CF: Role of CFTR Modulators in Nutrition Assessment 2020
Click here to see the explanation of recommendation ratings (Strong, Fair, Weak, Consensus, Insufficient Evidence) and labels (Imperative or Conditional). To see more detail on the evidence from which the following recommendations were drawn, use the hyperlinks in the Supporting Evidence Section below.
CF: CFTR Modulators in Nutrition Assessment
For individuals with cystic fibrosis (CF) of all ages who receive CFTR modulation therapy, the RDN or international equivalent should continue to conduct nutrition screening with nutrition assessment as indicated based on age, since these medications may change nutrient needs for some individuals with CF.
Risks/Harms of Implementing This Recommendation
There are no obvious risks or harms associated with this recommendation. The potential for desirable effects through individualized nutrition assessment and therapy is substantially greater than the potential for harm.
Conditions of Application
The decision of whether or not to implement a recommendation is retained by the individual with cystic fibrosis.
Potential Costs Associated with Application
Additional nutrition assessment should not require additional costly resources for individuals on CFTR modulator therapy. The cost of nutrition assessment and intervention is small in comparison to the overall cost of cystic fibrosis care.
Background. In the years since ivacaftor became the first commercially available CFTR restoration compound in 2010, the numbers of individuals with cystic fibrosis (CF) who qualify for this and subsequent modulation therapies has sharply increased. The goal of the CF Foundation is to provide some type of CFTR modulation therapy for 100% of individuals with CF (Cystic Fibrosis Foundation 2019). In clinical practice CFTR modulation therapy is highly important to people with CF due to its potential to increase life expectancy, improve quality of life, pulmonary outcomes, and nutritional and GI outcomes.
Evidence. The systematic review supporting this guideline elucidated that the effects of CFTR modulators on BMI and other anthropometric measures are dependent on formulation of the drug and the CFTR genotype of the individual. For individuals with at least one copy of a class III CFTR mutation (e.g. G551D), ivacaftor alone may increase WFA z-scores in pediatric individuals (Borowitz et al 2016, Davies et al 2013, Konstan et al 2015, Ramsey et al 2011, Stalvey et al 2017, De Boeck et al 2014) and BMI in adults (Borowitz et al 2016, Konstan et al 2015, Ramsey et al 2011, De Boeck et al 2014, Edgeworth et al 2017). Limited evidence suggested that ivacaftor had no effect on BMI in adults with class IV mutations (Moss et al 2015). When the combination of ivacaftor and lumacaftor was investigated, there was no effect of ivacaftor with lumacaftor on BMI-for-age z-score after 24 weeks in children 6-11 years of age who were homozygous for the F508del mutation (class II) (Ratjen et al 2017). However, there were mixed findings regarding the effect on BMI in individuals with class II mutations, with some evidence that this combination of modulators may increase BMI in adults who were homozygous, but not heterozygous, for the F508del mutation (Elborn et al 2016, Rowe et al 2017, Wainwright et al 2015). A combination of ivacaftor and tezacaftor did not change BMI z-scores in pediatric participants 12-20 years of age homozygous F508del mutations (class II), but evidence was limited (Taylor-Cousar et al 2017). Anthropometric measures were not primary outcomes in these pharmacological studies and some studies were not included since they did not report age-appropriate weight/growth measures. There were no included studies that examined the effect of CFTR modulators on body composition or the effect of diet on the relationship between CFTR modulators and weight/growth parameters. Stallings et al 2018 demonstrated that ivacaftor treatment in patients with CF with at least one CFTR gating mutation decreased resting energy expenditure, decreased fecal calprotectin (a measure of gut inflammation), and increased fat absorption, especially in those with exocrine pancreatic insufficiency (Stallings et al 2018). The full nutrition impact of different CFTR modulation therapies in individuals with CF is not understood at this time. More studies are needed regarding how CFTR modulators and dietary intake interact to affect nutrition status. This topic is particularly important since new CFTR "triple combination" therapy (elexacaftor-tezacaftor-ivacaftor) is now available and will reach individuals with CF with at least one F508del mutation, which constitutes up to 90% of the CF population. Phase III studies of elexacaftor-tezacaftor-ivacaftor therapy showed improvement in BMI and BMI-for-age z-scores in individuals who have either on or two copies of the F508del mutation (Middleton et al 2019, Heijerman et al 2019). RCTs that have examined the nutrition implications of CFTR modulation therapy have not reported nutrition-related measures other than weight-based parameters, and, thus, practitioners may need to depend on observational studies that track effects of more patient-centered, health outcomes over time.
Nutrition Prescription and PERT with CFTR Modulation Therapy. None of the included CFTR modulation therapy studies reported dietary intake data in subjects with CF, therefore, it is unknown how (or if) RDNs should modify nutrition recommendations once this therapy is started. In order to be well absorbed, genetic modulator agents need to be taken with an adequate amount of dietary fat (Vertex Pharmaceuticals Incorporated 2019) and the appropriate dose of PERT, when applicable. Meals and snacks can be scheduled to accommodate CFTR modulation therapy, which is given every 12 hours. Therefore, the role of the RDN in assessing and counselling patients as they commence on these therapies is paramount. Although there is limited evidence that bio-markers of intestinal absorption (Stallings et al 2018) and pancreatic function (Davies et al 2016, Rosenfeld et al 2019) are improved with ivacaftor, there is not enough evidence to warrant reduction or cessation of PERT therapy when patients begin taking CFTR modulators (Cystic Fibrosis Foundation 2019). In some cases, CFTR modulators may decrease energy expenditure and energy prescription may need to be decreased in order to avoid excessive weight gain and resulting health risks (Stallings et al 2018) Adherence to a diet that is closer to population norms may be challenging for individuals who have historically consumed high-calorie and high-fat, high-protein, high-salt diets. Therefore, individuals who begin CFTR modulation therapy must be fully and continually assessed to determine how these medications may be affecting nutrition status. Although it is not recommended at this time, if individuals/families consider stopping or have stopped PERT, RDNs should co-partner with individuals and healthcare team to monitor fecal elastase, weight changes, GI symptoms, and fat-soluble vitamin levels and, when possible, 72 hour fecal fat.
