1. Grace A McComsey, Douglas Kitch, Paul E Sax, Camlin Tierney, Nasreen C Jahed, Kathleen Melbourne, Belinda Ha, Todd T Brown, Anthony Bloom, Neal Fedarko, and Eric S Daar on behalf of the ACTG A5224s team

2.  Increased inflammation persists on ART and may drive clinical events and mortality  Several studies have found associations between single measurements of selective inflammatory markers and mortality  The purpose of this presentation is to present the associations between inflammatory markers (pre-ART and after ART initiation) and clinical events in a prospective clinical trial A5224s

3. A5224s design: Metabolic substudy of A5202 A5224s

4. Significant decreases in TNF- , sTNFR-I, sTNFR-II, sVCAM-1, and sICAM-1 levels within all arms, without differences between ABC/3TC and TDF/FTC or ATV/r and EFV More favorable changes in IL-6 at week 24 and hsCRP at weeks 24 and 96 with TDF/FTC vs. ABC/3TC McComsey, AIDS 2012 A5224s

5.  Exploratory analysis  To assess the association between baseline and time-updated inflammatory biomarker levels and time to first AIDS-defining and/or non-AIDS-defining events  Cox proportional hazards regression models  Only first event occurring in each category in each subject was used in analysis

6. N=244 Age years, median (Q1, Q3)39 (31, 44) Male (%)85% White non-Hispanic Race/Ethnicity (%)48% HIV-1 RNA log 10 c/mL, median (Q1, Q3)4.64 (4.26, 4.91) HIV RNA ≥ 100,000 c/mL Stratum (%)41% CD4 cells/mm 3, median (Q1, Q3)240 (106, 335) CD4 < 200 cells/mm 3 (%)43% hsCRP  g/mL, median (Q1, Q3) 1.7 (0.7, 4.0) IL-6 pg/mL, median (Q1, Q3) 0.8 (0.5, 1.4) TNF-α pg/mL, median (Q1, Q3) 11.0 (8.2, 14.7) sTNF-RI pg/mL, median (Q1, Q3) 1277 (1105, 1538) sTNFR-II pg/mL, median (Q1, Q3) 5350 (3965, 7756) sVCAM-1 ng/mL, median (Q1, Q3) 1187 (939, 1599) sICAM-1 ng/mL, median (Q1, Q3) 330 (267, 402) A5224s

7. Correlations Among Markers at Baseline A5224s Spearman’s rank correlation coefficient

8. Correlations Among Markers at Week 24 A5224s Spearman’s rank correlation coefficient

9. Description of Events  AIDS-defining events (CDC classification)  13 events: 9 OIs; 3 AIDS-cancers, 1 recurrent bacterial pneumonia  Events occurred between 2 and 133 weeks, median 16 weeks  Of these, 7 events occurred within first 24 weeks  Non-AIDS events  18 events: 6 diabetes, 4 cancers, 3 cardiovascular, 5 pneumonias  Events occurred between 3.5 and 165 weeks, median 81 weeks  Of these, 4 events occurred within first 24 weeks  AIDS- or Non-AIDS events  28 events  Events occurred between 2 and 164 weeks, median 32 weeks  Of these, 11 events occurred within first 24 weeks A5224s

11. HR= hazard ratio from Cox Proportional Hazard model

18. Other Results A5224s

19. HR= hazard ratio from Cox Proportional Hazard model

20.  15 (traumatic) fractures occurred  Considered separate from non-AIDS events  Neither baseline nor time-updated biomarker values were significantly associated with an increased risk of fracture

21.  At baseline, CD4 count correlated with IL6, sTNFR-I and II  Changes in CD4 correlated with changes in TNF- , sTNF-Rs and adhesion molecules  At baseline, HIV-1 RNA correlated with all markers except for hsCRP  Only change (0-24 w) in sTNFR-I level significantly different between suppressed subjects vs. those >50 copies/mL at week 24

22.  Higher levels of several inflammatory biomarkers were associated independently of CD4 count with increased risk of AIDS and non-AIDS events.  Time-updated levels in markers of TNF-  and/or sTNF receptors were associated with clinical events whereas this was not observed for hsCRP.

23.  Small number of events  Relatively short follow up  Time-updated for AIDS events driven by early events  Large number of analyses performed  Adjusted analyses to be interpreted with caution (small events n) Larger and longer studies needed to investigate the use of these markers as predictors of clinical endpoints.

24. Thank yous  Study Participants and ACTG sites  ACTG 5224s team: Douglas Kitch and Camlin Tierney (SDAC), Paul Sax, Eric Daar, Pablo Tebas, Nasreen Jahed, Laurie Myers, Belinda Ha, Kathleen Melbourne, Lynda Szczech, David Currin, Lori Mong-Kryspin  ACTG 5202 team  ACTG and NIH (NIAID) for supporting A5202/5224 studies  GSK and Gilead for supporting inflammatory markers cost A5224s