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.

Nucleoside/nucleotide reverse transcriptase inhibitor-associated weight gain in people living with HIV: data from the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

Weight gain effects of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in people with HIV (PWH) have been sparsely studied.Participants were enrolled in the Copenhagen Comorbidity in HIV Infection (COCOMO) study. PWH receiving a backbone of emtricitabine, or lamivudine combined with abacavir, tenofovir disoproxil, or tenofovir alafenamide were analysed. Weight gain according to ART backbone and to the third drug was analysed using a multiple linear regression model. Non-ART risk factors were also determined using multiple linear regression.A total of 591 participants were included in the analysis. The majority were middle-aged, virally suppressed males with a mean BMI just above the normal range. Both tenofovir disoproxil/emtricitabine or lamivudine and abacavir /emtricitabine or lamivudine, but not tenofovir alafenamide /emtricitabine or lamivudine were associated with weight gain over two years (0.6 kg, p = 0.025; 1.0 kg, p = 0.005). The third drugs associated with weight increase were non-nucleoside reverse transcriptase inhibitors (NNRTI) (p = 0.035), dolutegravir (p = 0.008) and atazanavir (p = 0.040). Non-ART risk factors for gaining weight were low or normal BMI, age <40 years, underweight, inactivity or highly active at baseline.Tenofovir disoproxil and abacavir-based ART regimens were associated with a small weight gain. Third drug NNRTI, dolutegravir and atazanavir were associated with an increase in weight.

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.

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.

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.

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.

Abdominal Adipose Tissue Is Associated With Alterations in Tryptophan-Kynurenine Metabolism and Markers of Systemic Inflammation in People With Human Immunodeficiency Virus.

BACKGROUND: While both adipose tissue accumulation and tryptophan metabolism alterations are features of human immunodeficiency virus (HIV) infection, their interplay is unclear. We investigated associations between abdominal adipose tissue, alterations in kynurenine pathway of tryptophan metabolism, and systemic inflammation in people with HIV (PWH). METHODS: Eight hundred sixty-four PWH and 75 uninfected controls were included. Plasma samples were collected and analyzed for kynurenine metabolites, neopterin, high-sensitivity C-reactive protein (hs-CRP), and lipids. Regression models were used to test associations in PWH. RESULTS: PWH had higher kynurenine-to-tryptophan ratio than uninfected individuals (P < .001). In PWH, increase in waist-to-hip ratio was associated with higher kynurenine-to-tryptophan ratio (P = .009) and quinolinic-to-kynurenic acid ratio (P = .006) and lower kynurenic acid concentration (P = .019). Quinolinic-to-kynurenic acid ratio was associated with higher hs-CRP (P < .001) and neopterin concentrations (P < .001), while kynurenic acid was associated with lower hs-CRP (P = .025) and neopterin concentrations (P = .034). CONCLUSIONS: In PWH, increase in abdominal adipose tissue was associated with increased quinolinic-to-kynurenic acid ratio, suggesting activation of proinflammatory pathway of kynurenine metabolism, with reduction of anti-inflammatory molecules and increase in systemic inflammation. Our results suggest dysregulation of kynurenine metabolism associated with abdominal fat accumulation to be a potential source of inflammation in HIV infection.

Pericardial Adipose Tissue Volume Is Independently Associated With Human Immunodeficiency Virus Status and Prior Use of Stavudine, Didanosine, or Indinavir.

BACKGROUND: Increased pericardial adipose tissue is associated with higher risk of cardiovascular disease. We aimed to determine whether human immunodeficiency virus (HIV) status was independently associated with larger pericardial adipose tissue volume and to explore possible HIV-specific risk factors. METHODS: Persons with HIV (PWH) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study and matched 1:1 on age and sex to uninfected controls. Pericardial adipose tissue volume was measured using cardiac computed tomography. RESULTS: A total of 587 PWH and 587 controls were included. Median age was 52 years, and 88% were male. Human immunodeficiency virus status was independently associated with 17 mL (95% confidence interval [CI], 10-23; P < .001) larger pericardial adipose tissue volume. Larger pericardial adipose tissue volume was associated with low CD4+ nadir and prior use of stavudine, didanosine, and indinavir. Among PWH without thymidine analogue or didanosine exposure, time since initiating combination antiretroviral treatment (per 5-year use) was associated with l6 mL (95% CI, -6 to -25; P = .002) lower pericardial adipose tissue volume. CONCLUSIONS: Human immunodeficiency virus status was independently associated with larger pericardial adipose tissue volume. Severe immunodeficiency, stavudine, didanosine, and indinavir were associated with larger pericardial adipose tissue volume. Persons with HIV with prior exposure to these drugs may constitute a distinct cardiovascular risk population.

