1. Pharmacologic Interventions for Unhealthy Drinking
David A. Fiellin, M.D.
VACS Co-PI
Chair, VACS Alcohol and Behavioral Change Committee
Associate Professor of Medicine and Investigative Medicine
Yale University School of Medicine

2. VACS
Successful in identifying the adverse impact of alcohol on outcomes in HIV
Alcohol and risky sexual behavior
Alcohol and HAART adherence
Alcohol and depressive symptoms
Ideal network of sites within which to investigate interventions to improve outcomes

3. Alcohol and Sexual Risk Cook, Medical Care, 2006

4. Alcohol and Adherence Braithwaite, ACER, 2005

5. Association Between Drinking Categories and Depressive Symptoms Over Time
Years

6. HIV-infected (n=718) Alcohol Treatment White (n=97) Black (n=530)
Latino
(n=58)
Other
(n=33) P
Inpatient Detox., n(%)
Any site VA
Non-VA
9 (9.3)
6 (6.2)
3 (3.1)
99 (18.7)
67 (12.6)
34 (6.4)
10 (17.2)
5 (8.6)
4 (12.1)
0 (0.0)
.13
.28
.21
Outpatient, n(%)
7 (7.2)
2 (2.1)
107 (20.2)
74 (14.0)
33 (6.2)
15 (25.9)
11 (19.0)
6 (10.3)
.03
.18
.07
Residential, n(%)
1 (1.0)
79 (14.9)
47 (8.9)
35 (6.6)
9 (15.5)
3 (9.1)
2 (6.1)
1 (3.0)
.80
.12
AA or 12-Step Program, n(%)
27 (27.8)
149 (28.1)
12 (20.7)
10 (30.3)
.66
Outpatient or Residential, n(%)
11 (11.3)
124 (23.4)
87 (16.4)
48 (9.1)
6 (18.2)
5 (15.2)
.05
.23
Any Treatment (VA or non-VA), n(%)
32 (33.0)
205 (38.7)
20 (34.5)
11 (33.3)

7. Pharmacotherapy for alcohol problems

8. Naltrexone Anton RF, NEJM Aug 14 2008
When an alcohol-dependent person consumes alcohol, dopamine is elevated in the nucleus accumbens. One mechanism of this elevation is the release of β-endorphin, which stimulates dopamine release either directly (in the nucleus accumbens) or indirectly (in the ventral tegmental area) by inhibiting the activity of -aminobutyric acid (GABA) neurons, thereby alleviating the blockade on dopamine cells. Naltrexone reverses both of these actions. Low dose etoh stimulates glutamate which increases dopamine. Higher dose augment GABA which suppress dopamine leading to sedation, etc.
Naltrexone blocks opioid receptors, including receptors for endogenous opioids. Since these receptors are in part responsible for feelings of pleasure during drinking, naltrexone blocking these receptors makes drinking less pleasurable. For this reason, rather than abstinence, the clinical trials of this drug have focused on relapse or return to heavy drinking rather than total abstinence.
Anton RF, NEJM Aug

9. Naltrexone Risk of relapse in alcohol dependence

10. Injectable Naltrexone: Mean Heavy Drinking Event Rate
Garbutt, J. C. et al. JAMA 2005;293:

11. Topiramate Reduces corticomesolimbic dopamine release Agonist at GABA
Antagonist at glutamate

12. Topiramate: Efficacy
Johnson BA, JAMA 2007

13. No published alcohol pharmacotherapy trials in patients with HIV!

14. Buprenorphine for opioid dependence in HIV Sullivan, Clinical Infectious Disease 2006
CD4 count
Illicit opioid use
Percent opioid positive
Viral load

15. Decreasing Alcohol With Naltrexone
Project
Decreasing Alcohol With Naltrexone

16. Purpose
To examine the efficacy of naltrexone versus placebo on drinking and HIV outcomes in HIV positive patients with unhealthy alcohol consumption

17. Subjects Inclusion criteria HIV-positive
Report heavy drinking 4 or more times in the past 4 weeks. Heavy drinking is defined as 4 or more drinks for women and 5 or more drinks for men on an occasion
Not abstinent from alcohol for greater than 30 days
Able to understand English and provide informed consent
Exclusion criteria
Psychotic or severely psychiatrically disabled
Medical conditions that would preclude completing or be of harm during the course of the study
ALT or AST greater than 3 times the upper limit of the normal range or cirrhosis
Known contraindication to naltrexone therapy (e.g. taking opioid medication for pain)
Pregnant, nursing or unable to use an effective method of birth control

18. Design Double-blind Placebo controlled Randomized 12 week pilot
40 subjects

19. Naltrexone Flexible dosing 25 mg by mouth daily
Titrate up to 100 mg per day
Based on craving and persistent alcohol consumption
In the absence of side effects or transaminase elevations

20. Counseling
Integrated Behavioral Treatment (IBT) is a manualized approach that combines elements from three standardized counseling interventions.
Eight counseling sessions
30 minutes each
Structured initial visit or progress note
Adherence Management (AM) is a counseling strategy focusing on HAART medication adherence in substance abusing populations
Uses strategies to increase medication (both HAART and naltrexone) adherence
Eight worksheets (15 minutes each): 1) Designing an individual adherence management plan, 2)Teaching self-monitoring techniques, 3)Increasing motivation and self-efficacy, 4) Engaging social support, 5) Building on adherence skills and client strengths, 6) Maintaining adherence, 7) Beginning termination, and 8) Review and planning for future adherence.

21. Assessments Weeks 1,2,3,4,6,8,10,12 Weeks 4,8,12
Alcohol consumption (Timeline Follow-back)
HAART adherence (CPCRA)
Side Effects (SAFTEE)
Weeks 4,8,12
CD4 lymphocyte
HIV RNA
HIV sexual risk behaviors (ARI)
AST, ALT

22. Outcomes Primary Secondary Alcohol consumption CD 4 lymphocyte count
HIV RNA
Secondary
HIV sexual risk behaviors
HAART adherence
Side effects

23. Summary
VACS successful in identifying the impact of alcohol on adverse outcomes in HIV
Effective pharmacologic interventions (e.g. naltrexone, topiramate) have not been evaluated in HIV positive patients
Integrated HIV care and addiction treatment shows promise and should be evaluated for unhealthy alcohol consumption