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Flucytosine plus high dose fluconazole is superior to high dose fluconazole alone: results of a randomized trial comparing cryptococcal meningits treatments in Malawi
A. Jackson1, J. Nussbaum1,2, D. Namarika1,3, P. Jacob1, J. Kenala1, C. Kenyamba1, J. Jarvis4,5,6, S. Jaffar7, M. Hosseinipour1,8, C. van der Horst8, T. Harrison4
1UNC Project, Lilongwe, Malawi, 2University of California at San Francisco, Division of Infectious Diseases, San Fransisco, United States, 3Kamuzu Central Hospital, Department of Medicine, Lilongwe, Malawi, 4St George's University of London, Division of Infectious Diseases, London, United Kingdom, 5Desmond Tutu HIV Centre, Cape Town, South Africa, 6University of Cape Town, Cape Town, South Africa, 7London School of Hygiene and Tropical Medicine, Department of Epidemiology and Population, London, United Kingdom, 8University of North Carolina, Chapel Hill, United States
Background: Cryptococcal meningitis (CCM) is a major cause of HIV-associated morbidity and mortality in Africa, estimated to kill 500,000 people/year. Improved oral treatment regimens are needed as IV amphotericin B therapy is neither available nor feasible in most centres. Fluconazole (FLU) 1200 mg/d is more rapidly fungicidal than 800 mg/d, but mortality remains high. Therefore, we examined the effect of adding oral flucytosine (FC) to FLU 1200 mg/d.
Methods: Between February and December 2008 44 HIV-seropositive, antiretroviral-naive patients with a first-episode of CCM were randomized to receive FLU 1200 mg/day or FLU 1200 mg/day + FC 100 mg/kg/day for 14 days. Both groups then received fluconazole 800 mg/day. Patients were followed as inpatients for 2 weeks and as outpatients until week 10.
The primary endpoint was rate of clearance of infection from CSF, or early fungicidal activity (EFA), derived from quantitative CSF cultures on Days 1, 3, 7, 14. Secondary endpoints related to safety and mortality through 10 weeks.
Results: 41 patients (39% abnormal mental status (GCS< 15), 66% male) were analysed (3 withdrawn due to exclusion criteria). Baseline characteristics including mental status, cryptococcal CSF CFU, CSF opening pressure, CD4 count and HIV VL were similar between arms. EFA for the combination arm was significantly higher than for fluconazole alone: -0.28 +/- 0.17 log CFU/day versus -0.11 +/- 0.09 log CFU/day (p = 0.001). The combination arm had fewer deaths at 2 weeks (2/21, 10% versus 7/20, 37%, p=0.05) and 10 weeks (9/21, 43% versus 11/20 58%, p=0.25). There were more neutropenic episodes (5 versus 1, grade III and IV within 2 weeks (p=0.2)), but no increase in infection-related adverse events, in the combination arm.
Conclusions: The results suggest that optimal oral treatment for CCM is high dose fluconazole (1200 mg/d) with flucytosine. Efforts are needed to increase availability of flucytosine in Africa.
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