DoD-VA HIV Collaborations Infectious Diseases Clinical Research Program Uniformed Services University of the Health Sciences (USU) Department of Preventive Medicine and Biostatistics DoD-VA HIV Collaborations Brian Agan, MD Deputy Science Director VACS-COMpAAAS Scientific Meeting, 13 Dec 2016 A USU/DOD - NIAID Partnership National Institute of Allergy and Infectious Diseases Uniformed Services University, ‘America’s Medical School’

VACS Uniformed Services Workgroup David Rimland, MD Founding Director Vincent Marconi, MD Current Co-Director Brian Agan, MD Current Co-Director Members: Sheldon Brown, Adeel Butt, Sarah Felter, Matt Freiberg, Anu Ganesan, Cynthia Gilbert, Matt Goetz, Kirsha Gordon, Grace Macalino, James Mancuso, Sarah Nagy, Tom O’Bryan, Jason Okulicz, KrisAnn Oursler, Mona Rai, Maria Rodriguez, Christina Schofield, Melissa Skanderson, Julie Womack, Seung Hyun Won

Current Project Areas Cost Effectiveness Continuum of Care Outcomes Comparison – Guest PLoS ONE 2013 Covariate modeling – Rentsch PLoS ONE 2014 QALY comparison by CD4 initiation – Agan SF6D vs QALY modeling – Rai/Won CD4 modeling – Aldrete Continuum of Care Atlanta VAMC Continuum – Mangal ARHR 2014 Qualitative Saturation Methods – Hennink QHR 2016 Resilience in Veterans Predicts Retention – Wessinger submitted Navigating VA care model – Hennink Comparing retention in AVAMC to Grady – Fullard Biomarker Studies Longitudinal Biomarker Changes – So-Armah CHIVR 2014 Pre-HIV D-dimer predicts serious non-AIDS – Freiberg PLoS ONE 2016 HIV Biomarker Proteomics – Agan/Freiberg Overlap Cohort VACS Index – Won Concepts in Development – DM, Hepatitis, Alcohol, CVD, Mental Health, Neuro

Infectious Diseases Clinical Research Program Vision To substantially reduce the impact of infectious disease in the military population through collaborative clinical research. Mission To conduct multicenter infectious diseases clinical research, focusing on high-impact cohort and interventional trials, to inform and improve care of the Warfighter. Established 2005 - Uniformed Services University of the Health Sciences (USU) and National Institute Allergy & Infectious Diseases (NIAID/NIH) Interagency Agreement Chartered by ASD(HA) as a Tri-Service DoD research center at USU Oversight by Executive and Operational Steering Committees (incl VA Rep)

Infectious Diseases Clinical Research Program Tri-service Collaborative Clinical Research Partner Network USU Research Center Military hospitals and clinics (within US and overseas) Military Medical Research Lab Commands (involved in ID research) NIH, VA, Academia, and Industry collaborations Centralized scientific and IRB review [established via MOU approved by ASD(HA), Service SGs, and USU President] Programmatic regulatory compliance and monitoring Centralized data management, specimen repositories, and statistical support IDCRP Research Areas Human Immunodeficiency Virus Deployment / Travel-Associated Infections Skin and Soft-Tissue Infections Sexually Transmitted Infections Emerging Infectious Diseases and Antimicrobial Resistance Acute Respiratory Infections Trauma-Related Infections

U.S. Military HIV Natural History Study Ongoing prospective continuous enrollment observational cohort study HIV+ DoD Active Duty & Beneficiaries >18 y/o All subjects provide Informed Consent Visits q6 months  clinical data + repositoried blood Strengths of the cohort Screened population Racial diversity Access to healthcare and medications Stable socioeconomic status Educated Minimal substance abuse Excellent follow-up Approx 5950 enrolled, 3800 dated seroconverters, 1600 active Median seroconversion: 1.3 years (IQR 0.8-2.1) Median time to enrollment: 1.1 years (IQR 0.1-3.3) Mean age at enrollment: 31.7 years (SD 8.5 yrs) Active duty at enrollment: 87.3% Male gender: 90.7%

