Cystic fibrosis: Treatment with CFTR modulators

INTRODUCTION — 

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a class of drugs that act by improving production, intracellular processing, and/or function of the defective CFTR protein. These drugs represent an extraordinary advance in management of cystic fibrosis (CF) because they target the production or function of the mutant CFTR protein rather than its downstream consequences [1]. The most widely used approved modulator is the triple combination elexacaftor-tezacaftor-ivacaftor (ETI). Other approved modulators include the triple combination vanzacaftor-tezacaftor-deutivacaftor (VTD), the dual combinations tezacaftor-ivacaftor and lumacaftor-ivacaftor, and ivacaftor monotherapy. Their indications and efficacy depend on the CFTR gene mutations in an individual patient.

The CFTR modulators that have been approved in the United States are discussed in this topic review. CF-associated lung disease is discussed in the following topic reviews:

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Cystic fibrosis: Management of pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Management of advanced lung disease".)

The diagnosis and pathophysiology of CF and its manifestations in other organ systems are also discussed separately:

●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●(See "Cystic fibrosis: Genetics and pathogenesis".)

●(See "Cystic fibrosis-related diabetes mellitus".)

●(See "Cystic fibrosis: Overview of gastrointestinal disease".)

●(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

●(See "Cystic fibrosis: Nutritional issues".)

●(See "Cystic fibrosis: Hepatobiliary disease".)

DEFINITIONS

Types of CFTR modulators and their targeted mutations

●Potentiators, correctors, amplifiers, and stabilizers – The different types of CFTR modulators and the targeted classes of CFTR mutations are summarized in the table (table 1).

●Highly effective modulator therapy (HEMT) – HEMT refers to either elexacaftor-tezacaftor-ivacaftor (ETI), vanzacaftor-tezacaftor-deutivacaftor (VTD), or ivacaftor monotherapy, when used by those with at least one highly responsive CFTR mutation. In contrast, lumacaftor-ivacaftor and tezacaftor-ivacaftor have more modest effects for F508del homozygotes.

Other terms — In addition to their historical classifications, CFTR mutations have also been categorized by the severity of disease they cause and by their responsivity to existing CFTR modulators:

●Minimal function mutations – Mutations that have negligible function at baseline and do not respond to approved CFTR modulators. For example, in a clinical trial of triple combination ETI, a minimal function mutation was defined as one that produces no full-length CFTR protein (production mutation) or has a baseline chloride transport that is <10 percent of normal CFTR and increases <10 percent following incubation with tezacaftor, ivacaftor, or tezacaftor-ivacaftor [2].

●Residual function mutations – Mutations that retain some CFTR function and are often associated with a milder CFTR phenotype [3]. People with at least one residual function mutation are more likely to be pancreatic sufficient and may have later onset of disease manifestations. They usually respond to potentiators.

Clinical trials of CFTR modulators often enroll participants based on the functional activity of their mutations and their responsivity to approved modulators. For example, a clinical trial of tezacaftor-ivacaftor [4] enrolled participants with residual function mutations, which they defined as associated with average sweat chloride <86 mEq/L (1 standard deviation below the mean of F508del homozygotes) and an incidence of pancreatic insufficiency of <50 percent, based on information from publications or available databases [5]. Mutations also qualified as having residual function if in vitro testing showed an increase in chloride transport of >10 percent above the baseline level of normal cells following exposure to ivacaftor.

●Theratype – A classification of mutations based on their pattern of response to CFTR modulators, usually determined using model cell culture systems that measure the quantity, maturation, and/or function of CFTR protein [6]. Theratype classes include:

•Mutations responsive to potentiators alone (ivacaftor, deutivacaftor). Of note, elexacaftor has potentiator activity in addition to its corrector properties [7-9].

•Mutations with processing defects that are responsive to correctors (lumacaftor, tezacaftor, elexacaftor, vanzacaftor). These mutations usually require a combination of corrector(s) and potentiator to adequately recover ion channel function.

•Mutations that respond to none of the available modulators. These include nonsense, canonical splice site, frame shift, major deletion and duplication, and some missense mutations.

●Theranostics – An in vitro method to identify CFTR modulators that might benefit an individual who has no mutations approved for modulators [6]. Cells are harvested from bronchial or nasal mucosal brushings or rectal biopsies and their response to modulators tested in tissue culture.

DRUG SELECTION — 

We recommend treatment with a CFTR modulator for all people with CF, starting as soon as they are eligible by age and genotype. The indications and efficacy of these drugs depend on the CFTR mutations in the individual patient. Therefore, all people with CF should undergo CFTR genotyping to determine if they carry a mutation that is responsive to CFTR modulator therapy. If screening against a panel of CFTR mutations fails to identify two disease-causing mutations, more extensive testing such as CFTR sequencing should be used to ensure that all modulator-responsive mutations will be identified. (See "Gene test interpretation: CFTR (cystic fibrosis gene)", section on 'General principles'.)

Regulatory approvals — Our recommendations for drug selection are based primarily on regulatory approvals because these determine drug availability. Insurance companies will generally not cover the extremely high cost of modulators for off-label use. For people who are eligible for more than one approved drug, we provide guidance about the optimal drug selection, as discussed in the following sections. Ivacaftor, lumacaftor-ivacaftor, tezacaftor-ivacaftor, and ETI have received approval from the US Food and Drug Administration (FDA) in the United States, Health Canada, the European Medicines Agency, the Medicines and Healthcare products Regulatory Agency in the United Kingdom, the Australian Therapeutic Goods Administration, and others, although the approved age ranges and responsive mutations may differ [10]. Vanzacaftor-tezacaftor-deutivacaftor (VTD) is approved only in the United States.

Regulatory approvals are typically based on a few targeted short-term outcome measures. In the case of CFTR modulators, approval has been primarily based on improvements in forced expiratory volume in one second (FEV₁), symptom-related quality of life, and reduced frequency of acute pulmonary exacerbations. Of note, the extent of improvement in each of these endpoints may not track with each other. For example, in clinical trials of CFTR modulators, the frequency of pulmonary exacerbations was reduced irrespective of the change in FEV₁ [11]. Because the prevalence of the majority of CFTR mutations is to too low to allow randomized controlled clinical trials, the FDA has also approved modulator therapy for many mutations based solely on an in vitro assay (ie, theratyping) showing that a particular CFTR modulator increases chloride flux in a cell line or organoid that was genetically engineered to express a particular mutant CFTR protein [12].

The majority of the randomized controlled clinical trials of modulators have been performed in people ≥6 years old. Clinical trials of modulators in younger children have generally been smaller, open-label studies. Regulatory agencies always require demonstration of safety in younger age groups before granting approval but are willing to extrapolate evidence of efficacy from studies in older people, supplemented by favorable results using surrogate markers of efficacy, eg, improvement in sweat chloride and improved nutritional status. Of note, many children younger than six years have difficulty performing FEV₁ measurements, the primary endpoint used for approval of modulators in older people, but studies using lung clearance index, a more sensitive measure of CF-related pulmonary disease, show concordant results. It is also reassuring that studies in younger children have found reductions in sweat chloride and improvement in nutritional status similar to older people. The use of sweat chloride as a predictor of clinical benefit has been supported by studies in people with CF ≥12 years of age, which show that reductions in sweat chloride correlated with improvement in FEV₁, body mass index (BMI), rate of pulmonary exacerbations, and quality-of-life indices [13].

Because of their relatively recent introduction into CF care, extended long-term safety of these modulators has not been fully established. However, observational studies lasting up to 7.9 years for ivacaftor, 4.1 years for tezacaftor-ivacaftor, and 2.8 years for ETI have shown continuing clinical benefit and no new safety concerns [14-18].

General strategies

●Triple therapy versus dual or monotherapy – For patients with eligible genotypes, we suggest using triple combination therapy (VTD or ETI) whenever possible, rather than dual therapy or monotherapy (table 2). If a child is not eligible for a preferred therapy, due to age, we advance to that therapy when the patient meets the minimum required age. If a patient develops a clinically significant adverse reaction when changing therapies (eg, severe skin rash following start of VTD or ETI), we drop back to the prior treatment regimen.

●Age of initiation – The beneficial effects of highly effective modulator therapy (HEMT; ie, VTD or ETI for individuals with at least one copy of F508del or other highly responsive mutation or ivacaftor for those with a CFTR gating mutation) occur within days of their initiation and appear to be quite durable (see 'Elexacaftor-tezacaftor-ivacaftor' below and 'Vanzacaftor-tezacaftor-deutivacaftor' below and 'Ivacaftor monotherapy' below). Initiating HEMT at a younger age appears to improve pulmonary status later in life compared with delayed initiation of HEMT [19]. However, the effects of HEMT wane quite quickly when the drug is stopped, with sweat chloride and FEV₁ returning toward their pretreatment levels within days [20]. Severe pulmonary exacerbations that occur shortly after stopping HEMT have been reported in a small number of people [21-23].

Drug selection based on age and genotype — Our approach to modulator selection depends on the patient's age and genotype, as outlined below. The data supporting this approach are summarized in the subsequent sections focused on each drug or combination (see 'Details on specific drugs' below). Standards of care for use of CFTR modulators have been published by the United States CF Foundation, the European CF Society, and CF Canada [24-26]. Guidelines do not support the use of modulators for children with CFTR regulator-related metabolic syndrome/CF screen-positive, inconclusive diagnosis or those with CFTR-related disorder [25,27]. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

Eligibility for available CFTR modulator drugs by genotype is summarized in the table (table 2). Many people with CF will be eligible for more than one modulator drug. Our approach is based on the age group for which each drug is available (based on regulatory approvals in the United States) and relative efficacy, as outlined below.

Age <2 years

●Mutations responsive to ivacaftor alone – For infants with at least one ivacaftor-responsive mutation (G551D, other gating mutations, or residual function mutations), initiate ivacaftor at age ≥1 month (algorithm 1) [28].

●F508del homozygotes – For F508del homozygotes, initiate lumacaftor-ivacaftor at age ≥1 year.

These are the only CFTR modulator drugs approved for this age group. Children in both of these groups should be transitioned to ETI when they reach the age of ≥2 years, with the option of switching to VTD at age ≥6 years. All genotypes that are responsive to ivacaftor monotherapy are also responsive to ETI and VTD, and triple therapy is more effective compared with dual therapy or monotherapy [29,30].

