title: A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Medicine, University of Malawi, College of Medicine, Blantyre, Malawi.
authors.forename: Camilla
authors.initials: C
authors.lastname: Rothe
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Sloan
authors.forename: Patrick
authors.initials: P
authors.lastname: Goodson
authors.forename: Jean
authors.initials: J
authors.lastname: Chikafa
authors.forename: Mavuto
authors.initials: M
authors.lastname: Mukaka
authors.forename: Brigitte
authors.initials: B
authors.lastname: Denis
authors.forename: Tom
authors.initials: T
authors.lastname: Harrison
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.forename: Robert S
authors.initials: RS
authors.lastname: Heyderman
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.forename: Theresa
authors.initials: T
authors.lastname: Allain
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Feasey
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D015658:HIV Infections / Q000150:complications* / Q000401:mortality; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008295:Malawi; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole