Aspergillus is a saprophytic mold that commonly causes fungal infections in various areas of the body, particularly the lungs, resulting in invasive pulmonary aspergillosis (IPA) (Hajjeh and Warnock, 2001). IPA has been found to impact immunocompromised patients, leading to increased rates of morbidity and mortality. In addition, it has recently been recognized as a severe complication of influenza or coronavirus disease 2019 (COVID-19) in individuals who appear to have a normally functioning immune system (Lamoth and Calandra, 2022). The primary treatment options for IPA include azoles, lipid formulations of amphotericin B, amphotericin B, and echinocandins (Ledoux and Herbrecht, 2023).

In the past, dAmB was proven to be effective in treating aspergillosis (Stevens et al., 2000). Since the 1990s, lipid formulations of amphotericin B, such as L-AmB and ABCD, have been considered to be more selective because of less nephrotoxicity compared to dAmB (Tiphine et al., 1999; Hamill, 2013). Now, the guidelines demonstrate that second-generation triazole antifungal drugs are preferred as the standard of care for treating invasive aspergillosis (IA) (Patterson et al., 2016; Tissot et al., 2017; Ullmann et al., 2018). Pulmonary infection is the most common site of infection in IA. European Confederation of Medical Mycology and the European Respiratory Society recommended voriconazole or isavuconazole as the first-line treatment of IPA and L-AmB (3-5 mg/kg) as an alternative for salvage therapy (Ullmann et al., 2018). However, the treatment for IPA still needs to be improved due to the presence of adverse events, drug–drug interactions, and antifungal resistance (Neofytos et al., 2010; Andes et al., 2016). For example, the use of voriconazole in IPA may be associated with hepatotoxic disease, neurological and visual disturbances, phototoxic reactions skin disease (Benitez and Carver, 2019). In recent years, some RCTs have compared the effectiveness of voriconazole with isavuconazole and voriconazole with posaconazole for treating IPA. These trials provided substantial evidence endorsing posaconazole and isavuconazole as initial treatment options for IPA patients (Maertens et al., 2016; Maertens et al., 2021). However, no RCTs have reported the difference in efficacy between isavuconazole and posaconazole. Additionally, several studies suggest that combination therapy for IPA may yield potential benefits for certain patients (Singh et al., 2006; Caillot et al., 2007; Marr et al., 2015). However, the comparison of efficacy between combination therapy and monotherapy remains unclear.

A network meta-analysis of isavuconazole trials has indicated that the effectiveness of isavuconazole is similar to both L-AmB (3-5 mg/kg or 10 mg/kg) and voriconazole, and it outperforms dAmB (Herbrecht et al., 2018). Another meta-analysis suggested that combining liposomal amphotericin B with caspofungin could be a viable alternative for treating invasive aspergillosis (IA) and recommended second-generation triazole antifungal drugs as the primary therapy (Liu et al., 2024). However, there is insufficient evidence for using combination drugs as first-line treatment for anti-pulmonary aspergillosis, and there is a lack of comparative data on adverse reactions among different triazole drugs. To facilitate informed treatment decisions for patients with IPA, we undertake a comprehensive network meta-analysis. The patient population of our study is immunocompromised patients with proven or probable IPA. The interventions include antifungal agents such as isavuconazole, posaconazole, amphotericin B lipid formulations, and echinocandins. We compare voriconazole, commonly used in clinical practice, with these interventions. The primary outcome is the efficacy of different antifungal drugs in IPA, including the overall response and all-cause mortality. Our analysis provides more comprehensive information on common antifungal agents in initially treating IPA may guide the selection of interventions for clinicians.

The network meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA, doi: 10.1136/bmj.n71). The protocol of the study had been registered in the International Platform of Registered Systemic Review and Meta-analysis Protocols (INPLASY) under the registration number INPLASY202380105 (doi: 10.37766/inplasy2023.8.0105).

