Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (ß) = 0.15, 95% CI 0.02-0.29; FTL-by-sex ßinteraction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (FTL: rho = -0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.

Heroin Use Is Associated With Vascular Inflammation in Human Immunodeficiency Virus.

BACKGROUND: Heroin use may work synergistically with human immunodeficiency virus (HIV) infection to cause greater immune dysregulation than either factor alone. Unraveling how this affects end-organ disease is key as it may play a role in the excess mortality seen in people with HIV (PWH) who use heroin despite access to care and antiretroviral therapy. METHODS: This is a prospectively enrolled, cross-sectional study of adults with and without HIV who use and do not use heroin using (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to compare tissue-specific inflammation including aortic (target-to-background ratio [TBR]), splenic, and bone marrow (standardized uptake value [SUV]). RESULTS: A total of 120 participants were enrolled. The unadjusted mean difference in aortic TBR was 0.43 between HIV-positive [HIV+] heroin+ and HIV+ heroin-negative [heroin-] (P = .02); however, among HIV-, aortic TBR was similar regardless of heroin-use status. Further, HIV-by-heroin-use status interaction was significant (P = .02), indicating that the relationship between heroin use and higher aortic TBR depended on HIV status. On the other hand, both HIV (1.54 vs 1.68; P = .04, unadjusted estimated means for HIV+ vs HIV-) and heroin use were associated with lower bone marrow SUV, although the effect of heroin depended on sex (heroin-use-by-sex interaction, P = .03). HIV-by-heroin-use interaction was not significant for splenic or bone marrow SUV. CONCLUSIONS: Aortic inflammation was greatest in PWH who use heroin, but paradoxically, bone marrow activity was the least in this group, suggesting complex and possibly divergent pathophysiology within these different end organs.

Impact of Heroin and HIV on Gut Integrity and Immune Activation.

BACKGROUND: Altered gut integrity is central to HIV-related immune activation. Opioids may promote similar changes in gut permeability and/or increase systemic inflammation, potentially augmenting processes already occurring in people with HIV (PWH). SETTING: Urban hospital systems in Cleveland, Ohio, and surrounding communities. METHODS: This is a prospectively enrolled, cross-sectional study including people with and without HIV using heroin and people with and without HIV who have never used heroin, matched by age, sex, and CD4+ T-cell count (PWH only) to compare markers of gut integrity, microbial translocation, systemic inflammation, and immune activation. RESULTS: A total of 100 participants were enrolled. Active heroin use was associated with higher concentrations of lipopolysaccharide-binding protein (LBP), beta-D-glucan (BDG), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor-α-receptors I and II, soluble CD163, inflammatory monocytes, and activated CD4+ lymphocytes in adjusted models. HIV status tended to modify the effect between heroin use and LBP, BDG, hsCRP, patrolling monocytes, and activated CD4+ lymphocytes (P < 0.15 for interactions); however, it was not as expected. The effect of heroin on these markers (except patrolling monocytes) was greatest among those without HIV rather than among those with HIV. CONCLUSIONS: Heroin use is associated with heightened microbial translocation, systemic inflammation, and immune activation. Concurrent HIV infection in virologically suppressed individuals does not seem to substantially worsen the effects heroin has on these markers.

Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV.

BACKGROUND: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.

Short Communication: The Effect of Rosuvastatin on Vascular Disease Differs by Smoking Status in Treated HIV Infection.

