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Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

Ending HIV Transmission in Drug Users: Impact to the HIV Epidemic. Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health. Convergence of HIV Seroprevalence Among IDU and Non-IDU among Selected Cities.

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Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

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  1. Ending HIV Transmission in Drug Users: Impact to the HIV Epidemic Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

  2. Convergence of HIV Seroprevalence Among IDU and Non-IDU among Selected Cities Non-injecting drug use appears to be an important factor contributing to HIV infection due to their high-risk behaviors and overlapping social and sexual networks with IDUs Strathdee and Stockman Curr HIV/AIDS Rep. 2010 7(2):99-106.

  3. ` METHAMPHETAMINE 2000 1500 1000 500 0 Dose (mg/kg IV) 5 2.5 1 Dopamine (nM) frontal cortex 0 20 40 60 80min Time After Methamphetamine nucleus accumbens VTA/SN Natural & Drug Reinforcers Increase Dopamine in NAc SEX 200 150 Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction DA Concentration (% Baseline) 100 50 0 Sample Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Source: Melega; Di Chiara and Imperato, Fiorino and Phillips

  4. Intoxication with Drugs Can Enhance Sexual Behaviors p < 0.001 p < 0.005 Medial Amygdala Saline MA In female rats, proceptivity (measure of motivation for sexual behavior) is enhanced by progesterone (EB+P) and methamphetamine (MA), which is associated with activation of the medial amygdala In humans iv methylphenidate increased sexual arousal both in controls and in cocaine abusers Holder et al., Psychoneuroendocrinology. 2010. Volkow ND et al., AJP 2007 164: 157-160.

  5. Prefrontal Cortex (cognitive control) Regulates Limbic Activation (emotions and desires) Sexual Arousal Condition Brain regions implicated in Impulsivity (red) and Control (blue) Attempted Inhibition Condition Bechara A Nature Neuroscience 8, 1458 - 1463 (2005). Beauregard, M. et al., Journal of Neuroscience 21 RC165, 2001.

  6. Decreases prefrontal cortex cingulate gyrus Increases Amygdala, NAcc Alcohol Intoxication Decreases Control Effects of alcohol intoxication on brain glucose metabolism (measure of brain function) in controls Effects of alcohol intoxication on GoStop ratio (measure of impulsivity) in controls Low to moderate doses of alcohol increased impulsivity in controls Dougherty et al., Drug Alcohol Depend 2008. Alcohol decreased activity of control areas and increased activity of areas involved with impulsivity Zhu et al., Alcohol Alcohol 39: 53-58 2004.

  7. Dopamine D2 Receptors are Lower in Addiction DA DA Cocaine DA DA DA DA DA DA DA DA DA DA Reward Circuits Non-Drug Abuser Meth DA D2 Receptor Availability DA DA DA Alcohol DA DA DA Reward Circuits Drug Abuser Heroin Adapted from Volkow et al., Neurobiology of Learning and Memory 78:610-624, 2002. control addicted

  8. 90 80 70 60 50 40 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 Chronic Drug Users Have Low Striatal DA D2 Receptors and this is Linked with Impulsivity and Impaired Frontal Activity Correlations Between D2 Receptors in Striatum and Brain Metabolism Regions showing lower D2 receptors in Methamphetamine abusers than in controls CG Methamphetamine Abusers PreF OFC umol/100gr/min OFC Alcoholics Low D2 receptors in Methamphetamine abusers are associated with higher scores in impulsivity Impulsivity Score (z-score) control addicted D2 Receptors (BPND) D2R Binding Potential (z-score) Decreases in striatal D2 Receptors in SA are associated with reduced activity in frontal regions involved with control, which could underlie their impulsivity Volkow et al., PNAS in press Lee, B. et al. J. Neurosci. 2009.

  9. Among IDUs Drug Abuse Treatment is an Effective HIV/AIDS Prevention Strategy HIV Seroconversion at 18 MonthsBy Receipt of Treatment 25 No treatment 20 Partial treatment 15 Rate of Seroconversion (%) Continuous treatment 10 5 0 Treatment Status Metzger, et al. (1993). Acquired Immune Deficiency Syndromes, 6, 1049-1056.

  10. Although Treatments for Heroin Addiction Work There Are Major Challenges State Prisons Offering Opiate Replacement Tx * * Nunn et al., Drug and Alcohol Dependence 2009;105:83-88.

  11. Many Countries Do Not Implemented OST IDUs Receiving Gov’t-Funded Methadone or BuprenorphineTx, 2009 Wolfe D et al., Lancet 2010; 376: 35-366.