In our meta-analysis, we reviewed eight studies, which included 1,431 patients randomly assigned to different antifungal drugs in the initial treatment of IPA. We found second-generation triazole antifungal drugs, including voriconazole, isavuconazole, and posaconazole, exhibited significantly superior overall response compared to dAmB and ABCD. However, there was no difference between triazole antifungal drugs and L-AmB. In terms of safety, isavuconazole is likely to be better than voriconazole and posaconazole in the first-line treatment of IPA. The combination of voriconazole with anidulafungin may have a better safety profile than dAmB.

At present, voriconazole with the option of substituting dAmB is recommended as the first-line treatment for IPA patients by guidelines due to the unfavorable safety profile of dAmB (Herbrecht et al., 2002; Herbrecht et al., 2015; Patterson et al., 2016; Tissot et al., 2017). ABCD, as a high-affinity lipid complex composed of dAmB and sodium cholesteryl sulfate, exhibited superior renal safety compared to dAmB (White et al., 1997; White et al., 1998). However, its use showed more infusion-related toxicities resulting in premature discontinuation in patients who received ABCD in the study (Bowden et al., 2002). Triazole antifungal drugs have become the primary treatment options for patients diagnosed with IPA based on their better safety and tolerability (Maertens et al., 2016; Maertens et al., 2021). The results of our analysis showed that all voriconazole, isavuconazole, and posaconazole significantly improved survival compared to dAmB and ABCD.

L-AmB is associated with less nephrotoxicity and fewer infusion-related reactions than dAmB and ABCD (Leenders et al., 1998). By the IDSA guidelines, L-AmB can be recognized as the initial treatment option and a salvage option for patients who are not candidates for voriconazole treatment (Karthaus, 2010; Patterson et al., 2016). The recommended initial dosage of L-AmB to treat IPA is 3-5 mg/kg per day. The previous RCTs reported that L-AmB at 10 mg/kg did not provide any additional clinical benefit than the standard dosing (Cornely et al., 2007; Cornely et al., 2011). In our analysis, we found no statistically significant difference between triazole antifungal drugs and L-AmB at low, standard, or high doses. The result is consistent with a previous meta-analysis of trials involving isavuconazole (Herbrecht et al., 2018). Our analysis showed the overall SUCRA rank was higher for voriconazole but the probability of being the best agent was highest for L-AmB (1 mg/Kg). However, SUCRA with high values may provide supportive evidence for treatment options, but not conclusive evidence (Wang and Carter, 2018). The uncertainty of SUCRA rankings was also affected by a small number of trials or limited sample size (Trinquart et al., 2016). Although L-AmB (1 mg/kg) may rank better than triazole drugs in the small number of all-cause deaths by Supplementary Table S2, we found the median duration of treatment with L-AmB at any doses was shorter than those for triazoles in reviewed studies. For patients who need to receive sustaining treatment, triazoles may be preferred over L-AmB. In addition, oral triazoles may be more available to outpatients than intravenous L-AmB.

Studies have revealed that isavuconazole and posaconazole both exhibited comparable efficacy to voriconazole (Maertens et al., 2016; Maertens et al., 2021), but there are differences in the safety and tolerability of different triazoles. The use of voriconazole may be associated with drug–drug interactions, pharmacokinetic variability, and adverse events. The primary treatment-associated adverse effects of voriconazole include hepatotoxicity, neurological and visual disturbances, phototoxic reactions, tachyarrhythmias, and a high risk of nonmelanoma skin cancer (Benitez and Carver, 2019). Among the three triazole antifungals, isavuconazole may show the best safety profile. We found that isavuconazole and voriconazole demonstrated significantly better safety compared to AmB, but isavuconazole had significantly lower rates of hepatobiliary disorders (9% vs. 16%, p = 0.016), eye disorders (15% vs. 27%, p = 0.002), and skin or subcutaneous tissue disorders (33% vs. 42%, p = 0.037) compared to voriconazole in the 2016 study (Maertens et al., 2016). Posaconazole efficacy as well as isavuconazole is less affected than voriconazole by cytochrome P450 3A4 (CYP3A4) (Townsend et al., 2017; Chen et al., 2020). However, posaconazole may display a higher incidence of hepatobiliary disorders and renal and urinary disorders than isavuconazole. Our results suggested that posaconazole ranked lower than isavuconazole in terms of reducing ACM. When choosing posaconazole over isavuconazole to treat IPA, the monitoring of liver function and electrolytes is required throughout the treatment period.

