ETI therapy raises vitamin D levels in pediatric cystic fibrosis

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) was associated with increased serum vitamin D levels but not consistent changes in vitamins A or E among children with cystic fibrosis (CF), according to a longitudinal analysis of pediatric patients treated at a UK specialty center.¹

The findings add to a growing body of evidence on how highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators may alter nutritional parameters in this population. Fat-soluble vitamin deficiencies remain common in CF because of pancreatic insufficiency and malabsorption, even with enzyme replacement and supplementation.²

“Despite evidence for improvement in nutritional status, little evidence exists on the effect of ETI on vitamin levels in children, especially over extended periods,” wrote investigators.¹

Longitudinal pediatric cohort evaluates vitamin trends after ETI

Investigators sought to evaluate trends in vitamins A, D, and E before and after ETI initiation in a real-world pediatric cohort. This clinical service evaluation included 56 children aged 6 to 16 years receiving care at Nottingham University Hospitals NHS Trust who initiated ETI between April 2020 and March 2023.

Eligible patients had at least 1 measurement of fat-soluble vitamin levels both before and after treatment initiation. The cohort had a median age of 10 years, and most patients were pancreatic insufficient and homozygous for the F508del mutation.

Serum vitamin A, D, and E levels and supplementation doses were assessed across 7 predefined time points spanning up to 50 months before and 24 months after ETI initiation. Investigators used linear mixed-effects models to account for repeated measurements and evaluate changes associated with therapy, as well as interactions between supplementation dose and serum levels.

Vitamin D increases independent of supplementation

Among the 3 vitamins studied, only vitamin D demonstrated a statistically significant increase after ETI initiation. Median levels rose from 77 nmol/L before treatment to 85 nmol/L after treatment, with modeling showing an adjusted increase of approximately 19.9 nmol/L in the post-ETI period. This improvement appeared independent of supplementation, as vitamin D dose was not a significant predictor of serum levels.

Vitamin D deficiency was uncommon both before and after ETI, occurring in approximately 2% of measurements. No supratherapeutic levels were observed.

In contrast, vitamin A levels did not significantly change following ETI initiation despite a trend toward greater concentrations over time. Median levels increased modestly, and the proportion of deficient measurements declined from 11.5% before treatment to 2.9% after treatment. However, supratherapeutic levels were observed in both periods, affecting 10.2% of measurements before ETI and 13.3% after.

Notably, the relationship between vitamin A supplementation and serum levels shifted after ETI initiation. Investigators reported a negative association between supplementation dose and serum levels before treatment, which became a positive association after ETI. This finding suggests improved absorption or utilization of vitamin A following CFTR modulation.

Vitamin E levels remained largely unchanged, with no significant differences between pre- and posttreatment periods and no clear association with supplementation. Approximately one-quarter of measurements were below the reference range in both periods.

Clinical implications for monitoring and supplementation

Current guidelines recommend annual monitoring of fat-soluble vitamins in individuals with CF and adjustment of supplementation to maintain levels within target ranges. The present findings suggest that ETI therapy may differentially affect specific vitamins, particularly vitamin D, and may alter the relationship between supplementation and serum levels.

“Our results underscore the necessity of ongoing, vigilant monitoring of fat-soluble vitamins in the ETI era to ensure supplementation strategies are optimized and individualized,” wrote investigators.

References

1. Kimber F, Sills D. The impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin status and supplementation in a pediatric cystic fibrosis cohort. Pediatric Pumonology. 2026;61(4):e71596. doi:10.1002/ppul.71596
2. Chesdachai S, Tangpricha V. Treatment of vitamin D deficiency in cystic fibrosis. J Steroid Biochem Mol Biol. 2016;164:36-39. doi:10.1016/j.jsbmb.2015.09.013