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EBV AND CMV LEVELS IN BLOOD ARE ASSOCIATED WITH NON-AIDS EVENTS DURING ART
Sara Gianella1, Carlee Moser2, Andrej Vitomirov1, Ashley McKhann2, Laura Layman1, Brianna Scott1, Steven Lada1, Ronald Bosch2, Martin Hoenigl1, Nell Lurain3, Alan Landay3, Michael M. Lederman4, Peter W. Hunt5, Davey M. Smith1
1University of California San Diego, La Jolla, CA, USA,2Harvard University, Boston, MA, USA,3Rush University, Chicago, IL, USA,4Case Western Reserve University, Cleveland, OH, USA,5University of California San Francisco, San Francisco, CA, USA
Despite antiretroviral therapy (ART), HIV infection remains associated with higher morbidity/mortality, driven in part by increased inflammation. We sought to identify associations between cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) DNA in peripheral blood mononuclear cells (PBMC) with occurrence of non-AIDS events and mortality during ART.
Participants (140 cases, 305 controls, 929 samples) were selected from the ACTG ALLRT trial; all were HIV suppressed on ART at year 1 and thereafter. Blood was collected: pre-ART (baseline), 1-year post-ART, and immediately pre-event (for cases). Cases included myocardial infaction/stroke, malignancy, serious bacterial infection or death. Controls had an event-free follow-up equal or greater than the relevant case. Participants were matched on age (within 10 years), sex, pre-ART CD4+ count (within 50 cells/mm3), ART regimen, and parent study. At each time-point, levels of CMV and EBV DNA were measured in PBMC by ddPCR. Levels of CMV and EBV IgG were measured at year 1 in plasma by ELISA. Other cellular and soluble biomarkers were obtained from previous projects (see table). Conditional logistic regression analysis assessed associations of the biomarkers with events, adjusted for relevant covariates. Correlation between biomarker levels were assessed with Spearman's correlations among controls.
Cellular CMV DNA was detected in 25% of all time-points, while EBV was detected in >90%. Higher levels of EBV were associated with an increased risk of events at all time points (OR per one IQR = 1.5-1.7, all p<0.009), with the strongest associations at baseline. Associations remained unchanged when adjusting for relevant clinical factors. At year 1 (but not other timepoints), having detectable CMV DNA (yes/no) was associated with increased risk of events in most adjusted models (OR per one IQR = 1.4-1.8, p ranging 0.03-0.17). CMV and EBV levels were correlated only at the pre-event time point (r=0.18, p<0.0001). Levels of EBV DNA were associated with EBV IgG (r=0.37, p<0.0001), while CMV DNA was not associated with CMV IgG. Levels of CMV were correlated with all soluble markers at baseline, while EBV DNA was correlated with some biomarkers at each time point (see table).
Subclinical replication of EBV and (to lesser extent) CMV in blood were associated with increased inflammation and were predictive of non-AIDS events and mortality in ART suppressed HIV-infection.