2. WHO Draft Rapid Response + Containment, May 2006

3. Projected Outbreak of H5N1 in Thailand Red = new cases. Green = areas where the epidemic has finished. Ferguson et al. Nature 437:209, 2005 R 0 = 1.5

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. http://www.nigms.nih.gov/news/releases/08032005.html Projected Outbreak of H5N1 Influenza in Thailand

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 (R 0 < 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 Frequency of resistance OseltamivirM2 inhibitor Out-patient adults Out-patient children 0.4% 5.5% ~30% Inpatient children 18% 80% Immunocompromised ?>33% 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 Antiviral (Study) No. Contacts (age) Reduction in 2° influenza illness Reduction in influenza infection Oseltamivir (Welliver et al, 2000) 955 (13+ yr) 89% 49% Oseltamivir* (Hayden et al, 2004) 792 (1+ yr) 73%35% (Index +) Zanamivir* (Hayden et al, 2000) 837 (5+ yr) 79% 62% Zanamivir (Monto et al, 2002) 1,291 (5+ yr) 82% 59% *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