CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

mononuclear cells. We examined associations of viral persistence with IMT after adjusting for traditional risk factors, inflammatory markers, and HIV-related features. Our secondary objectives were to examine associations of viral persistence with inflammatory markers and mortality. Results: We studied 152 individuals (mean age 48.5 years, median CD4 count 461 cells/mm3, 92%male). The mean duration of followup was 4 years. Older age, smoking, and higher LDL were predictive of baseline mean IMT (p<0.01 for all), while viral persistence measurements were not. HIV-associated DNA was significantly associated with subsequent IMT progression (difference in CIMT: 0.015mm per doubling HIV DNA, p=0.043), and both HIV RNA (OR: 1.85 per doubling HIV RNA, p=0.003) and HIV DNA (OR: 1.60 per doubling HIV DNA, p=0.002) were predictive of incident plaque, which remained significant after adjusting for traditional risk factors, CD4 count, and CD4:CD8 ratio. In adjusted models, higher hsCRP was predictive of higher HIV RNA (p=0.012), whereas higher sCD14 was associated with HIV DNA (p=0.029). Higher RNA/DNA ratio was predictive of mortality (HR 1.66, p=0.024), along with higher IL6 (HR 2.1, p=0.002) and mean IMT (HR 8.47, p=0.015). Conclusion: Measurements of viral persistence in the setting of treated HIV are independently predictive of IMT progression and incident plaque. Furthermore, IL-6 and RNA/DNA ratio were associated with worse survival. The size of the reservoir during ART as estimated by HIV RNA and DNA measurements may be important contributors to HIV-associated atherosclerosis and mortality.

levels remained associated with higher plasma sTNF-R2 (P=0.002) across all timepoints. After adjustment for plasma HIV RNA levels, valganciclovir-treated participants continued to have a greater mean reduction in sTNF-R2 and sICAM-1 levels than placebo at weeks 4 and 8 (-49% to -53% of IQR, P≤0.034 for all). Adjustment for sTNF-R2 levels also abrogated the impact of valganciclovir on sICAM-1 levels. Conclusion: Treating asymptomatic CMV in HIV-infected individuals with incomplete ART-mediated CD4 recovery reduces a biomarker of TNF signaling - that strongly predicted cardiovascular events, Type 2 diabetes, and mortality in prior studies - and a soluble marker of vascular dysfunction. Longer trials of safer anti-CMV agents are needed to assess if treating asymptomatic CMV durably decreases vascular inflammation and cardiometabolic risk.

644 PLASMA TISSUE FACTOR AND MCP-1 PREDICTS CIMT PROGRESSION IN TREATED HIV Denise C. Hsu 1 , Yifei Ma 2 , Danny Li 2 , Meghann Williams 2 , Adam Rupert 3 , Rebecca Scherzer 2 , Steven G. Deeks 2 , Irini Sereti 1 , Priscilla Hsue 2 1 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 2 University of California San Francisco, San Francisco, CA, USA, 3 Leidos Biomedical Research, Inc, Frederick, MD, USA Background: Chronic inflammation plays a key role in the development of cardiovascular disease (CVD) among persons living with effectively treated HIV infection and likely occurs early in the disease process. We evaluated the role of biomarkers of immune activation with carotid artery intima-media thickness (CIMT) progression in treated, virologically suppressed individuals. Methods: We measured biomarkers of immune activation at baseline in 118 HIV-infected individuals with viral load <75 copies/mL from the SCOPE study, using cryopreserved mononuclear cells and plasma. CIMT was measured at baseline and longitudinally in the common, bifurcation and internal carotid artery regions using high resolution ultrasound. Plaque was defined as any focal measurement >1.5mm. Multivariable linear and logistic regression models controlled for demographics, CVD risk factors, and baseline CD4+ T cell count. The final model retained only biomarkers showing significant associations with CIMT. Results: The median age was 49 yrs and 91%were male, 36% had hypertension, 25%were smokers, and 5% had diabetes. The median duration of follow-up was 2 years. The overall median rate of CIMT progression for the mean of the 3 regions was 6.0%/yr. Progression was faster in the bifurcation (5.6%/ yr, p=0.006) and internal (6.5%/yr, p=0.0008) than common carotid regions (4.3%/yr). Incident plaque occurred in 13 of 52 individuals. After multivariable adjustment, doubling in plasma tissue factor and MCP-1 were associated with faster common CIMT progression, 0.058mm/year (p=0.0004) and 0.067mm/ year (p=0.017) respectively. Doubling in CD8+ T cell count and percentage of CD38+HLA-DR+CD8+ T cells were associated with faster internal CIMT progression, 0.10mm/yr (p=0.008) and 0.054mm/yr (p=0.045), respectively. Doubling in CD8+ T cell count was also associated with 0.068mm/yr (p=0.011) faster overall mean CIMT progression. Each 10% increase in CD4+ T cell count at baseline was associated with reduced odds of plaque progression [OR 0.66, 95% CI (0.47 to 0.93), p=0.018]. Conclusion: Residual immune activation and plasma tissue factor are independently predictive of CIMT progression in treated HIV infection. Tissue factor plays a key role in the extrinsic pathway of the coagulation cascade and is thought to underlie plaque thrombogenicity. Therapeutic interventions which target the coagulation and inflammatory pathways in HIV merit additional investigations to reduce CV risk.

