A community-targeted implementation of self-management for people with epilepsy and a history of negative health events (SMART): A research and community partnership to reduce epilepsy burden.

AIMS: Self-management for people with epilepsy and a history of negative health events (SMART) is a behavioral intervention that has been demonstrated to reduce epilepsy-related complications and improve physical and mental health functioning among people with epilepsy (PWE) [1]. The Community-SMART (C-SMART) initiative was a 4-month prospective implementation of feasibility and pre/post outcomes of SMART in a community setting and in collaboration with key epilepsy service stakeholders. METHODS: Self-management for people with epilepsy and a history of negative health events is a group-format, entirely virtual intervention delivered in eight 60-90 sessions over the course of 8-10 weeks. The C-SMART initiative used research staff to guide intervention performance evaluation and staff of a regional epilepsy advocacy agency to assist with community engagement. Process evaluations included outreach and engagement efforts needed to reach PWE, the barriers and facilitators to roll-out, and participant retention and satisfaction. Outcomes included depressive symptoms and epilepsy self-management competency. RESULTS: Thirty individuals were enrolled in 3 "cohorts" of approximately 10 PWE per cohort. Mean age of participants was 48.50 (standard deviation 16.15) years, 60% were female and 53.3% were African-American. Individuals had epilepsy, on average, for over 2 decades, were on approximately 2 prescribed antiepileptic drugs (AEDs) and had an average of just over 6 seizures in the last 30 days. Over 63% had a comorbid mental health condition. There were 23 individuals (76.7%) who were retained at the 4-month follow-up. Baseline to 4-month outcomes for depression and epilepsy self-management were significantly improved. Most (90%) of participants reported high levels of satisfaction with the program. CONCLUSIONS: The SMART epilepsy self-management program can be successfully implemented in partnership with epilepsy-focused community partners, is acceptable to participants and associated with improved outcomes. Future work might consider how to make virtual epilepsy self-management available to the full spectrum of PWE.

The Community-targeted Self-management of Epilepsy and Mental Illness (C-TIME) initiative: A research, community, and healthcare administration partnership to reduce epilepsy burden.

AIMS: Comorbid mental health conditions (MHCs) such as depression and anxiety are common in people with epilepsy. Targeted Self-Management for Epilepsy and Mental Illness (TIME) is a behavioral program that targets mood symptoms in adults with epilepsy and comorbid MHCs. Building upon positive findings of a randomized controlled study to establish the efficacy of TIME, the Community-TIME (C-TIME) initiative assessed the implementation feasibility and pre-/post-outcomes of this new evidence-based epilepsy self-management intervention in a community setting and in collaboration with key stakeholders. METHODS: The C-TIME program is a group-format curriculum-based intervention delivered in ten 60-90 sessions over the course of 12 weeks. The C-TIME initiative used research staff to guide intervention performance evaluation, staff of a regional epilepsy advocacy agency to assist with community engagement and a county mental health services agency to support the transition from science to service. Process evaluations included outreach and engagement efforts needed to reach people with epilepsy and MHCs, the barriers and facilitators to roll out, and the participants' retention and satisfaction. The primary intervention participant outcome was depressive symptom severity at 4-month follow-up. RESULTS: Referrals came from a variety of sources and approximately 1 in 3 referrals resulted in an enrollment. Thirty individuals were enrolled in 3 "cohorts" of 10. The most common reason for not being enrolled postscreening was that individuals did not show up for the baseline evaluation. Mean age of participants was 49.1 (12.8) years, 50% (N = 15) female, 55.2% (N = 16) white, 34.5% (N = 10) African-American. With respect to participation, 2/3 of the enrolled sample attended at least 7 out of the maximum 10 C-TIME sessions. Mean number of C-TIME sessions attended was 6.9 (4.1). Five participants (17%) had family members attend the C-TIME sessions, although family members were encouraged to play a supportive rather than primary role. Four-month follow-up outcome evaluation was available for 66% of the enrolled group. There was a significant reduction in depression severity, and patient satisfaction was over 90%. CONCLUSIONS: The C-TIME program can be successfully implemented in the community and is associated with improved outcomes in adults with epilepsy and comorbid MHCs. Continued and broader scale-up of C-TIME and similar approaches could reach larger groups of adults with epilepsy and improve the health of our communities.

Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy.

BACKGROUND: Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. METHODS: The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)-infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8(+)CD38(+)HLA-DR(+) ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). RESULTS: After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor-positive patrolling (CD14(Dim)CD16(+)) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. CONCLUSIONS: Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. CLINICAL TRIALS REGISTRATION: NCT01218802.

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.

Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients are at increased risk of cardiovascular disease, which may be related to chronic inflammation and endothelial dysfunction despite virological control with antiretroviral therapy. The relationship between carotid intima-media thickness (IMT), a surrogate marker for cardiovascular disease, proinflammatory cytokines, and endothelial activation markers has not been fully explored in HIV-infected patients who are receiving antiretroviral therapy. METHODS: We conducted a prospective, cross-sectional, observational study of treated HIV-infected patients and healthy control subjects to evaluate the relationship between carotid IMT, proinflammatory cytokines, endothelial activation biomarkers, and metabolic parameters in treated HIV-infected patients, compared with healthy control subjects. RESULTS: We enrolled 73 HIV-infected patients and 21 control subjects. Common carotid artery and internal carotid artery IMT measurements, as well as tumor necrosis factor-alpha, high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, and soluble vascular cell adhesion molecule-1 levels were higher in the HIV-infected group. High-sensitivity C-reactive protein was the only biomarker that was positively correlated with carotid IMT in both groups. In the HIV-infected group, soluble vascular cell adhesion molecule-1 was positively correlated with all inflammatory cytokine levels. In multiple regression analysis, soluble vascular cell adhesion molecule-1, myeloperoxidase, and tumor necrosis factor-alpha levels were all associated with internal carotid artery IMT in the HIV-infected group, whereas age was associated with both common carotid artery and internal carotid artery IMT. CONCLUSIONS: Enhanced endothelial activation, inflammation, and increased carotid IMT occur in HIV-infected patients despite antiretroviral therapy. Inflammatory markers are associated with endothelial activation, and both are associated with internal carotid artery IMT, supporting a potential role of inflammation in endothelial activation and cardiovascular disease in HIV infection.

Subjective clinical lipoatrophy assessment correlates with DEXA-measured limb fat.

OBJECTIVES: Although physician- and patient-rated diagnoses of lipoatrophy are currently used as a basis for inclusion into clinical trials, few studies have compared physician- or patient-rated lipoatrophy severity with objective measures. We aim to assess the validity of physician- and patient-rated diagnoses of lipoatrophy by evaluating the correlation between clinical assessments of lipoatrophy and objective fat indices. METHODS: This cross-sectional study evaluated the association between clinical lipoatrophy scores and DEXA-measured limb fat (n = 154) and subcutaneous fat mitochondrial DNA (mtDNA) levels (n = 80) in HIV+ individuals. RESULTS: There was a significant negative correlation between DEXA-measured limb fat and lipoatrophy scores generated by either the patients (r = -0.27, p = .008) or the physician (r = -0.48, p < .0001). Also, a significant positive correlation was found between the patient-generated lipoatrophy score and the physician score (r = 0.68, p < .0001). However, there was no correlation between fat mtDNA levels and DEXA-measured limb fat (r = -0.09, p = .42) or between physician- or patient-generated lipoatrophy scores (r = -0.09, p = .43, and r = 0.04, p = .71, respectively). CONCLUSION: These results suggest that physician- and patient-rated lipoatrophy scores may be useful surrogates for more expensive measures of lipoatrophy, which could be reserved for research studies.

Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection.

