Altered lipid and neurotransmitter metabolism as potential mechanisms of weight gain in women with HIV initiating INSTIs in a pilot study

Objective: This pilot study used metabolomics to provide insight into metabolic alterations of INSTI-associated weight gain among women with HIV (WWH). Methods: The study included 33 virally suppressed WWH who switched to or added an INSTI. Plasma samples collected 6-12 months pre- (Visit 1) and 1-6 months post INSTI add/switch (Visit 2) were analyzed with liquid chromatography-mass spectrometry-based high-resolution metabolomics. The baseline plasma metabolome and changes in metabolomic signatures (from Visit 1 to Visit 2) were compared in women who experienced ≥ 5% weight gain (n=18) over 1-2 years vs those who maintained/lost body weight (n=15). Results: Median age was 53 (Q1 47, Q3 55) yrs, 94% were Black, baseline BMI was 34.2 (Q1 30.6, Q3 38.5) kg/m 2 . Median weight change was +9.20 kg (Q1-Q3 6.77-15.13 kg) and -0.68 kg (Q1-Q3 -5.14 to 0.00 kg) for the weight gain vs maintained/lost weight groups, respectively. A total of 820 metabolites spanning 9 enriched metabolic pathways, including amino acid (e.g., tryptophan) and micronutrient pathways (e.g., vitamin E) differed between weight groups before INSTI use (p<0.05). A total of 1147 metabolites spanning 10 enriched pathways, particularly lipid pathways, exhibited a significant group x time interaction effect (p<0.05), with an overall pattern of decreased free fatty acids over time among women who gained weight. Conclusions: Several metabolic pathways at baseline and within 6 months were associated with weight gain in women initiating INSTIs. Acute changes in lipid metabolism following INSTI initiation provide potential insight into the pathophysiology of weight gain in this population.