, EFV
• Increased levels seen with nRTIs
• Heroin / morphine / codeine
• Levels decreased with UGT inhibition (ATV, IND)

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HAART and PCP

• Metabolized primarily by CYP 3A4
• Potential for drug interactions with IND, RTV,
  EFV, ketoconazole, nefazodone
• No documented case reports of significant
  interaction though

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HAART and MJ

• Metabolized by CYP 3A4
• No change in PI levels seen in studies but
  metabolism of THC slowed down.

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Take-Home Points

• MJ may increase number of cells infected and
  lower CD4 counts
• Cocaine may overdose if taking RTV, IND, EFV
• Heroin / opiates drug interactions variable,
  may have withdrawal due to increased metabolism
• EtOH may have subtherapeutic levels of PIs and
  NNRTIs
• MA / MDMA increases neurologic damage, may
  overdose with standard dosage after starting
  HAART

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Contact Info

• Rwilco_at_lsuhsc.edu
• Office 504-903-7301
• Pager 504-363-1692
• Delta AETC www.deltaaetc.org
• 504-903-0788