title: Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis:  a randomized controlled trial.
abstract: BACKGROUND
  Interferon-gamma (IFNγ) is of key importance in the immune response to Cryptococcus neoformans. Mortality related to cryptococcal meningitis remains high, and novel treatment strategies are needed. We performed a randomized controlled trial to determine whether addition of IFNγ to standard therapy increased the rate of clearance of cryptococcal infection in HIV-associated cryptococcal meningitis.
  
  
  METHODS
  Patients were randomized to amphotericin B 1 mg/kg per day and 5FC 100 mg/kg per day for 2 weeks (standard therapy), standard therapy and IFNγ1b 100 μg days 1 and 3 (IFNγ two doses), or standard therapy and IFNγ1b 100 μg days 1, 3, 5, 8, 10 and 12 (IFNγ six doses). Primary outcome was rate of clearance of cryptococcus from the cerebrospinal fluid (CSF) (early fungicidal activity, EFA) calculated from serial quantitative cultures, previously shown to be independently associated with survival.
  
  
  RESULTS
  Rate of fungal clearance was significantly faster in IFNγ containing groups than with standard treatment. Mean EFA [log colony forming unit (CFU)/ml per day] was -0.49 with standard treatment, -0.64 with IFNγ two doses, and -0.64 with IFNγ six doses. Difference in EFA was -0.15 [confidence interval (95% CI) -0.02 to -0.27, P=0.02] between standard treatment and IFNγ two doses, and -0.15 (95% CI -0.05 to -0.26, P=0.006) between standard treatment and IFNγ six doses. Mortality was 16% (14/88) at 2 weeks and 31% (27/87) at 10 weeks, with no significant difference between groups. All treatments were well tolerated.
  
  
  CONCLUSIONS
  Addition of short-course IFNγ to standard treatment significantly increased the rate of clearance of cryptococcal infection from the CSF, and was not associated with any increase in adverse events. Two doses of IFNγ are as effective as six doses.
authors.affiliation: Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Infectious Diseases Unit, GF Jooste Hospital, Cape Town, South Africa. joejarvis@doctors.net.uk
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Jarvis
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.forename: Kevin
authors.initials: K
authors.lastname: Rebe
authors.forename: Gertrude Ntombomzi
authors.initials: GN
authors.lastname: Williams
authors.forename: Tihana
authors.initials: T
authors.lastname: Bicanic
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Robin
authors.initials: R
authors.lastname: Wood
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; D000666:Amphotericin B / Q000008:administration & dosage; D000935:Antifungal Agents / Q000008:administration & dosage; D000998:Antiviral Agents / Q000008:administration & dosage*; D003455:Cryptococcus neoformans / Q000821:virology*; D003840:Deoxycholic Acid / Q000008:administration & dosage; D004338:Drug Combinations; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D000998:Antiviral Agents; D004338:Drug Combinations; D003840:Deoxycholic Acid; D000666:Amphotericin B; D007371:Interferon-gamma; C059765:amphotericin B, deoxycholate drug combination; D005437:Flucytosine