HIV/AIDS and Alcohol: Current and Future Directions for NIAAA Kendall J. Bryant, Ph.D. National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Bethesda, MD a) Framework/Overview b) Description of portfolio c) Comorbidities d) Interventions not talking about advances in alcohol measurement issues and prevention strategies

What Are the Some of the Most Important Questions Among HIV+ Individuals Who Drink? Is any pattern of alcohol use physiologically “safe”? Does alcohol use reinforce smoking, non adherence, risky sex, marijuana use and/or depression? How does multi substance use (and polypharmacy to treat comorbidities) influence harm from alcohol use? How should the pattern of alcohol use and other comorbidities alter choice of intervention(s)? How should interventions adapt to changes in individuals needs over the lifespan and success or failure of past pharmacological and/or behavioral interventions for both HIV and alcohol?

ALCOHOL AFFECTS EVERY STAGE HIV Treatment Cascade ALCOHOL AFFECTS EVERY STAGE ANY ALCOHOL HEAVY ALCOHOL Vagenas et al. Curr HIV/AIDS Rep 2015:12:421 Dominant approaches in HIV/AIDS

Acquisition and Progression of HIV and Co-infections (e.g., HCV, TB) Social and Environmental Context (e.g., stigma, discrimination, social determinants) Alcohol Use Biological Mechanisms (e.g., immune suppression, chronic inflammation, etc) Viral Suppression (via influences on HIV treatment cascade; e.g., ART adherence) Acquisition and Progression of HIV and Co-infections (e.g., HCV, TB) Behavioral Mechanisms (e.g., sex-risk behaviors, other substance use, overlapping vulnerabilities eg homelessness) Co-morbid Conditions (e.g., medical and mental health) Mortality

Impact of reducing alcohol use on HIV/AIDS Epidemic Validated Computer Simulation One study, which used a computer simulation model of an alcohol intervention, demonstrated that a  45% reduction in unhealthy alcohol consumption could prevent nearly half of new infections over 20 years in a nation with high rates of HIV, such as Kenya (Braithwaite et al., 2014). Attributable Fractions  The effects of alcohol on HIV/AIDS in the African Global Burden of Disease regions range from 3% to 34% for men and from 0% to 17% for women, depending on region and age category. The detrimental effect of alcohol consumption was statistically significant in every region and age category except for the North Africa/Middle East region. (Gmel, G., Shield, K. D., & Rehm, J. (2011) Braithwaite, R. S., Nucifora, K. A., Kessler, J., Toohey, C., Li, L., Mentor, S. M., . . . Bryant, K. (2014). How inexpensive does an alcohol intervention in Kenya need to be in order to deliver favorable value by reducing HIV-related morbidity and mortality? [Research Support, N.I.H., Extramural]. J Acquir Immune Defic Syndr, 66(2), e54-58. doi: 10.1097/QAI.0000000000000140  

Alcohol and HIV Cause Higher Mortality Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men Amy C. Justicea, b, , , Kathleen A. McGinnisc, Janet P. Tatea, b,R. Scott Braithwaited, Kendall J. Bryante, Robert L. Cookf,E. Jennifer Edelmana, b, Lynn E. Fiellinb, Matthew S. Freibergg, h,Adam J. Gordonc, i, Kevin L. Kraemerc, i, Brandon D.L. Marshallj, Emily C. Williamsk, David A. Fiellina, b Highlights •Individuals with HIV on antiretroviral treatment (ART) experience mortality at lower levels of alcohol use. •Individuals with HIV experience physiologic frailty at lower levels of alcohol use. •Alcohol consumption limits should be lower among HIV+ individuals. There may be no safe lower limit.

