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BackgroundAmong 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.MethodsCOVID-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.ResultsAmong 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.ConclusionsAmong 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 registrationNCT02344290 (ClinicalTrials.gov).

BackgroundPericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population.MethodsIn this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates.ResultsAmong 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001).ConclusionsAmong PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.

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.

BackgroundMechanisms contributing to COVID-19 severity in people with HIV (PWH) are poorly understood. We evaluated temporal changes in plasma proteins following SARS-CoV-2 infection and identified pre-infection proteomic markers associated with future COVID-19.MethodsWe leveraged data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Antiretroviral therapy (ART)-treated PWH with clinical, antibody-confirmed COVID-19 as of September 2021 were matched on geographic region, age, and sample timing to antibody negative controls. For cases and controls, pre COVID-19 pandemic specimens were obtained prior to January 2020 to assess change over time and relationship to COVID-19 severity, using false-discovery adjusted mixed effects modeling.FindingsWe compared 257 unique plasma proteins in 94 COVID-19 antibody-confirmed clinical cases and 113 matched antibody-negative controls, excluding COVID-19 vaccinated participants (age 50 years, 73% male). 40% of cases were characterized as mild; 60% moderate to severe. Median time from COVID-19 infection to follow-up sampling was 4 months. Temporal patterns of protein changes differed based on COVID-19 disease severity. Among those experiencing moderate to severe disease vs. controls, NOS3 increased whereas ANG, CASP-8, CD5, GZMH, GZMB, ITGB2, and KLRD1 decreased. Higher pre-pandemic levels of granzymes A, B and H (GZMA, GZMB and GZMH) were associated with the future development of moderate-severe COVID-19 and were related to immune function.InterpretationWe identified temporal changes in proteins closely linked to inflammatory, immune, and fibrotic pathways which may relate to COVID-19-related morbidity among ART-treated PWH. Further we identified key granzyme proteins associated with future COVID-19 in PWH.FundingThis study is supported through NIH grants U01HL123336, U01HL123336-06 and 3U01HL12336-06S3, to the clinical coordinating center, and U01HL123339, to the data coordinating center as well as funding from Kowa Pharmaceuticals, Gilead Sciences, and a grant award through ViiV Healthcare. The NIAID supported this study through grants UM1 AI068636, which supports the AIDS Clinical Trials Group (ACTG) Leadership and Operations Center, and UM1 AI106701, which supports the ACTG Laboratory Center. This work was also supported by NIAID through grant K24AI157882 to MZ. The work of IS was supported by the intramural research program of NIAID/NIH.

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.

BackgroundInflammasome activation is increased in people with human immunodeficiency virus (PWH), but its relationship with coronary plaque is poorly understood in this setting.MethodsIn 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.ResultsHigher IL-18 and IL-1β were associated with Leaman score, an integrative measure of plaque burden and composition.ConclusionsAs 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.

BackgroundCytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque.MethodsThe Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry.ResultsOf 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5.ConclusionsNo meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events.Clinical trials registrationNCT02344290.

BackgroundAmong people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein.MethodsREPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score.ResultsThe primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055).ConclusionsAmong US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

BackgroundAmong antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH.MethodsLeveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL).ResultsThe primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels.ConclusionsFactors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects.Clinical trials registrationNCT0234429.

Little is known regarding coronavirus disease 2019 (COVID-19) vaccination rates in people with HIV (PWH), a vulnerable population with significant morbidity from COVID-19. We assessed COVID-19 vaccination rates among 6952 PWH in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) compared to region- and country-specific vaccination data. The global probability of COVID-19 vaccination through end of July 2021 was 55% among REPRIEVE participants with rates varying substantially by Global Burden of Disease (GBD) superregion. Among PWH, factors associated with COVID-19 vaccination included residence in high-income regions, age, white race, male sex, body mass index, and higher cardiovascular risk. Clinical Trials Registration. NCT02344290.

