1. A Multimodal Intervention for Veterans with HIV Infection
Amy Justice for the VACS
Project Team

2. West Haven/Yale VACS Project Team

3. National VACS Project Team

4. Long Term Goal Use the VA as a laboratory to develop and
test innovative interventions to optimize care of chronic disease—start with HIV infection

5. VACS Approach to Intervention
Use observational data to design intervention
Characterize population
Identify modifiable mediators of outcomes
Study inter-relationships among mediators
Inform power calculations
Event rates
Effect size
Large multi-level, multi-modal, strategy trials
Translational research
Integrated into VA healthcare
Built from evidence based components
Focused on easily identified groups at increased risk
Individually tailored
Randomized at the clinic level

6. Compared to Uninfected, HIV Infected Veterans Have
More prevalent:
Liver disease
Renal disease
Pulmonary disease
Intracranial hemorrhage
Thrombosis
Cancer
Multi-morbidity
All cause mortality
Jury still out on:
Obesity
Diabetes
Hyperlipidemia
Hypertension
Cardiovascular disease

7. “Non AIDS” Causes of Death Since ~2000
Source
% Not AIDS of Known
Leading Causes (%)
Reference
NY State
Death Certificates
26%
Alcohol/drug abuse (31),
CVD (24), Cancer (21)
Ann Intern Med 2006;145:
Barcelona
60%
Liver ( 23), Infection (14),
Cancer (11), CVD (6)
HIV Med 2007:8;251-8
HOPS
Ascertainment
63%
Liver (18), CVD (18), Pulmonary (16), Renal (12), GI (11), Infection (10), Cancer (8)
J AIDS 2006;43:27-34
Cascade
Liver (20), Infections (24), Unintentional (33), Cancer (10), CVD (9)
AIDS 2006; 20;741-9

8. Liver Disease & Causes of Death
Vascular
Disease
Cancer
HCV and MI risk
Hepatotoma
Liver Disease

9. Markers of Liver Disease
Most never have liver biopsies
Noninvasive tests include
Ultra sound
Elaborate bench assays
Ratios of available tests (APRI & FIB-4)
FIB 4 =age X AST /(platelets X Sqrt of ALT)
>3.25 likely liver fibrosis/cirrhosis
<1.45 unlikely liver fibrosis/cirrhosis
<1.45: 89% Negative Predictive Value

10. Alcohol & Liver Disease
Percent FIB-4 >3.25
Lim et al, in preparation

11. Multiple, Overlapping Root Causes
Substance use
Drugs, ALCOHOL
Major cause of nonadherence
Viral hepatitis
Chronic Hepatitis C and B
Medication toxicity
Antiretrovirals (nevaripine, mitochondrially toxic D drugs)
non-HIV medications
HIV infection
Chronic inflammation
Immune compromise coupled with immune deregulation
Liver Disease

12. Veterans at Risk of Liver Injury
Fib-4>1.45
Outside “protected range”
23% HIV- in VACS
42% HIV+ in VACS
Rather than focusing on etiology, we focus on modifying clinical risk

13. The Intervention
Saving lives by minimizing liver injury among HIV infected veterans in care

14. Multi modal, Multi theory
Interactive behavior change technology
Adaptive prevention
Multiple health behavior change
“Five As”: assess, advise, agree, assist, arrange
Motivational interviewing
Behavioral cognitive therapy
Pharmacologic treatment

15. Key Concepts/Goals Concepts Goals No level of alcohol consumption safe
Early detection of risk of liver injury
Intervention targeted at multiple root causes
Local expert for pharmacologic treatment
Long term maintenance critical
Goals
Screen for contributing causes
Empower patient to “own” behavior and care
Provide decision support to MD
Coordination of new and existing services

16. Multi Modal Intervention
EMR to:
Identify those at risk
Alert for and coordinate existing care options
Identify liver toxic medications
Measure processes and outcomes
Offer decision tools
Coordinate care
“Health Coach” to:
Provide tailored risk education and personalized feedback
Empower patient to ask for care
Enhance and reflect patient’s motivations
Reinforce importance of and problem solve around adherence
Use biomarkers as feedback/motivator

17. Intervention Outline
Subjects: HIV infected veterans with FIB-4>1.45
Sites to be randomized: VACS HIV clinics
Data collection only, otherwise usual care
Intervention
Behavior Targets:
Patient
Any alcohol use
ARV adherence below 95%
Provider
Chronic viral hepatitis treatment
Liver toxic medications
Primary outcomes: Still being determined

