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Abstract WEAB0106LB, IAS 2014, July 23 rd , 2014

Comparison of Effects of Atazanavir, Raltegravir or Darunavir with FTC/Tenofovir on Biomarkers of Systemic Inflammation, Macrophage and T-Cell Activation: ACTG A5260s.

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Abstract WEAB0106LB, IAS 2014, July 23 rd , 2014

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  1. Comparison of Effects of Atazanavir, Raltegraviror Darunavir with FTC/Tenofovir on Biomarkers of Systemic Inflammation, Macrophage and T-Cell Activation: ACTG A5260s T. Kelesidis, T.T.T. Tran, G.A. McComsey, T.T. Brown, C. Moser, H.J. Ribaudo, J. Rothenberg, O.O. Yang, J.H. Stein, J.S. Currier Abstract WEAB0106LB, IAS 2014, July 23rd , 2014

  2. The differential impact of newer antiretroviral therapies (ART) on inflammation and immune activation has not been well described HIV infection Immune activation ART Systemic Inflammation End-organ disease Abstract WEAB0106LB Baker et al J Acquir Immune DeficSyndr 2011; 56: 36–43; NeuhausJet al J Infect Dis 2010; 201: 1788–1795; McComsey G et al AIDS 2012; 26: 1371–1385

  3. Plasma biomarkers of systemic inflammation and immune activation have been identified as predictors of morbidity and mortality after ART Circulating biomarkers Systemic inflammation (hs-CRP, IL-6) Immune activation (sCD14, sCD163) ART All cause mortality/end-organ disease Kuller L et al PLoS Med 2008; 5: e203; Sandler N et al J Infect Dis 2011; 203: 780–790; Boulware D et alJ Infect Dis 2011; 203: 1637–1646 Abstract WEAB0106LB

  4. It is unclear whether integrase inhibitors such as raltegravir (RAL) may reduce inflammation and immune activation compared to other ART RAL vs. PI/NNRTI ? ↑ penetration into the gut beneficial effects of RAL on lipid levels ↑ local control of viral replication and inflammation in other tissues? ? ? ↓ hepatic inflammation and steatosis ↓ formation of oxidized lipids ? Microbial translocation, immune activation and inflammation Patterson K et al AIDS 2013; 27: 1413–1419;HatanoH et al J Infect Dis 2013; 208: 1436–1442; BuzonM et al  Nat Med 2010; 16: 460–465; Vallejo A et al AIDS 2012; 26: 1885–1894; ByakwagaH et al J Infect Dis 2011; 204:1532–1540; Lam YM et al PLoS ONE 2012; 7: e3199 Abstract WEAB0106LB

  5. Study Aims / Hypothesis • To explore how markers of inflammation and immune activation behave after initial therapy with tenofovir/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), raltegravir (RAL) or darunavir/ritonavir (DRV/r) • Exploratory hypothesis based on prior findings • Greater reductions in inflammation and immune activation would result with RAL compared to the PI-based regimens and with ATV/r compared to DRV/r Patterson K et al AIDS 2013; 27: 1413–1419;HatanoH et al J Infect Dis 2013; 208: 1436–1442; BuzonM et al  Nat Med 2010; 16: 460–465; Vallejo A et al AIDS 2012; 26: 1885–1894; ByakwagaH et al J Infect Dis 2011; 204:1532–1540; Lam YM et al PLoS ONE 2012; 7: e3199 Abstract WEAB0106LB

  6. A5260s Study Schema A5257: Phase III, prospective, multi-center, randomized, open-label trial (N=1809) ART-naïve, HIV+ subjects ≥18 yr, VL ≥ 1000 c/mL Randomized 1:1:1 to three NNRTI-sparing ARV regimensStratified by screening HIV-1 RNA level (> or ≤100,000 copies/ml), Framingham 10-year CHD risk score (<6% vs ≥6% risk), and A5260s participation A5260s Substudy(N=328)No known CVD, diabetes mellitus, or use of lipid-lowering medicationsParticipants followed for 96 weeks after enrollment of last subject FTC/TDF +ATV/r (N=109) FTC/TDF + RAL(N=106) FTC/TDF +DRV/r(N=113) Biomarker Analysis Population (N=234)Completed A5260s on randomized treatmentAchieved HIV-1 RNA <50 copies/ml by week 24 and thereafter No ARV interruptions >7 days N=68 N=82 N=84 Abstract WEAB0106LB