Smoking is an important contributor to cardiovascular disease risk and is highly prevalent in the HIV population. In the Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV trial (SATURN-HIV), a 96-week, randomized placebo-controlled study testing the effect of rosuvastatin on subclinical vascular disease and immune activation in HIV-infected adults, rosuvastatin improved immune activation and arrested common carotid artery intima media thickness (CCA IMT) progression. In this exploratory analysis, ANOVA was used to test for effect modification by smoking. One-hundred forty-seven adults were included (72 in rosuvastatin group; 75 in placebo group). Groups were similar at baseline. Overall, mean ± SD age was 45.4 ± 9.9 years, 115 (78%) were men and 100 (68%) were African American. Ninety-three (63%) were current smokers (mean ± SD 0.6 ± 0.44 packs/day) and another 24 (16%) were smokers in the past. There were statistically significant randomization group by smoking status interactions for 0-24 (p = .01) and 0-48 (p < .01) week changes in proportion of activated CD4+ T cells and for 0-48 (p < .01) and 0-96 (trend only; p = .06) week changes in CCA IMT. No effect modification by smoking was detected for changes in markers of inflammation or monocyte activation. The beneficial effect of rosuvastatin on CCA IMT was not apparent in smokers although T cell activation improved to a greater degree in this subgroup.

The effects of HIV and smoking on aortic and splenic inflammation.

OBJECTIVE: To determine the association of smoking and HIV status with tissue-specific inflammation measured by flurodeoxyglucose positron emission tomography (PET). DESIGN: A cross-sectional study. METHODS: We prospectively enrolled 55 HIV study participants on stable antiretroviral therapy and 19 age-matched HIV-uninfected controls without known cardiovascular disease. We measured aortic target-to-background ratio (TBR) and spleen standardized uptake values (SUV) 3-h post-FDG, and used regression models to examine the independent association of HIV and smoking status with PET variables. RESULTS: Overall, median (interquartile range) age was 50 (42-55) years; 81% were men and 54% were current smokers (median 0.5 packs/day, 25 pack-years]. Median CD4 of HIV study participants was 690 cells/ml and 88% had HIV-1 RNA less than 20 c/ml; 43% were on a protease inhibitor. In fully adjusted models, HIV was associated with 0.16 (95% confidence interval 0.04-0.27; P = 0.009) higher aortic TBR, whereas current smoking was marginally associated with a lower TBR [-0.11 (95% confidence interval -0.23 to 0.01); P = 0.07]. Spleen SUVmean was not associated with HIV or smoking, and there was no evidence for an HIVsmoking interaction for aortic or spleen models (all P > 0.1). Spleen SUVmean was positively associated with biomarkers of inflammation and coronary artery calcium, but adjustment for traditional cardiovascular disease risk factors attenuated these relationships. CONCLUSION: The FDG-PET study of HIV study participants suggests that HIV is associated with increased aortic inflammation independent of traditional risk factors, but smoking is not. Future studies should continue to explore the mechanistic roles of smoking and inflammation at various stages of clinical and subclinical atherosclerotic vascular disease in HIV.

Incidental findings on chest computed tomography are common and linked to inflammation in HIV-infected adults.

BACKGROUND: Chest imaging is performed for a variety of reasons in HIV-infected adults. There are limited data on the prevalence of incidental findings, progression of these findings over time and the relationship with inflammation in antiretroviral therapy (ART)-treated HIV-infected adults. METHODS: This study utilized data from a randomized clinical trial of rosuvastatin in HIV-infected adults on ART. Incidental findings were reported from chest computed tomography (CT) scans obtained for coronary artery calcium score at entry, week 48 and 96. Markers of immune activation and inflammation were measured concurrently. Poisson regression and generalized estimating equations were used. RESULTS: A total of 147 participants were enrolled. Median age was 46 years, 78% were male, 68% African American and 63% current smokers. At baseline, 57% of participants had at least one incidental lung finding (ILF) and four additional participants had at least one ILF by week 96. At baseline, older age, current smoking, lower nadir CD4+ T-cell count and low-density lipoprotein and higher lipoprotein-associated phospholipase A2 (Lp-PLA2) were independently associated with having a greater number of ILFs. In the longitudinal analyses, older age, lower nadir CD4+ T-cell count and higher baseline soluble tumour necrosis factor α-receptor I (sTNF-RI) were independently associated with having a greater number of ILFs over 96 weeks. CONCLUSIONS: Over half of participants had at least one incidental finding on chest CT. Beyond traditional factors of older age and smoking, lower nadir CD4+ T-cell count and higher markers of inflammation were associated with having a greater number of ILFs in HIV-infected adults on ART.

