Durban University of Technology, Durban, South Africa.
Harvard TH Chan School of Public Health, Boston, Massachusetts, and The Biostatistics Center, The George Washington University, Rockville, Maryland, United States of America.
PLoS One. 2023 Feb 13;18(2):e0281580. doi: 10.1371/journal.pone.0281580. eCollection 2023.
The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal 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.
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.
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.
Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.
在 2018 年之前，世界卫生组织（WHO）建议在无法获得两性霉素 B（AMB）的地区，将氟康唑（FCZ）的诱导期剂量设定为 1200mg/天，用于治疗 HIV 合并隐球菌性脑膜炎（CM）。本研究旨在评估在成人 CM 患者中采用更高剂量氟康唑（1200mg-2000mg/天）进行诱导-巩固治疗方案的最大耐受剂量和安全性/疗效，该方案根据体重和肾功能（eGFR）进行剂量调整。
在第一阶段，以序贯队列的方式测试了氟康唑（1200mg/天、1600mg/天和 2000mg/天）的三个诱导剂量，并与 AMB 以 3:1 的比例进行比较。如果存在显著的预定安全性或疗效问题，则不会在第二阶段测试特定剂量。在第二阶段，根据方案排除了 1200mg 剂量，因为该剂量组死亡率增加，参与者被随机分配至 1600mg、2000mg FCZ 或 AMB 组，比例为 1:1:1。
共纳入了 168 名参与者，其中 AMB、1600mg 和 2000mg 组分别有 48、50 和 48 名参与者。AMB 组 10 周和 24 周的死亡率（90%CI）的 Kaplan-Meier 比例分别为 17%（10，29）和 24%（15，37），而 1600mg 组分别为 20%（12，32）和 30%（20，43），2000mg 组分别为 33%（23，46）和 38%（27，51）。除了 2000mg 组胃肠道副作用发生率较高外，两种氟康唑诱导剂量均安全且耐受良好。氟康唑和 AMB 的所有剂量组心电图 QTc 均无危及生命的变化，且变化相似。从第 0 周至第 2 周，对数 10 个隐球菌菌落形成单位（CFU）的中位数（IQR）变化分别为 AMB 组为-8（-4.1，-1.9）；1600mg FCZ 组为-2.5（-4.0，-1.4）；2000mg FCZ 组为-8（-3.2，-1.0）。第 10 周时脑脊液 CM 阴性的比例分别为 AMB 组为 81%（71，90）；1600mg FCZ 组为 56%（45，69）；2000mg FCZ 组为 60%（49，73）。
CM 诱导期的氟康唑体重和肾功能调整剂量为 1600mg 和 2000mg/天，除了 2000mg/天剂量组胃肠道副作用增加外，均安全且耐受良好，与 AMB 相比，达到 CSF 灭菌的时间相似，但时间明显长于 AMB。WHO 推荐的 1200mg FCZ 与高死亡率相关。尽管没有统计学意义，但与 1600mg 和 2000mg FCZ 相比，AMB 组的死亡率数值较低。这些数据为研究更高剂量 FCZ 提供了依据。
