Summary HIV-1 elite controllers (EC) spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary CT angiography (CTA) in: 1) EC, 2) non EC, chronically HIV-1 infected, ART-treated patients with undetectable viral load (“chronic HIV”), and 3) HIV-negative controls. Prevalence of atherosclerosis (78% vs. 42%, P<0.05) and markers of immune activation were increased in EC compared to HIV-negative controls. sCD163, a monocyte activation marker, was increased in EC compared to chronic HIV-1 (P<0.05) and compared to HIV-negative controls (P< 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among EC.
Background No studies have yet assessed the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in HIV-infected patients, a population with elevated risk of myocardial infarction. Methods In a randomized, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose positron emission tomography (FDG-PET) and low density lipoprotein(LDL)-cholesterol <3·37mmol/L(130mg/dL) were randomized to one year of treatment with atorvastatin (n=19) or placebo (n=21). Randomization was carried out by the MGH Clinical Research Pharmacy using a permuted-block algorithm, stratified by gender with a fixed block size of four, with 1:1 allocation to atorvastatin or identical matching placebo. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation, as assessed by FDG-PET of the aorta. Additional prespecified endpoints included coronary atherosclerotic plaque as assessed by coronary computed tomography angiography. We quantitatively assessed non-calcified and calcified plaque and high risk plaque features. Analysis was performed using intention-to-treat principle, using all available data, without imputation for missing data. Findings Thirty seven out of forty (92·5%) subjects completed the study, with equivalent discontinuation rates in both groups. Baseline parameters were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could only be assessed in a subset of patients (atorvastatin Δ −0·03 [95% CI: −0·17, 0·12] vs. placebo Δ −0·06 [−0·25, 0·13], p=0·77, n=21). Change in plaque could be assessed in all subjects completing the study. Atorvastatin reduced noncalcified coronary plaque volume compared to placebo (−19·4%(IQR: −39·2%, 9·3%) vs. +20·4%(−7·1%, 94·4%), p=0·009, n=37). In addition, the number of high risk plaques was significantly reduced by atorvastatin compared to placebo (change in number of low attenuation plaques −0·2[95% CI: −0·6, 0·2] vs. 0·4[0·0, 0·7], p=0·03, n=37 and change in number of positively remodeled plaques −0·2[95% CI −0·4, 0·1] vs. 0·4[−0·1, 0·8], p=0·04, n=37). Direct LDL-cholesterol (−1·00[95% CI −1·38, 0·61] vs. 0·30[0·04, 0·55] mmol/L, p<0·0001) and lipoprotein-associated phospholipase A2 (−52·2[95% CI −70·4, −34·0] vs. −13·3[−32·8, 6·2] ng/mL, p=0·005, n=37) significantly decreased with atorvastatin compared to placebo. Statin therapy was well-tolerated, with low incidence of clinical adverse events. Interpretation Compared to placebo, statin therapy reduces noncalcified plaque volume and high risk plaque features in HIV-infected patients with subclinical coronary atherosclerosis. Significant effects of statin therapy...
These data demonstrate that intensive lifestyle modification significantly improved important cardiovascular risk indices in HIV-infected patients with the metabolic syndrome. Lifestyle modification may be a useful strategy to decrease cardiovascular risk in this population.
Objective Metabolic abnormalities including diabetes, dyslipidemia, hypertension, and abdominal obesity occur commonly in HIV patients, are associated with increased coronary artery calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population. We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in HIV patients with metabolic syndrome. Design A randomized, placebo controlled trial to investigate LSM and metformin, alone and in combination, over one year, among 50 HIV-infected patients with metabolic syndrome. Methods We assessed CAC, cardiovascular and metabolic indices. Results Among the participants, duration of HIV-infection was 14±1 yr and duration of antiretroviral therapy was 6±1 yr. Metformin-treated subjects demonstrated significantly less progression of CAC (−1±2 vs. 33±17, P=0.004, metformin vs. placebo) whereas the effect of LSM on CAC progression was not significant (8±6 vs. 21±14, P=0.82, LSM vs. no LSM). Metformin had a significantly greater effect on CAC than LSM (P=0.01). Metformin-treated subjects also demonstrated less progression in calcified plaque volume (−0.4±1.9 vs. 27.6±13.8 mm3, P=0.008) and improved HOMA-IR (P=0.05) compared to placebo. Subjects randomized to LSM vs. no LSM showed significant improvement in HDL (P=0.03), hsCRP (P=0.05), and cardiorespiratory fitness. Changes in CAC among the 4 groups: 1) no LSM, placebo (43±30); 2) LSM, placebo (19±7); 3) no LSM, metformin (1±1); and 4) LSM, metformin (−4±6) were different (P=0.03 for ANOVA and linear trend across groups), the majority of this effect was mediated by metformin. Results are mean ± SEM. Conclusion Metformin prevents plaque progression in HIV-infected patients with the metabolic syndrome.
