Dataset Information

1169. In Vitro Activity of Posaconazole versus Voriconazole for the Treatment of Invasive Aspergillosis in Adults Enrolled in a Clinical Trial

ABSTRACT: Abstract

Background

Invasive aspergillosis (IA) is a life-threatening disease with limited treatment options and is associated with delays in effective treatment and significant early mortality. Posaconazole (POS) is a broad-spectrum triazole antifungal, that exhibits potent activity against yeasts and molds. We evaluated the antifungal susceptibility profiles of isolates collected during a randomized, prospective, phase 3, double-blind, double-dummy study comparing posaconazole with voriconazole (1:1 randomization) given for ?12 weeks in the primary treatment of IA (ClinicalTrials.gov, NCT01782131; EudraCT, 2011-003938-14) using CLSI and EUCAST reference testing methodologies.

Methods

More than 90 study sites located in 23 countries enrolled subjects in the clinical trial. A total of 127 isolates were recovered from documented infections during 2013 through 2019. Fungal isolates were identified using molecular methods and antifungal susceptibility testing was performed by reference broth microdilution methods. The following antifungal agents tested were: posaconazole, itraconazole, voriconazole, caspofungin, and amphotericin B

Results

Of the 127 samples tested, 119 were identified as Aspergillus species. Aspergillus fumigatus (N=76) was the most prevalent species, followed by A. flavus species complex (N=19), A. section Nigri (N=10), A. section Terrei (N=7). Overall, posaconazole (MIC50/MIC 90, 0.5/1 mg/L) displayed similar activity to voriconazole (MIC50/MIC90, 0.5/1 mg/L) and itraconazole (MIC50/MIC90, 1/2 mg/L) against 119 Aspergillus species Isolates, by both, CLSI and EUCAST method. Posaconazole (MIC50/MIC90, 0.5/0.5 mg/L) and voriconazole (MIC50/MIC90, 0.25/0.5 mg/L) inhibited all 76 A. fumigatus isolates at MIC of 1 mg/L. Among 19 A. flavus species complex isolates recovered from this study, posaconazole (MIC50/MIC90, 0.5/1 mg/L), voriconazole (MIC50/MIC90, 1/1 mg/L) and itraconazole (MIC50/MIC90, 0.5/1 mg/L) displayed equivalent activity.

Conclusion

Posaconazole displayed good activity against all Aspergillus species isolates included in this study. In addition, posaconazole in vitro activity against Aspergillus species was similar to that observed by voriconazole and itraconazole.

Disclosures

Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Leah Woosley, n/a, Merck & Co, Inc. (Research Grant or Support) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) Seongah Han, PhD, Merck & Co, Inc. (Employee) Havilland Campbell, BS, Merck & Co, Inc. (Employee)

SUBMITTER: Castanheira M

PROVIDER: S-EPMC7777633 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:According to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System. METHODS:An economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables. RESULTS:According to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763-16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively. CONCLUSION:According to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan-positive patients in Spain who have hematologic disease or hematopoietic stem cell transplant, compared with VOR monotherapy.

Project description:BackgroundVoriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden.MethodsThe cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs.ResultsThe base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%.ConclusionsThis model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective.