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

4. 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?

5. Desired clinical or epidemiological endpoint alters strategy chosen UseDesired 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

6. Duration of illness: Influenza-infected patients, n=475 Nicholson et al. Lancet 2000; 355: 1845-50. 116.5 Median Duration of illness (h) Placebo75 mg150 mg n=161n=158n=156 87.4 81.8 29.1 h 34.7 h p=0.02 for placebo vs oseltamivir 75 mg p=0.01 for placebo vs oseltamivir 150 mg

7. Severity of illness: Influenza-infected patients, n=475 Nicholson et al. Lancet 2000; 355: 1845-50. 943 Median Total Symptom Score (AUC) Placebo75 mg150 mg n=161 n=158n=156 773 709 18% 25% p<0.01 for placebo vs oseltamivir 75 mg p<0.003 for placebo vs oseltamivir 150 mg

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

9. Kaiser L et al. Arch Intern Med. 2000;160:3234-3240. Early inhaled zanamivir for influenza: effect on complications and antibiotic use Respiratory events leading to antibiotics Placebo n = 765 Zanamivir n = 807 Risk Reduction (%) Any event18 (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

10. 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 0 ComplicationsOtitis mediaAntibiotics Patients (%) placebo oseltamivir  40%  44%  24% * **

11. 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

12. Prevention of influenza in long term care zanamivir 10mg (2 puffs) o.d. in outbreak Placebo N=249 Zanamivir N=240 Efficacy Lab-confirmed ILI14 (6%)4 (2%)65% (.05) Lab confirmed, any symptoms 23 (9%)15 (6%)29% (NS) Withdrawal for AE6 (2.5%)2 (0.8%) Ambrozaitis JADA 2005;6:367

13. Earliest treatment is associated with maximum clinical benefit (open-label; n=1426) 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 d –1.2 d –2.2 d 1224 36 –3.8 d 0 Aoki et al Journal of Antimicrobial Chemotherapy 2003: 51:123-129

14. 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

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

16. 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

17. 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

18. 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

19. 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)

20. 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