Impact of early azole therapy on chronic colonisation with Aspergillus fumigatus during cystic fibrosis

Objectives. Early azole therapy during cystic fibrosis (CF) remains debated : when to start ? with which azole ? when to stop ? The ATCF (Antifungal Therapy during Cystic Fibrosis) is an exploratory longitudinal phase III study with the following objectives :
-	the primary objective was to assess the effect of azole therapy on the negativation of sputum cultures for Aspergillus on 2 consecutive samples.
-	Secondary objectives were to compare the course and outcome of FEV1, clinical signs and quality of life, the impact on co-prescription of antibiotic courses and steroid therapies, the speed of negativation of sputum cultures for Aspergillus, the efficacy of treatments on outcome of other diagnostic criteria (Aspergillus precipiting IgG, total and specific IgE, eosinophil counts), and safety profiles of the azoles.
Methods. The ATCF study followed 11 patients presenting with a chronic colonisation with A. fumigatus and randomized to receive an early azole therapy for 4 to 6 months in a phase III study. Treatments evaluated were itraconazole (ITRA) oral solution or voriconazole (VORI) oral suspension at the following regimens: 2x200 mg/day for patients > 40kg and 2x100 mg/day for patients <40 kg. A long-term follow-up was conducted until 2 months after end of treatment.
Results. Six patients were included in the ITRA arm and 5 in the VORI arm. The Delta F508 mutation was present in 91% of the patients ; the mean predicted FEV1 at inclusion was of 50.39% ± 18.01 (44.22% ± 14.71 in ITRA arm and 57.79% ± 20.36
in the VORI arm). Four patients stopped treatments (1 ITRA and 3 VORI) prematurely because of intolerance. Seven/7 (100%) assessable patients had a successfull outcome, with a negativisation of sputums after 4 to 6 months of treatment (5/5 ITRA et 2/2 VORI). Increase in FEV1 was observed as soon as 4 weeks after treatment initiation for 6/9 patients, from 50.39% ± 18.01 to 63.30% ± 30.21. The number of patients not receiving antibiotics grew from 18.2% at day0 to 82% and 89% at weeks 2 and 4, respectively. Aspergillus precipiting IgG as well as total and specific IgE also significantly decreased. However, 2 months after the end of treatment, most of assessment criteria were similar to the baseline values.
Conclusion. While only a limited number of patients were included, the strict and meticulous longitudinal phase III design of ATCF study underlines the need for azole therapy rationalisation during CF. When a chronic colonisation with A. fumigatus is associated with clinical signs, early azole therapy can temporarily reduce airway infection and inflammation, thus extending the periods of stable disease status and stable lung function with a positive collateral consequence of antibiotic savings.