The treatment with Elexacaftor/Tezacaftor/Ivacaftor significantly increases serum bilirubin and decreases blood platelets in children and adolescents with cystic fibrosis homozygous or double heterozygous for the F508del CFTR variant.

The Elexacaftor/Tezacaftor/Ivacaftor (ETI) combination of cystic fibrosis transmembrane regulator modulators is safe and effective even in children with at least one F508del variant. However, cases of liver damage have been reported, and we observed an increase of serum bilirubin and alanine aminotransferase (ALT) in Cystic Fibrosis (CF) adults homozygous or compound heterozygous for the F508del after one year of ETI treatment. In the present study we followed 106 people with CF (pwCF) aged 8-15 years, who were homozygous or compound heterozygous for the F508del variant and treated with ETI, monitoring liver biochemical indices, lipid profile, and circulating cells. Treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s in both pwCF homozygous and compound heterozygous for the F508del variant (p < 0.001). On the other hand, ETI treatment caused a significant increase in total and conjugated bilirubin in both subgroups (p < 0.001). These changes were mostly found after six months of therapy but not continued after one and two years. Furthermore, we observed a significant reduction in the number of blood platelets after ETI treatment. These data suggest to further investigate the effects of ETI therapy on bilirubin metabolism and to search for biomarkers that can predict its increase, whereas we hypothesize that the reduction in platelet count may depend on the reduced systemic inflammation due to ETI treatment.