Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Adherence to therapies in cystic fibrosis: a

targeted literature review

Siva Narayanan, Jochen G. Mainz, Smeet Gala, Harold Tabori & Daniel
Grossoehme

To cite this article: Siva Narayanan, Jochen G. Mainz, Smeet Gala, Harold Tabori & Daniel
Grossoehme (2017): Adherence to therapies in cystic fibrosis: a targeted literature review,
Expert Review of Respiratory Medicine, DOI: 10.1080/17476348.2017.1280399

To link to this article: http://dx.doi.org/10.1080/17476348.2017.1280399

Published online: 20 Jan 2017.

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Download by: [University of Newcastle, Australia] Date: 23 January 2017, At: 00:48
EXPERT REVIEW OF RESPIRATORY MEDICINE, 2017
http://dx.doi.org/10.1080/17476348.2017.1280399

REVIEW

Adherence to therapies in cystic fibrosis: a targeted literature review

Siva Narayanana, Jochen G. Mainzb, Smeet Galaa, Harold Taborib and Daniel Grossoehmec
a
Market Access Solutions LLC. (MKTXS), Raritan, NJ, USA; bCystic Fibrosis Center for Children and Adults, Jena University Hospital, Jena, Germany;
c
Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

ABSTRACT ARTICLE HISTORY

Introduction: Cystic fibrosis (CF) is a life-shortening condition with no cure. Available therapies Received 21 October 2016
relieving the symptoms of CF are complex and time-consuming. A comprehensive review assessing Accepted 6 January 2017
adherence to different CF therapies, association of adherence with outcomes, and factors influencing KEYWORDS
adherence could inform optimal patient management strategies. Adherence; outcomes;
Areas covered: A targeted literature review of studies published from 2010–2016 assessed adherence barriers; cystic fibrosis;
to CF therapies. Nineteen studies qualified for inclusion. Adherence to CF therapies was sub-optimal, drivers; therapies
and varied by treatment, mode of treatment administration, age, season, time and method of adher-
ence measurement. Adherence to ivacaftor and inhaled antibiotics were reported higher than dornase
alfa or hypertonic saline, oral pancreatic enzyme and vitamin supplements, and airway clearance
therapy. Several patient, healthcare provider and treatment related factors influenced adherence.
Sub-optimal adherence was shown to impact clinical and economic burden of the disease.
Expert commentary: Higher adherence to CF therapies can lower disease burden, and improve patient
outcomes. Healthcare providers and policy makers should devise patient-centered and caregiver-
enabled interventions to improve adherence. Research on long-term adherence and outcomes asso-
ciated with promising oral treatments such as CFTR modulators is needed. Identifying ways to overcome
key barriers to adherence can positively affect outcomes associated with CF.

1. Introduction Non-adherence to therapies in CF can increase the already

high clinical, humanistic, and economic burden of disease.
Cystic fibrosis (CF) is an inherited and life-shortening, autoso-
Medication non-adherence is associated with poorer out-
mal recessive disease with significant clinical, humanistic, and
comes such as increased risk of hospitalization, longer hospital
economic burden. It is caused by mutation of the cystic fibro-
stay, and pulmonary exacerbations and destruction, which
sis transmembrane conductance regulator (CFTR) gene,
remains to be the primary reason for premature death in CF
located on chromosome 7, and is most common in
[9,10]. An analysis of a US national commercial claims data-
Caucasians of Northern European ancestry [1]. In addition to
base showed that CF patients with low and moderate adher-
clinical burden, CF poses a significant economic burden [2,3]
ence had 35% and 25% more CF-related hospitalizations,
and humanistic burden, owing to diminished quality of life
respectively, which predicted higher concurrent healthcare
(QoL), psychosocial burden, and treatment regimen bur-
costs by $14,211 and $8493, respectively, compared with
den [4].
high adherence [11].
Currently, there is no cure for CF, but several therapies have
Past studies have depicted mixed levels of adherence to
been developed in the last two decades that alleviate the
treatments in CF; however, it has not been comprehensively
symptoms of CF [5]. In addition to recommending nutrition
assessed by examining the recently available literature. There
and fitness, medications and chest physiotherapy are pre-
is a lack of clarity about the overall adherence in CF, associa-
scribed to clear the airways [6]. Basic treatments available are
tion of adherence with outcomes, and factors influencing
inhaled, oral, and intravenous antibiotics, anti-inflammatory
adherence. The objective of this study is to review the
therapies, pancreatic enzymes and supplemental nutrients
reported short-term and long-term adherence to CF therapies,
and vitamins, bronchodilators, agents that promote airway
review associated outcomes and drivers and barriers to adher-
secretion clearance (inhaled dornase alfa, hypertonic saline,
ence to better understand CF management, and address the
N-acetylcysteine, and mannitol), supplemental oxygen, CFTR
gaps therein for optimal patient management in routine clin-
modulators (ivacaftor and lumacaftor), and lung transplanta-
ical practice as well as for future research.
tion [5,7]. It is important that the patient is adherent to the
prescribed therapy to manage CF successfully. Since CF man-
agement requires multiple therapies every day throughout the 2. Methods
life and most therapies are complicated as well as time con-
A targeted literature review was conducted to assess adher-
suming, adherence to such routines is a concern [8].
ence associated with CF treatments. The MEDLINE database

