WHO Draft Rapid Response + Containment, May 2006

2. WHO Draft Rapid Response + Containment, May 2006

3. Projected Outbreak of H5N1 in Thailand R0 = 1.5 Red = new cases. Green = areas where the epidemic has finished. Ferguson et al. Nature 437:209, 2005

4. Left: uncontrolled outbreak. Red = new cases. Green = areas where the epidemic has finished. Above: Controlled outbreak. Red = areas of infection. Blue = areas where a combination of control measures implemented. Projected Outbreak of H5N1 Influenza in Thailand http://www.nigms.nih.gov/news/releases/08032005.html

5. Elimination of a pandemic virus at its source? • Ring chemoprophylaxis feasible if: • Geographically targeted in non-urban setting • Early intervention within 1-3 wks • Virus of low-moderate transmissibility (R0 < 1.8) • Chemoprophylaxis of 80 - 90% of population • High compliance • Movement restrictions; social distancing • Maximum of 1-3 million courses needed • 300,000 may be sufficient Ferguson et al. Nature 437:209, 2005

6. Rapid Response: Antiviral Deployment • Rapid use of antiviral prophylaxis is key component. • Mass targeted antiviral prophylaxis: • Goal of 90% coverage • Geographic radius of 5-10 km from each detected case OR • Administrative area of “at-risk” population of 10-50,000 • Multiple logistical hurdles • WHO donation of 3.0 M courses • 440 courses = 7.8 kg • 100,000 courses = 19 shipping pallets • Start dispensing within 12 hrs of receipt WHO Draft Rapid Response + Containment Document, May 2006

7. Antiviral Resistance in Influenza Viruses • M2 inhibitors: • Primary resistance in epidemic (>90% of recent H3N2) or pandemic virus possible; frequent with Rx • Confers cross-resistance to entire class • Resistant variants virulent and transmissible • NA inhibitors: • No primary resistance; active for all 9 NA types • Inhibitory for M2 resistant-variants • Variable NAI cross-resistance depending on type/subtype and drug • Most NAI resistance causes infectivity and virulence in animals NISN. Weekly Epi Record 33:306, 2004

8. Detection Of Antiviral Resistant Influenza During Treatment Roberts N. Phil Trans R Soc Lond 356:1895, 2001 Kiso et al. Lancet 364: 759, 2004

9. Pharyngeal Viral Loads during Oseltamivir Treatment of H5N1 de Jong et al. NEJM 353:25, 2005

10. Neuraminidase Inhibitor Treatment : Antiviral Resistance • Emergence of oseltamivir-resistant variants may be associated with prolonged viral detection in A/H3N2-infected children and in H5N1-infected patients. • Resistance due to H274Y mutation may compromise clinical efficacy in some H5N1 patients. • No transmission of oseltamivir-resistant variants detected in house-hold based studies or in prophylaxis failures to date. • Some resistant variants are transmissible in ferret model (including H274Y mutation in N1)

11. Influenza Prevention In Households: PEP *Index case given treatment

12. Interval from PEP Initiation to Secondary Illness Onset in Household Contacts (N = 1,291) Note: zanamivir PEP started < 36 hr of index illness onset Monto et al. JID 186:1582, 2002

13. Influenza Post-exposure Prophylaxis (PEP) with Neuraminidase Inhibitors: Summary • Socially targeted antiviral prophylaxis (PEP) is highly effective in protecting contacts in households during seasonal influenza. • Reductions in illness > infection. • Secondary cases occur early, often in first few days after index case recognition. • Rapid initiation is essential. • Inhaled zanamivir is also effective for prevention. • Unstudied in human H5N1 infections to date.

14. Rapid Response: Antiviral Deployment • Mass targeted antiviral prophylaxis: • Goal of 90% coverage • Geographic radius of 5-10 km from each detected case OR • Administrative area of “at-risk” population of 10-50,000 • Minimal duration of 10 days • Multiple logistical hurdles • 100,000 courses = 19 shipping pallets • Start dispensing within 12 hrs of receipt WHO Draft Rapid Response + Containment Document, May 2006