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

ANRS, Emerging Infectious Diseases41 enrolled

Overview

The aim of the trial is to demonstrate that in a sub-Saharan African setting, the association of: 1. Oral treatment : high dose of fluconazole (1600mg/d) associated with flucytosine (100 mg/kg/j) as induction therapy 2. 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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Cryptococcal Meningitis HIV

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (7)

CHU Kamenge

Bujumbura, Burundi

Hôpital Prince Régent Charles

Bujumbura, Burundi

Hôpital général

Bururi, Burundi

Hôpital général

Kayanza, Burundi

Hôpital général

Muyinga, Burundi

Service de Maladies Infectieuses & Tropicales - Hôpital Triechville

Abidjan, Côte d’Ivoire

Service de Neurologie - Hôpital Cocody

Abidjan, Côte d’Ivoire

Outcomes

Primary Outcomes

Mortality rate

Time frame: 10 weeks

Secondary Outcomes

Mortality rate

Time frame: 14 days and 24 weeks

Percentage of patients with negative cerebrospinal fluid (CSF) cultures

Time frame: 14 days and 10 weeks

Number of relapses of cryptococcal throughout the monitoring period

Time frame: 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.

Time frame: up to 24 weeks

Number and severity of adverse events

Time frame: up to 24 weeks

Cerebrospinal fluid pressure evolution

Time frame: up to 24 weeks

Percentage of patients with undetectable viral load

Time frame: 24 weeks

CD4 count

Time frame: 24 weeks

Concentration of flucytosine in cerebrospinal fluid

Time frame: 28 days or 10 weeks

Sensitivity of cryptococcal antigen by strip method LFA (lateral-flow immunoassay)

on urines, plasma, CSF and whole blood fingerstick

Time frame: at study entry

CSF total volume discharged

Time frame: up to 24 weeks

Number of lumbar punctures performed

Time frame: up to 24 weeks

Concentration of fluconazole in plasma

Time frame: 28 days or 10 weeks

Concentration of fluconazole in cerebrospinal fluid

Time frame: 28 days or 10 weeks

Concentration of flucytosine in plasma

Time frame: 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

Time frame: 28 days