CONTACT Siva Narayanan snarayanan@mktxs.com MKTXS, Market Access Solutions, LLC, 575 West Rt. 28, Suite 207, Raritan, NJ 08807, USA
© 2017 Informa UK Limited, trading as Taylor & Francis Group
2 S. NARAYANAN ET AL.
Figure 1. Flow diagram of study inclusion and exclusion.
was searched for English-language studies using search terms
related to CF and adherence. The search was limited to the
following: studies published from January 2010 to August
2016 to capture the most up-to-date recommended therapies
and current/recent care patterns for CF patients; in English
language; related to human subjects; and peer-reviewed jour-
nals. The bibliography of review articles identified as part of
this search was further screened for relevant articles not iden-
tified in the original search.
The resulting title and abstracts were screened methodi-
cally, adhering to the inclusion/exclusion criteria and exported
to Microsoft Excel for an additional review. An article was
retrieved for full review if the abstract met each of the follow-
ing criteria: measured adherence to any of the CF therapies,
namely, inhaled treatments, oral treatments, airway clearance
therapy (ACT), and mixed mode of treatments, i.e. regimen
involving multiple inhaled/oral/ACT therapies, and published
in a peer-reviewed journal and in English language. Articles
were excluded from full review if the abstract met any of the
following criteria: study examined adherence to exercise, phy-
siotherapy, and alternative therapy (e.g. dance therapy), mea-
sured adherence after an educational or behavioral
intervention or reported adherence for two different doses
of same medication; study measured adherence to screening,
monitoring, and diagnosis guidelines; study was a case report,
case series, editorial, or commentary; and study did not report
quantitative adherence data and reported only qualitatively.
From full-text reviews, study details including study char-
acteristics, population characteristics, sample size, CF treat-
ments administered, method of adherence, and adherence
rates reported were extracted.
3. Results
Of 473 titles screened, a total of 131 abstracts qualified for
further screening, and 342 titles were excluded as they were
genetic, clinical, or epidemiological studies. A total of 19 stu-
dies qualified for inclusion in the review: 12 retrospective
studies, three randomized trials, two prospective studies, one
was a combination of retrospective and prospective data, and
one open-label study. A flow diagram summarizing the study
selection and inclusion is reported in Figure 1. The mode of
treatment administration was inhalation in seven studies, oral
in four studies, ACT in three studies, and mixed mode (inhala-
tion and oral) in five studies. Adherence to CF treatments was
studied by 10 studies in the US, four studies in the UK, two in
Australia, and one each in US–Canada, Netherlands–Italy, and
Brazil. The adherence was studied for treatments such as
inhalation with tobramycin and other antibiotics (aztreonam
and colistin), oral anti-inflammatory therapy with azithromy-
cin, inhaled dornase alfa and hypertonic saline, ivacaftor, pan-
creatic enzyme replacement therapy (PERT, also referred to as
pancreatic enzymes) and multivitamin supplements, as well as
ACT via chest physiotherapy or vest. Adherence was com-
monly measured using medication possession ratio (MPR),
self-reported questionnaire, or electronically via electronic
pill-caps (i.e. medication event monitoring system).
Table 1 provides the study details including study charac-
teristics, population characteristics, sample size, and treat-
ments administered for the included studies. Table 2
provides details on method of adherence, reported adherence
rates, and outcomes associated with adherence.
3.1. Inhaled treatments
Of the seven studies reporting adherence to inhaled CF treat-
ments, three were retrospective studies [13,14,16], two were
randomized controlled trials (RCTs) [15,18], one was a combi-
nation of retrospective and prospective data [12], and one was
an open-label study [17]. The inhaled drugs studied were
tobramycin inhaled solution (TIS), tobramycin inhaled powder
(TIP), dornase alfa, colistin, tobramycin, and hypertonic saline
(one study explored the use of inhaled hypertonic saline
before, during, or after the ACT). The mean age of CF patients
varied from <1 year to 31 years, and most studies had higher
proportion of males. The study period was 12 months for the
two studies reporting adherence to tobramycin [12,13], includ-
ing the two formulations (i.e. TIS and TIP), 1 month [15] to
Table 1. Patient characteristics in the included studies.
Study (country) Mean %FEV1
Study type Population (n) Treatment (study period) Mean age (SD) in years % Males predicted (SD)
Inhaled treatments
Harrison 2014 [12] Adult CF patients chronically infected with Pseudomonas TIP or TIS (12 months) 26.3 (16–56)a 59.0 63.5 (45.5–74.0)a
(Ireland, UK) aeruginosa offered TIS at baseline and TIP (n = 78)
Combination of
retrospective and
prospective study
Briesacher 2011 [13] Patients with at least two inpatient or outpatient claims with a TIS (12 months) Mean age NR <6: 13.2% 52.7 NR
(US) Retrospective diagnosis of CF (n = 804) Retrospective cohort analysis
study 6–10: 12.2% 11–17: 31.5%
18–25: 22.0% ≥26: 21.1%
Nasr 2013 [14] (US) Patients >4 years treated with dornase alfa during a 2-year Dornase alfa (13 months) 19.5 (11.5) 50.9 NR
Retrospective cohort period (n = 907)
analysis
Bakker 2011 [15] Patients aged 6–18 years, in stable condition and with small Dornase alfa (1 month) Large airways deposition group: Large airways Large airways deposition
(Netherlands and airway obstruction (n = 49) 13.3 (3.4) deposition group: 81.8 (13.1)
Italy) RCT group: 56
Small airways deposition group: Small airways Small airways deposition
12.7 (3.5) deposition group: 80.4 (15.6)
group: 50
Ball 2013 [16] (England, Patients aged between 11 and 17 years or starting secondary Colistin, tobramycin, and dornase alfa but 13.9 (11.1–16.8)a 58.0 78 (43–105)a
UK) school, established on therapy through the I-neb using
™ not hypertonic saline using I-neb ™
Retrospective study standard tidal breathing mode of inhalation (n = 24) adaptive aerosol delivery device (Philips
Respironics, Parsippany, NJ) (12 months)
Rosenfeld 2011 [17] (US Patients with CF aged 12–30 months (n = 20) Inhaled hypertonic saline (0.5 months) 20.3 (5.2) months 35.0 NR
and Canada) Open-
label study
Dentice 2012 [18] Patients ≥18 years, confirmed CF diagnosis with sweat testing Inhaled hypertonic saline before, during, or 31 (10) 44.0 57 (22)
(Sydney, Australia) or genotyping, able to perform ACT and hypertonic saline after the ACT (3 days)
Randomized, inhalation on a regular basis, and clinically stable with FEV1
crossover trial within 10% of the best recorded value for the past
6 months (n = 50)
Oral treatments
Barker 2016 [19] (US) Patients aged 1–13 years with at least 1 year since diagnosis Pancreatic enzyme supplements (3 months) 6.4 (3.0) 51.0 87.9 (25.1)
Prospective study (n = 83)
Williams 2015 [20] Adult patients with at least one copy of the G551D mutation Ivacaftor (NR) NR NR NR
(Australia) (n = 20)
Retrospective study
of prospectively
collected data
Siracusa 2015 [21] (US) Patients with CF and CFTR-G551D mutation, ≥6 years, and Ivacaftor (4 months) 20.8 (9.9) 50.0 100.7 (18.2)
Prospective study prescribed ivacaftor for at least 1 month (n = 12)
Suthoff 2016 [22] (US) Patients diagnosed with CF aged ≥6 years prescribed ivacaftor Ivacaftor (12 months) 20.8 (11.8) 45.6 NR
Retrospective study between 1 January 2012 and 31 July 2014 with 12 months
of continuous insurance coverage prior to and following the
prescription (n = 79)
ACT
Modi 2010 [23] (US) Patients ≥7 years of age with confirmed diagnosis of CF based ACT by postural drainage and percussion, 14.3 (7.9) 55.0 86.7 (19.1)
Retrospective study on either a sweat chloride or two documented CFTR flutter, or HFCWO vest therapy
EXPERT REVIEW OF RESPIRATORY MEDICINE

mutations and FEV1% predicted of at least 45% (n = 153) (16 months)

(Continued )
3
 4

Table1. (Continued).
S. NARAYANAN ET AL.

