Management of cystic fibrosis

Cystic fibrosis (CF) is a lifelong, hereditary disease that is predominantly associated with Caucasian populations. The incidence in the UK is 1 in 2500 and current figures indicate just over 10,000 individuals affected, managed by 48 specialist Adult and Paediatric CF centres.(1) The disease is autosomal recessive and is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent chloride ion channel present at the apical membrane of most luminal surfaces in the body. Nearly 2000 mutations (grouped into six classes) have been discovered to cause dysfunction in CFTR; however, F508del (DF508), which results in a deletion of phenylalanine at position 508 on the CFTR protein and causes CFTR misfolding and degradation (class II), is the most common (over 90% of individuals with CF have this mutation on one or both alleles).(2) The symptoms of CF are commonly associated with respiratory disease due to the presence of thick, sticky mucus which blocks the airways and causes lung tissue damage. Airways disease in CF is progressive resulting in vicious cycles of infection and inflammation, which require intensive management with periods of hospitalisation. Over time, lung function declines due to irreversible tissue damage leading to pulmonary failure.

Highly viscous mucus plugs can also impact on the function of the gastrointestinal tract and reproductive system.(3) Pancreatic insufficiency, which is treated with nutritional enzymes and supplements, is the most common gastrointestinal complication of CF and diabetes is the most common comorbidity. The prevalence of CF-related diabetes (CFRD) increases with age and is caused by relative insulin deficiency due to the destruction of insulin-secreting beta cells in the pancreas, and potentially a resistance to insulin that worsens with increasing pulmonary disease severity and systemic inflammation.(4,5)

Life expectancy has, however, continued to increase over the last number of decades due to effective newborn screening programmes, the advent of new therapeutics, aggressive use of antibiotics, and specialist CF centres with multidisciplinary teams delivering nationally recognised standards of care. Even in recent years, the median survival for the CF population in the UK has risen from 38.8 (for the population in 2008) to 43.5 years, with 46.3% of patients aged 20 years or older.(2)

Fundamental care in CF is focused on keeping the lungs healthy and maintaining good lung function for as long as possible, which means daily clearance of mucus from the airways to avoid infection. In addition to chest physiotherapy utilising a variety of airways clearance techniques, medications such as bronchodilators and mucolytics are used. Short- and long-term administration of b2-adrenergic receptor agonists, or anti-cholinergic agents can benefit individuals with bronchial hyper-responsiveness(6,7) and may be used with exercise and as an adjunct to physiotherapy. Long-term usage of macrolides such as azithromycin, have well established anti-inflammatory effects;(8) however, leukotriene inhibitors/antagonists have also become more routine.

Recombinant DNase (Dornase alfa, Pulmozyme^®) reduces sputum viscosity by degrading large amounts of negatively charged DNA, derived from neutrophils and other cell types, that is complexed with positively charged mucins. Over 50% of patients over eight years of age receive nebulised DNase in the UK.(2) However, recommendations from both the European Cystic Fibrosis Society and the CF Foundation (US) state that all individuals with CF, aged six years and older should be started on DNase to improve lung function and reduce risk of exacerbation.(9,10) Hypertonic saline (Mucoclear 3 or 6%; Pari) or Nebusal 7%; Forest) can also be used to loosen mucus consolidation and may improve lung function in DNase non-responders; temporary irritation may include bronchoconstriction and therefore, pre-treatment with an inhaled bronchodilator must always be carried out. For adults who do not respond to DNase and cannot tolerate hypertonic saline, dry powder mannitol (Bronchitol^®; Pharmaxis) may be recommended which is inhaled from a hand-held, breath-activated device, with patients pre-treated with a bronchodilator 15 minutes prior to administration.(11,12) Mannitol is a sugar alcohol which, when inhaled, creates an osmotic gradient that draws water into the airways lumen, thereby facilitating the removal of sputum through improved mucociliary and cough clearance with potential benefits to lung function.(13,14)

