Isavuconazole for the Treatment of Fungal Infections: A Real-life Experience From the Fungal Infection Network of Switzerland (FUNGINOS)

Abstract This analysis of 116 isavuconazole therapy courses shows that hepatic test disturbances (HTDs) were relatively frequent (29% of cases) but rarely led to treatment interruption (5%). Importantly, patients with baseline HTDs, including those attributed to a first-line triazole, did not exhibit a higher risk of subsequent HTD under isavuconazole therapy.

Invasive fungal infections (IFIs) are important causes of mortality among patients who are immunocompromised, such as those with hematologic cancer or long-term immunosuppressive therapies [1,2].The limited therapeutic options and their associated toxicities are factors that may contribute to poor outcomes [3,4].Triazoles are widely used antifungals for the treatment of IFI because of their large antifungal spectrum and the availability of intravenous and oral formulations [5].However, their drug-drug interactions and liver toxicity limit their use [5].Isavuconazole (ISA), the most recently marketed triazole, displays some advantages over other drugs of this class, such as broad antimold activity, fewer drug-drug interactions, and less hepatotoxicity [6].
ISA has been approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) [7][8][9][10].It has been available in Switzerland since 2017.This study of the Fungal Infection Network of Switzerland (FUNGINOS) aimed to investigate the current place of ISA for the treatment of IFI in Switzerland, as well as its related outcomes and safety in a real-life clinical setting.

MATERIALS AND METHODS
Patients treated with ISA between 1 January 2017 and 31 December 2020 were identified via the pharmacology databases in 3 university hospitals (Geneva, Lausanne, and Zurich).Patients having received ≥7 days of ISA therapy with clinical follow-up were included.Demographic characteristics, underlying diseases, characteristics of IFI, type and duration of antifungal therapy, outcomes, and potential adverse events were collected in medical records.When ISA was administered as a second or subsequent therapeutic line, the reason for therapy change was analyzed.Patients were retrospectively followed until the end of ISA therapy or the date of last follow-up and no later than 31 December 2021.IFIs were classified according to criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium [11].
The outcome analysis included only patients fulfilling criteria of proven, probable, or possible IFI.Patients who received ISA as a subsequent line of therapy beyond 28 days from the start of antifungal treatment, which was considered maintenance therapy, were excluded.Response to therapy was assessed at week 6 from the start of ISA therapy.Success was defined as complete or partial response and failure as stable disease, progression, or death, according to standard criteria [12].
For the safety analysis, medical records were screened for adverse events that led to interruption of ISA or were potentially attributed to ISA.Hepatic test values-such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase, and total bilirubin-were recorded just before and until the end of ISA therapy.Hepatic test disturbance (HTD) was defined as a ≥2-fold increase from the baseline value of any of the aforementioned liver parameters during ISA therapy.
The response to therapy could be assessed in 62 cases for which ISA was administered as a first line or subsequent therapeutic line within 28 days from the start of antifungal treatment.The success rate for all IFIs was 36 of 62 (58%) at week 6.No significant difference was observed between patients with and without hematologic cancer (63% vs 44%, respectively, P = .2).Among proven/probable IFIs, the success rate was 22 of 41 (54%) and did not differ between IA (52%) and other IFI (55%).
For the analysis of adverse events, all 116 ISA therapy courses were included.A total of 34 (29%) patients experienced HTD (Table 2), occurring at a median 20 days (range, 2-318) from   the start of ISA therapy.Mild HTD (2-to 5-fold increase of any parameter) and moderate HTD (5-to 10-fold increase) were observed in 26 (76%) and 8 (24%) cases, respectively.Alkaline phosphatase/gamma glutamyl transferase rise was the predominant HTD.Among the 34 patients with HTD, ISA therapy was interrupted in 6 cases (18%) for attributed hepatotoxicity and in 2 cases for other causes (rash, therapy failure).The rate of discontinuation was similar between patients with mild and moderate HTD (23% and 25%, respectively).Considering the entire population, the rate of ISA discontinuation for attributed hepatotoxicity was 6 of 118 (5%).Following ISA interruption, partial resolution of HTD was observed in 4 cases, while 2 patients died from causes not attributed to hepatotoxicity.When ISA therapy was continued despite HTD (n = 26), complete/partial resolution was observed in 15 (58%) cases, while it remained stable in other cases.
Half of patients (n = 58) received ISA despite baseline HTD (mild in 60% of cases and moderate in 40%).The occurrence of HTD under ISA therapy in these patients did not significantly differ from that in patients without baseline HTD (31% vs 28%, P = .8;Table 2).Among patients with baseline HTD attributed to first-line azole therapy (voriconazole or posaconazole, n = 19), 3 (16%) experienced recurrent HTD under subsequent ISA therapy.
Other ISA-attributed adverse events leading to its interruption were skin rash (n = 1) and gastrointestinal disorders (n =

