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.
Background: Network-based interventions against epidemic spread are most powerful when the full network structure is known. However, in practice, resource constraints require decisions to be made based on partial network information. We investigated how the accuracy of network data available at individual and village levels affected network-based vaccination effectiveness. Methods: We simulated a Susceptible-Infected-Recovered process on static empirical social networks from 75 rural Indian villages. First, we used regression analysis to predict the percentage of individuals ever infected (cumulative incidence) based on village-level network properties for simulated datasets from 10 representative villages. Second, we simulated vaccinating 10% of each of the 75 empirical village networks at baseline, selecting vaccinees through one of five network-based approaches: random individuals (Random); random contacts of random individuals (Nomination); random high-degree individuals (High Degree); highest degree individuals (Highest Degree); or most central individuals (Central). The first three approaches require only sample data; the latter two require full network data. We also simulated imposing a limit on how many contacts an individual can nominate (Fixed Choice Design, FCD), which reduces the data collection burden but generates only partially observed networks. Results: In regression analysis, we found mean and standard deviation of the degree distribution to strongly predict cumulative incidence. In simulations, the Nomination method reduced cumulative incidence by one-sixth compared to Random vaccination; full network methods reduced infection by two-thirds. The High Degree approach had intermediate effectiveness. Somewhat surprisingly, FCD truncating individuals’ degrees at three was as effective as using complete networks. Conclusions: Using even partial network information to prioritize vaccines at either the village or individual level, i.e. determine the optimal order of communities or individuals within each village, substantially improved epidemic outcomes. Such approaches may be feasible and effective in outbreak settings, and full ascertainment of network structure may not be required.
Background: People with HIV (PWH) on antiretroviral therapy (ART) still experience an increased risk of morbidity and mortality, presumably driven by chronic inflammation, yet predictors of discrete or combinatorial outcomes remain unclear. Galectin-9 (Gal-9), a driver of both inflammatory and immunosuppressive responses, has been associated with HIV disease progression and multimorbidity. Objective: To determine whether plasma Gal-9 levels are associated with the occurrence of specific non-AIDS events (NAEs) in PWH initiating ART. Design: We performed a nested case–control study of PWH enrolled from 2001 to 2009 and evaluated pre-ART (66 cases, 97 controls), a year post-ART (112 cases, 211 controls), and immediately preceding an event (89 cases, 162 controls). Events included myocardial infarction/stroke, malignancy, serious bacterial infection, or death. Methods: Plasma Gal-9 levels were assessed by ELISA. Conditional logistic regression assessed associations with NAEs and Spearman's correlations compared Gal-9 with other previously assessed biomarkers. Results: NAEs occurred at a median of 2.8 years (1.7–4.6) after ART initiation. Higher Gal-9 levels were associated with increased risk of NAEs at year 1 and preevent [odds ratio (OR) per 1 interquartile range = 1.4–1.6; all P < 0.05], specifically myocardial infarction/stroke at year 1 (OR = 1.9; P = 0.029). Gal-9 also correlated with multiple inflammatory and immune activation predictors of NAEs (all timepoints). Conclusion: Elevated Gal-9 levels are predictive of deleterious NAEs, particularly cardiovascular complications. Whether the Gal-9 pathway, potentially binding to its putative ligands, is active in the pathogenesis of these outcomes warrants further investigation to determine if targeting Gal-9 may slow or reverse the risk of NAEs.
Background Although cell surface immune checkpoint proteins (ICPs) such as PD-1 expressed on T cells are associated with T cell exhaustion, HIV disease progression, and AIDS events, they have shown limited utility in predicting non-AIDS morbidity. Given that ICPs also exist in soluble forms and are elevated in ART-treated HIV infection, we tested the hypothesis whether soluble ICPs are predictive of non-AIDS events in adults initiating ART. Methods Utilizing a nested case-control study from the AIDS Clinical Trials Group ALLRT cohort we measured plasma levels of 15 soluble inhibitory and activating ICPs by Luminex. Participants (134 cases, 292 matched controls) were evaluated pre-ART, a year post-ART, and immediately preceding a non-AIDS event, which included myocardial infarction (MI)/stroke, malignancy, serious bacterial infection, and non-accidental death. Results Conditional logistic regression analysis determined that higher levels of soluble CD27 were associated with increased risk of non-AIDS events at all time points. Higher levels of CD40 at baseline and pre-event, and CD80 at pre-event were associated with increased risk of non-AIDS events. Examining specific non-AIDS events, multiple ICPs were associated with malignancy at baseline and pre-event whereas only higher CD27 levels were associated with increased risk of MI/stroke at year 1 and pre-event. Conclusions While select soluble ICPs were associated with non-AIDS events, CD27 emerged as a consistent marker irrespective of ART. Our data may offer guidance on new targets for early clinical monitoring in people with HIV who remain at greater risk of specific non-AIDS events.
Background Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. Methods A5324 was a randomized, double-blind, placebo-controlled trial of ART intensification with dolutegravir (DTG)+MVC, DTG+Placebo, or Dual-Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. Assessments were repeated at 24, 48, 72, and 96 weeks. The primary outcome was the change from baseline to week 48 on the normalized total z-score (i.e., the mean of the individual NC test z-scores). Results Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (p=0.19). Total z-score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z-score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, p=0.006) and did not differ between arms (p>0.10). Conclusions This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.
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