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Scientific Planning Committee

Scientific Planning Committee. Program Support. This program is endorsed by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) Unrestricted educational grant support was provided by Gilead Sciences GlaxoSmithKline Roche Labs

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Scientific Planning Committee

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  1. Scientific Planning Committee

  2. Program Support • This program is endorsed by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) • Unrestricted educational grant support was provided by • Gilead Sciences • GlaxoSmithKline • Roche Labs • MedImmune • Sanofi Pasteur • Biota Holdings • BioCryst Pharmaceuticals

  3. A Note on CME Credit • This slide kit is an accompaniment to the printed monograph, and is not certified for CME credit • CME credit can be earned only by reading the monograph, answering the posttest questions with a minimum passing grade of 70%, and completing the evaluation form

  4. Seasonal and Pandemic Influenza Background

  5. Influenza A Virus Hemagglutinin (H)–16 subtypes(attachment, penetration) Neuraminidase (NA)–9 subtypes(release) 8 viral genes(assembly, replication) M2 protein(penetration)

  6. Influenza: Antigenic Drift and Shift Hemagglutinin Neuraminidase Drift Shift Influenza Virus

  7. Past Antigenic Shifts

  8. The Influenza Pandemic of 1918-1919 • 25%-30% of world’s population (~500 million people) fell ill • >40 million deaths worldwide; ~60% in people ages 20-45 • >500,000 deaths in United States; 196,000 in October, 1918 alone Heinig R. The Flu Pandemic. New York Times Magazine. November 29, 1992.

  9. SeasonalInfluenzaPreparedness PandemicInfluenzaPreparedness

  10. Seasonal Influenza Countermeasures Vaccines and Prevention

  11. US Seasonal Influenza VaccineProduction and Use Data from US National Vaccine Program Office

  12. Influenza Is the Leading Cause of US Vaccine-Preventable Disease Deaths VPD Cases & Deaths, US 1989-1998 CDC. MMWR. 2006;55;511-515. Thompson W et al. JAMA. 2003;289:179-186. Felkin D et al. Am J Public Health. 2000;90:223-229.

  13. Epidemic Influenza Has a Substantial Impact *Average respiratory & circulatory = 294,000 (1979-80 through 2000-01) †Average all cause (1976-77 through 1998-99) ‡Average all cause (1990-91 through 1998-99) Adapted from CDC. MMWR Recomm Rep. 2005;54 (RR-8):1-40. Thompson W et al. JAMA. 2003;289:179-186. Thompson W et al. JAMA. 2004;292:1333-1340. Adams P et al. Vital Health Stat. 1999;10:1-203.

  14. Influenza-Associated Deathsby Age Group, 1976-1999 120 98.3 100 80 Respiratory & Circulatory Deaths Per 100,000 Person Years 60 40 20 7.5 0.6 0.4 0.5 0 <1 y 1 - 4 y 5 - 49 y 50 - 64 y 65+ y Age Group Adapted from Thompson W et al. JAMA. 2003;289:179-186.

  15. Influenza Vaccines A Trivalent Defense TypeAH1N1 TypeAH3N2 InfluenzaProtection Type B CDC. MMWR Recomm Rep. 2005;54(RR-8):1-40.

  16. Trivalent Inactivated and Live Attenuated Influenza Virus Vaccines CDC. MMWR Recomm Rep. 2005;54(RR-8):1-40.

  17. Outcome Measures • Vaccine Efficacy • Reduction in illness incidence in the treated compared to the control groups • Absolute Risk (AR) • Number of events (good or bad) in treated (ART) or control (ARC) groups, divided by the number of people in that group • Relative Risk (RR) • RR = ART / ARC • Relative Risk Reduction (RRR) • RRR = 1 - RR • RRR = (ARC-ART) / ARC • Vaccine Effectiveness • Vaccine Effectiveness = (1 - RR) x 100 ARC • Values expressed as %, often followed by 95% confidence interval

  18. Influenza Vaccine EfficacyChildren: Meta Analyses 1. Jefferson T et al. Lancet. 2005;365:773-780. 2. Negri E et al. Vaccine. 2005;23:2851-2861.

  19. Influenza Vaccine Effectiveness Elderly Ohmit S et al. J Am Geriatr Soc. 1999;47:165-171.

  20. Influenza Vaccine EfficacyHealthy Adults: Meta Analyses Demicheli V et al. Cochrane Database Syst Rev. 2004;(3):CD001269.

  21. Effectiveness of Influenza Vaccinationby Risk Groups ARD = acute respiratory disease, CVD = cardiovascular disease Hak E et al. Arch Intern Med. 2005;165:274-280.

