Oseltamivir+Zanamivir combination therapy vs monotherapy for seasonal influenza

A Combination Lock

In infectious diseases, there is always the trade-off between treating the individual patient and the population effects of antimicrobial resistance.  One way to counteract the development of resistance might be combination therapy (eg HIV ART) but this would only apply if the combination provided an added benefit to the individual patient with minimal side effects.  To answer this question for influenza, researchers in France in fall 2009 (85% H3N2 virus) conducted an RCT comparing oral oseltamivir 75 mg twice daily plus zanamivir 10 mg by inhalation twice daily to oral oseltamivir monotherapy or inhaled zanamivir monotherapy. The primary outcome was the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2. They also tracked symptom resolution out to day 14 among other outcomes.

The researchers planned to enroll 900 patients with ILI<36 hours and a positive rapid influenza A test, however the RCT was halted after only 541 (447 with confirmed virus) were enrolled.  In the intention to treat analysis, 46% in the O+Z group reached RCT-PCR<200, while this was achieved in 59% of the oseltamivir monotherapy and 34% of the zanamivir monotherapy groups.  Nausea and/or vomiting was more frequent in the combination arm.  Thus, the trial was ended early. The authors concluded: "Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice."

Duval et al. PLoS Medicine November 2, 2010