Fraction of Exhaled Nitric Oxide Levels Are Elevated in People Living With Human Immunodeficiency Virus Compared to Uninfected Controls, Suggesting Increased Eosinophilic Airway Inflammation.

BACKGROUND: Increased risk of asthma and chronic obstructive pulmonary disease has been reported in people living with human immunodeficiency virus (PLWH). Fraction of exhaled nitric oxide (FeNO) is a marker of eosinophilic airway inflammation. We assessed FeNO levels in PLWH and matched uninfected controls and investigated whether human immunodeficiency virus (HIV) status is independently associated with elevated FeNO. METHODS: FeNO was quantified by NIOX Vero and pulmonary function was assessed by spirometry in 432 PLWH from the Copenhagen Comorbidity in HIV Infection Study and in 1618 age- and sex-matched uninfected controls from the Copenhagen General Population Study. Elevated FeNO was defined as ≥25 parts per billion. Associations between FeNO and HIV status were adjusted for known potential confounders. RESULTS: Mean age of PLWH was 50.7 (standard deviation [SD], 11.1) years and 97.4% received combination antiretroviral therapy. PLWH had higher FeNO than uninfected controls (median, 17.0 [interquartile range {IQR}, 11.0-26.0] vs 13.0 [IQR, 9.0-19.0]; P < .001). Also, PLWH had a higher prevalence of elevated FeNO than uninfected controls (27.5% vs 12.3%; P < .001). This association remained after adjusting for age, sex, height, smoking status, use of airway medication, blood eosinophils, and immunoglobulin E (adjusted OR [aOR], 3.56 [95% CI, 2.51-5.04]; P < .001). Elevated FeNO was associated with self-reported asthma (aOR, 2.65 [95% CI, 1.66-4.24]; P < .001) but not with airflow limitation (aOR, 1.07 [95% CI, .71-1.62]; P = .745). CONCLUSIONS: HIV status was independently associated with elevated FeNO, suggesting increased eosinophilic airway inflammation. The potential impact on chronic lung disease pathogenesis needs further investigation.

Impact of Human Immunodeficiency Virus-Related Gut Microbiota Alterations on Metabolic Comorbid Conditions.

BACKGROUND: We aimed to identify a human immunodeficiency virus (HIV)-related microbiota signature, independent of sexual preferences and demographic confounders, in order to assess a possible impact of the microbiome on metabolic comorbid conditions. METHODS: Bacterial 16S ribosomal RNA analyses were performed on stool samples from 405 HIV-infected and 111 uninfected participants of the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Individuals were stratified according to sexual behavior (men who have sex with men [MSM] vs non-MSM). RESULTS: After excluding MSM-associated microbiota traits and adjusting for confounders, we identified an HIV-related microbiota signature, consisting of lower biodiversity, increased relative abundance of the bacterial clades Gammaproteobacteria and Desulfovibrionaceae and decrease in several Clostridia. This microbiota profile was associated with a 2-fold excess risk of metabolic syndrome, driven by increase in Desulfovibrionaceae and decrease in Clostridia (Butyrivibrio, Coprococcus 2, Lachnospiraceae UCG-001 and CAG-56). This association was accentuated (5-fold excess risk) in individuals with previous severe immunodeficiency, which also modified the association between HIV-related microbiota signature and visceral adipose tissue (VAT) area (P for interaction = .01). Accordingly, HIV-related microbiota was associated with 30-cm2 larger VAT in individuals with history of severe immunodeficiency, but not in those without. CONCLUSION: The HIV-related microbiota was associated with increased risk of metabolic syndrome and VAT accumulation, particularly in individuals with previous severe immunodeficiency, driven by increased Desulfovibrionaceae and lower abundance of several Clostridia. Our findings suggest a potential interplay between HIV-related microbiota, immune dysfunction and metabolic comorbid conditions. Interventions targeting the gut microbiome may be warranted to reduce cardiovascular risk, particularly in individuals with previous immunodeficiency.

No evidence of a synergistic effect of HIV infection and diabetes mellitus type 2 on fat distribution, plasma adiponectin or inflammatory markers.

