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

Abstract WEAB0106LB

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)

Abstract WEAB0106LB

Results: Hs-CRP declined with ATV/r and RALResults (2)- Markers of Inflammation and Coagulation:

Hs-CRP declined with ATV/r and RAL

Abstract WEAB0106LB

Fo

ld C

han

ge:

hs-

CR

P

Study week

Abstract WEAB0106LB

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)

Abstract WEAB0106LB

Results: Il-6 did not consistently declineResults (3)- Markers of Inflammation and Coagulation:

IL-6 did not consistently decline

Abstract WEAB0106LB

Fo

ld C

han

ge:

IL

-6

Study week

Abstract WEAB0106LB

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)

Abstract WEAB0106LB

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

Abstract WEAB0106LB

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)

Abstract WEAB0106LB

Results (5)- Markers of Macrophage Activation:sCD163 declined similarly across groups

Fo

ld C

han

ge:

sCD

163

Study week

Abstract WEAB0106LB

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)

Abstract WEAB0106LB

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

Abstract WEAB0106LB

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)

Abstract WEAB0106LB

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