Age ≥2 to <6 years — For all children with CF and any ETI-responsive mutation, initiate or switch to ETI at age ≥2 years (algorithm 2). This includes >90 percent of people with CF, including those with F508del mutations.

Although some of these children are also eligible for ivacaftor monotherapy and/ or lumacaftor-ivacaftor, ETI has superior efficacy, based on indirect evidence from older age groups [30,31]. (See 'Age ≥6 years' below.)

Age ≥6 years — After age six years, treat with either ETI or VTD rather than other CFTR modulators for all people with responsive mutations.

ETI and VTD are approved for all mutations that are approved for other CFTR modulator drugs; the VTD approval includes more than 30 additional mutations (all of which are rare). Although some may be eligible for other modulators, ETI and likely VTD have superior efficacy. Although VTD and ETI appear to have similar clinical effects, VTD has the additional advantage of once-daily dosing. It also causes a greater reduction in sweat chloride, which suggests greater correction of CFTR channel function. As a result, we anticipate that clinicians will offer VTD to many people with CF who are eligible for both ETI and VTD. However, for people with CF who have been doing well on ETI, it is reasonable to continue it rather than switching to VTD. Switching to VTD would entail more frequent blood testing for liver injury that is indicated during the first 18 months of VTD therapy. Furthermore, ETI may be less costly and there is a longer-term experience with its benefits and safety. (See 'Vanzacaftor-tezacaftor-deutivacaftor' below.)

Special populations

People with no eligible mutations — Approximately 5 percent of people with CF in the United States have no mutations that are FDA approved for modulator therapy [32]. This group includes people with nonsense mutations, canonical splice site variants, frameshifts, exon duplications/deletions, and some missense mutations. The number of people with CF who are ineligible for modulator therapy was slightly reduced by the FDA approval of an expanded list of eligible mutations in 2021 and again in 2024. The psychological burden of being in the small minority of people not eligible for HEMT, while most of the CF population qualifies for such treatment, is considerable [33,34].

Certain subgroups of people with CF, based on self-reported race and ethnicity, are more likely to have no mutations approved for modulator therapy [35]. For example, of the people enrolled in the 2023 CF Foundation Patient Registry, only 3.4 percent self-identified as Black or African American, but they represented 13.6 percent of those who are ineligible for modulator therapy; 10.6 percent of the registry population identified as Hispanic, but they represented 22.4 percent of those ineligible for modulators [36].

For people with Asian ancestry, genotypes that are ineligible for CFTR modulator therapy are even more common. In a study from the United States, Canada, and the United Kingdom, ineligible CFTR genotypes were present in 40 to 50 percent of people with South Asian ancestry and 20 to 40 percent of those with other Asian ancestry, primarily due to lower frequency of the F508del variant [37]. The existence of people with CF ineligible for modulators continues to be a substantial source of health care disparity and calls for continued efforts toward new drug development [38].

Even with the expanded list of mutations eligible for modulator therapy, there may be some people with unapproved mutations that will respond to modulators [39]. However, the high cost of modulator therapy makes third-party payors reluctant to cover off-label use, even for a brief trial. There are several strategies for building the evidence needed to support modulator use in these people:

●Theratyping using genetically modified cells – As of December 2024, the FDA had approved more than 260 mutations for ETI and/or VTD therapy based on changes in chloride flux in cells in culture (in addition to the mutations approved based on clinical outcomes). For in vitro testing, a response is defined as baseline CFTR functional activity <10 percent of normal but an increase of >10 percent of normal activity when exposed to the drug [40].

●Theranostics – Another approach to identifying people whose mutations may be responsive to HEMT is to harvest their epithelial cells from nasal, bronchial, or rectal mucosa and test the effects of modulators on cells that are cultured on porous membranes under an air-liquid interface or as monolayers or organoids [41]. Importantly, the effect of modulators on cultured nasal epithelial cells accurately predicted the person's clinical response [42]. To standardize this approach and make testing widely available, the CF Foundation is supporting a laboratory to perform testing with the expressed purpose to use the data to encourage health insurers to cover this off-label use on a case-by-case basis [43].

●Medication trials – A different innovative approach has been implemented in France, where people with CF-related advanced lung disease and no F508del mutation (which is required for ETI prescription in France) were given a four- to six-week trial of ETI under a compassionate use program and evaluated for clinical response [44]. A centralized adjudication committee identified responders based on their change in symptoms, need for supplemental oxygen or noninvasive ventilation, sweat chloride concentrations, and FEV₁. Responders were offered long-term ETI therapy that was fully reimbursed by the French national health care system. Of the 360 participants in the program who had no FDA-approved mutations, 49 percent were responders (mean increase in percent predicted FEV₁ [ppFEV₁] of 13.2 points) and therefore qualified for continued ETI therapy. There is no similar program in the United States.

People with eligible mutations but limited access to modulator drugs — The high price of CFTR modulators precludes their availability to many people. A survey published in 2024 reported that ETI was reimbursed in 35 high-income countries but only in one low-income country [45]. Providing access for all people with CF globally remains a significant challenge.

People with advanced lung disease — We recommend that people with advanced CF lung disease be treated with a CFTR modulator as indicated for their genotype and age, as outlined above (table 2 and algorithm 2) [46,47] (see "Cystic fibrosis: Management of advanced lung disease"). The evidence for use of these drugs in people with advanced lung disease is discussed in the linked sections:

●ETI (see 'Elexacaftor-tezacaftor-ivacaftor' below)

●Ivacaftor (see 'Ivacaftor monotherapy' below)

●Tezacaftor-ivacaftor (see 'Tezacaftor-ivacaftor' below)

By contrast, lumacaftor-ivacaftor is associated with high rates of adverse events in people with advanced CF lung disease [48]. (See 'Lumacaftor-ivacaftor' below.)

DETAILS ON SPECIFIC DRUGS

Elexacaftor-tezacaftor-ivacaftor — The triple drug combination of elexacaftor-tezacaftor-ivacaftor (ETI) is an important therapy for individuals who have at least one F508del mutation and for those with any other CFTR gene mutation that is responsive, based on in vitro and/or clinical trial data. ETI is approved in the United States and many other parts of the world, including countries in Europe, South and Central America, the Middle East, Asia, and Oceania [10].

Approximately 95 percent of people with CF in the United States have a CFTR genotype that makes them eligible for this therapy once they reach two years of age, which is the threshold approved by the US Food and Drug Administration (FDA) [36]. Vanzacaftor-tezacaftor-deutivacaftor (VTD) is a similar combination drug that is approved for use beginning at six years of age. (See 'Vanzacaftor-tezacaftor-deutivacaftor' below.)

Indications — ETI is a first-line therapy for people with CF ≥2 years of age with at least one ETI-responsive mutation. This includes F508del homozygotes or heterozygotes and more than 270 other mutations. The list of approved mutations differs slightly between the United States and Europe, as outlined in the table (table 2) [40,49]. In particular, genotypes approved in Europe include all those approved in the United States, plus some additional nonclass I CFTR mutations. ETI is not approved for children <2 years. (See 'Age <2 years' above.)

All genotypes that are eligible for ETI are also eligible for VTD, and clinical effects are generally similar. Considerations for selecting between these drugs are outlined below. (See 'Vanzacaftor-tezacaftor-deutivacaftor' below.)

Some people who have mutations approved for ETI also meet the eligibility criteria for dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) or monotherapy with ivacaftor. For these people, we suggest starting on the maximal therapy available for the age group (ie, ETI > dual therapy > monotherapy). We then advance the therapy when the patient meets the age criterion for each drug combination. If a patient develops a clinically significant adverse reaction when changing therapies (eg, skin rash following start of ETI), we drop back to the prior treatment regimen. There are no data regarding the safety of starting VTD in those who previously discontinued modulators due to adverse reactions.

Dosing and administration — ETI is dosed as follows [40]:

●Age ≥2 to <6 years:

•Weight <14 kg – One combination packet (containing elexacaftor 80 mg, tezacaftor 40 mg, and ivacaftor 60 mg) taken orally in the morning and one ivacaftor packet (containing ivacaftor 59.5 mg) taken orally in the evening

•Weight ≥14 kg – One combination packet (containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) taken orally in the morning and one ivacaftor packet (containing ivacaftor 75 mg) taken orally in the evening

●Age ≥6 to <12 years:

•Weight <30 kg – Two combination tablets (each containing elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg) taken orally in the morning and one ivacaftor tablet (containing ivacaftor 75 mg) taken orally in the evening

•Weight ≥30 kg – Two combination tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) taken orally in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken orally in the evening

●Age ≥12 years – Two combination tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) taken orally in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken orally in the evening

ETI should be taken with fat-containing food. It should not be used in people with severe hepatic impairment (Child-Pugh C) but may be used at reduced dose in people with mild or moderate hepatic impairment (Child-Pugh A or B) if there is a clear medical need and the clinician judges that the benefit outweighs the risk [40]. Liver-related tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase, and bilirubin) should be measured before starting ETI and then monthly during the first six months, every three months during the next year, and annually thereafter. Treatment should be interrupted for those with significant elevations (see 'Drug-induced liver injury' below). Dose alterations for those taking drugs that effect cytochrome P450 3A (CYP3A) activity are listed in the prescribing information [40].

Drug and food interactions — ETI (and other CFTR modulators) should be taken with fat-containing foods because it improves absorption 1.9- to 2.5-fold for elexacaftor and 2.5- to 4-fold for ivacaftor [40]. Dose reductions are needed for people with moderate hepatic impairment (Child-Pugh class B) or those who are taking drugs that are inhibitors of CYP3A4 such as itraconazole, clarithromycin, fluconazole, or nirmatrelvir-ritonavir (an antiviral agent for coronavirus disease 2019 [COVID-19]). Coadministration of ETI with CYP3A4 inducers such as rifampin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended, because these drugs markedly decrease ivacaftor exposure and are expected to decrease elexacaftor, vanzacaftor, and tezacaftor exposure as well, which may reduce ETI efficacy [40]. However, the inhibitory effect of rifabutin on CYP3A4 is less than rifampin and preliminary evidence suggests that it may be used in conjunction with ETI or ivacaftor without losing modulator effectiveness [50]. Grapefruit also inhibits CYP3A4 and should be avoided [51].

