The application of treatment response biomarkers in clinical trials for cryptococcosis, invasive aspergillosis and candidiasis

Just three classes of antifungals are available for the treatment of WHO critical priority fungal pathogens Cryptococcus, Candida and Aspergillus spp. Drug development and optimization via phase II and III clinical trials is reliant on binary composite endpoints (clinical/radiological/mycological), requiring large patient cohorts with challenging logistics at great expense. The validation and implementation of continuous mycological treatment response biomarkers have the potential to facilitate smaller investigator-led trials to optimize existing and novel drugs and combinations, as demonstrated in cryptococcal meningitis, where early fungicidal activity is now a primary endpoint in phase II trials and a secondary endpoint in phase III trials. In invasive aspergillosis, serum galactomannan holds promise: numerous studies show a decline on treatment to be associated with clinical outcome, however, further prospective, standardized studies are required before inclusion in clinical trial response criteria. In invasive candidiasis, while beta-D-glucan (BDG) and qPCR in invasive candidiasis decline during treatment, studies are limited to inadequately powered retrospective cohorts with simple correlation analyses. We include preliminary data from our ongoing prospective study showing an overall decline on treatment, with qPCR clearing more rapidly than BDG, with considerable heterogeneity of kinetics in this complex population. Future analyses must account for baseline values and inter-patient variation. This article is part of the Theo Murphy meeting issue 'Evaluating anti-infective drugs'.