DUET: Azole-echinocandin combination therapy for invasive aspergillosis. A randomized pragmatic superiority trial (BeNeFIT18558)

Summary (French or Dutch)

Patients with a malignant haematological disease become neutropenic (condition in which the number of white bloods cells called neutrophils is abnormally low) as a result of their intensive chemotherapy or stem-cell transplantation and are at increased risk for life-threatening infectious complications during this period of immunodeficiency. One of these infections is invasive aspergillosis (IA). This fungal infection is also occasionally diagnosed in otherwise immunocompromised patients (e.g. organ transplant patients). For more than 15 years voriconazole, a drug of the triazole class, has been the recommended treatment for this life-threatening infection. However, even with voriconazole as therapy the mortality remains high at 25-40%. Therefore, a pivotal randomized clinical trial recruited patients from 2008-2011 and studied if the mortality of IA can be reduced by adding a second antifungal agent to the voriconazole. The 6-week mortality with combination therapy was 30% lower (19.3%) than with voriconazole monotherapy (27.5%) but this mortality reduction in favour of combination therapy was not statistically significant. Thus, combination therapy has not (yet) been implemented in international guidelines. Besides, there is another important reason to study combination therapy in patients with IA. In the Netherlands, the prevalence of voriconazole resistance has increased from 0% in 2000 to 14.7% in 2017. Infections with voriconazole resistant aspergillus result in a much longer hospital stay, higher costs and are associated with a substantially higher mortality. Also, in Belgium voriconazole resistance has now been repeatedly documented.

The study that we describe here has a double goal:

- Study the impact on mortality of combination therapy for the treatment of IA caused by a voriconazole sensitive Aspergillus

- Increase the knowledge on the clinical impact of IA caused by a voriconazole resistant Aspergillus in hospitals where state-of-the-art diagnostic tests regarding determining azole resistance are used.