Statin therapy decreases N-terminal pro-B-type natriuretic peptide in HIV: randomized placebo-controlled trial.

OBJECTIVE: HIV-infected participants are at a higher risk for cardiovascular disease (CVD). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population and is associated with mortality in HIV. DESIGN AND METHODS: The 96-week Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy with low-density lipoprotein-cholesterol level lower than 130 mg/dl and without overt heart failure to 10 mg daily rosuvastatin or placebo. We measured NT-proBNP levels by enzyme-linked immunosorbent assay (ELISA). Baseline and changes in NT-proBNP were compared between groups. Spearman correlation was used to explore relationships between baseline NT-proBNP, inflammation, and CVD risk markers. Multivariable analyses were conducted to assess associations with NT-proBNP levels. RESULTS: Median age was 46 years, 80% were men, 69% were African American, and 46% were on protease inhibitors. At baseline, median (Q1, Q3) NT-proBNP was higher in the rosuvastatin group than placebo [41 (20, 66.5) versus 25 pg/ml (11, 56), P = 0.012)]. Baseline NT-proBNP correlated with bulb and common carotid artery intima-media thickness, coronary calcium score, interleukin 6, and cystatin C. After 96 weeks, median NT-proBNP decreased significantly in the rosuvastatin group versus placebo (-1.50 versus +4.50 pg/ml, P = 0.041). Within the rosuvastatin group, changes in NT-proBNP were negatively correlated with changes in insulin resistance and total limb fat. CONCLUSION: Rosuvastatin reduces plasma NT-proBNP in HIV-infected participants on antiretroviral therapy. NT-proBNP correlated with several measures of CVD risk, independent of inflammation markers.

Differential Reduction in Monocyte Activation and Vascular Inflammation With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among HIV-Infected Individuals.

BACKGROUND: Little is known about how different antiretrovirals effect inflammation and monocyte activation in human immunodeficiency virus (HIV) infection. METHODS: We examined plasma specimens obtained during a randomized, double-blinded trial in antiretroviral therapy (ART)-naive HIV-infected adults which compared the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) with that of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). From a random sample achieving an HIV type 1 RNA load of <50 copies/mL by week 48, changes over 24 and 48 weeks in levels of biomarkers of monocyte activation (soluble CD14 [sCD14] and soluble CD163 [sCD163]), systemic inflammation (soluble tumor necrosis factor α receptor I [sTNF-RI], interleukin 6 [IL-6], and high-sensitivity C-reactive protein [hsCRP]), and vascular inflammation (lipoprotein-associated phospholipase A2 [Lp-PLA2]) were compared. Multivariable linear regression was used. RESULTS: A total of 200 participants were included. Significant differences favoring EVG/c/FTC/TDF were noted for changes in sCD14, hsCRP, and Lp-PLA2 levels. Factors independently associated with a larger decrease in the sCD14 level included random assignment to receive EVG/c/FTC/TDF, higher baseline sCD14 level, and larger decreases in hsCRP and sCD163 levels; factors associated with a larger Lp-PLA2 decrease included higher baseline Lp-PLA2 and IL-6 levels, smaller increases in total cholesterol and triglycerides levels, a larger decrease in the sCD14 level, and a smaller decrease in the sCD163 level. CONCLUSIONS: EVG/c/FTC/TDF led to greater decreases in sCD14, hsCRP, and Lp-PLA2 levels, compared with EFV/FTC/TDF. Randomization group independently predicted the change in sCD14 level, and changes in monocyte activation independently predicted the change in Lp-PLA2 level. There appears to be a more favorable effect of the integrase inhibitor EVG over efavirenz on immune activation, which may affect vascular inflammation.

Rosuvastatin preserves renal function and lowers cystatin C in HIV-infected subjects on antiretroviral therapy: the SATURN-HIV trial.

