2. Antiviral therapy the evidence base and clinical trials Theo Verheij

3. Conflict of interest disclosure I have the following, real or perceived direct or indirect conflicts of interest that relate to this presentation: Affiliation / financial interestNature of conflict / commercial company name Tobacco-industry and tobacco corporate affiliate related conflict of interest no Grants/research support (to myself, my institution or department): Grant for trial on the effects of pneumococcal vaccination (Pfizer) Honoraria or consultation fees:no Participation in a company sponsored bureau:no Stock shareholder:no Spouse/partner:yes * Other support or other potential conflict of interest:no * Why do you always have to work on a Saturday?

4. What to expect before lunch The trials on oseltamivir and their full results Conclusions New agents Where do we stand now?

5. Oseltamivir, the idea

6. Chronology 1993 discovery by Gilead 1996 patents bought by Roche 1999 licensed by FDA 2002 licensed by EMA

7. Patient characteristics in oseltamivir trials Influenza like illness and fever during an influenza epidemic Symptoms < 36 – 48 hours Immunocompetent Is some trials chronic diseases and pregnancy were exclusion criteria On average 67% of study subjects had a proven influenza infection Only blinded RCTs on which full reports were available are discussed here

8. The trials I Jefferson et al BMJ 2014

9. The trials II Jefferson et al BMJ 2014

10. MGAS was funded unconditionally by Roche, who was not involved in analyses and publishing Individual patient data analysis Only trials on treatment of adult patients Primary endpoint: duration until alleviation of symptoms (hours)

11. Dobson et al, Lancet 2015

12. Subgroup analyses Dobson et al, Lancet 2015

13. Effects on lower respiratory tract complications (reduction from 8,4 to 4,3%) Dobson et al, Lancet 2015

14. Effects on lower respiratory tract complications (reduction from 7,9 to 4,5%)

15. Effects on hospital admission (reduction from 2,2 to 0,7%)

16. Effects on hospital admission (reduction from 1,8% to 1,0%, not statistically significant)

17. Side effects

18. Effects and side effects in children Jefferson et al. BMJ 2014

19. Jefferson et al, BMJ 2014

20. Observational data from patients in hospital I Freemantle et al, BMJ 2014

21. Observational data from patients in hospital II Muthuri et al, Lancet Inf Dis 2014

22. Conclusions on effects of oseltamivir Reduction in number of hours with relevant symptoms of around 18 hours in adults and 8 hours in children Reduction in number of (mild) complications but absolute risks very small Observational studies suggest that oseltamivir reduces mortality, but there are methodological issues and no conclusions can yet be drawn Gives nausea in around 10% of users Low number of elderly and high risk patients in studies No cost-effectiveness studies Beneficial effects will be smaller in populations with lower influenza rates (so we need better diagnosis on site)

23. New antiviral drugs Nitazoxanide as an example Haffizula et al, Lancet Inf Dis 2014 Thiazolide that blocks maturation of viral haemagglutinine Side effects Intervention placebo Diarrhoea8%3% Vomiting4%1%

24. Where do we stand now? Modest effects on symptomatic influenza in outpatients Insufficient information on important subgroups: elderly, children and high-risk patients No information on cost-effectiveness Need for better point-of-care tests to detect influenza

25. Funded by the European Union Influenza like Illness? A rCt of Clinical and Cost effectiveness in primary CarE (ALIC 4 E ) Chris Butler, Theo Verheij, Alike van der Velden, Johanna Cook Venice 2015. Funded by the European Union

26. ALIC 4 E: aim and design Aim: 1.To assess cost effectiveness of oseltamivir and nitazoxanide in children, adults and elderly with influenza-like illness in primary care 2.To assess the diagnostic value of a new rapid influenza test Design: Adaptive open clinical trial in 20 EU countries among around 4800 study subjects Data collection October 2015- April 2018

27. MCQ 1 Oseltamivir has antiviral effects against a.Influenza A but not against Influenza B b.Influenza B but not against Influenza A c.All types of Influenza viruses, and effect size is more pronounced in elderly than in adults d.All Influenza strains, but effects size is more proncounced in adults than in elderly

28. MCQ 2 Observational studies suggest that oseltamivir reduce mortality in hospital a.In all types of patients b.In children and adults but not in elderly c.In pregnant women, children and elderly d.In all critical care patients

29. MCQ 3 The following statement on the side effects of oseltamivir is incorrect a.Diarrhoea is not a side effect of oseltamivir in children b.Adults on profylactic use of oseltamivir have a higher risk for headache c.Nausea and vomiting are side effects both in adults and children d.The incidence of neurological disorders in adults is not elevated by therapeutic use of oseltamivir