  22. Influenza Vaccine OutcomesCommunity Dwelling Elderly: Two Meta Analyses Vu T et al. Vaccine. 2002;20:1831-1836. Jefferson T et al. Lancet. 2005;366:1165-1174.

  23. Influenza Vaccine EfficacyLTCF Elderly: Two Meta Analyses LTCF = long-term care facility Gross P et al. Ann Intern Med. 1995;123:518-527. Jefferson T et al. Lancet. 2005;366:1165-1174.

  24. Influenza and Pneumococcal Vaccination Rates Remain Low 2010 Goal Percent Vaccinated CDC. MMWR. 2005;54:1-40. http://www.cdc.gov/flu/professionals/vaccination/coveragelevels.htm.

  25. High Priority for Vaccination 2006-2007Advisory Committee on Immunization Practices (ACIP) • Persons at high risk for influenza-related complications and severe disease, including • Children aged 6–59 months • Pregnant women • Persons aged 50 years • Persons of any age with certain chronic medical conditions • Persons who live with or care for persons at high risk, including • Household contacts who have frequent contact with persons at high risk and who can transmit influenza to those persons at high risk • Health care workers CDC. MMWR. 2006;55:1-41.

  26. Seasonal Influenza Vaccines and Prevention: Summary • Influenza remains the leading cause of vaccine preventable adult mortality • Seasonal influenza is associated with substantial morbidity and mortality in all age groups • Current trivalent inactivated and live attenuated vaccines are safe and effective for children, adults, and elders • Influenza vaccines are cost saving or cost effective in children, working adults, and elders • Influenza and pneumonia vaccine coverage is far below societal goals

  27. Seasonal Influenza Countermeasures Prophylaxis and Treatment

  28. Seasonal Influenza Prophylaxis and Treatment • Antiviral therapies for influenza • Oseltamivir data overview • Zanamivir data overview • Influenza in children • Influenza in other special populations

  29. Antiviral Therapies for Influenza Neuraminidase (NA) • NA Inhibitors • Oseltamivir • Zanamivir Matrix protein (M2 ) • M2 Inhibitors • Amantadine • Rimantadine

  30. Antiviral Chemoprophylaxis of Influenza 1. Monto A et al. JAMA. 1999;282:31. 2. Hayden F et al. N Engl J Med. 1999; 341:1336. 3. Hayden F et al. N Engl J Med. 2000;343:12882. 4. Gravenstein S et al. J Am Med Dir Assoc. 2005;6:359. 5. Peters P et al. J Am Gerontol Soc. 2001;404:1025.

  31. Approved Antiviral Agents for Influenza Treatment and Prophylaxis *CDC recommends that the previously approved M2 inhibitors amantadine (Symmetrel) and rimantadine (Flumadine) not be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006). Treanor J. Influenza Virus. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious diseases. 6th ed. New York: Elsevier/Churchill Livingstone; 2005:2072. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01341.html.

  32. Recommended Daily DosageTreatment and Prophylaxis of Influenza A and B *Zanamivir approved for treatment in children >7 years, for prophylaxis in children >5 years CDC recommends that the previously approved M2 inhibitors amantadine (Symmetrel) and rimantadine (Flumadine) not be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006). http://www.cdc.gov/flu/professionals/antiviralback.htm#table1

  33. Oseltamivir: Resolution of All Flu SymptomsIntent to Treat and Laboratory Documented Influenza Groups Difference = 32 hours* Difference = 21 hours† *P < .001 †P = .004 Treanor J et al. JAMA. 2000;283:1016-1024.

  34. Oseltamivir TreatmentCombined RCT Database, Confirmed Influenza *P = .02; †P < .001 Kaiser L et al. Arch Intern Med. 2003;163:1667.

  35. Oseltamivir ResistanceEmergence During Treatment Kaiser L et al. Arch Intern Med. 2003;163:1667-1672. Whitley R et al. Pediatr Infect Dis J. 2001;20:127-133. Kiso M et al. Lancet. 2004;364:759-765.

  36. Oseltamivir: Time to Return to NormalImportant Quality of Life Assessments Health Status Activity Level 12 Difference = 1.9 days* Difference = 2.8 days† 10 8 Days 6 4 2 0 Placebo(n = 129) Oseltamivir75 mg BID(n = 124) Placebo(n = 129) Oseltamivir75 mg BID(n = 124) *P < .001 †P = .02 Treanor J et al. JAMA. 2000;283:1016-1024.

