Elexacaftor/tezacaftor/ivacaftor’s effects on cystic fibrosis infections are maintained, but not increased, after 3.5 years of treatment

To the Editor: Elexacaftor/tezacaftor/ivacaftor (ETI) is the most effective modulator drug currently available for most people with cystic fibrosis (PwCF) (1).Data after 0.5-1 year of use show that ETI rapidly reduces sputum CF-pathogen density, although most PwCF remain infected by the bacteria present prior to treatment (1, 2).The durability of ETI-associated infection responses are uncertain, as bacterial genetic or phenotypic adaptations could reverse the improvements in pathogen density.Indeed, our previous work on the first-available modulator (ivacaftor) found that pathogen density rebounded after approximately 1-2 years in a small cohort of adults with relatively advanced lung disease (3).Here, we studied sputum collected by the prospective 27-center PROMISE-Micro study to test the hypothesis that ETI produces durable effects on the prevalence and sputum density of CF pathogens.We analyzed microbiological outcomes through 3.5 years of ETI treatment from 177 participants (see demographics in Supple- mental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI184171DS1)providing sputum before and after ETI.Data from the first 6 months, consent, methods, and cohort clinical responses were detailed previously (1).Study limitations are described in Nichols et al. (1) and include limitations inherent to studying sputum, reduced sputum production after treatment, and droplet-digital PCR's (ddPCR's) inability to distinguish live from dead bacteria.Notably, participants reported decreased use of other medicines that could improve infection outcomes after ETI initiation, including inhaled antibiotics, hypertonic saline, and recombinant human DNase (Supplemental Figure 1A).We began by measuring the prevalence of pathogen-positive sputum cultures to gauge cohort-level infection burden.Staphylococcus aureus (Sa) prevalence decreased at 2.5 years (16.2% relative reduction, P = 0.0125) but not at other time points (Figure 1A).Pseudomonas aeruginosa (Pa), and Stenotrophomonas maltophilia (Sm) prevalence decreased after 1 month (Pa relative reduction 24.8%, P = 0.0009; Sm relative reduction 61.3%, P = 0.0009), but not further through 3.5 years (Figure 1A).Eradicating infections is highly desirable, but difficult to prove using sputum.We measured the proportion of baseline culture-positive participants that had 3 or more consecutive cultureand ddPCR-negative samples, including the last provided sample, as a proxy for infection clearance.Only 1.3% (1 of 79) baseline Sa-positive and 10% (5 of 50) baseline Pa-positive participants with sufficient sputum for both analyses became repeatedly negative (Figure 1B).In contrast, 50% (11 of 22) of baseline Sm-positive participants became repeatedly negative.More participants were negative by culture alone (i.e., ignoring ddPCR results) (Figure 1B).We previously found that a similar proportion of participants became culture negative after 6 months (1); thus, 3.5 years of ETI did not substantially increase the proportion of participants becoming repeatedly negative.Notably, the probability of a participant becom-