(223) Divergent liver enzyme tests across the first year of Elexacaftor/Tezacaftor/Ivacaftor therapy

Background: Highly effective CFTR modulators significantly improve lung health in people with CF (pwCF), but little is known of their extra-pulmonary effects on organs such as the liver. Cystic Fibrosis related liver disease (CFRLD) is a common co-morbidity in CF and Elexacaftor/Tezacaftor/Ivacaftor (Elex/Tez/Iva) therapy has been associated in some patients with worsening liver function as a direct side effect of treatment. Whether these drugs may also improve liver function in pwCF and CFRLD is presently unknown.

Aims:

• To determine the frequency, severity and type of hepatic side effects seen in pwCF taking Elex/Tez/Iva therapy


• To assess the effects of Elex/Tez/Iva therapy on known CFRLD

Methods: A prospective observational clinical study was undertaken in adult patients commencing Elex/Tez/Iva therapy. Alanine aminotransferase (ALT), Bilirubin and Alkaline phosphatase levels were taken at baseline, 1,3,6,9 and 12 months after commencing therapy.

Results: Consecutive data from 126 adult pwCF are available at the time of submission. 57% were male. 33 of the 126 (26.1%) had known CFRLD, with one patient having had a previous liver transplant.

29 pwCF (23%) experienced an ALT rise, of which 75% were male and 35% had CFRLD. 6 pwCF (4.8%) required a temporary or permanent cessation of Elex/Tez/Iva due to a marked elevation in ALT. Of these, 50% had CFRLD and 83% had a BMI above 25kg/m². Bilirubin elevation was observed in 23 pwCF (18%), with only 1 person requiring cessation of treatment due to a markedly elevated bilirubin. These were seen equally in males and females. 39% had CFRLD.

Unexpectedly, a reduction in Alkaline phoshatase (Alk Phos) was seen in 2/3 of all pwCF, with a mean reduction of 11.5U/L at 3 months. This was reduction was greater (28.5U/L) in pwCF with known CFRLD. These reductions persisted at 1 year (5.6U/L and 15.1U/L for all pwCF and those with CFRLD respectively).

Conclusions: Divergent responses are seen in liver enzyme testing with Elex/Tez/Iva treatment. Increased ALT and Bilirubin are common, with ALT rises being more common in males and those with CFRLD, and more significant in those with a BMI above 25kg/m². Elex/Tez/Iva was however associated with a reduction of Alk Phos levels following treatment which was more significant in those with known CFRLD. Our findings suggest that aside from the side effects of transient raises in transaminases in some patients, Elex/Tez/Iva may improve liver function in people with CFRLD.

Acknowledgements: This work was supported by all the clinical staff at the Scottish Adult Cystic Fibrosis Service, Edinburgh, UK.

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