WHO Draft Rapid Response + Containment, May 2006

Projected Outbreak of H5N1 in Thailand

Red = new cases. Green = areas where the epidemic has finished.

Ferguson et al. Nature 437:209, 2005

R0 = 1.5

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

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

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

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

Detection Of Antiviral Resistant Influenza During Treatment

Frequency of resistance

Oseltamivir M2 inhibitor

Out-patient adults

Out-patient children

0.4%

5.5%

~30%

~30%

Inpatient children 18% 80%

Immunocompromised

? >33%

Roberts N. Phil Trans R Soc Lond 356:1895, 2001

Kiso et al. Lancet 364: 759, 2004

Pharyngeal Viral Loads during Oseltamivir Treatment of H5N1

de Jong et al. NEJM 353:25, 2005

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)

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

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

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.

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