CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Univ Hosp Duisburg-Essen, Essen, Germany, 2 Ruhr-Univ Bochum, Bochum, Germany, 3 City Hosp Dortmund, Dortmund, Germany, 4 Univ Leipzig, Leipzig, Germany, 5 Univ Hosp Essen, Essen, Germany, 6 Cardiologic Outpatient Clinic Staubach, Bochum, Germany, 7 Alfried Krupp Hosp, Essen, Germany Background: In the aging HIV-positive patients (HIV+) cardiovascular events (CVE) and strokes are more frequent than in the general population. Traditional risk scores underestimate the rates. The increased risk of HIV+may be explained by effects of the HIV infection itself, antiretroviral treatment (ART), drug use, coinfections and vascular inflammation. Methods: We investigated the effect of known cardiovascular risk factors (CRF) and HIV-specific risk factors (HRF) on CVE (Figure 1) in 1481 HIV+ outpatients of the prospective multicenter HIV HEART cohort study (HIVH) performed in the German Ruhr area since 2004. CVE were defined as a diagnosis of myocardial infarction, stroke, coronary heart disease, heart failure or death of any reason. CRF are smoking behavior, diabetes mellitus, arterial hypertension and age. Cox proportional hazard models were used to determine the effect of CRF and HSF on CVE. We calculated hazards ratios (HR) and corresponding 95% confidence intervals. As time to event we define the duration from study start to the first CVE or last contact. Results: The mean age of the 1481 HIV+ at their last follow-up visit was 50.8±10.7 years (Y) and the mean duration of HIV-infection of 14.7±7.6 Y (84%male, 88% Caucasian, 51.8%MSM). 33% of the HIV+ had already AIDS in their medical history. Mean CD4-cell count was 639±306 cells/µl and the mean CD4/CD8 ratio 0.9±3.0. 84.9% of the 1428 ART-treated HIV+ had an HIV-RNA below the level of detection (<50 Copies (c)/ml). The mean duration of ART was 13.6±8.2 Y. Most HIV+ get two NRTIs combined with one NNRTI (35.2%), PI (35.8%) or INI (13.3%). Chronic HCV-coinfection was diagnosed in 161 (11%) HIV+. Mean Framingham risk score was 8.3±7.7 (diabetes 8.6%, current smoker 43.6%, arterial hypertension 30.4%). During a follow-up period of 6.9±3.0 Y 373 CVE in 215 HIV+ had been observed. HRF at Baseline (BL) which were independently associated with a shorter time to the first CVE, were AIDS (Adjusted HR 1.41 [1.06 to 1.89]; p=0.018), lower CD4/CD8 Ratio [decline of one unit] (HR 2.19 [1.18 to 4.03]; p=0.012) and detectable HIV-RNA [≥ 50 c/ml] (HR 1.49 [1.10 to 2.00]; p=0.009). Smoking at BL was the traditional CRF with the highest HR (3.20 [2.33 to 4.41]; p<0.001). Conclusion: HIV specific factors, such as AIDS, CD4/CD8 ratio or detectable HIV RNA were independently associated with an increased cardiovascular risk but not the duration of ART. Traditional CRF maintained a major effect on CVE. 634 IMPAIRED ANTIVASCULAR CONTRACTION OF PERIVASCULAR ADIPOSE TISSUE IN HIV INDIVIDUALS Dan Wang , Cheng Wang, Cuiwei Wang, Chenglong Liu, Jennifer Verbesey, Philena Sun, Seble Kassay, Mary Young, Christopher Wilcox, for the Hypertension, Kidney, andVascular Research Center and DCWomen’s Interagency HIV Study Georgetown Univ, Washington, DC, USA Background: Perivascular adipose tissue (PVAT) exhibits anti-contractile capacity to regulate vascular tone, whereas reactive oxygen species (ROS) impair vascular function. But PVAT effects on microvessels in HIV are unexplored. We previously reported an enhanced vascular contraction in subcutaneous microvascular arterioles (SMAs) dissected from a gluteal skin biopsy in HIV infected individuals. We tested the hypothesis that HIV associated microvascular dysfunction, at least partially by augmented microvascular ROS and impaired PVAT anti-contractile function and signaling. Methods: SMAs were prepared from HIV-infected (n=8) and matched HIV-uninfected young African American women (n=6) enrolled in the DC Women’s Interagency HIV Study (DC-WIHS). HIV-infected participants were virally suppressed on HAART and had no identified other CVD risk factors. The concentration-contractile responses to U-46,619 and phenylephrine (PE) in PVAT-intact or denuded SMAs were recorded by a wire myograph. Microvascular cellular ROS generation (temp-9AC fluorescence) and mitochondria ROS (MitoSOX Red fluorescence) were quantitated by RatioMaster