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 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

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

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 10:1 (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 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

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 MAR=mutations 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, • 24-72+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

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; 21:107-19

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

32. 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

33. Localizing Drug EffectsNIDA.gov

35. PET studies of drug addiction T stat 7.0 7.0 T-value 4.5 3.5 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 INMETHAMPHETAMINE 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 2002;8:240-9 • Human research: • Crystal depletes dopamine in the nigro-striatal tract: Parkinson’s disease risk Volkow Am J Psychiatry 2001;158:377-82

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 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

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 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

42. 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

43. 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

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

45. 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!

46. 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)