Chairs: Ed Deshmukh-Reeves and Rebecca McHugh

Background: Highly effective CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor (ETI) has revolutionised clinical outcomes for adults with CF (awCF) eligible for treatment. However little is understood about the long-term impact of ETI on the respiratory microbiota. In this multi-centre study, we investigated changes to the respiratory microbiota from before onset of ETI therapy to on-ETI therapy of up to 3 years. Methods: Respiratory samples were collected from 303 awCF from 6 centres in the UK, Canada and USA. This consisted of pre-ETI samples and on-ETI samples taken at approximately 6 months, 1, 2, & 3 years. Samples from 11 non-CF healthy participants were included as a comparator group. Microbiota sequencing was performed on all samples. Results: Microbiota diversity increased with therapy duration. With diversity at years 2 and 3 being comparable (P>0.05) to that observed in the mild disease pre-ETI and healthy groups. Microbiota composition became increasingly similar to mild CF/healthy with increasing therapy duration but was still significantly different (P<0.05) at 3 years. Dominance of CF pathogens reduced with therapy duration but still persisted, and the microbiota became characterised by strict anaerobes associated with better clinical outcomes. Conclusions: Long-term ETI therapy resulted in positive changes in the respiratory microbiota, typically associated with better clinical outcomes and microbiota more closely resembling mild CF/healthy microbiota. Despite a positive trajectory towards a healthy-like microbiota, we posit that progression in awCF is impeded by the cumulative effects of airway and lung parenchymal damage, and long-term and continued antibiotic therapy.