Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C.

BACKGROUND

In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV).

SETTING

Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2-4 as "possible" MD.

METHODS

Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression.

RESULTS

Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06-25.92] for FGF21 and 3.5 (95%CI: 1.19-10.25) for GDF15. Relationships persisted after covariate adjustments.

CONCLUSION

FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.

Déclaration de conflit d'intérêts

MEG has a research contract with NovoNordisk; is a member of advisory boards for Daiichi Sankyo, Ferring, Novo Nordisk, Nutritional & Growth Solutions, Millendo, Pfizer, and Spruce Biosciences; serves on data safety monitoring boards for Ascendis, Millendo, and Tolmar; and receives royalties from UpToDate and McGraw-Hill. MG has been a consultant for Abbott and Oncolys Biopharma. Mr. Karalius reports grants from National Institutes of Health, grants from US Department of Health and Human Services, grants from NICHD, grants from NIDCR, grants from NINDS, grants from NIDCD, grants from NIAID, grants from NIMH, grants from NIDA, grants from NIAAA, grants from NCI, grants from OAR, grants from NHLBI, grants from Harvard TH Chan School of Public Health, grants from Tulane University School of Medicine, during the conduct of the study. Dr. Jao reports grants from National Institutes of Health, during the conduct of the study. Dr. Van Dyke reports grants from National Institutes of Health, during the conduct of the study. Dr. Gerschenson reports grants from National Institutes of Health, grants from US Department of Health and Human Services, grants from NICHD, grants from NIDCR, grants from NINDS, grants from NIDCD, grants from NIAID, grants from NIMH, grants from NIDA, grants from NIAAA, grants from NCI, grants from OAR, grants from NHLBI, grants from Harvard TH Chan School of Public Health, grants from Tulane University School of Medicine, during the conduct of the study.