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ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA IOM Briefing April 4, 2005

ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA IOM Briefing April 4, 2005. Frederick G. Hayden, M.D. Division of Infectious Diseases and International Health University of Virginia School of Medicine. Antiviral Agents for Influenza. Amantadine Prophylaxis During Pandemic Influenza.

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ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA IOM Briefing April 4, 2005

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  1. ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZAIOM Briefing April 4, 2005 Frederick G. Hayden, M.D. Division of Infectious Diseases and International Health University of Virginia School of Medicine

  2. Antiviral Agents for Influenza

  3. Amantadine Prophylaxis During Pandemic Influenza Hayden. J Infect Dis 176:S56, 1997

  4. Chemoprophylaxis of Epidemic Influenza Efficacy(vs placebo or no drug) ?= No placebo-controlled study or not reported

  5. Oseltamivir PEP in Households: Reduction in Influenza Illness, 2000-01 Note: All index cases influenza-positive and treated with oseltamivir (ITTI) Hayden et al. JID 189:440, 2004

  6. Antiviral Treatment of Influenza ?= No placebo-controlled study or not reported

  7. Oseltamivir Treatment: Effect on Hospitalizations Kaiser et al. Arch Intern Med 163:1667, 2003

  8. Oseltamivir and Complications: Retrospective Cohort Study, USA Nordstrom et al. 44th ICAAC, abst no. V-1260, 2004

  9. Anti-Influenza Agents: Adverse Drug Reaction Profiles

  10. Influenza Antivirals: Pregnancy Risks * Animal models + Case reports in humans

  11. Drug Resistance in Influenza A Viruses M2 Inhibitor Oseltamivir Magnitude of resistance High High Primary resistance 1-2.5% No Frequency during therapy High Low Rapid development Yes Variable Person-person transmission Yes Not-to-date Pathogenicity Yes Reduced* Competition with wild-type Yes* Reduced* *Animal models

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

  13. Oseltamivir Resistance In N1 Neuraminidase Single nucleotide substitution (His274Tyr) → ↓oseltamivir susceptibility (≥ 400–fold) Frequency drug therapy Children: 16% (7/43) Adults: 4% (2/50) Reduced replication in cell culture (> 2.0 log10) ↓infectivity in mouse (1,000-fold) and ferret (100-fold) Variable↓pathogenicity in ferret Transmissible in ferret model Ives et al. Antiviral Res 5:307, 2002 Herlocher et al. JID 190:1627, 2004

  14. Inhibitors of Influenza A and B Virus Neuraminidases • Potent and specific inhibitors of influenza NAs in nM range • Varied potencies for NAs of different types (A and B) and subtypes • Zanamivir (RelenzaTM) and oseltamivir (TamifluTM) are commercially available • Peramivir (BCX-1812, RWJ - 270201) and A-315675 are investigational.

  15. NA Inhibitor Resistance Profiles Gubareva LV. Virus Res 103:199, 2004; Wetherall et al. AAC 41:742, 2003

  16. Antiviral and Immunotherapy Research Topics in Pandemic Influenza • Current agents • Decreased/increased dose and duration • Other risk populations; infants, pregnant women, immunocompromised, hospitalized • Delayed treatment benefit (>48 hr) • Parenteral route of administration • Resistance prevention and management • Combinations of antivirals • New antiviral targets

  17. Oseltamivir Treatment in Adults: Antiviral Effects Median viral titer, log10 TCID50/ml Treanor et al. JAMA 283:1016, 2000

  18. Oseltamivir Treatment in Children:Antiviral Effects Viral titer log10 TCID/mL Days Whitley et al. PIDJ 20:127, 2001

  19. Palese P. Nature Med 10:S82, 2004

  20. IV Zanamivir in Experimental Influenza A • Double-blind, randomized, placebo-controlled • Healthy adults with serum HAI titers < 1:8 • IV zanamivir 600 mg q12 hr or saline starting 4 hr before intranasal inoculation with 105 TCID50 A/Texas/36/91(H1N1) • Nasal wash ZNV median 10-12 ng/ml • Outcomes (saline [n=8] vs ZNV [n=7]): • Infection- 100% vs 14%, P<0.005 • Virus shedding- 100% vs 0%, P<0.005 • URI- 100% vs 0%, P<0.005 Calfee et al. Antimicrob Agents Chemother 43:1616, 1999

