Comparison of flucytosine and fluconazole combined with amphotericin B for the treatment of HIV-associated cryptococcal meningitis: a systematic review and meta-analysis

Abstract

Treatment guidelines recommend combination antifungal therapy with amphotericin B (AmB) as an induction therapy for cryptococcal meningitis. The objective of this study was to compare the survival benefit between 5-FC (flucytosine) and fluconazole as second-line drugs given in combination with AmB. We carried out a systematic review and meta-analysis of prospective controlled studies reporting early combination treatment for human immunodeficiency virus (HIV)-associated cryptococcal meningitis. We searched MEDLINE, EMBASE and the Cochrane Library up to October 2013. Randomised trials and prospective cohort studies were selected. The primary outcome was mortality in the first 14 and 70 days. The secondary outcome was early fungicidal activity (EFA) in the first 2 weeks. Four trials were included in our study. All included studies could be considered to be of fair quality in their methodology. The meta-analysis suggested that mortality was lower in patients who were given AmB and 5-FC at the 2 weeks point (Fig. 2); the overall reduction in mortality with the 5-FC combination group was 44% [risk ratio (RR) 0.56, 95% confidence interval (CI) 0.33-0.95, p = 0.03]. EFA was significantly shorter in patients receiving AmB plus 5-FC [mean difference (MD) -0.10 log10 colony-forming units (CFU) per day, 95 % CI -0.11-0.09, p < 0.00001]. Mortality was no different between the 5-FC and fluconazole groups at the 3 months time point (p = 0.15) (Fig. 4). Adverse events occurred with similar frequency between the two treatment groups. There was no statistically significant difference in the survival rate between AmB in combination with high-dose fluconazole and the current standard of AmB plus 5-FC therapy for HIV-associated cryptococcal meningitis.

Combination Antifungal Therapy: When, Where, and Why

“…However, the beneficial effect was transient, and at 3 months after starting induction therapy, there were no differences between using 5-FC or fluconazole when used in combination with AmB. Importantly, in the AmB plus fluconazole combinations, higher fluconazole doses of at least 800 mg daily were associated with better outcomes compared to lower fluconazole doses [29].…”

“…Their data identified four prospective randomized studies that demonstrated HIV-infected patients who received AmB + 5-FC had a 44 % reduction in mortality and improved EFA of their cerebrospinal fluid (CSF) with this combination compared to AmB or fluconazole monotherapy [29]. However, the beneficial effect was transient, and at 3 months after starting induction therapy, there were no differences between using 5-FC or fluconazole when used in combination with AmB.…”

“…A meta-analysis by Yao et al has attempted to reinforce the use of either 5-FC or fluconazole combined with AmB [29]. Their data identified four prospective randomized studies that demonstrated HIV-infected patients who received AmB + 5-FC had a 44 % reduction in mortality and improved EFA of their cerebrospinal fluid (CSF) with this combination compared to AmB or fluconazole monotherapy [29].…”

“…As such, combining fluconazole with AmB is often employed to address this lack of access to 5-FC, and although less effective immediately, CAF therapy with AmB and fluconazole appears at higher doses to be useful in these resource-limited settings [29][30][31][32]. With LAmB formulations rarely available outside Western countries and the high toxicity of conventional AmB especially with renal dysfunction, short courses of AmB with high doses of fluconazole (1,200 mg/day) have been employed and demonstrated rapid EFA in the CSF, and little toxicity but no clinical outcomes data has been included [32].…”

Outcome Assessments in Clinical Trials of Cryptococcal Meningitis: Considerations on Use of Early Fungicidal Activity as a Potential Surrogate Endpoint for All-Cause Mortality

“…higher-quality studies or by types of drug regimens). One recent meta-analysis including only four studies and combined observational and randomized trials claimed a treatment effect on both EFA and ACM only at 14 days post-randomization but not at day 70 [24]. This study excluded many randomized trials in CM and does not determine whether EFA is a universally applicable surrogate endpoint for ACM.…”