Elexacaftor may increase exposures to statins, glyburide, nateglinide, and repaglinide because it is an inhibitor of the organic anion-transporting polypeptide (OATP) 1B1 and 1B3. By contrast, vanzacaftor does not inhibit OATPs and is not expected to cause the increases in serum bilirubin that occurs in some people with ETI. For details and guidance on drug interactions and dose reductions, refer to the drug interactions program, the drug monograph on elexacaftor-tezacaftor-ivacaftor, or the manufacturer's prescribing information [40].

The manufacturer's prescribing information makes no recommendation regarding measuring serum drug levels or making dose adjustments based on them. However, of note, postmarketing studies have reported considerable variation in levels between individuals taking ETI [52,53]. There are no studies that show a correlation between blood levels and the amount of clinical improvement or incidence of adverse effects.

Efficacy — Elexacaftor was identified by the same high-throughput screening strategy that identified other CFTR modulators. The combination of elexacaftor with tezacaftor-ivacaftor increased the level of chloride transport in human bronchial epithelial cells heterozygote for F508del to approximately 50 percent of normal and even higher in homozygous F508del cells [54]. ETI causes large increases in CFTR channel function in people homozygous or heterozygous for F508del, as measured by changes in sweat chloride, nasal potential difference, and intestinal electrical current [55]. Although sweat chloride decreases in virtually all people with CF following initiation of highly effective modulator therapy (HEMT), 21 percent of those on ETI and 36 percent of those on ivacaftor continue to have a sweat chloride level >60 mmol/L, which is in the range needed to support a CF diagnosis [56,57].

ETI was approved in the United States for adults and adolescents ≥12 years in 2019 [2,29] and extended to children ≥6 years in 2021 and to children ≥2 years in 2023 [40].

Survival — The introduction of ETI has been associated with a dramatic, unprecedented increase in predicted survival in the CF population (figure 1). The CF Foundation Patient Registry reported that, in 2023, the median predicted age of survival of people with CF reached 68.0 years, an increase from 48.4 in 2019, which was the last year before widespread use of ETI in the United States [36]. The death rate declined from 1.2 deaths per 100 individuals in 2019 to 0.7 in 2023. The increased longevity has been accompanied by improved wellbeing in both pulmonary and nonpulmonary manifestations of the disease.

Pulmonary outcomes — The key clinical trials are:

●Age >12 years with at least one F508del mutation

•Effect on pulmonary function – Multiple clinical trials have demonstrated substantial benefits of ETI for individuals with at least one F508del mutation [2,16,17,29,30,58-60]. This includes trials in F508del homozygotes or heterozygotes with a second minimal function mutation, in which ETI improved forced expiratory volume in one second (FEV₁) by 10 to 15 percentage points. There were associated improvements in respiratory symptoms, reductions in pulmonary exacerbation rates by 63 to 73 percent, reductions in sweat chloride concentrations by 42 to 46 mEq/L, and large increases in a quality-of-life index.

In almost three years of follow-up including open-label extensions of randomized clinical trials, participants treated with ETI experienced no loss in FEV₁, in contrast with the FEV₁ decline observed in untreated control populations. Fewer than 3 percent of trial participants had adverse events that led to discontinuation of ETI [17,61]. An observational registry-based study following people on ETI for two years likewise reported sustained improvement in FEV₁ and reduction in pulmonary exacerbation rate [62], but a retrospective, single-center study found that the reduction in exacerbations was more pronounced in males than in females for unknown reasons [63]. The symptomatic improvements from ETI are easily perceived by most people with CF and help explain the ≥90 percent adherence rate, which is much higher than the rates for other CF pulmonary therapies [64]. Observational studies using chest computed tomography (CT) imaging before and after one year of treatment with ETI showed reduction in trapped air, mucus plugging, and bronchial wall thickening but not bronchiectasis scores [65,66]. Magnetic resonance imaging (MRI) showed significant improvements from baseline in measures of bronchiectasis/wall thickening and mucus plugging after at least one month of ETI compared with a control group [67]. Of note, a study of 235 adults treated with ETI reported that 5 percent of participants showed a significant reduction in CT evidence of cylindrical bronchiectasis, contrary to the common assumption that bronchiectasis is irreversible in adults [68]. Other studies have shown reduction in CF-related cavitary lesions following ETI [69,70].

•Comparison with other modulators – For individuals who are eligible for more than one type of CFTR modulator (ie, those with F508del and a second gating or residual function mutation), ETI treatment improved respiratory symptoms compared with active control (tezacaftor-ivacaftor or ivacaftor), with more modest improvement in percent predicted FEV₁ (ppFEV₁; 3.5 points compared with active control at eight weeks) [30]. These findings support our recommendation for using ETI rather than dual therapy or monotherapy for people who are eligible. (See 'General strategies' above.)

•Implications for other treatments – With the marked improvement in respiratory status from HEMT (ie, ETI for individuals with at least one copy of F508del or ivacaftor for those with a CFTR gating mutation), many people with CF and caregivers have asked whether any of the frequently prescribed pulmonary therapies can be discontinued without causing adverse effects. As a partial answer to this question, both prospective and retrospective studies have shown that withdrawal of inhaled dornase alfa (DNase), hypertonic saline, or both does not reduce mucociliary clearance rates and has no short-term adverse clinical consequences, even for those with advanced lung disease [1,71-74]. However, even before these results became available, the use of inhaled medications had begun to decrease following approval of ETI as people with CF and/or their clinicians began to scale back treatments [36]. The advisability of reducing chronic treatments beyond DNase and hypertonic saline will need to await results from additional clinical studies, such as one that is underway in the United Kingdom [75]. Meanwhile, some clinicians have expressed concern that discontinuing DNase, particularly in those with advanced CF lung disease, may be ill advised, given the evidence of continuing airway infection and inflammation despite ETI [76]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Inhaled airway clearance agents'.)

•Effect on chronic airway infection – In those people with CF who have chronic airway infection, ETI often reduces the density of bacteria but rarely eradicates the species. A prospective study of 177 people who were followed for 3.5 years after starting ETI found it uncommon for those chronically infected with Staphylococcus aureus or Pseudomonas aeruginosa to become consistently negative by culture or nonculture-based methods [77]. Of those remaining culture positive, there were modest decreases in bacterial densities. In contrast, 50 percent of those with Stenotrophomonas maltophilia became consistently negative. A retrospective study reported that one year of ETI was associated with small decreases in the prevalence of positive cultures for P. aeruginosa, S. aureus (methicillin-sensitive and -resistant), S. maltophilia, and Achromobacter species [78]. Regarding nontuberculous mycobacteria, a small retrospective study reported that the frequency of positive cultures obtained during the year after initiating ETI decreased compared with the rate during the preceding two years [79]. A majority of the participants (9 of 16) became culture negative, most of whom had been infected with Mycobacterium abscessus complex. ETI also reduced the frequency of positive tests for Aspergillus fumigatus from 28 percent to 4.6 percent in a study of 114 people with CF using a polymerase chain reaction-based assay [80]. ETI also reduced biomarkers of inflammation in sputum, nasal sinuses, blood, and stool [81-87].

●Younger children – Trials of ETI in younger children yielded similar results. A randomized study of children 6 to 11 years old who were heterozygous for F508del and minimal function mutations found that 24 weeks of ETI improved ppFEV₁ by 11 points compared with placebo [60]. Similar increases in FEV₁ were seen in open-label trials, with sustained effects for at least 96 weeks [16,59]. Open-label studies of ETI in children 2 to <6 years reported improvements in lung clearance index and an MRI assessment of anatomic lung disease [88].

●Other mutations – Many CFTR mutations that are proven to be disease causing are too rare to be studied individually in clinical trials of CFTR modulators. In recognition of this fact, the FDA approved ETI for 237 of these rare mutations based on its ability to improve chloride transport by >10 percent of the normal CFTR level using a validated cell culture system [12,39,40]. A registry-based study confirmed that in vitro responsivity to ETI translated into clinical benefit for those with non-F508del-responsive mutations [89]. Specifically, ETI treatment increased ppFEV₁ by 3.4 points for the full group of 546 participants and by 4.6 points for those not on previous modulator therapy. The frequency of pulmonary exacerbations treated with intravenous antibiotics decreased by 45 percent.

●People with mild lung disease – The randomized controlled trials of ETI that led to regulatory approval enrolled participants with mild to moderate CF-related lung disease (ppFEV₁ between 40 and 90). However, efficacy of ETI for people with even milder disease was demonstrated in a subsequent randomized controlled trial in which approximately one-third of the children enrolled had a baseline ppFEV₁ between 70 and 90 and one-half had a baseline ppFEV₁ >90 [60]. Following regulatory approval, another large prospective study that enrolled people with a baseline ppFEV₁ >90 percent reported a ppFEV₁ increase of 6.5 points and improvement in a quality-of-life index [90]. This and other studies support the use of ETI in those with normal-range FEV₁ [62,91].

●People with advanced lung disease – In an observational study in France of 434 people with advanced CF lung disease, treatment with ETI for one to two years was associated with marked improvement in lung function [47]. After one month of therapy, the mean increase in ppFEV₁ was 14.2 points (95% CI 13.1-15.4) and this improvement persisted throughout the study. During the two-year follow-up, the proportion of participants prescribed oxygen therapy decreased from 45 to 5 percent, noninvasive ventilation decreased from 24 to 10 percent, and few participants proceeded to lung transplantation (5 of the 69 candidates). There were fewer hospitalizations for pulmonary exacerbations, and there were measurable improvements in nutritional status and CF-related diabetes. Similar levels of clinical improvement in people with advanced CF lung disease were observed in two smaller retrospective studies performed in the United States and Ireland [92,93].

Of note, studies from France and Germany reported more than 50 percent reductions in CF lung transplants in the years immediately following ETI approval [94,95]. The timing and pattern of the decrease was most compatible with an ETI effect and not merely secondary to the COVID-19 pandemic, during which rates of lung transplantation fell off initially for all indications [96]. Among 65 candidates for lung transplantation, initiation of ETI was associated with a 13.4-point improvement in ppFEV₁ that then remained stable after a median follow-up of one year [97]. Sixty-one of these people were removed from transplant consideration and remained off of the transplant list during the one-year follow-up. Similar reduction in the rate of lung transplantation following initiation of ETI was seen in studies and a patient registry from the United States (figure 2) [62,98]. These observations have led the International Society for Heart and Lung Transplantation to recommend that all individuals with eligible genotypes have a trial of ETI before their assessment for lung transplant listing [99].

