Antiviral therapy the evidence base and clinical

trials

Theo Verheij

Conflict of interest disclosureI have the following, real or perceived direct or indirect conflicts of interest that relate to this presentation:

Affiliation / financial interest Nature 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?

What to expect before lunch

• The trials on oseltamivir and their full results

• Conclusions

• New agents

• Where do we stand now?

Oseltamivir, the idea

Chronology

• 1993 discovery by Gilead

• 1996 patents bought by Roche

• 1999 licensed by FDA

• 2002 licensed by EMA

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

The trials IJefferson et alBMJ 2014

The trials II Jefferson et alBMJ 2014

MGAS was funded unconditionally by Roche, who was not involved in analyses and publishing

Individual patient data analysisOnly trials on treatment of adult patients

Primary endpoint: duration until alleviation of symptoms (hours)

Dobson et al, Lancet 2015

Subgroup analyses Dobson et al, Lancet 2015

Effects on lower respiratory tract complications (reduction from 8,4 to 4,3%)

Dobson et al, Lancet 2015

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

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

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

Side effects

Effects and side effects in childrenJefferson et al. BMJ 2014

Jefferson et al, BMJ 2014

Observational data from patients in hospital IFreemantle et al, BMJ 2014

Observational data from patients in hospital IIMuthuri et al, Lancet Inf Dis 2014

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)

New antiviral drugsNitazoxanide as an exampleHaffizula et al, Lancet Inf Dis 2014

Thiazolide that blocks maturation of viral haemagglutinine

Side effects

Intervention placebo

Diarrhoea 8%3%

Vomiting 4%1%

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

Funded by the European Union

Influenza like Illness? A rCt of Clinical and Cost

effectiveness in primary CarE (ALIC4E)

Chris Butler, Theo Verheij, Alike van der Velden, Johanna Cook

Venice 2015.

Funded by the European Union

Funded by the European Union

ALIC4E: 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

MCQ 1

Oseltamivir has antiviral effects against

a. Influenza A but not against Influenza Bb. Influenza B but not against Influenza Ac. All types of Influenza viruses, and effect size is

more pronounced in elderly than in adultsd. All Influenza strains, but effects size is more

proncounced in adults than in elderly

MCQ 2

Observational studies suggest that oseltamivir reduce mortality in hospital

a. In all types of patientsb. In children and adults but not in elderlyc. In pregnant women, children and elderlyd. In all critical care patients

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