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In a trial involving participants with HIV infection receiving antiretroviral therapy, the use of pitavastatin resulted in a lower risk of a major adverse cardiac event than placebo at a median of 5.1 years.

People with HIV (PWH) appear to be at higher risk for suboptimal pathogen responses and for worse COVID-19 outcomes, but the effects of host factors and COVID-19 on the humoral repertoire remain unclear. We assessed the antibody isotype/subclass and Fc-receptor binding Luminex arrays of non-SARS-CoV-2 and SARS-CoV-2 humoral responses among antiretroviral therapy-treated (ART-treated) PWH. Among the entire cohort, COVID-19 infection was associated with higher cytomegalovirus (CMV) responses (vs. the COVID- cohort ), potentially signifying increased susceptibility or a consequence of persistent inflammation. Among the COVID+ participants, (a) higher BMI was associated with a striking amplification of SARS-CoV-2 responses, suggesting exaggerated inflammatory responses, and (b) lower nadir CD4 was associated with higher SARS-CoV-2 IgM and FcγRIIB binding capacity, indicating poorly functioning extrafollicular and inhibitory responses. Among the COVID-19- participants, female sex, older age, and lower nadir CD4 were associated with unique repertoire shifts. In this first comprehensive assessment of the humoral repertoire in a global cohort of PWH, we identify distinct SARS-CoV-2-specific humoral immune profiles among PWH with obesity or lower nadir CD4+ T cell count, underlining plausible mechanisms associated with worse COVID-19-related outcomes in this setting. Host factors associated with the humoral repertoire in the COVID-19- cohort enhance our understanding of these important shifts among PWH.

BACKGROUNDStatin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond LDL-cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin-responsive and other inflammatory and metabolic pathways with MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).METHODSCox proportional hazards models were used to assess the relationship between MACE and proteomics measurements at study entry and year 2, adjusting for time-updated statin use and the baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine-learning (ML) model to predict MACE using baseline protein values with significant associations.RESULTSFor 765 individuals (age: 50.8 ± 5.9 years, 82% men, 18% women), among 7 proteins changing with statin versus placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (adjusted HR [aHR]: 2.31 per 2-fold-higher levels; 95% CI: 1.11-4.80; P = 0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins that did not change in response to statin therapy, 26 were associated with MACE at a FDR below 0.05. These proteins represented a predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomics ML model achieved a 10-fold cross-validated concordance index (C-index) of 0.74 ± 0.11 to predict MACE, improving on models using traditional risk prediction scores only (C-index: 0.61 ± 0.18).CONCLUSIONSANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C.TRIAL REGISTRATIONClinicalTrials.gov: NCT02344290.FUNDINGNIH, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare.

Abstract Background Among people with HIV (PWH), COVID-19 is common and potentially severe. We leveraged REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) to assess the effects of statin therapy for cardiovascular disease prevention on COVID-19 outcomes (incidence and serious cases) among a global cohort of PWH. Methods COVID-19 data collection was implemented April 2020 to capture events from January 2020. COVID-19 was defined by positive test result or clinical diagnosis and serious COVID-19 according to the International Conference on Harmonisation definition. Among participants in follow-up on 1 January 2020, Cox proportional hazards modeling was used to estimate the hazard ratio (HR) of COVID-19 (pitavastatin/placebo), stratified by Global Burden of Disease region. Modification of statin effect following COVID-19 vaccination was evaluated via interaction with time-updated vaccination status. Results Among 6905 PWH, 32% were natal female and 41% were Black or African American. The median age was 53 years and the 10-year atherosclerotic cardiovascular disease risk score 4.5%. Statin therapy did not reduce COVID-19 incidence (HR, 1.05; 95% CI, .95–1.15) but appeared to reduce incidence of serious COVID-19 (HR, 0.75; 95% CI, .52–1.09). Among 1701 PWH with COVID-19, the relative risk (pitavastatin/placebo) for serious COVID-19 was 0.73 (95% CI, .52–1.03). The treatment effect size for serious COVID-19 fell within the hypothesized range, but the 95% CI crossed 1 given fewer-than-anticipated cases (117 vs 200). Furthermore, 83% reported COVID-19 vaccination by end of study, with a strong protective effect on serious COVID-19 (HR, 0.27; 95% CI, .14–.53; P < .0001). A protective statin effect was observed prior to vaccination. Conclusions Among PWH, statin therapy had no effect on COVID-19 incidence but showed potential to reduce risk of serious COVID-19 prior to COVID-19 vaccination. Clinical Trials Registration NCT02344290 (ClinicalTrials.gov). In a global cohort of people with HIV with low to moderate traditional atherosclerotic cardiovascular disease risk, statin therapy had no effect on COVID-19 incidence but showed potential to reduce the risk of serious COVID-19 prior to COVID-19 vaccination.

Abstract Background Inflammasome activation is increased in people with human immunodeficiency virus (PWH), but its relationship with coronary plaque is poorly understood in this setting. Methods In a large human immunodeficiency virus cardiovascular prevention cohort, relationships between caspase-1, interleukin (IL)-1β, and IL-18 and coronary plaque indices were assessed by multivariate logistic regression. Results Higher IL-18 and IL-1β were associated with Leaman score, an integrative measure of plaque burden and composition. Conclusions As Leaman score >5 is associated with cardiovascular events in the general population, future work is needed to determine how the inflammasome relates to events and whether strategies to reduce its activation affect events or plaque progression among PWH. Among ART-treated people with HIV at low-moderate traditional cardiovascular disease risk, inflammasome activation markers were associated with Leaman score, a composite index of plaque burden and severity, which has been associated with major cardiovascular events in the general population.

BACKGROUND. Statin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond LDL-cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin-responsive and other inflammatory and metabolic pathways with MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). METHODS. Cox proportional hazards models were used to assess the relationship between MACE and proteomics measurements at study entry and year 2, adjusting for time-updated statin use and the baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine-learning (ML) model to predict MACE using baseline protein values with significant associations. RESULTS. For 765 individuals (age: 50.8 + 5.9 years, 82% men, 18% women), among 7 proteins changing with statin versus placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (adjusted HR [aHR]: 2.31 per 2-foldhigher levels; 95% CI: 1.11-4.80; P = 0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins that did not change in response to statin therapy, 26 were associated with MACE at a FDR below 0.05. These proteins represented a predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomics ML model achieved a 10-fold cross-validated concordance index (C-index) of 0.74 + 0.11 to predict MACE, improving on models using traditional risk prediction scores only (C-index: 0.61 + 0.18). CONCLUSIONS. ANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C.

Abstract Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290. Among people with HIV (PWH), the VEGF coreceptor neuropilin-1 was most strongly associated with an increased hazard of mortality and type 2 myocardial infarction, as well as multiple cancers, suggesting relevance to the pathogenesis of these age-related comorbidities among PWH. Graphical Abstract Graphical Abstract