  21. Peramivir Single-Dose Pharmacokinetics Mean plasma concentrations in healthy males: oral solution ng/ml Time

  22. Peramivir Phase 3 Treatment: Quantity of Viral Shedding

  23. Investigational Anti-Influenza Agents • Neuraminidase (NA) inhibitors - Peramivir (oral/IV), A-315675 (oral) • Long-acting NA inhibitors (LANI) • R-118958 (topical), Flunet (topical) • Conjugated sialidase • Fludase™ (topical) • HA inhibitors- cyanovirin-N • Polymerase inhibitors • siRNA; ribavirin (aerosol/IV/PO) • Protease inhibitors • Aprotinin

  24. Yamashita et al. 43rd ICAAC, abst. no. F-1830, 2003

  25. Absence of Interferon in Lungsfrom Fatal Cases of Influenza National Institute for Medical Research, Mill Hill, London Interferon and Influenza, S Baron and A Isaacs, January 1962 Summary A quantitative assay for human interferon is described. Analysis of lung specimens from 11 fatal cases of influenzal pneumonia revealed a complete absence of interferon. The implications of this finding are discussed.

  26. Potential Immunomodulatory Therapies • Replacement of deficient responses • Stimulation of protective innate immune responses • TLR-4 agonists* • Modulation of immunopathologic host responses • Pro-inflammatory cytokines/chemokines/NO • Anti-TNF*, corticosteroids • Statins, fluoroquinolones, macrolides • Reactive oxygen species • N-acetylcysteine, allopurinol*, superoxide dismutase* • Potentiation of viral replication combined antiviral and anti-mediator therapies *Beneficial in murine models of influenza

  27. Effect of Prior Statin Therapy on Sepsis • Prospective, observational cohort study • 361 hospitalized pts with proven/suspected acute bacterial infection • Statin therapy > 1 mo in 23% • Pneumonia 49%, UTI 39%, cellulitis 12% • Outcomes (no statin vs statin): • Severe sepsis- 19.0% vs 2.4% (RR 0.13, 0.03-0.52) • ICU admit- 12.2% vs 3.7% (RR 0.30, 0.1-0.95) • Mortality day 28- 8.6% vs 3.7% (RR 0.43, 0.13-1.38) Almog et al. Circulation 110:880, 2004

  28. Oseltamivir reduces cytokine levels Drug administration IL-6 12 * Placebo 9 Oseltamivir 6 3 * p0.01 † p0.001 ‡ p0.05 0 0.6 * TNF 0.4 Median concentration pg/mL 0.2 0.0 † 12 IFN 9 ‡ 6 3 Hayden et al.JAMA 1999 Time, h 0 -24 0 24 48 72 96 120 144 156 -36 -12 12 36 60 84 108 132 Drug administration

  29. Research Priorities: Short-term (1-2 Years) • Obtain data on virologic course and host immune responses in human H5 infections • License orally inhaled zanamivir for prophylaxis • Study oseltamivir PK + tolerance in infants <1 yr • Determine PK and tolerability of IV/IM peramivir • Assess long-term (8 –12 weeks) tolerability of oseltamivir and inhaled zanamivir prophylaxis • Trial in risk populations in SE Asia • Study H5N1 resistance emergence in animal models and strategies for prevention

  30. Research Priorities: Mid-term (2-5 Years) • Test oseltamivir monotherapy vs combination with M2 or ribavirin in high-risk population • Develop contemporary virus challenge pools for studies of experimental human influenza • Test candidate immunomodulators and antivirals • Test therapeutic efficacy of IVIM peramivir in hospitalized influenza patients • Test prophylactic efficacy and tolerability of topical LANI • Trial combination of antiviral and immunomodulator therapy

  31. Research Priorities: Longer-term (5-10 Years) • siRNA as systemic or topical antiviral • New antiviral agents (eg, polymerase) • Innate immune effector molecules • Surfactants • Mannose-binding lectins • Defensins • Innate immune activation • TLR-3, 4, 7, 8. 9 agonists • NOD receptors • Modulation of inflammatory cascades

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