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

Focused proteomic analysis of plasma specimens from a prior randomized, double-blind, placebo-controlled clinical trial.

“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.”

Men and women aged 18–70 years with documented HIV infection and liver steatosis (hepatic fat fraction ≥ 5%) on stable antiretroviral therapy.

“We enrolled 61 men and women 18–70 years old who had documented HIV infection and liver steatosis as defined by hepatic fat fraction ≥ 5% on 1H-magnetic resonance spectroscopy (1H-MRS).”

44 participants with paired plasma protein data at baseline and 12 months (20 assigned to tesamorelin, 24 assigned to placebo).

“Moreover, 44 of these individuals (20 assigned to tesamorelin, 24 assigned to placebo) had a plasma protein panel repeated at 12 months.”

12 months.

“We previously conducted a randomized, double blind trial in which PLWH with NAFLD were assigned to receive the GHRH analogue tesamorelin 2 mg daily or identical placebo for 12 months7.”

Tesamorelin treatment resulted in significant reductions in plasma levels of VEGFA, TGFB1, and CSF1 compared to placebo.

“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 and CSF1 correlated with a decline in NAFLD activity score.

“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.”

Among tesamorelin-treated participants, decreases in plasma TGFB1 and CSF1 were associated with a reduced gene-level fibrosis 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.”

The study had a small sample size for the proteomic analysis, and the observed effect sizes were modest (15–25%), requiring further investigation in large-scale studies.

“Our analysis detected effect sizes of approximately 15–25% in key proteins between treatment and placebo groups.”