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Background

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.

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  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 Associations of Inflammatory Markers with AIDS and non-AIDS Clinical Events after Initiation of Antiretroviral Therapy (ART): AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202

  2. Background • 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. Biomarker Substudy • 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. Study Objective and Statistical Methods • 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. Baseline characteristics A5224s

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

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

  9. Description of Events A5224s • 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

  10. AIDS Defining Events

  11. Baseline associations with time to first AIDS-defining event HR= hazard ratio from Cox Proportional Hazard model

  12. Time-updated associations with time to first AIDS-defining event HR= hazard ratio from Cox Proportional Hazard model

  13. Non- AIDS Defining Events

  14. Baseline associations with time to first non-AIDS defining event HR= hazard ratio from Cox Proportional Hazard model

  15. Time-updated associations with time to first non-AIDS defining event HR= hazard ratio from Cox Proportional Hazard model

  16. AIDS and Non- AIDS Defining Events Combined

  17. Baseline associations with time to first AIDS or non-AIDS Event HR= hazard ratio from Cox Proportional Hazard model

  18. Other Results A5224s

  19. Time-updated associations with time to first AIDS or non-AIDS defining event HR= hazard ratio from Cox Proportional Hazard model

  20. Bone Fractures • 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. Correlation of markers with CD4 count and HIV-1 RNA levels • 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. Conclusion • 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. Study Limitations • 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 A5224s 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

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