Safety, Resistance, and Efficacy Results from a Phase IIIb Study of Conventional- and Double-Dose Oseltamivir Regimens for Treatment of Influenza in Immunocompromised Patients

Essack Mitha, Gergely Krivan, Frederique Jacobs, Arnon Nagler, Sally Alrabaa, Analia Mykietiuk, Andrew Kenwright, Sophie Le Pogam, Barry Clinch, Loreta Vareikiene, Essack Mitha, Gergely Krivan, Frederique Jacobs, Arnon Nagler, Sally Alrabaa, Analia Mykietiuk, Andrew Kenwright, Sophie Le Pogam, Barry Clinch, Loreta Vareikiene

Abstract

Introduction: Immunocompromised patients infected with influenza exhibit prolonged viral shedding and higher risk of resistance. Optimized treatment strategies are needed to reduce the risk of antiviral resistance. This phase IIIb, randomized, double-blind study (NCT00545532) evaluated conventional-dose or double-dose oseltamivir for the treatment of influenza in immunocompromised patients.

Methods: Patients with primary or secondary immunodeficiency and influenza infection were randomized 1:1 to receive conventional-dose oseltamivir (75 mg adolescents/adults [≥ 13 years]; 30-75 mg by body weight in children [1-12 years]) or double-dose oseltamivir (150 or 60-150 mg, respectively), twice daily for an extended period of 10 days. Nasal/throat swabs were taken for virology assessments at all study visits. Co-primary endpoints were safety/tolerability and viral resistance. Secondary endpoints included time to symptom alleviation (TTSA) and time to cessation of viral shedding (TTCVS).

Results: Of 228 patients enrolled between February 2008 and May 2017, 215 (199 adults) were evaluable for safety, 167 (151 adults) for efficacy, and 152 (138 adults) for resistance. Fewer patients experienced an adverse event (AE) in the conventional-dose group (50.5%) versus the double-dose group (59.1%). The most frequently reported AEs were nausea, diarrhea, vomiting, and headache. Fifteen patients had post-baseline resistance, more commonly in the conventional-dose group (n = 12) than in the double-dose group (n = 3). In adults, median TTSA was similar between arms, while median TTCVS was longer with conventional dosing.

Conclusions: Oseltamivir was well tolerated, with a trend toward better safety/tolerability for conventional dosing versus double dosing. Resistance rates were higher with conventional dosing in this immunocompromised patient population.

Trial registration: ClinicalTrials.gov identifier: NCT00545532.

Funding: F. Hoffmann-La Roche Ltd.

Keywords: Efficacy; Immunocompromised; Influenza; Oseltamivir; Phase IIIb; Resistance; Safety.

Figures

Fig. 1
Fig. 1
Disposition of patients (mITTi, adults and children combined). Intent-to-treat infected population: all patients randomized and with central laboratory confirmation of influenza infection, excluding patients infected with oseltamivir-resistant influenza at baseline. mITTi population: all patients randomized to a particular treatment, regardless of whether they received that treatment or not, and received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding patients infected with oseltamivir-resistant influenza at baseline. mITTi modified intent-to-treat infected
Fig. 2
Fig. 2
Evaluating the impact of treatment-emergent resistance on a time to cessation of viral shedding and b time to alleviation of symptoms (median [95% CI]; mITTi, adults only). All patients with baseline resistance were excluded from this analysis. *Patients who were still shedding virus (TTCVS)/symptomatic (TTAS) at end of study were censored from the analysis. CI confidence interval, mITTi modified intent-to-treat infected, TTAS time to symptom alleviation, TTCVS time to cessation of viral shedding

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