Nonpulmonary outcomes — The primary endpoint for the phase 3 clinical trials of CFTR modulators have been based on changes in pulmonary status, namely FEV₁. However, some of the secondary endpoints and other data collected during these and subsequent studies address a variety of extrapulmonary effects of modulator therapy. The following discussion reviews these findings, with particular focus on ETI.

●Quality of life – The pivotal studies of ETI used the respiratory domain of a quality-of-life questionnaire, Cystic Fibrosis Questionnaire-Revised (CFQ-R) [100], as a secondary efficacy endpoint and found striking improvements [2,29]. Further analysis of CFQ-R data has shown that the benefits extend to other quality-of-life domains such as overall physical and emotional functioning [101].

●Gastrointestinal disease and nutrition – Previous studies have shown that people with CF often have low body mass index and reduced lean body mass and fat mass relative to the general population [102]. In all of the clinical trials described above, ETI increased body weight and BMI compared with control groups [2,29,30,58] (see "Cystic fibrosis: Overview of gastrointestinal disease"). However, of note, much of the weight gain appears to be in adipose tissue and much less in muscle [103].

A beneficial effect of ETI on gastrointestinal absorption can be inferred by the observation that ETI increased serum concentrations of vitamins A and D, which are fat-soluble vitamins that are frequently low in people with CF, as well as improvements in measures of iron stores [60,104-107]. In fact, some people who were taking high doses of vitamin A supplements developed toxic levels after beginning ETI [108,109]. Other benefits from ETI include more rapid small bowel transit time, which is typically delayed in people with CF [110]. The effects of ETI on gastrointestinal symptoms such as abdominal pain and bloating have been mixed. In a prospective study of 438 people with CF age >12 years, ETI treatment for six months was associated with modest improvement in gastrointestinal symptom scores that were probably not clinically significant [111]. However, a study of 107 people with CF at eight European CF centers reported significant improvements using a validated patient-reported symptom score [82]. A reduction in gastroesophageal reflux symptoms has also been reported [112].

●Liver disease – Hepatobiliary disease is a common manifestation of CF with advanced disease (cirrhosis), reported in 2.9 percent of people in the CF Foundation Patient Registry [36]. Theoretically, ETI could reduce progression of CF-related liver disease by restoring CFTR function or could worsen it in those people who develop increased concentrations of transaminases [113]. Fortunately, in a study of 74 adults with CF-related liver disease, elastography, an ultrasound-based technique that detects fibrosis, found no evidence of increased liver stiffness after a median of 21 months of ETI [114]. In a cohort of children with CF-related liver disease, ETI reduced liver stiffness and improved liver function tests [115].

There is little information about the use of modulators in more advanced liver disease. The manufacturer's prescribing information states that ETI should not be used in severe hepatic impairment (Child-Pugh C) and only if the benefits outweigh the risk in those with moderate impairment (Child-Pugh B) [40]. In a study of 11 children with portal hypertension (but still Child-Pugh A), ETI improved FEV₁ and nutritional status without worsening hepatic biochemistries or the clinical course of the liver disease [116]. (See "Cystic fibrosis: Hepatobiliary disease".)

●Pancreatic insufficiency – Preliminary evidence suggests that HEMT may be effective at preventing, delaying, or, possibly, reversing pancreatic insufficiency when begun in early childhood [77,117,118]. For example, open-label studies of ivacaftor in infants and children with gating mutations and ETI in children with responsive mutations showed improvement in exocrine pancreatic function [88,119,120].

By contrast, it is unlikely that modulators will reverse longstanding pancreatic insufficiency (see "Cystic fibrosis: Assessment and management of pancreatic insufficiency"). In fact, a small observational study reported no improvement in fecal elastase during ivacaftor treatment in adolescents and adults with a CFTR gating mutation despite the known benefits of ivacaftor on the lung disease in these people [121] (see 'Ivacaftor monotherapy' below). A prospective study of 99 people with CF 12 years and older showed a small but clinically insignificant increase in fecal elastase measured six months after starting ETI [111].

A survey of people with CF and their clinicians found that, following initiation of ETI, some decreased and occasionally discontinued their pancreatic enzyme replacement therapy [122]. One explanation is that, prior to ETI therapy, these people had malabsorption due to poor hydration of the intestinal mucosa, which caused them to escalate enzyme doses beyond the level required for digestion. The ETI therapy restored mucosal hydration and absorption, thus permitting deescalation of the enzyme dose. Therefore, following initiation of ETI, we suggest that clinicians reassess enzyme doses to determine if reductions are appropriate.

●Pancreatitis – Acute pancreatitis is a known complication of the subgroup of people with CF who have residual pancreatic function (see "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'). Limited evidence from case series suggest variable effects of CFTR modulators on pancreatitis; most people with recurrent pancreatitis due to CF have an improved course after beginning CFTR modulators [117,123-125]. This is probably because these individuals had moderately impaired pancreatic function at baseline and modulator therapy improved pancreatic function sufficiently to put them out of the risk range for pancreatitis. Conversely, a few reports describe people with CF who first developed pancreatitis after starting CFTR modulators [126,127]. This is probably because they had pancreatic insufficiency at baseline and the modulator improved CFTR function sufficiently to move them into the risk range for pancreatitis. (See "Pancreatitis associated with genetic risk factors", section on 'CFTR modulator therapy'.)

●CF-related diabetes – Several observational studies of people without diagnosed CF-related diabetes reported improvement in glycemic control following initiation of ETI, while another did not [128-132]. The studies had conflicting results regarding effects of ETI on glycemic control in individuals who had been diagnosed with CF-related diabetes, but more recent studies suggest some benefit [133-135]. (See "Cystic fibrosis-related diabetes mellitus".)

●Sinonasal disease – The majority of people with CF have symptoms of nasal congestion and sinusitis, often requiring chronic treatment and, occasionally, surgery. Initiation of ETI improves sinusitis symptoms, nasal polyps, sense of smell, and CT manifestations of CF sinonasal disease [67,136-139]. People taking ETI are also less likely to undergo fiberoptic sinus surgery [140].

Adverse effects — ETI was generally well tolerated during the clinical trials described above. In particular, discontinuation of study drug due to adverse events during a 24-week trial of subjects heterozygous for F508del occurred in 1 percent of those receiving ETI and 0 percent of those receiving placebo [2]. Serious adverse events occurred less frequently in the group receiving ETI (13.9 percent) compared with placebo (20.9 percent).

Adverse reactions that occurred more frequently in the ETI group compared with placebo included (reported here as percentages): abdominal pain (14 versus 9), diarrhea (13 versus 7), rash (10 versus 5), increased blood alanine aminotransferase (ALT; 10 versus 5) or aspartate aminotransferase (AST; 9 versus 2), increased blood creatine phosphokinase (9 versus 4), rhinorrhea (8 versus 3), and "influenza" (7 versus 1). These rates of adverse events are similar to those reported in other prospective placebo-controlled trials of ETI in people homozygous for F508del [58].

The safety of ETI in younger children was evaluated in two 24-week open-label studies in children with at least one F508del mutation who were 6 to 11 years old (n = 66) or 2 to <6 years (n = 75) [59,60,88]. The safety profile and pharmacokinetics were similar to those in older individuals, with improvements in secondary efficacy measures (see 'Efficacy' above). On the basis of this study, the drug combination was approved by the FDA for these age groups [40].

Specific safety concerns include:

Drug-induced liver injury — Severe liver injury leading to liver transplantation or death has been observed infrequently during clinical trials and postmarketing in people taking ETI. The events occurred as early as the first month and as late as 15 months of drug exposure in those with and without underlying liver disease. These reports prompted the FDA to require a boxed warning on the manufacturer's prescribing information that included an increased frequency of blood test monitoring (see below) [40].

●Incidence and severity – Determining the true rate of modulator-induced liver injury is confounded by the relatively high background prevalence of CF-related liver disease [113,141]. Increased ALT and/or AST occurred in 5 to 7 percent more subjects receiving ETI compared with placebo in the phase 3 clinical trials [40]. However, only approximately 0.6 percent of participants in the various placebo-controlled clinical trials had to permanently stop taking ETI due to transaminase elevations. Similar frequencies of discontinuation for elevated transaminases were seen in long-term open-label trials of lumacaftor-ivacaftor [142,143] and tezacaftor-ivacaftor [15]. Real-world experience found results similar to those reported in the clinical trials [144]. (See "Cystic fibrosis: Hepatobiliary disease", section on 'CFTR modulator-induced liver injury'.)

Analysis of cases that were submitted postmarketing to the FDA's Adverse Event Reporting System found a statistically significant association between ETI and liver injury in a pattern that suggested a possible causal relationship [145].

●Monitoring for liver injury – The FDA labeling instructs that AST, ALT, alkaline phosphatase, and bilirubin should be measured before starting ETI and then monthly during the first six months, every three months during the next year, and annually thereafter. This represents an increased frequency of blood testing during the first 18 months of therapy compared with the original label instructions.

●Modulator drug interruption – ETI treatment should be interrupted for people with any of the following:

•Clinical signs and symptoms of liver injury

•ALT or AST is >5× the upper limit of normal (ULN)

•ALT or AST is >2× the ULN in conjunction with total bilirubin >2× ULN

A combined increase in both transaminases and bilirubin is indicative of a more severe liver injury because both hepatocyte integrity (transaminase leak) and synthetic function (decreased bilirubin clearance) are compromised.

●Reinitiation of ETI treatment – A thorough search for other causes of liver disease should be performed because alternative etiologies are frequently found, allowing reinitiation of treatment [146] (see "Approach to the patient with abnormal liver tests"). After resolution of signs and symptoms of liver disease and normalization of liver function tests, ETI treatment may be restarted if the treatment benefit is considered to outweigh the risk but only with frequent transaminase monitoring. However, in the absence of an alternative diagnosis, the presence of both transaminase and bilirubin elevation is associated with a higher risk of severe liver injury following rechallenge. There is no evidence that restarting at a reduced dose is more successful than using the full recommended dose. During the clinical trials of ETI that supported regulatory approval, the majority of those who interrupted treatment due to liver test abnormalities successfully restarted ETI at full dose [40].

