CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

composed of distinct subsets of the cytokines (Table). IL6, IP10, KT Ratio, sCD14, sCD163, sTNFrI, sTNFrII, and suPAR primarily contributed to PC1 (consistent with the a priori list); CMV IgG, EBV IgG, and EBV DNA primarily contributed to PC2. Higher levels of PC1 were associated with increased risk of non-AIDS events and the subset of MI/Strokes; effect sizes were similar to those reported individually for sTNFrI and II and suPAR (Tenorio 2014, Hoenigl 2018). Conclusion: PCA is a useful high-dimensional analytic approach to reduce the number of statistical comparisons, to characterize unique, meaningful cytokine profiles, and to identify specific biomarkers to consider for endpoints in future interventional trials. In our analysis we confirmed that sTNFrI and II and suPAR were the strongest predictors of non-AIDS events, supporting sTNFrII as the primary endpoint of ACTG studies of letermovir and anti-CMV vaccine.

245 SYSTEMIC AND VASCULAR INFLAMMATION PREDICT COMORBIDITIES IN TREATED HIV INFECTION Padraig McGettrick 1 , Willard Tinago 1 , Alejandro A. Garcia 1 , Stefano Savinelli 1 , Emma Haran 1 , Aoife G. Cotter 2 , Eoin Feeney 1 , John Lambert 1 , Gerard Sheehan 2 , Alan Landay 3 , Patrick W. Mallon 1 1 University College Dublin, Dublin, Ireland, 2 Mater Misericordiae University Hospital, Dublin, Ireland, 3 Rush University Medical Center, Chicago, IL, USA Background: Although inflammation and immune dysfunction are implicated in pathogenesis of comorbidities in treated people with HIV (PWH), whether an immune risk profile can predict PWH at higher risk of comorbidities is unclear. Methods: In the UCD Infectious Diseases cohort study of PWH on anti-retroviral therapy, we measured 24 biomarkers using bead based quantitative ELISA, covering pathways of systemic inflammation (hsCRP, IL6, TNFR1,2, TNFa), innate immune activation (sCD14, sCD163, MCP1, MIP1, sCD40), endothelial function (Pselectin, Eselectin, sVCAM, sICAM), coagulation (Ddimer, vWF) and intestinal permeability (IL18, LBP). Principal component analysis was performed followed by unsupervised hierarchical clustering to partition subjects into biomarker derived clusters. Logistic regression assessed association between clusters and prevalent comorbidities (CVD, kidney, liver, hypertension, dyslipidemia). Data are median[IQR] or odds ratio (OR) [95%CI]. Results: We included 99 PWH, age 41 (36,48) years; 44%male; 54% African; 93%with HIVVL<40cps/ml, duration of ART 7.1 (2.3,10.8) years. We observed 3 distinct clusters, two characterized by higher inflammation; cluster 2 (19% subjects) reflecting platelet/macrophage pathways and cluster 3 (34% subjects), systemic, vascular and endothelial pathways (see Table 1). PWH in cluster 3 were older, more likely male and Caucasian. Although prevalence of comorbidities was higher in cluster 2 (42%) and 3 (48.9%) versus cluster 1 (20%), only cluster 3 was associated with prevalent comorbidites in regression analysis (OR 3.1 [1.1, 8.3] p= 0.03). This association remained significant after adjustment for CMV seropositivity, smoking and CD4:CD8 ratio, (OR 3.3 [1.1, 9.8] p=0.03). Further adjustment for age, gender and ethnicity attenuated the relationship (OR 2.4 [0.7, 7.9] p=0.16). Conversely Cluster 1, characterized by lower levels of inflammation, was associated with reduced risk of comorbidities (OR 0.28 [0.10, 0.74] p=0.01), an association which persisted after adjustment for baseline demographics, smoking and T cell ratio (OR 0.29 [0.10, 0.85] p=0.02). Conclusion: We have identified distinct inflammatory patterns in treated PWH that predict prevalent co-morbidities. That these patterns, characterized by pathways including systemic and vascular inflammation remain associated with clinical outcomes even after correction for CMV and CD4:CD8 ratio suggest a number of distinct pathways contributing to co-morbidities in PWH.

Poster Abstracts

244 AGING, TRENDS IN CD4/CD8 RATIO, AND CLINICAL OUTCOMES WITH HIV SUPPRESSION Richard M. Novak 1 , Carl Armon 2 , Kate Buchacz 3 , Jun Li 3 , Douglas Ward 4 , Frank J. Palella 5 , for the CDC HOPS 1 University of Illinois at Chicago, Chicago, IL, USA, 2 Cerner Corp, Kansas City, MO, USA, 3 CDC, Atlanta, GA, USA, 4 Dupont Circle Physicians Group, Washington, DC, USA, 5 Northwestern University, Chicago, IL, USA Background: Data addressing aging’s effects on T cell phenotype suggest that age blunts CD4 cell count (CD4) improvements observed with ART-induced viral suppression. Prolonged viral suppression reduces immune activation, reflected by a rising CD4/CD8 ratio (T4/T8). We studied T4/T8 over time to determine whether it could predict risk for select comorbidities or mortality among aging persons with HIV (PWH) and ≥1year (y) virologic control. Methods We analyzed data from HIV Outpatient Study (HOPS) participants (ppts) seen at 12 U.S. HIV clinics who were followed from 2000-2018 with known baseline CD4, ART initiation date, all viral loads (VL) <200 copies/mL during 1st observation y, ≥1y of follow up with ≥2 T4/T8 measures. We analyzed T4/T8 <0.7 by age group. Cochran-Armitage trend tests were used to compare proportions across time, and by baseline age. Clinical outcomes included any cancer, dyslipidemia and all-cause mortality. Case-control analyses were performed using conditional logistic regression (CLR) to assess for associations of T4/T8 with outcomes matching 1:1 for smoking, hepatitis C, nadir CD4, race/ethnicity, sex and insurance, with age as an independent variable. Results: 1,910 ppts were included. Median follow up was 7.2y. At date of first VL <200 copies/mL, 908 (46%) were <40y, 626 (33%) 40-49y, and 376 (20%) ≥50y; 82%male; 50% Non-Hispanic (NH) white, 34% NH black, and 12% Hispanic; 62%were on their 1stART regimen, 20% on their ≥4thregimen; 38% had a nadir CD4 <200 cells/mm 3 . Baseline T4/T8 was 0.3 (interquartile range: 0.2-0.6), not statistically different for the 3 age groups. T4/T8 increases by baseline age differed through 4y of follow up (P<0.001 for each year). Over time, the percentage of ppts with T4/T8 ≥0.7 increased for all ages, but less among 40-49y and ≥50y than <40y group (Figure). In clinical outcomes analyses (n=77 deaths, n=167 cancer, and n=461 dyslipidemia) using CLR, accounting for age, T4/T8 <0.7 at last measurement was associated with mortality (Odds Ratio [OR] 2.96, 95% Confidence Interval [CI] 1.30-6.74), cancer (OR 1.83, CI 1.11-3.02), and dyslipidemia (OR 4.02, CI 2.90-5.58). Conclusion: Pre-treatment immune injury may persist as assessed by T4/T8 which may not resolve even with prolonged viral suppression and may have clinical consequences in aging PWH

83

CROI 2020