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

Abstract

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.

Figure 1. A shows survival on fluconazole therapy for all 60 patients.

The solid line shows estimated proportion of survivors and the dotted lines show 95% confidence intervals. Amongst the 47 patients who did not survive on fluconazole to 52 weeks, two had positive CSF cultures at 10 weeks and were switched to fluconazole. The remaining 45 died. B shows survival on fluconazole stratified by baseline GCS. 2 patients (one who died in the first week and one who survived to 52 weeks) were excluded from this analysis as no baseline GCS was recorded. The solid line represents patients with baseline GCS≥14 and the dotted line represents patients with baseline GCS<14. Hazard ratio for death or treatment failure by 52 weeks: 2.09, 95% CI: 1.07–4.06 p = 0.030.