Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial

Background: Interferon-gamma (IFN gamma) 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 IFN gamma 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 IFN gamma 1b 100 mu g days 1 and 3 (IFN gamma two doses), or standard therapy and IFN gamma 1b 100 mu g days 1, 3, 5, 8, 10 and 12 (IFN gamma 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 IFN gamma 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 IFN gamma two doses, and -0.64 with IFN gamma six doses. Difference in EFA was -0.15 [confidence interval (95% CI) -0.02 to -0.27, P = 0.02] between standard treatment and IFNg gamma two doses, and -0.15 (95% CI -0.05 to -0.26, P = 0.006) between standard treatment and IFN gamma 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. Conclusion: Addition of short-course IFN gamma 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 IFN gamma are as effective as six doses. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins