Abstract WEAB0106LB, IAS 2014, July 23 rd , 2014
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Transcript of 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
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
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: 1371–1385Abstract WEAB0106LB
Immune activation
Systemic Inflammation
HIV infection
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
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
Abstract WEAB0106LB
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; 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
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
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=82 N=84N=68
Biomarker Analysis Population (N=234)Completed A5260s on randomized treatment
Achieved HIV-1 RNA <50 copies/ml by week 24 and thereafterNo ARV interruptions >7 days
FTC/TDF + RAL(N=106)
FTC/TDF + ATV/r (N=109)
FTC/TDF + DRV/r(N=113)
Abstract WEAB0106LB
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 Abstract WEAB0106LB
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/r vs. DRV/r;; ATV/r vs. RAL; DRV/r vs. RAL
• Multiple comparisons• Benjamini-Hochberg methods for
false discovery rate control
Abstract WEAB0106LB
Results (1)- Baseline Characteristics
Characteristic Total (n=234)
Treatment Group
ATV/r (n=68)) RAL (n=82) DRV/r (n=84)
Sex Female 10% 7% 11% 12%
Age (years) Mean 38 38 37 38
Race
White Non-His. 48% 51% 44% 49%
Black Non-His. 29% 31% 28% 29%
Hispanic 19% 16% 20% 21%
CD4+cells (/mm3) Median (Q1,Q3) 338
(191, 448)294
(180, 461)347
(246, 450)337
(172, 424)
HIV-1 RNA (log10 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 WEAB0106LBAbstract WEAB0106LB
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Overall at Baseline
Median (Q1,Q3)
1.48 ug/ml (0.78, 3.18)
Mean Fold Change (95% CI) from Baseline
Week 48 Week 96
ATV/r0.57
(0.40,0.82)0.64
(0.46,0.90)
RAL0.78
(0.59,1.04)0.66
(0.51,0.87)
DRV/r0.90
(0.69,1.16)1.21
(0.91,1.62)
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Results: Hs-CRP declined with ATV/r and RALResults (2)- Markers of Inflammation and Coagulation:
Hs-CRP declined with ATV/r and RAL
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Fo
ld C
han
ge:
hs-
CR
P
Study week
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Overall at Baseline
Median (Q1,Q3)
0.28 pg/ml (0.08, 0.46)
Mean Fold Change (95% CI) from Baseline
Week 48 Week 96
ATV/r0.66
(0.52,0.83)0.87
(0.69,1.09)
RAL0.85
(0.67,1.07)0.76
(0.65,0.88)
DRV/r0.83
(0.67,1.02)0.97
(0.78,1.22)
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Results: Il-6 did not consistently declineResults (3)- Markers of Inflammation and Coagulation:
IL-6 did not consistently decline
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Fo
ld C
han
ge:
IL
-6
Study week
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Overall at Baseline
Median (Q1,Q3)
0.26 ug/ml (0.14, 0.56)
Mean Fold Change (95% CI) from Baseline
Week 48 Week 96
ATV/r0.58
(0.42,0.80)0.48
(0.35,0.66)
RAL0.93
(0.72,1.19)0.82
(0.65,1.03)
DRV/r0.60
(0.44,0.82)0.65
(0.48,0.87)
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Results (4)- Markers of Inflammation and Coagulation: D-dimer declined with ATV/r and DRV/r
Fo
ld C
han
ge:
D-d
imer
Study week
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Overall at Baseline
Median (Q1,Q3)
1090 ng/ml (773, 1560)
Mean Fold Change (95% CI) from Baseline
Week 48 Week 96
ATV/r0.56
(0.51,0.61)0.50
(0.45,0.56)
RAL0.59
(0.54,0.64)0.55
(0.50,0.61)
DRV/r0.61
(0.56,0.67)0.58
(0.52,0.65)
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Results (5)- Markers of Macrophage Activation:sCD163 declined similarly across groups
Fo
ld C
han
ge:
sCD
163
Study week
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Overall at Baseline
Median (Q1,Q3)
8.2% (5.7, 13.0)
Mean Fold Change (95% CI) from Baseline
Week 48 Week 96
ATV/r0.58
(0.46,0.72)0.58
(0.47,0.70)
RAL0.93
(0.71,1.23)0.85
(0.66,1.10)
DRV/r0.78
(0.61,1.02)0.71
(0.54,0.93)
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Results (6)- Markers of Macrophage Activation:pMNCs decreased more in ATV/r and DRV/r groups
Fo
ld C
han
ge:
%M
NC
: C
D14
+C
D16
+
Study week
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Overall at Baseline
Median (Q1,Q3)
42.9% (34.4, 53.9)
Mean Fold Change (95% CI) from Baseline
Week 48 Week 96
ATV/r0.49
(0.44,0.56)0.33
(0.29,0.37)
RAL0.55
(0.50,0.61)0.36
(0.30,0.42)
DRV/r0.52
(0.47,0.58)0.34
(0.29,0.34)
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Results (7)- Markers of T-Cell Activation:%CD38+DR+ of CD8+ T-cells declined similarly
across groups
Fo
ld C
han
ge:
%C
D8+
:CD
38+
HL
AD
R+
Study week
• 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 WEAB0106LBAbstract WEAB0106LB
Conclusions
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 MembersM. Dube, R. Murphy, H. Hodis, C. GodfreyB. Jarocki, A. Benns, K. Braun, J. Rothenberg
This research was supported byNHLBI grants R01 HL095132, R01 HL095126 and the NIAID AIDS Clinical Trials Group.AI068636
ACTG 5257/5260sMerck, Bristol Myers Squibb, Janssen