title: Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients.
abstract: BACKGROUND
  Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint.
  
  
  METHODS
  We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses.
  
  
  RESULTS
  The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-gamma levels.
  
  
  CONCLUSIONS
  The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.
authors.affiliation: Centre for Infection, St. George's University of London, United Kingdom.
authors.forename: Tihana
authors.initials: T
authors.lastname: Bicanic
authors.forename: Conrad
authors.initials: C
authors.lastname: Muzoora
authors.forename: Annemarie E
authors.initials: AE
authors.lastname: Brouwer
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.forename: Nicky
authors.initials: N
authors.lastname: Longley
authors.forename: Kabanda
authors.initials: K
authors.lastname: Taseera
authors.forename: Kevin
authors.initials: K
authors.lastname: Rebe
authors.forename: Angela
authors.initials: A
authors.lastname: Loyse
authors.forename: Joseph
authors.initials: J
authors.lastname: Jarvis
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Robin
authors.initials: R
authors.lastname: Wood
authors.forename: Direk
authors.initials: D
authors.lastname: Limmathurotsakul
authors.forename: Wirongrong
authors.initials: W
authors.lastname: Chierakul
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Shabbar
authors.initials: S
authors.lastname: Jaffar
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Harrison
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D002555:Cerebrospinal Fluid / Q000382:microbiology; D015331:Cohort Studies; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000134:cerebrospinal fluid; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D013019:South Africa; D013785:Thailand; D013997:Time Factors; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D000935:Antifungal Agents; D007371:Interferon-gamma; D015725:Fluconazole