●Bilirubin elevations – Bilirubin increase in conjunction with elevated transaminases is indicative of a severe drug-induced liver injury, as outlined above. In contrast, isolated elevations of total and indirect serum bilirubin are common in people receiving ETI because elexacaftor is an inhibitor of OATP1B1 and OATP1B3, which facilitate uptake of unconjugated bilirubin from blood into hepatocytes. People with CF who also have Gilbert syndrome (which may not have been previously recognized) are more likely to have bilirubin elevations after starting ETI [147,148] (see "Gilbert syndrome"). In the absence of concomitant elevations in transaminases or symptoms of liver injury, ETI does not need to be interrupted.

Other adverse effects

●Blood pressure elevations – Mild increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were noted during controlled clinical trials in subjects randomized to ETI (SBP increased by 3.5 mmHg and DBP by 1.9 mmHg) compared with placebo (SBP increased by 0.9 mmHg and DBP by 0.5 mmHg) [40]. SBP elevations above 140 mmHg with an increase of at least 10 mmHg above baseline on two occasions occurred in 4 percent in the ETI group compared with 1 percent in the placebo group. Similar changes were found in a retrospective single-center study of 134 people in whom initiation of ETI was associated with an increase of 4.8 mmHg in mean SBP and 3.5 mmHg in DBP [128]. Postmarketing, a case series reported four individuals who were started on antihypertensive treatment soon after beginning ETI [149].

●Mental health effects – The possibility of adverse mental health effects of ETI is discussed below. (See 'Mental health effects' below.)

●Cataracts – When cataracts were detected during preclinical studies of juvenile rats exposed to ivacaftor in the early postnatal period, a cataract warning was added to the package inserts of all CFTR modulators. Noncongenital cataracts have been reported postmarketing in children with CF, but some of them had other risk factors for developing cataracts, such as corticosteroid use. Of note, people with CF have a higher incidence of cataracts compared with the general population, based on analysis of a large United States health insurance claims database performed before approval of ETI [150]. The package inserts recommend that children and adolescents undergo an ophthalmologic examination before and during treatment with ivacaftor-containing medications. The interval between starting medication and follow-up ophthalmologic examination is not stipulated in the package insert. Clinical trial protocols for ETI conducted the second examination as long as 48 weeks after starting ETI (NCT04043806). A common clinical practice is to repeat examinations annually until age 18 years.

Cataracts were not observed in newborn rats or ferrets exposed to ivacaftor in utero [151,152]. However, a study of 23 neonates born to mothers with CF who took ETI during pregnancy and lactation reported bilateral cataracts in three [153]. Although the cataracts were described as causing no significant visual impairment and were nonprogressive, this observation should be shared with women considering use of ETI during pregnancy and lactation. Some CF centers are routinely performing ophthalmologic examinations on infants born to mothers who took ETI during pregnancy and lactation.

●Creatine phosphokinase elevation – Routine safety monitoring during ETI clinical trials noted that episodic creatine phosphokinase elevations of greater than 10 times the ULN were seen more frequently in study participants receiving active drug (9 percent) than placebo (4 percent) [40]. Some, but not all, of the participants reported recent heavy exercise. ETI was occasionally interrupted because of these elevations, but no study participants permanently discontinued treatment. Postmarketing, a case series described four cases in which ETI was interrupted or discontinued in part due to elevated creatine phosphokinase levels [154]. The low frequency of significant elevations and lack of meaningful consequences suggest that routine monitoring is not indicated.

●Serum lipid alterations – Historically, coronary artery disease has been considered rare in people with CF, a finding that is attributed to the CF population being younger and having low rates of obesity and serum cholesterol. However, cases of myocardial infarction have been reported [155] and there is concern that HEMT will increase the rate of cardiovascular disease. A worrisome driver of this is the finding that ETI is associated with increases in serum cholesterol, low-density lipoprotein cholesterol, and prevalence of obesity [128,156,157]. The mechanism responsible for the increased serum cholesterol appears to be enhanced absorption from the intestinal tract [158]. The frequency of people with CF meeting criteria for metabolic syndrome increased following start of ETI [159]. When data from people with CF are entered into cardiac risk assessment tools developed for the general population, the results show that many people with CF have elevated risk levels, but it is uncertain if these tools are valid for people with CF [160,161].

●Raised intracranial pressure – A few case reports describe raised intracranial pressure after initiating ETI therapy [16,108,162]. Presenting symptoms included headache, papilledema, and (in two cases) sixth cranial nerve palsy. The overall rate in clinical trials was low (0.2 per 1000 patient-years) and may be within the background rate for the CF population [16,163]. Increased vitamin A concentrations have been suggested but not established as a causative mechanism.

Mental health effects — A preponderance of clinical evidence indicates that ETI has a net beneficial effect on mental health. Nonetheless, monitoring of mental health remains an important part of care for people with CF and is particularly relevant during initiation or escalation of CFTR modulator therapy.

A net benefit on mental health is suggested by the highest-quality evidence, collected during the pivotal phase 3 clinical trials of ETI [2,29], in which the CFQ-R (a validated CF-specific patient-reported outcome survey) detected improvements in "emotional functioning" and "social functioning/school functioning," in addition to improvements in respiratory symptom scores and all other CFQ-R domains [101]. Furthermore, none of these clinical trials found an association between ETI and adverse psychiatric events. These studies included randomized placebo-controlled trials in those age six years and older [2,29,30,58,60] and their open-label extensions [16,17,59,164,165]. Another phase 3 open-label trial in two- to five-year-olds likewise reported no adverse mental health events above that seen in the general population [88,166]. These findings are further supported by subsequent observational studies [167-172]. As examples, a longitudinal study of 150 adolescents and young adults with CF who were monitored from 2016 to 2021 showed overall improvement in mean scores on the Patient Health Questionnaire-9 (PHQ-9; a measure of depression) and the Generalized Anxiety Disorder-7 (GAD-7; a measure of anxiety) and the improvement correlated with increased use of more effective CFTR modulators [173]. Similarly, a prospective study of 93 adolescents and adults following initiation of ETI found improvements in a cognitive functioning test and in mean values of PHQ-9 and GAD-7 and no increases in the number of participants in the moderate or severe categories of depression or anxiety [167]. Finally, a comprehensive analysis of clinical trial results, postmarketing reports, and a registry-based safety study found no evidence indicating a causal relationship between ETI and depression [171].

However, the possibility of adverse mental health effects of ETI has been raised in the postmarketing period. This is based on a steady stream of inconclusive evidence (case series, retrospective studies, a few prospective studies, and pharmacovigilance reports), mostly in adolescents and adults, reporting increased frequency of depression, anxiety, insomnia, and/or "fogginess" after starting ETI [168,174-182]. Similar symptoms have been reported following initiation of lumacaftor-ivacaftor [169,175,183].

These observational reports of an association between CFTR modulator treatment and worsening mental health do not establish a causal relationship, a determination that is made difficult by the high background prevalence and fluctuating course of anxiety and depression in people with CF [184]. A systematic review and meta-analysis of publications from 1989 to 2020 reported that the prevalence of depression and anxiety in adults with CF was 27.2 and 28.4 percent, respectively, and in adolescents was 18.7 and 26.0 percent, respectively [185]. An additional confounder is that ETI became commercially available just prior to the start of the COVID-19 pandemic, which is known to have had adverse effects on mental health in the general population [164,165]. In a report of 81 people with CF who were experiencing increased symptoms of depression and/or anxiety, 40 percent attributed their worsened symptoms to COVID-19 and 9 percent to ETI [186]. Reassuringly, it is noteworthy that even in a large observational study in two- to five-year-olds that reported a high incidence of adverse mental health effects after starting ETI, very few stopped their treatment [187]. In this study, no correlation was found between blood levels of ETI and the incidence of mental health complaints. Nonetheless, recommendations for dose reductions have been published for those whose mental health declines were temporally related to starting ETI [52,176,177,188].

It is possible that people experiencing mental health problems are more likely to attribute them to ETI because of the increasing public speculation about a causal effect, including in social media posts (a nocebo effect) [178,179,187]. Another possible factor is that starting ETI presents the challenge of adjusting to the responsibilities of a much longer life expectancy that is less dominated by the effects of CF; this mechanism has been suggested by mental health clinicians who work with this population but not yet explored in clinical research.

Despite the limitations of these anecdotal postmarketing reports of depression in patients treated with ETI, the European Medicines Agency added a warning to the ETI product information stating that people treated with ETI should be alerted to monitor and seek medical advice for depressed mood, suicidal thoughts, or unusual changes in behavior [189]. The advisory statement also comments that these problems usually occur within three months of starting treatment and in those with a history of psychiatric disorders. Guidelines from the European CF Society recommend screening for mental health problems prior to and within three months after starting modulator therapy [25]. The FDA has not required a similar warning on the package labeling [40].

While clinical studies have supported a net mental health benefit of ETI, only large placebo-controlled trials can definitively determine whether there exists a small number of people who develop worsening mental health effects due to a direct effect of ETI. However, it is unlikely that such trials should or will be performed, given the many established benefits of ETI. In the absence of randomized, placebo-controlled trials, continued monitoring for the impact of ETI on mental health via phase 4 studies remains important.

Considerations for special populations

Pregnancy and lactation

●Effects on fertility – Following approval of ETI, the average number of pregnancies per year among people with CF in the United States rose sharply from 264 (2012 through 2019) to 651 (2020 through 2023) (figure 3) [36]. Possible explanations for this large increase are an ETI-induced improvement in overall health leading to a decision to become pregnant, the reversal of some of the abnormal properties of cervical mucus that were impairing sperm penetration and fertilization, and better overall health leading to fewer anovulatory cycles.

●Safety during pregnancy – All of the approved CFTR modulators cross the placenta. In preclinical studies in rats, there was no evidence of teratogenicity at clinically relevant doses [40]. Data from humans regarding modulator use during pregnancy are very limited, but small retrospective surveys and case reports have reported outcomes similar to that expected from CF pregnancies [190-192]. A study of three maternal-infant pairs reported that cord blood of babies born to CF mothers taking ETI had levels of each of the modulators similar to those measured in maternal blood [193]. Cataracts have been reported in newborn children exposed to ETI in utero. (See 'Other adverse effects' above.)

A few case reports describe carriers (heterozygotes) for a disease-causing CFTR mutation who were pregnant with a fetus that had CF and had findings consistent with meconium ileus on prenatal ultrasound [194-197]. If the pregnant woman initiated ETI by 32 weeks gestation (an off-label use), the ultrasound abnormalities resolved and the infant did not have meconium ileus at birth.

