ECDC expert opinion in progress on the efficacy, effectiveness and safety of influenza neuraminidase inhibitors presented at the annual European Influenza Surveillance Network meeting, Stockholm, June 2015

1. ECDC expert opinion
on the efficacy, effectiveness and safety
of influenza neuraminidase inhibitors
Pasi Penttinen
Head of influenza and other respiratory viruses DP (acting)
Office of Chief Scientist, ECDC

2. Background
• Each year 10-15% of European population acquire
influenza. Complications such as pneumonia, hospitalizations
and deaths occur, mostly among the vulnerable.
• Neuraminidase inhibitors (NAIs; oseltamivir and zanamivir)
have been subject to much debate about the effectiveness
and cost-benefit ratio in preventing and treating influenza.
• Request was made in the ECDC Advisory Forum to assess
the evidence base for public health use of antivirals in
outbreak settings, specifically in nursing home outbreaks
(2013).
• EU Health Security Council requested a review of the
evidence from EC and ECDC (2014).
• ECDC convened an expert group to review new evidence
with the aim to develop an “ECDC Expert opinion” on the
evidence base for public health recommendations

4. Process – expert review and public
consultation
 Expert meeting held 10-11 February
– Agreement of interpretation of new reviews/ analyses
– Conclusions for public health recommendations
 11-20 February
– Drafting of ”expert opinion”
– Review with experts
 27 February
– Outcomes shared with EU Health security committee
 August – public consultation on ECDC website (1 month)+
 September – finalisation of Expert opinion+
*In addition, additional systematic reviews, RCTs and observational studies were considered, when appropriate
+ Estimated

5. Independent* experts consulted
Experts
Barbara Michiels
Kari S. Lankinen (EMA rapporteur-FI)
Regine Lehnert
Darina O’Flanagan
Anders Tegnell
Johan Giesecke
Peter Horby
John Watson
Angela Campbell
Frederick Hayden
Filip Josephson (EMA rapporteur-SE)
Observers
Manuela Mura –
European Medicines Agency
Nikki Shindo –
WHO Headquarters
Caroline Brown –
WHO Regional Office for Europe
Presenters External to Expert Group
(present on day one of meeting only)
Arnold Monto Jonathan Nguyen-Van-Tam
* Declarations of interest declared according to ECDC independence policy

6. Current recommendations for antivirals in
EU/EEA MS (VENICE)
 Currently 22 EU/EEA MS have recommendations on antiviral
use according to recent survey conducted by the VENICE
network. Antivirals are recommended
– in 22 MS in patients with severe or progressive influenza
requiring hospitalisation;
– in 14 MS in residents of long-term care facilities in case of
influenza outbreak.

7. 3.65 treatment courses/ 1000 inhabitants/ year

8. Evidence reviewed included meta-analyses of
RCTs and pooled observational studies
 The Cochrane Collaboration (2014) Intervention Review
‘Neuraminidase inhibitors for preventing and treating
influenza in adults and children’.
 The MUGAS (Multiparty Group for Advice on Science) group
published ‘Oseltamivir treatment for influenza in adults: a
meta-analysis of randomised controlled trials’ in 2015
 The PRIDE (Post-pandemic review of anti-influenza drug
effectiveness) Consortium investigators published
‘Effectiveness of neuraminidase inhibitors in reducing
mortality in patients admitted to hospital with influenza
A(H1N1)pdm09 virus infection: a meta-analysis of individual
participant data’ in 2014

9. Oseltamivir vs placebo for treatment.
Time to alleviation of first symptoms in adults
Source: Jefferson 2014 (COCHRANE)

10. Risk of lower respiratory tract symptoms
among oseltamir-treated groups vs placebo
Source: Dobson 2014 (MUGAS)

11. Survival by time to treatment (PRIDE study)

12. Preliminary Conclusions – as treatment NAI’s:
 Decrease time to alleviation of symptoms of uncomplicated
influenza-like illness in previously healthy adults by ~15 - 25
hours
 Results on effect on lower respiratory tract
infection/pneumonia or hospitalisation in healthy individuals
mixed. However, these trials were not designed and
powered to assess these outcomes
 Decrease mortality among hospitalised adult patients with
laboratory-confirmed/clinically confirmed influenza but not in
children <16 years in a large world-wide observational study
 In current studies the reasons for a more limited effect in
children is unknown

13. Preliminary Conclusions – as prophylaxis
NAI’s
 Reduce the individual and household risk of symptomatic
and laboratory-confirmed influenza infection in previously
healthy adults
 In out-patient settings and in institutions for long-term care,
reduce the risk of symptomatic and laboratory-confirmed
influenza in vulnerable individuals due to age, cardiovascular
disease, diabetes and immunosuppression

14. Preliminary Conclusions for public health
 No evidence was revealed to support a change to the
recommended use of NAIs in EU/EEA Member States.
However, further studies in children are needed.
 Recommendations to treat patients with severe influenza and
provide prophylaxis to the most vulnerable and their families
is supported by the expert opinion.
 This position is consistent with guidance from the World
Health Organization (WHO) and many national public health
organizations in Europe, North America, South East Asia,
Australia, Japan and New Zealand.
 There is room for improvement in efficacy and effectiveness
of the NAIs and several new antivirals are being tested alone
or in combination with one of the authorised NAIs in on-
going RCTs.