1 / 59

ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA NVAC Pandemic Influenza Working Group Briefing April 20, 2005

brilliant
Download Presentation

ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA NVAC Pandemic Influenza Working Group Briefing April 20, 2005

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA NVAC Pandemic Influenza Working Group Briefing April 20, 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. Anti-Influenza Agents: Adverse Drug Reaction Profiles

    4. Influenza Antivirals: Pregnancy Risks

    6. Amantadine Prophylaxis During Pandemic Influenza

    7. Chemoprophylaxis of Epidemic Influenza

    8. Oseltamivir PEP in Households: Reduction in Influenza Illness, 2000-01

    9. Relenza� (zanamivir for inhalation) Rotadisk� and Diskhaler�

    10. Epidemic Curve of Influenza A Outbreak in a Long-term Care Facility

    11. INFLUENZA PROPHYLAXIS IN NURSING HOMES: Zanamivir vs Rimantadine Randomized, multicenter comparison study Inhaled zanamivir 10 mg/d or oral rimantadine 100 mg/d (placebo for B) for 14 days Rimantadine for non-participating residents 375 residents over 3 influenza seasons Mean age 76 yrs; immunized 98%; respiratory disease 40% Influenza A in 95% of outbreaks Comparable tolerability

    12. ZANAMIVIR COMPARED WITH RIMANTADINE � Distribution of influenza cases

    13. Laboratory confirmed influenza (days 1-15): ZNV 2.9% vs control 7.4% Additional protective efficacy = 61% Illness milder in ZNV recipients (complications 40% vs 22%) Antiviral drug resistance: Rimantadine resistance in 38% of 93 isolates 8/18 (44%) prophylaxis failures Zanamivir resistance not detected INFLUENZA PROPHYLAXIS IN NURSING HOMES: Zanamivir vs Rimantadine Outcomes

    14. Antiviral Treatment of Influenza

    15. AMANTADINE TREATMENT OF INFLUENZA A/HONG KONG/68 ILLNESS

    17. Indirect Effects of Amantadine Treatment

    19. Oseltamivir Treatment in Adults: Antiviral Effects

    20. Oseltamivir Treatment in Children: Antiviral Effects

    21. EFFECTS OF OSELTAMIVIR TREATMENT ON RETURN TO NORMAL ACTIVITIES

    23. Oseltamivir Treatment: Effect on Hospitalizations

    24. Impact of Antiviral Therapy on Influenza Complications in Nursing Home Residents, Canada

    25. Oseltamivir and Complications: Retrospective Cohort Study, USA

    26. Treatment of Influenza in Immunocompromised

    27. Pneumococcal Adherence To Human Lung Cells

    30. 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*

    31. Influenza A/H5N1 In Humans

    35. Influenza Prevention In Households: PEP without index treatment

    36. Influenza Prevention In Households: Combined index treatment and PEP

    37. NEURAMINIDASE INHIBITORS: Resistance Mechanisms HA mutations Mutations near receptor binding site ??affinity of HA for sialic acid ? dependence on NA for release NA mutations- vary by type/subtype and drug Framework- variable cross-resistance Glu119 (?Gly, Ala, Asp, Val), His274Tyr, Asp198Asn Catalytic site Arg292Lys, Arg152Lys

    38. Detection Of Antiviral Resistant Influenza During Treatment

    39. 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

    40. TRANSMISSION OF OSELTAMIVIR-RESISTANT VIRUSES IN FERRETS

    41. 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.

    42. NA Inhibitor Resistance Profiles

    43. 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

    44. Oseltamivir Inhibition of Avian Influenza Viruses

    45. Oseltamivir in Experimental A/HK/156/97 (H5N1) Infection of Mice

    47. 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

    50. Peramivir Phase 3 Treatment: Quantity of Viral Shedding

    51. 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); T-705 Protease inhibitors Aprotinin

    53. siRNA Treatment of Influenza A in Mice

    55. 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

    56. 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)

    57. Oseltamivir reduces cytokine levels

    58. 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 (12 �20 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

    59. 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

    60. 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

More Related