Cerebrospinal fluid fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated cryptococcal meningitis. The identification of factors associated with mortality informs strategies to improve outcomes.

Background Cryptococcal meningitis is a major cause of HIV-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed, as amphotericin B is neither available nor feasible in many centers. Fluconazole 1200 mg/d is more fungicidal than 800 mg/d, but mortality remains unacceptably high. Therefore we examined the effect of adding oral flucytosine to fluconazole. Methods HIV-seropositive, antiretroviral-naive patients with their first episode of cryptococcal meningitis were randomized to 14 days fluconazole 1200 mg/d alone, or with flucytosine 100 mg/kg/d, followed by fluconazole 800 mg/d with 10 weeks followup. The primary endpoint was early fungicidal activity (EFA), derived from quantitative cerebrospinal fluid cultures on Days 1, 3, 7, and 14. Secondary endpoints were safety, and 2- and 10-week mortality. Results Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4 count, and HIV viral load were similar between groups. Combination therapy was more fungicidal than fluconazole alone: EFA −0.28 +/− 0.17 log CFU/ml/d vs. −0.11 +/− 0.09 log CFU/ml/d (p < 0.001). The combination arm had fewer deaths by 2 weeks (10% vs. 37%) and 10 weeks (43% vs. 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs. 1, within first 2 weeks, p=0.2), but there was no increase in infection-related adverse events. Conclusions The results suggest that optimal oral treatment for cryptococcal meningitis is high dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa.

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Background Cryptococcal meningitis (CM) in Africa is associated with up to 70% mortality at 3 months and 500,000 deaths annually. We examined strategies to improve on fluconazole monotherapy: addition of flucytosine (5-FC); and/or addition of short-course amphotericin B (AmB). Methods In step 1, previously reported, patients were randomized to receive FLU 1200 mg/d with or without 5-FC 100 mg/kg/day for 14 days. In step 2, 43 patients were similarly randomised, with addition of AmB 1 mg/kg/d for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. Results 40 patients (25% with Glasgow Coma Scale < 15) were analyzed. EFA for the triple combination arm was greater than for AmB+FLU: −0.50 ± 0.15 log CFU/day vs. −0.38 ± 0.19 log CFU/day (p = 0.03); and greater than step 1 with FLU+5-FC (−0.28 ± 0.17) or FLU alone (−0.11 ± 0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, p = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, p = 0.1). Conclusions Addition of 5-FC and short course AmB to high-dose FLU significantly enhance EFA and may be associated with favourable trends in survival. Both these strategies should be tested in a larger phase III study.