Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach.

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division.

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

Background: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).

Methods: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months.

Coronary Vasculature and Myocardial Structure in HIV: Physiologic Insights From the Renin-Angiotensin-Aldosterone System.

The landscape of HIV medicine dramatically changed with the advent of contemporary antiretroviral therapies, which has allowed persons with HIV (PWH) to achieve good virologic control, essentially eliminating HIV-related complications and increasing life expectancy. As PWH are living longer, noncommunicable diseases, such as cardiovascular disease (CVD), have become a leading cause of morbidity and mortality in PWH with rates that are 50% to 100% higher than in well-matched persons without HIV. In this review, we focus on disease of the coronary microvasculature and myocardium in HIV.

Effects of Integrase Inhibitor-Based ART on the NLRP3 Inflammasome Among ART-Naïve People With HIV.

The NOD-like receptor protein family pyrin domain containing 3 (NLRP3) inflammasome, activated in the setting of HIV, contributes to pro-atherogenic inflammation. Among antriretroviral therapy-naïve people with HIV (vs controls), levels of caspase-1-a key component of the NLRP3 inflammasome-were significantly increased. Six months of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate significantly decreased caspase-1 levels in association with CD4+/CD8+ ratio recovery.

Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.

Context: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD).

Objective: To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs.

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV.

Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) affects more than one-third of people living with human immunodeficiency virus (HIV). Nonetheless, its natural history is poorly understood, including which patients are most likely to have a progressive disease course.

Methods: We leveraged a randomized trial of the growth hormone-releasing hormone analogue tesamorelin to treat NAFLD in HIV.

Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.

Background: Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD.

Methods: This randomised, double-blind, multicentre study with identical placebo as a comparator was done in a hospital and a medical research centre in the USA.

Comparison of visceral fat measurement by dual-energy X-ray absorptiometry to computed tomography in HIV and non-HIV.

Background/objectives: Individuals with HIV are susceptible to visceral fat accumulation, which confers an increased risk of cardiometabolic disease. Advanced software to ascertain visceral fat content from dual-energy X-ray absorptiometry (DXA) has not been validated among this population. We sought to compare DXA with computed tomography (CT) in the measurement of visceral fat cross-sectional area (VAT) in HIV and non-HIV using Bland-Altman analyses.

Effects of Pitavastatin on Insulin Sensitivity and Liver Fat: A Randomized Clinical Trial.

Context: 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are widely prescribed. Statins may have important metabolic effects on insulin sensitivity and liver fat, but limited studies have assessed these effects by using euglycemic hyperinsulinemic clamp, stable isotopes, and 1H magnetic resonance spectroscopy (MRS) for liver fat quantification.

Objective: To study the effects of pitavastatin on hepatic fat and insulin sensitivity.

Fibroblast growth factor 21 decreases after liver fat reduction via growth hormone augmentation.

Objective: Fibroblast growth factor 21 (FGF21) ameliorates steatohepatitis but is increased in humans with fatty liver, potentially due to compensatory mechanisms and/or FGF21 resistance. Further, animal models suggest that GH increases serum FGF21. Tesamorelin, a growth hormone releasing hormone agonist, reduces liver fat in HIV-infected individuals.

HDL Cholesterol Efflux Capacity in Newly Diagnosed HIV and Effects of Antiretroviral Therapy.

Context: In the general population, high-density lipoprotein (HDL) cholesterol efflux capacity (HCEC) relates inversely to incident cardiovascular events. Previous studies have suggested that HCEC is decreased in HIV and that antiretroviral therapy (ART) initiation might improve HCEC.

Objective: To evaluate HCEC in the context of ART initiation and immune activation in HIV.

Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV.

Objective: Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Design And Methods: We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity.

Biomarkers and Clinical Indices of Aging with HIV.

HIV infection may potentiate specific biomarkers that influence the development of premature clinical indices commonly associated with aging. Therefore, predicting mortality outcomes in people living with HIV is extremely important as this population ages. This chapter describes biomarkers associated with inflammation, coagulation, and immune activation in HIV, and reviews the association between specific biomarkers and the development of co-morbid conditions in individuals with HIV.

Effects of Antiretroviral Therapy on Immune Function and Arterial Inflammation in Treatment-Naive Patients With Human Immunodeficiency Virus Infection.

Importance: Individuals with human immunodeficiency virus (HIV) infection receiving combined antiretroviral therapy (ART) have an increased risk of myocardial infarction. Effects of ART on arterial inflammation among treatment-naive individuals with HIV are unknown.

Objective: To determine the effects of newly initiated ART on arterial inflammation and other immune/inflammatory indices in ART-naive patients with HIV infection.

Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial.

Context: Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed.

Objective: To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects.

Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial.

Importance: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown.

Objective: To investigate the effect of tesamorelin on visceral and liver fat.

Discordance of IGF-1 and GH stimulation testing for altered GH secretion in obesity.

Objective: To investigate the concordance/discordance of IGF-1 and peak stimulated GH in identifying subjects with reduced GH secretion and to determine the physiological significance of any discordance in obese subjects.

Design, Patients And Methods: 95 obese and 43 normal weight men and women underwent measurement of IGF-1 and GH stimulation testing with GH releasing hormone (GHRH)-arginine. Reduced IGF-1 and GH secretion were defined using pre-determined cut-points.

The effects of tesamorelin on phosphocreatine recovery in obese subjects with reduced GH.

Context: Few studies have assessed the relationship between GH and mitochondrial function.

Objective: The objective of this study was to determine the effects of improving IGF-I using a GHRH analog, tesamorelin, on mitochondrial function assessed by phosphocreatine (PCr) recovery using (31)P magnetic resonance spectroscopy in obese adults with reduced GH.

Design: A total of 39 obese men and women with reduced GH secretion as determined by GHRH-arginine stimulation tests underwent magnetic resonance spectroscopy as part of a 12-month, double-blind, randomized, placebo-controlled trial comparing tesamorelin vs placebo.

Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial.

Context: Obesity is associated with reduced GH secretion and increased cardiovascular disease risk.

Objective: We performed this study to determine the effects of augmenting endogenous GH secretion on body composition and cardiovascular disease risk indices in obese subjects with reduced GH secretion.

Design, Patients And Methods: A randomized, double-blind, placebo-controlled study was performed involving 60 abdominally obese subjects with reduced GH secretion.

Reduced growth hormone secretion in obesity is associated with smaller LDL and HDL particle size.

Objective: Reduced growth hormone (GH) secretion is observed in obesity and may contribute to increases in cardiovascular disease (CVD) risk. Lipoprotein characteristics including increased small dense low-density lipoprotein (LDL) particles are known independent risk factors for CVD. We hypothesized that reduced GH secretion in obesity would be associated with a more atherogenic lipid profile including increased small dense LDL particles.