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Despite inflammation being implicated in cardiovascular disease (CVD) in people with human immunodeficiency virus (PWH), considerable heterogeneity within populations of PWH exists. Stratifying CVD risk based on inflammatory phenotype could play an important role. Using principal component analyses and unsupervised hierarchical clustering, we examined 38 biomarkers to identify inflammatory phenotypes in 2 independent cohorts of PWH. We identified 3 distinct inflammatory clusters present in both cohorts that were associated with altered risk of both subclinical CVD (cohort 1) and prevalent clinical CVD (cohort 2) after adjusting for CVD risk factors. These data support precision medicine approaches to enhance CVD risk assessment in PWH., Competing Interests: Potential conflicts of interest. P. W. G. M. and/or his institution has received grants, honoraria, and/or speaker’s fees from Gilead Sciences, ViiV Healthcare, BMS, MSD, and Janssen-Cilag. A. L. has acted as consultant to Abbott, Merck Group, and Gilead Sciences. A. G.-C. has received honorarium, educational/travel support, or unrestricted research grants from Gilead Sciences, MSD, ViiV Healthcare, and Janssen-Cilag. C.S. has received honoraria for preparation and delivery of educational materials from Gilead Sciences and ViiV Healthcare. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Non-communicable diseases (NCDs) are increased amongst people living with HIV (PLWH) and are driven by persistent immune activation. The role of socioeconomic status (SES) in immune activation amongst PLWH is unknown, especially in low-income sub-Saharan Africa (SSA), where such impacts may be particularly severe., Methods: We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031), as well as volunteers without HIV infection. Clinical assessment, socioeconomic evaluation, blood draw for immune activation markers and carotid femoral pulse wave velocity (cfPWV) were carried out at 2- and 42-weeks post-ART initiation. Socioeconomic risk factors for immune activation and arterial stiffness were assessed using linear regression models., Results: Of 279 PLWH, the median (IQR) age was 36 (31-43) years and 122 (44%) were female. Activated CD8 T-cells increased from 70% amongst those with no education to 88% amongst those with a tertiary education (p = 0.002); and from 71% amongst those earning less than 10 USD/month to 87% amongst those earning between 100-150 USD/month (p = 0.0001). Arterial stiffness was also associated with higher SES (car ownership p = 0.003, television ownership p = 0.012 and electricity access p = 0.029). Conversely, intermediate monocytes were higher amongst those with no education compared to a tertiary education (12.6% versus 7.3%; p = 0.01) and trended towards being higher amongst those earning less than 10 USD/month compared to 100-150 USD/month (10.5% versus 8.0%; p = 0.08). Water kiosk use showed a protective association against T cell activation (p = 0.007), as well as endothelial damage (MIP1β, sICAM1 and sVCAM1 p = 0.047, 0.026 and 0.031 respectively)., Conclusions: Socioeconomic risk factors for persistent inflammation amongst PLWH in SSA differ depending on the type of inflammatory pathway. Understanding these pathways and their socioeconomic drivers will help identify those at risk and target interventions for NCDs. Future studies assessing drivers of inflammation in HIV should include an SES assessment., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: There is increasing evidence pointing toward an important role of heightened immune activation and inflammation in people living with HIV contributing to the development of non-AIDS comorbidities. This review aims to explore low bone mineral density (BMD) in HIV with a focus on the underlying mechanisms and relationships between the immune and skeletal systems., Recent Findings: Baseline immune activation and inflammation negatively impact BMD at antiretroviral therapy (ART) initiation. B- and T-cell alterations in HIV lead to an imbalance in the osteoblastic osteoprotegerin (OPG) and osteoclastic receptor activator of NF-κB ligand (RANKL) cytokines which favours osteoclastogenesis and bone resorption. These findings suggest an important role for immune-mediated mechanisms in the pathogenesis of low BMD in HIV., Summary: Bone homeostasis is in part regulated by cells of the immune system through complex interactions with the RANK/RANKL/OPG axis. Disturbances in the normal functioning of T, B cells, and monocytes in HIV and the resulting proinflammatory state may contribute to dysregulation of this finely controlled balance leading to increased bone loss. Pre-ART levels of immune activation and inflammation have a consistently negative effect on BMD and further suggest the immunocentric basis of bone loss in HIV alongside supporting the benefits of earlier ART initiation. Further longitudinal studies will help determine the effect this will have on fracture risk in people living with HIV.

Background: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen., Methods: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants., Findings: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group)., Interpretation: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide., Funding: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. Methods We recruited Malawian adults with CD4 <100 cells/μL 2 weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse-wave velocity (cfPWV) measured arterial stiffness 2, 12, 24, and 42 weeks post–ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. Results 211 participants with HIV grouped into 3 inflammatory clusters representing 51 (24%; cluster-1), 153 (73%; cluster-2), and 7 (3%; cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD-1 versus cluster-2 and cluster-3 (all P <.0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P <.001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI,.86–1.14; P =.91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01–2.09; P =.045). Conclusions Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk. Clinical Trials Network NCT01825031. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease (CVD) is one of the leading causes of mortality in virally suppressed people living with HIV (PLWH) and with an aging population, is likely to become one of the leading challenges in maintaining good health outcomes in HIV infection. However, factors driving the risk of CVD in PLWH are multiple and may be different from those of the general population, raising challenges to predicting and managing CVD risk in this population.Areas Covered: In this review, we examine the relevant data regarding CVD in HIV infection including CVD prevalence, pathogenesis, and other contributing factors. We review the data regarding CVD risk prediction in PLWH and summarize factors, both general and HIV specific, that may influence CVD risk in this population. And finally, we discuss appropriate management of CVD risk in PLWH and explore potential therapeutic pathways which may mitigate CVD risk in the future in this population.Expert Opinion: Following a comprehensive review of CVD risk in PLWH, we give our opinion on the primary issues in risk prediction and management of CVD in HIV infected individuals and discuss the future direction of CVD management in this population. [ABSTRACT FROM AUTHOR]