  12. Medication for Opiate Addiction: Agonists (Methadone and Buprenorphine) and Antagonists (Naloxone and Naltrexone) Agonist (Methadone) Antagonist (Naloxone) Adapted from Johnson, et al., 2000

  13. Long-ActingInjectable Medications (i.e., Depot Naltrexone) IM Injection every 4 weeks for 24 weeks Placebo: N=124 XR-NTX: N=126 JAMA 2011

  14. Immunotherapies for Addiction Treatment (i.e., Vaccines) Antibodies Reduce Brain Concentrations VACCINE Binding Site Antibodies Targeting the drugs, not the receptors Capillary Blood Flow Capillary Blood Flow Brain Brain

  15. New Heroin Vaccine(s)K.D. Janda & G.F. Koob Laboratories at TSRI The Vaccine(s) Hot Plate Test Heroin 1 mg/kg, s.c. 30 min ##p<0.01, ###p<0.001, significant reduction of analgesia vs. Control/KLH group, ### p<0.001, significant reduction of analgesia vs. Control/KLH group

  16. IDU Are Less Likely To Receive ART Despite Their Higher Rates of HIV IDUs as Share of Total HIV Cases & of Patients Receiving ART, 2008 Wolfe D et al., Lancet 2010; 376: 35-366.

  17. HAART as HIV Prevention Montaner et al., Lancet 2008

  18. Incidence/yr Acquired resistance falling 90 80 70 60 Plasma viral load suppression rising Viral load < 50/mL (%) Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection

  19. Seek, Test, Treat and Retain: Addressing HIV Among Vulnerable Populations (R01) (RFA-DA-11-001) (With NIMH) HIV/AIDS Implementation Science Targeting Drug Using Populations: A Collaboration with PEPFAR (R01) (RFAAI-12-002) Application Due Date: August 1, 2011

  20. 2009 Dr. Benjamin Chen Mt. Sinai School of Medicine Visualizing early events of parenteral HIV transmission (cell-cell vs. free virus) 2009 Dr. Dana Gabuzda Dana Farber Cancer Institute & Harvard Medical School Control of T cell restoration in HIV-infected IV drug abusers 2009 Dr Jonathan Karn Case Western Reserve University Developing strategies for long-term HIV suppression 2010 Dr. Eric Verdin Gladstone Institutes New methods to detect and model HIV latency 2008 Dr. Ileana Cristea Princeton University Quantifying HIV –host interactome and regulation of gene expression 2009 Dr. Rafick-Pierre Sekaly Vaccine & Gene Therapy Institute, FL Novel pathways for purging the HIV reservoir 2008 Dr. Julio Montaner University of British Columbia HIV treatment as prevention in drug using populations 2008 Dr. Jerome Groopman Beth Israel Medical Center & Harvard Medical School Blocking HIV transmission at the immune synapse NIDA’s Avant-Garde Award Program Is Now Open to International Applicants

  21. Decline in Community Viral Load is Strongly Associated with Declining HIV Incidence among IDUs (ALIVE) GD Kirk, N Galai1, J Astemborski, B Linas, D Celentano, SH Mehta, D Vlahov HIV incidence risk declined by 5% (3-8%) for each 1% increase in the proportion of HIV+ on HAART. In a community-based IDU cohort (4546 Ss), increasing HAART uptake appears linked to reduced HIV transmission.

  22. Long-term cocaine treatment (72 hrs) strongly induces HIV transcription and reverses epigenetic restrictions in latently infected T-cells Chromatin immunoprecipitation assay (HIV Nuc-1 region) Input DNA (%) Data from: Mudit Tyagi, Fatah Kashanchi, Kurt Hauser and Jonathan Karn

  23. Estimated # of New Infections in US by Transmission Category Source: Hall, H.I., et al. JAMA, August 6, 2008—Vol 300, No. 5, 520-529

  24. Many Offenders Have a Drug Use Disorder But Few Receive Treatment Mumola & Karberg. Drug use and dependence, state and federal prisoners, 2004. BJS, 2006 (rev 07)

  25. Das M, et al. (2010) PLoS ONE 5(6)

  26. Wood et al, BMJ, 2009

  27. Global prevalence of IDU in 2008 HIV prevalence among IDU in 2008 Source: Mathers, et al., Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. Lancet, 2008

  28. Chronic Drug Exposure can Exacerbate the Neurotoxic Effects of HIV Chang et al., Neuroimage, 42:869-78, 2008.

  29. Syringe-Exchange Program are Effective Prevention Strategies for HIV infection HIV Incidence Among Injection Drug Users in New York City 6.23 5.26 Per 100 person-years at risk Vaccine Preparedness Initiative National AIDS Demonstration Research 1.38 Des Jarlais DC et al. The Lancet, 1996; 348: 987-991.

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