Presentation on theme: "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."— Presentation transcript:
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
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. Convergence of HIV Seroprevalence Among IDU and Non-IDU among Selected Cities
VTA/SN nucleus accumbens nucleus accumbens frontal cortex frontal cortex Source: Melega; Di Chiara and Imperato, Fiorino and Phillips ` ` Time After Methamphetamine Dopamine (nM) METHAMPHETAMINE 2000 1500 1000 500 0 2000 1500 1000 500 0 5 5 1 1 2.5 Dose (mg/kg IV) 0 20 40 60 80min 100 150 200 DA Concentration (% Baseline) SEX 50 0 0 Sample Number Sample Number 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 11 12 13 14 15 16 17 Natural & Drug Reinforcers Increase Dopamine in NAc Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction
Intoxication with Drugs Can Enhance Sexual Behaviors Volkow ND et al., AJP 2007 164: 157-160. In humans iv methylphenidate increased sexual arousal both in controls and in cocaine abusers 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 SalineMA Medial Amygdala p < 0.005 p < 0.001 Holder et al., Psychoneuroendocrinology. 2010.
Brain regions implicated in Impulsivity (red) and Control (blue) Bechara A Nature Neuroscience 8, 1458 - 1463 (2005). Beauregard, M. et al., Journal of Neuroscience 21 RC165, 2001. Sexual Arousal Condition Attempted Inhibition Condition Prefrontal Cortex (cognitive control) Regulates Limbic Activation (emotions and desires)
Alcohol decreased activity of control areas and increased activity of areas involved with impulsivity Decreases prefrontal cortex cingulate gyrus Increases Amygdala, NAcc Zhu et al., Alcohol Alcohol 39: 53-58 2004. 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.
Dopamine D2 Receptors are Lower in Addiction DA D2 Receptor Availability Cocaine Alcohol DA Reward Circuits DA Reward Circuits DA Drug Abuser Non-Drug Abuser Heroin Meth control addicted Adapted from Volkow et al., Neurobiology of Learning and Memory 78:610-624, 2002.
Lee, B. et al. J. Neurosci. 2009. Chronic Drug Users Have Low Striatal DA D2 Receptors and this is Linked with Impulsivity and Impaired Frontal Activity Impulsivity Score (z-score) D2R Binding Potential (z-score) Volkow et al., PNAS in press Correlations Between D2 Receptors in Striatum and Brain Metabolism control addicted OFC umol/100gr/min 3030 4040 5050 6060 7070 8080 9090 2. 9 33. 1 3. 2 3. 3 3. 4 3. 5 3. 6 D2 Receptors (BP ND ) CG PreF OFC Methamphetamine Abusers Alcohol ics Decreases in striatal D2 Receptors in SA are associated with reduced activity in frontal regions involved with control, which could underlie their impulsivity Regions showing lower D2 receptors in Methamphetamine abusers than in controls Low D2 receptors in Methamphetamine abusers are associated with higher scores in impulsivity
HIV Seroconversion at 18 Months By Receipt of Treatment 0 0 5 5 10 15 20 25 Rate of Seroconversion (%) Treatment Status No treatment Partial treatment Continuous treatment Metzger, et al. (1993). Acquired Immune Deficiency Syndromes, 6, 1049-1056. Among IDUs Drug Abuse Treatment is an Effective HIV/AIDS Prevention Strategy
State Prisons Offering Opiate Replacement Tx Nunn et al., Drug and Alcohol Dependence 2009;105:83-88. Although Treatments for Heroin Addiction Work There Are Major Challenges * *
IDUs Receiving Gov’t-Funded Methadone or BuprenorphineTx, 2009 Wolfe D et al., Lancet 2010; 376: 35-366. Many Countries Do Not Implemented OST
Agonist (Methadone)Antagonist (Naloxone) Adapted from Johnson, et al., 2000 Medication for Opiate Addiction: Agonists (Methadone and Buprenorphine) and Antagonists (Naloxone and Naltrexone)
JAMA 2011 Placebo: N=124 XR-NTX: N=126 IM Injection every 4 weeks for 24 weeks Long-Acting Injectable Medications (i.e., Depot Naltrexone)
Binding Site Capillary Blood Flow Brain Antibodies VACCINE Antibodies Reduce Brain Concentrations Immunotherapies for Addiction Treatment (i.e., Vaccines) Capillary Blood Flow Brain Targeting the drugs, not the receptors
## 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 Heroin 1 mg/kg, s.c. 30 min Hot Plate Test The Vaccine(s) New Heroin Vaccine(s) K.D. Janda & G.F. Koob Laboratories at TSRI
IDUs as Share of Total HIV Cases & of Patients Receiving ART, 2008 Wolfe D et al., Lancet 2010; 376: 35-366. IDU Are Less Likely To Receive ART Despite Their Higher Rates of HIV
HAART as HIV Prevention Montaner et al., Lancet 2008
90 80 70 60 Incidence/yr Viral load < 50/mL (%) Acquired resistance falling Plasma viral load suppression rising Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection
Seek, Test, Treat and Retain: Addressing HIV Among Vulnerable Populations (R01) (RFA-DA-11-001) (With NIMH) 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
2010 Dr. Eric Verdin Gladstone Institutes New methods to detect and model HIV latency 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 2009 Dr. Rafick-Pierre Sekaly Vaccine & Gene Therapy Institute, FL Novel pathways for purging the HIV reservoir 2008 Dr. Jerome Groopman Beth Israel Medical Center & Harvard Medical School Blocking HIV transmission at the immune synapse 2008 Dr. Julio Montaner University of British Columbia HIV treatment as prevention in drug using populations 2008 Dr. Ileana Cristea Princeton University Quantifying HIV –host interactome and regulation of gene expression NIDA’s Avant-Garde Award Program Is Now Open to International Applicants
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 In a community-based IDU cohort (4546 Ss), increasing HAART uptake appears linked to reduced HIV transmission. HIV incidence risk declined by 5% (3-8%) for each 1% increase in the proportion of HIV+ on HAART.
Long-term cocaine treatment (72 hrs) strongly induces HIV transcription and reverses epigenetic restrictions in latently infected T-cells Input DNA (%) Chromatin immunoprecipitation assay (HIV Nuc-1 region) Data from: Mudit Tyagi, Fatah Kashanchi, Kurt Hauser and Jonathan Karn
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
Many Offenders Have a Drug Use Disorder Mumola & Karberg. Drug use and dependence, state and federal prisoners, 2004. BJS, 2006 (rev 07) But Few Receive Treatment
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
Chang et al., Neuroimage, 42:869-78, 2008. Chronic Drug Exposure can Exacerbate the Neurotoxic Effects of HIV
Per 100 person-years at risk 1.38 5.26 6.23 Vaccine Preparedness Initiative National AIDS Demonstration Research HIV Incidence Among Injection Drug Users in New York City Syringe-Exchange Program are Effective Prevention Strategies for HIV infection Des Jarlais DC et al. The Lancet, 1996; 348: 987-991.