Biomarker 1 Specimen Selection Map: Biomarker 1 Specimen Selection Map: (note that time axis is not consistent) HIV+

HIV Biomarker Proteomics Co-PIs: Agan, Freiberg, Ganz, Hsue Population: HIV Seroconverters with Pre-HIV, Post-HIV, and Post-ART/VS samples (N=1240) Data Sources: HIV NHS: demographic, clinical, pharmacy, lab data; Post-HIV/ART samples Military Health System: add’l clinical outcomes, pharmacy, lab data; Pre-HIV samples SOMAscan (SomaLogic): 1130 plasma proteins at each time point Specific Aims Aim 1: To discover which protein biomarkers/protein biologic pathways are associated with HIV seroconversion Aim 2: To discover which protein biomarkers/protein biologic pathways are and are not “affected ” by ART initiation and HIV viral suppression after HIV seroconversion Aim 3: To determine if protein biomarkers/protein biologic pathways associated with HIV seroconversion, but not returned to pre HIV seroconversion levels with ART and viral suppression, are associated with future non-AIDS diseases and mortality

QALYs do not differ by CD4 at ART initiation (350-500 vs >500) Objective: Evaluate longitudinal health state utility values (HSUV; surrogate for QALYs) as a measure of potential early ART benefit Hypothesis: Longitudinal HSUV will differ by CD4 at ART initiation Population: NHS and HAVACS HIV+ subjects with CD4>500 prior to ART and >1 yr f/u after Outcome: HSUV with contributions from CD4, AIDS defining conditions, and non-AIDS defining conditions

Health State Utility Values

Combination of HSUV Most subjects have multiple conditions associated with HSUV decrements – How to combine these? Use the minimum HSUV (i.e. greatest decrement) Mathematically combine the HSUV Data HSUV Year Non-AIDS Dx Code Utility Value (UV) From Method 1 From Method 2 1 509 0.76 2 150 0.97 0.745 3 127 0.844 0.672 4 231 0.90 0.641 5 121, 652 {0.81, 0.827} 0.543 6 109 0.79 0.496

DoD-VA HIV Collaborations: Next Steps Cost Effectiveness Use of SF-12/36 data to evaluate HSUV model Addition of granular cost data  ICER analysis Funding options: AHRQ, PCORI, DoD, VA Continuum of Care Transition of HIV care from DoD to VA Joint analysis of longitudinal care continuum in DoD/VA (e.g. viral suppression at 5, 10, 15 years) Biomarker Studies Biomarker Proteomics Cancer, CVD, others  We invite collaboration!

DoD-VA HIV Collaborations: Next Steps Overlap Cohort Update data set Concepts for analyses: DM, Hepatitis, Alcohol, CVD, Mental Health, Neuro Incorporate DoD HIV Virtual Cohort [in IRB review] 1743 Subjects (2012)

Acknowledgements USUHS / IDCRP NMCP VA / VACS CAPT Timothy Burgess CDR Karl Kronmann Amy Justice David Tribble Tahaniyat Lalani Sheldon Brown Grace Macalino Susan Banks Janet Tate Daniel Rosenberg Luca Illinik David Rimland Guido Pelaez MAMC Vincent Marconi Seung Hyun Won Matthew Freiberg Christina Schofield Xun Wang Kaku So-Armah Mary Fairchok Morgan Byrne Cynthia Baker Tigiste Girma Ramona Rai TAMC Meg Glancey Emory COL Tomas Ferguson WRNMMC Jodie Guest LTC J. Hawley-Molloy CAPT Timothy Whitman Joseph Lipscomb Emily Hui Anuradha Ganesan University of Vermont DCC David Wallace Russell Tracy Ed Parmelee NMCSD SPL Xiuping Chu CAPT Mary Bavaro William (Chip) Bradley Sheila Peel Robert Deiss Chris Olsen Mark Manak Nichol Kirkland Pamela Wright Janice Darden SAMMC Kimberly Blankenship NIAID LtCol Jason Okulicz SAR COL(Ret) Edmund Tramont Thomas O’Bryan Charlotte Rhodes Sophia Siddiqui Terry Sjoberg Scott Merritt John Powers