Poster Abstracts

643 VALGANCICLOVIR REDUCES STNF-R2 AND VASCULAR DYSFUNCTION MARKERS IN TREATED HIV Gabriele B. Beck-Engeser 1 , Frank Maldarelli 2 , Vanessa A. York 1 , Steven G. Deeks 1 , Jeffrey N. Martin 1 , Elizabeth Sinclair 1 , Priscilla Hsue 1 , Russell Tracy 3 , Yong Huang 1 , Peter W. Hunt 1 1 University of California San Francisco, San Francisco, CA, USA, 2 National Cancer Institute, Frederick, MD, USA, 3 University of Vermont, Burlington, VT, USA Background: Valganciclovir reduced T cell activation (but not IL-6, D-dimer, or sCD14) in an earlier trial of HIV/CMV co-infected individuals with incomplete antiretroviral therapy (ART)-mediated CD4 recovery, but its impact on vascular dysfunction and biomarkers that more consistently predict morbidity and mortality remain uncertain. Methods: Plasma was assessed from a placebo-controlled trial of valganciclovir (900mg daily for 8 weeks) among 30 HIV/CMV co-infected individuals with incomplete ART-mediated CD4 recovery and high CD8+ T cell activation (>10% CD38+HLA-DR+ CD8+ T cells). sTNF-R2, IP-10, sICAM-1, sVCAM-1 (by ELISA), kynurenine/tryptophan (KT) ratio (by LC-MS), and HIV RNA levels (by single-copy assay, SCA, for values <75 copies/ml) were assessed every 4 weeks. Changes from baseline at each timepoint were compared between arms with linear mixed models, log10-transforming variables and normalizing to the baseline interquartile range (IQR) to facilitate comparisons between biomarkers. Results: Among 14 valganciclovir-treated and 16 placebo-treated participants, most (93%) were men, 9 (30%) had detectable plasma HIV RNA levels, and median CD4 count was 190 cells/mm3. Baseline sTNF-R2 levels were highly correlated (rho) with KT ratio (0.80), %CD38+HLA-DR+ CD8+ T cells (0.66), IP-10 (0.52), sVCAM-1 (0.72), sICAM-1 (0.52, all P<0.01), and plasma HIV RNA levels (0.45, P=0.015), but not sCD14 (-0.01, P=0.98). Compared to those on placebo, valganciclovir-treated participants had a mean -55% of an IQR greater decline from baseline in sTNF-R2 levels at week 4 (P=0.006) and -45% at week 8 (P=0.041). Similar effects on sICAM-1 were observed. Higher plasma HIV RNA

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