A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi

TY - JOUR

T1 - A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi

AU - Rothe, Camilla

AU - Sloan, Derek J

AU - Goodson, Patrick

AU - Chikafa, Jean

AU - Mukaka, Mavuto

AU - Denis, Brigitte

AU - Harrison, Tom

AU - van Oosterhout, Joep J

AU - Heyderman, Robert S

AU - Lalloo, David G

AU - Allain, Theresa

AU - Feasey, Nicholas A

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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. 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.METHODS: From 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.RESULTS: Sixty 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.CONCLUSIONS: Mortality 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.

AB - 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. 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.METHODS: From 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.RESULTS: Sixty 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.CONCLUSIONS: Mortality 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.

KW - Adolescent

KW - Adult

KW - Antifungal Agents

KW - Female

KW - Fluconazole

KW - HIV Infections

KW - Humans

KW - Induction Chemotherapy

KW - Kaplan-Meier Estimate

KW - Longitudinal Studies

KW - Malawi

KW - Male

KW - Meningitis, Cryptococcal

KW - Middle Aged

KW - Multivariate Analysis

KW - Proportional Hazards Models

KW - Prospective Studies

KW - Treatment Failure

KW - Young Adult

U2 - 10.1371/journal.pone.0067311

DO - 10.1371/journal.pone.0067311

M3 - SCORING: Journal article

C2 - 23840659

VL - 8

SP - e67311

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 6

ER -