Altered Intestinal Permeability and Fungal Translocation in Ugandan Children With Human Immunodeficiency Virus.

BACKGROUND: Children with perinatally acquired human immunodeficiency virus (HIV; PHIVs) face a lifelong cumulative exposure to HIV and antiretroviral therapy (ART). The relationship between gut integrity, microbial translocation, and inflammation in PHIV is poorly understood. METHODS: This is a cross-sectional study in 57 PHIVs, 59 HIV-exposed but uninfected children, and 56 HIV-unexposed and -uninfected children aged 2-10 years old in Uganda. PHIVs were on stable ART with HIV-1 RNA <400 copies/mL. We measured markers of systemic inflammation, monocyte activation, and gut integrity. Kruskal-Wallis tests were used to compare markers by group and the Spearman correlation was used to assess correlations between biomarkers. RESULTS: The mean age of all participants was 7 years and 55% were girls. Among PHIVs, the mean CD4 % was 34%, 93% had a viral load ≤20 copies/mL, and 79% were on a nonnucleoside reverse transcriptase inhibitor regimen. Soluble cluster of differentiation 14 (sCD14), beta-D-glucan (BDG), and zonulin were higher in the PHIV group (P ≤ .01). Intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide binding protein (LBP) did not differ between groups (P > .05). Among PHIVs who were breastfed, levels of sCD163 and interleukin 6 (IL6) were higher than levels in PHIV who were not breastfed (P < .05). Additionally, in PHIVs with a history of breastfeeding, sCD14, BDG, LBP, zonulin, and I-FABP correlated with several markers of systemic inflammation, including high-sensitivity C-reactive protein, IL6, d-dimer, and systemic tumor necrosis factor receptors I and II (P ≤ .05). CONCLUSIONS: Despite viral suppression, PHIVs have evidence of altered gut permeability and fungal translocation. Intestinal damage and the resultant bacterial and fungal translocations in PHIVs may play a role in the persistent inflammation that leads to many end-organ diseases in adults.Despite viral suppression, children with perinatally acquired human immunodeficiency virus (HIV) in Uganda have evidence of alterations in intestinal permeability and fungal translocation, compared to HIV-exposed but uninfected and HIV-unexposed children, which may play a role in HIV-associated chronic inflammation.

Lower Pretreatment Gut Integrity Is Independently Associated With Fat Gain on Antiretroviral Therapy.

BACKGROUND: Fat accumulation and insulin resistance remain a threat to the success of antiretroviral therapy (ART). The role of gut dysfunction in metabolic complications associated with ART initiation is unclear. METHODS: Human immunodeficiency virus (HIV)-infected ART-naive participants were randomized to tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (RAL). Changes in the gut integrity markers zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid and ileal bile acid binding proteins (I-FABP and I-BABP) were assessed over 96 weeks. Wilcoxon rank-sum tests were used to compare changes between groups and linear regression models to quantify associations between gut markers, insulin resistance, body mass index (BMI), and visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT). RESULTS: : 90% were male and 48% were White non-Hispanic. The median age was 36 years, HIV-1 ribonucleic acid was 4.56 log10 copies/mL, and CD4 count was 338 cells/µL. An overall 1.7-fold increase in I-FABP was observed throughout 96 weeks, with no difference between arms. Zonulin levels increased with RAL compared to protease inhibitor-based regimens (week 96, P = .02); minimal changes in I-BABP or LBP levels were observed. Higher baseline I-FABP levels were associated with increases in VAT, TAT, and BMI (16%, 9%, and 2.5%, respectively; P < .04) over 96 weeks. CONCLUSIONS: While ART induces changes in the markers of gut barrier dysfunction, the extent to which they improve or worsen the gut barrier function remains unclear. Nevertheless, markers of gut barrier dysfunction in ART-naive individuals predict increases in total and visceral abdominal fat with treatment initiation.

Statin Therapy Does Not Reduce Liver Fat Scores in Patients Receiving Antiretroviral Therapy for HIV Infection.

