Bruce Kinley

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.

Voiding function in obese and type 2 diabetic female rats

The effects of obesity and type 2 diabetes (DMII) on the lower urinary tract (LUT) were characterized by evaluating voiding function and anatomy in female Zucker diabetic fatty (ZDF) rats. Age-matched female virgin rats were separated into three experimental groups: Zucker lean rats (control; normal diet, n = 22), ZDF rats (obese+nondiabetic; low-fat diet, n = 22), and ZDF rats (obese+diabetic; high-fat diet, n = 20). Rats were placed on their specified diet for 10 wk before urodynamic LUT evaluation. A suprapubic catheter was implanted 2 days before urodynamic studies. Voiding function was evaluated by cystometric and leak point pressure (LPP) testing. The bladder, urethra, and vagina were immediately excised for qualitative histological evaluation. Compared with control rats, obese+nondiabetic and obese+diabetic rats had significantly decreased contraction pressure (P = 0.003) and increased cystometric filling volume (P < 0.001). Both obese groups exhibited significantly higher voided volumes (P = 0.003), less frequent urinary events (P < 0.001), and increased residual volumes (P = 0.039). LPP studies showed a nonsignificant decrease in LPP (P = 0.075) and baseline pressure (P = 0.168) in both obese groups compared with control. Histology of the external urethral sphincter in obese rats showed increased fibrosis, leading to disruption of the skeletal muscle structure compared with control. Additionally, the bladder wall of the obese+nondiabetic and obese+diabetic rats demonstrated edema and vasculopathy. Voiding dysfunction was evident in both obese groups but with no significant differences due to DMII, suggesting that voiding dysfunction in DMII may be attributable at least in part to chronic obesity.

The effect of physical activity on cardiometabolic health and inflammation in treated HIV infection.

BACKGROUND In HIV-uninfected populations, physical activity decreases mortality and inflammation. Inflammation is a potential cause of comorbidities in HIV+ adults, the evidence examining the effect of physical activity on cardiometabolic health is limited. This analysis examines the relationship between physical activity, cardiometabolic health and inflammation. METHODS We conducted a nested study within the SATURN-HIV trial in which 147 HIV+ adults were randomized to 10 mg daily rosuvastatin or placebo. Measures of physical activity, cardiometabolic health, inflammation and vascular disease (carotid artery intima media thickness and computed tomography-acquired measures pericardial fat volume) were assessed at baseline and through 96 weeks. Spearman correlations and multivariable analyses were used to explore relationships between physical activity, cardiometabolic health and inflammation. RESULTS Median age (Q1, Q3) was 46 (40.4, 52.7) years, 80% were male, 69% were African American and 46% were on protease inhibitors. Baseline median physical activity was 44 min per week (0, 150), 24% of participants performed greater than 150 min per week. At baseline, physical activity correlated with several markers of cardiometabolic health and inflammation (all P≤0.05). Over all time points median physical activity was independently associated with carotid distensibility (β=2.53; P=0.008), pericardial fat volume (β=-6.13; P=0.001) and interleukin-6 (β=-0.468; P<0.001). CONCLUSIONS Physical activity is associated with vascular disease, endothelial function, and may be an adjuvant to decreasing comorbidities in HIV+ adults. Further studies should examine long-term effects of physical activity on cardiometabolic health and inflammation in this population. Clinicaltrials.gov NCT01218802.

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.

Rosuvastatin Decreases Intestinal Fatty Acid Binding Protein (I-FABP), but does not Alter Zonulin or Lipopolysaccharide Binding Protein (LBP) Levels, in HIV-Infected Subjects on Antiretroviral Therapy

Introduction: Altered gastrointestinal (GI) barrier integrity and subsequent microbial translocation may contribute to immune activation in HIV infection. We have reported that rosuvastatin improved several markers of immune activation in HIV+ participants, but the effect of statin treatment on markers of GI barrier dysfunction is unknown. Methods: SATURN-HIV is a randomized, double-blind, placebo-controlled trial assessing the effect of rosuvastatin (10mg/daily) on markers of cardiovascular disease, inflammation, and immune activation in ART-treated patients. Gut-barrier integrity was assessed by the surrogate markers intestinal fatty acid binding protein (I-FABP), a marker of enterocyte death, and zonulin-1, a marker of gut epithelial cell function. Levels of lipopolysaccharide binding protein (LBP) were measured as a marker of microbial translocation. Results: Rosuvastatin significantly reduced levels of I-FABP during the treatment period compared to the placebo. There was no effect of rosuvastatin treatment on levels of zonulin or LBP. Baseline levels of LBP were directly related to several markers of immune activation in samples from all participants, including soluble CD163, IP-10, VCAM-1, TNFR-II, and the proportion of CD4+ and CD8+ T cells expressing CD38 and HLA-DR. Many of these relationships, however, were not seen in the statin arm alone at baseline or over time, as inflammatory markers often decreased and LBP levels were unchanged. Conclusions: Forty-eight weeks of rosuvastatin treatment reduced levels of I-FABP, but did not affect levels of zonulin or LBP. The reduction in levels of inflammatory markers that we have reported with rosuvastatin treatment is likely mediated through other mechanisms not related to gut integrity or microbial translocation. SATURN-HIV is registered on clinicaltrials.gov; Identifier: NCT01218802

The Impact of Mental Wellness on HIV Self-Management

As people living with HIV age, they face increasing self‐management work related to HIV infection plus the prevention and mitigation of multiple chronic health conditions, including daily health practices (i.e., physical activity, nutrition), engaging in a supportive community, and accepting the chronicity of HIV. Our purpose was to describe the relationship between HIV self‐management practices and mental wellness (depressive symptoms, perceived stress). Ninety‐three adult people living with HIV on antiretroviral therapy were enrolled and completed a survey. We used descriptive statistics to summarize variables, and Spearman rank correlation and quantile regression to study associations between variables. Participants’ average age was 48.6 years, 56% were male, and 87% were African American. Daily self‐management practices were associated with depressive symptoms (r = −0.19; p ≤ .01) and perceived stress (r = −0.14; p = .06); engaging with a supportive community and accepting the chronicity of HIV were not associated with mental wellness (all p > .05).