Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials

Abstract

Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

What Is the Most Appropriate Induction Regimen for the Treatment of HIV-Associated Cryptococcal Meningitis When the Recommended Regimen Is Not Available? Evidence From a Network Meta-Analysis

“…We extracted the following data for further analysis: (1) characteristics of studies: first author, date of publication, study type, study duration, and country/area; (2) characteristics of patients: number, age, timing of ART initiation after antifungal therapy; (3) interventions included induction therapeutic regimens and consolidation therapeutic regimens; (4) outcomes included 10-week mortality, 2-week mortality, EFA over the first 2 weeks ( Pullen et al., 2020 ), adverse events, and drug cost. Induction therapeutic regimens were as follows: 1 week of AmB plus 5-FC followed by 1 week of fluconazole (Regimen A), 1 week of AmB plus fluconazole followed by 1 week of fluconazole (Regimen B), 2 weeks of AmB plus 5-FC (Regimen C), and 2 weeks of AmB plus fluconazole (Regimen D).…”

Combination Therapy for HIV-Associated Cryptococcal Meningitis—A Success Story

“…As a continuous measure, comparisons of EFA in relatively small numbers of patients (15-20 per arm) were able to demonstrate significant differences between arms [4,22,28,54,55]. EFA was subsequently shown to be independently associated with reduced mortality in large African combined clinical trial cohorts [52,56,57] The development of EFA as a statistically powerful phase II surrogate endpoint for induction regimen efficacy (although not capturing issues of toxicity), and the success of FCZ consolidation therapy in preventing disease relapse represented a step change on the path to CM treatment optimisation.…”

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches

“…Culture remains a gold standard to assess live pathogens in the CSF or blood, by measuring colony-forming units (CFU/mL) growth on Sabouraud dextrose agar for 48 h at 30 • C. An important prognostic parameter, such as early fungicidal activity (EFA), can be calculated from recurrent cultures during induction regimens (described below). Microbiological clearance is measured as log 10 clearance of Cryptococcus yeasts per mL of CSF and serves as an important predictor of increased mortality, including that from C-IRIS [49]. Cultured isolates can subsequently be serotyped by real-time PCR assay, and mating type can be determined by amplified fragment length polymorphism (AFLP) or PCR-restriction fragment length polymorphism (PCR-RFLP) [34,50].…”