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Ending HIV Transmission in Drug Users: Impact to the HIV Epidemic

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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 The distribution of AIDS diagnoses by transmission category has shifted since the beginning of the epidemic. In 1985, male-to-male sexual contact accounted for an estimated 65% of all AIDS diagnoses; this proportion reached its lowest point in 1999 at 40% of diagnoses. Since then, the percentage of AIDS diagnoses attributed to male-to-male sexual contact has increased and in 2009 this transmission category accounted for 49% of all AIDS diagnoses. The estimated percentage of AIDS diagnoses attributed to injection drug use increased from 20% to 32% during 1985–1993 and decreased since that time accounting for 15% of diagnoses in 2009. The estimated percentage of AIDS diagnoses attributed to male-to-male sexual contact and injection drug use decreased from 9% in 1985 to 5% in 2009. The estimated percentage of AIDS diagnoses attributed to heterosexual contact increased from 3% in 1985 to 31% in 2009. The remaining AIDS diagnoses were those attributed to hemophilia or the receipt of blood or blood products and those in persons without an identified risk factor. All displayed data have been estimated. Estimated numbers resulted from statistical adjustment that accounted for reporting delays and missing risk-factor information, but not for incomplete reporting. Heterosexual contact is with a person known to have, or to be at high risk for, HIV infection.

3 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 (2):

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

5 Intoxication with Drugs Can Enhance Sexual Behaviors
p < 0.005 p < 0.001 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 Volkow ND et al., AJP :

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

7 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 Decreases prefrontal cortex cingulate gyrus Increases Amygdala, NAcc 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:

8 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 Alcohol DA DA DA DA Reward Circuits Drug Abuser Heroin Adapted from Volkow et al., Neurobiology of Learning and Memory 78: , 2002. control addicted

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

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

11 State Prisons Offering Opiate Replacement Tx
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.

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

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

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

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

16 New Heroin Vaccine(s) K.D. Janda & G.F. Koob Laboratories at TSRI
The Vaccine(s) Heroin 1 mg/kg, s.c. 30 min Hot Plate Test ##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

17 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:

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

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

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

21 NIDA’s Avant-Garde Award Program
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. 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 NIDA’s Avant-Garde Award Program Is Now Open to International Applicants

22 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.

23 in latently infected T-cells
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 (%) Cocaine is a very potent inducer of HIV transcription in latently infected T-cells. The induction infect is not nearly as rapid as induction by TNF-a but instead builds up over the first 72 hrs of exposure. This chromatin immunoprecipitation experiment measures the levels of various factors just downstream of the promoter of proviruses in latently infected T-cells. Cocaine induction of HIV proviruses is associated with a strong recruitment of RNA polymerase and induction of positive histone marks inducing histone acetylation and the histone H3 lysine 4 trimethylation (H3K4me3). By contrast, histone H3 lysine27 trimethylation is lost, consistent with the idea that cocaine induction of the provirus is associated with the removal of the polycomb respressive complex-2. Data from: Mudit Tyagi, Fatah Kashanchi, Kurt Hauser and Jonathan Karn

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

25 Many Offenders Have a Drug Use Disorder But Few Receive Treatment
1) Dependent & abuse: 40% state, 28% fed; dep only: 1% state, 1% fed; abuse only: 17% state, 17% fed; dep &/or abuse: 53% state,46% fed (Table 5) 2) “Treatment is defined as substance care received under the supervision of a trained professional, including treatment in a special residential facility, professional counseling, detoxification unit, or use of a maintenance drug.” (p. 8, Table 9) Mumola & Karberg. Drug use and dependence, state and federal prisoners, BJS, 2006 (rev 07)

26 Mean CVL and New HIV Infections, 2004–2008
Mean CVL and New HIV Infections, 2004–2008. There was a statistically significant decline in annual measures of mean CVL from 2004–2008 (p = 0.037). Newly diagnosed cases of HIV (shown in red with {) decreased in San Francisco from 798 (2004) to 434 (2008) (p,0.005). The point estimates of HIV incidence (shown in dark red with n) using the CDC methods also declined from 935 [95% CI 658–1212] in 2006, to 792 [552– 1033] in 2007 and 621 [462–781] in 2008, although the change was not statistically significant (trend p = 0.29). The reductions in annual measures of mean CVL were significantly associated with decreases in newly diagnosed and reported HIV cases from 2004–2008 (p = 0.003). Longitudinal reductions in estimated HIV incidence were consistent with the trends in mean and total CVL, but the association in the meta-regression was not statistically significant (p.0.3). Das M, et al. (2010) PLoS ONE 5(6)

27 Wood et al, BMJ, 2009

28 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

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

30 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:

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