18. Manualized Screens/Prioritization Directly Administered
Health Coach Manualized Care Summary
Manualized Screens/Prioritization
Treatments
Assessment
Issues Identified
Directly Administered
Gives MD
Orders
Risk
Level of mortality risk
Level of liver risk
Risk module
Activation module
Risk echo
life expectancy
Irrelevant measures
Biomarkers 
(Before Visit)
Medication
Reconciliation
Liver Toxic Meds
OTC, Non VA, & VA
Need Refills
OTC module
VA, non VA toxic Med alert, Refill alert
Alcohol
Any
Hazardous
Abuse or dependence
Alcohol module
Alcohol echo
Treatment referral
Viral Hepatitis
Not completely tested
Active HCV, not Rxd
Active HBV, not Rxd
HCV module
HBV module
HCV referral
Rx. recommendation
HCV,HBV tests
Vaccinations
ARV Adherence
Homelessness
Side Effects
Poor Adherence
ARV Side Effects
Adherence module
Adherence echo
Side effects alert
Social work referral  
Depression 
Depressive Symptoms/ Suicidal Ideation 
None
SSRI or mental health Ref. recommendation
Drugs
Active
Illicit /Prescription Drug Abuse
Drugs alert
Tobacco
Tobacco Use
Smoking alert

19. Health Coach Patient Contacts
First Contact
Tailored risk assessment/interpretation/advice
Means of decreasing risk (adherence, alcohol, Hepatitis Rx)
Targeted advice re discussion with provider
Medication reconciliation
Case Management
Vaccinate for hepatitis A or B if negative and not previously done
3 additional face to face treatments first month
Update medication reconciliation, Pill counts
Barrier identification and problem solving
Review, encourage, action plan
FU phone/ /website/chat room at monthly, more if needed
As requested by patient additional face to face
Final treatment visit at 6 months face to face
Updated 5As with new behavior, biomarker, and medication data
Support phone/ /website/chat room, by request, throughout

20. Alcohol Pharmacotherapy
Screened for hazardous or worse alcohol
Referral recommended to provider
Patient activated to request/accept referral
Trained alcohol pharmacotherapy doctor
Can use: Naltrexone, Topiramate, or Disulfiram
(Acomprosate is nonformulary)
Manages and titrates medications
Monitors toxicity and outcomes
May choose to refer to substance use clinic

21. Provider Contacts Orientation/education re liver injury
Initial encounter
Risk assessment
Very specific recommendations for
Non-action (irrelevant performance measures)
Action (echo, treat, refer)
Medication reconciliation with liver summary (all sources)
Patient receptivity/ requests
Subsequent contacts
Alert if risk changes
Alert if new liver toxic medication
Additional visits if patient requests them

22. MD Relief Medication reconciliation Performance measure resolution
Alcohol
Depression
Tobacco (partial)
Turn off screens that don’t apply
Colon cancer

23. MD Advice Requests Liver risk—reduction
OTC toxic medications—avoidance
Any alcohol use—abstinence
Not adherent—improvement

24. MD Medication Requests
Depression medication (SSRI) or referral
If depressed
Pick ARV active against HBV
If HBV+
Consider discontinuation of toxic medications
Treat patient reported side effects of ARVs
If nonadherent

25. MD Referral Requests Alcohol pharmacotherapy Hepatology (HCV Clinic)
If dependent
Hepatology (HCV Clinic)
If patient willing
If no absolute contraindications to treatment
Mental health (or SSRI Rx)
If depressed

26. Graded Alcohol Treatment
All receive
Risk assessment, medication reconciliation
Patient activation
Advice to quit drinking (health coach and MD)
Evaluation for viral hepatitis
Evaluation of ARV adherence
Hazardous and above drinkers receive
Request for pharmacologic treatment
May also be referred to substance use clinic
If referred for pharmacologic treatment
Selection of medications
Graded dosing
Continued monitoring

27. Primary and Secondary Outcomes
Months of Follow Up 3 6 9 12 18 24
All Cause Mortality x
FIB-4 and APRI
Decompensated cirrhosis
Biomarker Index
SF 12 PCS
Alcohol (TLFB)
Active Medications
Adherence fill and pill cnt
Spec.Rx Referrals

28. VACS HIV+ Demographics
FIB-4
>1.45
<1.45
Proportion of all HIV+
42.3%
57.7%
Age (years)
52.3%
46.1%
Female
1.6%
3.4%
Black
69.1%
65.0%
Hispanic
8.9%
9.5%
White
18.7%
21.6%