A large prospective study of modulators in pregnancy is underway to assess the effects of CFTR modulators during and for two years following pregnancy (NCT04828382) [198].

●Effects on newborn screening – Children with CF born to mothers taking ETI may have negative newborn screening tests for CF due to a beneficial effect of ETI exposure on pancreatic development/function [194,199,200]. In fact, a case report describes a mother and father without CF (both F508del heterozygotes) with a fetus diagnosed with CF by amniocentesis that developed ultrasound findings of meconium ileus in utero [194]. The mother was given off-label ETI, after which the ultrasound abnormalities resolved. The child was born healthy and had a negative newborn screening test for CF. Analysis of newborn screening data from Indiana showed that immunoreactive trypsinogen levels were lower in infants of mothers taking ETI during pregnancy [200].

●Safety during lactation – All of the approved CFTR modulators were detectable in the milk of lactating rats [40,201]. At present, minimal information is available regarding levels of ETI in human breast milk but, of note, the aforementioned study of three maternal-infant pairs reported detectable levels of ETI in breast milk [193].

Post-transplant

●Lung transplant – Because donor lungs have normal CFTR function, CFTR modulator therapy would be expected to have no direct benefit for the transplanted lungs. However, ETI is increasingly prescribed to lung transplant recipients because of their beneficial effects on other organs (see 'Nonpulmonary outcomes' above). Thus, it is reasonable to offer CFTR modulators after lung transplantation for people with burdensome nonpulmonary signs and symptoms, consistent with guidelines from the European CF Society [25].

Information regarding the use of CFTR modulators after lung transplantation is limited to retrospective case series and clinician surveys [202]. Virtually all lung transplant recipients continue to have significant nonpulmonary CF disease manifestations that can respond to HEMT. In a case series of 94 people who were prescribed ETI after lung transplantation, the predominant indications for the CFTR modulator were sinus disease (68 percent), gastrointestinal symptoms (39 percent), low BMI (19 percent), and/or patient preference (45 percent) [203]. Little information was collected regarding benefits or adverse effects after initiating the CFTR modulator, but it was noted that BMI did not change and that hemoglobin A1c decreased slightly. Of note, 42 percent of the participants discontinued modulator therapy after a median of 56 days, primarily due to gastrointestinal symptoms or no perceived benefit.

Smaller studies reported that ETI after lung transplantation was associated with slight improvement in BMI, nonpulmonary symptoms, and fasting glucose level [204,205]. Sinus and gastrointestinal symptoms improved in the majority. Drug-drug interactions were reported to have caused minimal problems with immunosuppressive therapy.

If ETI is used post-transplant, drug-drug interactions require special attention. For example, the dose of tacrolimus often needs to be reduced and its serum level carefully monitored when ETI is added to the medical regimen [202,206]. Tacrolimus does not affect ETI dosing. If posaconazole or voriconazole is prescribed, the ETI dose must be considerably reduced, following recommendations in the manufacturer's prescribing information [40].

●Liver transplant – ETI has been prescribed for people with CF who have received liver transplants. Despite concern regarding possible drug-induced hepatotoxicity, a small case series found no liver problems and noted both pulmonary and extrapulmonary benefits [207]. Similar to the situation post-lung transplant, in liver transplant recipients, tacrolimus dose reductions are needed, but standard doses of ETI can be used [208]. (See "Cystic fibrosis: Hepatobiliary disease", section on 'Use of CFTR modulators post-liver transplant'.)

Vanzacaftor-tezacaftor-deutivacaftor — VTD is a triple combination CFTR modulator therapy for people with CF with a wide range of CFTR mutations (table 2), including F508del and all other mutations that are approved by the FDA for ETI, plus more than 30 additional mutations. VTD was approved by the FDA for ages ≥6 years in December 2024 [209]. The FDA approval was based on the results of three clinical trials that demonstrated that the pulmonary benefits and safety profile of VTD are similar to those of ETI [210,211].

Although VTD and ETI appear to have similar clinical effects, VTD has the additional advantages of once-daily dosing and a greater reduction in sweat chloride, which suggests greater correction of CFTR channel function. However, ETI may be less costly and more data are available on medium-term outcomes. There are no data regarding the safety of starting VTD in those who previously discontinued modulators due to adverse reactions [209]. The decision to do so should be based on the type and severity of the intolerance and should be done only with close monitoring.

VTD differs from ETI in that vanzacaftor, a CFTR corrector, replaces elexacaftor, and deutivacaftor, a CFTR potentiator, replaces ivacaftor. Tezacaftor is present in both. Deutivacaftor is basically the same as ivacaftor, except that deuterium atoms replace hydrogen atoms at designated positions in the molecule [212]. This alteration slows its metabolism by CYP3A relative to ivacaftor, which allows for once-daily dosing. Otherwise, the pharmacologic benefits and risks of deutivacaftor appear to be the same as those of ivacaftor.

Indications — VTD is a first-line therapy for people with CF ≥6 years of age with at least one VTD-responsive mutation. This includes F508del homozygotes or heterozygotes and more than 300 other mutations (table 2). All genotypes that are responsive to ETI are also responsive to VTD. VTD is not approved for children <6 years.

Dosing and administration — VTD is dosed as follows [209]

●Age ≥6 to <12 years:

•Weight <40 kg – Three tablets (each containing vanzacaftor 4 mg, tezacaftor 20 mg, and deutivacaftor 50 mg) taken orally once daily

•Weight ≥40 kg – Two tablets (each containing vanzacaftor 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg) taken orally in the morning

●Age ≥12 years – Two tablets (each containing vanzacaftor 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg) taken orally in the morning

VTD should be taken with fat-containing food. It should not be used in people with severe hepatic impairment (Child-Pugh C) but may be used in people with moderate hepatic impairment (Child-Pugh B) at full dose if there is a clear medical need and the clinician judges that the benefit outweighs the risk [209]. Liver tests (AST, ALT, alkaline phosphatase, and bilirubin) should be measured before starting VTD and then monthly for the first six months, every three months for the next year, and then yearly thereafter with treatment interrupted as described for ETI (see 'Elexacaftor-tezacaftor-ivacaftor' above). Dose alterations for those taking drugs that effect CYP3A activity are listed in the prescribing information [209] and are similar to those of ETI. (See 'Drug and food interactions' above.)

Efficacy — In phase 3 clinical trials, VTD demonstrated pulmonary benefits similar to those of ETI and had an additional theoretical advantage of inducing a greater reduction in sweat chloride, which is an indicator of improved CFTR function in people with CF. The safety profiles of VDT and ETI were similar.

Following promising results from phase 2 studies [213], a pair of phase 3 randomized clinical trials compared VTD with ETI in 971 people with CF 12 years of age and older (93 percent >18 years) [210]. Trial 1 enrolled only F508del heterozygotes with a minimal function mutation, while trial 2 enrolled F508 homozygotes and other variants. Both trials found no difference in ppFEV₁ between VTD and ETI and no differences in pulmonary exacerbations or a respiratory symptom-related quality-of-life score. In both trials, VTD decreased sweat chloride slightly more compared with ETI (trial 1 mean difference -8.4 mmol/L [95% CI -10.5 to -6.3], trial 2 mean difference of -2.8 mmol/L [95% CI -4.7 to -0.9]). Moreover, in pooled data, VTD was more likely to reduce sweat chloride to <60 mmol/L (86 versus 77 percent of study participants) and <30 mmol/L (23 versus 31 percent). The clinical relevance of this finding is suggested by studies of other CFTR modulators in which improvements in sweat chloride concentrations correlated with improvements of pulmonary function [90,214]. The safety profile of VTD was generally similar to that of ETI. (See 'Adverse effects' below.)

Randomized trials are lacking for children <12 years. However, a third phase 3 open-label study enrolled 78 children with CF 6 to 11 years of age who had at least one mutation responsive to ETI [211]. After a four-week run-in period during which ETI was administered, all participants were switched to VTD and followed for 24 weeks. Compared with baseline at the end of the ETI run-in period, ppFEV₁ was unchanged. The absolute mean sweat chloride decreased by -8.6 mmol/L (95% CI -11.0 to -6.3). After 24 weeks, sweat chloride concentrations were <60 mmol/L in 95 percent of participants and <30 mmol/L in 53 percent. The respiratory symptom-related quality-of-life score was slightly improved (mean change 3.9 points [95% CI 1.5-6.3], where 4 points is considered a clinically important difference). The safety results were similar to what has been reported for ETI in this age group and for VTD in those >6 years old.

Adverse effects — VTD was generally well tolerated during the clinical trials described above. The safety profile appears very similar to that of ETI.

In the randomized trials, aminotransferase elevations were slightly more common in the participants treated with VTD versus ETI during the first three months of therapy [210] but were less frequent than what was reported in the earlier ETI trials. Most were mild and rarely required treatment discontinuation. The lower rate in the VTD trials probably reflects that most of the participants had been exposed to and tolerated ETI prior to enrollment. Of note, unlike elexacaftor, vanzacaftor does not inhibit OATP, which mediates the transport of organic anions into hepatocytes, and is not expected to cause the increases in serum bilirubin that occurs in some people with ETI.

The manufacturer's prescribing information for VTD includes a boxed warning that cases of serious and potentially fatal drug-induced liver injury and liver failure leading to transplantation and death were reported for ETI, which prompted a similar warning for VTD, although cases of severe liver injury in those on VTD have not been reported. (See 'Drug-induced liver injury' above.)

Other warnings include cataract formation in children and drug-drug interactions involving CYP3A (which are similar to ETI) (see 'Other adverse effects' above and 'Drug and food interactions' above). Adverse reactions included rash (generally mild and during the first month after treatment initiation), increased creatine phosphokinase, and increased blood pressure.

The incidence of neuropsychiatric events in clinical trials was similar between the VTD and ETI groups and consistent with the background rate in people with CF not taking CFTR modulator therapy [210]. (See 'Mental health effects' above.)

Ivacaftor monotherapy — Ivacaftor is a small molecular weight oral drug that was specifically designed to treat people who have a G551D mutation in at least one of their CFTR genes. The G551D mutation, which occurs in approximately 4.5 percent of people with CF, is called a "gating mutation" because it impairs the regulated opening of the ion channel that is formed by the CFTR protein. The use of ivacaftor monotherapy has now been expanded to include many other mutations (table 2). (See "Cystic fibrosis: Genetics and pathogenesis", section on 'Class III mutations: Abnormal channel regulation'.)

