th9507 and HIV-Infections

Treatment with highly active antiretroviral drugs (HAART) is associated with several endocrine and metabolic comorbidities. Pituitary growth hormone (GH) secretion seems to be altered in human immunodeficiency virus (HIV) infection, and about one-third of patients have biochemical GH deficiency (GHD). We undertake a historical review of the functioning of the GH/insulin-like growth factor-1 (IGF-1) axis in patients with acquired immunodeficiency syndrome, and provide an overview of the main changes of the GH/IGF-1 axis occurring today in patients with HIV. Both spontaneous GH secretion and GH response to provocative stimuli are reduced in patients with HIV infection, especially in those with HIV-related lipodystrophy. The role of fat accumulation on flattened GH secretion is discussed, together with all factors able to potentially interfere with the pituitary secretion of GH. Several factors contribute to the development of GHD, but the pathophysiologic mechanisms involved in the genesis of GHD are complex and not yet fully elucidated owing to the difficulty in separating the effects of HIV infection from those of HAART, comorbidities and body changes. An update on the putative mechanisms involved in the pathogenesis of altered GH secretion in these patients is provided, together with an overview on the therapeutic strategies targeting the GH/IGF-1 axis to counteract fat redistribution associated with HIV-related lipodystrophy. The clinical significance of GHD in the context of HIV infection is discussed. The administration of tesamorelin, a GH releasing hormone analogue, is effective in reducing visceral fat in HIV-infected patients with lipodystrophy. This treatment is promising and safer than treatment with high doses of recombinant human growth hormone, which has several side-effects.

Topics: Adult; Antiretroviral Therapy, Highly Active; Comorbidity; Female; Growth Hormone-Releasing Hormone; HIV Infections; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Lipodystrophy; Male; Pituitary Gland

Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles?. Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments. Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted. Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied. Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered. Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin. Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice.. Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Cholesterol; Dyslipidemias; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Lipodystrophy; Pyrazines; Risk Factors

Patients infected with HIV have a high risk of developing dyslipidemia. Effective therapeutic strategies can be challenging due to an increase risk of drug interactions and other comorbidities. Understanding the underlying pathophysiology and the principles of pharmacological and non-pharmacological therapeutic interventions can be of value in the appropriate management of dyslipidemia in the HIV-infected patient.

Topics: Anti-HIV Agents; Anticholesteremic Agents; Azetidines; Cholesterol, HDL; Cholesterol, LDL; Diet Therapy; Dyslipidemias; Exercise Therapy; Ezetimibe; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Fibric Acids; Glutathione; Growth Hormone-Releasing Hormone; HIV Infections; Human Growth Hormone; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Niacin; Pyrazines; Thiazolidinediones; Triglycerides

This review addresses our current understanding of the pathogenesis of HIV-associated lipohypertrophy and describes an evidence-based approach to treatment.. Although the pathogenesis of HIV-associated lipohypertrophy remains elusive, recent clinical and laboratory investigations in fatty acid metabolism and growth hormone dynamics have furthered our understanding of the condition. These findings have also paved the way for new therapeutic interventions, of which tesamorelin, an analog of growth hormone-releasing hormone (GHRH), has gained recognition as a promising treatment strategy against visceral fat accumulation. Recent randomized placebo-controlled trials of tesamorelin demonstrated significant reductions in visceral adipose tissue, improvement in lipid parameters, and minimal adverse effects on glucose tolerance. Optimal therapeutic dosing and treatment duration, though, are not yet known. Whether treatment with GHRH-analogs will translate into improved long-term metabolic and cardiovascular outcomes also remains to be seen.. Although the pathogenesis of HIV lipohypertrophy remains unclear, several theories and observations have led to the development of treatment strategies to counter fat accumulation and its accompanying metabolic complications. Based on clinical trials, analogs of the growth hormone (GH)/GHRH axis appear to be most effective in reducing visceral adipose tissue.

Topics: Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Hormones; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT).. Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat.. Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension.. A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197).. Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily.. We evaluated percent change in VAT by computed tomography scan at wk 26.. At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P < 0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P < 0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P < 0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P < 0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P < 0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P < 0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52.. Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.