system. The ROS biomarkers (malondialdehyde, MDA) and adipokines were measured in adipose fat homogenate and/or plasma. Results: HIV-infected participants had significantly increased (P<0.05) adipose MDA (15.1 ± 2.5 vs 10.9 ± 2.6 ng/mg protein) and adipose leptin (40 ± 9 vs 28 ± 7 ng/mg protein); and reduced adiponectin in plasma (14 ± 2 vs 23 ± 2 ng/ml and in PVAT (2.1 ± 0.3 vs 4.6 ± 1.3 ng/mg protein, p<0.05. U-46,619 induced contraction (199 ± 22 vs 131 ± 16%, P<0.05), endothelin-1 induced cellular ROS (Δ0.32 ± 0.05 vs 0.10 ± 0.02 fluoresce unit) and mitochondria ROS (Δ0.10 ± 0.04 vs 0.09 ± 0.04 fluoresce unit) were significantly increased in PVAT-denuded vessels from HIV-infected participants (p<0.05). PVAT significantly (p<0.05) reduced contraction response to U-46,619 in both groups, but the reduction (anti-contraction) of U46,619 response was smaller in the PVAT intact-vessel (47 ± 3 vs 68 ± 4%, P<0.05). The contraction and anti-contractile response to PE had no difference between HIV and control group. Conclusion: HIV-infected individuals have increased intrinsic vascular effects of ROS leading to reduction of the beneficial microvascular PVAT signaling pathway on microvascular contractile reactivity. Therapeutic targets for vascular dysfunction in HIV should include ROS elimination and its extravascular actions on PVAT. 635LB NOVEL IMAGING STRATEGY SHOWS HIGH-LEVEL AORTIC CD206+ MACROPHAGE INFILTRATION IN HIV Markella V. Zanni 1 , Mabel Toribio 1 , Moses Q. Wilks 1 , Michael T. Lu 1 , Tricia H. Burdo 2 , Fred Cope 3 , Udo Hoffmann 1 , Kenneth C. Williams 4 , Georges El-Fakhri 1 , Steven K. Grinspoon 1 1 Massachusetts General Hosp, Boston, MA, USA, 2 Temple Univ, Philadelphia, PA, USA, 3 Navidea Biopharmaceuticals, Dublin, OH, USA, 4 Boston Coll, Chestnut Hill, MA, USA Background: Systemic monocyte activation and arterial macrophage infiltration are thought to contribute to heightened cardiovascular disease (CVD) risk in HIV. Current in vivo investigative techniques including 18-F fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT) do not allow for quantification of macrophage-specific arterial inflammation. Methods: We performed a first-in-human investigation testing whether systemic administration of 99mTc-tilmanocept (which specifically binds CD206+macrophages) would enable quantification of arterial macrophage infiltration. Our primary outcome measure, aortic 99mTc-tilmanocept uptake on SPECT/CT, was assessed among 6 HIV-infected subjects with subclinical atherosclerosis and 3 non-HIV-infected subjects with similar Framingham Risk Scores. The clinical significance of aortic 99mTc-tilmanocept uptake was established through relation to atherosclerotic plaque burden on computed tomography angiography (CTA) and to measures of systemic immune activation. Results: 99mTc-tilmanocept uptake localized to three regions: kidney, liver, and aorta. High-level 99mTc-tilmanocept uptake (>/=5x uptake in muscle as a reference region representing non-specific tissue and blood pool uptake) was apparent across 20.4% of the aortic surface volume in HIV-infected subjects versus 4.3% in controls (P=0.009). Among all subjects, aortic high-level 99mTc-tilmanocept uptake related robustly to non-calcified plaque volume (r=0.78, P=0.01) and to circulating levels of soluble CD14 (ρ=0.72, P=0.03), CD14+CD16- monocytes (ρ=0.77, P=0.02), CD8+ T cell count (ρ=0.73, P=0.02), and CD8+PD1+ T cells (ρ=0.70, P=0.04). Ex vivo experiments on banked aortic tissue demonstrated increased CD206+macrophage infiltration among HIV-infected subjects vs. controls (30.1±7.9 vs. 14.2±7.0 macrophages/mm2, P=0.0002) and significant tilmanocept co-localization with CD206+macrophages. Figure 1. Conclusion: Application of a novel macrophage-specific molecular imaging strategy highlights the high degree of aortic macrophage infiltration among HIV-infected subjects with low Framingham Risk Scores and shows that aortic macrophage infiltration relates strongly to CV risk parameters and select systemic immune parameters. Macrophage- specific imaging strategies may help elucidate immune mechanisms of macrophage-mediated end-organ damage in HIV and may identify HIV-infected patients at risk for such complications.

Poster and Themed Discussion Abstracts

CROI 2017 271