While it is relatively uncommon for the annually circulating seasonal influenza viruses to lead to severe influenza in humans, for certain influenza viruses, such as A(H5N1) and A9H7N9), severe influenza is a common outcome. It is not yet clear how best to treat severe influenza and whether the duration of illness can be shortened and survival improved with appropriate antiviral drug treatment. There are a limited choice of drugs to treat severe influenza.
This double-blind randomised control trial was conducted in 13 hospitals in Indonesia, Singapore, Thailand, and Vietnam. The study included 326 patients (including 246 (75.5%) children aged <15 years), with 165 and 161 patients randomised to double or standard dose oseltamivir, respectively, for five days. Children in the study were given a graded twice daily oral dose (according to body weight) of either the regular dose or the double dose oseltamivir for five days. The primary endpoint was the proportion of patients with no detectable viral RNA by rapid antigen test in a combined nasal and throat swab on day five after oseltamivir treatment. Several secondary endpoints included mortality, admission to intensive care, mechanical ventilation, symptoms, and resumption of activity.
The investigators found no virological or clinical benefits in patients receiving the double dose of oseltamivir compared with the regular dose. Of the 17 patients with avian H5N1 virus, however, only three survived until day five, which makes it impossible to determine with certainty if there was any virological or clinical benefit with double dose of oseltamavir.
An accompanying editorial published in BMJ highlights several limitations with the study:
• Most patients enrolled were children, and, although the same conclusions were reached for adults, the smaller number of adults in the study make these findings less conclusive.
• As most of the patients enrolled were infected with seasonal or pandemic virus rather than the more serious A(H5N1) virus, their findings are not conclusive for A(H5N1) patients.
• There is a lack of data on plasma concentrations of oseltamivir with the two treatments, and the absorption and conversion of oseltamivir in seriously ill patients might be reduced.
• The choice of the primary endpoint could also be a limitation as more importance might be placed on viral loads in the lower respiratory tract as a predictor of disease outcome rather than those in the upper respiratory tract
• The translation of these findings to other geographical locations and populations might be limited. For example, the delay in seeking treatment and admission to hospital (a median of 5 days overall and 7 days for A(H5N1)) in this study might not be typical in more industrialised countries.
The author of the editorial concludes that double dose oseltamivir is unlikely to significantly improve the clinical outcomes of severe cases of seasonal influenza, but there is probably insufficient data to determine if this was also true for people infected with A(H5N1).
NICE recommends oseltamivir as an option for the treatment of influenza if all of the following criteria are met:
• national surveillance schemes indicate that influenza virus A or B is circulating
• the person is in an 'at-risk' group
• the person presents with an influenza-like illness and can start treatment within 48 hours (or within 36 hours for zanamivir treatment in children) of the onset of symptoms as per licensed indications.