Topics: Abdominal Fat; Adult; Algorithms; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Middle Aged; Multicenter Studies as Topic; Obesity, Abdominal; Placebos; Randomized Controlled Trials as Topic

Subcutaneous atrophy and central fat accumulation are common among HIV-infected patients receiving highly active antiretroviral therapy, and may be accompanied by dyslipidemia and insulin resistance. These fat changes, although commonly referred to together as lipodystrophy, are best considered as separate disorders, with distinct pathogeneses and treatment approaches. These morphological and metabolic abnormalities first appeared after introduction of protease inhibitors more than 10 yr ago, but research has demonstrated that their pathogenesis is multifactorial, with contributions from other antiretroviral medications, patient-related factors, and HIV itself. Switching to a less toxic highly active antiretroviral therapy regimen has shown partial effectiveness for the management of fat atrophy and lipid abnormalities. Lifestyle modification or surgical approaches are the treatment of choice for lipohypertrophy, although novel therapies targeting the GH axis show promise. HIV-related dyslipidemia may be difficult to treat, and can be complicated by drug-drug interactions between some lipid-lowering medications and antiretroviral medications. Treatment of diabetes in HIV-infected patients should generally follow established guidelines, but thiazolidinediones, rather than metformin, may be considered first-line treatment in a patient with lipoatrophy, given their potential to increase sc fat. The contribution of body fat changes and metabolic abnormalities to cardiovascular risk and the changing risk profiles of newer antiretroviral regimens are under intense investigation.

Topics: Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Diabetes Mellitus; Dyslipidemias; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Risk Factors

Topics: Anti-HIV Agents; Circumcision, Male; Drug Resistance, Viral; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Patient Compliance; Reverse Transcriptase Inhibitors; Treatment Failure

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).. 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.. Analysis of data from a randomized clinical trial of GHRH.. Two US academic medical centers.. Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy.. Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis.. Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6.. These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.

Topics: Adult; Blood Glucose; Double-Blind Method; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; HIV; HIV Infections; Humans; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Severity of Illness Index

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. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.

Topics: Carcinoma, Hepatocellular; Female; Gene Expression; Growth Hormone; Growth Hormone-Releasing Hormone; Hepatitis; HIV Infections; Humans; Insulin-Like Growth Factor I; Liver; Liver Neoplasms; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Oxidative Phosphorylation; Placebos; Prognosis

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.. 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. People with HIV infection and a hepatic fat fraction (HFF) of 5% or more by proton magnetic resonance spectroscopy were eligible. Participants were randomly assigned (1:1) to receive either tesamorelin 2 mg once daily or placebo once daily for 12 months, followed by a 6-month open-label phase during which all participants received tesamorelin 2 mg daily. The randomisation list was prepared by the study statistician using a permuted block algorithm within each stratum with randomly varying block sizes. The primary endpoint was change in HFF between baseline and 12 months. The primary safety endpoint was glucose. Analysis was by intention to treat using all available data. This trial is registered with ClinicalTrials.gov, number NCT02196831.. 61 patients were enrolled between Aug 20, 2015, and Jan 16, 2019, of whom 30 received tesamorelin and 30 received placebo. Patients receiving tesamorelin had a greater reduction of HFF than did patients receiving placebo, with an absolute effect size of -4·1% (95% CI -7·6 to -0·7, p=0·018), corresponding to a -37% (95% CI -67 to -7, p=0·016) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a HFF of less than 5% (p=0·0069). Changes in fasting glucose and glycated haemoglobin were not different between groups at 12 months. Individuals in the tesamorelin group experienced more localised injection site complaints than those in the placebo group, though none were judged to be serious.. Tesamorelin might be beneficial in people with HIV and NAFLD. Further studies are needed to determine the long-term effects of tesamorelin on liver histology.. National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Topics: Adult; Aged; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome; United States

Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown.. The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area).. Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials.. U.S. and Canadian sites.. People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease ≥8%).. Tesamorelin or placebo.. Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm.. Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p<0.005), and the lean anterolateral/abdominal and rectus muscles (1.39 and 1.78 Hounsfield units; both p<0.005) compared to placebo. Significant increases were also seen in total area of the rectus and psoas muscles (0.44 and 0.46 centimeters2; p<0.005), and in the lean muscle area of all four truncal muscle groups (0.64-1.08 centimeters2; p<0.005).. Among those with clinically significant decrease in visceral adipose tissue on treatment, tesamorelin was effective in increasing skeletal muscle area and density. Long term effectiveness of tesamorelin among people with and without HIV, and the impact of these changes in daily life should be further studied.

Topics: Adult; Canada; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Male; Muscle, Skeletal

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. The objectives of this study were to investigate changes in FGF21 during tesamorelin treatment, to elucide the interplay between FGF21, GH augmentation, and liver fat reduction in humans.. 50 HIV-infected men and women with increased abdominal adiposity participated in this randomized, placebo-controlled trial of tesamorelin, 2mg vs. identical placebo daily for six months. Fasting laboratory measures, liver fat by. In HIV-infected individuals, FGF21 is significantly positively associated with liver fat. FGF21 decreases in association with reductions in liver fat, GGT, and FIB4, suggesting that FGF21 is upregulated in the context of steatosis and steatohepatitis and is reduced when these conditions improve. Moreover, these data suggest that tesamorelin improves liver fat via pathways other than increasing serum FGF21.. clinicaltrials.govNCT01263717.

