Recommendations on antivirals in European countries are appropriate, but remain underutilised in practice
Current recommendations in EU countries to use neuraminidase inhibitors (antivirals) for patients with severe influenza are supported by the available evidence, concludes a new expert opinion report from ECDC which is now open for public consultation. The effectiveness of antivirals has been the subject of debate, resulting in their underutilisation. Consequently, public health benefits may be being missed.
In forming its expert opinion, ECDC reviewed three large systematic reviews and meta-analyses on the use of neuraminidase inhibitors. The report finds that the evidence from the meta-analyses support the use of antivirals for both treatment and the prevention of influenza.
Two of the main reviews considered by ECDC found that antivirals reduced the amount of time until the first relief of symptoms; one also found that all symptoms were alleviated more than one day earlier with antiviral use. When administered early, antivirals proved to be useful as prophylaxis and reducing the effects on those already exposed.
Reports to the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) database, also coordinated by ECDC, suggest there is significant variation in actual use of antivirals across the EU and that they are infrequently used as a medical and public health countermeasure. The underutilisation may be explained by the difficulty of timely diagnosis of influenza, as well as the public debate around their efficacy and effectiveness creating doubt for prescribers.
“In a season such as the one we are having at the moment, with healthcare services—including intensive care departments—under pressure due to severe influenza cases, antivirals can play a vital role in helping to treat individuals and decrease pressures on healthcare systems,” said Mike Catchpole, ECDC Chief Scientist.
“This expert opinion demonstrates that from a public health perspective there are important benefits associated with the use of antivirals. They can help to reduce the length and severity of influenza disease. Most EU countries have policies in place for the use of antivirals, and the evidence from these reviews should further encourage prescribing doctors to put these policies into practice.
“There remains a need for a strengthening of the evidence base for their use and the development of new antivirals would be welcome,” Mike Catchpole also said.
The Expert Opinion on neuraminidase inhibitors for prevention and treatment of influenza – review of recent systematic reviews and meta-analyses is open for public consultation for all interested parties.
ECDC Expert Opinion
Three new large systematic reviews and meta-analyses assessing efficacy, effectiveness and safety of two licensed neuraminidase inhibitors, oral oseltamivir and inhaled zanamivir, were reviewed: The 2014 Cochrane Collaboration report (Jefferson et al.), the 2015 MUGAS study (Dobson et al.) and the 2014 PRIDE study (Muthuri et al.). Additional reviews and studies were considered where appropriate.
ECDC convened a meeting of public health experts to review the data presented in these three reviews and to provide the basis for the development of the expert opinion.
The reviews by Jefferson et al. and Dobson et al. conclude that, for adults, oseltamivir decreases the time to first alleviation of symptoms of influenza-like illness (ILI) by 16.8 hours and 17.8 hours, respectively. The time to alleviation of all symptoms among those confirmed to have influenza was decreased by 25.2 hours. From the observational studies, analysed by Muthuri et al., decreased mortality among hospitalised patients was associated with antiviral usage during the three pandemic waves of influenza A(H1N1)pdm09 in 2009–2011.
All three reviews point to the importance of initiating treatment early, ideally within 48 hours (within 36 hours in the case of zanamivir in children) of the onset of symptoms. However, observational studies, including the analysis by Muthuri et al, indicate some benefit for antiviral therapy started up to 4–5 days after symptom onset in hospitalised patients. Further, as noted by the two reviews of conducted randomised clinical trials, observed efficacy is better when the neuraminidase inhibitors are used as prophylaxis than as treatment.
NOTES TO EDITORS
- The use of antivirals is authorised in the EU for treatment and prophylaxis of influenza disease (including seasonal, pandemic and zoonotic influenza), although vaccination is viewed as the primary tool for prevention.
- Regardless of vaccination status, the use of antivirals is recommended alongside clinical supportive care for the treatment of severe, complicated or progressive illness or for patients at high risk of complications.
- The efficacy of current antivirals is limited and there is an urgent need for new influenza antivirals with greater efficacy. Research and development work on new neuraminidase inhibitor formulations, new antivirals and also combination therapies is ongoing.
- Further studies are needed to strengthen the evidence base overall. Given that both oseltamivir and zanamivir are licensed and no further regulatory requirements are expected, it is highly unlikely that any new placebo controlled randomised clinical trials will be conducted. High-quality observational studies are more feasible and such studies would strengthen the evidence base for individual risk groups.
- Uncertainties have arisen from the lack of randomised controlled trials to directly support the full range of treatment recommendations of oseltamivir and zanamivir; however, their efficacy in reducing the time to first and all alleviation of symptoms is demonstrated.
- The expert opinion considered the use of antivirals from a public health perspective only. Other aspects necessary to make informed decisions on stockpiling, such as cost-effectiveness; opportunity cost; and public perception of the risks and benefits of the threat and intervention, were not addressed.
- National recommendations regarding influenza antiviral use are available in 24 EU/EEA Member States. These policies generally recommend use of antivirals for patients with severe or progressive influenza requiring hospitalisation. EU/EEA Member States recommend antiviral use as treatment (14 Member States) or prophylaxis (9 Member States) in case of outbreaks for residents of nursing homes or other long-term care facilities at risk of severe disease. A minority of EU/EEA Member States recommend use as treatment or prophylaxis for outpatients who may have a higher risk of severe outcomes of influenza (See Tables 50-53 in National seasonal influenza vaccination survey for 2012-13 influenza season in EU/EEA).
- Infrequent use of antivirals is indicated by ESAC-Net data (Figure 1 in the report).
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