Elevated plasma apolipoprotein E levels in people living with HIV: Associations with biomarkers and HIV-specific risk factors.

BACKGROUND AND AIMS: Apolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. METHODS: We included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. RESULTS: Mean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39-3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. CONCLUSIONS: PWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH.

Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV.

BACKGROUND: The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases. METHODS: Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114). RESULTS: Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-7.2; P = .048). CONCLUSIONS: PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.

Clonal hematopoiesis of indeterminate potential in persons with HIV.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with older age, inflammation and with risk of coronary artery disease (CAD). We aimed to characterize the burden of CHIP, and to explore the association between CHIP, inflammatory markers, and CAD in older persons with HIV (PWH). METHODS: From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included 190 individuals older than 55 years of age. We defined CHIP as variant allele fraction at least 2%. CAD was categorized according to the most severe coronary artery lesion on coronary computed tomography (CT) angiography as no coronary atherosclerosis; any atherosclerosis defined as at least 1% stenosis and obstructive CAD defined as at least 50% stenosis. RESULTS: In the entire population (median age 66 years, 87% men), we identified a total of 62 mutations distributed among 49 (26%) participants. The three most mutated genes were DNMT3A , TET2 , and ASXL1 , accounting for 49, 25, and 16% of mutations, respectively. Age and sex were the only variables associated with CHIP. IL-1ß, IL-1Ra, IL-2, IL-6, IL-10, soluble CD14, soluble CD163 and TNF-α were not associated with CHIP, and CHIP was not associated with any atherosclerosis or with obstructive CAD in adjusted analyses. CONCLUSION: In older, well treated, Scandinavian PWH, more than one in four had at least one CHIP mutation. We did not find evidence of an association between CHIP and inflammatory markers or between CHIP and CAD. CHIP is an unlikely underlying mechanism to explain the association between inflammation and CAD in treated HIV disease.

The Interplay between Adipose Tissue Properties and Levels of NT-proBNP in People with HIV.

Objective: We aimed to assess the association between low N-terminal pro-brain natriuretic peptide (NT-proBNP) and body mass index (BMI), adipose tissue distribution, adiponectin, and HIV-specific risk factors among people with HIV (PWH). Methods: We included 811 PWH with measurement of height, weight and waist circumference, blood samples analyzed for NT-proBNP, and visceral-(VAT) and subcutaneous (SAT) adipose tissue areas measured from CT-scans. Low concentrations of NT-proBNP were defined as concentrations below the limit of quantification (5.9 pmol/L). Associations were explored with multivariable logistic regression analyses adjusted for relevant confounders. Results: We identified 471 (58%) individuals with low concentrations of NT-proBNP. Increasing BMI was associated with higher odds of low NT-proBNP (adjusted OR (aOR) 1.06 (95% CI: 1.01-1.11) per 1 kg/m2). Central obesity and large areas of VAT were associated with higher odds of low NT-proBNP (aOR 1.66 (1.16-2.36) and aOR 1.69 (1.09-2.62), respectively). Higher adiponectin was associated with lower odds of low NT-proBNP (aOR 0.86 (0.79-0.95) per 10% increase). No associations were found between low NT-proBNP and HIV-specific risk factors. Conclusions: In PWH, low NT-proBNP is associated with an adverse adipose tissue profile with high BMI, central obesity, accumulation of VAT, and low adiponectin.

Metabolic syndrome, soluble CD40L, and biomarkers of endothelial dysfunction in people living with HIV.

In the present study, we aimed to investigate the association between soluble CD40 ligand (sCD40L, a marker of platelet activation), soluble thrombomodulin, and syndecan-1 (both well-described markers of endothelial dysfunction) and metabolic syndrome in a large cohort of well-treated people with HIV (PWH) and to elucidate their association with HIV-specific variables. We included 862 PWH with undetectable viral replication. Our hypotheses were tested using uni- and multivariable logistic regression models a priori adjusted for well-known confounders. While no association of soluble thrombomodulin and syndecan-1 with MetS was found, high levels of sCD40L (aOR 1.54 [1.07-2.22]) were associated with excess risk of MetS. Given the previously described association between sCD40L, vascular inflammation and endothelial damage, the results presented in our study may suggest a potential role for sCD40L in the well-known association between cardiometabolic comorbidity and HIV infection.

