CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

inflammation (e.g., IL-6R, IL-1b) and cardiometabolic proteins (e.g., VEGF-D, VCAM-1, Neuropilin-1, FABP-4) declined more in the letermovir than control arms (FDR-adjusted P<0.05 [red] and P<0.10 [blue], Figure). Letermovir caused a greater decline in 3 of 5 proteins recently causally linked to vascular events in treated HIV by Mendelian Randomization (AXL, GAS6, and IL-6R; nominal P≤0.02). Conclusion: Suppression of asymptomatic CMV in PWH on ART increased plasma sTNFR2, but decreased markers of IL-10 receptor signaling and several inflammation and cardiometabolic proteins, some of which are causally linked to cardiovascular risk. While the clinical significance remains unclear, this is the first study to show that a specific inhibitor of CMV – without direct activity against other herpesviruses – is safe and has broad impact on immunologic and cardiometabolic biomarkers in PWH.

subgroups. Participants were evaluated at one-year post-ART during viral suppression (HIV RNA <400 copies/mL). We measured an exploratory panel of 37 immunoregulatory proteins in the plasma by Luminex assay. Differences among CD4 groups were evaluated by Mann-Whitney U tests and multivariate logistic regressions adjusted for pertinent covariates. A boosted decision tree machine learning algorithm was used to determine biomarker signatures classifying individuals by CD4 group. Results: Circulating immunoregulatory proteins Galectin-1 (Gal-1), Galectin-9 (Gal-9), ICOS, CD276 (B7- H3), BAFF and OX40 were significantly higher in PWH with poor CD4 recovery as compared to those with normalized CD4 count (all p<0.05) [Figure 1A]. Gal-9, CD276, and OX40 remained significant in logistic regressions adjusted for age (all p<0.05). Further, a boosted decision tree model consisting of age and the six differential immunoregulatory proteins accurately classified individuals with poor CD4 recovery from those with reconstituted CD4 counts (AUC=0.902 +/- 0.078) [Figure 1B]. In this model, Gal-9, ICOS and Gal-9 had the highest feature importance [Figure 1B]. Conclusion: We found a novel signature of circulating lymphocyte-associated immunoregulatory proteins indicative of poor CD4 recovery and potential targets to monitor immune perturbations in PWH during suppressive ART.

Poster Abstracts

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DNA Methylation-Based Telomere Length Is Associated With HIV Infection and Cancer in Relation to HIV Xiaoyu Liang 1 , Brad Aouizerat 2 , Lesley S. Park 3 , Kaku So-Armah 4 , Vincent Marconi 5 , Ke Xu 6 , Amy C. Justice 7 1 Michigan State University, East Lansing, MI, USA, 2 New York University, New York, NY, USA, 3 Stanford University, Stanford, CA, USA, 4 Boston University, Boston, MA, USA, 5 Emory University, Atlanta, GA, USA, 6 Yale University, New Haven, CT, USA, 7 VA Connecticut Healthcare System, West Haven, CT, USA Background: Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, increased cancer risk, and osteoporosis. However, due to technical issues, directly measuring TL remains a challenge. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed. In this study, we determined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV. Methods: Data analyzed were from the Veterans Aging Cohort Study Biomarker Cohort. DNAm was assessed from peripheral blood mononuclear cells (Illumina HumanMethylation450 BeadChip and Illumina Human Methylation EPIC BeadChip). DNAmTL was subsequently estimated based on methylation profiles of 140 CpGs that prior work identified by regressing measured leukocyte TL on blood methylation data. Cancer prevalence was estimated from electronic medical records and cancer registry data. Mortality risk was estimated by the VACS Index 2.0, a measure of physiologic frailty, and by deaths from any cause over time. We used multivariable linear regression to estimate the association between DNAmTL and cancer, and VACS Index 2.0. We utilized Cox Proportional Hazards models to assess how DNAmTL is associated with the risk of all-cause mortality. Models were adjusted for self-reported race/ethnicity, batch, smoking status, alcohol consumption, and six cell types (CD4, CD8, NK, B cell, Monocyte, and Granulocyte). Results: People with HIV (N=1,147) had shorter average DNAmTL than those without HIV infection (N=104) [beta=-0.24, 95% confidence interval (-0.31, -0.17), p=4.54E-12]. VACS Index 2.0 [beta=-0.0023 (-0.0034, -0.0012), p=2.32E 05] and higher cancer prevalence [beta= -0.03 (-0.06, 0.00), p=4.49E-02] were associated with shortened DNAmTL. One unit decrease in DNAmTL was associated with a 40% increase in mortality risk [Hazard Ratio: 0.60 (0.44,0.82), p=1.42E-03]. Conclusion: Physiologic frailty, cancer, and mortality are associated with DNAmTL.

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Suppressing Asymptomatic CMV With Letermovir Reshapes Cardiometabolic Proteome in Treated HIV

Sara Gianella Weibel 1 , Douglas W. Kitch 2 , Gabriele B. Beck-Engeser 3 , Milenka Meneses 1 , Scott L. Letendre 1 , Michael Dube 4 , Lawrence Fox 5 , John Koethe 6 , Priscilla Y. Hsue 3 , Ahmed A. Tawakol 7 , Adam Olshen 3 , Michael L. Freeman 8 , Davey M. Smith 1 , Peter W. Hunt 3 1 University of California San Diego, La Jolla, CA, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 University of California San Francisco, San Francisco, CA, USA, 4 University of Southern California, Los Angeles, CA, USA, 5 National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 6 Vanderbilt University, Nashville, TN, USA, 7 Massachusetts General Hospital, Boston, MA, USA, 8 Case Western Reserve University, Cleveland, OH, USA Background: People with HIV (PWH) and CMV have higher cardiometabolic disease risk than those without HIV despite antiretroviral therapy (ART), but mechanisms are unclear. Methods: We performed a randomized trial of letermovir (CMV terminase inhibitor, 480 mg daily) in ART- suppressed CMV-seropositive PWH to assess whether letermovir therapy for 48 weeks reduced plasma sTNFR2 levels (primary endpoint) and other inflammation and cardiometabolic indices vs. no anti-CMV treatment. A planned futility analysis was performed after 40 (of planned 180) participants reached week 8. Continuous changes in plasma biomarkers (ELISA and Olink Inflammation and Cardiometabolic Explore panels) and binary CMV shedding in genital secretion and saliva were compared between arms with linear mixed or logistic models, adjusting proteomic analyses for False Discovery Rate (Benjamini-Hochberg). Results: Of 42 participants enrolled, 40 contributed to the week 8 per-protocol analysis, stratified by CD4 count (45% <350 cells/mm 3 ) and sex at birth (29% female). Adverse events were similar between arms. Letermovir suppressed CMV DNA at all on-treatment timepoints. Unexpectedly, plasma sTNFR2 levels increased in the letermovir arm at week 8 (P<0.001, between-arms P=0.059) and the trial was stopped for futility. We hypothesized that suppression of CMV's immunoregulatory viral IL-10 may have caused the increase in plasma sTNFR2. Consistent with this hypothesis, plasma IL-10RA – a marker of IL-10 receptor signaling – declined 28% more in the letermovir than control arms (P=0.009), while human IL-10 levels were unchanged. While sTNFR2 increased, 30 plasma

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CROI 2024