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

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Presentation on theme: "Comparison of Effects of Atazanavir, Raltegravir or Darunavir with FTC/Tenofovir on Biomarkers of Systemic Inflammation, Macrophage and T-Cell Activation:"— Presentation transcript:

1 Comparison of Effects of Atazanavir, Raltegravir or 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 23 rd, 2014

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

3 Plasma biomarkers of systemic inflammation and immune activation have been identified as predictors of morbidity and mortality after ART Circulating biomarkers Immune activation (sCD14, sCD163) Systemic inflammation (hs-CRP, IL-6) All cause mortality/end-organ disease ART 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 ↑ local control of viral replication and inflammation in other tissues? ↑ penetration into the gut Microbial translocation, immune activation and inflammation Patterson K et al AIDS 2013; 27: 1413–1419; Hatano H et al J Infect Dis 2013; 208: 1436–1442; Buzon M et al Nat Med 2010; 16: 460–465; 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 beneficial effects of RAL on lipid levels ↓ formation of oxidized lipids ↓ hepatic inflammation and steatosis ? ? ? ? Abstract WEAB0106LB

5 Study Aims / Hypothesis u 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) u 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; Hatano H et al J Infect Dis 2013; 208: 1436–1442; Buzon M et al Nat Med 2010; 16: 460–465; 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

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 regimens Stratified by screening HIV-1 RNA level (> or ≤100,000 copies/ml), Framingham 10-year CHD risk score (<6% vs ≥6% risk), and A5260s participation Abstract WEAB0106LB A5260s Substudy (N=328) No known CVD, diabetes mellitus, or use of lipid-lowering medications Participants followed for 96 weeks after enrollment of last subject N=82N=84N=68 Biomarker Analysis Population (N=234) Completed A5260s on randomized treatment Achieved HIV-1 RNA <50 copies/ml by week 24 and thereafter No ARV interruptions >7 days FTC/TDF + RAL (N=106) FTC/TDF + ATV/r (N=109) FTC/TDF + DRV/r (N=113)

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

8 Abstract WEAB0106LB Results (1)- Baseline Characteristics Characteristic Total (n=234) Treatment Group ATV/r (n=68))RAL (n=82)DRV/r (n=84) SexFemale10%7%11%12% Age (years)Mean Race White Non-His.48%51%44%49% Black Non-His.29%31%28%29% Hispanic19%16%20%21% CD4+cells (/mm 3 ) Median (Q1,Q3) 338 (191, 448) 294 (180, 461) 347 (246, 450) 337 (172, 424) HIV-1 RNA (log 10 c/ml) Median (Q1,Q3) 4.6 (4.0,5.0) 4.8 (4.0, 5.2) 4.5 (4.0, 5.0) 4.6 (4.0, 5.0) Abstract WEAB0106LB

9 Overall at Baseline Median (Q1,Q3) 1.48 ug/ml (0.78, 3.18) Mean Fold Change (95% CI) from Baseline Week 48Week 96 ATV/r 0.57 (0.40,0.82) 0.64 (0.46,0.90) RAL 0.78 (0.59,1.04) 0.66 (0.51,0.87) DRV/r 0.90 (0.69,1.16) 1.21 (0.91,1.62) Abstract WEAB0106LB Results: Hs-CRP declined with ATV/r and RAL Results (2)- Markers of Inflammation and Coagulation: Hs-CRP declined with ATV/r and RAL Abstract WEAB0106LB Fold Change: hs-CRP Study week

10 Abstract WEAB0106LB Overall at Baseline Median (Q1,Q3) 0.28 pg/ml (0.08, 0.46) Mean Fold Change (95% CI) from Baseline Week 48Week 96 ATV/r 0.66 (0.52,0.83) 0.87 (0.69,1.09) RAL 0.85 (0.67,1.07) 0.76 (0.65,0.88) DRV/r 0.83 (0.67,1.02) 0.97 (0.78,1.22) Abstract WEAB0106LB Results: Il-6 did not consistently decline Results (3)- Markers of Inflammation and Coagulation: IL-6 did not consistently decline Abstract WEAB0106LB Fold Change: IL-6 Study week

11 Abstract WEAB0106LB Overall at Baseline Median (Q1,Q3) 0.26 ug/ml (0.14, 0.56) Mean Fold Change (95% CI) from Baseline Week 48Week 96 ATV/r 0.58 (0.42,0.80) 0.48 (0.35,0.66) RAL 0.93 (0.72,1.19) 0.82 (0.65,1.03) DRV/r 0.60 (0.44,0.82) 0.65 (0.48,0.87) Abstract WEAB0106LB Results (4)- Markers of Inflammation and Coagulation: D-dimer declined with ATV/r and DRV/r Fold Change: D-dimer Study week

12 Abstract WEAB0106LB Overall at Baseline Median (Q1,Q3) 1090 ng/ml (773, 1560) Mean Fold Change (95% CI) from Baseline Week 48Week 96 ATV/r 0.56 (0.51,0.61) 0.50 (0.45,0.56) RAL 0.59 (0.54,0.64) 0.55 (0.50,0.61) DRV/r 0.61 (0.56,0.67) 0.58 (0.52,0.65) Abstract WEAB0106LB Results (5)- Markers of Macrophage Activation: sCD163 declined similarly across groups Fold Change:sCD163 Study week

13 Abstract WEAB0106LB Overall at Baseline Median (Q1,Q3) 8.2% (5.7, 13.0) Mean Fold Change (95% CI) from Baseline Week 48Week 96 ATV/r 0.58 (0.46,0.72) 0.58 (0.47,0.70) RAL 0.93 (0.71,1.23) 0.85 (0.66,1.10) DRV/r 0.78 (0.61,1.02) 0.71 (0.54,0.93) Abstract WEAB0106LB Results (6)- Markers of Macrophage Activation: pMNCs decreased more in ATV/r and DRV/r groups Fold Change: %MNC: CD14+CD16+ Study week

14 Abstract WEAB0106LB Overall at Baseline Median (Q1,Q3) 42.9% (34.4, 53.9) Mean Fold Change (95% CI) from Baseline Week 48Week 96 ATV/r 0.49 (0.44,0.56) 0.33 (0.29,0.37) RAL 0.55 (0.50,0.61) 0.36 (0.30,0.42) DRV/r 0.52 (0.47,0.58) 0.34 (0.29,0.34) Abstract WEAB0106LB Results (7)- Markers of T-Cell Activation: %CD38+DR+ of CD8+ T-cells declined similarly across groups Fold Change: %CD8+:CD38+HLADR+ Study week

15 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 Conclusions

16 Acknowledgements ACTG Sites  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 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 HL and the NIAID AIDS Clinical Trials Group.AI ACTG 5257/5260s Merck, Bristol Myers Squibb, Janssen


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