Nebulised antibiotic therapy has been widely used throughout the UK since the 1980s and was introduced as a means of minimising systemic exposure while maximising the concentration of antibiotic directly to the lungs.(15) Early childhood infections include Haemophilus influenza and Staphylococcus aureus; however, colonisation with pathogens such as Pseudomonas aeruginosa commonly occur as the patient becomes older.(16) Aggressive treatment is often required to prevent chronic P. aeruginosa infection, and nebulised anti-pseudomonals are well-established agents in this regard.(17–19) Inhaled colistimethate sodium (Colistin; Colomycin^®; Forest; Promixin^®; Profile), tobramycin (TOBI^®; Novartis) and aztreonam lysate (Cayston^®; Gilead) have been shown to improve lung function, reduce the number of exacerbations and improve quality of life (QoL).(20–23) Recent advances however, include approval of dry powder inhalers (DPI) such as Colobreathe® (Forest) and TOBI^® Podhaler^TM (Novartis) by the National Institute of Health and Care Excellence.(24–26) These novel devices will mean faster administration time (Podhaler^TM, five to six min compared with 19.7 min for TOBI^® Inhalation Solution) and greater convenience; although cough and other adverse events may be more frequent.(27) The development and use of inhaled antibiotics has undoubtedly contributed to the improved life expectancy of people with CF but debate still continues in regard to optimal prophylaxis, eradication and antimicrobial maintenance therapies, particularly as microbes adapt to the CF lung environment and develop antibiotic resistance.(28)

Acute pulmonary exacerbation, indicated by an increase in symptoms and a fall in lung function, should be treated promptly with high dose antibiotics administered intravenously over a period of at least two weeks, with studies suggesting better outcome for patients if treated in hospital rather than at home.(29) These episodes contribute to the long-term deterioration in lung function of CF patients as a significant proportion of patients may fail to recover baseline lung function even three months post IV treatment.(30) Poor response to IV antibiotics, associated with breathlessness and wheeze, may suggest allergic bronchopulmonary aspergillosis (ABPA) with treatment requiring prolonged administration of high-dose systemic corticosteroids (prednisolone) often associated with an anti-fungal agent.(29)

Novel therapies of CF include the development of CFTR potentiators and correctors and have signalled a major advance in the treatment of the underlying cause of the disease.(31,32) Ivacaftor (VX-770/Kalydeco; Vertex) is a first in class CFTR potentiator, specifically designed to correct ‘gating mutations’ (class III), with studies predominantly focusing on the treatment of individuals with a G551D ‘Celtic’ mutation.(33) This mutation, which has a prevalence of 4–5% in the population, involves a substitution of a glycine for an aspartic acid residue at position 551 which causes functional disruption of the CFTR regulatory domain, limiting chloride transport. Sweat chloride levels are normalised by ivacaftor and importantly lung function has been found to improve with the number of patients experiencing an exacerbation reducing by 22% (total number of exacerbations by 70%). A concomitant reduction in a requirement for IV antibiotics and hospitalisation has also been observed.(34,35)  The CFTR corrector VX-809 (Vertex), targeted at the rescue and correction of DF508-CFTR (class II), is currently being assessed in combination with ivacaftor (Phase III TRAFFIC and TRANSPORT studies, Vertex; data expected mid-2014).

Medical advances have improved survival in CF; however, as CF lung disease progresses, treatment regimens intensify with an associated increase in costs. Several cost-analyses have been conducted worldwide, although the last detailed analysis of UK costs was conducted in 1992, which detailed the average cost of care/patient to be £8241.(36) Tur-Kaspa et al reported that the average annual direct medical costs per CF patient (without lung transplant), at the CF Centre at the Lutheran General Hospital, Illinois, US during 2006 was $63,127.(37) Treatment costs for even mild lung impairment can exceed $43,000.(38)

Medications account for the single highest expenditure, at approximately 65% of costs, followed by hospitalisation.39 An average inpatient cost per day is estimated at $932 (~£617) whereas a two-week hospitalisation can range from £8000 to £20,000 depending on the level of care required.(36,39-41) It is expected, however, that a proportion of total costs associated with medication will continue to rise due to the approval of new therapies, for example, daily treatment with Pulmozyme costs £7500 a year per patient.(9) Ivacaftor has a basic annual cost to the National Health Service in the UK of £182,625 but a patient access scheme (PAS) has been agreed with Vertex.(42) Mannitol DPI has an annual cost for daily treatment of £6061;(43) TOBI® Podhaler^TM has annual costs of £11,667 (based on 28 days on, 28 days off over a period of a year) compared with £7737 for tobramycin inhalation solution, and Colobreathe is £12,629 compared with £5037 for Promixin and £1971 for Colomycin, although a PAS has also been agreed by both Novartis and Forest Laboratories to enable these novel DPIs to be a cost-effective option.(44)