  7. Biomarker Analysis • Timepoints • Baseline (prior to drug initiation) • Week 24 (cellular markers); Week 48 (plasma markers) • Week 96 • Inflammation and coagulation • hs-CRP, IL-6, D-dimer • Macrophage activation • Plasma sCD14, sCD163, %CD14+CD16+ of monocytes • T-cell activation • sIL-2r, %CD38+HLADR+ of CD8+ T-cells • Change from baseline over time • Measured as ratio of follow-up to baseline (mean fold change) • Ratio of 1.0 indicating no change • Pairwise comparisons • Wilcoxon rank-sum test • ATV/rvs. DRV/r;;ATV/rvs. RAL;DRV/rvs. RAL • Multiple comparisons • Benjamini-Hochberg methods for false discovery rate control Abstract WEAB0106LB

  8. Results (1)- Baseline Characteristics Abstract WEAB0106LB Abstract WEAB0106LB

  9. Results: Hs-CRP declined with ATV/r and RAL Results (2)- Markers of Inflammation and Coagulation: Hs-CRP declined with ATV/r and RAL Fold Change: hs-CRP Study week Abstract WEAB0106LB Abstract WEAB0106LB

  10. Results: Il-6 did not consistently decline Results (3)- Markers of Inflammation and Coagulation: IL-6 did not consistently decline Fold Change: IL-6 Study week Abstract WEAB0106LB Abstract WEAB0106LB

  11. Results (4)- Markers of Inflammation and Coagulation: D-dimer declined with ATV/r and DRV/r Fold Change: D-dimer Study week Abstract WEAB0106LB

  12. Results (5)- Markers of Macrophage Activation:sCD163 declined similarly across groups Fold Change:sCD163 Study week Abstract WEAB0106LB

  13. Results (6)- Markers of Macrophage Activation:pMNCs decreased more in ATV/r and DRV/r groups Fold Change: %MNC: CD14+CD16+ Study week Abstract WEAB0106LB

  14. Results (7)- Markers of T-Cell Activation:%CD38+DR+ of CD8+ T-cells declined similarly across groups Fold Change: %CD8+:CD38+HLADR+ Study week Abstract WEAB0106LB

  15. Conclusions • Biomarker changes varied by regimen • Hs-CRP declined with ATV/r and RAL throughout 96 weeks • IL-6 declined with RAL, but not with ATV/r and DRV/r at 96 weeks • D-dimer declined with ATV/r and DRV/r • After ART initiation, T cell activation, sCD163 (but not sCD14) declined similarly across groups • Over 96 weeks of follow-up RAL does not have differential effects on systemic inflammation and immune activation compared to PIs (Vallejo A et al AIDS 2012; 26: 1885–1894; Byakwaga H et al J Infect Dis 2011; 204:1532–1540; Lam YM et al PLoS ONE 2012; 7: e3199). • These results suggest incomplete reversal of inflammation and immune activation in the setting of effective treatment with these different therapeutic agents. • Longer follow-up may better define regimen difference and correlations between these measures and long term complications. Abstract WEAB0106LB Abstract WEAB0106LB

  16. Acknowledgements ACTG Sites Study Participants ACTG 5260s Team Members M. Dube, R. Murphy, H. Hodis, C. Godfrey B. Jarocki, A. Benns, K. Braun,J. Rothenberg This research was supported by NHLBI grants R01 HL095132, R01 HL095126 and the NIAID AIDS Clinical Trials Group.AI068636 ACTG 5257/5260s Merck, Bristol Myers Squibb, Janssen • BETH ISRAEL DEACONESS MED. • BRIGHAM AND WOMENS HOSP. • JOHNS HOPKINS ADULT AIDS CRS • NY UNIV. HIV/AIDS CRS • UCLA CARE CENTER • HARBOR-UCLA MED. CTR. • UCSF AIDS CRS • PITT CRS UNIV. OF ROCHESTER ACTG • AIDS CARE • USC UNIVERSITY OF WASHINGTON AIDS • DUKE UNIV. MED. CTR. • WASHINGTON U • THE OHIO STATE UNIV. AIDS • UNIV. OF CINCINNATI • CASE CRS • METROHEALTH • NORTHWESTERN UNIVERSITY • RUSH UNIV. MED. CTR. ACTG • UNC AIDS CRS • VANDERBILT THERAPEUTICS CRS • THE PONCE DE LEON CTR. CRS • UNIVERSITY OF COLORADO HOSPITAL CRS • HOUSTON AIDS RESEARCH TEAM CRS • NEW JERSEY MEDICAL SCHOOL

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