Study (country) Mean %FEV1

Study type Population (n) Treatment (study period) Mean age (SD) in years % Males predicted (SD)
Flores 2013 [24] (Brazil) Patients ≥16 years, with a diagnosis of CF, and were clinically ACT via chest physiotherapy (NR) 23.1 (6.3) 49.0 High vs. moderate vs.
Retrospective cross- stable (i.e. no exacerbation, therapeutic modification, or poor adherence: 53.9
sectional study of hospitalization in past 30 days) (n = 63) (26.3) vs. 68.2 (32.4) vs.
prospectively 71.8 (27.8)
collected data
Oates 2015 [25] (US) Pediatric patients with CF who perform ACT with HFCWO ACT via HFCWO vest (1 month) 11.2 (4.7) NR <85%: 21.82% 85–99%:
Retrospective cross- device (vest) (n = 110) 34.55% ≥100%: 27.27%
sectional study NA: 16.36%
Mixed modes of treatments
Eakin 2011 [10] (US) Patients ≥6 years seen at clinic for at least 18 months, Dornase alfa, inhaled tobramycin, oral 20.9 (11.9) 48.9 80.1 (24.8)
Longitudinal prescribed at least one of the treatments for a minimum of azithromycin, or inhaled hypertonic saline
retrospective analysis 12 months (n = 95) (12 months)
Quittner 2014 [26] (US) Patients with two or more diagnoses 30 days apart, prescribed Oral azithromycin, dornase alfa, hypertonic 22.8 (13.0) 51.0 NR
Retrospective cohort at least one of the treatments (n = 3287) saline, or an inhaled antibiotic (aztreonam,
analysis colistin, or tobramycin) (12 months)
Shakkottai 2015 [27] Confirmed diagnosis of CF with a sweat chloride measurement PERT, inhaled hypertonic saline, dornase alfa, 0–5 years group (n = 58): 2.69 0–5 years group: 0–5 years group: 96.85
(US) Retrospective ≥60 mEq/L and/or two disease-causing mutations, TIS and azithromycin (12 months) (2.13) 6–12 years group 43.1 6–12 years (19.23) 6–12 years
cohort analysis prescribed at least one of the treatments for a minimum of (n = 83): 9.25 (1.28) group: 50.6 group: 96.93 (14.56)
3 months (n = 204) 13–21 years group (n = 63): 13–21 years 13–21 years group:
15.39 (1.96) group: 46.0 79.72 (23.15)
Goodfellow 2015[28] Patients had a consultant confirmed diagnosis of CF and were PERT, vitamins and chest physiotherapy 10.1 (0.2–18.6)a 44.0 84 (4.54)a
(Ireland, UK) Cross- aged ≤18 years (n = 100) (12 months)
sectional multi-
method study
McCormack 2011 [29] Clinically stable CF patients (5–16 years) with P. aeruginosa Colistin given TIM versus standard TBM TIM: 11.7 (8.7–15.9)a TIM: 70.0 TBM: 70.0 TIM: 74 (60–105)a
(England, UK) RCT infection established on long-term (>3 months) antibiotic (2 months) TBM: 10.6 (5.2–16.9)a TBM: 80 (53–100)a
therapy through the I-neb using standard tidal breathing
™
mode of inhalation (n = 20)
a
Median (range).
ACT: airway clearance techniques; CF: cystic fibrosis; FEV1: forced expiratory volume in 1 s; HFCWO: high-frequency chest wall oscillation; NA: not available; NR: not reported; PERT: pancreatic enzyme replacement therapy; RCT:
randomized controlled trial; TBM: tidal breathing mode; TIM: target inhalation mode; TIP: tobramycin inhaled powder; TIS: tobramycin inhaled solution; SD: standard deviation; CFTR: cystic fibrosis transmembrane
conductance regulator.
Table 2. Adherence to treatments reported in the included studies.
Study (country) Therapy (time period of study) Measurement of adherence
Inhaled treatments
Harrison 2014 TIP or TIS (12 months) Adherence was recorded as excellent (>80% adherence to
[12] (Ireland, therapy, score = 3), moderate (50–80% adherence to
UK) therapy, score = 2), or poor (<50% adherence to
therapy, score = 1) by patient self-reporting using a
modified version of a self-report adherence assessment
tool.
Briesacher 2011 TIS (12 months) Adherence was calculated as the sum of the days’ supply
[13] (US) dispensed during the year divided by 56. Overall
adherence categories were defined as: low utilization ≤2
cycles, medium utilization >2 to <4 cycles, and high
utilization ≥4 cycles. Adherence, as defined by these
annual utilization thresholds, was measured only during
the first year of observation and did not include
extemporaneously compounded aerosolized
tobramycin.
Nasr 2013 [14] Dornase alfa (13 months) Adherence was measured with MPR. MPR was calculated
(US) by summing the days’ supply for all dornase alfa
prescriptions in the 13-month post-index period and
dividing it by total days in the period. Low adherence
group had MPR <0.5, moderate had MPR between 0.5
and <0.8, and high had between 0.8–1.0.
Bakker Dornase alfa (1 month) The Akita monitored adherence by recording on the
™ ● 85% (but patients with baseline daily-dose
2011 [15] smartcard the date, time. and number of breaths of each
(Netherlands nebulization treatment. For each patient, daily dose
and Italy) adherence was calculated, which expresses the
percentage of days a patient adhered correctly to the
prescribed once-daily nebulization of dornase alfa.
Ball 2013 [16] Colistin, tobramycin, and Adherence was calculated as the percentage of the
(England, UK) dornase alfa but not number of treatments taken divided by number of
hypertonic saline using prescribed treatments. Adherence was then calculated
I-neb adaptive aerosol
™ for weekdays and weekends, and term-times and
delivery device (12 months) holidays over the year, based on the dates of school
holidays for all patients.
Adherence
● Adherence to TIS at baseline (n = 49) as low ● NR
vs. moderate vs. excellent: 24% vs. 31% vs.
45%
● Adherence to TIP at 12 months (n = 40) as low
vs. moderate vs. excellent: 4% vs. 14% vs. 63%
● Low utilization ≤2 cycles (n = 570): 71%
● Medium utilization >2 to <4 (n = 180): 22%
● High utilization ≥4 cycles (n = 54): 7%
● Overall MPR = 59%
● Mean adherence in low vs. moderate vs. high
adherence group was 28% vs. 65% vs. 93%
● Among patients who did not use dornase alfa
for at least 12 months before index date vs.
those who used before: 39% vs. 66%
● Adherence by age (p < 0.001):
o 5–12 years (n = 274): 66%
o 13–20 years (n = 337): 57%
o 21–30 years (n = 140): 54%
o ≥31 years (n = 156): 56%
● Adherence by season (p < 0.001):
o Fall and winter: 61%
o Spring: 59%
o Summer: 56%
adherence <70% were excluded which may
bias the results)
● Mean overall adherence through the I-neb
was 65% with 12/24 (50%) patients achieving
an overall adherence of over 75%
● Mean adherence on weekdays vs. weekends:
67% vs. 60%
● Mean adherence during school term-time vs.
holidays: 66% vs. 51%
Outcomes associated with adherence
● Low vs. moderate vs. high utilization
o Median inpatient costs: $23,619 vs. $16,814 vs.
$20,610
o Median outpatient costs (excludes drug costs): $6317
vs. $5463 vs. $4033
o Median outpatient prescription drug costs: $17,850 vs.
$35,892 vs. $46,708
● Low vs. moderate vs. high adherence group:
o Any inpatient respiratory exacerbation: 24.5% vs.
22.3% vs. 19.1%
o Length of stay, mean (SD)a: 17.3 (19.1) vs. 12.6 (15.2)
vs. 10.8 (10.0)
o Any ED visit for respiratory exacerbation: 5.0% vs.
2.6% vs. 4.0%
o No. of outpatient visits for respiratory exacerbations,
mean (SD): 1.3 (3.7) vs. 1.3 (2.9) vs. 1.2 (2.4)
o No. of fills of oral or IV antibiotics, mean (SD): 3.9 (3.6)
vs. 4.4 (4.2) vs. 5.1 (4.6)
o Total healthcare charges, mean (SD): $58,612 (81,959)
vs. $67,565 (68,380) vs. $69,427 (56,110)
o Total respiratory exacerbation-related charges, mean
(SD): $17,163 (48,469) vs. $13,408 (41,265) vs. $9264
(30,159)
● NR
● NR
™
EXPERT REVIEW OF RESPIRATORY MEDICINE
(Continued )
5
 6

Table2. (Continued).
Study (country) Therapy (time period of study) Measurement of adherence
Rosenfeld 2011 Inhaled hypertonic saline Adherence was evaluated by the number of returned
[17] (US and (0.5 months) treatment ampoules, by the number of reported
Canada) treatment days, and by responses to diary adherence
questions. Families were instructed to complete a daily ● Based on the diary entries, treatment was
diary electronically via a secure website or on paper,
covering treatment adherence and symptoms. Dairy
questions were based on the receipt of hypertonic saline
Adherence Outcomes associated with adherence
● Median of 25 drug ampoules used during ● NR
median of 13 days of treatment (expected
two ampoules/day/participant)
received by 75–100% of participants and
lasted for at least 10 min in 78–100%
depending on the day
S. NARAYANAN ET AL.

by the child and included the time of day, amount of ● Median percentage of total days on which
time taken, manner of child, child’s coughing, and each participant received the treatment: 100%
breathing as well as spit up.
Dentice 2012 Inhale hypertonic saline before, Adherence was assessed by counting unused sachets of ● 99% ● NR
[18] (Sydney, during, or after the ACT hypertonic saline and through documentation of each
Australia) (3 days) session of ACT and hypertonic saline in the participant’s
hospital case records. Adherence was calculated as the
total number of airway clearance sessions performed
divided by the total number of sessions scheduled and
reported as a percentage.
Oral treatments
Barker 2016 Pancreatic enzyme supplements Adherence was measured with electronic pill-caps (MEMS) ● 49% adherent to taking pancreatic enzymes ● Average weight change among children who were
[19] (US) (3 months) and cutoff was considered as that given by Cystic with 3.0 (confidence interval: 2.6–3.7) meals >50% adherent at home vs. those who were <33%
Fibrosis Foundation recommendations (three meals and or snacks per day adherent measured at the next clinic visit: weight gain
three snacks per day) ● Only four children (5%) routinely met or of 0.5 standardized unit vs. loss of 0.1 standardized
exceeded the recommendations unit
● Children of parents with symptoms of
depression (35%) were less adherent than
those without symptoms (49%)
● Adherence at school vs. home: 94% vs. 42%
● Adherence in toddlers vs. school-aged chil-
dren: 51% vs. 38%

