title: Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence.
abstract: BACKGROUND
  Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM.
  
  
  METHODS
  We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias.
  
  
  RESULTS
  Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM.
  
  
  CONCLUSIONS
  Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Jairo M
authors.initials: JM
authors.lastname: Montezuma-Rusca
authors.affiliation: Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Powers
authors.affiliation: Mathematical Statisticians, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Dean
authors.initials: D
authors.lastname: Follmann
authors.affiliation: Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Institutes of Health Library, Office of Research Services, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Brigit
authors.initials: B
authors.lastname: Sullivan
authors.affiliation: Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002423:Cause of Death; D016208:Databases, Factual; D006801:Humans; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D015415:Biomarkers