BACKGROUND & AIMS: Therapies are needed to limit progression of fatty liver diseases in patients with human immunodeficiency virus (HIV) infection. We analyzed data from a prospective study of the effects of rosuvastatin (a statin) on hepatic steatosis in HIV-positive adults. METHODS: We performed a secondary analysis of data from a double-blind trial of adult patients with HIV infection (78% male; 68% African American; mean age, 46 y; body mass index, 29 kg/m2; HIV1 RNA < 1000 copies/mL; low-density lipoprotein cholesterol, <130 mg/dL) receiving antiretroviral therapy. The patients were randomly assigned to groups given 10 mg daily rosuvastatin (n = 72) or placebo (n = 75). Demographic and clinical data were collected, and blood samples were analyzed. Changes in liver fat score (LFS, a composite score calculated from metabolic and liver function parameters) and markers of systemic inflammation and immune activation were assessed through 96 weeks of drug or placebo administration. We performed multivariable linear and logistic regressions to study relationships among variables. RESULTS: The placebo and rosuvastatin groups each had significant increases in LFS, compared with baseline, at 96 weeks (P = .01 and P < .01; P = .49 for difference increase between groups). Baseline LFS was independently associated with blood level of C-X-C motif chemokine ligand 10 (P = .04) and the soluble CD163 molecule (P = .01). After we adjusted for baseline characteristics, an increase in LFS over time was significantly associated with the blood level of C-X-C motif chemokine ligand 10 (P = .04), insulin resistance (P < .01), and viral load (P = .02), but not rosuvastatin use (P = .06). CONCLUSIONS: In a secondary analysis of data from a trial of patients receiving treatment for HIV infection, hepatic steatosis increased over time, regardless of statin treatment, and was independently associated with markers of immune activation. Patients who received rosuvastatin appeared to have a nonsignificant increase in hepatic steatosis over 96 weeks. Despite their ability to reduce the risk of cardiovascular disease, statins do not appear to reduce hepatic steatosis. Clinicaltrials.gov no: NCT01218802.

New-onset sarcoidosis in a patient with long COVID.

Long COVID, often following SARS-CoV-2 infection, may stem from sustained inflammation, overlapping with autoimmune diseases like sarcoidosis. Though specific treatments lack, this link could shape future diagnostic and therapeutic methods.

Comprehensive assessment of neurocognitive function, inflammation markers, and adiposity in treated HIV and control.

To compare the neurocognitive scores between persons living with human immunodeficiency virus (PLWH) and persons without human immunodeficiency virus (HIV) and assess the relationship between neurocognition, HIV status and variables, inflammation, and body composition measures. Cross-sectional study involving 225 participants (126 PLWH on antiretroviral therapy [ART] and 99 persons without HIV). For the first time in HIV, we used Cognivue®, an food and drug administration (FDA)-approved computer-based test to assess cognitive function. The test was calibrated to individuals' unique cognitive ability and measured 6 cognitive domains and 2 performance parameters. Markers of inflammation, immune activation, insulin resistance, and body fat composition (using dual-energy X-ray absorptiometry scan) were collected. Classical t tests, chi-square tests, and spearman correlations were used to compare and explore relationships between variables. Inverse probability weighting adjusted average treatment effect models were performed to evaluate the differences between PLWH and persons without HIV, adjusting for age, race, sex, and heroin use. Overall, 64% were male, 46% were Black, with a mean age of 43 years. Among PLWH, 83% had an undetectable HIV-1 RNA level (≤20 copies/mL). Compared persons without HIV, PLWH performed poorer across 4 domains: visuospatial (P = .035), executive function (P = .029), naming/language (P = .027), and abstraction (P = .018). In addition, PLWH had a significantly longer processing speed time compared to controls (1686.0 ms vs 1606.0 ms [P = .007]). In PLWH, lower cognitive testing domain scores were associated with higher inflammatory markers (high sensitivity C-reactive protein [hsCRP]) and with higher total fat and visceral adipose tissue (P < .05). Neurocognitive impairment (NCI) in HIV is associated with inflammation and total and central adiposity.

Advanced Glycation End Products Associated With Cardiometabolic Biomarkers in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: Despite advances in antiretroviral therapy (ART), people living with human immunodeficiency virus (HIV) continue to be at increased risk of cardiometabolic complications compared to HIV-uninfected individuals. Advanced glycation end products (AGEs) are implicated in the development and progression of cardiometabolic complications in the general population. Their role in HIV remains unclear. METHODS: ACTG A5260s is a prospective open-label randomized trial in which ART-naive people living with HIV were randomized to tenofovir disoproxil fumarate /emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir over 96 weeks. Changes in circulating AGEs with ART initiation were assessed, and linear regression was used to examine the associations between serum AGEs with carotid intima-media thickness (cIMT), visceral and subcutaneous adipose tissue, total fat, lean mass, body mass index, insulin resistance, leptin, and adiponectin. RESULTS: Overall, 214 participants were included. Ninety percent were male, 48% were White, the median age was 36 years, median HIV-1 RNA was 4.58 log10 copies/mL, and median CD4 count was 338 cells/µL. Most AGEs remained relatively unchanged following 96 weeks of ART initiation, except for methylglyoxal-derived hydroimidazolone 1 (MG-H1), which increased following 96 weeks of ART (mean fold change, 1.15 [95% confidence interval, 1.02-1.30]). No differences were detected across ART regimens. Increases in AGE levels over time were associated with worsening body fat composition measures, insulin resistance, and cIMT, even after adjusting for clinically relevant factors. CONCLUSIONS: AGE levels did not decrease following ART initiation. Most AGE levels remained stable, except for MG-H1, which increased. In people with HIV on ART, the accumulation of circulating AGEs over time appears to be independently associated with worsening cardiometabolic biomarkers.Summary: Antiretroviral therapy (ART) does not appear to be effective in reducing advanced glycation end product (AGE) levels. On the contrary, AGE levels seem to increase following ART initiation. Accumulation of AGEs was found to be independently associated with cardiometabolic complications in treated people living with HIV.

Brief Report: Gut Structural Damage: an Ongoing Process in Chronically Untreated HIV Infection.

OBJECTIVE: To investigate the longitudinal changes of gut structural damage in chronically untreated HIV infection. DESIGN: This is a 96-week prospective, single-site, cohort study of antiretroviral therapy-naive HIV-infected participants. METHODS: Intestinal fatty acid-binding proteins (I-FABP) were used as a surrogate marker of gut structural damage. We assessed changes in I-FABP over 96 weeks and examined the associations between I-FABP, HIV variables, and inflammation. Spearman's correlations and linear mixed-effect models were used to study relationships among variables. RESULTS: A total of 63 HIV-infected, antiretroviral therapy-naive patients were included in this analysis. At baseline, 76% were male; 62% were African American, with median age and body mass index of 40 years and 27 kg/m, respectively. Median HIV-RNA and CD4 T-cell counts were 5520 copies per milliliter and 588 cells per mm, respectively. I-FABP significantly increased from baseline to week 96 (mean change +333.9 pg/mL; P = 0.03), and this increase was associated with viral replication (rho = +0.4; P = 0.03). I-FABP levels were found to be associated with markers of inflammation: sTNFR-II (rho = 0.4, P = 0.02) and sVCAM-1 (rho = 0.04; P < 0.01) at all study time points. Lower baseline CD4 T-cell counts was found to be independently associated with I-FABP progression after adjusting for baseline characteristic variables (P = 0.02). CONCLUSION: Gut structural damage is an ongoing process in the chronic phase of untreated HIV infection and is largely dependent on viral replication. I-FABP was found to be associated with worse immune function, increased inflammation, and viremia in chronically untreated HIV infection, supporting its role as a biomarker of intestinal barrier dysfunction.

HIV-1 elite controllers: an immunovirological review and clinical perspectives.

HIV type 1 (HIV-1) elite controllers (ECs) represent a rare group of individuals with an ability to maintain an undetectable HIV-1 viral load overtime in the absence of previous antiretroviral therapy. The mechanisms associated with this paradigm remain not clearly defined. However, loss of virological control, morbidity and mortality persist in these individuals, such as progress to AIDS-defining conditions together with persistent high rate of immune activation. Further insight into potential therapeutic options is therefore warranted. In this review, we discuss recent data on the type of immune responses understood to be associated with chronic virological control, the potential for disease progression and therapeutic options in ECs.

Advanced Glycation End Products Are Associated With Inflammation and Endothelial Dysfunction in HIV.

OBJECTIVE: To compare levels of advanced glycation end products (AGEs) between HIV-infected patients and uninfected controls and assess the relationship between AGEs, HIV, inflammation, and endothelial dysfunction. DESIGN: Cross-sectional study involving 90 individuals (68 HIV+ and 22 healthy controls matched by age and sex). METHODS: AGE levels were assessed using 3 different modalities: free AGEs were measured in the serum, skin autofluorescence (AF) was determined with a noninvasive reader, and dietary AGEs were estimated using 24-hour dietary recalls. Markers of inflammation, immune activation, and endothelial dysfunction were also measured. Wilcoxon rank-sum and χ tests were used to compare AGEs between groups. Spearman correlations were used to explore relationships between variables while adjusting for different covariates. RESULTS: Overall, 71% were men and 68% were African American, with a median age of 53 years. Among HIV-infected individuals, all participants were on antiretroviral therapy by design, and most participants (78%) had an undetectable HIV-1 RNA level (≤20 copies/mL). Skin AF and serum AGEs were significantly higher in HIV-infected participants compared with uninfected controls (P < 0.01), whereas no differences in dietary AGEs were found between groups (P = 0.2). In the HIV-infected group, but not in controls, skin AF and circulating AGEs were significantly associated with inflammatory and oxidative markers, and with markers of endothelial dysfunction. CONCLUSIONS: These results suggest intrinsic production of AGE in HIV-infected individuals. The relationship between serum/skin AGE and inflammatory, oxidative, and cardiovascular markers highlights the potential implications of AGEs in chronic inflammation and endothelial dysfunction in HIV, suggesting a new potential target for HIV-associated heightened inflammation and cardiovascular risk.

Fungal Translocation Is Associated with Immune Activation and Systemic Inflammation in Treated HIV.