Williams 2015 Ivacaftor (NR) A placebo-controlled trial consisted of two active phasesa
[20] during which participants were randomized to ivacaftor
(Australia) or placebo. On completion, all participants entered an
open-label extension. During the open-label extension,
pharmacy dispensing was recorded. Patients self-
reported a percentage adherence during active phases 1
and 2 and also during the open-label extension.
Siracusa 2015 Ivacaftor (4 months) MEMS was used to objectively monitor adherence. For
[21] (US) each patient, overall adherence rate was defined as total
doses taken/total days monitored × two doses per day,
and the weekly adherence rate was defined as total
doses taken every 7 days/7 days × 2 doses per day.
Secondary medication adherence rates were
documented using self-report and pharmacy refill data.
Self-report adherence data were obtained using the self-
reported treatment adherence and barriers assessment.
Prescription refill data were obtained from each
patient’s pharmacy over the study period; MPR was
calculated using these data.
● Patient reported vs. actual adherence during: ● NR
o Active phase 1: 96.7% vs. 97.6%
o Active phase 2: 96.9% vs. 96.3%
o Open-label extension: 94.4% vs. 94.5%
● Electronic monitoring: 61%, range: 4–99% ● NR
● Self-report: 100% (except one patient with
<20% adherence)
● Pharmacy refill history (MPR): 84%, range:
13–124% (due to over-refilling by one patient)
Adherence decreased over time at a rate of
1.93% per week
(Continued )
Table2. (Continued).
Study (country) Therapy (time period of study) Measurement of adherence Adherence Outcomes associated with adherence
Suthoff 2016 Ivacaftor (12 months) Adherence was assessed in the post-index period by the ● Number of ivacaftor claims per patient, mean ● NR
[22] mean number of ivacaftor claims per patient during the (SD) 8.8 (3.6)
(US) post-index period, MPR (total days supplied from all ● Mean MPR (SD) = 0.8 (0.3)
ivacaftor refills divided by 365 days of the post-index ● Patients with single-month supply claims,
period), and the overall proportion with a high mean (SD) = 0.8 (0.3)
adherence rate (defined as the proportion of patients ● Patients with multi-month supply claims,
with an MPR of 0.80) mean (SD) = 0.9 (0.2)
● MPR >0.80 = 58 (73.4%)

ACT
Modi 2010 [23] ACT by percussion, flutter, and Adherence was assessed using daily phone diary. For all ● Mean adherence (SD) at: ● NR
(US) vest therapy (16 months) activities lasting 5 min or longer, participants (e.g. o Pre-randomization: 36.1% (30.4%)
caregivers of children 7–13 years of age, adolescents o 4-month: 57.5% (37.2%)
14–18 years of age, and adults 18 years and older) o 8-month: 54.5% (41.5%)
reported the type of activity, duration, and who was o 12-month: 58.0% (42.8%)
present. As the phone diary was conducted, each o 16-month: 55.9% (35.6%)
activity was recorded by the interviewer on a computer ● Proportion of patients with various level of
screen with clock hands which rotated through a 24-h adherence to ACT by percussion vs. flutter vs.
clock, a set of activities, companions, and a rating of vest therapy
mood ranging from 1 (extremely negative) to 5 o Low adherence (n = 22): 14% vs. 15% vs.
(extremely positive). 14%
o Medium adherence (n = 75): 40% vs. 67%
vs. 42%
o High adherence (n = 56): 46% vs. 14% vs.
44%

Flores 2013 [24] ACT via chest physiotherapy (NR) Adherence was assessed via questionnaire and response ● High adherence = 60% ● NR
(Brazil) choices for frequency of chest physiotherapy were ‘every ● Moderate adherence = 19%
day or almost every day,’ (high adherence), ‘about ● Poor adherence = 21%
3–5 days a week,’ (moderate adherence) or ‘<3 days a
week’ (poor adherence).
Oates 2015 [25] ACT via HFCWO vest (1 month) HFCWO vests are equipped with a built-in chronometer ● Mean adherence rate: 61% ● An association between current adherence to HFCWO
(US) that records cumulative utilization time of the device (in o High adherence = 35% and lung function over 12 months was not observed
hours and minutes). Two such readings were obtained o Medium adherence = 37%
from each patient’s HFCWO vest via telephone. The first o Poor adherence = 28%
reading was obtained within 2 days of study enrollment;
the second reading was obtained 4 weeks after the
baseline reading. The difference between the two
cumulative utilization readings divided by the number
of days between them provided an average daily use of
the HFCWO vest. Adherence rate was represented as a
ratio (%) between the average daily use and the
prescribed daily use of the HFCWO vest. Information on
prescribed daily use was provided by the CF center
respiratory therapist. Adherence rates were coded in
three categories: low (<35%), medium (36–79%), and
high (≥80%).
Mixed modes of treatments
EXPERT REVIEW OF RESPIRATORY MEDICINE