DISCUSSION
In this multicenter retrospective study, we analyzed the practices of ISA prescription in Switzerland and its related outcomes and toxicity.While the efficacy and safety of ISA for the treatment of IFI have been assessed in randomized controlled trials [8,9], post hoc surveillance studies are needed to assess the drug profile in real clinical settings that differ from the selected population of clinical trials [13][14][15][16][17][18].
ISA is currently approved for the treatment of IA and IM [7,10].In our study, these IFIs accounted for most cases (87%) where ISA was used as targeted therapy.The success rate for proven/probable IFI was 54%, which is superior to rates reported in prospective trials [8,9] but similar to those of other reallife observational studies [14,17].In addition, ISA was used as empiric therapy for possible IFI.In this setting, ISA represents an alternative to amphotericin B because of its broad spectrum, oral bioavailability, and lower risk of nephrotoxicity.As observed in other settings [15,17], ISA was mainly used as a second-line therapy in our study (57% of cases).Toxic issues of previous antifungal drugs motivated the switch to ISA in about half of cases.When compared with other antimold triazoles, ISA has fewer drug-drug interactions and a lower risk for hepatotoxicity [6].In the SECURE trial, ISA was associated with less hepatobiliary disorders when compared with voriconazole [8].A meta-analysis confirmed the lower rate of ISA-related hepatotoxicity when compared with other antifungals [19].Similar observations were made when ISA was used as prophylaxis, with a hepatotoxicity-related ISA discontinuation rate of about 5% (lower vs voriconazole or posaconazole) [20][21][22][23].
We observed a similarly low rate of hepatotoxicity-related ISA discontinuation in our study, although HTD occurred in about 30% of cases when based on a low cutoff (≥2-fold increase of any hepatic test).At least partial resolution of HTD was observed in more than half of these cases despite ISA continuation, which suggests that their origin was possibly not ISA related.Indeed, causes and mechanisms of HTD under azole therapy are often multiple and complex [24].Most interesting, half the patients in our study had baseline HTD at the start of ISA therapy.In that sense, our patient population differed from that of previous prospective trials excluding such patients [8,9].The main observation of our relatively large cohort (n = 116) was that patients with baseline HTD or previous hepatotoxicity attributed to another triazole were not more susceptible to develop HTD under ISA therapy, which is in line with results of previous smaller studies [13,15,25].
In conclusion, this study shows that HTD under ISA therapy, albeit frequent, rarely requires its interruption.In particular, ISA could be safely used in patients with mild/moderate baseline HTD, provided that liver tests are closely monitored.ISA may also be used as second-line therapy in patients who needed to interrupt first-line voriconazole or posaconazole therapy because of hepatotoxicity, as it is associated with a low rate of HTD recurrence in this setting.

Notes
Financial support.This work was supported by a grant from Pfizer.Potential conflicts of interest.Outside the submitted work: F. L. received research funding from Gilead, MSD, and Novartis and speaker honoraria from Pfizer, Gilead, MSD, Mundipharma, and Becton-Dickinson.All contracts were made with and fees paid to his institution.P. W. S. received travel grants from Pfizer and Gilead, speaker honorary from Pfizer, and fees for advisory board activity from Pfizer and Gilead.All other authors report no potential conflicts.

Table 1 . Characteristics of Patients, IFIs, and Isavuconazole Therapy Courses
Abbreviations: EORTC-MSGERC, European Organization for Research and Treatment of Cancer-Mycoses Study Group Education and Research Consortium; HSCT, hematopoietic stem cell transplantation; IFI, invasive fungal infection; PCR, polymerase chain reaction.a One patient developed 2 IFIs at 202 days apart.