The University of Nottingham

Practical issues related to pandemic deployment of antivirals

Jonathan Van-Tam, MBE, DM, FFPH, FRIPH, Professor of Health Protection

Maiden Castle, Dorset, 450 BC

Layered defence offers greatest chance of overall protective effect

Pre-pandemic vaccine?

Antivirals

AntibioticsPublic Health

Measures Pandemic

Vaccine

The University of Nottingham

Public health purpose of antiviral use

• Protection of HCWs

• Protection of workers within CNI

• Population level usage

• Can priority groups be identified in advance?

• Would priority groups be ethically and publicly acceptable?

Desired clinical or epidemiological endpoint alters strategy chosen

Use Desired outcomes

Treatment Reduction in severity/duration

Reduction in transmission

Reduction in complications

Reduction in hospitalization

Reduction in death

ProphylaxisProtection from symptomatic infection; reduction in secondary cases

Duration of illness:Influenza-infected patients, n=475

Nicholson et al. Lancet 2000; 355: 1845-50.

0

20

40

60

80

100

120

140

116.5

Med

ian D

ura

tion o

f ill

ness

(h

)

Placebo 75 mg 150 mg

n=161 n=158 n=156

87.4 81.8

29.1 h 34.7 h

p=0.02 for placebo vs oseltamivir 75 mgp=0.01 for placebo vs oseltamivir 150 mg

Severity of illness:Influenza-infected patients, n=475

Nicholson et al. Lancet 2000; 355: 1845-50.

0

200

400

600

800

1000943

Med

ian T

ota

l S

ym

pto

m S

core

(A

UC

)

Placebo 75 mg 150 mg

n=161 n=158 n=156

773709

18% 25%

p<0.01 for placebo vs oseltamivir 75 mgp<0.003 for placebo vs oseltamivir 150 mg

0

1

2

3

4

Overall Healthy At risk

Kaiser et al. Arch Intern Med 2003;163:1667–72

*p<0.001 vs placebo**p<0.05 vs placeboLRT=lower respiratory tract

Early oral oseltamivir for influenza (adults)Effect on antibiotic use and hospitalizations (meta-analysis; n=3564)

0

5

10

15

All Bronchitis Pneumonia

LRT complicationsleading to use of antibiotics

Pat

ient

s (%

)

*

55%

52%

61%

Placebo Oseltamivir

All hospitalizations

59%

62%

50%

*

**

Early oral oseltamivir for influenza (children)Effect on antibiotic use and complications (n=252)

Whitley et al. Pediatr Infect Dis J 2001;20:127–33*p<0.05**p<0.01 vs placebo

50

40

30

20

10

0Complications Otitis media Antibiotics

Pat

ient

s (%

)

placebo

oseltamivir

40%

44%

24%

*

**

Cohort studies: Improved outcomes with oseltamivir

• Bowles et al. J Am Geriatr Soc. 2002;50:608-16 – Reduction in complications/hospitalization in treated nursing

home residents

• Nordstrom et al. Curr Med Res Opin. 2005;21:761-8 – 26% reduction in hospitalization in patients with ILI treated with

oseltamivir

• McGeer et al. Clin Infect Dis. 2007;45:1568-75– 70% reduction in mortality in hospitalized adults

• Lee et al. Antivir Therapy. 2007; 12:501-8– Shorter length of stay in hospitalized adults treated early

• Barr et al. Curr Med Res Opin. 2007;23:523-31– 50% reduction in pneumonia in treated children

Prevention of influenza in long term carezanamivir 10mg (2 puffs) o.d. in outbreak

Placebo

N=249

Zanamivir

N=240

Efficacy

Lab-confirmed ILI 14 (6%) 4 (2%) 65% (.05)

Lab confirmed, any symptoms

23 (9%) 15 (6%) 29% (NS)

Withdrawal for AE 6 (2.5%) 2 (0.8%)

Ambrozaitis JADA 2005;6:367

Earliest treatment is associated with maximum clinical benefit (open-label; n=1426)

-4

-3

-2

-1

0

Reduction of Illness Duration (Days) Compared With Intervention at 48 h

Time From Symptom Onset to Treatment (h)

Modelled time to treatment P < 0.0001.

––3.1 d3.1 d ––1.2 d1.2 d––2.2 d2.2 d

12 24 36

––3.8 d3.8 d

0

Aoki et al Journal of Antimicrobial Chemotherapy 2003: 51:123-129

Operational framework for delivery: stockpiling

• Secure storage, yet compatible with rapid delivery (local/regional equity in distribution)

• Seasonal use too low to allow storage within community seasonal supply chain (true pandemic stockpile)

• Choice of agents (licensed indications e.g. age, propensity for resistance, ease of use by patient, pack size in storage)

• Choice of formulations (capsules in different sizes, diskhalers, suspension, dry active)

• Timing of procurement – timing of replacement/rejuvenation

Global usage of oseltamivir across influenza seasons

* Influenza season reflected as 12 months of data (Sept –Aug)

Stockpiling options (oseltamivir)

• 30, 45 and 75 mg capsules– Long shelf-life– Flexibility with dosing possible

• Pediatric Oral Suspension– Short shelf-life

• Active Pharmaceutical Ingredient (API)– Needs preparation – time; expertise;

equipment

Management of expiry of oseltamivir government stockpiles • Oseltamivir has an approved shelf life of 5 years in most

markets • Recent extension to 7 years in US; similar data filed

elsewhere

• Internal longer term stability data and governments can choose to extend the shelf life of their stockpiles, based on these data

• Roche is developing a method for extracting the active ingredient from expiring capsules for reprocessing into new capsules, thus ‘re-setting’ the clock on existing procurement

Operational framework for delivery: distribution

• Defined access points (general practices, community pharmacies)

Other options include:

• Telephone diagnosis and remote prescribing

• Influenza Tx centres?

• Home visiting teams?

• Pre-issue?

• Operational research/simulations may be needed to determine throughput and most efficient approach

Operational framework for delivery: usage

• Timing of release from stockpile into HC system

• Equitable distribution by locality and region (regional and local positioning of stockpiles)

• Familiarity of HCWs with drugs themselves (clinical recognition of treatment success/failure)

• Devolution of prescribing to professions allied to medicine (training and familiarity)

• GPs reserved for children and complicated cases

• Protocols/treatment guidance and ability to modify rapidly

• Patient consulting behaviour (e.g. Ross et al, Comm Dis Publ Health 2000;3:256-60)

The University of Nottingham

• Decision to stockpile neuraminidase inhibitor is central to an overall package of pandemic preparedness measures

• Ultimate benefit depends not only on choice of strategy but slickness/sophistication of execution

• Large number of practical issues that together require consideration to build an effective operational strategy

• As bad to procure antivirals and then fail in delivery, than to have none at all

Jonathan Van-Tam

Conclusions