FROM THE ACADEMY Evidence Analysis Center Effect of CFTR Modulators on Anthropometric Parameters in Individuals with Cystic Fibrosis: An Evidence Analysis Center Systematic Review Julianna Bailey, MS, RDN, LD; Mary Rozga, PhD, RDN; Catherine M. McDonald, PhD, MS, RDN, CSP; Ellen K. Bowser, MS, RDN, LDN, RN, FAND; Kristen Farnham, MSH, RD, CSP, LDN; Mark Mangus; Laura Padula, MS, RD, LDN, CSP; Kathleen Porco, MS, CDCES; Jessica A. Alvarez, PhD, MS, RDN ABSTRACT There is a strong positive association between nutrition status and lung function in cystic fibrosis (CF). Improvements in clinical care have increased longevity for individuals with CF, and it is unknown how cystic fibrosis transmembrane regulator (CFTR) modulation therapy affects nutrition status over time. The objective of this systematic review of the literature was to examine anthropometric (height, weight, and body mass index [BMI; calculated as kg/m 2 ]) and body composition outcomes of CFTR modulation therapy. A literature search of Medline (Ovid), Embase, and CINAHL (EBSCO) databases was conducted for randomized controlled trials examining the effect of CFTR modulation therapy on anthropometric and body composition parameters, published in peer-reviewed journals from January 2002 until May 2018. Articles were screened, data were synthesized qualitatively, and evidence quality was graded by a team of content experts and systematic review method- ologists. Significant weight gain with ivacaftor was noted in children and adults with at least 1 copy of G551D mutation. In adults with at least 1 copy of R117H the effect of ivacaftor on BMI was not significant. Effects on BMI were mixed in adults with class II mutations taking ivacaftor with lumacaftor. There was no significant change in BMI in children homozygous for F508del who took ivacaftor with tezacaftor. Elexacaftor- tezacaftor-ivacaftor increased BMI and body weight in individuals 12 years of age and older who were hetero- or homozygous for the F508del mutation. The effect of CFTR modulation therapy on anthropometric parameters depends on the genetic mutation and the type of modulation therapy used. More research is needed to understand the long-term clinical impact of these drugs on nutritional status, including body composition and the role of dietary intake. J Acad Nutr Diet. 2020;-(-):---. Supplementary materials: Figure 1 is available at www.jandonline.org C YSTIC FIBROSIS (CF) IS A LIFE- threatening autosomal reces- sive genetic disease caused by a mutation of the cystic fibrosis transmembrane regulator (CFTR) gene, leading to dysregulation of chloride and bicarbonate transport, thick fluid secretions, and severe down- stream impacts on the respiratory and gastrointestinal systems. 1 Nearly 85% to 90% of individuals with CF develop exocrine pancreatic insufficiency, result- ing in malabsorption of fat; carbohy- drates; protein; and fat-soluble vitamins A, D, E, and K. 2 Malnutrition, and subsequent poor growth in chil- dren, is a common problem in CF due to malabsorption, increased work of breathing, chronic inflammation, and chronic lung infection. Nutritional status in both children and adults is closely associated with lung function in CF, with better growth and higher weight, body mass index (BMI; calculated as kg/m 2 ) and fat-free mass being associ- ated with better lung function. 3,4 In addition, malnutrition and low BMI are associated with poorer survival in chil- dren and adults with CF. 5 For these rea- sons, a high-calorie, unrestricted fat diet is currently recommended for children and adults with CF. 3 The degree of pancreatic insufficiency, malnutrition, and poor growth often depends on the severity of the CFTR mutation. 6 There are more than 2,000 variants of the CFTR mutation, with approximately 350 mutations known to cause CF. 7 The mutations are classified based on the mechanism by which the defective gene disrupts normal CFTR function. 1 Class I mutations impair the production of the CFTR protein completely. In class II mu- tations, the CFTR protein is misfolded and unable to reach the cell surface. The most common CF mutation, F508del (a class II mutation), falls into this category, and 88% of individuals with CF have at least 1 copy of this mutation. 7 Class III mutations (“gating mutations”) prevent the CFTR protein channel from opening once it reaches the cell surface. Class IV muta- tions interfere with conductance of chlo- ride ions, 1,8 and class V mutations produce insufficient quantities of CFTR protein. CFTR mutation classes I, II, and III represent the more severe disease phe- notypes. 6 During the past decade, several drugs have been developed that specif- ically target the underlying defective CFTR protein. These drugs are known as CFTR modulators, and their mechanism of action varies based on the CFTR defect. Ivacaftor (a potentiator) acts on cell surface CFTR protein channels allowing for improved chloride transport, and lumacaftor and tezacaftor (correctors) improve the structure of the CFTR pro- tein and its trafficking to the cell sur- face. 9 As some mutations have multiple defects, CFTR modulators are often used in combination with each other. CFTR modulator therapy has been shown to be effective in improving clinical outcomes, 2212-2672/Copyright ª 2020 by the Academy of Nutrition and Dietetics. https://doi.org/10.1016/j.jand.2020.03.014 ª 2020 by the Academy of Nutrition and Dietetics. JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS 1