(Continued )
7

Table2. (Continued).
Study (country) Therapy (time period of study)
Eakin 2011 [10] Dornase alfa, inhaled Patient pharmacy refill records were used to calculate MPR.
(US) tobramycin, oral azithromycin,
or hypertonic saline
(12 months)
Quittner 2014 Oral azithromycin, dornase alfa, For each long-term pulmonary medication filled ≤90 days ● Average CMPR: 48%
[26] (US) hypertonic saline, or an
inhaled antibiotic (aztreonam,
colistin, or tobramycin)
(12 months)
Shakkottai 2015 PERT, inhaled hypertonic saline,
[27] (US) dornase alfa, TIS, and oral
azithromycin (12 months)
Measurement of adherence Adherence
● CMPR: 63%
The MPRs of each medication were averaged across all noneMedian MPR was 49% for hypertonic saline,
medications to obtain the CMPR. ~65% for inhaled tobramycin, ~70% for dornase
alfa, and 76% for azithromycin
before the index date, adherence was calculated as MPR. ● Mean MPR highest for dornase alfa (57%)
Drug-specific MPRs were calculated for each pulmonary followed by inhaled tobramycin (51%), azi-
medication and then averaged to obtain a CMPR. CMPR thromycin (50%), inhaled aztreonam (47%),
was classified as low (< 0.50), moderate (0.5–0.8), and inhaled colistin (42%), and hypertonic saline
high (≥0.80). (40%)
● Adherence by age groups (all p < 0.001)
o 6–10 years: 59%
o 11–17 years: ~50%
o 18–25 years: ~45%
o 26–35 years: ~43%
o ≥36 years: ~50%
● Adherence in males vs. females: 50% vs. 45%
● Mean CMPR, 41%, 51%, 56%, 60%, and 62%
for one, two, three, four, and five medications
filled, respectively.
Adherence was calculated as a modified MPR. The actual ● Median % filled for 0–5 vs. 6–12 vs.
number of prescriptions filled in a 12-month period was 13–21 years:
divided by the number of prescriptions that should have o Inhaled hypertonic saline (n = 37 vs. 61 vs.
been filled based on the prescribed amount and that 49): 80.0 vs. 66.7 vs. 54.5
value was multiplied by 100 to generate % adherence. o Dornase alfa (n = 31 vs. 37 vs. 23): 83.3 vs.
MPR was modified in order to better assess annual 72.9 vs. 64.7
trends in adherence. o TIS (n = 12 vs. 19 vs. 15): 85.7 vs. 66.7 vs.
66.7
o CF multivitamins (n = 50 vs. 71 vs. 44): 74.2
vs. 55.6 vs. 58.3
o PERT (n = 42 vs. 43 vs. 28): 73.0 vs. 70.0 vs.
46.2
8
Outcomes associated with adherence
● Lower CMPR significantly predicted having one or
more courses of IV antibiotics to treat a pulmonary
S. NARAYANAN ET AL.
exacerbation during the year
● When analyses with the MPR of each individual drug
were repeated, a trend was evident for an association
between lower azithromycin MPR and having a pul-
monary exacerbation
● Mean (SD) healthcare costs (hospitalization +
outpatient + ED costs, in 2011 USD) in low vs.
moderate vs. high CMPR group in first year after study
index date:
● All cause, mean (SD): $54,190 (143,267) vs. $45,239
(97,007) vs. $34,432 (77,088)
● CF related: $36,605 (107,876) vs. $33,210 (73,861) vs.
$23,525 (54,879)
● Mean (SD) healthcare costs (hospitalization + outpatient
+ ED costs, in 2011 USD) in low vs. moderate vs. high
CMPR group in second year after study index date:
● All cause, mean (SD): $46,379 (97,170) vs. $44,824
(85,135) vs. $37,067 (81,845)
CF related: $31,183 (75,462) vs. $33,055 (65,837) vs.
$24,003 (49,620)
● NR
(Continued )
Table2. (Continued).
Study (country) Therapy (time period of study) Measurement of adherence Adherence Outcomes associated with adherence
Goodfellow Enzyme supplements, vitamins, Adherence was assessed using ● Using pharmacy PMRs, low-adherers were: ● NR
2015 [28] and chest physiotherapy (a) scores from parent and/or child MARS: The MARS o Enzyme supplements: 60%
(Ireland, UK) (12 months) questionnaire was used to measure the frequency of o Vitamins: ~53%
non-adherence to pancreatic enzyme supplements, o Chest physiotherapy: NA
vitamins, and chest physiotherapy with separate ● Using GP prescription data, low-adherers
versions administered to parents and children were:
(≥11 years). Each question was scored on a 1–5 Likert o Enzyme supplements: ~55%
scale (always-never). Answers to each questions were o Vitamins: ~48%
summed and transformed to range from 0 to 100, with o Chest physiotherapy: NA
higher scores indicating higher levels of self-reported ● Using parents vs. child self-reported MARS,
adherence. low-adherers were:
(b) PMR from each patient’s community pharmacist: o Enzyme supplements: ~45% vs. ~8%
children were classified as low-adherers to pancreatic o Vitamins: ~19% vs. ~10%
enzyme supplements or vitamins if their community o Chest physiotherapy: ~49% vs. ~39%
pharmacy records illustrated that they were dispensed ● Using composite adherence measurement
<80% of the prescribed amounts during the previous approach, low-adherers were:
12 months. This was calculated using the medication o Enzyme supplements: 72%
refill adherence (MRA) method. o Vitamins: 59%
(c) prescription records from the patient’s GP: patients o Chest physiotherapy: 49%
were classified as low-adherers if the prescription issue ● 79 patients were prescribed all three treat-
records for pancreatic enzyme supplements or vitamins ments, of which 14 were high adherers and
disclosed by their GP indicated that <80% were issued 25 were low adherers
in the previous 12 months using the MRA method
A composite adherence measurement approach was
used so that a child was designated as a low-adherer if
they scored less than 80% in any one of the methods
described.
McCormack Colistin given TIM versus Adherence was measured by electronic data capture using ● Mean adherence at baseline vs. end of study ● NR
2011 [29] standard TBM (2 months) a docking station for the I-neb device and software.
™ o TBM (n = 10): 72% vs. 65%
(England, UK) At all times, I-neb calculates the volume of each
™ o TIM (n = 10): 86% vs. 89%
inhalation and once the pre-programmed total dose of
drug is delivered, gives audio and visual feedback
informing the patient that treatment is complete.
Percentage adherence was defined as the number of
treatments taken/number of prescribed treatments ×
100.
a
Only abstract of this study was available, and it did not provide details of the two phases.
ACT: airway clearance techniques; CF: cystic fibrosis; CMPR: composite medication possession rate; ED: emergency department; GP: general practitioner; MARS: medication adherence report scale; MEMS: medication event
monitoring system; MPR: medication possession rate; NA: not available; NR: not reported; PERT: pancreatic enzyme replacement therapy; PMR: patient medication record; TBM: tidal breathing mode; TIM: target inhalation
mode; TIP: tobramycin inhaled powder; TIS: tobramycin inhaled solution; IV: intravenous.
EXPERT REVIEW OF RESPIRATORY MEDICINE
9
10 S. NARAYANAN ET AL.
13 months[14] for dornase alfa, 12 months for colistin, tobra-
mycin, and dornase alfa using I-neb™ adaptive aerosol deliv-
ery device [16], and short duration of 3 days [18] to 0.5 months
[17] for hypertonic saline. A large variation was observed in
the methods used to measure adherence, with usage of self-
reported adherence assessment tool, utilization of dispensed
medication, MPR, monitoring device such as Akita™ (Activaero
Technologies, Gemuenden, Germany), diary responses, by
counting of unused medication, and a combination of these
methods. Depending upon the measure used to assess adher-
ence, it varied from low to excellent.
The proportion of patients with excellent adherence (63%
and 45%) to TIP at 12 months versus TIS at baseline were more
compared to moderate (14% and 31%) and low adherence
(4% and 24%), with adherence favoring TIP than TIS [12].
Similarly, only 7% of 804 CF patients had high adherence
which was defined as high utilization (four cycles or more) of
TIS per year while most (71%) had low adherence with utiliza-
tion of two cycles or less of TIS as recommended by CF
pulmonary guidelines. High adherence was associated with
decreased likelihood of hospitalization and lower outpatient
costs ($2159–$8444 vs. $2410–$14,423), but higher prescrip-
tion costs ($35,125–$60,969 vs. $10,353–$46,768) due to
higher utilization compared to low adherence [13]. The overall
adherence to dornase alfa ranged from 59% (measured via
MPR) [14] to 85% (measured via Akita™) [15]. Adherence was
better in fall and winter than in spring and summer, and no
variation was observed in the proportion of patients with
respiratory exacerbations requiring inpatient care across
these three adherence groups (i.e. low, moderate, and high
adherence based on MPR). The mean length of stay and mean
total respiratory exacerbation-related charges were signifi-
cantly low in high adherence (10.8 days, $9264) group com-
pared to moderate (12.6 days, $13,408) and low (17.3 days,
$17,163) adherence groups [14]. The long-term adherence to
nebulized therapies such as colistin, tobramycin, and dornase
alfa (but not hypertonic saline) via breath-activated data log-
ging nebulizer (I-neb™) varied largely and was significantly
better during term-time compared to holidays, with weekday
adherence better than weekend adherence in term-time but
not in holidays. Patients prescribed once-daily nebulized treat-
ment took on average 0.8 treatments/day over the course of
the year, whereas those prescribed two or three treatments a
day took on average 1.4 treatments/day, meaning that the
three treatments per day may be difficult to manage in
some teenagers with CF [16]. The adherence to 6%/7% inhaled
hypertonic saline was good, overall among very young
patients (<1 year) and among old patients (31 years) with
before, during, or after ACT, but adherence was studied for a
very short duration [17,18].
3.2. Oral treatments
Of the four studies reporting adherence to oral treatments,
two were retrospective studies with 12 months of follow-up
reported in one study and partially reported as 6 months
(reported only for one part of the study), and other two
were prospective studies with 3 to 4 months of follow-up.
Three studies examined the adherence to ivacaftor and one
study to PERT. The mean age of CF patients in these studies
varied from 6.4 to 20.8 years, and about 50% were males.
Adherence was measured differently in each study, by electro-
nic pill-caps, by patient self-reports, or via MPR, with one study
using combination strategy to assess adherence.
Adherence to oral PERT given as per recommendation (i.e.
with three meals and three snacks per day as per Cystic
Fibrosis Foundation [CFF] recommendations) over 3 months
using electronic pill-caps was 49%, and it was higher at school
(94%) than at home (42%) and higher for toddlers (51%) than
for school-aged children (38%). Children of parents with symp-
toms of depression were less adherent (35%) than those with-
out symptoms (49%). Since children were expected to have
one meal at school and two meals and four snacks at home,
this may have affected adherence rates [19]. All three studies
involving ivacaftor reported high adherence to ivacaftor. In
one study, actual adherence was greater than 96% at all
times, and patient-reported adherence was similar to actual
adherence, decreasing slightly when receiving open-label iva-
caftor but remain higher than 94% [20], while the mean
adherence assessed electronically was 61% and ranged from
4% to 99%; while it was 84% when assessed by MPR and
ranged from 13% to 124% (>100% due to over-refilling by
one patient) in another study [21]. It was found that adher-
ence decreased over time at a rate of 1.93% per week [21]. A
study assessing long-term adherence to ivacaftor using com-
mercial claims database in the U.S. found that majority of
patients (73%) were highly adherent to ivacaftor therapy at
12 months, and it was similar in patients with single-month
supply claims and multi-month claims [22]. The effect of
adherence to oral treatments on outcomes and overall patient
management costs was not assessed in any study and remains
to be seen.
3.3. Airway clearance therapy
A total of three retrospective studies assessed adherence to ACT
among CF patients with mean age ranging from 11.2 to 23.1 years.
The study period varied from 1 to 16 months, while one study did
not report the duration. The method of adherence measurement
was daily phone diary, questionnaire, or a built-in chronometer in
the vests that assist in ACT, and ACT was given via postural
drainage and percussion (PD&P), flutter device, high-frequency
chest wall oscillation (HFCWO) vest therapy, or chest therapy. The
adherence varied depending on the method used to measure
adherence as well as the method used to provide ACT in the
study. Proportion of CF patients with high adherence to ACT via
one or multiple techniques of autogenic drainage, active cycle of
breathing, positive expiratory pressure, flutter device, or PD&P
ranged from 14% to 60% [23–25]. It was found that patients with
less severe disease had poor adherence to ACT, likely resort to ACT
only when irreversible lung damage has occurred [24]. As reported
in one study, the reasons for poor adherence to ACT were ‘not
enough time to do ACT’ (28%), ‘cannot be bothered’ (16%), and ‘do
not enjoy ACT technique’ (8%), while 32% could not provide any
reason [24]. Moreover, high socioeconomic status as well as more
number of adults in household was also found to be associated
with better adherence rates and high lung function, with exposure

