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

Stanley, Takara L.; Fourman, Lindsay T; Feldpausch, Meghan N.; Purdy, Julia B.; Zheng, Isabel; Pan, Chelsea S; Aepfelbacher, Julia; Buckless, Colleen; Tsao, Andrew; Kellogg, Anela; Branch, Kelley R.; Lee, Hang; Liu, Chia-Ying; Corey, Kathleen E.; Chung, Raymond T.; Torriani, Martin; Kleiner, David E.; Hadigan, Colleen; Grinspoon, Steven

doi:10.1016/s2352-3018(19)30338-8

Cited by 54 publications

(54 citation statements)

References 30 publications

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“…Moreover, tesamorelin has also been shown to reduce liver fat and pretreatment elevated transaminases in responders 255,256 . Indeed, one study showed a significant reduction of hepatic fat and prevention of progression of fibrosis, without improvement in existing fibrosis, in treated PLWH with hepatic steatosis 257 . This finding is important as liver fibrosis is a predictor of mortality in persons with NAFLD, an emerging non-AIDS complication in PLWH 258 .…”

Section: Modulation Of the Growth Hormone Axismentioning

confidence: 99%

HIV and antiretroviral therapy-related fat alterations

Koethe

Lagathu

Lake

et al. 2020

Nat Rev Dis Primers

128

144

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Adipose tissue accounts for ~20-30% of total body weight in non-obese or overweight persons and for up to 50% in individuals with obesity and is a primary energy store with important endocrine and immunomodulatory functions. Most adipose tissue depots are comprised of white fat, which is responsible for energy storage and release in response to food intake and energy demand. In humans, brown and beige fat are minor components of adipose tissue and can dissipate energy as heat. White adipocytes sequester dietary lipids in adipose tissue depots to serve as energy stores during periods of fasting and prevent toxic lipid accumulation in other tissues such as muscle, liver, pancreas and heart 1. In addition, white adipocytes have a role in glucose and lipid metabolism and respond differentially to physiological cues or metabolic stresses by releasing adipokines and lipokines that regulate energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation, immune function and tissue repair 2. Although adipose tissue is mainly comprised of adipocytes, it also contains mesenchymal stem cells (which can differentiate into adipocytes, myoblasts, osteoblasts and chondroblasts), immune cells (including M1 and M2 phenotype macrophages, CD4 + T cells and CD8 + T cells) and fibroblasts, in addition to blood vessels and nerves. Fat expands owing to excess energy supply either through hypertrophy (increased size of existing adipocytes) or hyperplasia (the formation of new adipocytes from mesenchymal stem cells in adipose tissue). In obesity, hypertrophic adipocytes have different biochemical properties to smaller adipocytes, including increased lipolysis, inflammatory cytokine production and reduced secretion of anti-inflammatory adipokines, such as adiponectin, that are also involved in insulin sensi tivity 1. Such alterations in fat depots predispose to ectopic lipid accumulation and the development of comorbidities, including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), sarcopenia, atherosclerosis and heart failure 2. During physiological ageing, fat is lost from lower limbs and increases in the trunk, alongside accumulation of senescent adipocytes that have altered adipogenic potential and increased secretion of proinflammatory cytokines 3. Fat alteration became a major concern in Western countries in the mid-1990s, when people living with HIV (PLWH) receiving combination antiretroviral therapy

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Section: Modulation Of the Growth Hormone Axismentioning

confidence: 99%

HIV and antiretroviral therapy-related fat alterations

Koethe

Lagathu

Lake

et al. 2020

Nat Rev Dis Primers

128

144

View full text Add to dashboard Cite

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“…Furthermore, 35% of patients in the tesamorelin group returned to liver fat values below 5% in comparison to only 4% of patients on placebo ( P = 0.007). ( 39 ) The study also concluded that 10.5% of patients in the tesamorelin group experienced progression of liver fibrosis compared with 37.5% in patients receiving a placebo ( P = 0.04) (Table 3). ( 39 ) The DDI potential of tesamorelin has been evaluated with simvastatin, a cytochrome P4503A4 (CYP3A4) sensitive substrate, and the HIV protease inhibitor ritonavir.…”

Section: Current Trials For Nash In Hivmentioning

confidence: 94%

“…( 39 ) The study also concluded that 10.5% of patients in the tesamorelin group experienced progression of liver fibrosis compared with 37.5% in patients receiving a placebo ( P = 0.04) (Table 3). ( 39 ) The DDI potential of tesamorelin has been evaluated with simvastatin, a cytochrome P4503A4 (CYP3A4) sensitive substrate, and the HIV protease inhibitor ritonavir. Tesamorelin (2 mg, multiple doses) was shown to have a minimal effect on simvastatin (80 mg) and ritonavir (100 mg) pharmacokinetics in healthy volunteers, ( 40 ) suggesting that tesamorelin is unlikely to alter the exposure of antiretroviral drugs (Table 2).…”

Section: Current Trials For Nash In Hivmentioning

confidence: 94%

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

et al. 2020

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on behalf of the SHIVER Network In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies. (Hepatology 2020;71:1831-1844).

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“…A recent review suggests that GH or IGF1 might be applicable for the treatment of steatohepatitis or cirrhosis (9). A trial investigating the effectiveness of GH treatment in reducing HCL levels in patients with NAFLD is currently underway (NCT02217345), and a very recent study investigating tesamorelin, a GH-releasing hormone analog that restores endogenous pulsatile GH secretion, showed a significant reduction of HCL levels as well as a reduced progression of fibrosis in HIV-positive patients with NAFLD (11). Therefore, a better understanding of the molecular mechanisms underlying low HCL levels in ACRO could help identify GH-regulated pathways providing the chance for discovering novel therapeutic targets for treating NAFLD.…”

Section: Introductionmentioning

confidence: 99%