TOPLINE

The specific antiretroviral therapy (ART) regimen dominated plasma metabolic profiles in virally suppressed children living with perinatally acquired HIV (CLWH), significantly influencing metabolic sexual dimorphism. Among well-controlled CLWH on the same regimen, 2 distinct CD4%-associated metabotypes emerged, suggesting divergent subclinical responses to treatment.

METHODOLOGY

• A cross-sectional metabolomics analysis compared 155 prepubescent, virally suppressed CLWH (median age, 7.85 years) to 155 uninfected control children from the CHANGES cohort in Johannesburg, South Africa.
• CLWH were stratified by ART regimen: 101 received efavirenz (EFV)-based therapy and 54 received lopinavir-ritonavir (LPV)-based therapy, with most on two nucleoside reverse transcriptase inhibitors (abacavir and lamivudine).
• Plasma samples underwent untargeted ultra high-performance liquid chromatography/tandem mass spectrometry metabolomics analysis, yielding 1220 metabolites.
• Median ART duration was 7.17 years, initiated at a median age of 5.53 months; 81.94% had undetectable viral load (<50 HIV RNA copies/mL) at sampling.
• Researchers applied various analysis and statistical methods to identify metabolic patterns associated with ART regimen, sex, and CD4%.

TAKEAWAY

• ART regimen was the strongest driver of metabolic variation among CLWH, with bile acids, bilirubin catabolites, and androgenic steroids most frequently distinguishing EFV-treated from LPV-treated children (Kruskal-Wallis with Dunn, false discovery rate [FDR] < .05).
• Metabolic sexual dimorphism differed by HIV status and ART regimen; cholesterol sulfate was the only metabolite consistently higher in females across all groups (FDR < .05).
• Within EFV-treated, long-term well-controlled CLWH on identical regimens, unsupervised clustering identified 2 metabotypes differing significantly in CD4% (metabotype A: lower CD4%, P = .0007; metabotype B: higher CD4%), with metabotype A showing elevated ketone bodies, fatty acids, and acylcarnitines suggestive of impaired mitochondrial oxidative metabolism.
• Phospholipids and unannotated metabolites were the most consistent classifiers of HIV status independent of ART regimen, though regimen effects remained a strong confounder.

IN PRACTICE

"Understanding how clinical factors shape the metabolic profile is critical for optimizing the use of metabolomics in HIV research and clinical management," the authors wrote.

SOURCE

The study was led by Chandre Herbert, National Institutes for Communicable Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. It was published online on July 20 in iScience.

LIMITATIONS

The study lacked dietary, pharmacogenetic, and gut microbiota data, which may confound metabolic profiles. CYP2B6 genotype, which affects efavirenz metabolism, was not assessed and may contribute to metabotype divergence. The population-specific findings from South Africa may not generalize to other geographic or socioeconomic contexts. The cross-sectional design precludes causal inference regarding the relationship between metabolic alterations and CD4%.

DISCLOSURES

The study was supported by grants from the National Institute of Dental and Craniofacial Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.