BACKGROUND: The aim of this study was to assess the effect of antiretroviral therapy (ART) versus HIV on mitochondria in fat. METHODS: Subcutaneous fat was collected from 45 HIV-infected patients on ART with lipoatrophy, 11 HIV-infected ART-naive patients and nine healthy controls. Three mitochondrial transcripts: NADH dehydrogenase subunit 1 (ND1), cytochrome B (CYTB) and NADH dehydrogenase subunit 6 (ND6) genes were quantitated using TaqMan probes and normalized to nuclear-encoded ribosomal L13. RESULTS: ND1/L13 and CYTB/L13 were lower in HIV-positive patients on ART with lipoatrophy versus ART-naive patients (3.4 versus 7.2 [P=0.017] and 2.5 versus 4.6 [P=0.006], respectively). No difference was found between ART-naive patients and controls (P>0.70). ND6/L13 was similar between all groups. Dual-energy X-ray absorptiometry-measured limb fat and mitochondrial DNA in fat were also lower in HIV-positive patients on ART with lipoatrophy versus HIV-infected, ART-naive patients (4,382 versus 7,662 g [P=0.02] and 726 versus 1,372 copies/cell [P=0.03], respectively), but no difference was found between ART-naive and controls. In a multiple regression analysis, limb fat correlated with all three mitochrondrial RNA, whereas mitochondrial DNA did not correlate with mitochondrial RNA or limb fat. CONCLUSIONS: In contrast to ART-naive patients, HIV-positive patients on ART with lipoatrophy had significant depletion in mitochondrial DNA in fat and mitochondrial RNAs. This suggests that mitochondrial toxicity in lipoatrophy could be driven by ART and not by HIV itself. In addition, mitochondrial RNA abnormalities, and not mitochondrial DNA depletion, could be a key driving force behind lipoatrophy.

Increased carotid intima media thickness and cardiac biomarkers in HIV infected children.

OBJECTIVES: To assess carotid intima media thickness (IMT) and cardiac biomarkers in HIV infected children on antiretroviral therapy (ART). METHODS: This was a single site, cross sectional, controlled observational study. We assessed carotid IMT, homocysteine, high-sensitivity C-reactive protein and myeloperoxidase levels in HIV infected children on stable ART for >or= 6 months. Carotid IMT was reported as internal carotid artery (ICA) and common carotid artery (CCA) thickness; left and right sides were measured separately. Groups were compared using appropriate two-sample tests. RESULTS: Of the 62 subjects enrolled, 31 were HIV positive (50%), 66% were female, and 69% were African-American. Median CD4% was 32% and 26 patients (84%) had HIV-1 RNA< 400 copies/ml. Sixteen patients had been taking protease inhibitors for a median duration of 27 months. None had hypertension or smoked. HIV infected children had higher HOMA-IR, waist-to-hip ratio, cholesterol, triglycerides, myeloperoxidase and lower homocysteine levels. Left and right CCA IMT, and left and right ICA IMT were significantly higher in the HIV infected group. Significant predictors of carotid IMT measurements in uninfected controls were body mass index and homocysteine, but only the duration of ARV therapy was predictive of IMT in the HIV infected group. CONCLUSION: Higher levels of carotid IMT and some cardiac markers were found in ART treated HIV infected children when compared to matched uninfected controls. These results suggest that HIV infected children receiving ART may be at increased risk of cardiovascular disease.

HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4.

OBJECTIVE: To determine the relationships between Krüppel-like factors (KLF) 2 and 4, immune-activation, and subclinical vascular disease in HIV-infected patients on antiretroviral therapy (ART). DESIGN: Double-blind, randomized, placebo-controlled trial. METHODS: We studied 74 HIV-infected adults on ART enrolled in a randomized clinical trial of statin therapy. KLF2 and KLF4 gene expression was measured by quantitative PCR from peripheral blood mononuclear cells (PBMCs) at baseline and after 24 weeks of 10 mg daily rosuvastatin or placebo. At the same time points, T-cell and monocyte activation were assessed by flow cytometry and vascular health was assessed by cardiac computed tomography and carotid ultrasound. RESULTS: KLF4 expression was negatively correlated with duration of ART (r = -0.351, P = 0.004) and positively correlated with measures of immune activation: proinflammatory monocytes [CD14CD16 (r = 0.343, P = 0.003)], patrolling monocytes [CD14CD16 (r = 0.276, P = 0.017)], and activated CD8 T-lymphocytes [CD8DRCD38 (r = 0.264, P = 0.023)]. KLF2 expression was negatively correlated with subclinical atherosclerosis: mean-mean common carotid artery intima-media thickness (r = -0.231, P = 0.048), mean-max carotid artery intima-media thickness (r = -0.271, P = 0.020), and coronary artery calcium score (r = -0.254, P = 0.029). There were no statistically significant changes in KLF2/4 expression in PBMCs after 24 weeks of rosuvastatin. CONCLUSION: Expression of KLF4 in PBMCs positively correlates with cellular markers of immune activation, whereas KLF2 expression negatively correlates with markers of subclinical atherosclerosis in this HIV-infected population on ART. Additional studies are needed to determine if targeted interventions might alter KLF2/4 expression to reduce inflammation and vascular risk in humans.