Limited Competition FY2016: The NIAAA CHAART Consortia: Meeting the Highest Priority Areas of HIV/AIDS Research as outlined by the NIH Office of AIDS Research Limited Competition FY2016: Consortia for HIV/AIDS and Alcohol-Related Research Trials (CHAART) RFA-AA-16-001 Project Collaborative U01 RFA-AA-16-002 Administrative Resource Core U24 RFA-AA-16-003 U24 Resource Core Yale University: PI: Amy Justice Consortium to improve OutcoMes in HIV/AIDS, Alcohol, Aging, and Multi-Substance Use (COMpAAS) & Veterans Aging Cohort Study (VACS) VACS is one of the largest ongoing observational studies of HIV (n=125,000) examines impact of aging and alcohol use among those with and without chronic HIV infection Brown University: PI: Peter Monti Alcohol Research Center on HIV (ARCH) reducing the impact of alcohol on the breadth and depth of the HIV epidemic interventions in HIV+ gay populations The Johns Hopkins University: PI: Mary (Betsy) MCCaul Alcohol Research Consortium in HIV (ARCH) addresses clinical epidemiology of hazardous alcohol use in HIV-infection and determine best treatment interventions, ehealth Alcohol and HIV Don’t Mix Boston University: PI: Jeffrey Samet Uganda Russia Boston Alcohol Network for Alcohol Research Collaborations on HIV/AIDS (URBAN ARCH) interdisciplinary research on understanding how alcohol use impacts HIV+ individuals develops interventions to reduce alcohol use and HIV-related consequences in populations Progress Meeting highest NIH OAR Priorities (Prevention, Treatment, Comorbidities, Health Disparities, translational behavioral and biological work to inform interventions) 5 Consortia basis for collaborative research Multiple large cohorts of HIV+ individuals and matched case controls Over 250 publications, many in collaboration with other ICs Focus of critical comorbidities   Veterans Aging Cohort (VACS) is certainly the most impressive with over 250 publications , index of frailty (VACS index web site with over 50,000 hits), VA sample of HIV+ of over 25 thousand veterans and matched case controls, across the consortia testing of multiple interventions including stepped care, multiple ehealth approaches including computer based interventions, addressing critical cohorts including community cohorts in the highest impacted areas of Florida, CNICS cohorts NIAID (8 sites across the US and 25k HIV+),  International Cohorts in Africa and Russia, and advanced analytic strategies (marginal structural equations modelling, g-estimation) to identify the impact of alcohol and related comorbidities focused on use of multiple data sources - electronic medical records and improved assessment methodology. GOALS: To advance prevention, treatment, operations and implementation research in the context of alcohol and HIV/AIDS in order to: 1) continue to develop a broader systems approach for monitoring complex HIV and alcohol-related morbidity and mortality; and 2) intervene to reduce the impact of alcohol and HIV disease progression and transmission. . The University of Florida: PI: Robert Cook Southern HIV and Alcohol Research Consortium (SHARC) research to improve health outcomes (neurological) and reduce HIV transmission among diverse populations

Alcohol and HIV Research: A Decade of NIAAA Support Urban ARCH - Boston Alcohol and HIV Research: A Decade of NIAAA Support Disease Progression Bone Health International Issues Adherence Alcoholism Pharmacotherapy Unsafe Sex Drug Use Inflammation Prevalence Cardiovascular Disease

Three New NIAAA HIV/AIDS Funding Opportunities Just Published in the NIH Guide for FY 2017 RFA-AA-17-013: Model Continuums of Care Initiative (MCCI) for Women and Girls at Risk and Living with HIV/AIDS and Harmful Alcohol and Associated Comorbidities Planning Cooperative Agreement (U34) RFA-AA-17-014: Collaborative Research in HIV/AIDS, Alcohol, and Related Comorbidities (U01) RFA-AA-17-015: Expanding Alcohol-Focused High-Priority Translational Research for HIV/AIDS (UH2/UH3) Add neuroscience (Receipt Date is January 4th)

HIV and Alcohol Comorbidity High priority for NIH, Office of AIDS Research and NIAAA Improve measurement of comorbid conditions: HIV and alcohol direct effects, immune senescence, inflammation, and hypercoagulability Premature aging (“inflamaging”) Illnesses assoc w/alcohol use seen in older adults without HIV infection now occurring in younger PLWH despite HVL suppression Develop and Test “Combined” Interventions Bryant et al. Alcohol Res Health 2010;33: 167 Justice & Falutz. Curr Opin HIV AIDS 2014;9: 291

High Priority Research Areas For Use of AIDS Funds include: Critical to ensure that NIH/NIAAA AIDS funds are supporting the highest priorities? Comorbidities HIV-associated comorbidities and co-infections (targeting interventions to Alcohol Users) and NIAAA Strategic Plan to Address Co-occurring conditions are aligned Prevention and treatment of HIV-associated comorbidities, coinfections, and related complications of particular significance for drinkers’ morbidity and mortality including HCV, TB, HBV, Hepatic, Cardiovascular, and Neurological disorders. HIV/Alcohol translational research that addresses health and behavioral/social issues clearly linked with HIV (transmission/acquisition, pathogenesis, morbidity and mortality, stigma, adherence) and examines them in the context of HIV such as other infectious pathogens and diseases, non-infectious pathogens and diseases, other substance use/addiction, and mental health disorders; AUD frequently co-occurs with other SUDs and mental health conditions, including major depressive disorder, anxiety disorders, bipolar disorder, antisocial and borderline personality disorders, and post-traumatic stress disorder (PTSD). Individuals suffering from psychiatric comorbidity tend to have a poorer prognosis, higher risk for treatment dropout, less support for sobriety from their families and in the workplace, and a higher risk for suicide. Alcohol misuse also contributes to over 200 diseases and injury-related health conditions, including alcoholic liver disease. In fact, alcohol is involved in nearly half of all liver disease deaths in the United States each year. Alcohol misuse frequently co-occurs with HIV, contributes to HIV transmission, reduces HIV screening, makes it difficult to follow complex HIV medication regimens, and contributes to or exacerbates other health conditions in HIV-infected individuals. NIAAA will continue to support research to investigate the relationships between AUD and co-occurring conditions and to develop interventions to prevent and treat them.

