Abstract:
Background
The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of crypto-
coccal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was
unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum
tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses
FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with
CM was undertaken.
Methods
In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day)
were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose
was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns.In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality,
and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio.
Findings
One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB,
1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and
24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30%
(20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the
exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both
induction doses of FCZ were safe and well tolerated. There were no life-threatening
changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB.
The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to
week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for
2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for
AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ.