Who Benefited Most From Immediate Treatment in START A Subgroup Analysis JM Molina, B Grund, F Gordin, I Williams, M Schechter, M Losso, M Law, E Ekong, N Mwelase, A Skoutelis, MJ Wiselka, L Vendekerckhove, T Benfield, D Munroe, JD Lundgren and JD Neaton for the INSIGHT START Study Group 21 st International AIDS Conference, July 18-22, 2016, Durban, South Africa Abstract: THAB0201

Background START has shown a net clinical benefit of immediate vs. deferred antiretroviral therapy (ART) in asymptomatic HIV- infected adults with CD4+ T-cells > 500/mm 3 This relative clinical benefit was consistent across all baseline subgroups supporting the recommendation of universal treatment of HIV-infection We wished to assess whether some subgroups benefited more than others from immediate ART Such data may help doctors and policy makers to prioritize immediate ART in people with asymptomatic HIV-infection and high CD4+ counts

START Study Design HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 Immediate ART Group Initiate ART immediately following randomization N=2,326 Deferred ART Group Defer ART until CD4+ count drops to <350 cells/mm 3 or AIDS develops N=2,359 We use data accrued through May 27, 2015, when the START study results were unblinded Primary endpoint: Serious AIDS Serious non-AIDS conditions CVD (stroke, MI, revascularization), ESRD, decompensated liver disease, non-AIDS cancer All-cause death

Baseline Characteristics -1 N=4,685 CharacteristicMedian [IQR] or % Age (years)36 [ ] Female sex26.8 Race Black30.1 White44.5 Other25.4 Geographic Region High income46.0 Low/moderate income54.0 Likely mode of infection MSM55.2 Heterosexual contact38.2 Other6.6 4

Baseline Characteristics -2 CharacteristicMedian [IQR] or % CD4 count (cells/mm 3 )651 [584 – 765] CD4:CD8 ratio0.66 [0.48 – 0.89] Plasma HIV RNA (cp/mL)12,759 [3,019 – 43,391] Framingham 10-yr CHD risk (%)1.9 [0.5 – 5.1] Current smoker31.9 Hepatitis B/C coinfection6.4 Anemia* *Anemia = Hb <12 g/dL in women, Hb <13 g/dL in men

Methods Subgroups were pre-specified for analysis by the protocol, except for the CD4:CD8 ratio (post-hoc). Within each subgroup, we estimated: –Primary event rates per 100 PY –HR (Imm/Def) (with 95% CI) using Cox models –Absolute risk reduction (ARR= rate Def – rate Imm ), using Wilson’s score method for the 95% CI –Number need to treat immediately for one year to prevent one event compared with deferred ART, NNT=100/ARR Heterogeneity across subgroups was assessed using –Interaction tests in Cox models for the HR –Bootstrap tests for the ARR and NNT Subgroups with < 10 events (both arms combined) were not considered

Immediate ART Deferred ART No. with Event 4296 Rate/100PY HR (Imm/Def) % CI: p <0.001 START: Primary Endpoint Lundgren et al NEJM 2015

Immediate ART Deferred ART No. with Event 4296 Rate/100PY HR (Imm/Def) % CI: p <0.001 ARR/100PY (Def-Imm) %CI: NNT128 START: Primary Endpoint Lundgren et al NEJM

Hazard Ratios* in Subgroups -1 9 Immediate ART better Deferred ART better * Primary endpoint

ARR and NNT in Subgroups Deferred ART better Immediate ART better

Hazard Ratios* in Subgroups Immediate ART better Deferred ART better * Primary endpoint

ARR and NNT in Subgroups Deferred ART better Immediate ART better

Primary Endpoint by Age Kaplan-Meier Estimates 13

Primary Endpoint by CD4:CD8 Ratio Kaplan-Meier Estimates 14

Primary Endpoint by HIV RNA Kaplan-Meier Estimates 15

Primary Endpoint by Framingham 10 yr CHD risk 16

Limitations We considered a large number of subgroups without adjustment for Type I error inflation Each subgroup was considered univariately ARR and NNT are estimated with substantial uncertainty (large confidence intervals) NNT estimates can be unstable when event rates are small, and need to be interpreted with caution. 17

Conclusions In asymptomatic ART-naïve adults with > 500 CD4 + cells/mm 3, immediate ART was superior to deferred ART across all subgroups with similar relative risk reduction Higher absolute risk reduction and lower NNT were found in participants with: –Age > 50 years –Plasma HIV RNA level > 50,000 c/mL –CD4:CD8 ratio < 0.5 –Framingham 10 year risk score > 10% These patients might be prioritized for immediate access to ART Immediate ART also reduces transmission risk which is essential for cost-effectiveness considerations 18

Acknowledgments START study participants START study site research staff INSIGHT International Coordinating Center staff INSIGHT Minnesota Coordinating Center staff University of Minnesota (Study Sponsor) 19

START Study Funding - 1 PRIMARY FUNDER - Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) Award Numbers: UM1-AI and UM-1AI OTHER NIH SUPPORT Department of Bioethics, NIH Clinical Center Division of Clinical Research (NIAID) National Cancer Institute (NCI) National Heart, Lung, and Blood Institute (NHLBI) National Institute of Child Health and Human Development (NICHD) National Institute of Mental Health (NIMH) National Institute of Neurological Disorders and Stroke (NINDS) National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) 20

START Study Funding - 2 INTERNATIONAL FUNDING SUPPORT Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS, France) Bundesministerium für Bildung und Forschung (BMBF, Germany) NEAT - European AIDS Treatment Network Australian National Health and Medical Research Council (NHMRC) UK National Institute for Health Research & Medical Research Council Danish National Research Foundation PHARMACEUTICAL SUPPORT AbbVie, Inc. Bristol-Myers Squibb Gilead Sciences, Inc. GlaxoSmithKline/ViiV Healthcare Janssen Scientific Affairs, LLC Merck & Co., Inc. 21

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