  37. Zanamivir Resistance • Resistance not recorded in results from clinical trials1, 2, 3 • The only zanamivir-resistant mutant identified was in a virus from an immunocompromised child4 • Particular binding mechanisms may account for low levels of resistance to zanamivir5, 6 • Particular mutants are resistant to zanamivir in vitro7, 8 1. Monto A et al. Antimicrob Agents Chemother. 2006;50:2395-2402. 2. Ambrozaitis A et al. J Am Med Dir Assoc. 2005;6:367-374. 3. Herlocher M et al. J Infect Dis. 2003;188:1355-1361. 4. Gubareva L et al. J Infect Dis. 1998;178:1257-1262. 5. Moscona A. N Engl J Med. 2005;353:2633-2636. 6. Gupta R and Nguyen-Van-Tam J. N Engl J Med. 2006;354:1423-1424. 7. Yen H et al. Antimicrob Agents Chemother. 2005;49:4075-4084. 8. Mishin V et al. Antimicrob Agents Chemother. 2005;49:4515-4520.

  38. Inhaled Zanamivir for Influenza Meta Analysis *Reduction of risk of antibiotic prescription †P < .05 Kaiser L et al. Arch Intern Med. 2000;160:3234-3240.

  39. Fatal Influenza in ChildrenTiming of 153 Cases US 2004-2005 Influenza Season 2-Week Reporting Periods 9 8 7 6 5 No. of Cases 4 3 2 1 0 Jun 24 Jun 24 Mar 20 Apr 17 Oct-4 Nov 1 Dec 27 Nov 29 Date of Onset of Illness Bhat N et al. N Engl J Med. 2005;353:2559-2567.

  40. Influenza in ChildrenOverview • Flu symptoms in school-age children and adolescents are similar to those in adults • Temperature of 101°F or above, cough, muscle ache, headache, sore throat, chills, fatigue, general malaise • Public advised to contact physician for these symptoms • Children tend to have higher temperatures than adults, ranging from 103°F to 105°F • Flu in preschool children and infants is hard to pinpoint, since its symptoms are so similar to infections caused by other viruses

  41. Underlying Health Status of Children with Fatal Influenza, 2003-2004 Season Bhat N et al. N Engl J Med. 2005;353:2559-2567.

  42. Oseltamivir for Influenza in Children *P < .001 compared to placebo recipients, using weighed Mantel-Henszel test, stratified for region and otitis media Whitley R et al. Pediatr Infect Dis J. 2001 Feb;20:127-133.

  43. Zanamivir for Influenza in Children Study 1 Hedrick et al. 2000; Pediatr Infect Dis J.;19(5):410-417. Study 2 Cooper NJ 2003; BMJ; 7;326:1235.

  44. Influenza in Immunocompromised Patients • Immunocompromised patients suffer more complications and have higher morbidity and mortality from influenza infection • High rate of hospitalization and ICU admissions • Higher rate of pulmonary complications • 50% of BMT and 13% renal transplant patients had lower respiratory tract infections • 50% of BMT and 7% of renal transplant patients with influenza complicated by pneumonia • 63% progressed to pneumonia • 43% mortality http://www.shea-online.org/Assets/files/W_-_Seasonal_and_Pandemic_Influenza_-_Children__Immunocompromised_Hosts__Pregnant_Women__and_Nursing_Home_Residents.ppt.

  45. Adjusted Incidence Rates of Acute CardiopulmonaryEvents per 10,000 Women-Months for High Risk Women Influenza In Pregnant Women * Events per 10,000women-months Pregnancy Status (Weeks) *November 1-April 30 period with no influenza activity Neuzil K et al. Am J Epidemiol. 1998;148:1094-1102.

  46. Seasonal Influenza Prophylaxis and Treatment: Summary • Efficacious and well-tolerated medications are available for prophylaxis and treatment of seasonal influenza • Neuraminidase inhibitors are useful to limit durationand severity of influenza if taken early • Use of M2 inhibitors is limited by widespread resistance • Influenza prevention and treatment remain challenging in special populations such as children, pregnant women, and immunocompromised individuals like transplant recipients

  47. Pandemic Influenza Lessons from the 1918 Pandemic

  48. 70 60 50 1918 Flu Epidemic 40 30 1900 1950 1970 1990 1930 US Life Expectancy1900-1990 Age (y) Year

  49. No Treatment 20% stockpile – treat all groups 10% stockpile – treat all groups Estimated Pandemic Mortality1918-1919 60 50 40 30 Estimated Deathsper 100,000 Population 20 10 0 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18 1918 1919 Week no. Gani R et al. Emerg Infect Dis. 2005;11:1355-1362.

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