A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

Camilla Rothe,Nicholas A Feasey,Robert S Heyderman,Brigitte Denis,Joep J Van Oosterhout,Patrick Goodson,David G Lalloo,Jean Chikafa,Mavuto Mukaka,Tom Harrison,Theresa Allain,Derek J Sloan,Robert J Wilkinson

doi:10.1371/journal.pone.0067311

Abstract

IntroductionCryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data.MethodsFrom July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation.ResultsSixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score <14 of 15), moderate/severe neurological disability (modified Rankin Score >3 of 5) and confusion (Abbreviated Mental Test Score <8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes.ConclusionsMortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit.

Highlights

Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer
There is no evidence that mortality in Sub Saharan Africa (SSA) has improved since the roll-out of antiretroviral therapy (ART) and uncertainty over optimal treatment regimens for resource limited settings is partially responsible for this. ’’Goldstandard’’ therapy involves a two week induction phase with the fungicidal combination amphotericin B and flucytosine prior to consolidation and maintenance therapy with fluconazole [7]
Cryptococcal meningitis may impair a patient’s cognitive function to the extent that assistance of a guardian was required for discussions with the study team and verbal consent was requested to approach all patients on diagnosis of the condition

Summary

Introduction

Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Cryptococcal meningitis, caused by the encapsulated saprophytic yeast Cryptococcus neoformans, occurs most commonly in HIV infected patients with CD4 counts of 100 cells/ml or less [1,2]. As a consequence of the HIV epidemic, it is the most common cause of meningitis amongst adults in Sub Saharan Africa (SSA) [3,4,5]. There is no evidence that mortality in SSA has improved since the roll-out of antiretroviral therapy (ART) and uncertainty over optimal treatment regimens for resource limited settings is partially responsible for this.

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