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
HIV infection
Immune
activation
Systemic
Inflammation
ART
End-organ disease
Abstract WEAB0106LB
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
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
Abstract WEAB0106LB
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
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
↑ local control of viral replication
and inflammation in other tissues?
beneficial effects of
RAL on lipid levels
?
?
↓ hepatic inflammation
and steatosis
↓ formation of
oxidized lipids
?
Microbial translocation, immune activation and inflammation
Abstract WEAB0106LB
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
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
Abstract WEAB0106LB
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 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
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
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 treatment
Achieved HIV-1 RNA <50 copies/ml by week 24 and thereafter
No ARV interruptions >7 days
N=68
Abstract WEAB0106LB
N=82
N=84
Biomarker Analysis

Timepoints
Change from baseline over
time

•
Baseline (prior to drug initiation)
•
Week 24 (cellular markers);
Week 48 (plasma markers)
•
Measured as ratio of follow-up to
baseline (mean fold change)
•
Week 96
•
Ratio of 1.0 indicating no change
Inflammation and coagulation

•
hs-CRP, IL-6, D-dimer
Pairwise comparisons

•
•
Macrophage activation

•
Plasma sCD14, sCD163,
%CD14+CD16+ of monocytes
Wilcoxon rank-sum test
•
Multiple comparisons
•
T-cell activation

•
sIL-2r, %CD38+HLADR+ of CD8+
T-cells
Abstract WEAB0106LB
WEAB0106LB
Abstract
ATV/r vs. DRV/r;; ATV/r vs. RAL;
DRV/r vs. RAL
Benjamini-Hochberg methods
for false discovery rate control
Results (1)- Baseline Characteristics
ATV/r (n=68))
RAL (n=82)
DRV/r (n=84)
10%
7%
11%
12%
38
38
37
38
White Non-His.
48%
51%
44%
49%
Black Non-His.
29%
31%
28%
29%
Hispanic
19%
16%
20%
21%
Characteristic
Sex
Female
Age (years)
Mean
Race
Treatment Group
Total
(n=234)
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 WEAB0106LB
WEAB0106LB
Abstract
Results (2)- Markers of Inflammation and Coagulation:
Results:
Hs-CRP
declined
with
ATV/r
and
RAL
Hs-CRP declined with ATV/r and RAL
Overall at Baseline
Fold Change: hs-CRP
Median
(Q1,Q3)
Mean Fold Change
(95% CI) from Baseline
Week 48
Week 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)
Study week
Abstract WEAB0106LB
WEAB0106LB
Abstract
1.48 ug/ml (0.78, 3.18)
Results (3)- Markers of Inflammation and Coagulation:
Results:
Il-6
did
not
consistently
decline
IL-6 did not consistently decline
Overall at Baseline
Fold Change: IL-6
Median
(Q1,Q3)
Mean Fold Change
(95% CI) from Baseline
Week 48
Week 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)
Study week
Abstract WEAB0106LB
WEAB0106LB
Abstract
0.28 pg/ml (0.08, 0.46)
Results (4)- Markers of Inflammation and Coagulation:
D-dimer declined with ATV/r and DRV/r
Overall at Baseline
Fold Change: D-dimer
Median
(Q1,Q3)
Mean Fold Change
(95% CI) from Baseline
Week 48
Week 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)
Study week
Abstract WEAB0106LB
0.26 ug/ml (0.14, 0.56)
Results (5)- Markers of Macrophage Activation:
sCD163 declined similarly across groups
Overall at Baseline
Fold Change:sCD163
Median
(Q1,Q3)
Mean Fold Change
(95% CI) from Baseline
Week 48
Week 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)
Study week
Abstract WEAB0106LB
1090 ng/ml (773, 1560)
Results (6)- Markers of Macrophage Activation:
pMNCs decreased more in ATV/r and DRV/r groups
Fold Change: %MNC: CD14+CD16+
Overall at Baseline
Median
(Q1,Q3)
Mean Fold Change
(95% CI) from Baseline
Week 48
Week 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)
Study week
Abstract WEAB0106LB
8.2% (5.7, 13.0)
Results (7)- Markers of T-Cell Activation:
%CD38+DR+ of CD8+ T-cells declined similarly
across groups
Fold Change: %CD8+:CD38+HLADR+
Overall at Baseline
Median
(Q1,Q3)
Mean Fold Change
(95% CI) from Baseline
Week 48
Week 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)
Study week
Abstract WEAB0106LB
42.9% (34.4, 53.9)
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
AbstractWEAB0106LB
WEAB0106LB
Acknowledgements
Study Participants
ACTG Sites
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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
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