1. Pandemic Influenza Antiviral Strategies and Priority Groups Andrew T. Pavia M.D. University of Utah

2. Outline • Process • Principles, Key Data, Assumptions • Working Group Recommendations • Optimal size and minimal size • Drugs of choice • Priority Groups and Strategies for Limited Supply • International containment • Critical research issues

3. Working Group Process • Meeting April 19-20, 2005 • Construction of “Straw Man” proposal • Conference Call with Wisconsin DOH • Conference Call May 24, 2005 • Joint meeting in Atlanta June 15-16, 2005 • Coordination with Vaccine working sub-group

4. Presentations – June 15, 16 Meeting • Goals • Estimates of pandemic influenza impact • Impact of annual and pandemic flu in different age and risk groups • Impact of pandemic influenza on the healthcare system and options for prioritizing among healthcare workers • Definition of critical infrastructure and possible prioritization of infrastructure support groups

5. Presentations – June 15, 16 Meeting • Ethical considerations • Impacts of oseltamivir in a mouse model of H5N1 infection • Mathematical modeling of strategies to contain an influenza outbreak and prevent pandemic spread • CDC antiviral planning activities • Implementation of an antiviral response at the State level.

6. Principles of Antiviral Drug Use - 1 • Primary goal of response is to decrease pandemic health impacts (social secondary; economic tertiary) • Given the uncertainties about antiviral drug use and supply, strategies must be flexible, and must be re-addressed as a pandemic unfolds • National guidelines provide guidance and achieve consistency. However, State and local health departments should have flexibility to meet local needs

7. Principles of Antiviral Drug Use - 2 • Delivery of antiviral drugs should be equitable within target populations and not constrained by ability to pay • Antiviral drug use strategies must be • Feasible to implement • Acceptable to the public • Transparent

8. Key Data • Treatment with a NA inhibitor within 48 hours decreases lower respiratory complications and hospitalizations (RCT data). In BM transplant recipients and NH residents it can reduce mortality (uncontrolled observational studies) • Earlier treatment has a greater impact • Most isolates from SE Asia are resistant to M2 inhibitors. When used as treatment, they will result in shedding of resistant, virulent virus • Mouse studies with H5N1 suggest shedding and replication are at higher levels and last longer • ? need for longer treatment

9. Assumptions - 1 • Priority groups must be designated because the amount of antiviral drug available is likely to be less than the demand. • Antiviral drug use will prevent or treat infection in the recipient but will have little impact on the course of the pandemic • Given the supplies will be limited, strategies that require less drug and yield greater health impact per course are preferred

10. Assumptions - 2 • Military needs are a priority – but we assume that a separate stockpile will be established • We assume attack rate of 35%; 75% will present within 48 hours for treatment • Prophylaxis course estimated at 40 days; equivalent to 4 treatment courses • Optimal dosing and duration for H5N1 could change • Distribution to states and Tribal governments will be pro rata from SNS. A small reserve will be held back for outbreak response

11. Recommendations -1 • Sufficient antiviral drugs should be stockpiled to support a robust response because of the key role that antiviral drugs can play in reducing health impact. • 133 million courses would provide drug to treat all who are infected and support prophylaxis of health care workers and highest risk patients • 40 million courses is the minimum that would support critical pandemic responses

12. Recommendations - 2 • Oseltamivir should be the primary drug stockpiled. • Zanamavir should also be included because it is effective against most oseltamivir resistant viruses and to support ongoing production and protect against disruption of supply • M2 inhibitors, beyond the 5 million courses currently in the SNS should not be stockpiled due to the likelihood of resistance

13. Hospitalized patients with influenza HCWs and EMS workers with direct patient contact Highest risk outpatients Pandemic health responders, public safety & key government decision makers Other high risk outpatients Outbreak response (eg PEP in nursing homes) Prophylaxis HCWs in ER, ICU, EMS, dialysis Pandemic societal responders & other HCWs Other outpatients Prophylaxis for highest risk outpatients Prophylaxis for other HCWs w/ patient contact Recommendations - 3 Priority groups

14. Proposed Priority Target Groups

15. Size of Priority Groups and Cumulative Need

16. Recommendations - 4 • Use of antivirals as part of an international response to contain an outbreak and prevent or delay a pandemic is recommended if the following conditions are met: • International guidelines are developed • Field exercises in the country suggest an ability to effectively respond and contain the spread • Other countries with antiviral stockpiles contribute to the effort

17. Recommendations - 5 • Critical research should be conducted to support optimal use of antivirals, including: • Impact of treatment at hospital admission on outcomes • Optimal treatment dose and schedule in a ferret model with H5N1 and other strains • Sensitivity of rapid diagnostic tests for H5N1 and other strains with pandemic potential • Safety and pharmacokinetics of oseltamivir among infants <1 year old • Investigation of the impact of other agents

18. Ongoing issues • Only the first 2 of these 4 steps were addressed in the charge to the subgroup: • Stockpile purchase • Priority allocation • Distribution • Dispensing • Ongoing work is needed to further refine definition of target groups and to refine estimates of the population size