Study Evaluating Efficiency and Tolerance of High-dose Fluconazole Associated With Flucytosine as Induction Therapy for Cryptococcal Meningitis Associated With HIV in Sub-saharan Africa

Study Overview
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Brief Summary
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The aim of the trial is to demonstrate that in a sub-Saharan African setting, the association of: Oral treatment : high dose of fluconazole (1600mg/d) associated with flucytosine (100 mg/kg/j) as induction therapy lumbar punctures to control intracranial pressure can decrease mortality rate below 35% at 10 weeks. This is a non-randomized open label pilot study, with standardized management of cryptococcoses meningitis and follow-up in Burundi and Ivory Coast. A total of 41 patients will be enrolled.

Official Title
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Prospective Pilot Study to Evaluate a Standardized Management of Cryptococcal Meningitis in Patients Infected With HIV in Sub-Saharan Africa Involving an Initial Combination Therapy With Fluconazole and Flucytosine in High Doses, Complemented by Repeat Lumbar Punctures

Conditions
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Cryptococcal Meningitis, HIV

Intervention / Treatment
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* Drug: Fluconazole
* Drug: Flucytosine
* Procedure: lumbar punctures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: > 18 years HIV Infection First episode of cryptococcal meningitis on basis CSF India ink and/or CSF cryptococcal antigen. Glasgow > 9 after lumbar punctures Absence of peripheral focal deficit in the limbs informed consent signed Exclusion Criteria: Hemoglobin <7.5 g / dl; neutrophils count <500/mm3; Platelets count <50 000/mm3; transaminases > 5 times upper limit of normal; Troubles with severe mental alertness Glasgow <9 after the initial lumbar puncture; focal neurological deficit in the limbs; Pregnancy or lactation on going; Ongoing systemic antifungal treatment; History of cryptococcal meningitis; Ongoing rifampicin and ritonavir treatment; Subject participating in another study with a risk of mutual interference on the interpretation of results.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: oral treatment<br>Drug: Fluconazole and flucytosine Induction treatment for 2 weeks: Fluconazole (1600mg/j) + flucytosine (100 mg/kg/j) lumbar punctures to control intracranial pressure Consolidation treatment for 8 weeks: fluconazole (800 mg/j) | Drug: Fluconazole<br>* Induction treatment for 2 weeks: Fluconazole (1600mg/j) Consolidation treatment for 8 weeks: fluconazole (800 mg/j)<br>Drug: Flucytosine<br>* Flucytosine (100 mg/kg/j) for 2 weeks<br>Procedure: lumbar punctures<br>* lumbar punctures to control intracranial pressure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate |  | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate |  | 14 days and 24 weeks | 
| Percentage of patients with negative cerebrospinal fluid (CSF) cultures |  | 14 days and 10 weeks | 
| Number of relapses of cryptococcal throughout the monitoring period |  | up to 24 weeks | 
| Number of Immune Reconstitution Inflammatory Syndrome (IRIS) throughout the monitoring period | The IRIS diagnosis criteria will be those given in: Bicanic T, et al. Immune Reconstitution Inflammatory Syndrome in HIV-associated cryptococcal meningitis: a prospective study, J Acquir Immune Defic Syndr 2009; 51:130-134. | up to 24 weeks | 
| Number and severity of adverse events |  | up to 24 weeks | 
| Cerebrospinal fluid pressure evolution |  | up to 24 weeks | 
| Percentage of patients with undetectable viral load |  | 24 weeks | 
| CD4 count |  | 24 weeks | 
| Concentration of flucytosine in cerebrospinal fluid |  | 28 days or 10 weeks | 
| Sensitivity of cryptococcal antigen by strip method LFA (lateral-flow immunoassay) | on urines, plasma, CSF and whole blood fingerstick | at study entry | 
| CSF total volume discharged |  | up to 24 weeks | 
| Number of lumbar punctures performed |  | up to 24 weeks | 
| Concentration of fluconazole in plasma |  | 28 days or 10 weeks | 
| Concentration of fluconazole in cerebrospinal fluid |  | 28 days or 10 weeks | 
| Concentration of flucytosine in plasma |  | 28 days or 10 weeks | 
| MICs of fluconazole | MICs of fluconazole for cryptococcus strains, if CSF cultures ar positive at 28 days or 10 weeks or in case of relapse | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cryptococcal meningitis, HIV Infections, Oral treatment, High dose of fluconazole, Flucytosine, Burundi, Ivory Coast