Presence of asymptomatic cytomegalovirus and Epstein--Barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events

Abstract

Background: Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity and mortality. Cytomegalovirus (CMV) and Epstein--Barr virus (EBV) co-infections likely exacerbate inflammatory-related diseases. Objective: To determine if presence of detectable CMV or EBV DNA in peripheral blood mononuclear cells (PBMC) is associated with non-AIDS events among PWH receiving modern ART. Design: We performed a case--control study of PWH starting ART and HIV-suppressed at year 1 and thereafter, 140 cases who experienced non-AIDS events and 305 matched controls. Events included myocardial infarction, stroke, malignancy, serious bacterial infection or death. Methods: Blood samples were studied pre-ART, 1-year post-ART and pre-event. Controls had an event-free follow-up equal or greater than cases. CMV and EBV DNA levels were measured in PBMC. Conditional logistic regression analysis assessed associations and adjusted for relevant covariates; Spearman's correlations compared CMV and EBV DNA levels with other biomarkers. Results: CMV DNA was detected in PBMC of 25% of participants, EBV DNA was detected in more than 90%. Higher EBV DNA levels were associated with increased risk of events at all time points (odds ratio (OR) per one IQR = 1.5–1.7, all P < 0.009). At year 1, detectable CMV DNA was associated with increased risk of events in most adjusted models (OR = 1.4–1.8, P values ranging 0.03–0.17). Higher levels of CMV and EBV DNA correlated with multiple inflammatory markers and lower CD4+/CD8+ ratio. Conclusion: In PWH starting ART, detection of CMV and EBV DNA in PBMC was associated with development of non-AIDS events. Clinical trials will be needed to understand causal mechanisms and ways to interrupt them.

Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder

“…It is conceivable that CRP does not adequately capture this brain-immune relationship, since the aforementioned studies reported associations between FA and inflammatory cytokines rather than CRP. Specific markers of viral infection such as CXCL10/IP-10 or macrophage activation such as sCD14 may also be more sensitive to HCMV reactivation than CRP [122]. Another possibility is that that the single time point at which CRP was measured did not always overlap with viral shedding since the two studies were not designed to enroll participants with an active HCMV infection.…”

CD4+:CD8+ T Cell Ratio Normalization and the Development of AIDS Events in People with HIV Starting Antiretroviral Therapy

“…4,7,9,[25][26][27] Furthermore, our analyses may be restricted by the lack of information on several unmeasured confounders in UK CHIC known to modulate immune responses, including infection by cytomegalovirus and other human herpesvirus, tobacco, and alcohol use. [28][29][30][31][32] Finally, the small number of new AIDS events in the study means that our analyses may be underpowered to detect some associations.…”

The Role of Coinfections in the EBV–Host Broken Equilibrium

“…For instance, Kenyan children on ART exhibited a correlation between EBV primary infection and HIV viremia, which supports that EBV influences HIV reactivation [ 140 ]. Similarly, detectable EBV load at the initiation of ART or post-ART was associated with positive markers of inflammation, non-AIDS defined malignancies, and other PLWH morbidities, such as cardiovascular disease [ 141 ]. EBV load in the peripheral blood correlates with hypergammaglobulinemia and with the presence of LMP1-transcripts in cells, despite ART-suppressive HIV viremia and increased CD4 numbers [ 142 ].…”