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

West Haven/Yale VACS Project Team

National VACS Project Team

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

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

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

“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;145:397-406 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

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

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

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

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

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

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

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

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

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

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

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

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/email/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/email/website/chat room, by request, throughout

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

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

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

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

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

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

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

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

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%

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%

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%

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%

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

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.

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

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

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.