Distinct Lipidomic Signatures in People Living With HIV: Combined Analysis of ACTG 5260s and MACS/WIHS

• Published in: The journal of clinical endocrinology and metabolism 2022-01, Vol.107 (1), p.119-135
• Main Authors: Jao, Jennifer, Balmert, Lauren C, Sun, Shan, McComsey, Grace A, Brown, Todd T, Tien, Phyllis C, Currier, Judith S, Stein, James H, Qiu, Yunping, LeRoith, Derek, Kurland, Irwin J
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Cardiometabolic Risk Factors; Case-Control Studies; Clinical s; Clinical Trials, Phase III as Topic; Drug Therapy, Combination - adverse effects; Drug Therapy, Combination - methods; Exhibitions; Female; Health aspects; Highly active antiretroviral therapy; HIV (Viruses); HIV infection; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - metabolism; HIV patients; Humans; Inflammation - blood; Inflammation - diagnosis; Inflammation - immunology; Inflammation - metabolism; Insulin resistance; Insulin Resistance - immunology; Lipid Metabolism - drug effects; Lipidomics; Lipids - blood; Male; Medical research; Medicine, Experimental; Metabolic Syndrome - blood; Metabolic Syndrome - diagnosis; Metabolic Syndrome - etiology; Metabolic Syndrome - metabolism; Middle Aged; Multicenter Studies as Topic; Observational Studies as Topic; Prospective Studies; Raltegravir; Randomized Controlled Trials as Topic
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgab663

Disentangling contributions of HIV from antiretroviral therapy (ART) and understanding the effects of different ART on metabolic complications in persons living with HIV (PLHIV) has been challenging. We assessed the effect of untreated HIV infection as well as different antiretroviral therapy (ART) on the metabolome/lipidome. Widely targeted plasma metabolomic and lipidomic profiling was performed on HIV-seronegative individuals and people living with HIV (PLHIV) before and after initiating ART (tenofovir/emtricitabine plus atazanavir/ritonavir [ATV/r] or darunavir/ritonavir [DRV/r] or raltegravir [RAL]). Orthogonal partial least squares discriminant analysis was used to assess metabolites/lipid subspecies that discriminated between groups. Graphical lasso estimated group-specific metabolite/lipid subspecies networks associated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Correlations between inflammatory markers and metabolites/lipid subspecies were visualized using heat maps. Of 435 participants, 218 were PLHIV. Compared to HIV-seronegative individuals, ART-naive PLHIV exhibited higher levels of saturated triacylglycerols/triglycerides (TAGs) and 3-hydroxy-kynurenine, lower levels of unsaturated TAGs and N-acetyl-tryptophan, and a sparser and less heterogeneous network of metabolites/lipid subspecies associated with HOMA-IR. PLHIV on RAL vs ATV/r or DRV/r had lower saturated and unsaturated TAGs. Positive correlations were found between medium-long chain acylcarnitines (C14-C6 ACs), palmitate, and HOMA-IR for RAL but not ATV/r or DRV/r. Stronger correlations were seen for TAGs with interleukin 6 and high-sensitivity C-reactive protein after RAL vs ATV/r or DRV/r initiation; these correlations were absent in ART-naive PLHIV. Alterations in the metabolome/lipidome suggest increased lipogenesis for ART-naive PLHIV vs HIV-seronegative individuals, increased TAG turnover for RAL vs ATV/r or DRV/r, and increased inflammation associated with this altered metabolome/lipidome after initiating ART. Future studies are needed to understand cardiometabolic consequences of lipogenesis and inflammation in PLHIV.