29. VACS HIV+ Substance Use (last 12 months)
FIB-4
>1.45
<1.45
Binge weekly or more
18.0%
15.0%
Abuse or Dependence Alc.
29.7%
17.2%
Hazardous Alcohol
52.6%
36.7%
Cocaine
26.8%
20.9%
Opioids
12.2%
4.6%
IV Drugs
11.0%
5.1%

30. VACS HIV+ Adherence, Hepatitis, and Liver Toxic Medications
FIB-4
>1.45
<1.45
ARV Adherence (<95%)
51.2%
53.2%
HCV (treatment)
66.3 (4.1)%
47.4 (4.3)%
HBV (treatment)
8.8 (51.5)%
3.5 (0)%
Acetominophen (opioid)
8.1%
10.6%
Sulfa drugs
26.2%
1.4%
Other Antibiotics
6.8%
6.2%
Statins
18.4%
9.6%
Epileptic Drugs
2.7%
1.9%
TB Drugs
0.6%
0.8%
Any L. toxic medication
47.9%
42.6%

31. VACS Outcomes FIB-4 >1.45 <1.45 12 month mortality (%) 5.2 1.8
SF12 PCS Score
(out of 100)
42.1
44.2
End Stage Liver Disease
7.1%
0.9%

32. Expected HIV Infected Sample
In VACS
~3500
Have FIB-4>1.45
1470

33. Possible Trial Endpoints
Event
HIV+
(n=970)
2 yr. Mortality
101
Decomp. Cirrhosis
21-28
FIB-4 Progression** ??
Biomarker Progression**
*Assuming 2/3 of eligible patients in VACS enroll.
**Analyses underway to determine these rates.

34. Remaining Questions
Endpoint: an issue of power (ICC) and time, possibilities include
Combine death and decompensated liver cirrhosis
Progression of biomarkers
FIB 4/APRI
Biomarker index
Details of health coach interactions
Face to face difficult for patient
Maintenance phase

35. Implementation Plan This fall/winter Next spring/summer Next fall
Estimate expected effect size using VACS longitudinal data
Pilots of Naltrexone, Adherence, Life expectancy
CDA application for adherence intervention
Work on computer automation of study components
LOI to Cooperative Studies/possibly other funders as well
Next spring/summer
Analyze, report results from pilots
Launch computerized surveys in VACS full study
Finalize primary endpoint, sites, subjects, and time horizon
Next fall
Launch 6 month pilot of full trial

36. Veterans Aging Cohort Study
PI and Co-PI: AC Justice, DA Fiellin
Scientific Officer (NIAAA): K Bryant
Participating VA Medical Centers: Atlanta (D. Rimland, C Jones-Taylor), Baltimore (KA Oursler, R Titanji), Bronx (S Brown, S Garrison), Houston (M Rodriguez-Barradas, N Masozera), Los Angeles (M Goetz, D Leaf), Manhattan-Brooklyn (M Simberkoff, D Blumenthal, J Leung), Pittsburgh (A Butt, E Hoffman), and Washington DC (C Gibert, R Peck)
Core Faculty: K Mattocks (Deputy Director), S Braithwaite, C Brandt, K Bryant, R Cook, J Conigliaro, K Crothers, J Chang, S Crystal, N Day, J Erdos, M Freiberg, M Kozal, M Gaziano, M Gerschenson, B Good, A Gordon, J Goulet, M Hernan, K Kraemer, J Lim, S Maisto, P Miller, L Mole, P O’Connor, R Papas, H Paek, J Robins, C Rinaldo, M Roberts, J Samet, B Tierney, J Whittle
Staff: D Cohen, A Consorte, K Gordon, F Kidwai, F Levin, K McGinnis, M Rambo, J Rogers, M Skanderson, F Whitsett
Major Collaborators: Immunology Case Registry, Pharmacy Benefits Management, Framingham Heart Study, Women’s Interagency HIV Study, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Health Economics Research Center (HERC), Center for Health Equity Research and Promotion (CHERP), ART-CC, NA-ACCORD
Funded by: National Institute on Alcohol Abuse and Alcoholism (2U10 AA 13566); National Institute on Aging (K23 G00826); Robert Wood Johnson Generalist Faculty Scholar Award; an Inter-Agency Agreement between National Institute on Aging, National Institute of Mental Health, and the Veterans Health Administration; the VHA Office of Research and Development; and, VHA Public Health Strategic Health Care Group.