BackgroundIn addition to traditional cardiovascular (CV) risk factors, antiretroviral therapy, lifestyle, and human immunodeficiency virus (HIV)-related factors may contribute to future CV events in persons with HIV (PWH).MethodsAmong participants in the global REPRIEVE randomized trial, we characterized demographics and HIV characteristics relative to ACC/AHA pooled cohort equations (PCE) for atherosclerotic CV disease predicted risk and CV health evaluated by Life's Simple 7 (LS7; includes smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and glucose).ResultsAmong 7382 REPRIEVE participants (31% women, 45% Black), the median PCE risk score was 4.5% (lower and upper quartiles Q1, Q3: 2.2, 7.2); 29% had a PCE score

BackgroundEmerging data demonstrate that the use of integrase inhibitor (INSTI)-based antiretroviral treatment (ART) is associated with increased weight, but the cardiometabolic health consequences of increased weight remains poorly understood.MethodsThis analysis examined INSTI use (>6 months) at entry among REPRIEVE participants enrolled in High Income and Latin America/Caribbean Global Burden of Disease regions. Primary analyses used linear and logistic regression; secondary analyses used quantile regression to examine differences across the full data distribution. Characteristics of those with and without INSTI use were balanced using inverse probability of treatment weighting.ResultsAmong 4500 REPRIEVE participants, 1848 were on an INSTI-based regimen at entry for an average of 2.1 ± 1.8 years. Integrase inhibitor use (vs no INSTI use) was associated with higher odds of obesity (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.4-1.9) and higher mean body mass index ([BMI] +1.5kg/m2; 95% CI, 1.0-1.9) and waist circumference (+3.6cm; 95% CI, 2.6-4.6). Differences in weight related to INSTI use were greater in the upper tails of the distribution (+3.1kg/m2 [95% CI, 1.9-4.4] at the 90th centile vs +0.7kg/m2 [95% CI, 0.2-1.2] at the 50th centile) and among women and nonwhite participants, with sex and race having an additive effect on BMI. Conversely, INSTI use was not associated with differences in glucose, low-density lipoprotein cholesterol, or higher odds of metabolic syndrome or hypertension.ConclusionsDifferences in weight and waist circumference associated with INSTI use are (1) not uniform across people with human immunodeficiency virus, (2) greatest among women and nonwhites, and (3) concentrated at the upper tails of weight distribution. These data identify at-risk subgroups for whom long-term cardiovascular disease outcomes should be carefully assessed.

BackgroundAt interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.MethodsWe enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.ResultsThe trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.ConclusionsThe mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

BackgroundPatterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.MethodsThe REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.ResultsA total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.ConclusionsThere were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.Clinical trials registrationNCT02344290.

BackgroundCardiovascular disease (CVD) is more frequent among people with HIV (PWH) and may relate to traditional and nontraditional factors, including inflammation and immune activation. A critical need exists to develop effective strategies to prevent CVD in this population.MethodsThe Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (A5332) is a prospective, randomized, placebo-controlled trial of a statin strategy for the primary prevention of major adverse cardiovascular events (MACE) in PWH with low to moderate traditional risk. At least 7,500 PWH, 40-75 years of age, on stable antiretroviral therapy, will be randomized to pitavastatin calcium (4 mg/d) or identical placebo and followed for up to 8 years. Participants are enrolled based on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score and low-density lipoprotein cholesterol (LDL-C) level with a goal to identify a low- to moderate-risk population who might benefit from a pharmacologic CVD prevention strategy. Potential participants with a risk score ≤ 15% were eligible based on decreasing LDL-C thresholds for increasing risk score >7.5% (LDL-C 7,500 participants at approximately 120 sites across 11 countries, generating a diverse and representative population of PWH to investigate the primary objective of the trial.ConclusionsREPRIEVE is the first trial investigating a primary CVD prevention strategy in PWH. REPRIEVE will inform the field of the efficacy and safety of a statin strategy among HIV-infected participants on antiretroviral therapy and provide critical information on CVD mechanisms and non-CVD events in PWH.