Transcriptomics age acceleration in prolonged treated HIV infection.

Biological aging in people with HIV (PWH) with prolonged successful antiretroviral therapy (ART) is convoluted and poorly defined. Here, we aimed to investigate the transcriptomics age estimator (TAE) in a cohort of 178 PWH on prolonged successful ART with immune reconstitution and viral suppression from the Copenhagen Comorbidity (COCOMO) cohort. We also used 143 clinical, demographical, and lifestyle factors to identify the confounders potentially responsible or associated with age acceleration. Among the PWH, 43% had an accelerated aging process (AAP), and 21% had decelerated aging process (DAP). DAP is linked with older age, European ancestry, and higher use of tenofovir disoproxil/alafenamide fumarate. A directionally class-based gene set enrichment analysis identified the upregulation of inflammatory pathways (e.g., cytokine and Retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathways) and immune response like T-cell receptor signaling, antigen processing, and presentation in AAP and the downregulation of metabolic processes like oxidative phosphorylation, pyruvate metabolism.

Mpox Incidence and Vaccine Uptake in Men Who Have Sex with Men and Are Living with HIV in Denmark.

(1) Background: Here, we investigate the incidence of mpox and factors associated with vaccine uptake in mainly well-treated men who have sex with men and are living with HIV (MSMWH). (2) Methods: This study included 727 MSMWH from the Copenhagen co-morbidity in HIV infection (COCOMO) study from 1 May to 31 October 2022. Mpox infection and vaccination status were obtained from the Danish Microbiology Database and The Danish Vaccination Register. Vaccination willingness was assessed through an online survey. (3) Results: At a median follow-up of 180 days, 13 (1.8%) participants had laboratory-confirmed mpox infections. Furthermore, 238 (32.7%) had received the mpox vaccine. A sexually transmitted disease (STD) in the preceding two years was associated with a higher risk of mpox infection (hazard ratio 7.1; 95% confidence interval (CI) [1.9-26.9]) and with higher odds of vaccination (adjusted odds ratio 3.1; 95% CI [2.2-4.6]). 401 (55.2%) participants responded to the survey. 228 (57.0%) reported very high vaccination willingness. The self-perceived risk of infection was associated with vaccine uptake. (4) Conclusions: The incidence of mpox was low. A prior STD was associated with both a higher risk of mpox infection and higher odds of vaccination. Despite high-risk sexual behavior and high vaccination willingness, a sizable fraction of participants had not been vaccinated.

Incidence of hypertension in people with HIV infection: a longitudinal observational study.

OBJECTIVE: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in people with HIV (PWH). Although hypertension is a well-known risk factor for CVD, studies investigating incident hypertension in PWH and its risk factors are scarce. In the present study, we set out to investigate incident hypertension and its predictors in the context of well-treated HIV infection. METHODS: We included 532 PWH from the Copenhagen Comorbidity in HIV (COCOMO study). All included individuals took part in both baseline and 2.5 years follow-up examinations. Linear and Poisson regression were used to test our hypotheses, both before and after adjusting for confounders. RESULTS: One hundred and five (19.7%) cases of incident hypertension occurred during 1217 person-years of follow-up (PYFU), corresponding to 8.5 cases per 100 PYFU. Waist-hip-ratio (relative risk (RR) 1.61 [1.34-1.94] and adjusted RR (aRR) 1.54 [1.24-1.91]) and central obesity (RR 2.41 [1.61-3.61] and aRR 2.29 [1.49, 3.52]) were significantly associated with this condition. No HIV-specific factors were found to be associated with incident hypertension. CONCLUSIONS: In the present study, the incidence rate of hypertension in well-treated PWH was comparable to that of the general population from similar socio-economic settings. Traditional risk factors, in particular age and indices of adipose tissue accumulation, were associated with incident hypertension.Our results may further underline the pivotal importance of focusing on lifestyle changes and weight loss, rather than on HIV-specific factors, in order to prevent incident hypertension in well-treated PWH.

Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection.

Multiomics technologies improve the biological understanding of health status in people living with HIV on antiretroviral therapy (PWH). Still, a systematic and in-depth characterization of metabolic risk profile during successful long-term treatment is lacking. Here, we used multi-omics (plasma lipidomic, metabolomic, and fecal 16 S microbiome) data-driven stratification and characterization to identify the metabolic at-risk profile within PWH. Through network analysis and similarity network fusion (SNF), we identified three groups of PWH (SNF-1-3): healthy (HC)-like (SNF-1), mild at-risk (SNF-3), and severe at-risk (SNF-2). The PWH in the SNF-2 (45%) had a severe at-risk metabolic profile with increased visceral adipose tissue, BMI, higher incidence of metabolic syndrome (MetS), and increased di- and triglycerides despite having higher CD4+ T-cell counts than the other two clusters. However, the HC-like and the severe at-risk group had a similar metabolic profile differing from HIV-negative controls (HNC), with dysregulation of amino acid metabolism. At the microbiome profile, the HC-like group had a lower α-diversity, a lower proportion of men having sex with men (MSM) and was enriched in Bacteroides. In contrast, in at-risk groups, there was an increase in Prevotella, with a high proportion of MSM, which could potentially lead to higher systemic inflammation and increased cardiometabolic risk profile. The multi-omics integrative analysis also revealed a complex microbial interplay of the microbiome-associated metabolites in PWH. Those severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their dysregulated metabolic traits, aiming to achieve healthier aging.

Insulin resistance in people living with HIV is associated with exposure to thymidine analogues and/or didanosine and prior immunodeficiency.

BACKGROUND: As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance is a key determinant. In this study, we aimed to investigate risk factors associated with insulin resistance in PLWH. METHODS: We included well-treated PLWH without hepatitis co-infection, and with available fasting serum insulin and plasma glucose (n = 643) from the Copenhagen Comorbidity in HIV Infection Study. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the association between risk factors and high HOMA-IR in a logistic regression model adjusted for age, sex, abdominal obesity, smoking status, and origin. When including use of thymidine analogues and/or didanosine in the model, we also adjusted for time with HIV. RESULTS: Median (IQR) age of PLWH was 52 years (46-61), and 87% (n = 557) were male. Median (IQR) HOMA-IR was 1.86 (1.23-3.14) mmol/L × mU/L. Risk factors significantly associated with high HOMA-IR included older age, BMI ≥ 25, abdominal obesity, waist circumference, use of thymidine analogues and/or didanosine, time with HIV, and CD4+ nadir < 200 cells/µL. CONCLUSIONS: Insulin resistance in PLWH is associated with both use of thymidine analogues and/or didanosine and prior immunodeficiency suggesting that increased attention on blood glucose in these patients could be beneficial.

Monocyte count and soluble markers of monocyte activation in people living with HIV and uninfected controls.

