Transcript Slide 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
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.
Natural & Drug Reinforcers Increase Dopamine in NAc
METHAMPHETAMINE
2000
Dopamine (nM)
frontal
cortex
Dose (mg/kg IV)
1500
`
1000
500
0
0
VTA/SN
Drugs of abuse increase DA in the Nucleus
Accumbens, which is believed to trigger the
neuroadaptions that
result in addiction
DA Concentration (% Baseline)
nucleus
accumbens
5
2.5
1
20
40
60
80min
Time After Methamphetamine
SEX
200
150
100
50
0
Sample1 2 3 4 5 6 7 8
Number
9 1011121314151617
Source: Melega; Di Chiara and Imperato, Fiorino and Phillips
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
Holder et al., Psychoneuroendocrinology. 2010.
In humans iv methylphenidate increased
sexual arousal both in controls and in
cocaine abusers
Volkow ND et al., AJP 2007 164: 157-160.
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, 1458 - 1463 (2005).
Beauregard, M. et al., Journal of Neuroscience 21 RC165, 2001
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 200
Alcohol decreased activity of control areas
and increased activity of areas involved
Zhu et al., Alcohol Alcohol 39: 53-58 2004.
with impulsivity
Dopamine D2 Receptors are Lower in Addiction
DADA
Cocaine
DA
DA DA DA
DA
DADA
DADA
DA
Reward Circuits
Non-Drug Abuser
Meth
DA
DA
DA
Alcohol
DA
DA
DA
Reward Circuits
Drug Abuser
Heroin
control
addicted
Adapted from Volkow et al.,
Neurobiology of Learning and
Memory 78:610-624, 2002.
Chronic Drug Users Have Low Striatal DA D2 Receptors and this is
Linked with Impulsivity and Impaired Frontal Activity
CG
PreF
Metabolism OFC
OFC
(micromol/100g/min)
umol/100gr/min
OFC
Low D2 receptors in
Methamphetamine abusers
are associated with higher
scores in impulsivity
Metabolism CG
(micromol/100g/min)
Impulsivity Score
(z-score)
50
45
40
35
30
control
2
2. 5
addicted
3
3. 5
D2 R VS
(Bmax /Kd )
Lee, B. et al. J. Neurosci. 2009.
Methamphetamine
Abusers
3
3.
1
3.
2
3.
3
3.
4
3.
5
3.
6
Alcohol
ics
38
36
34
32
30
28
26
24
25
1. 5
D2R Binding Potential
(z-score)
9
0
8
0
7
0
6
0
5
0
4
0
3
0 2.
9
Metabolism Prefrontal
Regions showing lower D2
receptors in
Methamphetamine abusers
than in controls
Correlations Between D2
Receptors in Striatum and Brain
Metabolism
4
22
1. 5
2
2. 5
3
3. 5
D2 R VS
Receptors
(Bmax /Kd )
D2
(BPND)
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
4
Rate of Seroconversion (%)
Among IDUs Drug Abuse Treatment is an
Effective HIV/AIDS Prevention Strategy
HIV Seroconversion at 18 Months
By Receipt of Treatment
25
No treatment
Partial treatment
Continuous treatment
20
15
10
5
0
Treatment Status
Metzger, et al. (1993). Acquired Immune Deficiency Syndromes, 6, 1049-1056.
Although Treatments for Heroin Addiction Work
There Are Major Challenges
State Prisons Offering Opiate
Replacement Tx
*
*
Nunn et al., Drug and Alcohol Dependence
Many Countries
Do Not Implemented OST
IDUs Receiving Gov’t-Funded
Methadone or BuprenorphineTx, 2009
Wolfe D et al., Lancet 2010; 376: 35-366.
Medication for Opiate Addiction: Agonists (Methadone and
Buprenorphine) and Antagonists (Naloxone and Naltrexone)
Agonist (Methadone)
Antagonist (Naloxone)
Adapted from Johnson, et al., 2000
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
Immunotherapies for Addiction Treatment (i.e., Vaccines)
Antibodies Reduce Brain Concentrations
VACCINE
Binding Site
Antibodies
Capillary
Blood Flow
Brain
Targeting the drugs,
not the receptors
Capillary
Blood Flow
Brain
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
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.
HAART as HIV Prevention
Montaner et al., Lancet 2008
Viral load
< 50/mL (%)
Incidence/yr
Improved Virological Outcomes in British Columbia
Concomitant with Decreasing Incidence of
HIV Type 1 Drug Resistance Detection
Acquired resistance
falling
90
80
70
60
Plasma viral load
suppression rising
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
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 longterm 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
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.
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)
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Control
24 Hrs
Data from: Mudit Tyagi, Fatah Kashanchi, Kurt Hauser and Jonathan Karn
72 Hrs
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
But Few Receive Treatment
Federal Prison
State Prison
0%
10%
20%
Drug Dependence or Abuse
30%
40%
50%
60%
70%
80%
Other Programs: Education, self-help
Treatment from a Professional
Mumola & Karberg. Drug use and dependence, state and federal prisoners, 2004. BJS,
2006 (rev 07)
Das M, et al. (2010) PLoS ONE 5(6)
Wood et al, BMJ, 2009
Global prevalence of IDU in 2008
HIV prevalence among IDU in 2008
Source: Mathers, et al., Global epidemiology
injecting drug use and HIV among people wh
inject drugs: a systematic review. Lancet, 200
Chronic Drug Exposure can
Exacerbate the Neurotoxic Effects of HIV
Chang et al., Neuroimage, 42:869-78, 2008.
Syringe-Exchange Program are Effective Prevention
Strategies for HIV infection
Per 100 person-years at risk
HIV Incidence Among Injection Drug Users in New York City
6.23
5.26
1.38
Des Jarlais DC et al. The Lancet, 1996; 348: 987-991.
Vaccine
Preparedness
Initiative
National AIDS
Demonstration Research