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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 that soluble ICPs may be 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 nonaccidental 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. [ABSTRACT FROM AUTHOR]

Background Development of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome. Methods AIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies. Results Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, P  = .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation. Conclusions Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission. [ABSTRACT FROM AUTHOR]