Antifungal Treatment Regimens as Primary Therapy for Invasive Aspergillosis: A Systematic Review and Network Meta-analysis.

backgroundInvasive aspergillosis (IA) is an invasive fungal disease associated with high mortality. Triazoles are the primary therapy for IA, while amphotericin B, echinocandins, and antifungal combined therapy are commonly considered as alternative treatment options although their efficacy and safety remain subjects of debate. We employed Bayesian network meta-analysis (NMA) to synthesize evidence and evaluate the efficacy and safety of different primary antifungal treatment regimens for IA.

methodsA literature search was done in PubMed, EMBASE, Cochrane, and Web of Science databases for clinical studies on primary treatment for patients with IA published before 28 March 2024. We included randomized controlled trials (RCTs) and cohort studies involving patients with proven or probable IA who underwent primary treatment. The primary treatment regimens comprised different types or dosages of monotherapy or combination therapy involving triazoles, echinocandins, and amphotericin B. The primary outcome was cumulative all-cause mortality. Secondary outcomes included all-cause mortality at day 42, day 84, or end of treatment (EOT); the overall response at day 42, day 84, or EOT; invasive aspergillosis-associated mortality on day 42, day 84, and EOT; the incidence of adverse events (AEs), serious adverse events (SAEs), and treatment-related AEs; and treatment discontinuation due to AEs.

resultsThe primary network meta-analysis for cumulative all-cause mortality (5 RCTs, 6 regimens, n = 1293) revealed no statistically significant differences among treatment regimens compared with voriconazole (VOR; surface under the cumulative ranking curve [SUCRA] 56.3%), including VOR combined with anidulafungin (ANI; risk ratio [RR] 0.74, 95% credible interval [CrI] 0.43-1.28; SUCRA 84.3%; moderate confidence), isavuconazole (ISA; RR 0.79, 95% CrI 0.45-1.40; 79.4%; moderate confidence), and posaconazole (POS; RR 1.20, 95% CrI 0.72-2.02; 34.6%; moderate confidence). Sensitivity analyses confirmed the robustness of these findings. Regarding safety, no significant differences were observed in SAEs for ISA (RR 0.91, 95% CrI 0.75-1.11; 85.7%; moderate confidence), POS (RR 1.03, 95% CrI 0.87-1.23; 40.8%; low confidence), and VOR combined with ANI (RR 1.09, 95% CrI 0.88-1.36; 20.8%; moderate confidence) compared with VOR (52.6%). Integrated efficacy-safety analysis suggested a favorable risk-benefit profile for isavuconazole.

conclusionsISA, POS, and VOR are the preferred antifungal agents for primary treatment of IA, with ISA demonstrating a higher likelihood of an optimal efficacy-safety balance. The combination of VOR and ANI may be considered for a subset of severe cases. REGISTRATION: PROSPERO identifier number CRD42024561215.