Long-term changes in carotid intima-media thickness among HIV-infected children and young adults.

BACKGROUND: HIV-infected patients are at increased risk of cardiovascular disease (CVD). This study assessed long-term changes in carotid intima-media thickness (IMT) as a surrogate marker for CVD risk in HIV-infected children and young adults. METHODS: This was a longitudinal, observational study comparing carotid IMT in HIV-infected subjects who were 2-21 years old to matched controls over 144 weeks. RESULTS: A total of 34 HIV-infected subjects and 29 controls were included in the analyses. Among the HIV-infected group, median age was 10 years, 74% were black, and 65% were female. Overall, 91% were perinatally-infected with 82% on antiretroviral therapy and a median CD4(+) T-cell count of 681 cells/mm(3). At baseline, HIV-infected subjects had increased internal carotid artery (ICA) and common carotid artery (CCA) IMT (ICA, HIV-infected 0.90 mm versus controls 0.73 mm; P<0.01; CCA, HIV-infected 1.00 mm versus controls 0.90 mm; P=0.02). Relatively large changes in ICA and CCA IMT were seen from year to year in both groups. However, by week 144, there were no net changes in ICA or CCA IMT within the HIV-infected group. In the controls, CCA increased 0.1 mm and ICA increased 0.17 mm from baseline to week 144. ICA and CCA IMT were similar between groups by 144 weeks. CONCLUSIONS: Despite variations from year to year in carotid IMT in HIV-infected children and healthy controls, likely due to arterial growth and/or luminal diameter change, little or no net change occurred in carotid IMT over the entire 144-week study period. This suggests that only small net changes occur over time in HIV-infected children despite an increased long-term risk of CVD.

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.

Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection.

OBJECTIVE: To use multimodality imaging to explore the relationship of biomarkers of inflammation, T-cell activation and monocyte activation with coronary calcification and subclinical vascular disease in a population of HIV-infected patients on antiretroviral therapy (ART). DESIGN: Cross-sectional. METHODS: A panel of soluble and cellular biomarkers of inflammation and immune activation was measured in 147 HIV-infected adults on ART with HIV RNA less than 1000 copies/ml and low-density lipoprotein cholesterol (LDL-C) 130  mg/dl or less. We examined the relationship of biomarkers to coronary calcium (CAC) score and multiple ultrasound measures of subclinical vascular disease. RESULTS: Overall, median (interquartile range, IQR) age was 46 (40-53) years; three-quarters of participants were male and two-thirds African-American. Median 10-year Framingham risk score was 6%. Participants with CAC more than 0 were older, less likely to be African-American and had higher current and lower nadir CD4 T-cell counts. Most biomarkers were similar between those with and without CAC; however, soluble CD14 was independently associated with CAC after adjustment for traditional risk factors. Among those with a CAC score of zero, T-cell activation and systemic inflammation correlated with carotid intima-media thickness and brachial hyperemic velocity, respectively. Compared with normal participants and those with CAC only, participants with increasing degrees of subclinical vascular disease had higher levels of sCD14, hs-CRP and fibrinogen (all P<0.05). CONCLUSION: Soluble CD14 is independently associated with coronary artery calcification, and, among those with detectable calcium, predicts the extent of subclinical disease in other vascular beds. Future studies should investigate the utility of multimodality imaging to characterize vascular disease phenotypes in this population.

The relationship between vitamin D status and HIV-related complications in HIV-infected children and young adults.

