th9507 and Fatty-Liver

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 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