Recently REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV), a large, global, randomized clinical trial, demonstrated that administration of pitavastatin calcium could prevent major cardiovascular events among people with HIV. However, a modest increase in diagnosis of diabetes mellitus (DM) occurred in those receiving the drug compared with placebo. In this substudy of REPRIEVE, predictors of development of DM in the pitavastatin and placebo groups were assessed over a long follow-up period. Visual Abstract. Diabetes Risk Factors in People With HIV Receiving Pitavastatin Versus Placebo for Cardiovascular Disease Prevention: Recently REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV), a large, global, randomized clinical trial, demonstrated that administration of pitavastatin calcium could prevent major cardiovascular events among people with HIV. However, a modest increase in diagnosis of diabetes mellitus (DM) occurred in those receiving the drug compared with placebo. In this substudy of REPRIEVE, predictors of development of DM in the pitavastatin and placebo groups were assessed over a long follow-up period. Background: REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) led to new guidelines for statin use among people with HIV (PWH) with low to moderate risk for atherosclerotic cardiovascular disease (ASCVD). Little is known about the natural history of diabetes mellitus (DM) or mechanisms contributing to statin effects on DM among this population. Objective: To determine the contribution of known DM risk factors to excess risk for DM with pitavastatin in REPRIEVE. Design: Phase 3, primary ASCVD prevention trial over a median of 5.6 years of follow-up. (ClinicalTrials.gov: NCT02344290) Setting: Global, multicenter trial. Participants: 7731 PWH aged 40 to 75 years with low to moderate ASCVD risk (by the pooled cohort equations from the American College of Cardiology and American Heart Association) without DM at study entry. Intervention: Random 1:1 assignment to pitavastatin, 4 mg daily, or placebo. Measurements: New-onset DM was determined at each visit by clinical diagnosis requiring initiation of medication treatment for DM. The incidence of new-onset DM was assessed in relation to predefined demographic and metabolic risk factors, stratified by treatment group. Treatment effects of pitavastatin on progression to new DM in key subgroups were determined. Results: Participants with at least 3 DM risk factors (vs. no risk factors) had increased risk for DM in each treatment group (incidence rate, 3.24 per 100 person-years [PY] vs. 0.34 per 100 PY [pitavastatin] and 2.66 per 100 PY vs. 0.27 per 100 PY [placebo]). The incidence of DM was highest in South Asia. In adjusted analyses, high body mass index, prediabetes, and metabolic syndrome components were strongly associated with new-onset DM (all P  < 0.005). Limitation: Pitavastatin was the only statin assessed; DM was assessed clinically. Conclusion: Metabolic risk factors, including prediabetes and obesity, contributed to new-onset DM in statin- and placebo-treated participants. A clinically significant effect of pitavastatin on DM was seen primarily among those with multiple risk factors for DM at entry. Strategies targeting key metabolic risk factors, like obesity and prediabetes, may help protect against DM among PWH. Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health. [ABSTRACT FROM AUTHOR]

BackgroundSystemic inflammation persists in chronic HIV infection and is associated with increased rates of non-AIDS events such as cardiovascular and liver disease. Increased gut permeability and systemic exposure to microbial products are key drivers of this inflammation. Serum-derived bovine immunoglobulin/protein isolate (SBI) supports gut healing in other conditions such as inflammatory bowel disease.MethodsIn this randomized, double-blind study, participants receiving suppressive antiretroviral therapy (ART) with chronic diarrhea received placebo or SBI at 2.5 g BID or 5 g BID for 4 weeks, followed by a 20-week placebo-free extension phase with SBI at either 2.5 or 5 g BID. Intestinal fatty acid binding protein (I-FABP), zonulin, flagellin, lipopolysaccharide (LPS) and LPS-binding protein, and inflammatory markers were measured by ELISA or multiplex assays. Non-parametric tests were used for analysis.ResultsOne hundred three participants completed the study. By week 24 SBI significantly decreased circulating levels of I-FABP (-0.35 ng/μL, P=0.002) and zonulin (-4.90 ng/μL, P=0.003), suggesting improvement in gut damage, and interleukin-6 (IL-6) (-0.40 pg/μL, P=0.002), reflecting improvement in systemic inflammation. In participants with the lowest quartile of CD4+ T-cell counts at baseline (189-418 cells/μL), CD4+ T-cell counts increased significantly (26 cells/μL; P=0.002).ConclusionsOral SBI may decrease inflammation and warrants further exploration as a potential strategy to improve gut integrity and decrease systemic inflammation among persons receiving prolonged suppressive ART.

