Impact of Elexacaftor/Tezacaftor/Ivacaftor (ETI) Treatment on Clinical Outcomes in a Single Centre Cohort of Paediatric Patients With Cystic Fibrosis

Cystic Fibrosis (CF) affects approximately 3800 Australians, including 42% aged under 18 years [1]. CF is associated with significant morbidity, with many people spending at least 60 min per day on treatment. Life expectancy has progressively improved due to the development of new therapies: median survival is now 60.6 years, increased from 47 years in 2008 [1]. Elexacaftor, Tezacaftor and Ivacaftor (ETI) (Trikafta), the first triple-therapy CF transmembrane conductance regulator modulator, became available in Australia on the Pharmaceutical Benefits Scheme in 2022. This study aimed to measure changes in the clinical status of adolescents with CF who have completed 12-months of treatment with ETI in a real-world setting. Adolescents with CF aged ≥ 12 years managed at the Royal Children's Hospital (RCH), Melbourne who had completed 12 months of ETI treatment by August 2023 were included. Demographic data and clinical outcomes, including lung function, weight, nutritional status, hospitalisations and microbiology were extracted from the electronic medical record and the Australian Cystic Fibrosis Data Registry (ACFDR). ‘Best’ and ‘mean’ values in the 12-month period pre- and post-ETI initiation were compared. Data analysis was performed in PRISM GraphPad V10.0.3. Rate of change of forced expiratory volume in 1-s (FEV1) per annum was calculated using linear regression; for each individual, a regression line was fitted across all FEV1 measurements within each 12-month period. Paired t-tests and Wilcoxon signed rank tests were used to compare normally and non-normally distributed data, respectively. The study was approved by RCH Human Research Ethics Committee (#101289). Sixty-eight adolescents were included in this study (54% male, 51% F508del homozygous, mean age 15.29 ± 1.96 years) (an additional nine patients had commenced ETI prior to 12 years (i.e., via clinical trials), and four had completed < 12 months treatment at the time of analysis). Forty study participants (59%) had prior modulator exposure (Lumacaftor-Ivacaftor 55%; Tezacaftor-Ivacaftor 37.5%; Ivacaftor 7.5%). ETI was associated with significant changes in several clinical outcomes (Table 1). Fewer lung function tests were performed following the introduction of ETI (median six and four per patient pre- and post-ETI respectively (p < 0.00001)). Most patients achieved an increase in FEV1%-predicted of 1%–10% (Figure 1a), and the rate of change in FEV1 increased after ETI commencement (p = 0.06). Although there was no significant change in weight or BMI post-ETI initiation, four patients (5.9%) moved from an ‘optimal’ BMI category (50th–85th percentile) to a ‘high’ BMI category (> 85th percentile). There were significant reductions in hospitalisation frequency and duration post-ETI initiation. The total number of hospital admissions decreased from 84 to 34; all patients saw a reduction in the number of days spent admitted to hospital in the 12 months post-ETI (Figure 1b). Total hospital and intravenous antibiotic days per year decreased from 766 to 221 and 686 to 198 days respectively. Significantly fewer airway microbiology samples, particularly sputum and bronchoalveolar lavage (BAL), were obtained post-ETI (4.44 ± 3.32 versus 2.69 ± 1.58 per patient; p < 0.0001); of those obtained, fewer were positive for pro-inflammatory pathogens [2], including Pseudomonas aeruginosa. Our study demonstrates significant clinical benefits of ETI in the real-world setting. Mean FEV1 improved by 7.3%-predicted in the 12 months post-ETI initiation (Figure 1a). Although this is less than the 10.3%-predicted improvement reported in a meta-analysis of existing randomised control trials [3], it likely reflects the younger age and milder lung disease of our cohort, most of whom had a baseline FEV1 > 90%-predicted pre-ETI and is consistent with mean improvement of 6.5%-predicted in the subset of PROMISE study participants with baseline FEV1 ≥ 90%-predicted [4]. In our study, the pre-ETI period coincided with the COVID-19 pandemic and related lockdowns, when community rates of viral infection and hospitalisation were reduced [5]; the decrease in hospitalisation frequency and duration reported here may therefore under-represent the true impact of ETI. The decrease in number and type of airway microbiological samples is consistent with previous reports [6], likely reflecting reduced mucus load and decreased spontaneous expectoration, as well as reduced exacerbations and hospitalisation. Genomic-based studies have reported a reduction in bacterial DNA load, but not pathogen eradication following ETI. Reduced sputum expectoration in patients treated with ETI leads to reliance on upper airway sampling methods, highlighting new diagnostic challenges. Previous CF Nutrition Guidelines have recommended a BMI target between the 50th and 85th percentiles. ETI can result in increased BMI and weight [4], due to multiple factors including reduced resting energy expenditure, increased appetite, and reduced fat malabsorption. ETI treatment may therefore result in increased rates of obesity. The increased proportion of overweight and obese adolescents in our study (total 19.2%) brings new clinical challenges, including modification of dietary recommendations and monitoring for long-term complications of obesity. A continued proactive approach to dietary advice will be essential. It is likely that small sample size, relatively short follow-up period, and inclusion of a relatively healthy baseline population, influenced the magnitude and statistical significance of our findings, for example, rate of change of FEV1. Large IQR/SD may reflect heterogeneity within our cohort—underlying CFTR genotype/residual protein function and baseline disease severity directly influence CFTR-modulator response, as will adherence, tolerance and potentially dosing in this real-world study [2, 3, 5]. Importantly though, our study cohort, is representative of Australian adolescents with CF, with no significant differences in FEV1 or weight compared with the 2023 ACFDR data for people with CF aged 12–17 years. Overall, we demonstrate the significant impact of ETI for Australian adolescents with CF, with an anticipated substantial impact on the landscape of CF care. Improvements in lung function, seen here over the first 12 months, are likely to correlate with substantial decreases in care burden and increases in life expectancy [1]. Care recommendations require updating, including increased awareness of the risks of obesity and a focus on long-term health, anticipating survival into late adulthood. This study, which demonstrates the extensive clinical and healthcare benefits of modulator access for Australia's children, provides evidence to argue for quicker funding approval and more equitable access to future novel therapies [7]. Several key research priorities remain to optimise long-term outcomes. Longitudinal studies are needed to assess the durability of ETI's benefits, as well as the emergence of adverse effects when initiated in early childhood. Questions remain about whether early therapy can prevent or fully reverse structural lung damage and reduce long-term complications such as CF-related diabetes. Future work could explore changes in body composition, fat metabolism, and potential risks of altered glucose homeostasis in treated children—developing new nutritional monitoring frameworks that reflect these metabolic shifts will be essential. Future research should aim to inform personalised treatment and monitoring approaches, ensuring that the early benefits of ETI translate into sustained health gains for patients. Development of new therapies is urgently required for patients who are ineligible for, or unable to tolerate, ETI. The study was conducted at the RCH Melbourne, Australia, supported by and using data hosted by the Australian Cystic Fibrosis Data Registry. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.