BACKGROUND: In HIV-infected adults, we and others have shown that vitamin D deficiency is independently associated with increased carotid intima-media thickness (cIMT), a surrogate marker for cardiovascular disease (CVD). This study explored for the first time the relationship between vitamin D and CVD risk in HIV-infected youth. METHODS: This is a cross-sectional assessment of cIMT, inflammation, metabolic markers and vitamin D status in HIV-infected youth and healthy controls. We measured serum 25-hydroxyvitamin D (25(OH)D), fasting lipids, insulin, glucose, inflammatory markers and cIMT. RESULTS: Thirty HIV-infected subjects and 31 controls were included. Among HIV-infected subjects, median age was 11 years (37% males; 73% black; similar to controls). HIV-infected subjects' mean (standard deviation) serum 25(OH)D was 24 (35) ng/mL; 70% had 25(OH)D<20 ng/mL (deficient), 23% between 20-30 ng/mL (insufficient) and 7%>30 ng/mL (sufficient); proportions were similar to controls (P=0.17). After adjusting for season, sex and race, there was no difference in serum 25(OH)D between groups (P=0.11). Serum 25(OH)D was not significantly correlated with cIMT, inflammatory markers or lipids. Serum 25(OH)D was negatively correlated with body mass index, insulin resistance, HIV duration, and cumulative use of antiretroviral therapy, non- and nucleoside reverse transcriptase inhibitors. CONCLUSIONS: Most HIV-infected youth have vitamin D deficiency or insufficiency. Despite no direct association between serum 25(OH)D and cIMT, there were notable associations with some CVD risk factors, particularly inverse correlation with insulin resistance. Studies are needed to determine whether CVD risk, including insulin resistance, could be improved with vitamin D supplementation.

Short communication: High prevalence of vitamin D deficiency in HIV-infected and HIV-uninfected pregnant women.

Vitamin D deficiency is common in HIV-infected populations. In resource-limited settings, vitamin D deficiency has been shown to affect HIV disease progression and mortality in pregnant women, and also increases mother-to-child HIV transmission and mortality in their infants. This study sought to investigate vitamin D status in HIV-infected women compared to healthy controls in a high-income country setting and determine variables associated with vitamin D deficiency. We prospectively enrolled 40 women/infant pairs (16 HIV-infected women/HIV-exposed infant pairs and 24 uninfected/unexposed pairs). In serum cord blood, 25-hydroxyvitamin D [25(OH)D] concentrations were suboptimal (<30 ng/ml) in 100% of subjects from both groups. White race, non-Hispanic ethnicity was the only variable associated with higher serum 25(OH)D concentrations. This high prevalence of vitamin D deficiency, especially among HIV-infected women and their infants, deserves further investigation, as it may have a negative impact on maternal and infant health.

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.

Perivascular fat, inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy.

BACKGROUND: HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown. METHODS: In a cross-sectional study, epicardial (EAT) and thoracic periaortic (TAT) adipose tissue volumes were measured by computed tomography in 100 HIV-infected adults, on stable ART, with LDL-cholesterol ≤130 mg/dL and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2 mg/L). RESULTS: Overall, 77% were males and 70% African American. Mean (standard deviation) age and body mass index were 47 (10) years and 28 (6.4) kg/m(2), respectively. All subjects had HIV-1 RNA <1000 copies/mL with mean (standard deviation) CD4+ T cell count of 665 (280) cells/µL; 50% were on a protease inhibitor. EAT and TAT were correlated with each other (r = 0.766, p < 0.0001). Both were associated with metabolic syndrome, atherogenic lipid profile, insulin resistance, total and central body fat, serum biomarkers of inflammation, and soluble CD163, but not with cellular immune activation markers. In multivariable models that adjusted for age, sex, and other measures of adiposity, both perivascular fat depots were independently associated with the presence of coronary calcium. CONCLUSIONS: Perivascular fat is associated with soluble CD163, biomarkers of inflammation, insulin resistance, and subclinical atherosclerosis in this population of virologically suppressed HIV-infected patients on ART. The association of perivascular fat with coronary artery calcification appears to be independent of other measures of adiposity.

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.

Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir.