The mechanisms causing HIV-associated immune activation remain incompletely understood. Alteration of intestinal integrity with subsequent translocation of bacterial products appears to play an important role; however, little is known about the impact of fungal translocation. We assessed the effect of fungal translocation and its association with immune activation in people living with HIV (PLWH) compared with uninfected controls. We measured serum levels of ß-D-glucan (BDG) and anti-Saccharomyces cerevisiae antibodies (ASCA) immunoglobulin G (IgG) and immunoglobulin A (IgA) and markers of systemic inflammation and immune activation in virally suppressed PLWH on antiretroviral therapy (ART) and uninfected controls. T-test and Mann-Whitney tests were used to compare markers by HIV status and correlation and regression analyses were used to assess associations of fungal translocation markers with markers of inflammation. One hundred seventy-six participants were included (128 HIV+ and 48 HIV-); 72% male, 65% African American, median age was 50 years, and CD4 was 710 cells/cm3. Levels of BDG tended to be lower in HIV+ when compared with controls (p = .05). No significant difference in levels of ASCA IgG and IgA was seen between groups (p > .75). There was a significant correlation between BDG and several markers of inflammation and immune activation in PLWH, not seen in uninfected controls. In contrast, no correlations were seen between levels of ASCA IgG and IgA with inflammatory markers. PLWH on ART do not have higher levels of BDG or ASCA when compared with uninfected controls, however, the association found between BDG and several inflammation markers suggests a potential role of fungal translocation in the heightened immune activation seen in treated HIV.

Changes in the Fungal Marker ß-D-Glucan After Antiretroviral Therapy and Association With Adiposity.

BACKGROUND: Bacterial translocation in HIV is associated with inflammation and metabolic complications; few data exist on the role of fungal translocation. METHODS: A5260s was a substudy of A5257, a prospective open label randomized trial in which treatment-naïve people with HIV (PWH) were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) over 96 weeks. Baseline was assessed, and changes in ß-D-glucan (BDG) were assessed at weeks 4, 24, and 96. Wilcoxon rank-sum tests were used to compare distribution shifts in the changes from baseline between treatment arms and linear regression models to assess associations between BDG and measures of inflammation, body composition, and insulin resistance. RESULTS: Two hundred thirty-one participants were randomized; 90% were male, the median age was 36 years, HIV-1 RNA was 4.56 log10c/mL, and CD4 cell count was 338 cells/mm3. There was an overall increase in BDG over 96 weeks (1.57 mean fold-change; 95% confidence interval, 1.39 to 1.77) with no differences between arms. Twofold higher BDG levels at week 96 were associated with increases in trunk fat (8%) and total fat (7%) over 96 weeks (P ≤ .035). At week 4, BDG correlated with I-FABP, a marker of enterocyte damage, and zonulin, a marker of intestinal permeability (r = .19-.20; P < .01). CONCLUSIONS: In treatment-naïve participants initiating antiretroviral therapy (ART) with TDF/FTC and either RAL or ATV/r, DRV/r, BDG, a marker of fungal translocation, increased similarly in all arms over 96 weeks. This may represent continued intestinal damage during ART and resulting fungal translocation. Higher BDG was associated with larger fat gains on ART.

Effect of statin on arginine metabolites in treated HIV-infection.

BACKGROUND AND AIMS: Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide and an independent risk factor for cardiovascular disease. We examined the effect of statin on ADMA in HIV + patients on stable ART, and whether such an effect contributes to the favorable changes on carotid intima media thickness. METHODS: This is a secondary analysis of SATURN-HIV, in which HIV + adults on stable ART with HIV-1 RNA< 1000 copies/mL and LDL-cholesterol <130 mg/dL were randomized to 10 mg daily rosuvastatin or placebo. Arginine metabolites, ADMA, and markers of inflammation were assessed at baseline and 48 weeks. Carotid intima media thickness (c-IMT) was measured at baseline, 48 and 96 weeks. Spearman correlations, and linear mixed-effect models were used to study relationships among variables. RESULTS: Overall, 79% were male, 68% African Americans, with a median age of 46 years. In the statin arm, no change in ADMA levels was observed at 48 weeks (0.70%), whereas a trend towards an increase in ADMA levels (23.78%) was observed in the placebo group (p = 0.06). Elevated baseline ADMA (highest tertile) was associated with a 0.04 mm increase in c-IMT (p = 0.03) after adjusting for statin and study duration. No interaction was seen between baseline ADMA and statin randomization on change in c-IMT (p = 0.21). CONCLUSIONS: In HIV + subjects on ART, rosuvastatin suppressed the increase over time in ADMA levels. Elevated baseline levels of ADMA were associated with increases in c-IMT, regardless of statin assignment. The favorable effect of rosuvastatin on c-IMT appears to be independent of the arginine pathway.