Topics: Adiposity; Adolescent; Adult; Aged; Fatty Liver; Female; Fibroblast Growth Factors; gamma-Glutamyltransferase; Gene Expression Regulation; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Inflammation; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Magnetic Resonance Spectroscopy; Male; Middle Aged; Tomography, X-Ray Computed; Young Adult

Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequently, the aim of this study was to characterize the population pharmacokinetics of tesamorelin in HIV-infected patients and healthy subjects.. A total of 38 HIV-infected patients and healthy subjects receiving subcutaneous tesamorelin doses of 1 or 2 mg administered daily during 14 consecutive days were included in the analysis. An open one-compartment model with first- and zero-order absorption and first-order elimination was developed to best describe the data using NONMEM(®) VII. The effect of different covariates on tesamorelin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap.. Plasma clearance and its interindividual variability [% coefficient of variation (CV)] was estimated to be 1,060 L/h (33.6 %). Volume of distribution was calculated to be 200 L (17.7 %). Age, body size measures, race and health status were not related to tesamorelin pharmacokinetic parameters within the range of covariates studied. The fraction of tesamorelin absorbed by a first-order process is 13.1 % higher on day 14 compared with day 1. Predictive checks and non-parametric bootstrap demonstrated that the model is appropriate in describing the time course of tesamorelin plasma concentrations in both HIV-infected patients and healthy subjects.. An open one-compartment model with first and zero order absorption processes and linear elimination is suitable to characterize the pharmacokinetics of tesamorelin. The fraction of tesamorelin absorbed by a first-order process evolves with time. No clinically relevant covariates were identified as predictors of tesamorelin pharmacokinetics.

Topics: Body Mass Index; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Male; Middle Aged

The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.

Topics: Adult; Dose-Response Relationship, Drug; Female; Growth Hormone-Releasing Hormone; Healthy Volunteers; HIV Infections; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Models, Biological

Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%-20% over 6-12 months in individuals with human immunodeficiency virus (HIV)-associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes.. In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with ≥8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders.. Compared with tesamorelin nonresponders, responders experienced greater mean (±SD) reduction in triglyceride levels (26 weeks: -0.6 ± 1.7 mmol/L vs -0.1 ± 1.2 mmol/L [P = .005]; 52 weeks: -0.8 ± 1.8 mmol/L vs 0.0 ± 1.1 mmol/L [P = .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 ± 16 mg/dL vs 5 ± 14 mg/dL [P = .01]; 52 weeks: -1 ± 14 mg/dL vs 8 ± 17 mg/dL [P < .001]), hemoglobin A1c levels (26 weeks: 0.1 ± 0.3% vs 0.3 ± 0.4% [P < .001]; 52 weeks: 0.0 ± 0.3% vs 0.2 ± 0.5% [P = .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT.. In contrast to nonresponders, HIV-infected patients receiving tesamorelin with ≥8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. CLINICALTRIALS.GOV REGISTRATION: NCT00123253, NCT00435136, NCT00608023.

Topics: Adiposity; Adolescent; Adult; Aged; Anti-HIV Agents; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Metabolome; Middle Aged; Placebos; Treatment Outcome; Young Adult

To report the effects of tesamorelin, a growth hormone-releasing hormone analogue, on inflammatory and fibrinolytic markers and to relate these effects to changes in visceral adipose tissue (VAT).. Four hundred and ten HIV-infected patients with abdominal adiposity were randomized to 2 mg tesamorelin (n = 273) or placebo (n = 137) subcutaneously daily for 26 weeks. Circulating plasminogen activator inhibitor-1 (PAI-1) antigen, tissue plasminogen activator (tPA) antigen, C-reactive protein (CRP), and adiponectin were assessed.. At baseline, VAT was significantly associated with PAI-1 antigen (ρ = 0.36, P < 0.001), tPA antigen (ρ = 0.29, P < 0.001), CRP (ρ = 0.18, P < 0.001), and adiponectin (ρ = -0.22, P < 0.001). Treatment with tesamorelin resulted in a significant decrease from baseline in tPA antigen (-2.2 ± 2.5 vs. -1.6 ± 2.9 ng/ml, tesamorelin vs. placebo, P < 0.05). Changes in PAI-1 antigen were not significant in the tesamorelin group compared to placebo. Among patients receiving tesamorelin, changes in inflammatory markers were associated with change in VAT (PAI-1 antigen: ρ = 0.16, P = 0.02; tPA antigen: ρ = 0.16, P = 0.02; adiponectin: ρ = -0.27, P < 0.001), and these associations remained significant when controlling for changes in insulin-like growth factor-1.. In HIV patients with abdominal adiposity, tesamorelin may have a modest beneficial effect on adiponectin and fibrinolytic markers in association with changes in VAT. Further studies are needed to determine the clinical significance of these changes. These data further highlight the deleterious role of excessive VAT and the utility of strategies to improve VAT in this population.