BACKGROUND: Lipoatrophy modestly improves when the thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) is removed. In vitro, uridine (NucleomaxX(®); Pharma Nord, Vojens, Denmark) reversed tNRTI mitochondrial toxicity. METHODS: All patients had lipoatrophy on a tNRTI-containing regimen with HIV RNA<400 copies/ml. A randomized 48-week study switched patients from tNRTI to tenofovir (TDF) or added uridine (continuing tNRTI). End points were changes in limb fat (DEXA), subcutaneous abdominal fat mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), inflammation markers (soluble tumour necrosis factor receptors, high-sensitivity C reactive protein [hsCRP], interleukin-6 [IL-6], soluble vascular cell adhesion molecule 1), bone mineral density (BMD) of the hip and spine, HIV-1 RNA, CD4(+) T-cells and fasting metabolic parameters. RESULTS: Fifty patients were enrolled (n=24 TDF switch; n=26 uridine); median age 48 years; 54% white; 86% male; limb fat 4,494 g. Baseline characteristics were similar between groups. In the NucleomaxX(®) arm, mtRNA increased (all P<0.001), hsCRP and IL-6 increased (both P=0.02), whereas fat mtDNA decreased without changes in limb fat. In the TDF-switch arm, fat mtDNA and inflammation markers did not change; however, significant increases in mtRNAs (P<0.001), limb fat (409 g; IQR -59-1,155) and CD4(+) T-cell count (P=0.03), and decreases in total and hip BMD (median -3.3%; IQR -5.1-0; P=0.005) were observed. Between-group changes were significant for fat mtDNA, hsCRP, IL-6, limb fat and hip BMD. No correlation was found between changes in limb fat and those of fat mtRNA, inflammation markers or protease inhibitor duration. CONCLUSIONS: In HIV lipoatrophy, NucleomaxX(®) improved mtRNA, but worsened inflammation markers and fat mtDNA without changes in limb fat. Switching from a tNRTI to TDF for 48 weeks increased limb fat and fat mtRNA. Large decreases in total and hip BMD were seen after TDF switch.ClinicalTrials.gov identifier: NCT00119379.

Changes in Inflammation, Oxidative Stress, Mitochondrial DNA Content after Rosiglitazone in HIV Lipoatrophy.

OBJECTIVE: We aim to evaluate the mechanisms of rosiglitazone-induced fat recovery in HIV+ patients with lipoatrophy on thymidine Nucleoside Reverse Transcriptase Inhibitors (NRTI) sparing regimens. METHOD: Measures of limb fat (DXA), oxidative stress (F2 isoprostanes) and inflammation [High-sensitivity C-reactive protein (hsCRP), soluble Tumor Necrosis Factor Receptors (sTNFR)-I, sTNFR-II, and interleukin (IL)-6] were performed. Gluteal fat mitochondrial DNA (mtDNA) and peroxisome proliferator-activated receptor (PPAR)-γ RNA [expressed as PPAR-γ/Glyceraldehyde 6-Phosphate Dehydrogenase (GAPDH) RNA ratio] were measured by quantitative PCR. RESULT: 71 patients on thymidine NRTI-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. Duration off thymidine NRTIs was similar between groups. From week 0-48, limb fat increased significantly (p=0.02) more in the rosiglitazone than in the placebo group. Within both groups, F2-isoprostanes, sTNFR-I and sTNFR-II increased significantly (p ≤ 0.003), hsCRP decreased significantly (≤ 0.02), and IL-6 did not change. No differences were seen between groups in any of the inflammation markers. Fat mtDNA (copies/cell) increased nonsignificantly: +41(p=0.08) and +29(p=0.38) within rosiglitazone and placebo group; respectively. PPAR-γ/GAPDH ratio did not change within or between groups. CONCLUSION: Limb fat improvements seen after rosiglitazone were not associated with changes in mtDNA, oxidative or inflammation markers, or PPAR-γ expression. F2 isoprostanes and some of the inflammation markers worsened over time in these subjects on stable ART, regardless of the rosiglitazone assignment. Thus, lipoatrophy can be in part overcome by a separate pathway independent of mitochondrial DNA depletion, such as PPAR-γ.

Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial.

BACKGROUND: Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD). RESULTS: Baseline demographics were similar except for age (vitamin D versus placebo, mean ±sd 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6-4.8] for vitamin D versus 2.5% [IQR 1.7-6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR -0.9-7.4] versus -1.9 ng/ml [IQR -4.0-0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR -1.05-2.13] versus 0.29% [IQR -1.61-1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance. CONCLUSIONS: Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.