In adults with seasonal influenza A virus infection, the combination of the drugs oseltamivir (tamiflu) and zanamivir (relenza) is less effective than oseltamivir monotherapy and not significantly more effective than zanamivir monotherapy. This key finding comes from a randomized, placebo-controlled trial— in adults presenting with influenza symptoms at general practices throughout France during the seasonal influenza epidemic in 2008-2009— carried out by Catherine Leport from the University of Paris, France, and colleagues, and reported in this week's PLoS Medicine.
In the past few years oseltamivir and zanamivir have been key drugs for limiting the impact of seasonal influenza both in individuals (by reducing morbidity and mortality) and collectively (by slowing the virus' spread to buy time for vaccine production). In order to inform future influenza pandemic planning, the authors compared the effectiveness of monotherapy with either oseltamivir or zanamivir with the effectiveness of an oseltamivir-zanamivir combination.
Adults who visited their GP with symptoms of an influenza-like illness for less than 36 hours and who had a positive influenza A rapid test were randomized to one of three arms: 1) oral oseltamivir 75 mg twice daily plus zanamivir 10 mg by inhalation twice daily 2) oral oseltamivir 75 mg twice daily plus inhaled placebo or 3) zanamivir 10 mg by inhalation twice daily plus oral placebo. 541 patients were enrolled in the study (192 in group 1; 176 in group 2; and 173 in group 3) of whom 447 were infected with influenza A. Overall the oseltamivir-zanamivir combination was both virologically and clinically less effective than oseltamivir monotherapy. In addition, the clinical effects of the oseltamivir-zanamivir combination on time to resolution of symptoms were not significantly different from that of zanamivir monotherapy.
The authors conclude that their findings call for caution in the use of the oseltamivir-zanamivir combination in treatment of adult outpatients with influenza. Furthermore, as the virological effects of oseltamivir monotherapy over zanamivir monotherapy were superior in this trial, the authors say:
"Oseltamivir should be the recommended primary anti-influenza treatment during influenza seasons with predominant H3N2 viruses naturally susceptible to oseltamivir."
Funding: This work was supported by a research grant from the French Ministry of Health. The sponsor was: Departement a la Recherche Clinique et au Developpement, Assistance Publique a` Hopitaux de Paris (Programme hospitalier de recherche clinique, AOM 06060 and AOM 08209). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: XD has had a conference invitation from GSK and lecture fees from Roche and Gilead. AM has membership in the ministry of health advisory board on influenza; involvement in some epidemiological studies partially or fully granted by Roche and GSK, and travel grants from Roche for participation in scientific meetings. SVDW has had a conference invitation from GSK; research grant from GSK on unrelated subject; joint patent from institution with GSK on unrelated subject; travel grants for meetings from GSK; contribution to clinical trial financed by Roche; member of the advisory committee on influenza of the French ministry of health; is a member of ESWI; is a member of the scientific committee of the GEIG; and is vice-president of the GROG network. FM received fees from Roche, preclinical pharmacokinetic department, for a course on MONOLIX in December 2008. BL has had paid consultancy and board membership (Roche, GSK, Novartis, BioCryst, MedImmune), has had research grants from Roche and Sanofi-Pasteur, and had received travel grants and honoraria for speaking or participation at meetings (Roche, Sanofi-Pasteur).
Citation: Duval X, van der Werf S, Blanchon T, Mosnier A, Bouscambert-Duchamp M, et al. (2010) Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial. PLoS Med 7(11): e1000362. doi:10.1371/journal.pmed.1000362
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