Abstract
Background: Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined in vitro with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole. Method: A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg/day) combined with amphotericin (1mg/kg/day) and fluconazole (800mg/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing ≈80% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU/ml/day, respectively. Discussion: The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation. Trial registration: Clinicaltrials.gov NCT03112031 (11/04/2017).
Highlights
Worldwide cryptococcal meningitis results in approximately 625 000 deaths each year, most occurring within 3 months of diagnosis[1]
Isolates will be securely stored in Oxford University Clinical Research Unit (OUCRU), Hospital for Tropical Diseases (HTD)
The result will be recorded in the case record form (CRF)
Summary
Worldwide cryptococcal meningitis results in approximately 625 000 deaths each year, most occurring within 3 months of diagnosis[1]. It is the leading cause of death in HIV patients in Asia and Africa affecting 3.2% of the HIV infected population per year[1]. Fluconazole is effective for cryptococcosis outside the induction period (consolidation, maintenance, asymptomatic CrAg antigenemia), though no mortality benefit has ever been convincingly demonstrated for fluconazole as part of combination induction therapy. In other words, demonstrating efficacy of tamoxifen in this study might be difficult using EFA as primary endpoint given presence of potent regimen containing amphotericin. If no improvement in EFA is observed during this trial, would the idea of tamoxifen as treatment for Cryptococcus be abandoned? If no improvement in EFA is observed during this trial, would the idea of tamoxifen as treatment for Cryptococcus be abandoned? Perhaps there would still be room for evaluating outcomes outside of the induction period?
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