In real world, Kaftrio seen to lower risk of CF liver disease progression
Study compared rates of severe liver complications before, after therapy launch
In people with cystic fibrosis (CF), treatment with Kaftrio (elexacaftor, tezacaftor, and ivacaftor) may reduce the risk of CF-related liver disease (CFLD) progression, according to a real-world study in France.
Rates of severe liver complications were significantly lower among people with CF who were followed during the period after Kaftrio — sold as Trikafta in the U.S. — became available, compared with those followed before the now-approved treatment’s introduction, the data showed.
Indeed, the risk of severe liver issues among patients was seen to be reduced by more than 70% in the years since the triple-combination therapy was approved, the team noted in the study highlights.
Still, the researchers cautioned against assuming cause and effect.
“While these findings suggest a possible association between [Kaftrio] availability and improved liver outcomes, unmeasured confounders and concurrent changes in [disease] management may have contributed,” the researchers wrote, adding that “further studies are needed to confirm causality and understand underlying mechanisms.”
The study, “Cystic Fibrosis Liver Disease Progression in the Era of Elexacaftor-Tezacaftor-Ivacaftor,” was published in JHEP Reports, a journal of the European Association for the Study of the Liver.
CF is caused by mutations in the CFTR gene, which provides instructions for making a protein that helps regulate the movement of salt and water in and out of cells. When this protein is missing or is not functioning properly, thick, sticky mucus accumulates in the lungs, digestive tract, and liver.
About 20% to 40% of people with CF develop CFLD, according to the researchers. Signs include jaundice, a yellowing of the skin and whites of the eyes, itching, and an enlarged liver or spleen. In some cases, however, CFLD progresses to liver fibrosis, or scarring, and eventually cirrhosis, where scar tissue replaces healthy tissue and limits liver function.
This can lead to portal hypertension, or high blood pressure in the portal vein that runs through the liver. That, in turn, raises the risk of gastroesophageal variceal bleeding — serious bleeding caused by swollen veins in the esophagus or stomach that can rupture. Cirrhosis can also raise the risk of liver cancer among patients, and increase the need for a liver transplant.
Kaftrio first became available in France in late 2019
Kaftrio, a CFTR modulator that helps defective CFTR proteins work more effectively, has revolutionized CF care in recent years, effectively improving patients’ lung function and quality of life. Emerging studies suggest it may also benefit liver health in adults, as well as in children and adolescents, with CFLD.
“In France, [Kaftrio] became available via early access program in December 2019. Over the subsequent five years, significant advancements in managing pulmonary complications have been documented,” the researchers wrote. “However, the impact of [Kaftrio] on CFLD progression remains uncertain.”
To address this evidence gap, a research team from Paris analyzed data from more than 10,000 people with CF, ages 14 to 29. The team used the French National Hospital Discharge Database, and their study involved people with CF who had been hospitalized between 2014 and 2023 due to lung or digestive symptoms related to the disease.
Among patients, the median age at study entry was 19, and slightly more than half were male.
Due to the absence of individual treatment data, the researchers used calendar dates to estimate exposure. Patients whose medical records ended before December 2019, when Kaftrio became available in France, were assigned to the pre-Kaftrio era. People followed after that time were considered part of the Kaftrio era, based on the likelihood they had access to therapy.
Overall, 24.6% of patients were included in the pre-Kaftrio era group, while the remaining 75.4% were classified as part of the Kaftrio era.
People in the Kaftrio era group were significantly older and had longer follow-up times. They also were more likely to have a history of smoking and obesity. Meanwhile, diabetes and social deprivation were more common in the pre-Kaftrio era group. Rates of alcohol use disorders, HIV infection, and overall comorbidity burden, meaning the presence of other health conditions alongside CF, were similar between the two groups.
Team cautions that more research is needed to confirm causality
The team’s findings showed that the overall rate of CFLD progression dropped significantly after Kaftrio’s introduction, from 25.4 to 1.2 cases per 1,000 person-years, a measure that takes into account the number of people in a study and the length of time they were followed.
Advanced or decompensated advanced cirrhosis rates fell from 20.1 to 0.9, while gastroesophageal variceal bleeding rated dropped from 8.8 to 0.4. Rates of hepatocellular carcinoma, a primary cancer of the liver, were reduced from 1.4 to 0.06, and liver transplants dropped from 4.1 to 0.04 cases per 1,000 people per year. The overall death rate declined by more than 15 times, the data showed.
While the median age at which CFLD complications appeared remained similar between groups, people in the Kaftrio era lived about 10 years longer, on average, according to the researchers.
[We] observed [a] 72% lower risk of severe liver complications — such as portal hypertension bleeding, decompensated cirrhosis, or liver transplantation — after [Kaftrio’s] introduction.
In a matched analysis that accounted for key risk factors, people with CF followed during the Kaftrio era had a reduced risk — by more than 70% — of experiencing CFLD progression compared with those observed before the therapy’s use, the team noted.
Specifically, “[we] observed [a] 72% lower risk of severe liver complications — such as portal hypertension bleeding, decompensated cirrhosis, or liver transplantation — after [Kaftrio’s] introduction,” the researchers wrote.
The team cautioned, however, that the study lacked detailed information on when patients began Kaftrio, how long they stayed on the treatment, how consistently they used it, or whether they had received previous CFTR modulators. As such, “the results do not establish causality, but they provide a strong rationale for further research,” the scientists wrote.
“In summary, we report a temporal association between the [Kaftrio] era and a lower burden of CFLD progression and mortality in [people with CF] at the national level,” the researchers wrote. Still, they emphasized that the findings “should be interpreted as preliminary and exploratory.”
The team also noted that some of the observed improvements, such as a lower death of rate, may reflect broader advances in CF care over time — beyond Kaftrio’s potential effects on CLFD.
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