Topics: Abdominal Fat; Adult; Aged; Analysis of Variance; Biomarkers; C-Reactive Protein; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-1; Humans; Inflammation; Intra-Abdominal Fat; Male; Middle Aged; Placebos; Plasminogen Activator Inhibitor 1; Treatment Outcome

HIV-infected patients receiving antiretroviral therapy often demonstrate excess visceral fat. A growth hormone-releasing factor, tesamorelin, may selectively reduce visceral fat in this population. We investigated the effects of tesamorelin (GHRH(1-44)) in HIV-infected patients with central fat accumulation.. A 12-month study of 404 HIV-infected patients with excess abdominal fat in the context of antiretroviral therapy was conducted between January 2007 and October 2008. The study consisted of 2 sequential phases. In the primary efficacy phase (months 0-6), patients were randomly assigned to receive tesamorelin [2 mg subcutaneous (SC) every day] or placebo in a 2:1 ratio. In the extension phase (months 6-12), patients receiving tesamorelin were rerandomized to continue on tesamorelin (2 mg SC every day) or switch to placebo. Patients initially randomized to placebo switched to tesamorelin. Patients and investigators were blinded to treatment assignment throughout the study. The primary endpoint was visceral adipose tissue (VAT). Secondary endpoints included body image, IGF-I, safety measures, including glucose, and other body composition measures.. VAT decreased by -10.9% (-21 cm(2)) in the tesamorelin group vs. -0.6% (-1 cm(2)) in the placebo group in the 6-month efficacy phase, P < 0.0001. Trunk fat (P < 0.001), waist circumference (P = 0.02), and waist-hip-ratio (P = 0.001) improved, with no change in limb or abdominal SC fat. Insulin-like growth factor-1 increased (P < 0.001), but no change in glucose parameters was observed. Patient rating of belly appearance distress (P = 0.02) and physician rating of belly profile (P = 0.02) were significantly improved in the tesamorelin vs. placebo-treated groups. The drug was well tolerated. VAT was reduced by approximately 18% (P < 0.001) in patients continuing tesamorelin for 12 months. The initial improvements over 6 months in VAT were rapidly lost in those switching from tesamorelin to placebo.. Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose.

Topics: Abdominal Fat; Adult; Anti-HIV Agents; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Intra-Abdominal Fat; Male; Middle Aged; Placebos; Treatment Outcome

Topics: Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Lipodystrophy; Male; Placebos

Visceral adipose tissue accumulates during antiretroviral therapy in many patients who are infected with the human immunodeficiency virus (HIV); this process is associated with an increased cardiovascular risk. We assessed the use of a growth hormone-releasing factor analogue, tesamorelin, to decrease visceral adiposity.. We randomly assigned 412 patients with HIV (86% of whom were men) who had an accumulation of abdominal fat to receive a daily subcutaneous injection of either 2 mg of tesamorelin or placebo for 26 weeks. The primary end point was the percent change from baseline in visceral adipose tissue as shown on computed tomography. Secondary end points included triglyceride levels, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, the level of insulin-like growth factor I (IGF-I), and self-assessed body image. Glycemic measures included glucose and insulin levels.. The measure of visceral adipose tissue decreased by 15.2% in the tesamorelin group and increased by 5.0% in the placebo group; the levels of triglycerides decreased by 50 mg per deciliter and increased by 9 mg per deciliter, respectively, and the ratio of total cholesterol to HDL cholesterol decreased by 0.31 and increased by 0.21, respectively (P<0.001 for all comparisons). Levels of total cholesterol and HDL cholesterol also improved significantly in the tesamorelin group. Levels of IGF-I increased by 81.0% in the tesamorelin group and decreased by 5.0% in the placebo group (P<0.001). Adverse events did not differ significantly between the two study groups, but more patients in the tesamorelin group withdrew from the study because of an adverse event. No significant differences were observed in glycemic measures.. Daily tesamorelin for 26 weeks decreased visceral fat and improved lipid profiles, effects that might be useful in HIV-infected patients who have treatment-associated central fat accumulation. (ClinicalTrials.gov number, NCT00123253 [ClinicalTrials.gov] .).