to smoking in the household reduced the likelihood of high lung
function by a staggering 85% [25]. Similar to oral treatments, the
impact of adherence to ACT on clinical and cost outcomes was not
evaluated by any study, except one [25] that found no association
between adherence and lung function.
3.4. Mixed modes of treatments
Of five studies reporting adherence to mixed modes of treat-
ments, four were retrospective studies with 12 months of
follow-up data [10,26–28] and one was an RCT with 2 months
of follow-up [29]. One study measured 12-month adherence
over 5 years [27]. The treatments with various modes of
administration studied were inhaled dornase alfa, inhaled
tobramycin, inhaled hypertonic saline, inhaled antibiotics,
colistin given as target inhalation mode (TIM) or tidal breath-
ing mode (TBM), oral azithromycin, PERT, vitamins, or chest
physiotherapy. The mean age varied from 3 to 23 years, and
studies included 43–70% of males. Adherence measure varied
by study and included assessment via pharmacy refill records
to further measure composite MPR across various therapies,
self-reported questionnaire, general practitioner prescription
data, or electronic data capture via I-neb™ device.
Adherence varied largely depending on the measure used to
assess adherence, with adherence varying from 50% to 76% for
oral azithromycin, 57% to 70% for inhaled dornase alfa, 51% to
65% for inhaled tobramycin, 40% to 49% for inhaled hypertonic
saline, 47% for inhaled aztreonam, and 42% for inhaled colistin
[10,26]. The difference in proportion of low-adherers to enzyme
supplements varied from 8% to 72%, vitamins varied from 10% to
59%, and chest physiotherapy from 39% to 49% based on the
method used to measure adherence [28]. The adherence increased
from baseline to end of the study at 2 months for TIM while it
decreased for TBM, and all patients agreed that TIM was easy to
understand and easy to use, and they were able to use it straight
away [29]. Adherence varied by age, with younger patients (0–
10 years) more adherent to therapies compared to adolescents
and adults [26,27]; however, the overall adherence remained same
across 5 years (2008–2012) in younger patients, with marginal
increases in 2010 among 6–12-year-old patients and slight
decrease from 2009 to 2011 among 13–21-year-old patients [27].
Younger patients (0–5 years) had highest adherence to inhaled
therapies such as tobramycin, dornase alfa, and hypertonic saline
and lower to oral therapies such as PERT and vitamins, and similar
trend was observed in older patients [27]. As compared to patients
with high adherence, patients with low or moderate adherence
had more CF-related hospitalizations, all-cause hospitalizations,
and CF-related and all-cause acute care use (hospitalizations +
emergency department [ED]), and higher healthcare costs, in the
first and second year after study index, indicating increased cost
and resource utilization burden among low-adherers [26].
4. Discussion
The chronic nature of CF requires long-term treatment and
management. However, this study finds that the long-term
(≥12 months) adherence to ivacaftor is high, but it is low for
other CF treatments such as antibiotics, dornase alfa, hyper-
tonic saline, PERT, ACT, and vitamins. Patients with CF are
EXPERT REVIEW OF RESPIRATORY MEDICINE 11
more adherent to inhaled therapies compared to oral thera-
pies such as PERT and vitamins, and among inhaled treat-
ments, more patients are adherent to tobramycin inhalations
at 12 months than dornase alfa or hypertonic saline.
Adherence to ACT via flutter device is lower compared to
ACT via PD&P or HFCWO vest therapy and all other inhaled/
oral treatments. Among oral treatments, 12-month adherence
to ivacaftor is high, and 3-month as well as 12-month adher-
ence is low for pancreatic enzymes. The adherence varies
largely by treatment type, mode of treatment administration,
method of adherence measurement, and also by age, season,
and time. Moreover, higher rates of exacerbations and longer
length of inpatient stays as well as increase in some healthcare
costs are observed among groups with suboptimal adherence.
These findings are similar to a recent study conducted by
Quittner et al. which highlighted the elevated costs among
CF patients with suboptimal adherence [30].
To our knowledge, this is the first review that has assessed
the recent literature on rate of adherence to different CF
treatments as well as the impact of adherence on patient
outcomes.
Adherence appears to decline with increasing age
[14,26,27]. Puberty and emerging adulthood (ages
18–25 years) in which individuals undergo various role transi-
tions such as starting college/career, development of relation-
ships, and transitioning healthcare teams may influence
treatment adherence [31–33]. Adherence in children may
also be negatively affected when their parents show high
rates of depressive symptoms [19]. It is found that children/
adolescents are more adherent in school than at home, espe-
cially when medications are to be taken with day meals and
snack [19] and on weekdays and during school-term than on
weekends or during holidays [16]. Children with overall poor
adherence show more apparent disparity between weekday/
weekend and holiday/term-time compared to adolescents
who take their medications more than 90% of the time [16].
Moreover, adherence varies to some extent by season, with
slightly higher adherence observed during winter or fall com-
pared to summer or spring [14], potentially due to higher risks
of infection during winters [34]. Thus, adherence to CF treat-
ments is affected by various factors including time and place,
and these factors must be taken into consideration when
measuring adherence and developing strategies to improve it.
Adherence varies based on the type of treatment and
patient’s preference for that treatment. A study assessing
treatment preference of CF patients showed that participants
preferred a dry powder inhaler to nebulized therapy provided
their out-of-pocket costs were the same. Their preference was
also based on the time spent on the treatment, ease of setup
and cleaning, and the ability to administer treatment any-
where [35]. A study found that the median number of daily
therapies was 7, with a median of 3 inhaled and 3 oral thera-
pies, and the mean time spent on treatment activities was
approximately 2 h daily [36,37], which is almost double of that
consumed in diabetes and 20 times that spent in asthma [37],
indicating an extremely high treatment burden in CF which
could possibly affect adherence. Often, the timing of treat-
ment does not affect the outcomes, but patients perceive
greater efficacy and satisfaction for treatments given at certain
12 S. NARAYANAN ET AL.
times, which may improve adherence rates. In a randomized
trial, CF patients reported significantly worse satisfaction when
hypertonic saline was inhaled after the ACT compared to
before or during ACT [18]. In addition to CF medications, it is
also important to adhere to nutritional and exercise recom-
mendations [38]. When assessing adherence to a particular
therapy, it is of utmost importance to measure adherence to
other accompanying therapies as well as nutrition and
exercise.
The adherence to oral treatments for CF needs to be ade-
quately studied in larger population. Studies (albeit, with small
sample sizes) showed that adherence to ivacaftor was high
(>90%) while those studying PERT or vitamins showed much
lower level of adherence compared to some inhaled therapies.
Higher adherence to ivacaftor could potentially be attributed
to its superior efficacy; however, the effect of better adherence
in turn on clinical outcomes and the overall costs of CF
management remain to be explored. Since most patients pre-
fer quick and convenient treatments, oral treatments may
prove beneficial to improve long-term adherence and subse-
quently, patient outcomes. Ivacaftor and lumacaftor/ivacaftor
combination is significantly efficacious but need to be taken
every 12 h with foods that contain fat, such as eggs, avocados,
nuts, butter, and peanut butter [39]. While studying adherence
to therapies with such dietary restrictions, it is important to
evaluate if patients follow the recommendation closely in
order to ensure better absorption in the body for optimal
outcomes. The few studies that have reported the adherence
to ivacaftor (among patients with G551D mutation) either had
a short-term follow-up period [21] or were associated with a
small sample size [20,22], making it difficult to extrapolate the
results to the broader CF population. Moreover, these studies
lacked a homogenous measure of adherence, and therefore
adherence varied based on the applied method. It is also
important to note that in addition to disliking the taste of
some antibiotics, children with CF may experience difficulty in
swallowing pills [40]. The degree of adherence to lumacaftor/
ivacaftor combination among patients with homozygot
deltaF508 mutation (who are often sicker than patients with
G551D mutation) has yet to be demonstrated. In light of the
above shortcomings and restrictions, additional real-world
studies (outside of clinical trial settings) assessing adherence
to disease-modifying oral therapies and profiling patients at
risk for lower adherence warrant further exploration.
Measures applied to quantify adherence in CF are self-
reports, electronic monitors, and pharmacy records, but each
method has their particular advantages and disadvantages.
Self-reported adherence by patients is mostly higher than
that perceived by health professionals [41] or that assessed
by other methods [21] and thus underscoring the potential
measurement bias associated with this modality. However,
self-report questionnaires are easy to administer, are inexpen-
sive, and can measure each component of the treatment regi-
men from the patient’s perspective [42]. Currently, no
validated questionnaires exist to measure adherence in CF
[41,43]. There is also less clarity in the measurement criteria
such as the number of doses missed per day or per week that
may hold the same degree of clinical significance across the
different treatments. Patterson et al. developed a new ‘Living
with CF Questionnaire’ to capture multiple aspects of adher-
ence; however, not all domains had sufficient reliability, and
the study had a low response rate [43]. Thus, there is a need to
develop appropriate tools to adequately capture patient-
reported outcomes for CF. Electronic monitors provide the
date, time, and duration of treatment behaviors and are avail-
able for oral medications, metered-dose inhalers, and some
nebulized treatments (I-neb™ and Akita™) but are not avail-
able for all components of the CF treatment regimen, such as
airway clearance; and employing these monitors at the (CF)
population level may prove cost-prohibitive. Although phar-
macy records provide an objective adherence measure,
records of at least 1 year need to be analyzed for reliable
estimates, and thus short-term changes may not be captured
accurately [44]. Also, pharmacy records indicate if the medica-
tion has been refilled, but cannot document if the medication
was taken [22,42].
Lower adherence with CF treatments may be observed
due to various barriers. Barriers and drivers influencing
adherence to CF therapies are summarized in Figure 2. In a
study by Bregnballe et al., over 60% of patients and their
parents encountered barriers such as lack of time, forgetful-
ness, and unwillingness to take medication in public [45].
Other barriers commonly reported in the literature are treat-
ment-related adverse effects, longer and inconvenient
administration, high frequency of therapy, and previous
experience with the treatment [14,27,40]. A high level of
polypharmacy, poor patient–provider communication, and
lack of disease- and treatment-related knowledge are also
identified as barriers to adherence [40]. A study found that
CF patients with a low socioeconomic status had lower
forced expiratory volume in 1 s (FEV1%) predicted, lower
weight and height, more likely to require treatment for a
pulmonary exacerbation and associated with poorer out-
comes compared to those not having a low socioeconomic
status [46]; similar association was found between lower
adherence to ACT and lower socioeconomic status [25]. As
out-of-pocket cost could be a key barrier that often adds to
the disease burden and affects adherence [13], patients in
families with low socioeconomic status may be at risk for
lower adherence. Patients and their parents’ beliefs and
attitudinal patterns may also contribute to adherence
[28,47] and play a key role in devising patient programs to
increase adherence in CF. Symptoms of depression are also
associated with poor adherence and lower QoL in adult CF
patients [48], which highlights the importance of depression
screening at various stages of CF management. Due to the
complex nature of the treatment regimens in CF and its
accompanying barriers, it is important to adopt targeted
approaches to improve adherence.
Diabetes commonly occurs in patients with CF, and a
unique clinical entity – cystic fibrosis–related diabetes
(CFRD), primarily caused by insulin insufficiency – is a common
comorbidity in CF. Clinical guidelines recommend regular
screening for CFRD and management with insulin therapy
with thorough monitoring [49]. This may further add to the
already high patient burden in CF. Although it was not a key
objective to study the adherence to insulin therapy in patients
with CFRD, we did not find any relevant literature during the

