Does the evidence demonstrate conclusive proof of benefit over harm?
Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved by the FDA in 1999. The majority of the evidence supporting the use of the medication came from trials funded by Roche, the maker of the drug. Safety issues with the drug began sprouting up in 2009, due to case reports in Japan of neuropsychiatric events. Eventually, these events led to a label warning. The Cochrane collaboration published analyses of the available data in 1999, 2003 and 2006, supporting the use of the drug.
In 2009, the Cochrane collaboration began to question Roche about the completeness of the data they were using, which was data from another meta-analysis with 10 RCTs. Only two of those RCTs (Nicholson 2000 and Treanor 2000) were published in peer-reviewed journals. The other eight RCTs were presented as proceedings of Congress or abstracts in meetings. Cochrane decided to undertake a complete analysis of full clinical trial data, however Roche refused to release most of the data for more than four years until 2013.
In 2014, Jefferson T et al published the updated Cochrane review in the BMJ [1]. This was a systematic review of randomized placebo-controlled trials on adults and children with confirmed or suspected exposure to influenza. The outcomes were divided into treatment and prophylaxis outcomes. Twenty trials were used for their formal analysis (11 trials on treatment in adults, five trials on prophylaxis in adults and four trials on treatment in children).
In adults, Oseltamivir reduced time to first alleviation of symtpoms by about 16.7 hours, however increased nausea (NNH = 28), vomiting (NNH = 22), headaches (NNH = 32) and neuropsychiatric events (NNH = 94). There was no difference in admission to hospital, sinusitis or otitis, media between groups. In prophylaxis trials, Oseltamivir reduced symptomatic influenza participants by 55% (NNT = 33) and households (NNT = 8).
In children, Oseltamivir reduced time to first alleviation of symptoms by 29 hours. There was no difference in unverified pneumonia, unverified bronchitis, otitis media, or sinusitis. Oseltamivir did increase the risk of vomiting compared to placebo (NNH = 19).
This meta-analysis/systematic review is the first review that includes all of the collected data as opposed to the data selectively released by Roche initially. Prior studies only had a proportion of the results due to unpublished or selectively unpublished data. Previous findings that symptoms can be reduced by about half a day remain, but with all the evidence available, it has become clear that reductions in risk of hospitalizations or objective patient-oriented outcomes are lacking. This Cochrane analysis was published after Roche finally revealed all the trial data however, Roche has benefited by >$18 billion since its launch of Oseltamivir in 1999.
In both treatment and prophylactic studies, Oseltamivir minimally reduced time to first alleviation of symptoms and the proportion of symptomatic influenza patients, however this came at the expense of increased nausea/vomiting, headaches and neuropsychiatric illness. Furthermore, most if not all the studies evaluated Oseltamivir vs. placebo (not standard supportive care – APAP, NSAID, etc…). Additionally, there was no benefit for hospitalization, or other objective outcomes.
Neuraminidase inhibitors may provide some effectiveness to direct transmission of influenza at the individual and household level, but there is no evidence that confirms or refutes the impact at a community transmission level.
Despite the recommendations from the WHO, advocating for the use of Oseltamivir, health care providers should discuss the available evidence of benefit, harms and costs of this medication. Until new evidence demonstrates conclusive proof of benefit over harm, Oseltamivir should not be routinely recommended as treatment or prophylaxis in adults or children.
References:
- Jefferson T et al. Oseltamivir for Influenza in Adults and Children: Systematic Review of Clinical Study Reports and Summary of Regulatory Comments. BMJ 2014. PMID: 24811411
- Krumholz HM et al. Neuraminidase Inhibitors for Influenza: The Whole Truth and Nothing but the Truth. BMJ 2014. PMID: 24811413
- Okoli GN et al. Use of Neuraminidase Inhibitors for Rapid Containment of Influenza: A Systematic Review and Meta-Analysis of Individual and Household Transmission Studies. PLOS One 2014. PMID: 25490762
- Qiu S et al. Effectiveness and Safety of Oseltamivir for Treating Influenza: An Updated Meta-Analysis of Clinical Trials. Infectious Diseases 2015. PMID: 26173991
- Heneghan CJ et al. Neuraminidase Inhibitors for Influenza: A Systematic Review and Meta-Analysis of Regulatory and Mortality Data. Health Technology Assessment 2016. PMID: 27246259
