SynthesisPloS one2016
Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence.
Synthesis in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed, 2 syntheses or guidelines pooled it, 19 citations in OpenAlex.
- Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.The Journal of antimicrobial chemotherapy · 2022Pooled it
- Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis.Antimicrobial agents and chemotherapy · 2018Pooled it
- Iron starvation confers azole tolerance inmBio · 2026Article
- Assessing Statistical Methods for Estimating the Cerebrospinal Fluid Early Fungicidal Activity as an Endpoint for Cryptococcal Meningitis Clinical Trials: A Systematic Review and Simulation Study.Open forum infectious diseases · 2026Article
- Analytical validation: Comparison of two laboratory-based methods for CSF quantitative cryptococcal cultures.Medical mycology · 2026Article
- Innovation in the Design of Clinical Trials for Infectious Diseases: Focusing on Patients Over Pathogens.Pharmaceutical medicine · 2025Review
- Cryptococcal Meningitis Developing in a Patient with Neurosarcoidosis.Internal medicine (Tokyo, Japan) · 2023Article
- Noninvasive Testing and Surrogate Markers in Invasive Fungal Diseases.Open forum infectious diseases · 2022Article
- Treatment recommendations for non-HIV associated cryptococcal meningoencephalitis including management of post-infectious inflammatory response syndrome.Frontiers in neurology · 2022Review
- Associations betweenJournal of fungi (Basel, Switzerland) · 2021Review
- Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2020Article
- Diagnosis and Management of Central Nervous System Cryptococcal Infections in HIV-Infected Adults.Journal of fungi (Basel, Switzerland) · 2019Review
- Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis.mBio · 2019Article
- Article
- Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis.Antimicrobial agents and chemotherapy · 2018Article
- Diagnostic and therapeutic strategies in cryptococcosis: impact on outcome.Memorias do Instituto Oswaldo Cruz · 2018Review
- Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy.Frontiers in immunology · 2018Review
- Choroid Plexitis and Ependymitis by Magnetic Resonance Imaging are Biomarkers of Neuronal Damage and Inflammation in HIV-negative Cryptococcal Meningoencephalitis.Scientific reports · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundCryptococcal 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.
methodsWe 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.
resultsTwenty-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.
conclusionsMortality 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.