Ivacaftor was developed using high-throughput screening of large chemical libraries, by which candidate molecules (called "potentiators") were identified that increased chloride ion flux in cultured cells expressing G551D CFTR [215]. From these candidate molecules, ivacaftor was developed and approved by the FDA in the United States for people with this mutation [28]. Subsequent clinical trials have shown that ivacaftor benefits people with other CFTR gating mutations [216] and with CFTR mutations of a type that allows a low level of CFTR function but not enough to prevent CF disease, known as "residual function" mutations [217-221] (see 'Other terms' above). Subsequently, additional mutations have been approved for ivacaftor, based on results of in vitro studies and supporting clinical trials [28,217].

●Indications – The main clinical utility of ivacaftor monotherapy is for children between one month and two years of age who have at least one ivacaftor-responsive mutation and are not eligible for ETI or VDT, because of age or availability (table 2). Children can switch to elexacaftor-tezacaftor-ivacaftor (ETI) when they reach two years of age.

This approach reflects our suggestion to treat with the maximum number of modulators that are approved for the patient's age group (triple therapy > dual therapy > monotherapy). This is based on indirect evidence that the combination therapies are more effective compared with ivacaftor monotherapy and are well tolerated. (See 'General strategies' above.)

●Dosing and administration – Dosing for ivacaftor is as follows [28]:

•Age <6 months:

-Age ≥1 to <2 months and weight ≥3 kg (and no hepatic impairment) – 5.8 mg packet taken orally every 12 hours

-Age ≥2 to <4 months and weight ≥3 kg (and no hepatic impairment) – 13.4 mg packet taken orally every 12 hours

-Age ≥2 to <6 months and weight ≥5 kg (and no hepatic impairment) – 25 mg packet taken orally every 12 hours

•Age ≥6 months to <6 years:

-Weight 5 kg to <7 kg – 25 mg packet taken orally every 12 hours

-Weight 7 kg to <14 kg – 50 mg packet taken orally every 12 hours

-Weight ≥14 kg – 75 mg packet taken orally every 12 hours

•Age ≥6 years – 150 mg tablet taken orally every 12 hours

Ivacaftor should be taken with fat-containing foods. If oral granule packets are used, the dose should be mixed with a small amount (1 teaspoon) of soft food or liquid. It should not be used in infants <6 months old who have any level of hepatic impairment [28]. It should be used with heightened precaution for people with severe hepatic impairment (Child-Pugh C) and only if the benefit outweighs the risk. Dose reduction is advised for those with moderate or severe hepatic impairment (Child-Pugh B and C). Transaminases (AST and ALT) should be measured before starting ivacaftor and then every three months for the first year and annually thereafter. Dose alterations for those taking drugs that effect CYP3A activity are listed in the prescribing information [28] and are similar to those of ETI. (See 'Drug and food interactions' above.)

Of note, a study of people taking the ivacaftor dose recommended by the manufacturer reported that serum and tissue level concentrations were consistently higher than that needed to achieve maximal effect [222].

●Efficacy – Approximately 8 percent of people with CF have CFTR mutations that are responsive to ivacaftor monotherapy. Most trial evidence is from individuals with at least one G551D mutation [223-226] or another gating mutation [216,227]. As an example, in a trial in people 12 years of age or older with a G551D mutation, ivacaftor resulted in a placebo-adjusted 10.6 improvement in mean percent predicted FEV₁ (ppFEV₁), as well as improved pulmonary symptoms and weight gain [224]. Benefits were confirmed in subsequent observational studies with long-term follow-up [14,228-234], including in people with advanced CF lung disease [46,235]. In particular, an analysis of data from two national CF Registries (12 percent age <12 years, 24 percent age 12 to <18 years) found that treatment with ivacaftor for up to five years was associated with preserved lung function and reduced frequency of pulmonary exacerbations, hospitalization, and P. aeruginosa infection compared with matched controls on no CFTR modulator therapy [234]. In addition to the gating mutations that were tested in clinical trials, many residual function mutations are considered responsive based on clinical [216,218-221,236] and in vitro studies in which ivacaftor increased stimulated chloride flux [217-221,236]. (See 'Other terms' above.)

Ivacaftor is the only CFTR modulator that is approved in the United States for infants ≥1 month old. The approval was based on a series of small studies enrolling progressively younger children [119,120,237-239]. Clinical efficacy in the younger cohorts is largely extrapolated from results in older people and observation of similar reductions in sweat chloride and improvements in nutritional status and pancreatic function (as measured by fecal elastase) [120,237,239]. Treatment of infants and young children with ivacaftor is further bolstered by the knowledge that the mode of action of modulators should be age independent.

We recommend switching to ETI when children reach two years of age. The clinical evidence supporting this approach is strongest for those who are heterozygous for F508del, which responds robustly to ETI [30,90]. In addition, in vitro studies have shown that ETI causes greater increases in CFTR channel function compared with ivacaftor alone in cells expressing gating or residual function mutations [7,9,31].

●Adverse effects – Elevations in serum hepatic enzyme levels were noted in a small number of subjects during clinical trials of ivacaftor.

A possible risk for cataract formation in young people was raised by studies done in juvenile rats given ivacaftor at higher doses than those recommended for humans. Noncongenital lens opacities have also been reported in children up to 12 years of age receiving ivacaftor [28]. Although other risk factors for cataracts were often present (eg, glucocorticoid use), the FDA recommended that baseline and follow-up ophthalmologic examinations should be performed in children and adolescents receiving ivacaftor. Otherwise, the adverse events seen in younger people are similar in frequency and type to those observed in older individuals [28,119,120,237,238].

Most of the other adverse events recorded during the placebo-controlled trials were similar to those experienced by many people with CF as part of their disease. However, of these, headache, nasopharyngeal pain, and upper respiratory tract infection were consistently reported more frequently in those receiving ivacaftor.

Tezacaftor-ivacaftor — For individuals who are homozygous for F508del mutations, treatment with the combination of tezacaftor and ivacaftor yields modest improvement in pulmonary function, reduces the risk of pulmonary exacerbations, and has fewer adverse effects compared with lumacaftor-ivacaftor [240,241]. The F508del mutation interferes with CFTR protein folding and channel gating activity. Tezacaftor partially corrects the CFTR misfolding, while ivacaftor improves the gating abnormality.

Tezacaftor-ivacaftor is approved by the FDA for individuals who are six years and older and are homozygous for F508del or have ≥1 other mutation that is sensitive to tezacaftor-ivacaftor [242].

●Indications – There is no role for tezacaftor-ivacaftor where the triple combination modulators elexacaftor-tezacaftor-ivacaftor (ETI) and VTD are available, except in cases of drug intolerance. ETI and VTD are approved for all of the mutations that are responsive to tezacaftor-ivacaftor (table 2) and are more effective (direct evidence for ETI, indirect evidence for VTD) [30]. (See 'Elexacaftor-tezacaftor-ivacaftor' above and 'Vanzacaftor-tezacaftor-deutivacaftor' above.)

●Dosing and administration – Dosing for tezacaftor-ivacaftor is as follows:

•Age ≥6 years:

-Weight <30 kg – One combination tablet (containing tezacaftor 50 mg and ivacaftor 75 mg) orally in the morning and ivacaftor 75 mg orally in the evening

-Weight ≥30 kg – One combination tablet (containing tezacaftor 100 mg and ivacaftor 150 mg) orally in the morning and ivacaftor 150 mg orally in the evening

Tezacaftor-ivacaftor should be taken with fat-containing foods. Transaminases (AST and ALT) should be measured before starting ivacaftor and then every three months for the first year and annually thereafter [242], with treatment interrupted as described for ETI (see 'Dosing and administration' above). There is no experience with tezacaftor-ivacaftor in individuals with severe hepatic impairment, and it should be used only if the benefit outweighs the risks. Dose adjustments are recommended for moderate or severe hepatic impairment (Child-Pugh B and C) and those taking drugs that effect CYP3A activity, as listed in the prescribing information, similar to ETI. (See 'Drug and food interactions' above.)

●Efficacy and adverse effects – Evidence for efficacy of tezacaftor-ivacaftor comes from clinical trials in individuals with homozygous F508del mutations or F508del heterozygotes if the second mutation has some residual function [4,15,240,243-245]. It has also been approved for individuals with CF caused by two separate residual function mutations based on in vitro testing [242]. There appears to be no benefit for F508del heterozygotes whose second mutation has minimal function [246] or is a gating mutation beyond the benefit of ivacaftor alone [247]. Tezacaftor-ivacaftor is generally well tolerated, with no increase in chest discomfort, bronchospasm, dyspnea, or wheezing (in contrast with the chest symptoms that some people experience with lumacaftor-ivacaftor). Drug-drug interactions are similar to those for ETI.

Tezacaftor-ivacaftor is less effective than triple therapy for people with eligible genotypes. This was shown in clinical trials in people homozygous for the F508del mutation or heterozygous for F508del plus a second gating or residual function mutation, in which ETI achieved much greater improvements in FEV₁ and symptom-related quality of life compared with tezacaftor-ivacaftor [29,30]. Further evidence comes from indirect comparisons between clinical trials that enrolled participants with similar characteristics, in which ETI or VTD achieved greater improvements in key outcomes compared with tezacaftor-ivacaftor. Furthermore, all genotypes that are eligible for tezacaftor-ivacaftor are also eligible for ETI and VTD. These findings lead us to recommend triple therapy (ETI or VTD) rather than tezacaftor-ivacaftor for all patients. (See 'Drug selection based on age and genotype' above.)

Lumacaftor-ivacaftor — For individuals who are homozygous for the F508del mutation, treatment with the combination of lumacaftor and ivacaftor yields modest improvements in pulmonary function and reduces the risk of pulmonary exacerbations [241,248]. The F508del mutation interferes with CFTR protein folding and channel gating activity. Similar to tezacaftor, lumacaftor partially corrects the CFTR misfolding, while ivacaftor improves the gating abnormality. Neither lumacaftor nor ivacaftor is effective when used alone for F508del homozygotes [249,250].

●Indications – We suggest treatment with lumacaftor-ivacaftor for children with homozygous F508del mutations who are 1 to <2 years of age (algorithm 1). It is not approved for any other CFTR genotype. Therapy should be switched to elexacaftor-tezacaftor-ivacaftor (ETI) when the child reaches two years of age, with the option of switching to VTD when the child is eligible by age.

