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Abstract
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, log2-fold change − 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, − 0.35 ± 0.56 vs. − 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, − 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV.
Clinical Trials Registry Number: NCT02196831
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1 Massachusetts General Hospital and Harvard Medical School, Metabolism Unit, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
2 Harvard School of Public Health, Harvard Chan Bioinformatics Core, Department of Biostatistics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
3 Massachusetts General Hospital and Harvard Medical School, Liver Center, Gastroenterology Division, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
4 Massachusetts General Hospital and Harvard Medical School, Department of Radiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
5 National Cancer Institute, Laboratory of Pathology, Center for Cancer Research, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075)
6 National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165)