Alcohol and HIV Multiple Comorbidities Hepatitis C Neurological, neurodegeneration, pain Tuberculosis Cardiovascular disease Cancer Metabolic Falls and injury Other substance use Mental health Outcomes: Mortality, Frailty

Hepatitis C 25-30% co-infection HIV and heavy drinking affect progression Heavy drinking increases HCV RNA, which in turn is assoc w/Rx outcomes Drinking affects efficacy of treatment? Effects of low level alcohol on progression and treatment efficacy (particularly new treatments) not clear Abstinence thought safest Reducing/eliminating short term alcohol use could lead to more effective Hep C treatment and reductions in mortality (6/100PY – 2/100py) Platt Lancet Infect Dis 2016 Sulkowski JID 2013;207 Suppl 1:S26

HCV as a cofactor with HIV and alcohol? Figure 1. Mortality Rates by AUDIT-C Groups, Stratified by HIV/HCV (n=60,427) HIV Only 12,500 (21%); HCV Only 6791 (11%); HIV/HCV Coinfected 5661 (9%) No Infection 35,475: (59%) Figure 1 illustrates the unadjusted association between all cause mortality and AUDIT-C (Alcohol) values. It demonstrates that HIV and HCV have a strong influence on observed mortality with HIV and HCV co infected (virally suppressed) individuals having the highest rates of mortality and a steep association with increasing mortality by AUDIT-C value, those with only HIV or only HCV having intermediate rates and those free of both infections having much lower rates and a less steep association with increasing AUDIT-C values. (Veteran’s Aging Cohort)

Other substance use 42% smoke (46-84% in some samples)(c/w 19% US) bacterial pneumonia, COPD), CHD, decreased bone mineral density, mixed evidence re: HIV disease progression, associated with alcohol use Alcohol and smoking: additive inflammatory effects>>pneumonia, CHD Alcohol and Marijuana: Contradictory effects Other drug use not uncommon, injection risk factor Cascade Neurological Co-infections: e.g. up to 82% who inject have HCV Alcohol increases overdose risk (greater effect of lower dose in HIV) Cooperman Curr Addict Rep 2016;3:19 Braithwaite AIDS Behav 2016;20: 566 Armah Clin Infect Dis 2012;55:126 Platt & Terrault Lancet Infect Dis 2016 Hauser & Knapp Internat Rev Neurobiol 2014;118:231 McGinnis KA et al. AIDS Behav 2016;20:504

Interventions:. To increase adherence/reduce viral load Interventions: To increase adherence/reduce viral load To reduce alcohol use and consequences To translate “basic” behavioral and biological mediational/causal models into new interventions

Brief Priorities: Interventions Develop new integrated interventions and decision models for interventions with comorbid conditions Understand pathophysiological mechanisms and translate this knowledge into interventions to ameliorate organ and tissue injury (gut, liver, brain). Develop a comprehensive integrated national and international research framework for intervention implementation Support the develop of collaborative activities between investigators, institutes, and relevant agencies (OGAC, PEPFARS, etc) to achieve 90-90-90 goals

HIV and Alcohol Multiple Interventions Mhealth (range of Interventions) Avatars “smart technology” (CNICS Cohort) SBIRT, SMS Adaptive, Multisession, CBT Philani (Health workers) Structural – Algorithmic Strategic Decision Mixtures (Value of Information0 “In-the-moment” (EMA) Pharmacological (long acting) Multilevel implementation (India) New Alcohol Measurement technology

Pathophysiology (Basic Translational) Program Announcements 2018- 2020 “Collaborative” Activities Pathophysiology (Basic Translational) Neuroscience*, Hepatology, Cardiovascular Secondary Analysis Comorbidities Data Harmonization, Analytic Approaches Enhanced Prevention in At-Risk Populations Adolescent, Women, Sexual Minorities Enhanced Treatment Approaches ehealth, Decision Algorithms Comparative Effectiveness, Cost Effectiveness and Implementation Research

Thank You Three Key Points Current portfolio needs to expand to address comorbidities and associated interventions Assessing comorbidities across the lifespan and identifying individuals using informative behavioral and biological measures Developing, Testing, and Implementing New Interventions using new measurement technologies Develop a comprehensive integrated national and international research framework for assessment and intervention implementation Support the develop of collaborative activities between investigators, institutes, and relevant agencies to achieve 90-90-90 goals