Topics: Adipose Tissue; Anti-Retroviral Agents; Body Composition; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Insulin-Like Growth Factor I; Lipids; Lipodystrophy; Male; Middle Aged

To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation.. Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters.. TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose.. TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.

Topics: Abdomen; Adipose Tissue; Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Peptides; Treatment Outcome; Waist-Hip Ratio

Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density = smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density.. Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated.. CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader.. Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, P = 0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, P = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P < 0.0001; SAT: +4.0 (8.7) HU tesamorelin, +0.3 (4.8) HU placebo, P < 0.0001]. The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT [+2.3 HU, 95% confidence interval (4.5-7.3), P = 0.001) or SAT (+3.5 HU, 95% confidence interval (2.3-4.7), P < 0.001] area change.. In PWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.

Topics: Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Intra-Abdominal Fat; Male; Subcutaneous Fat

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. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log

Topics: Adolescent; Adult; Aged; Blood Proteins; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; Growth Substances; HIV Infections; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Placebos; Proteomics; Randomized Controlled Trials as Topic; Transcriptome; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Young Adult

Topics: Double-Blind Method; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Liver; Non-alcoholic Fatty Liver Disease

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).. We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period.. At baseline, VAT was positively associated with ALT (P = 0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30 U/l, VAT responders experienced greater reductions in ALT (-8.9 ± 22.6 vs. 1.4 ± 34.7 U/l, P = 0.004) and AST (-3.8 ± 12.9 vs. 0.4 ± 22.4 U/l, P = 0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT.. A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Anti-Obesity Agents; Aspartate Aminotransferases; Clinical Trials, Phase III as Topic; Fatty Liver; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Intra-Abdominal Fat; Male; Middle Aged; Obesity; Placebos; Treatment Outcome; Young Adult

Topics: Anti-HIV Agents; Child; Controlled Clinical Trials as Topic; Dideoxynucleosides; Drug Approval; Drug Labeling; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Infant, Newborn; Male; Nitriles; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

Metabolic complications are common in treated HIV patients. Their etiology is multifactorial and the development of increased abdominal fat contributes to cardiovascular risk and impaired quality of life. Treated patients with fat mass distribution changes have relative growth hormone deficiency. Both pharmacologic and physiologic doses of growth hormone reduce the increased visceral adipose tissue and improve the associated abnormal lipid profiles in short-term studies. However, impaired glucose homeostasis changes and significant musculoskeletal toxicity occurs. A novel growth hormone-releasing factor analogue, tesamorelin, provides a physiologic means of restoring a normal growth hormone secretion profile and reduces increased visceral adipose tissue, improving both abnormal lipid profiles and patients' quality of life. Glucose homeostasis is generally well maintained. Cessation of treatment with either growth hormone or tesamorelin results in a prompt return of truncal obesity. Management strategies for the long-term maintenance of the reduced visceral adipose tissue have not yet been clarified and long-term effects on decreasing cardiovascular risks and improving clinical outcomes are uncertain.

Topics: Amino Acid Sequence; Antiretroviral Therapy, Highly Active; Body Composition; Clinical Trials as Topic; Growth Hormone-Releasing Hormone; HIV Infections; Human Growth Hormone; Humans; Intra-Abdominal Fat; Molecular Sequence Data

Topics: Anti-Retroviral Agents; Cardiovascular Diseases; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Lipodystrophy; Risk Factors

Topics: Adipose Tissue; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Body Composition; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Insulin-Like Growth Factor I; Lipodystrophy; Male

As the use of highly active antiretroviral therapy (HAART) became widespread, HIV positive individuals and their physicians began to notice changes in body fat distribution, with excess fat or fat loss noted in different areas. These body shape changes are sometimes accompanied by metabolic abnormalities, such as insulin resistance and elevated blood fats. Collectively, these changes are known as lipodystrophy syndrome. Treatment options for lipodystrophy are somewhat limited. Growth hormone has been used with success in clinical trials to reduce visceral adipose tissue, fat that collects around the abdominal organs. A new product, TH9507, a synthetic growth hormone releasing hormone analog made by the Canadian pharmaceutical company Theratechnologies, is currently showing promise in clinical trials and may represent a new treatment option for people with some types of lipodystrophy.

Topics: Antiretroviral Therapy, Highly Active; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Lipodystrophy

Topics: Anti-HIV Agents; Clinical Trials, Phase II as Topic; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Lipodystrophy; Peptides; Randomized Controlled Trials as Topic