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

3. Pre-pandemic vaccine? Layered defence offers greatest chance of overall protective effect Antivirals Antibiotics Public Health Measures Pandemic Vaccine

4. 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?

5. Desired clinical or epidemiological endpoint alters strategy chosen

6. Duration of illness:Influenza-infected patients, n=475 p=0.02 for placebo vsoseltamivir 75 mg p=0.01 for placebo vsoseltamivir 150 mg 116.5 29.1 h 34.7 h 87.4 81.8 Median Duration of illness (h) n=161 n=158 n=156 Placebo 75 mg 150 mg Nicholson et al. Lancet 2000; 355: 1845-50.

7. Severity of illness:Influenza-infected patients, n=475 943 18% 25% 773 709 Median Total Symptom Score (AUC) n=158 n=156 n=161 Placebo 75 mg 150 mg p<0.01 for placebo vs oseltamivir 75 mg p<0.003 for placebo vs oseltamivir 150 mg Nicholson et al. Lancet 2000; 355: 1845-50.

8. Early oral oseltamivir for influenza (adults)Effect on antibiotic use and hospitalizations (meta-analysis; n=3564) Placebo Oseltamivir LRT complicationsleading to use of antibiotics All hospitalizations 50% 55% 52% 59% Patients (%) 62% * * 61% ** *p<0.001 vs placebo **p<0.05 vs placeboLRT=lower respiratory tract Kaiser et al. Arch Intern Med 2003;163:1667–72

9. Early oral oseltamivir for influenza (children)Effect on antibiotic use and complications (n=252) 50 40 30 20 10 0 placebo oseltamivir 24% 40% * 44% Patients (%) ** Complications Otitis media Antibiotics *p<0.05**p<0.01 vs placebo Whitley et al. Pediatr Infect Dis J 2001;20:127–33

10. 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

11. Prevention of influenza in long term carezanamivir 10mg (2 puffs) o.d. in outbreak Ambrozaitis JADA 2005;6:367

12. Earliest treatment is associated with maximum clinical benefit (open-label; n=1426) Time From Symptom Onset to Treatment (h) 12 24 0 36 –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 < 0.0001. Aoki et al Journal of Antimicrobial Chemotherapy 2003: 51:123-129

13. 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

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

15. 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

16. 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

17. 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

18. 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)

19. 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