Title: Practical issues related to pandemic deployment of antivirals
1Practical issues related to pandemic deployment
of antivirals
Jonathan Van-Tam, MBE, DM, FFPH, FRIPH, Professor
of Health Protection
2Maiden Castle, Dorset, 450 BC
3Layered defence offers greatest chance of overall
protective effect
4Public 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?
5Desired 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
Prophylaxis Protection from symptomatic infection reduction in secondary cases
6Duration of illnessInfluenza-infected patients,
n475
p0.02 for placebo vs oseltamivir 75 mg p0.01
for placebo vs oseltamivir 150 mg
116.5
29.1 h
34.7 h
87.4
81.8
Median Duration of illness (h)
n161
n158
n156
Placebo
75 mg
150 mg
Nicholson et al. Lancet 2000 355 1845-50.
7Severity of illnessInfluenza-infected patients,
n475
943
18
25
773
709
Median Total Symptom Score (AUC)
n158
n156
n161
Placebo
75 mg
150 mg
plt0.01 for placebo vs oseltamivir 75 mg plt0.003
for placebo vs oseltamivir 150 mg
Nicholson et al. Lancet 2000 355 1845-50.
8Early oral oseltamivir for influenza
(adults)Effect on antibiotic use and
hospitalizations (meta-analysis n3564)
LRT complicationsleading to use of antibiotics
All hospitalizations
?50
?55
?52
?59
Patients ()
?62
?61
plt0.001 vs placebo plt0.05 vs placeboLRTlower
respiratory tract
Kaiser et al. Arch Intern Med 2003163166772
9Early inhaled zanamivir for influenzaeffect on
complications and antibiotic use
Respiratory events leading to antibiotics Placebo n 765 Zanamivir n 807 Risk Reduction ()
Any event 18 (2.4) 13 (1.6) 28
Upper respiratory 8 (1.0) 7 (0.8) 10
Lower respiratory Acute bronchitis Pneumonia 9 (1.2) 7 2 5 (0.65) 5 1 40
Hospitalizations
Kaiser L et al. Arch Intern Med.
20001603234-3240.
10Early oral oseltamivir for influenza
(children)Effect on antibiotic use and
complications (n252)
50 40 30 20 10 0
placebo oseltamivir
?24
?40
?44
Patients ()
Complications
Otitis media
Antibiotics
plt0.05plt0.01 vs placebo
Whitley et al. Pediatr Infect Dis J 20012012733
11Cohort studies Improved outcomes with
oseltamivir
- Bowles et al. J Am Geriatr Soc. 200250608-16
- Reduction in complications/hospitalization in
treated nursing home residents - Nordstrom et al. Curr Med Res Opin. 200521761-8
- 26 reduction in hospitalization in patients with
ILI treated with oseltamivir - McGeer et al. Clin Infect Dis. 2007451568-75
- 70 reduction in mortality in hospitalized adults
- Lee et al. Antivir Therapy. 2007 12501-8
- Shorter length of stay in hospitalized adults
treated early - Barr et al. Curr Med Res Opin. 200723523-31
- 50 reduction in pneumonia in treated children
12Prevention of influenza in long term
carezanamivir 10mg (2 puffs) o.d. in outbreak
Placebo N249 Zanamivir N240 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 20056367
13Earliest treatment is associated with maximum
clinical benefit (open-label n1426)
Time From Symptom Onset to Treatment (h)
12
24
36
0
1.2 d
2.2 d
3.1 d
3.8 d
Reduction of Illness Duration (Days) Compared
With Intervention at 48 h
Modelled time to treatment P lt 0.0001.
Aoki et al Journal of Antimicrobial Chemotherapy
2003 51123-129
14Operational 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
15Global usage of oseltamivir across influenza
seasons
Influenza season reflected as 12 months of data
(Sept Aug)
16Stockpiling 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
17Management 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
18Operational 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
19Operational 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 20003256-60)
20Conclusions
- 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