BACKGROUND: Monocytes play an important role in inflammation, and monocytosis and monocyte activation are features of chronic inflammation. We aimed to investigate if HIV status was associated with monocyte count and monocyte activation and to assess the relationship between monocyte count and monocyte activation markers and HIV-related factors. METHODS: Persons living with HIV (PLWH) with measured monocyte count and sCD14 and sCD163 were included from the Copenhagen Comorbidity in HIV infection (COCOMO) study and matched 1:5 on sex and age with uninfected controls. In addition, 74 uninfected individuals from COCOMO with measured sCD14 and sCD163 were included. Identical protocols and equipment were used to determine monocyte counts and monocyte activation in PLWH and uninfected controls. Linear regression adjusted for age, sex, smoking and waist-to-hip-ratio was used to analyze the association between possible risk factors and monocyte outcomes. RESULTS: We included 871 PLWH and 4355 uninfected controls. PLWH had - 0.021 [- 0.031 - 0.011] × 109/L) lower monocyte count than uninfected controls, and in adjusted analyses HIV status was independently associated with - 0.035 [- 0.045, - 0.025] × 109/L lower monocyte count. In contrast, PLWH had higher sCD163 and sCD14 concentrations than uninfected controls. After adjustment, HIV-status was associated with higher sCD14 and sCD163 concentrations (588 [325, 851] ng/ml, and 194 [57, 330] ng/ml, respectively). CONCLUSION: PLWH had lower monocyte counts than controls, but the absolute difference was small, and any clinical impact is likely limited. In contrast, concentrations of monocyte activation markers, previously implicated as drivers of non-AIDS comorbidity, were higher in PLWH than in controls.

The central role of the glutamate metabolism in long-term antiretroviral treated HIV-infected individuals with metabolic syndrome.

Metabolic syndrome (MetS) is a significant factor for cardiometabolic comorbidities in people living with HIV (PLWH) and a barrier to healthy aging. The long-term consequences of HIV-infection and combination antiretroviral therapy (cART) in metabolic reprogramming are unknown. In this study, we investigated metabolic alterations in well-treated PLWH with MetS to identify potential mechanisms behind the MetS phenotype using advanced statistical and machine learning algorithms. We included 200 PLWH from the Copenhagen Comorbidity in HIV-infection (COCOMO) study. PLWH were grouped into PLWH with MetS (n = 100) defined according to the International Diabetes Federation (IDF) consensus worldwide definition of the MetS or without MetS (n = 100). The untargeted plasma metabolomics was performed using ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS/MS) and immune-phenotyping of Glut1 (glucose transporter), xCT (glutamate/cysteine transporter) and MCT1 (pyruvate/lactate transporter) by flow cytometry. We applied several conventional approaches, machine learning algorithms, and linear classification models to identify the biologically relevant metabolites associated with MetS in PLWH. Of the 877 identified biochemicals, 9% (76/877) differed significantly between PLWH with and without MetS (false discovery rate < 0.05). The majority belonged to amino acid metabolism (43%). A consensus identification by combining supervised and unsupervised methods indicated 11 biomarkers of MetS phenotype in PLWH. A weighted co-expression network identified seven communities of positively intercorrelated metabolites. A single community contained six of the potential biomarkers mainly related to glutamate metabolism. Transporter expression identified altered xCT and MCT in both lymphocytic and monocytic cells. Combining metabolomics and immune-phenotyping indicated altered glutamate metabolism associated with MetS in PLWH, which has clinical significance.

An Observational Prospective Cohort Study of Incidence and Outcome of Streptococcus pneumoniae and Hemophilus influenzae Infections in Adult Solid Organ Transplant Recipients.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) and Hemophilus influenzae (H. influenzae) are among the main vaccine-preventable bacterial infections in immunocompromised individuals including solid organ transplant (SOT) recipients. There is a lack of information about incidence and outcomes of these infections in SOT recipients. METHODS: We determined the incidence of S. pneumoniae and H. influenzae, the related hospitalization, and 30- and 180-days mortality in a large cohort of 1182 adult SOT recipients. We calculated 95% confidence intervals (CI) of incidence rate (IR) using Byar's approximation to the Poisson distribution. RESULTS: The overall IR of S. pneumoniae and H. influenzae were 1086 (95% CI, 796-1448) and 1293 (95% CI, 974-1687) per 100,000 person-years of follow-up (PYFU), respectively. The IR of invasive infections were 76 (95% CI, 21-202) and 25 (95% CI, 2.3-118) per 100,000 PYFU, respectively. Hospital admission was required in >50%, 30-days mortality was 0, and 180-days mortality was 8.8% and 4.5% after S. pneumoniae and H. influenzae infections, respectively. CONCLUSIONS: The IR of invasive S. pneumoniae and H. influenzae infections in SOT recipients were much higher than reports from the general population in Denmark. Furthermore, a large proportion of infected SOT recipients were hospitalized. These findings highlight the need for further studies to assess uptake and immunogenicity of vaccines against S. pneumoniae and H. influenzae in SOT recipients.

