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

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.

A Prospective Study of Mortality from Cryptococcal Meningitis following Treatment Induction with 1200mg Oral Fluconazole in Blantyre, Malawi

“…Expanded access to ART in Malawi [12] meant that more patients had received ART before recruitment to the current cohort than in our previous study of fluconazole 800mg/day [8]. This raises the possibility that Immune Reconstitution Inflammatory Syndrome (IRIS) masked a benefit from the higher dose of fluconazole, however in the current study, there was slightly higher survival in patients on ART and in a combined analysis of both studies the effect of prior ART was non-significant.…”

Cryptococcal Meningitis: Diagnosis and Management Update

“…While clearly suboptimal compared to combination amphotericin therapy, fluconazole remains the only therapeutic option for the treatment of cryptococcal meningitis in much of the world, where amphotericin or flucytosine are unavailable. A recent study in Malawi demonstrated high morality (43% at 4 weeks) and treatment failure (77% at 1 year) with the use of 800 mg/day of fluconazole monotherapy for induction therapy (37). Fluconazole doses of 1,200 mg/day for the first two weeks of induction therapy were associated with an increase in EFA as compared to 800 mg/day, although no differences in mortality were seen at either 2 or 10 weeks (38).…”

Cryptococcal meningitis: epidemiology and therapeutic options

“…Classical features of “meningism” (eg, neck stiffness) occur in less than 20% of patients 86. Altered mental state is associated with higher mortality 5,50,87…”

“…Clinical studies in Uganda and Malawi based on 800 mg od induction and 400 mg od consolidation therapy reported improved 10-week mortality rates of 58%–60% 87,126. A further induction-phase dose increase to 1,200 mg was associated with faster EFA126 but did not improve survival,126,127 and a pharmacokinetic–pharmacodynamic bridging study from a mouse model indicated that 1,200 mg od will fail to achieve fungal stasis in the CSF of 33% of patients 128.…”