The population of people living with HIV (PLWH) is growing older with an estimated 4 million over the age of 50 years, a figure which has doubled since the introduction of effective antiretroviral therapy (ART) and which is increasing globally. Despite effective ART, PLWH still experience excess morbidity and mortality compared to the general population with increased prevalence of age-related, non-AIDS illnesses (NAI) such as cardiovascular disease, malignancies, cognitive impairment and reduced bone mineral density, which impact disability and everyday functioning. This review will discuss the challenges presented by comorbidities in ageing PLWH and discuss the aetiology and management of age-related illnesses in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Obesity is increasingly described in people living with HIV (PLWH), but its impact on immune activation and inflammation in HIV is still poorly characterized. We aimed to analyze the difference in circulating cytokines involved in pathways associated with comorbidities in PLWH according to the presence or absence of obesity. Methods: Age- and sex-matched PLWH with and without obesity (body mass index ≥30 kg/m²) from a multicenter, prospective cohort were recruited with a 1:2 ratio. Twenty-three biomarkers covering pathways associated with systemic inflammation (high sensitivity C-Reactive Protein [hsCRP], interleukin (IL)-2, IL-6, tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, tumor necrosis factor-alpha, interferon-gamma, IL-18), coagulation (von Willebrand Factor [vWF], D-dimer, soluble CD40 ligand), endothelial function (E-selectin, P-selectin, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1), atherosclerosis (myeloperoxidase [MPO], lipoprotein-associated phospholipase A2), immune regulation (IL-1 receptor antagonist [IL-1RA]), innate immune activation (macrophage inflammatory protein-1, monocyte chemoattractant protein-1, soluble CD163, soluble CD14), and microbial translocation (lipopolysaccharide binding protein) were measured in the 2 groups. Between-group difference in biomarkers were assessed using Mann--Whitney test. Associations between obesity and biomarkers were assessed using logistic regression adjusted for age, sex, ethnicity, smoking status, and antiretroviral therapy. Results: Ninety-nine antiretroviral therapy--treated PLWH were included in the analysis (33 with obesity, 66 without obesity). PLWH with obesity had higher levels of hsCRP, IL-6, vWF, D-dimer, E-selectin, MPO, IL-1RA, and lipopolysaccharide binding protein. Six markers (hsCRP, IL-6, vWF, E-selectin, MPO, IL-1RA), reflecting systemic inflammation, coagulation, and atherosclerosis pathways, were associated with increased odds of obesity in the adjusted logistic regression model: hsCRP (adjusted odds ratio 2.7, 95% CI: [1.7 to 4.29]), IL-6 (3.77 [1.43-9.93]), vWF (5.33 [1.51-18.75]), E-selectin (6.28 [1.36-29.04]), MPO (6.85 [1.87-25.04]), and IL-1RA (6.45 [2.28-18.2]). No association was observed between obesity and markers of innate immune activation and gut microbial translocation. Conclusions: Obesity in PLWH was associated with activation of systemic inflammatory, endothelial, atherosclerosis, and coagulation pathways, rather than those associated with innate immune activation and gut microbial translocation. These pathways point toward an unfavorable cardiovascular profile in PLWH with obesity, which will have to be further explored in future studies on long-term outcomes. [ABSTRACT FROM AUTHOR]

Systemic inflammation and innate immune activation are associated with COVID-19 disease severity. Knowledge gaps remain in the relationships between microbiome, inflammation and COVID-19 disease severity. To better characterise these associations, we performed 16SrDNA analysis of stool samples in COVID-19 subjects to explore diversity and taxanomic composition. We correlated these to host inflammatory profiles, derived from soluble plasma biomarkers measured by bead-based fluorescence and electrochemiluminescence immunoassays. Associations of microbial diversity and inflammatory biomarkers on maximal COVID-19 severity (mild, moderate v severe/critical) was explored using logistic regression and weighted gene correlation network analysis (WGCNA). Of 79 subjects, 58% were male and 88% were Caucasian with 36% experiencing mild disease, 22% moderate disease and 40% critical/severe COVID-19. Hierarchical clustering and principal component analysis (PCo) revealed distinct inflammatory clusters that were found to correlate with 4 modules of microbiome profiles. Modules 3 and 4 were associated with both older age and severe/critical disease outcomes. These modules were enriched in pathogenic and inflammatory bacteria that mapped to a pro-inflammatory biomarker cluster. In contrast, module 1 exhibited enrichment of anti-inflammatory bacteria, was associated with younger age and mild/moderate disease outcomes and mapped to a less-inflamed biomarker cluster. This study provides further insights into links between host microbiome, inflammatory responses to SARS-CoV-2 infection and clinical COVID-19 disease severity, suggesting a role for the microbiome in shaping distinct host inflammatory responses to infection. [ABSTRACT FROM AUTHOR]