Recently, a network meta-analysis showed that AmB + 5-FC + Azole was superior to all other investigated induction regimens in HIV-positive CM patients. Previously, a retrospective study also confirmed that traditional triple antifungal therapy was superior to double fungal therapy as the induction regimen in non-HIV-positive CM patients in a Chinese tertiary hospital[12, 22]. The reasons we chose the new triple therapy instead of the traditional triple therapy were as follows: first, with the extensive use of fluconazole, resistance is increasing, and second, voriconazole has been shown to be more potent and effective than fluconazole in vitro and in animal models [14, 23–25].
In our study, we compared three antifungal therapies (new triple therapy, traditional triple therapy and double therapy) for the treatment of CM in the induction period. Although there was no statistically significant difference among these three groups in terms of the clinical manifestation and treatment response, the new triple therapy had 3 obvious advantages: first, it substantially shortened the hospital stay; second, it rapidly cleared the cryptococci from the CSF; and third, it decreased the incidence of some adverse events (hypokalemia and gastrointestinal discomfort) associated with antifungal drugs.
The clearance of cryptococci from the CSF is an important predictive factor for the prognosis of CM, and a slow rate of clearance of cryptococci was found to be independently associated with increased mortality at 2 and 10 weeks[26]. The patients who received new triple therapy achieved CSF sterility earlier than the patients who received traditional therapy and double therapy and consequently had a shorter hospital stay.
AMB is an antifungal drug that has many adverse effects, such as hypokalemia and gastrointestinal discomfort[27]. Hypokalemia caused by amphotericin B is dose-dependent[28]. In our study, the new triple therapy obviously shortened the duration of hospitalization in non-HIV- and non-transplant-associated CM patients, and patients who received the new triple treatment had shorter durations of intravenous AMB treatment, which reduced the total dose of AMB. Therefore, the incidence of hypokalemia in the patients who received the new triple therapy was lower than those in the patients who received the traditional triple therapy and the patients who received the double therapy.
Unexpectedly, the improvement in neurological function and the clearance of cryptococci from CSF were not significantly different between groups II and III. These results are in contrast to those of a previous study in a Chinese tertiary hospital [12]. There are two possible reasons for these differences: (1) the sources of the enrolled cases were not identical (one was from the Third Affiliated Hospital of Sun Yat Sen University, and the other was from the Third Affiliated Hospital of Sun Yat Sen University and Jiangxi Chest Hospital); (2) the time spans of patient inclusion were different (one was from January 2011 to December 2020, and the other was from January 2006 to December 2014).
There were some limitations of our study. First, our study was a retrospective study, which meant that it was prone to produce selection bias and recall bias. Second, our data were obtained from a single center with a relatively small sample size. Consequently, a multicenter study with a larger sample size is needed in the future.