Background
INSTIs are known to induce weight/fat gain, the pathogenesis and reversibility of which remain unclear. The ongoing ADDORE study aimed to evaluate the evolution of adipose tissue (AT) between baseline and W48 in PWH with INSTI-associated weight gain switched to TDF/3TC/DOR. We present here preliminary adipocyte gene expression results.
Methods
PWH underwent two surgical AT biopsies from subcutaneous fat in the central abdominal area at inclusion and W48 following switch to TDF/3TC/DOR. AT samples were homogenized using a TissueLyser and RNA was isolated using the Macherey-Nagel method. 14 pairs of samples had a quality level that allowed mRNA quantification by RT-PCR. We evaluated the expression of 14 genes by RT-PCR in comparison with the expression of two reference genes (HPRT and PPIA).
Results
Of the 22 enrolled participants, 14 pairs of samples had a quality level that allowed mRNA quantification by RT-PCR. In these 14 PWH (median age: 46 years (IQR 42-57), FTM ratio: 3/11, median BMI: 30.4 kg/m2 (29.3-35.3) at baseline), weight was significantly reduced by 2.0 kg from 100.6 ± 4.1 to 98.6 ± 4.0 kg (p=0.03) after W48 corresponding to corresponding to a weight loss of 2.3 ± 1%.
At inclusion, as expected, the expression of the two genes involved in lipid accumulation, FASN, encoding the lipid storing enzyme fatty acid synthase, and SREBF1C, encoding the transcription factor Srebp-1c, were related (R=0.729, p=0.003). As well, the expression of ADIPOQ, encoding adiponectin, was related to that of PPARG encoding the adipogenic transcription factor PPAR-gamma (R=0.790, p=0.0008), as expected since ADIPOQ transcription is activated by PPAR-gamma.
After 48-week on TDF/3TC/DOR, we observed a reduction in the expression of PPARG (1.42 ± 0.11 to 1.23 ± 0.13 p=0.02) and of the two genes involved into lipid accumulation (SREBF1C 1.41 ± 0.18 to 1.03 ± 0.15 p=0.049 and FASN 1.36 ± 0.18 to 1.02 ± 0.14p=0.085). This suggests reduced adipocyte hypertrophy and lipid accumulation whereas the expression of genes involved in fibrosis, adipokines (leptin adiponectin) and macrophage infiltration was not modified.
Conclusions
These results suggest that switch from INSTI to TDF/3TC/DOR allowed a partial reversal of the INSTI-induced gene expression profile associated with adipocyte hypertrophy and lipid accumulation.
Larger clinical pathogenesis studies are needed to better understand the underlying mechanisms of INSTI-induced weight gain and its reversibility by doravirine.
Table or Figure
