(P20-071-25) Integration of Longitudinal Metabolome and Lipidome Changes Associated With Weight Gain in Women With HIV After Integrase Strand Transfer Inhibitor Initiation – A Pilot Study

Objectives: Women with HIV (WWH) are at high risk for excess weight gain after initiation of integrase strand transfer inhibitor (INSTI) antiretroviral treatment. In this pilot study, we investigated metabolomics and lipidomics signatures associated with weight gain in WWH and their longitudinal changes following INSTI initiation.

Methods: Virologically suppressed WWH from the Atlanta Women's Interagency HIV Study on INSTI therapy (N=33) were grouped based on weight change over 2 years (≥ 5% or < 5% change from INSTI initiation). Blood samples were collected at three time points: 6-12 months pre- (baseline), 1-6 months post-, and 1-2 years post-INSTI initiation. Targeted lipidomics and high-resolution metabolomics focusing on 40 oxylipins and 168 quantified metabolites, respectively, were conducted using liquid-chromatography and mass spectrometry. Partial least squares (PLS) correlation between the omics profiles was calculated at each timepoint. Multi-omics integration was performed using multiblock sparse partial least squares discriminant analysis (sPLS-DA) to identify clusters of correlated metabolites which differentiated between weight change groups.

Results: Fifteen WWH (45%) had clinically significant weight gain (≥5%). There was moderate-to-high metabolome-lipidome PLS correlation across time points (0.56 to 0.81). A cluster of 25 correlated metabolites was identified at baseline that contributed most to differentiating between weight change groups. This cluster included n-6 polyunsaturated fatty acids (PUFAs) such as linolenic acid (LA) and arachidonic acid (AA), along with two AA-derived oxylipins. At 1-6 months post-INSTI initiation, 22 metabolites were identified, including LA, an AA-derived oxylipin, and neurotransmitter-related metabolites (3-methoxytyrosine, glutamine, and glutamate). At 1-2 years post-INSTI, 26 metabolites were identified, including AA and neurotransmitter-related metabolites (tryptophan, kynurenine, and 3-methoxytyrosine).

Conclusions: Multi-omics integration revealed n-6 PUFAs and downstream oxylipins consistently linked with weight gain over time. Neurotransmitter metabolites were linked to weight gain at 1–6 months and 1–2 years post-INSTI. Further studies are needed to validate INSTI-related weight gain mechanisms.

Funding Sources: National Institutes of Health