One Flu Over the Cuckoo’s

Nest: Oseltamivir and

zanamivir in H5N1 avian flu
Wesley Tong
Outline
z Should we care?
z Influenza and the virus
z Avian flu
z Neuraminidase Inhibitors (NIs)
z Pandemic Planning
z Just over the horizon
Why Bother?
z H1N1; 1918-1920 = 20-50 million
z H2N2; 1957-1958 = 1 million
z H3N2 ; 1968 = 800,000 in 6 wks
Progression of H5N1 in the world

World Health Organization: http://gamapserver.who.int/mapLibrary/

Progression of H5N1 in the world

World Health Organization: http://gamapserver.who.int/mapLibrary/

Influenza Basics
What is Influenza: Clinically
z Not easy to diagnose influenza infections
z Share similar symptoms with other viruses
z symptoms can depend on subtype
z Can only determine influenza if it’s present in
the community
 What is Influenza: Clinically

Patients with ILI < 36 hours

Influenza in community Probably not influenza

YES
YES
Coughing purulent sputum Bacterial pneumonia
NO

< 65 yrs; no immunosuppression >65 with risk factors for flu

Vaccinated against flu Vaccinated and unvaccinated

YES NO
Probably not antiviral
influenza

Adapted from: Stiver, 2003

The Biology
z Influenza belongs to orthomyxovirus group of
RNA virus
z Three types (A,B and C)
z Virus capsid has two major antigenic proteins
z Haemagglutinin (HA)
z Neuraminidase (NA)
Influenza A Nomenclature
z 16 different HA subtypes
z 9 different NA subtypes

H5 N1

Haemagglutinin subtype 5 Neuraminidase subtype 1

Inside the Flu

Haemagglutinin

Viral RNA

M2

Neuraminidase
Adapted from: McClellan & Perry, 2001
Role of the Major Proteins
z Haemagglutinin
z Mediates attachment of virus to epithelial cells
z M2
z Permits H+ ions to enter
z Necessary for viral uncoating
z Neuraminidase
z Allows new viruses to detach from host cell
z Cleaves α-ketosidic bond in neuraminic acid
 Mechanism of Infection
Entrapment
in secretions

internalization liberation
binding
Synthesis of
uncoating viral protein

Assembly
& budding

Synthesis of viral RNA

Neuraminic acid
Adapted from: Gubareva et al, 2000
Avian Flu
Avian flu: It’s for the bird
z Is not just one specific type
z Wild birds natural hosts for all known
subtypes of Influenza A
z Typically don’t get sick
z Domestic birds do
Avian Flu in Humans
z Antigenic drift vs. Antigenic shift
z Drift: small gradual change in HA and NA
z Shift: rapid, major change to produce novel subtype in
humans
z Antigenic shifts can occur through:
z Direct animal-human transmission
z Human and animal influenza A mixing
How do we get a pandemic

z
The War on Flu
z Influenza shots as prophylaxis
z Antivirals
z Two groups
z M2 inhibitors (amantadine & rimantadine)
z Neuraminidase Inhibitors (oseltamivir & zanamivir)
Types of NI’s
Oseltamivir Zanamivir

Roche Pharmaceutical GlaxoSmithKline

75 mg po b.i.d 10 mg po inhalation bid

t1/2: 6-10h t1/2: 4.15-5.05h

90% oral bioavailability 1-5% oral bioavailability

Clinical Trials: Oseltamivir
z 2 double blind, placebo-controlled RCTs
z 1 open label study
z Almost 4000 patients
z Reduction of symptom duration: 1.7 days
z Normal activity resumed 2.4 days faster
Clinical Trials: Zanamivir
z 7 double-blind, placebo-controlled
randomized clinical trials
z Over 2500 patients
z Reduction of symptom duration: 1.72 days
z Normal activity resumed 2.1 days faster
Why two?
z Both are equally potent
z But most recommend oseltamivir
z Why?
z Lower serum levels and oral bioavailability
z Lack of H5N1 data
z Inhaled might be problematic for some
 Mechanism of NIs

z Recall:
Entrapment
in secretions

internalization liberation
binding
Synthesis of
uncoating viral protein

Assembly
& budding

Synthesis of viral RNA

Neuraminic acid
Mechanism of NIs

z Inhibits Neuraminidase enzyme

z Prevents release of virons
z Promotes clumping

Before After
Resistance Is Futile?
z Currently no naturally occurring resistance
z In clinical samples:
z Resistance seen in 0.33% of adults/teens
ƒ 4.0% of children

z When resistant mutants arise, they are

biologically impaired
Planning For the Worst
NIs and Pandemic Flu
Planning
z NIs are a major part of current pandemic
plans
z Involves stockpiling antivirals
z 25% of population for 4 weeks
z Canada has 35 million capsules of
Oseltamivir
z 5 million on order
The Cost of War
z Ontario Formulary Price: $3.9 / capsule
z 40 million capsules = $156 million

z Single treatment requires 10 capsules

z Cost per event = $39
z 40 million capsules = 12% of population
Race Against Time
z Peramivir (Johnson and Johnson)
z Oral Neuraminidase inhibitor
z Currently in Phase III trials
z Promising bench data

Inhibitor IC50 (nmol/L)

Zanamivir 0.5-2.5

Oseltamivir 0.3-1.0
Peramivir 0.2-1.4
Summary
z Living on borrowed time
z Not many preventative measures to take
z Get Flu Shot
z Basic hygiene
z Stay home if you’re sick
z Heavily dependent on NIs
z Priority for high risk and essential individuals
References
1. Ohuchi M, Asaoka N, Sakai T, Ohuchi R (2006). Roles of neuraminidase in the initial stage of
influenza virus infection. Microbes and Infection. 8: 1287-1293
2. Schmidth AC (2004). Antiviral therapy for influenza: a clinical and economic comparative review.
Drugs. 64: 2031-2046
3. Ward P, Small I, Smith J, Suter P, Dutkowski R (2005). Oseltamivir (Tamiflu®) and its potential for
use in the event of an influenza pandemic. Journal of Antimicrobial Chemotherapy. 55: Suppl. S1, i5-
i21
4. McNicholl IR, McNicholl J (2001). Neuraminidase Inhibitors: Zanamivir and Oseltamivir. The
Annals of Pharmacotherapy. 35: 57-70
5. Calfee DP, Hayden FG (1998). New Approaches to Influenza Chemotherapy: Neuraminidase
Inhibitors. Drugs. 56: 537-553
6. Stiver, G (2003). The treatment of influenza with antiviral drugs. Canadian Medical Association
Journal. 168: 59-57
7. Gubareva LV, Kaiser L, Hayden FG (2000). Influenza virus neuraminidase inhibitors. The Lancet.
355: 827-835
8. Wong SSY, Yuen KY (2006). Avian Influenza Virus Infections in Humans. Chest. 129: 156-168
9. Public Health Agency of Canada. The role of vaccines and antivirals in controlling and preventing
influenza. February 2006
References
10. GlaxoSmithKline. Relenza® Product Monograph. Last Updated June 23, 2006
11. Hoffmann – La Roche. Tamiflu ® Product Monograph. Last Updated January 27, 2006
12. Centers for Disease Control and Prevention. Avian Influenza (Bird Flu). November 18, 2005
13. McClellan K, Perry CM (2001). Oseltamivir: A review of its use in influenza. Drugs. 61: 263-283