Table 4: Summary of main clinical studies of antifungal induction phase for AIDS-associated cryptococcal meningitis since 1990.

Author, year of publication, referenceStudy design/locationDrugsDuration of treatmentNumber of cases versus comparatorsClinical response (%)Mycological response (%) or (EFA)Overall (clinical + mycological) response (%)Mortality (%)

Larsen et al., 1990 [177]RCT/USAFlu (400 mg) versus AmB (0.7 mg/kg) for 1 week then three-times weekly + 5FC (150 mg/kg)10 weeks14 versus 6637543 versus 10019 versus 0 ( )

Saag et al., 1992 [74]RCT (2 : 1)/USAFlu (200 mg) versus AmB (0.4 mg/kg)10 weeks131 versus 6360 versus 6743 versus 46 (10 weeks)44 versus 4015 versus 8 (2 weeks)
14 versus 18

De Gans et al., 1992 [178]RCT (non-blinded)/The NetherlandsItra (400 mg) versus AmB (0.3 mg/kg) + 5FC (150 mg/kg)6 weeks12 versus 10NRNR42 versus 1000

Coker et al., 1993 [179]OS/Multicentre (Europe)LAMB (4 mg/kg/d)2 weeks237466.7NR0

Menichetti et al., 1996 [180]Cohort/ItalyFlu (800–1000 mg/d)3 weeks1454.5 (10 weeks)NR67.118.2

van Der Horst et al., 1997 [76]RCT/USAAmB (0.7 mg/kg) + 5FC (100 mg/kg) versus AmB (0.7 mg/kg)2 weeks202 versus 17978 versus 8360 versus 51 (2 weeks)NROverall 5.5 (2 weeks); 3.9 (10 weeks)

Leenders et al., 1997 [181]RCT/The NetherlandsL-AmB (4 mg/kg) versus Amb (0.7 mg/kg)3 weeks15 versus 1387 versus 83 (10 weeks)73 versus 38 (3 weeks)Overall 10.7

Mayanja-Kizza et al., 1998 [182]RCT/UgandaFlu (200 mg/d) + 5FC (150 mg/kg/d) versus Flu (200 mg/d)8 weeks30 versus 28NRNR32 versus 1260 versus 84 (2 weeks);
68 versus 88 (6 months)

Brouwer et al., 2004 [183]RCT/ThailandAmB (0.7 mg/kg) + FC (100 mg/kg) versus AmB (0.7 mg/kg) versus AmB (0.7 mg/kg) + Flu (400 mg) + FC (100 mg/kg) versus
AmB (0.7 mg/kg) + Flu (400 mg)
2 weeks15 versus 16 versus 16 versus 16NR−0.54 versus –0.31 versus –0.38 versus –0.3964 (10 weeks)Overall 14.6 (2 weeks); 21.9 (10 weeks)

Schaars et al., 2006 [85]Retrospective chart review/South AfricaFlu (200 mg/d) year 1991–2000
Flu (400 mg/d) 2001
77 versus 128NRNRNR23.4 versus 26.6

Bicanic et al., 2007 [184]POT/South AfricaAmB (1 mg/kg) versus Flu 400 mg10 weeks49 versus 567 versus 25*−0.48 versus –0.0238 versus 0Overall mortality 17 (2 weeks); 37 (10 weeks)

Bicanic et al., 2008 [185]RCT/South AfricaAmB (1 mg/kg) + 5FC (100 mg) versus AmB (0.7 mg/kg) + 5FC (100 mg)2 weeks34 versus 3074 versus 79*−0.56 versus –0.45603 versus 9 (2 weeks); 21 versus 26 (10 weeks). Overall mortality 24 (10 weeks) and no differences between groups

Longley et al., 2008 [186]Cohort/UgandaFlu (800 mg) versus Flu (1200 mg) then 400 mg2 weeks + 8 weeks30 versus 30NR−0.07 versus –0.1840 versus 52*37 versus 22 (2 weeks) 
60 versus 48 (10 weeks)

Dammert et al., 2008 [187]Cohort/PerùAmB (0.7 mg/kg/d)2-3 weeks47NR25 (2 weeks)
68 (10 weeks)
70 (10 weeks)13 (2 weeks)
22 (10 weeks)