BACKGROUND: In chronic human immunodeficiency virus (HIV) infection, plasma cystatin C may be influenced by factors other than glomerular filtration rate such as inflammation. Statins may improve cystatin C by improving glomerular function or by decreasing inflammation. METHODS: The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy (ART) with low-density lipoprotein cholesterol ≤130 mg/dL to blinded 10 mg daily rosuvastatin or placebo. We analyzed relationships of baseline and 0- to 24-week changes in plasma cystatin C concentration with measures of vascular disease, inflammation, and immune activation. RESULTS: Median age was 46 (interquartile range, 40-53) years; 78% were male, 68% African American. Tenofovir and protease inhibitors were used in 88% and 49% of subjects, respectively. Baseline cystatin C was associated with higher carotid intima-media thickness and epicardial adipose tissue independent of age, sex, and race. Biomarkers of endothelial activation and inflammation were associated with cystatin C in a multivariable model independent of creatinine-based estimated glomerular filtration rate (eGFRcr). After 24 weeks, statin use slowed mean eGFRcr decline (1.61 vs -3.08 mL/minute/1.73 m(2) for statin vs placebo; P = .033) and decreased mean cystatin C (-0.034 mg/L vs 0.010 mg/L; P = .008). Within the statin group, changes in cystatin C correlated with changes in endothelial activation, inflammation, and T-cell activation. CONCLUSIONS: Rosuvastatin 10 mg daily reduces plasma cystatin C and slows kidney function decline in HIV-infected patients on ART. Reductions in cystatin C with statin therapy correlate with reductions in inflammatory biomarkers. Relationships between cystatin C, kidney function, and cardiovascular risk in HIV may be mediated in part by inflammation. Clinical Trials Registration. NCT01218802.

Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study.

OBJECTIVE: Antiretroviral therapy (ART) has been implicated in bone loss in HIV. The role of inflammation and vitamin D is unclear and better investigated in ART-naive individuals. DESIGN AND METHODS: This is a 48-week, prospective cohort study to compare baseline and change in hip and spine bone mineral density (BMD) measured by dual-energy X-ray absorptiometry in HIV-infected, ART-naive adults and healthy controls matched by age, sex, and race. We also studied associations between bone loss and inflammation markers and plasma 25-hydroxyvitamin D [25(OH)D] using logistic regression. RESULTS: Forty-seven HIV-infected adults and 41 controls were included. Baseline 25(OH)D, BMD at total hip, trochanter, and spine, and prevalence of osteopenia and osteoporosis were similar between groups. In the HIV-infected group, total hip and trochanter, but not spine, BMD decreased over 48 weeks [hip -0.005 (-0.026-0.008) g/cm², P = 0.02 within group; trochanter -0.013 (-0.03-0.003), P < 0.01]. BMD did not change at any site within controls. The HIV-infected group was more likely to have bone loss at the trochanter (P = 0.03). This risk persisted after adjustment for age, sex, race, BMI, smoking, and hepatitis C (odds ratio 4, 95% confidence interval 1.2-15.8). In the HIV-infected group, higher interleukin-6 concentrations (P = 0.04) and Caucasian race (P < 0.01) were independently associated with progression to osteopenia or osteoporosis, but not 25(OH)D levels. CONCLUSION: BMD at the total hip and trochanter sites decreased in the HIV-infected, ART-naive adults, but not controls, over this 48-week study. Higher serum interleukin-6 concentrations were associated with progression to osteopenia or osteoporosis status in the HIV-infected group.

Rate and predictors of carotid artery intima media thickness progression in antiretroviral-naive HIV-infected and uninfected adults: a 48-week matched prospective cohort study.

