Practical issues related to pandemic deployment of antivirals

1
Practical issues related to pandemic deployment
of antivirals
Jonathan Van-Tam, MBE, DM, FFPH, FRIPH, Professor
of Health Protection
2
Maiden Castle, Dorset, 450 BC
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Layered defence offers greatest chance of overall
protective effect
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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?

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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
Prophylaxis Protection from symptomatic infection reduction in secondary cases
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Duration 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.
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Severity 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.
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Early 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
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Early 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.
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Early 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
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Cohort 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

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Prevention 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
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Earliest 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
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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

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Global usage of oseltamivir across influenza
seasons
Influenza season reflected as 12 months of data
(Sept Aug)
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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

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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

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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

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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 20003256-60)

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Conclusions

• 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