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Randomized Controlled Trial
. 2012 Jun 1;26(9):1105-13.
doi: 10.1097/QAD.0b013e3283536a93.

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

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Randomized Controlled Trial

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

Joseph N Jarvis et al. AIDS. .

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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Early fungicidal activity (EFA) by treatment group. The figure shows the individual patient slopes over the initial 14 days of treatment. The red line is a graphic representation of the mean slope in each treatment group. Mean slope (standard deviation) is given below each plot, with a p-value for both unadjusted and adjusted (for baseline CD4 cell count, CSF IFN γ and fungal burden) comparisons with control.

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References

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