Figure 2. Factors influencing adherence in Cystic fibrosis.
screening process. There is a need to understand the level of
adherence among these CF patients with special needs and
also to assess the impact of insulin therapy on adherence to
CF-related therapies.
Certain limitations should be considered before inferring
the results of this review. We limited the search of relevant
studies to MEDLINE, and literature databases such as
Embase and Cochrane were not explored; thus, few studies
may have been missed. Due to the systematic design of the
study which is governed by the inclusion and exclusion
criteria, certain studies may have been excluded as their
abstract did not mention reporting adherence. However, in
order to minimize such exclusions, we cross-referenced the
bibliographies of adherence-related reviews to ensure inclu-
sion of key studies. Of the 19 studies included in this
systematic literature review, 13 are retrospective in nature,
with most dependent on the pharmacy records to measure
adherence. Estimation of adherence by retrospective meth-
odology may have some limitations as it relies on the
validity of the collected data and the records indicate med-
ication dispensing but not utilization by patients; however,
it is one of the most economical way to obtain real-world
data [50].
5. Conclusion
In conclusion, adherence to current CF treatments is moder-
ate-to-low and varies based on several factors such as age,
type of treatment, time of treatment, and measure of adher-
ence. The effect of adherence on treatment outcomes, costs,
and QoL needs to be better understood, especially among
new oral therapies. Several barriers such as lack of time, for-
getfulness, unwillingness to take medication, treatment side
EXPERT REVIEW OF RESPIRATORY MEDICINE 13
effects, polypharmacy, poor patient–provider communication,
insufficient disease and regimen knowledge, and cost burden
are known to affect adherence. Thus, patient-centered and
family-focused multifaceted interventions are needed to
improve adherence to existing treatments.
6. Expert commentary
Although adherence varied by several factors such as treat-
ment type, duration of treatment, and measures to assess
adherence among others, it ranged from 4% to 100%.
Adherence to treatments among patients with chronic condi-
tions are typically lower compared to those with acute condi-
tions and vary widely, consistent with that observed in CF [51–
54]. In addition to the factors mentioned above, other factors
such as patients’ age, time of medication, mode of treatment
administration, and convenience also affect adherence. These
observations align with that observed in routine clinical prac-
tices in real-world while managing CF patients.
It is however important to evaluate the research results in
the context of complexity in managing CF patients in the real-
world and the barriers that exist in improving adherence.
Interventions aimed to enhance adherence by targeting CF
patients, their parents and families, caregivers, and healthcare
team could be effective. The ‘one-size-fits-all’ approach is not
appropriate for CF due to the complexity of care, and perso-
nalized, multicomponent interventions may work more effi-
ciently [55]. An intervention involving education, self-
monitoring, reminders, parent training, problem solving, moti-
vational interviewing, and behavioral therapy can be relatively
more effective in promoting adherence [56]. Research has
found that spirituality, involving positive spiritual coping, col-
laborative and active surrender coping, and body
14 S. NARAYANAN ET AL.
sanctification, is associated with higher self-efficacy and posi-
tive attitude towards CF treatment and thus can be explored
further as a part of an adherence-enhancing intervention [57–
59]. In addition to patients, their parents/caregivers, provider,
and specialist pharmacists can be involved to improve adher-
ence [60]. CF nurses and physical therapists can also play a key
role in managing CF as well as improving adherence. They can
serve as the primary contact, address concerns, and motivate
patients and their parents to enhance adherence [61]. Nurses
and other allied health professionals can partner with patients
and families to improve adherence through monitoring, com-
munication, education, and time-management, with a plan to
reward adherence [62]. Specialist nurses in multiple sclerosis,
another therapeutic area with complex treatment regimens
and high disease burden, are seen to build a strong collabora-
tive partnership with patients, their families, and also the
physician, which has improved adherence [63]. With the
advent of sophisticated electronic technologies, mobile and
telecommunications can be used to improve adherence.
Researchers have developed a web-enabled cell-phone tech-
nology, CFFONE™ (Dawkins Productions, Inc., Hudson, New
York), to enhance CF-related knowledge, adherence, and
peer support among adolescents and is tested in the US. It
included features for CF information, care management, social
networking, entertainment, and communication. This technol-
ogy was perceived as useful by health professionals, adoles-
cents, and parents [64]. Although CFFONE™ has not been
tested in real-world situations, it is an essential first-step
towards involving electronic technologies and social network-
ing to target adherence in adolescents and adults.
Interventions focusing on overall adherence to diverse
therapies a CF patient may be taking are more desirable
than those focusing on only one treatment or one aspect of
CF care, given the multimodal nature of CF. Patients may
benefit greatly from adherence tools/interventions which
take a holistic approach to enable and empower patients
(and their family members) to optimally manage the CF con-
dition. Patient organizations such as CFF and European Cystic
Fibrosis Society have been in the forefront of promoting
research to improve CF patient outcomes, including QoL of
patients and their caregivers; these organizations may have a
unique opportunity to advance the field of patient adherence
and expand the focus beyond single treatment-specific adher-
ence programs through targeted funding.
Also, healthcare providers can play an extremely important
role by personalizing disease management plans with a goal
of lowering treatment burden and alleviate patient symptoms,
keeping an awareness of potential adverse events of the
medication [65], and assisting in transitioning some of the
responsibility from the parents to adolescent child in relevant
patient subgroups [66].
It is imperative to improve adherence to CF treatments,
given the association with better outcomes such as decreased
risk of pulmonary exacerbations [10] and all-cause and CF-
related hospitalizations [26], thus lowering patient disease
burden as well as caregiver burden. Lower adherence to pan-
creatic enzymes may play an important role in frequency of
abdominal symptoms in CF patients with pancreatic insuffi-
ciency, thereby adversely impacting their QoL. Low adherence
to CF therapies in general is associated with 35% higher
healthcare utilization and approximately $14,000 in costs com-
pared to higher adherence [26], suggesting that payers can
benefit considerably from implementing multimodal interven-
tions aimed at improving adherence in CF patients. In addition
to costs related to lower efficacy due to non-adherence, a
substantial wastage of drug due to secondary non-adherence
(medication not being taken as prescribed) also results in
substantial cost burden to the healthcare system [67]. In an
era of highly efficacious and yet costly oral therapies, health-
care providers and policy makers must recognize the budget-
ary impact of non-adherence in CF and devise population-
level interventions to improve adherence to CF care.
Poor adherence to CF treatments may be associated with
clinical manifestations of the disease (such as pulmonary
exacerbations); however, even with adequate adherence to
regimen (containing ineffective treatments), disease worsen-
ing/progression may occur, resulting in high clinical and
humanistic burden on the patients, which in turn may
(adversely) influence adherence to treatment. This complex
nature of CF management needs to be recognized and
addressed at individual patient level in clinical practice set-
tings to achieve optimal outcomes.
Future research on improving the management of CF by
involving a multidisciplinary team including patients, par-
ents/caregivers, nurses, and CF specialists is warranted. CF
nurses and physiotherapists, via active engagement with
parents/caregivers (or with patients directly), can be crucial
in facilitating active communication between the patients
and their healthcare provider, which could have a positive
impact on adherence. Identification of key patient profiles
based on patient characteristics and disease stage who may
benefit with specific CF therapies and interventions could
influence treatment sequencing. This, in turn, will lessen the
complexity of the care and improve long-term adherence.
The potential impact of suboptimal adherence to a given
treatment (such as ACT) on the adherence of other concur-
rent or consequent treatments with different modes of
administration (such as oral therapies) warrants exploration.
On the other hand, the potential impact of highly efficacious
treatments (such as CFTR modulators) on the adherence to
other concurrent treatments (influenced by patient percep-
tion of significant improvement in disease symptomatology)
also warrants scrutiny. Studies evaluating comparative effec-
tiveness of different combination treatment regimens are
warranted to identify the optimal combination of CF treat-
ments that reduce treatment burden and improve adher-
ence while reducing the overall clinical, economic, and
humanistic burden of the disease.
7. Five-year view
Over the next 5 years, as more new treatment options
become available for CF patients, there is a potential to
significantly decrease patient morbidity and prolong survi-
val. Patient convenience, lower (overall) treatment burden,
and adherence are likely to become cornerstones of ‘value’
the CF therapies can bring forth to patients, complementing
their efficacy and safety attributes. Focus on CF therapy

adherence by matching patient profiles to the type of
adherence intervention (aided by healthcare provider and
family partnership and electronic technologies/tools) is
likely to optimize care delivery and improve patient out-
comes over the long term.
Key issues
● Disease burden on CF patients is significant due to lack of
curative treatments and complicated therapies that elevate
only the symptoms which negatively affects adherence
● The results of this review highlight the low adherence
associated with majority of CF therapies, and the variance
of adherence rates due to difference in the methods of
measuring adherence
● Sub-optimal adherence is associated with higher rates of
exacerbations and longer length of inpatient stays as well
as increase in some healthcare costs
● Most commonly reported driver of adherence is conveni-
ence, while the barriers are lack of time, polypharmacy and
forgetfulness
● There is a need to adequately study adherence to various
CF therapies including the newer oral CFTR modulators in a
larger, real-world population, and formulate interventions
to increase adherence by efficiently overcoming the barriers
● Patient convenience, lower overall treatment burden and
adherence are likely to become cornerstones of ‘value’ the
CF therapies can bring forth to patients, complementing
their efficacy and safety attributes
Funding
This paper was not funded.
Declaration of interest
S. Narayanan is a consultant for Abbott, AbbVie, Incyte, Johnson &
Johnson, Novartis, Pfizer, Teva, and Vertex. JG. Mainz has received a
research grant from Vertex for an investigator initiated trial and served
in advisory boards for Vertex, PTC and Teva. JG. Mainz lectures for Pari,
Vertex, Chiesi and Pharmaxis. S. Gala is a consultant for Abbott, AbbVie,
Johnson & Johnson, Novartis, Incyte and Pfizer. H. Tabori has received
Short-Term Grants (number: 57130097) of the German Academic
Exchange Service (DAAD). D. Grossoehme has received research grants
from the John Templeton Foundation, the Division of Pulmonary Medicine
and the Department of Pastoral Care, Cincinnati Children’s Hospital
Medical Center, and Vertex. The authors have no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials dis-
cussed in the manuscript apart from those disclosed.
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