BACKGROUND: Carotid intima media thickness (CIMT) progresses faster in HIV-infected adults on antiretroviral therapy (ART) than the general population. It is unclear if the rate of progression is similarly faster in ART-naive, HIV-infected adults. METHODS: This was a 48-week prospective cohort study to compare change in CIMT and inflammation markers in ART-naive, HIV-infected adults in no immediate need of ART (HIV-positive/ART-naive) and age/sex/body mass index (BMI)-matched controls (HIV-negative). RESULTS: A total of 85 HIV-positive/ART-naive and 45 HIV-negative participants were enrolled. In the HIV-positive/ART-naive group, median baseline CD4+ T-cell count and HIV-1 RNA were 535 cells/mm3 and 6,916 copies/ml. Baseline common carotid artery (CCA) and bulb CIMTs were similar between groups. Changes in CIMT to 48 weeks at both sites were not different within- or between-groups (median [IQR] change in HIV-positive/ART-naive versus HIV-negative CCA CIMT -0.0071 mm [-0.0267-0.0233] versus 0.0113 mm [-0.0117-0.0306]; P = 0.19 between-groups; and bulb CIMT 0.0017 mm [-0.0367-0.06167] versus 0.01 mm [-0.0383-0.0625]; P = 0.54). After adjustment for cardiovascular disease (CVD) risk factors, change in CCA CIMT was greater in HIV-negative participants (-0.0046 versus 0.0177 mm for HIV-positive/ART-naive versus HIV-negative; P = 0.01). In HIV-positive/ART-naive, interleukin (IL)-6, soluble tumour necrosis factor-α receptor (sTNFR)-II, vascular cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 were higher at both time points and D-dimer was higher at week 48 (P < 0.01 for all). IL-6, sTNFR-I and D-dimer increased over 48 weeks in HIV-positive/ART-naive participants (P < 0.01 for all). In HIV-positive/ART-naive participants, independent predictors of greater change in CCA CIMT were higher BMI (P = 0.05) and family history of CVD (P < 0.01) and of greater change in bulb CIMT were higher sTNFR-I (P = 0.03) and higher diastolic blood pressure (P < 0.01). CONCLUSIONS: In ART-naive HIV-infected adults at low risk of HIV disease progression and low cardiovascular risk, CIMT progression rate was similar to matched controls. In addition to traditional CVD risk factors, higher levels of sTNFR-I predicted greater bulb CIMT changes.

Bone effects of rosiglitazone in HIV-infected patients with lipoatrophy.

OBJECTIVES: Thiazoledinediones increase limb fat in HIV+ patients with lipoatrophy. However, their use in the general population has been associated with bone loss and fracture. We sought to determine the effects of rosiglitazone on bone metabolism in HIV-infected patients. METHODS: HIV+ patients with lipoatrophy were randomized to rosiglitazone versus placebo for 48 weeks in a double-blind, placebo-controlled trial. Limb fat, bone mineral density (BMD), bone formation markers (procollagen type 1 amino-terminal propeptide [P1NP], osteocalcin [OC]) and bone resorption markers (C-terminal telopeptide of type I collagen [CTX]) were measured, along with receptor activator for nuclear factor kappa ß ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines. RESULTS: Seventy-one subjects were randomized to rosiglitazone or placebo: 17% female and 51% white. Total BMD did not change significantly in either group. In the rosiglitazone group, P1NP showed statistically significant decreases at 24 and 48 weeks; however, changes compared to placebo were only significant at 24 weeks. OC decreased significantly in the rosiglitazone group at 24 weeks, but there were no between-group differences. CTX, RANKL, or OPG did not change for either group. Multivariable regression within the rosiglitazone arm showed P1NP changes were inversely associated with limb fat changes, protease inhibitors, and tenofovir use. CONCLUSION: Rosiglitazone use was associated with decreased bone formation, but it did not alter bone resorption or total BMD. The increase in limb fat that accompanies rosiglitazone use appears to be associated with decreased osteoblast activity. Further studies are needed to determine the effect of thiazoledinediones on bone health in HIV-infected persons.

Elevated D-dimer is independently associated with endothelial dysfunction: a cross-sectional study in HIV-infected adults on antiretroviral therapy.