For F508del homozygotes ≥2 years, we prefer ETI rather than lumacaftor-ivacaftor because ETI is approved for this age group and appears to have substantially fewer adverse effects (at least in adults), fewer drug-drug interactions compared with lumacaftor-ivacaftor, and considerably greater improvement in FEV₁ [241]. (See 'Elexacaftor-tezacaftor-ivacaftor' above.)

●Dosing and administration – Dosing for lumacaftor-ivacaftor is as follows:

•Children 1 to <2 years:

-Weight 7 to <9 kg – One packet of granules (containing lumacaftor 75 mg and ivacaftor 94 mg) taken orally every 12 hours

-Weight 9 to <14 kg – One packet of granules (containing lumacaftor 100 mg and ivacaftor 125 mg) taken orally every 12 hours

-Weight ≥14 kg – One packet of granules (containing lumacaftor 150 mg and ivacaftor 188 mg) taken orally every 12 hours

If lumacaftor is used after two years of age (although ETI is preferred), similar weight-based dosing is used.

Lumacaftor-ivacaftor should be taken with fat-containing foods. Transaminases (AST and ALT) and bilirubin should be measured before starting lumacaftor-ivacaftor and then every three months for the first year and annually thereafter [201], with treatment interrupted for significant transaminase elevations as described for ETI (see 'Drug-induced liver injury' above). Lumacaftor-ivacaftor should be used with caution in individuals with moderate or severe hepatic impairment (Child-Pugh B and C) and only if the benefit outweighs the risk. Dose reductions are needed for people with Child-Pugh B and C hepatic impairment and for those who are taking drugs that are inhibitors of CYP3A4, similar to ETI, as described above. (See 'Drug and food interactions' above.)

●Efficacy – Lumacaftor-ivacaftor is modestly effective for F508del homozygotes. Two randomized, blinded clinical trials of F508del homozygous subjects age 12 years and older showed a small but statistically significant improvement in percent predicted FEV1 (ppFEV₁) of 3.3 that was sustained in a 96-week extension study [248,251]. Compared with the placebo group, pulmonary exacerbations were significantly reduced by 30 percent, a benefit that occurred in subjects irrespective of their change in FEV₁ [11]. A smaller postmarketing study found no significant improvement in FEV₁ but did detect improvement in lung clearance index, a more sensitive measure of subtle changes in pulmonary disease [252]. Similar levels of improvement were seen in studies of F508del homozygous children age 1 to <12 years [142,143,253-256]. An imaging study prospectively enrolled 31 children age 6 to 11 years who underwent CT scans prior to and annually for two years after beginning lumacaftor-ivacaftor [257]. Measurements of air trapping improved, but there were worsening bronchiectasis scores and no changes in mucus plugging.

Lumacaftor-ivacaftor is substantially less effective compared with ETI or VTD for F508del homozygotes and also has more adverse respiratory effects, based on indirect evidence from separate trials [29,248]. These findings support our recommendation to switch to ETI or VTD as soon as a child becomes eligible for those drugs by age. (See 'Drug selection based on age and genotype' above.)

Lumacaftor-ivacaftor did not improve FEV₁ in a study of 126 adults who were heterozygous for F508del [258] and is therefore not approved by the FDA for use in any age group for those with fewer than two F508del mutations.

●Adverse effects – Lumacaftor-ivacaftor is generally less well tolerated compared with ETI, VTD, or tezacaftor-ivacaftor.

Soon after starting lumacaftor-ivacaftor, a subgroup of subjects developed chest discomfort and dyspnea, particularly those with worse baseline lung function [248]. Although the frequency of discontinuation due to adverse events was 4 to 7 percent during lumacaftor-ivacaftor phase 3 clinical trials and extension studies [142,248,251], a postmarketing report from the manufacturer indicates that 15 percent of people discontinued treatment within the first three months [259]. Other studies report discontinuation in more than 32 percent of people with a ppFEV₁ <40 at treatment initiation [48]. The adverse respiratory events that lead to discontinuation of lumacaftor-ivacaftor appear to be due to the lumacaftor component. A study of 98 people who had discontinued lumacaftor-ivacaftor for worsening respiratory symptoms were randomized to tezacaftor-ivacaftor or placebo [260]. The number of respiratory-related adverse events did not differ between groups. Of note, a separate open-label study in 46 people with severe lung disease (ppFEV₁ <40) reported fewer treatment discontinuations among people who initiated treatment with a one-half dose for the first one to two weeks of treatment before increasing to the full dose [261].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cystic fibrosis (The Basics)" and "Patient education: Bronchiectasis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – In clinical trials involving people with a wide range of cystic fibrosis (CF) genotypes, CF transmembrane conductance regulator (CFTR) modulators have been shown to improve forced expiratory volume in one second (FEV₁) and symptom-related quality of life and reduce acute exacerbations.

●Selection of CFTR modulator regimen – All people with CF should undergo CFTR genotyping to determine if they carry one of the mutations approved for CFTR modulator therapy. Many people with CF will be eligible for more than one modulator drug, as summarized in the table (table 2). Our approach to drug selection is based on the age group for which each drug is available (based on regulatory approvals in the United States) and relative efficacy, as outlined below (see 'Drug selection' above):

•Children <2 years (algorithm 1):

-Ivacaftor-responsive mutations – For infants with at least one ivacaftor-responsive mutation including G551D and other gating mutations and residual function mutations, we suggest treating with ivacaftor rather than no therapy, starting at age ≥1 month (Grade 2C). Early initiation of ivacaftor for infants with eligible genotypes is standard practice in most CF centers. Ivacaftor improves multiple outcomes, including respiratory symptoms, quality of life, pulmonary function, sweat chloride, and nutritional outcomes, based on randomized trials in older age groups and small open-label studies in infants and young children. (see 'Ivacaftor monotherapy' above)

-Homozygous F508del mutations – For F508del homozygotes, we suggest treating with lumacaftor-ivacaftor rather than no therapy, starting at age ≥1 year (Grade 2C). Lumacaftor-ivacaftor is the only CFTR modulator drug approved for this genotype and age group, and clinical trials demonstrated modest but statistically significant improvements in FEV₁. (See 'Lumacaftor-ivacaftor' above.)

Children with either of the above genotypes should be transitioned to a triple therapy agent once they qualify for it by age, as discussed below. Children with other genotypes are not eligible for CFTR modulator therapy prior to age 2 years.

•Children ≥2 to <6 years – For all children who have ETI-responsive mutations, we suggest treatment with triple therapy with ETI rather than dual therapy, monotherapy, or no CFTR modulator therapy (Grade 2C). Initiation of ETI for all eligible children is standard practice in most CF centers. There are no placebo-controlled trials in this age group, but prospective studies and other observational data suggest that ETI is well tolerated, improves some markers of pulmonary function, and reduces sweat chloride (see 'Pulmonary outcomes' above). If the child was previously started on ivacaftor, they should be switched to ETI at age two years, based on evidence from older age groups. (See 'Ivacaftor monotherapy' above.)

•Children ≥6 years and adults (algorithm 2):

-At least one F508del mutation – For this group, we recommend treatment with triple therapy (ETI or vanzacaftor-tezacaftor-deutivacaftor [VTD]) rather than dual therapy, monotherapy, or no CFTR modulator therapy (Grade 1B). ETI is well tolerated and improves pulmonary outcomes, quality of life, and nutritional status (multiple trials and observational studies) and improves survival (indirect evidence) compared with no therapy. Furthermore, ETI results in greater improvements in FEV₁ and quality of life than dual therapy and adverse effects were similar to those of tezacaftor-ivacaftor and less than those of lumacaftor-ivacaftor (direct evidence from randomized trials for ETI and indirect evidence from separate trials for VTD). Most of the trial data are from ages ≥12 years, but observational data in younger children show that ETI or VTD treatment is associated with improvements in measures of pulmonary function and support their safety. (See 'Efficacy' above.)

VTD and ETI have similar clinical effects, based on randomized trials involving primarily adult patients, supplemented by an open-label prospective study in children 6 to <12 years. VTD has the additional advantage of once-daily dosing and a greater reduction in sweat chloride, which suggests greater correction of CFTR channel function, while ETI may be less costly and more data are available on medium-term outcomes. Children are first eligible for ETI at age ≥2 years and for VTD for age ≥6 years. (See 'Vanzacaftor-tezacaftor-deutivacaftor' above.)

-Other ETI- and/or VTD-responsive mutations – For this group, we recommend triple therapy (ETI or VTD) rather than no therapy (Grade 1B) and we suggest it rather than dual or monotherapy (Grade 2C). This is based on indirect evidence from people with at least one F508del mutation, small cohorts with less common genotypes included in clinical trials, and evidence from in vitro testing, in which ETI or VTD substantially improved chloride transport (see 'Efficacy' above). This group includes patients with ivacaftor-responsive mutations (G551D and other gating mutations and residual function mutations), for whom ETI is more effective compared with ivacaftor, based largely on in vitro testing. (See 'Ivacaftor monotherapy' above.)

•People with no eligible mutations – In the United States, approximately 6 percent of non-Hispanic White people, 25 percent of Hispanic people, and 30 percent of Black/African American people with CF have no mutations approved by the US Food and Drug Administration (FDA) for modulator therapy; this is an important source of health disparity. However, in vitro and a few limited clinical studies have identified additional mutations that appear to be responsive to modulator therapy. These approaches have the potential to provide information that may be useful when petitioning insurers to cover modulators for these individuals. (See 'People with no eligible mutations' above.)

●Safety and monitoring – These drugs are generally well tolerated. Liver function tests and bilirubin should be monitored before and during treatment, and dose reductions are recommended for people with significant hepatic impairment (see 'Drug-induced liver injury' above). Ophthalmologic exams should be performed in children to monitor for cataracts. A preponderance of clinical evidence indicates that ETI has a net beneficial effect on mental health, but some regulatory agencies recommend monitoring for depression. (See 'Mental health effects' above.)

Each of these drugs has multiple drug interactions, which include cytochrome P450 3A4 (CYP3A4) inhibitors (eg, itraconazole, clarithromycin, fluconazole, nirmatrelvir-ritonavir [used for treatment of COVID-19]) or inducers (eg, rifampin, several antiseizure medications, St. John's wort). Grapefruit inhibits CYP3A4 and should be avoided. Details on drug interactions are available in the drug interactions program included in UpToDate. (See 'Dosing and administration' above.)