BACKGROUND: Altered fat distribution and chronic inflammation are found in both persons living with HIV (PLWH) and persons with diabetes mellitus type 2 (DM2) and are known risk factors for cardiovascular diseases (CVD). We aimed to investigate if a synergistic effect of HIV infection and DM2 was found on fat distribution and inflammation. METHODS: A cross-sectional study was performed including PLWH with HIV RNA < 200 copies/mL (18 with DM2 (HIV + DM2+), 18 without DM2 (HIV + DM2-)) and controls (19 with DM2 (controls with DM2) and 25 without DM2 (healthy controls). We measured fat distribution using dual-energy X-ray absorptiometry scan. Plasma concentrations of adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF- α) and soluble CD14 (sCD14) was measured using snap-frozen plasma. RESULTS: HIV + DM2+ and HIV + DM2- had comparable trunk/limb fat ratio. In contrast, HIV + DM2+ had a higher trunk/ limb fat ratio than controls with DM2 and healthy controls (p = 0.013 and p < 0.001, respectively). However, HIV + DM2+ and controls with DM2 had comparable amount of trunk fat mass (kg) (p = 0.254). A lower concentration of plasma adiponectin and higher concentration of IL-6 was found in HIV + DM2+ than in HIV + DM2-(p = 0.037 and p = 0.039) and in healthy controls (p = 0.001 and p = 0.012). In contrast, plasma adiponectin and IL-6 concentrations were comparable in HIV + DM2+ and controls with DM2 (p = 0.345 and p = 0.825). Concentration of sCD14 was comparable in HIV + DM2+ and HIV + DM2-(p = 0.850), but elevated in HIV + DM2+ compared to controls with DM2 (p < 0.001) and healthy controls (p = 0.007). No statistical interactions were found between HIV infection and DM2 for any of the depending variables. CONCLUSION: A synergistic effect of HIV and DM2 was not found for any of the outcomes. However, HIV + DM2+ had features related to both HIV infection and DM2 with a high trunk/limb ratio, high trunk fat mass, low concentration of plasma adiponectin and elevated concentrations of IL-6 and sCD14. This could contribute to elevated risk of CVD.

Long-lasting alterations in adipose tissue density and adiponectin production in people living with HIV after thymidine analogues exposure.

BACKGROUND: Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CT-scan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation. METHODS: Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome). RESULTS: prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [- 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]). CONCLUSIONS: We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH.

Higher Risk of Abdominal Obesity, Elevated Low-Density Lipoprotein Cholesterol, and Hypertriglyceridemia, but not of Hypertension, in People Living With Human Immunodeficiency Virus (HIV): Results From the Copenhagen Comorbidity in HIV Infection Study.

Background: People living with human immunodeficiency virus (PLWH) are characterized by excess risk of cardiovascular diseases (CVD) and CVD risk factors compared to uninfected individuals. We investigated the association between HIV infection and abdominal obesity, elevated low-density lipoprotein cholesterol (LDL-C), hypertriglyceridemia, and hypertension in a large cohort of predominantly well-treated PLWH and matched controls. Methods: 1099 PLWH from the Copenhagen Co-morbidity in HIV Infection Study and 12 161 age- and sex-matched uninfected controls from the Copenhagen General Population Study were included and underwent blood pressure, waist, hip, weight, and height measurements and nonfasting blood samples. We assessed whether HIV was independently associated with abdominal obesity, elevated LDL-C, hypertriglyceridemia, and hypertension using logistic regression models adjusted for known risk factors. Results: HIV infection was associated with higher risk of abdominal obesity (adjusted odds ratio [aOR], 1.92 [1.60-2.30]) for a given body mass index, elevated LDL-C (aOR, 1.32 [1.09-1.59]), hypertriglyceridemia (aOR, 1.76 [1.49-2.08]), and lower risk of hypertension (aOR, 0.63 [0.54-0.74]). The excess odds of abdominal obesity in PLWH was stronger with older age (p interaction, 0.001). Abdominal obesity was associated with elevated LDL-C (aOR, 1.44 [1.23-1.69]), hypertension (aOR, 1.32 [1.16-1.49]), and hypertriglyceridemia (aOR, 2.12 [1.86-2.41]). Conclusions: Abdominal obesity was associated with proaterogenic metabolic factors including elevated LDL-C, hypertension, and hypertriglyceridemia and remains a distinct HIV-related phenotype, particularly among older PLWH. Effective interventions to reduce the apparent detrimental impact on cardiovascular risk from this phenotype are needed.

Electronic applications for the CFQ-R scoring.