It is envisaged, in terms of budget impact, that the inclusion of these new therapies/delivery systems into a patient’s daily regimen may result in higher drug costs but that the resultant decrease in hospitalisations and the requirement for administration of IV antibiotics should translate to an overall decrease in medical care costs. A future detailed review of the health economics of CF care, encompassing the costs of these novel treatments, will be pertinent to the planning of CF services in coming years given recent advances in treatment, regulatory and costing approvals.

In terms of antibiotic prescribing, all patients should have a regular review of sputum microbiology to ensure continued appropriate treatment. Inhaled anti-pseudomonas antibiotics as detailed previously may be used routinely as a suppressive regimen, where appropriate however, if P. aeruginosa has not been isolated or has been replaced by a new organism (that is, Burkholderia cepacia) or if there is a continued loss in lung function then a change of therapy should be considered. Specific monitoring for tobramycin to check for systemic side effects, such as ototoxicity, should be carried out. For inhaled therapies, a regular assessment of lung function to ensure treatment tolerance as well as the identification of adverse effects must also be conducted on all patients.(45)

In particular, if there is evidence of bronchoconstriction associated with ongoing therapy, an alternative should be tried. The efficacy of DNase is independent of sputum microbiology and should only be used in those patients who have an adequate airways clearance technique. If lung function deteriorates after a trial period, treatment should be discontinued. For those eligible for ivacaftor, a patient’s sweat chloride test should indicate response and is recommended to be carried out six months from commencing treatment and then annually. If the expected reduction in sweat chloride does not occur (that is, >30% decrease), or if the patient does not exhibit an absolute improvement in FEV1 of at least 5%, then the dosing schedule should be reassessed before a retest and a withdrawal from treatment if the patient still does not meet the criteria.(46)

In terms of patient self-management, the validation of relevant biomarkers and the current development of point-of-care/home tests may provide an opportunity to routinely monitor disease activity, enabling the early identification of exacerbations for pre-emptive treatment. This could significantly reduce lung injury and the need for hospitalisation. Companion diagnostics may also facilitate the identification of responders and non-responders assisting in the development of future novel therapeutics.

A continuous challenge in CF is adherence to a complicated medical regimen, which can include a combination of inhaled mucolytics, antibiotics, bronchodilators and corticosteroids, in addition to nutritional management and possibly insulin or oral hypoglycaemic agents.(47,48) Physiotherapy and equipment maintenance also require a significant proportion of an individual’s time. Using objective data such as pharmacy refill history and electronic medication monitors, it is now possible to more accurately record adherence discretely and without further inconvenience to the individual. Analysis has shown that factors such as age, time of day, weekdays versus weekends, school routine versus holidays, can cause substantial variation even within individuals in terms of daily adherence,(49,50) with an average of 50% adherence reported.(51) This can have a significant impact on clinical outcome, increased risk of hospitalisation and increased health care costs.(51,52)

Nebulised antibiotics, in particular, can be particularly time and labour intensive, often requiring multiple sessions a day to deliver sufficiently high doses to exceed the minimal inhibitory concentration of the pathogen. The development of new products with improved pharmaceutical profiles that require only once daily dosing, or reduced treatment times, coupled with more rapid and efficient delivery devices (for example, the novel Pulmosphere^® technology used in the manufacture of tobramycin for the breath-actuated Podhaler^TM DPI)(53) should help reduce treatment burden, barriers to uptake and improve quality of life.(21,26) There may however be a ceiling to such improvements because faster delivery of high concentration drugs to the airways, compared with nebulised formulations, may have an increased incidence of local side effects.

Ultimately, for improved disease management, it is important that there be good communication between the clinician and the patient, that patients feels empowered in the management of their own disease and have confidence in treatment benefit with recognition that benefit in CF is measured in the maintenance of a stable health status with a low frequency of exacerbation.(48)

Early treatment with novel pharmacologicals, such as ivacaftor, which aim to treat the underlying cause of the disease, may in future prove effective in stalling the progression of the disease, which will have the associated benefit of reducing treatment intensity.