The comparison between combination therapy with antifungal agents and monotherapy remains uncertain despite preclinical studies both in vitro and in vivo consistently supporting the use of azoles in combination with echinocandins for the treatment of IPA (Singh et al., 2006; Vazquez, 2008). In this analysis, we found that combining voriconazole with anidulafungin may have an acceptable safety profile in the initial management of IPA. The combination of voriconazole with anidulafungin had a tendency to improve 6-week survival compared to voriconazole monotherapy, although the difference was not statistically significant (Marr et al., 2015). Our findings suggested that the ACM up until day 84 was significantly lower for the combination of anidulafungin and voriconazole compared to dAmB, indicating a potential safety advantage. However, we found that the combination therapy ranked lower than other triazole monotherapy in overall response. The findings were consistent with the earlier analysis (Liu et al., 2024). We also found that the combination therapy was associated with a high incidence of eye disorders and vascular disorders (Supplementary Tables S3, S4). Additionally, it is worth noting that the actual median duration of the combination therapy was 14 days (range, 14–29 days) in the 2015 study, which was shorter than those for the voriconazole monotherapy (Marr et al., 2015). Therefore, it is essential for doctors to make cautious decisions regarding the use of combination therapy for the first-line treatment of IPA, considering individualized assessments and carefully weighing the potential risks and benefits.

Our analysis has certain limitations. Firstly, there is a limited number of RCTs available for the treatment of IPA that meet our inclusion criteria. We have to rely only on direct comparisons to evaluate the efficacy of different treatments. Additionally, due to the limitations of the data we included, we were unable to perform more comprehensive analyses, such as subgroup analyses based on different patient conditions or age groups. Secondly, some studies included a portion of patients infected with other non-Aspergillus molds. The study comparing a high-loading dose of L-AmB with standard dosing included 97% of patients with invasive aspergillosis. In the study comparing isavuconazole and voriconazole, the isavuconazole group (approximately 13%) enrolled a relatively small percentage of patients with infections due to non-Aspergillus molds or other unidentified filamentous fungi, as well as the voriconazole group (approximately 17%). While the majority of patients included in each study had pulmonary infection, there were instances where some studies included patients without pulmonary infection. These could have potentially influenced the results of our analysis to some extent. Thirdly, the earlier study included in the analysis did not utilize the revised EORTC/MSG criteria published in 2008 for diagnosing invasive aspergillosis (IA) (Ellis et al., 1998). This discrepancy may introduce bias in the comparison results. In addition, we excluded a randomized pilot study exploring the combination of L-AmB and caspofungin for IPA, given the risk of bias in the estimation of relative efficacy due to the small number of patients enrolled in each group (n = 15) (Caillot et al., 2007). Notably, there is a lack of RCT reporting efficacy between triazole drugs and L-AmB or efficacy among new triazole drugs other than voriconazole. The findings of our analysis do provide some recommendations for future research endeavors. In the future, more high-quality randomized controlled trials are needed to compare the effects of different antifungal drugs on invasive pulmonary aspergillosis.

This network meta-analysis has provided an indirect comparison of the efficacy of various drugs for the first-line treatment of IPA. Our findings indicate that the second-generation triazole antifungal drugs might be comparable with L-AmB and associated with higher therapeutic efficacy than dAmB and ABCD in IPA treatment. The safety of isavuconazole is probably better than voriconazole and posaconazole. Combination therapy with voriconazole and anidulafungin may serve as an alternative option for IPA patients with limited drug tolerance.