Pappas et al., 2009 [188]RCT/USA and ThailandAmB (0.7 mg/kg) versus AmB (0.7 mg/kg) + Flu (400 mg) versus AmB (0.7 mg/kg) + Flu (800 mg)2 weeks46 versus 48 versus 4142.5 versus 28.3 versus 52.3NR71.4 versus 84.2 versus 83.3 (10 weeks)22 versus 17 versus 18.4 (10 weeks)

Hamill et al., 2010 [189]RCT/USA and CanadaLamB (3 mg/kg/d) versus LamB (6 mg/kg/d) versus AmB (0.7 mg/kg/d) 2 weeks (11–21 days)86 versus 94 versus 87 65.8 versus 75.3 versus 65.8 (2 weeks)
70.5 versus 72.9 versus 81.5 (10 weeks)
58.3 versus 48 versus 47.5 (2 weeks)
60 versus 70.7 versus 78.7
67.5 versus 73.7 versus 75.5 (10 weeks)14 versus 9.6 versus 11.5 (10 weeks)
Overall mortality at 10 weeks 11.6%

Lightowler et al., 2010 [190]Cohort/South AfricaAmB (0.7 mg/kg/d) versus Flu (400 mg/d)2 weeks148 versus 28NRNRFluconazole associated with 5.1 RR of death at 28 daysOverall 28 (2 weeks); 32.3 (10 weeks)

Falci et al., 2010 [191]Pilot/BrazilAmB (0.7 mg/kg/d) continuous infusion (24-h) + FC (100 mg/k/d)2 weeks12NR−0.378010 (2 weeks); 10 (10 weeks)

Nussbaum et al., 2010 [192]RCT/MalawiFlu (1200 mg/d) versus Flu (1200 mg/d) + FC (100 mg/kg/d)2 weeks20 versus 21NR−0.11 versus −0.28NR10 versus 37 (2 weeks); 43 versus 58 (10 weeks)
Overall 48.8

Jadhav et al., 2010 [193]RCT/IndiaLamB (1 mg/kg) versus LamB (3 mg/kg)3 weeks11 versus 15NRNR36.6 versus 54Overall 27 (10 weeks)

Loyse et al., 2012 [194]RCT/South AfricaAmB (0.7–1 mg/kg) + 5FC (100 mg/d) versus AmB (0.7–1 mg/kg/d) + Flu (800 mg/d) versus AmB (0.7–1 mg/kg) + Flu (1200 mg/d) versus AmB (0.7–1 mg/kg) + Vor (600 mg/d)2 weeks21 versus 22 versus 24 versus 14NR−0.41 versus −0.38 versus −0.41 versus −0.44NROverall 12 (2 weeks); 29 (10 weeks) (no statistically significant differences among groups)

Muzoora et al., 2012 [195]Cohort/UgandaFlu (1200 mg/d) + AmB (1 mg/kg/d)2 weeks30NR−0.31 (2 weeks)NR23 (2 weeks); 28 (10 weeks)

Jarvis et al., 2012 [196]RCT/South AfricaAmB (1 mg/kg/d) + 5FC (100 mg/kg/d) versus AmB (1 mg/kg/d) + 5FC (100 mg/kg/d) + IFNγ (100 μg) 2 doses versus AmB (1 mg/kg/d) + 5FC (100 mg/kg/d) + IFNγ (100 μg) 6 doses2 weeks31 versus 29 versus 30NR−0.49 versus 0.64 versus −0.64NR32 versus 33 versus 27 (10 weeks)
Overall 14 (2 weeks)
27 (10 weeks)

Jackson et al., 2012 [197]RCT/MalawiFlu (1200 mg/d) + AmB (1 mg/kg/d) versus Flu (1200 mg/d) + 5FC (100 mg/kg/d) + AmB (1 mg/kg/d for 7 days)2 weeks20 versus 20NR−0.38 versus −0.50NRNo statistically significant differences at 2 and 10 weeks between the arms

RCT: randomized controlled trial; OS: open label study; NR: not reported; EFA: early fungicidal activity expressed as mean log CFU/mL; Flu: fluconazole; amB: amphotericin B deox; Itra: itraconazole; 5FC: 5-fluorocytosine; LAMB: liposomal amphotericin B; IFNγ: interferon-gamma; Vor: voriconazole; *percentage of patients surviving at weeks 10: proportion of patients surviving after 1 year of followup.