BackgroundFibrosis in lymph nodes may limit CD4+ T-cell recovery, and lymph node and adipose tissue fibrosis may contribute to inflammation and comorbidities despite antiretroviral therapy (ART). We hypothesized that the angiotensin receptor blocker and peroxisome proliferator-activated receptor γ agonist telmisartan would decrease lymph node or adipose tissue fibrosis in treated human immunodeficiency virus type 1 (HIV) infection.MethodsIn this 48-week, randomized, controlled trial, adults continued HIV-suppressive ART and received telmisartan or no drug. Collagen I, fibronectin, and phosphorylated SMAD3 (pSMAD3) deposition in lymph nodes, as well as collagen I, collagen VI, and fibronectin deposition in adipose tissue, were quantified by immunohistochemical analysis at weeks 0 and 48. Two-sided rank sum and signed rank tests compared changes over 48 weeks.ResultsForty-four participants enrolled; 35 had paired adipose tissue specimens, and 29 had paired lymph node specimens. The median change overall in the percentage of the area throughout which collagen I was deposited was -2.6 percentage points (P = 0.08) in lymph node specimens and -1.3 percentage points (P = .001) in adipose tissue specimens, with no between-arm differences. In lymph node specimens, pSMAD3 deposition changed by -0.5 percentage points overall (P = .04), with no between-arm differences. Telmisartan attenuated increases in fibronectin deposition (P = .06). In adipose tissue, changes in collagen VI deposition (-1.0 percentage point; P = .001) and fibronectin deposition (-2.4 percentage points; P < .001) were observed, with no between-arm differences.ConclusionsIn adults with treated HIV infection, lymph node and adipose tissue fibrosis decreased with continued ART alone, with no additional fibrosis reduction with telmisartan therapy.

Objectives To evaluate serum-derived bovine immunoglobulin/protein isolate (SBI) for safety and impact on gastrointestinal (GI) symptoms in HIV patients with chronic idiopathic diarrhea. Methods A multi-center trial comprised of a double-blind, placebo (PBO)-controlled lead-in phase, (participants received PBO or SBI at 2.5 or 5.0 g BID for 4 weeks) followed by a 20-week, PBO-free phase (SBI at either 2.5 or 5.0 g BID). Participants included HIV-infected patients who were virologically suppressed with a history of chronic idiopathic diarrhea, defined as > 3 loose stools per day for ≥ 3 months without an identifiable cause. Safety was evaluated by monitoring adverse events (AEs) and clinical laboratory testing. Health status and changes in GI symptoms were assessed using validated questionnaires. Results SBI was well tolerated by the 103 participants with only 2 withdrawals due to AEs potentially associated with SBI. Mean number of daily unformed stools decreased from about 4 at baseline to less than 2 by week 4 for all study groups. Improvements in several other GI symptoms were also reported. Comparison of the PBO group to SBI groups showed no significant differences, although both SBI cohorts reported significantly improved health status scores. GI symptom improvements were maintained throughout the 20-week PBO-free phase. Conclusions Oral SBI is safe and well tolerated at the doses studied in HIV patients with chronic diarrhea. No conclusions could be drawn regarding impact on GI symptoms. Additional studies are ongoing to examine the biological and immunologic effects of SBI in virologically suppressed HIV-infected patients.

BackgroundLow levels of high-density lipoprotein cholesterol (HDL-C) are common in individuals with human immunodeficiency virus (HIV) infection, persist during antiretroviral therapy (ART), and are associated with increased cardiovascular disease (CVD) risk.MethodsVirologically controlled participants without CVD on stable ART with low HDL-C (men 150 mg/dL were randomized to receive open-label extended-release niacin 1500 mg/day with aspirin 325 mg/day or fenofibrate 200 mg/day for 24 weeks. The primary endpoint was the week 24 within-arm change in brachial artery flow-mediated dilation (FMD) in participants with complete follow-up scans.ResultsOf 99 participants, 74 had complete data (35 niacin, 39 fenofibrate). Median age was 45 years, 77% were male, median CD4(+) count was 561 cells/µL, and brachial FMD was 4.2%. Median HDL-C was 32 mg/dL for men and 38 mg/dL for women, low-density lipoprotein cholesterol was 103 mg/dL, and triglycerides were 232 mg/dL. In men, HDL-C increased a median of 3 mg/dL with niacin and 6.5 mg/dL with fenofibrate (P < .001 for both). In women, HDL-C increased a median of 16 mg/dL with niacin and 8 mg/dL with fenofibrate (P = .08 for both). After 24 weeks, there was no significant change in FMD in either arm; the median (interquartile range) change was +0.6% (-1.6 to 2.3) with niacin (P = .28) and +0.5% (-1.0 to 3.0) with fenofibrate (P = .19). Neither treatment significantly affected C-reactive protein, interleukin 6, or D-dimer levels.ConclusionsDespite improvements in lipids, niacin or fenofibrate treatment for 24 weeks did not improve endothelial function or inflammatory markers in participants with well-controlled HIV infection and low HDL-C.Clinical trials registrationNCT01426438.

UnlabelledAbnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.Clinical trials registrationNCT 01543958.

BackgroundNonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.ObjectiveTo evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.DesignA phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).Setting57 sites in the United States and Puerto Rico.PatientsTreatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors.InterventionAtazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.MeasurementsVirologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.ResultsAmong 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.LimitationThe trial was open-label, and ritonavir was not provided.ConclusionOver 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

This article explores the impact of open-label semaglutide on metabolic dysfunction-associated steatotic liver disease (MASLD) in individuals with HIV. MASLD is a condition characterized by fatty liver disease and cardiovascular disease risk factors. The study aimed to determine if semaglutide could reduce liver fat and improve cardiometabolic parameters in people with HIV and MASLD. The findings indicate that semaglutide effectively reduces liver fat and improves markers such as glucose regulation and triglyceride concentrations. Participants generally tolerated semaglutide well, with mild gastrointestinal symptoms being the most common adverse events. While the study has limitations, such as a small sample size and the absence of a control group, it suggests that semaglutide may be a promising treatment for MASLD in individuals with HIV, potentially offering broader cardiometabolic benefits. [Extracted from the article]

BackgroundLongitudinal follow-up of older persons living with HIV is essential for the ascertainment of aging-related clinical and behavioral outcomes, and self-administered questionnaires are necessary for collecting behavioral information in research involving persons living with HIV. Web-based self-reported data collection results in higher data quality than paper-and-pencil questionnaires in a wide range of populations. The option of remote web-based surveys may also increase retention in long-term research studies. However, the acceptability and feasibility of web-based data collection in clinical research involving older persons living with HIV have never been studied. ObjectiveThis study aims to assess the acceptability and feasibility of a web-based survey to collect information on sexual, substance use, and physical activity behaviors; compare the data quality of the web-based survey with that of a paper-and-pencil questionnaire; and summarize web-based survey metrics. MethodsThis pilot study took place within the AIDS Clinical Trials Group A5322 study, a longitudinal cohort of men and women living with HIV (aged ≥40 years), followed at 32 clinical sites in the United States and Puerto Rico. A total of 4 sites participated in this study. A web-based survey was created using self-administered questionnaires typically completed in A5322 via paper and pencil. Pilot study participants completed these questionnaires via web-based survey at one research visit in lieu of paper-and-pencil administration. Two questions were added to assess feasibility, defined as participants’ perception of the ease of web-based survey completion (very hard, hard, easy, very easy), and their preferred format (computer or tablet, paper and pencil, no preference) for completing the questions in the future (acceptability). Feasibility and acceptability were summarized overall and by demographic and clinical characteristics; the proportion of evaluable data by web-based survey versus previously administered paper-and-pencil questionnaires (data quality) was compared for each question. ResultsAcceptability and feasibility were high overall: 50.0% (79/158) preferred computer or tablet, 38.0% (60/158) reported no preference, and 12.0% (19/158) preferred paper and pencil; 93.0% (147/158) reported survey completion easy or very easy. Older age was associated with lower odds of preferring computer or tablet to paper and pencil (odds ratio per 1-year increase in age: 0.91, 95% CI 0.85-0.98). Individuals who found the survey hard or very hard had a lower median neurocognitive test score than those who found it easy or very easy. Data quality with web-based survey administration was similar to or higher than that with paper-and-pencil administration for most questions. ConclusionsWeb-based survey administration was acceptable and feasible in this cohort of older adults living with HIV, and data quality was high. Web-based surveys can be a useful tool for valid data collection and can potentially improve retention in long-term follow-up studies.