-Mitochondrial dysfunction may contribute to the development of insulin resistance and type 2 diabetes. Nucleoside reverse transcriptase inhibitors (NRTIs), specifically stavudine, are known to alter mitochondrial function in human immunodeficiency virus (HIV)-infected individuals, but the effects of stavudine on glucose disposal and mitochondrial function in muscle have not been prospectively evaluated. In this study, we investigated short-term stavudine administration among healthy control subjects to determine effects on insulin sensitivity. A secondary aim was to determine the effects of stavudine on mitochondrial DNA (mtDNA) and function. Sixteen participants without personal or family history of diabetes were enrolled. Subjects were randomized to receive stavudine, 30 -40 mg, twice a day, or placebo for 1 mo. Insulin sensitivity determined by glucose infusion rate during the hyperinsulinemic euglycemic clamp was significantly reduced after 1-mo exposure in the stavudine-treated subjects compared with placebo (Ϫ0.8 Ϯ 0.5 vs. ϩ0.7 Ϯ 0.3 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine-treated group showed significant reduction in mtDNA/ nuclear DNA (Ϫ52%, P ϭ 0.005), with no change in placebo-treated subjects (ϩ8%, P ϭ 0.9).31 P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures (r 2 ϭ 0.5, P ϭ 0.008). These findings demonstrate that stavudine administration has potent effects on insulin sensitivity among healthy subjects. Further studies are necessary to determine whether changes in mtDNA resulting from stavudine contribute to effects on insulin sensitivity. human immunodeficiency virus; insulin resistance; magnetic resonance spectroscopy RECENT DATA SUGGEST that mitochondrial dysfunction precedes the development of diabetes in insulin-resistant offspring of patients with type 2 diabetes mellitus (DM) (15). Resistance to insulin action at the skeletal muscle is the earliest abnormality in such patients. Evaluation of gene expression in muscle samples from individuals with type 2 DM and impaired glucose tolerance has identified alterations in several genes involved in mitochondrial oxidative phosphorylation (12,14). For example, both peroxisomal proliferator activator receptor-␥ coactivator (PGC1) and nuclear respiratory factor (NRF) are reduced in prediabetic and diabetic human muscle tissue. These data suggest that both individuals with diabetes and those in the prediabetic state without the clinical effect of hyperglycemia show diminished gene expression of elements essential for the mitochondrial respiratory chain oxidative phosphorylation.Animal and human models of DM suggest that mitochondrial dysfunction is significantly related to the development of insulin resistance. Analysis of the muscle tissue from the insulin-resistant obese ob/ob mice compared with thin ob/ϩ littermates revealed a reduction in the expression of a subunit of mitochondrial ATP synthase (20). In addition,...
These data suggest excess RAAS activation in relationship to visceral adiposity in HIV-infected patients that may independently contribute to insulin resistance. Mineralocorticoid blockade may have therapeutic potential to reduce metabolic complications in HIV-infected patients with increased visceral adiposity.
Background-Cardiovascular disease (CVD) is more frequent among people with HIV (PWH) and may relate to traditional and nontraditional factors, including inflammation and immune activation. A critical need exists to develop effective strategies to prevent CVD in this population. Methods-The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (A5332) is a prospective, randomized, placebo-controlled trial of a statin strategy for the primary prevention of major adverse cardiovascular events (MACE) in PWH with low to moderate traditional risk. At least 7500 PWH, 40-75yrs of age, on stable antiretroviral therapy (ART), will be randomized to pitavastatin calcium (4 mg/day) or identical placebo and followed for up to 7 years. Participants are enrolled based on the 2013 ACC/AHA ASCVD risk score and LDL cholesterol (LDL-C) level with a goal to identify a low to moderate risk population who might benefit from a pharmacologic CVD prevention strategy. Potential participants with a risk score ≤ 15% were eligible, based on decreasing LDL-C thresholds for increasing risk score > 7.5% [LDL-C<190 mg/dL for risk score <7.5%; LDL-C<160 mg/dL for risk score 7.6-10% and LDL-C<130 mg/dL for risk score 10.1-15%]. The primary objective is to determine effects on a composite endpoint of MACE. Formal and independent adjudication of clinical events will occur utilizing standardized criteria. Key secondary endpoints include effects on MACE components, all-cause mortality, specified non-CVD events, AIDS and non-AIDS events, and safety. Results-To date, REPRIEVE has enrolled over 7300 participants, at approximately 120 sites across 11 countries, generating a diverse and representative population of PWH, to investigate the primary objective of the trial. Conclusion-REPRIEVE is the first trial investigating a primary CVD prevention strategy in PWH. REPRIEVE will inform the field of the efficacy and safety of a statin strategy among HIVinfected participants on ART and provide critical information on CVD mechanisms and non-CVD events in PWH. Grinspoon et al.
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