Recommendation Strength Rationale
Conclusions supporting this recommendation were based on of the systematic review examining the effect of CFTR modulators on anthropometric outcomes (Grades II and III). Evidence examining the effect of CFTR modulation therapies on every class of CFTR mutation was not available, nor was there evidence regarding the effect of CFTR modulators on body composition or the modifying effect of dietary intake on weight/growth parameters.
- Risks/Harms of Implementing This Recommendation
The recommendations were created from the evidence analysis on the following questions. To see detail of the evidence analysis, click the blue hyperlinks below (recommendations rated consensus will not have supporting evidence linked).
In participants with CF and Class III mutations, what is the effect of ivacaftor on weight/growth parameters and body composition?
In participants with CF and Class II or IV mutations, what is the effect of ivacaftor on weight/growth parameters and body composition?
In participants with CF and Class II mutations, what is the effect of ivacaftor with lumacaftor on weight/growth parameters and body composition?
In participants with CF, what is the effect of ivacaftor with tezacaftor on weight/growth parameters and body composition?
Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, Schwarzenberg S. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. Digestive Diseases and Sciences 2016; 61:198-207
Davies J, Wainwright C, Canny G, Chilvers M, Howenstine M, Munck A, Mainz J, Rodriguez S, Li H, Yen K, Ordoñez C, Ahrens R. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. American Journal of Respiratory and Critical Care Medicine 2013; 187:1219-25
De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. Journal of Cystic Fibrosis 2014; 13:674-80
Edgeworth D, Keating D, Ellis M, Button B, Williams E, Clark D, Tierney A, Heritier S, Kotsimbos T, Wilson J. Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients: a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment. Clinical Science 2017; 131:2037-2045
Konstan M, Plant B, Elborn J, Rodriguez S, Munck A, Ahrens R, Johnson C. Efficacy response in CF patients treated with ivacaftor: post-hoc analysis. Pediatric Pulmonology 2015; 50:447-55
Ramsey B, Davies J, McElvaney N, Tullis E, Bell S, Devínek P, Griese M, McKone E, Wainwright C, Konstan M, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe S, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn J. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. The New England Journal of Medicine 2011; 365:1663-72
Stalvey MS, Pace J, Nikniar M, Higgins MN, Tarn V, Davis J, Heltshe SL, Rowe SM. Growth in Prepubertal Children With Cystic Fibrosis Treated With Ivacaftor. Pediatrics 2017; 139:2016-2522
Flume P, Liou T, Borowitz D, Li H, Yen K, Ordoñez C, Geller D. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142:718-724
Moss R, Flume P, Elborn J, Cooke J, Rowe S, McColley S, Rubenstein R, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. The Lancet. Respiratory Medicine 2015; 3:524-33
Elborn J, Ramsey B, Boyle M, Konstan M, Huang X, Marigowda G, Waltz D, Wainwright C. Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis. The Lancet Respiratory Medicine 2016; 4:617-626
Rowe S, McColley S, Rietschel E, Li X,Bell S, Konstan M, Marigowda G, Waltz D, Boyle M. Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR. Annals of the American Thoracic Society 2017; 14:213-219
Wainwright C, Elborn J, Ramsey B, Marigowda G, Huang X, Cipolli M, Colombo C, Davies J, De Boeck K, Flume P, Konstan M, McColley S, McCoy K, McKone E, Munck A, Ratjen F, Rowe S, Waltz D, Boyle M. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. The New England Journal of Medicine 2015; 373:220-31
Taylor-Cousar J, Munck A, McKone E, van der Ent C, Moeller A, Simard C, Wang L, Ingenito E, McKee C, Lu Y, Lekstrom-Himes J, Elborn J. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. The New England Journal of Medicine 2017; 377:2013-2023
Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, Milla C, Robinson P, Waltz D, Davies J. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. The Lancet. Respiratory Medicine 2017; 5:557-567
References not graded in Academy of Nutrition and Dietetics Evidence Analysis Process
- Cystic Fibrosis Foundation. Our Mission. https://www.cff.org/About-Us/About-the-Cystic-Fibrosis-Foundation/Our-Mission/. Published 2019. Accessed September 25, 2019.
- Cystic Fibrosis Foundation. Clinical Considerations: TRIKAFTA™. Bethesda, MD: Cystic Fibrosis Foundation; 2019.
- Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. The Lancet. Resp Med. 2016;4(2):107-115.
- Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019;394(10212):1940-1948.
- Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-1819.
- Rosenfeld M, Cunningham S, Harris WT, et al. An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5years (KLIMB). J Cyst Fibros. 2019;18(6):838-843.
- Stallings VA, Sainath N, Oberle M, Bertolaso C, Schall JI. Energy balance and mechanisms of weight gain with ivacaftor treatment of cystic fibrosis gating mutations. J Pediatr. 2018;201:229-237.e224.
- Vertex Pharmaceuticals Incorporated. Trikafta (elexaccaftor/tezacaftor/ivacaftor; ivacaftor) Tablets. In: Incorporated VP, ed2019:Table 4: Pharmacokinetic Parameters of TRIKAFTA Components.