Patient reported outcomes (PROs) have become widely accepted outcome measures in cystic fibrosis (CF) and other respiratory diseases. The Cystic Fibrosis-Questionnaire-Revised (CFQ-R) is the best validated and most widely used PRO for CF. Data collection can be time-intensive, and electronic platforms would greatly facilitate the feasibility, utility and accuracy of administration of the CFQ-R. Given that the CFQ-R is utilized in virtually all clinical trials worldwide and is increasingly integrated into clinical practice, we developed a software application that will help users to administer, score and save CFQ-R data for all versions. All codes are open access, which will enable other PRO users to design similar applications for other respiratory diseases, such as primary ciliary dyskinesia and non-CF bronchiectasis.

Tryptophan catabolism and immune activation in primary and chronic HIV infection.

BACKGROUND: Kynurenine/Tryptophan ratio (KTR) is increased in HIV infection, and linked to immune activation. We hypothesized that early cART initiation results in lower KTR compared to late initiation. Furthermore, we hypothesized that KTR prior to cART is a predictor of the magnitude of subsequent reduction in immune activation. METHODS: Prospective study including 57 HIV-infected individuals (primary HIV infection (N = 14), early presenters (>350 CD4+ T cells/µL, N = 24), late presenters (<200 CD4+ T cells/µL, N = 19)). Kynurenine and tryptophan were analysed by liquid chromatography-tandem mass spectrometry. Total CD4+ and CD8+ T cells were determined and proportion of activated CD38 + HLA-DR+ Tcells was measured using flow cytometry at baseline and after 6 and 12 months of cART. RESULTS: At baseline, primary HIV infection had higher KTR than early presenters. However, similar KTR in primary HIV infection and early presenters was found after cART initiation, while late presenters had higher KTR at all time points. In primary HIV infection and early presenters, KTR was positively associated with proportion of activated cells at baseline. Furthermore, in early presenters the KTR at baseline was associated with proportion of activated cells after 6 and 12 months. Interestingly, in primary HIV infection the KTR at baseline was positively associated with reduction in proportion of CD8 + CD38 + HLA-DR T cells after 6 and 12 months. CONCLUSIONS: Lower kynurenine/tryptophan ratio during follow-up was found after early initiation of cART. KTR in primary HIV infection and early presenters was positively associated with immune activation. Importantly, KTR in primary HIV infection predicted the magnitude of subsequent reduction in immune activation. Thus, a beneficial effect of early cART on KTR was suggested.

Immune recovery in acute and chronic HIV infection and the impact of thymic stromal lymphopoietin.

BACKGROUND: Symptomatic primary HIV infection is associated with an adverse prognosis, and immediate initiation of combination antiretroviral therapy (cART) is recommended. However, little is known about immunological predictors of immune recovery. Thymic Stromal Lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cells homeostatic polyclonal proliferation and regulates Th17/regulatory T-cell balance, immunological functions known to be affected during primary HIV infection. The aim of this study was to describe immune recovery in primary and chronic HIV infection and possible impact of TSLP. METHODS: Prospective study including 100 HIV-infected individuals (primary HIV infection (N = 14), early presenters (>350 CD4+ T cells/µL, N = 42), late presenters without advanced disease (200-350 CD4+ T cells/µL, N = 24) and with advanced disease (<200 CD4+ T cells/µL, N = 20) and). Immune recovery was defined as increase in CD4+ T cells count from baseline to a given time of follow-up. Plasma TSLP was determined using ELISA and CD4+ T cell subpopulations (recent thymic emigrants, naïve and memory cells) were measured using flow cytometry at baseline and after 6, 12 and 24 months of cART. RESULTS: Immune recovery was comparable in all groups, and no differences in immune homeostasis were found between primary HIV infection and early presenters, whereas differences in absolute counts and proportions of CD4+ T cell subpopulations were found between primary HIV infection and late presenters. TSLP was elevated in primary HIV infection at baseline and after 24 months of cART. Interestingly, TSLP was negatively associated with proportion of recent thymic emigrants (correlation coefficient -0.60, p = 0.030). TSLP was not associated with immune recovery in primary HIV infection. CONCLUSIONS: Immune recovery was comparable in primary and chronic HIV infection whereas differences in absolute counts and proportions of CD4+ T cell subpopulations were found between primary HIV infection and late presenters supporting early initiation of cART. Higher plasma TSLP was found in primary HIV infection, and TSLP was associated with lower thymic output, but not with immune recovery. These findings indicate a possible role of TSLP in immune homeostasis in HIV infection but do not support TSLP to affect immune recovery in primary HIV infection.

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.

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.

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.