HIV infection is associated with thoracic and abdominal aortic aneurysms: a prospective matched cohort study.

AIMS: Little is known about the prevalence of aortic aneurysms among people living with HIV (PLWH). We investigated whether HIV status is independently associated with having aortic aneurysms. Furthermore, we determined risk factors associated with aortic aneurysms in PLWH. METHODS AND RESULTS: PLWH aged ≥40 years (n = 594) were recruited from the Copenhagen Comorbidity in HIV Infection study and matched for age and sex with uninfected controls (n = 1188) from the Copenhagen General Population Study. Aortic dimensions were assessed using contrast enhanced computed tomography. Aortic aneurysms were defined according to the European Society of Cardiology guidelines, i.e. an aortic dilation of ≥50% or an infrarenal aortic diameter of ≥30 mm. Among PLWH and uninfected controls, the median (interquartile range) age was 52 (47-60) and 52 (48-61) and 88% and 90% were male, respectively. We found 46 aneurysms in 42 (7.1%) PLWH and 31 aneurysms in 29 (2.4%) uninfected controls (P < 0.001). PLWH had a significantly higher prevalence of ascending aortic aneurysms and infrarenal aortic aneurysms. In an adjusted model, HIV was independently associated with aortic aneurysms (adjusted odds ratio; 4.51 [95% confidence interval 2.56-8.08], P < 0.001). Within PLWH, obesity and hepatitis B co-infection were associated with aortic aneurysms. CONCLUSION: PLWH had four-fold higher odds of aortic aneurysms compared to uninfected controls, and HIV status was independently associated with aortic aneurysms. Among PLWH, age, obesity and hepatitis B co-infection were associated with higher odds of aortic aneurysms. Our findings suggest that increased attention to aortic aneurysms in PLWH may be beneficial.

The Danish comorbidity in liver transplant recipients study (DACOLT): a non-interventional prospective observational cohort study.

BACKGROUND: Liver transplantation is the only curative treatment for patients with end-stage liver disease. Short-term survival has improved due to improved surgical techniques and greater efficacy of immunosuppressive drugs. However, long-term survival has not improved to the same extent as the short-term survival, and the 10-year survival after liver transplantation is 60%. In addition to liver- and transplant-related causes, comorbidities such as cardiovascular, pulmonary, renal, and metabolic diseases have emerged as leading causes of morbidity and mortality in liver transplant recipients. The objective of this study is to assess the burden of comorbidities and identify both liver- and transplant-related risk factors as well as traditional risk factors that contribute to the pathogenesis of comorbidity in liver transplant recipients. METHODS/DESIGN: The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study is an observational, longitudinal study. We aim to include all adult liver transplant recipients in Denmark (n = approx. 600). Participants will be matched by sex and age to controls from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). Physical and biological measures including blood pressure, ankle-brachial index, spirometry, exhaled nitric oxide, electrocardiogram, transthoracic echocardiography, computed tomography (CT) angiography of the heart, unenhanced CT of chest and abdomen and blood samples will be collected using uniform protocols in participants in DACOLT, CGPS, and CCHS. Blood samples will be collected and stored in a research biobank. Follow-up examinations at regular intervals up to 10 years of follow-up are planned. DISCUSSION: There is no international consensus standard for optimal clinical care or monitoring of liver transplant recipients. This study will determine prevalence, incidence and risk factors for comorbidity in liver transplant recipients and may be used to provide evidence for guidelines on management, treatment and screening and thereby contribute to improvement of the long-term survival. Trial registration ClinicalTrials.gov: NCT04777032; date of registration: March 02, 2021.