BACKGROUND: D-Dimer elevations have been associated with a striking increase in mortality in HIV-infected patients. However, D-Dimer has not been directly linked to endothelial dysfunction in HIV. METHODS: In this cross-sectional study, we used flow-mediated dilation (FMD) of the brachial artery to measure endothelial function and several biomarkers to measure systemic inflammation and coagulation activation in HIV-infected adults on stable antiretroviral therapy with HIV-1 RNA levels <400 copies/ml. Multivariable linear regression was used to model FMD by these markers, traditional cardiovascular risk factors and HIV-related characteristics. RESULTS: Analysis included 98 subjects (88% male, median age 47.5 years, CD4(+) T-cells 578.5 cells/mm(3)); all on ART (52% on protease inhibitors). The only factors independently associated with FMD were D-Dimer and body mass index. CONCLUSIONS: We show for the first time an independent association between D-Dimer and endothelial dysfunction in virologically suppressed, HIV-infected adults on stable antiretroviral therapy, potentially explaining the link between D-Dimer and mortality in HIV.

Short communication: initiation of an abacavir-containing regimen in HIV-infected adults is associated with a smaller decrease in inflammation and endothelial activation markers compared to non-abacavir-containing regimens.

Abacavir has been associated with myocardial infarction in several studies. This may be related to inflammation and endothelial cell activation. We compared changes in inflammation and endothelial activation markers between antiretroviral-naive adults initiating zidovudine, lamivudine, abacavir, and nonnucleoside reverse transcriptase inhibitor (NNRTI) or this regimen without abacavir. Changes in soluble tumor necrosis factor receptors-I, -II (sTNFR-I, -II), high sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1 (sVCAM-1) from baseline (pre-ART) to a second time point about 24 weeks after initiating antiretroviral therapy (ART) were compared between groups using multivariable linear regression. A total of 37 met eligibility criteria; 12 received abacavir. The median (interquartile range) age was 37 years (27-45). Most were men (32/37), African-American (15/37), or white (15/37). The median nadir CD4(+) and baseline HIV-1 RNA were 230 cells/mm(3) (180-301) and 82,642 copies/ml (34,400-204,703). In all, 15/30 smoked, 7/37 had hypertension, 1/37 had diabetes, and 1/37 had hyperlipidemia. None had coronary or renal disease. Changes in CD4(+) and HIV-1 RNA level and timing of stored samples with regard to ART initiation were not different between groups. In univariable analysis, log transformed percent change in sTNFR-I (p=0.05) and -II (p=0.04) showed significant between-group differences and trended toward significance for sVCAM-1 (p=0.08). These markers decreased less in the abacavir group. After adjustment for confounders, significantly less decrease for sTNFR-II and sVCAM-1 was seen for those receiving the abacavir-containing regimen. When taken with an NNRTI, abacavir induced a smaller decrease in inflammation biomarkers in this cohort, suggesting a possible proinflammatory effect of this nucleoside analogue.

Omega-3 fatty acids do not improve endothelial function in virologically suppressed HIV-infected men: a randomized placebo-controlled trial.

Omega-3 fatty acids decrease cardiovascular disease (CVD) mortality possibly due to antiinflammatory effect. Inflammation and endothelial dysfunction likely play a role in the heightened CVD risk in HIV. Our goal was to evaluate the effect of omega-3 fatty acids primarily on endothelial function and inflammation in HIV-infected adults with moderate CVD risk on stable antiretroviral therapy. We conducted a 24-week, randomized, double-blind, placebo-controlled study to evaluate the effect of omega-3-acid ethyl esters 1 g twice a day. Flow-mediated dilation (FMD) of the brachial artery, lipoproteins and markers of inflammation, endothelial activation, coagulation, and insulin resistance were measured at entry and week 24. There were no within- or between-group differences in change in FMD over 24 weeks (mean change in FMD -0.13% vs. 1.5% for treatment vs. placebo; p=0.21). There were no between-group differences in changes in lipoprotein levels or biomarkers tested, except soluble tumor necrosis factor receptor-I, which favored omega-3-acid ethyl esters. Omega-3 fatty acids did not improve endothelial function or activation, coagulation, or insulin resistance in virologically suppressed, HIV-infected men with moderate CVD risk; however, inflammation tended to improve. This suggests that omega-3 fatty acids may not be potent enough to counteract the enhanced inflammation and endothelial dysfunction due to HIV and antiretrovirals.