Two analyses of the pooled data from the global phase 3 multicenter VITAL [NCT00412893] and SECURE [NCT00634049] trials have demonstrated the safety and effectiveness of the broad-spectrum triazole antifungal drug isavuconazole (ISA) in the treatment of invasive aspergillosis (IA) in patients with renal impairment. Renal dysfunction can occur in up to 40% of those with IA. ISA, which is available orally as water-soluble isavuconazonium sulfate, overcomes the limitations of other intravenous drugs available to treat IA that are associated with increased risk of renal toxicity in patients with preexisting renal dysfunction [Baddley J et al. Clin Infect Dis. 2010; Vandewoude K et al. J Hosp Infect. 2004].

SECURE was a double-blind, parallel-group noninferiority trial that compared ISA and voriconazole in the treatment of IA and, more broadly, invasive fungal disease in 527 patients. Some of these patients had renal impairment. VITAL was an open-label trial involving 149 patients, and it examined the use of ISA in both fungal diseases. Both trials used a loading dose of ISA (200 mg TID intravenously on days 1 and 2), followed by ISA 200 mg QD intravenously or orally from day 3 to the end of treatment (days 84 and 180 in SECURE and VITAL, respectively). Patients were aged ≥ 18 years with proven/probable IA, with or without renal impairment at baseline. The key end point was all-cause mortality through day 42. Secondary end points included all-cause mortality and probability of survival through day 84. Treatment success was the partial or complete resolution of clinical symptoms, physical findings, and radiological abnormalities. The type, frequency, and severity of treatment-emergent adverse effects (TEAEs) were recorded.

One of the pooled analyses was presented by Johan Maertens, MD, PhD, UZ Leuven, Leuven, Belgium. This analysis focused on 143 patients of the 676 in the pooled population who had proven/probable IA treated with ISA. Thirty-one patients had renal impairment, and the remaining 112 did not. Patient characteristics at baseline are summarized in Table 1.

All-cause mortality was similar in patients with (n = 31) or without (n = 112) renal impairment at baseline through day 42 (4 [13%] vs 21 [19%]) and day 84 (8 [26%] vs 32 [29%], respectively). Overall successful response to treatment was similar in patients with (10 [32%]) and without (40 [36%]) renal impairment. The probability of survival determined by the Kaplan-Meier method was also similar in those with or without baseline renal impairment.

TEAEs occurred in all renal-impaired patients and 96% of patients without renal impairment (Table 2). The most common TEAE was infections/infestations, which occurred in 10 of 31 (32%) of those with renal impairment and 25 of 112 (22%) of those without renal impairment, followed by respiratory/thoracic/mediastinal disorders (5 [16%] vs 21 [19%]). Doubling of serum creatinine was noted in 1 of 30 patients (3%) with renal impairment and 14 of 109 patients (13%) without renal impairment.

As discussed by William Hope, PhD, University of Liverpool, Liverpool, United Kingdom, the second analysis of the pooled SECURE and VITAL data focused on the minimum inhibitory concentration (MIC) of ISA on the various fungal pathogens.

Baseline susceptibility of Aspergillus isolates to ISA was assessed using criteria of the European Committee on Antimicrobial Susceptibility Testing’s definitive document E.DEF 9.1 [Rodriguez-Tudela JL et al. 2008]. Treatment success was the expert-assessed absence of clinical signs and symptoms at the end of treatment.

Aspergillus infection was confirmed microbiologically at baseline in 61 patients, comprising A fumigatus (n = 31), A flavus (n = 15), A niger (n = 9), A terreus (n = 5), and A westerdijkiae (n = 1). The MIC of ISA in these species ranged from 0.12 to > 16 mg/L. The assessed clinical success of treatment was 50% to 100% for species with MIC < 16 mg/L and was similar for A fumigatus (71.0%), A flavus (73.3%), A niger (66.7%), and A terreus (60.0%). The overall clinical success for all cases with microbiologic confirmation was 69% (42 of 61), indicating that the effectiveness of treatment may be unrelated to the MIC.

The analyses of the pooled SECURE and VITAL data substantiate the view that ISA is effective in the treatment of IA in patients with renal insufficiency, for whom other triazole antifungals may be restricted in use; they also indicate that dose adjustment for this patient population is not needed.

ISA has been approved for use in the United States for treatment of IA and mucormycosis in patients aged 18 years and older. Regulatory review in Europe is ongoing.