Early fungicidal activity (EFA) in cerebrospinal fluid (CSF) has been associated with all-cause mortality in cryptococcal meningitis; EFA <0.20 log10CFU/mL/day was significantly associated with 18-week mortality even after adjusting for confounders, according to results of a study published in Clinical Infectious Diseases.
Surrogate endpoints are critical to decrease costs and accelerate development of new therapies and have demonstrated efficacy in progress made towards treating neglected diseases. In cryptococcal meningitis, EFA has previously been used as a surrogate endpoint in phase II trials because it is a quantitative measure of the rate of fungal Cryptococcus yeast clearance from the CSF. Several studies have reported a relationship between EFA and all-cause mortality through 10-weeks when analyzing pooled individual-level or group-level data.
The United States Food and Drug Administration allows the use of surrogate endpoints for accelerated regulatory approval due to length of time that can be required to determine significance using all-cause mortality; however, clinical benefit of use of EFA as a surrogate for mortality required further validation. Pooling data from three clinical trials conducted from 2010 through 2017, investigators examined relationships between EFA and 18-week mortality.
This retrospective study used a cohort of participants with HIV (N=738) from Uganda who presented to Mulago National Referral Hospital, Kampala or Mbarara Regional Referral Hospital, between November 2010 and June 2017, and who were diagnosed with cryptococcal meningitis by CSF cryptococcal antigen. Participants were all enrolled in 3 sequential cryptococcal meningitis clinical trials that had been conducted to determine whether EFA for Cryptococcus clearance from CSF could be a valid surrogate endpoint for all-cause mortality. All participants had serial quantitative CSF cultures and were given amphotericin and fluconazole induction therapy.
Overall, 10-week mortality was 36%, and 18-week mortality was 40%. To more robustly validate EFA, researchers divided participants by EFA log10 CFU/mL/day and determined that 18-week mortality was 37% for participants with an EFA level >0.40, 39% for an EFA =0.30 to 0.39, 36% for EFA =0.20 to 0.29, and 50% for EFA <0.20. The 18-week mortality hazard ratio (HR) comparing participants with EFA <0.20 against those with EFA >0.20 log10CFU/mL/day was 1.60 (95% CI, 1.25-2.04; P =.002). The lowest EFA group had the lowest percentage of patients with CSF pleocytosis (30% with >5 white blood cells/µL CSF; P <.001) and lower median CD4 T-cell counts (median 11 cells/µL; P <.01). Compared with participants with EFA >0.20 log10 CFU/mL/day, 18-week mortality increased with EFA <0.20 log10CFU/mL/day (HR, 1.60; 95% CI, 1.25-2.04; P =.0002), and EFA <0.20 log10CFU/mL/day remained significantly associated with 18-week survival after adjusting for baseline Glasgow coma scale, biologic sex, CSF pleocytosis, CSF quantitative culture, hemoglobin, and cohort (adjusted HR, 1.83; 95% CI, 1.40-2.40; P <.0001).
Even when higher EFAs were examined by separating the >0.40 log10CFU/mL/day EFA group, mortality did not further improve in the highest CSF clearance participants. Eighteen-week mortality was 37% for EFA ≥0.60 log10CFU/mL/day (n=170) and 36% for EFA of 0.40 to 0.59 log10CFU/mL/day (n=182). Further, no inoculum effect was seen with amphotericin B combination therapy because EFA was not correlated with baseline CSF quantitative culture (r=-0.003, P =.93).
Study investigators concluded, “Given that the goal in using EFA as a surrogate marker is to decrease the time needed to determine the efficacy of novel antifungal agents in treating cryptococcal meningitis, adding this new facet to our understanding EFA’s role in patient outcome would accelerate the time to interpretable results. EFA should be a surrogate endpoint for accelerated regulatory approval of new antifungal therapies in cryptococcal meningitis, a neglected disease.”
Pullen MF, Hullsiek KH, Rhein J, et al. CSF early fungicidal activity as a surrogate endpoint for cryptococcal meningitis survival in clinical trials [published online January 8, 2020]. Clin Infect Dis. doi: 10.1093/cid/ciaa016