Amy C. Justice, MD, PhD For the VACS Project Team A Better Index of Mortality Risk: Combining HIV and “Non-HIV” Biomarkers Amy C. Justice, MD, PhD For the VACS Project Team

Veterans with HIV infection have… More prevalent: Liver disease Renal disease Pulmonary disease Intracranial hemorrhage Thrombosis Cancer Multi-morbidity Less prevalent (maybe): Obesity Diabetes Hyperlipidemia Hypertension Vascular disease …than age/site/race matched uninfected veterans

Suspected Root Causes Substance use Viral hepatitis Treatment toxicity More cigarettes, more drugs, similar alcohol Viral hepatitis More chronic Hepatitis C and B Treatment toxicity Antiretrovirals Others (some “non-HIV”) HIV infection Chronic inflammation Immune compromise, deregulation

Act in Concert, HIV Biomarkers Alone Do Not Capture Full Effect Aging Treatment Toxicity HIV Progression Substance Use and Other Behaviors

Developing a Unifying Index HIV biomarker with “Non-HIV” biomarkers

A Word on Biomarkers FIB-4 >3.25 for likely liver fibrosis/cirrhosis <1.35 for unlikely liver fibrosis/cirrhosis =age X AST /(platelets X Sqrt of ALT) eGFR <30 for stage IV renal insufficiency =186.3 X creatinine-1.154 X age-0.203 X (1-(0.258 X gender)) X (1+(0.21 X black))

Development Set Nested Models (Poisson) HIV Biomarkers "Non-HIV" Biomarkers Combined (c stat=0.69) (c stat=0.72) (c stat=0.74) CART 1999-2002 n=4813 IRR 95% CI log VL>5 copies/mm3 1.28 1.12 1.45   1.16 1.02 1.33 CD4 50-99 cells/mm3 0.79 0.65 0.96 0.76 0.62 0.93 CD4 100-199 cells/mm3 0.70 0.59 0.84 0.71 0.85 CD4 200-349 cells/mm3 0.57 0.48 0.68 0.64 0.53 0.77 CD4 350+ cells/mm3 0.45 0.37 0.54 0.46 0.69 AIDS Defining Diagnosis 1.55 1.37 1.76 1.44 1.26 1.64 Hemoglobin<10 g/dL 2.34 2.77 1.70 1.41 2.05 Hemoglobin 10-12 g/dL 2.02 1.78 2.3 1.58 1.83 FIB4 3.25+ 1.67 1.93 1.66 1.42 FIB4 <1.45 0.81 0.72 0.63 0.83 eGFR<30 ml/min 1.88 2.47 2.13 1.61 2.82 Viral Hepatitis 1.31 1.48 1.38 1.22 1.57 Development Set Nested Models (Poisson) All models also adjusted for substance abuse and dependence and age.

Mortality by Quintiles of Estimated Risk

HIV and “Non-HIV” Markers Percent Quintiles of Mortality Risk Based on “Non-HIV” Markers Only

Biomarker Index by FIB-4 <1.45 >1.45 Age 50+ years % 21.0 40.6 <0.0001 Alcohol or Drug Ad or Ab % 26.3 37.3 CD4 cell count >350 % 46.6 30.7 Viral Load <5 log % 85.3 77.2 AIDS Free 80.0 74.4 Hemoglobin <12 17.7 26.0 Chronic Hepatitis B or C 34.8 63.9 eGFR<30 1.3 2.8

Limitations Don’t know if changes in index equate to changes in mortality Have not elucidated causal chain, e.g. HIV to liver disease to death? Liver disease to HIV progression to death? Etc.

Conclusions Could be used to assess mortality risk Could be used as a surrogate outcome May inform prioritization of care

The VACS Project Team in West Haven, CT

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.