Alterations in the Kynurenine Pathway of Tryptophan Metabolism Are Associated With Depression in People Living With HIV.

BACKGROUND: People living with HIV have increased risk of depression compared with uninfected controls. The determinants of this association are unclear. Alterations in kynurenine (Kyn) metabolism have been associated with depression in uninfected individuals, but whether they are involved in the development of depression in the context of HIV infection is unknown. METHODS: A total of 909 people living with HIV were recruited from the Copenhagen Comorbidity in HIV infection study. Information regarding demographics and depression was obtained from questionnaires. HIV-related variables and use of antidepressant medication were collected from patient records. Logistic regression models before and after adjustment for confounders were used to test our hypotheses. RESULTS: The prevalence of depression was 11%. Among traditional risk factors, only being unmarried was associated with greater odds of depression. Higher levels of quinolinic-to-kynurenic acid ratio (P = 0.018) and higher concentrations of quinolinic acid (P = 0.048) were found in individuals with depression than in those without. After adjusting for confounders, high levels of quinolinic-to-kynurenic acid ratio and high concentrations of quinolinic acid remained associated with depression [adjusted odds ratio 1.61 (1.01; 2.59) and adjusted odds ratio 1.68 (1.02; 2.77), respectively]. CONCLUSIONS: The results from this study suggest that alterations in the kynurenine pathway of tryptophan metabolism are associated with the presence of depression in the context of HIV infection.

Hepatic Steatosis Associated With Exposure to Elvitegravir and Raltegravir.

Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with cumulative exposure to stavudine, elvitegravir, and raltegravir. Prospective trials are required to establish a causal association. Clinical Trials Registration. NCT02382822.

Integrative Lipidomics and Metabolomics for System-Level Understanding of the Metabolic Syndrome in Long-Term Treated HIV-Infected Individuals.

People living with HIV (PLWH) require life-long anti-retroviral treatment and often present with comorbidities such as metabolic syndrome (MetS). Systematic lipidomic characterization and its association with the metabolism are currently missing. We included 100 PLWH with MetS and 100 without MetS from the Copenhagen Comorbidity in HIV Infection (COCOMO) cohort to examine whether and how lipidome profiles are associated with MetS in PLWH. We combined several standard biostatistical, machine learning, and network analysis techniques to investigate the lipidome systematically and comprehensively and its association with clinical parameters. Additionally, we generated weighted lipid-metabolite networks to understand the relationship between lipidomic profiles with those metabolites associated with MetS in PLWH. The lipidomic dataset consisted of 917 lipid species including 602 glycerolipids, 228 glycerophospholipids, 61 sphingolipids, and 26 steroids. With a consensus approach using four different statistical and machine learning methods, we observed 13 differentially abundant lipids between PLWH without MetS and PLWH with MetS, which mainly belongs to diacylglyceride (DAG, n = 2) and triacylglyceride (TAG, n = 11). The comprehensive network integration of the lipidomics and metabolomics data suggested interactions between specific glycerolipids' structural composition patterns and key metabolites involved in glutamate metabolism. Further integration of the clinical data with metabolomics and lipidomics resulted in the association of visceral adipose tissue (VAT) and exposure to earlier generations of antiretroviral therapy (ART). Our integrative omics data indicated disruption of glutamate and fatty acid metabolism, suggesting their involvement in the pathogenesis of PLWH with MetS. Alterations in the lipid homeostasis and glutaminolysis need clinical interventions to prevent accelerated aging in PLWH with MetS.