ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA NVAC Pandemic Influenza Working Group Briefing

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ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC
INFLUENZANVAC 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

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Antiviral Agents for Influenza
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Anti-Influenza Agents Adverse Drug Reaction
Profiles
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Influenza Antivirals Pregnancy Risks
Animal models Case reports in humans
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Amantadine Prophylaxis During Pandemic Influenza
Hayden. J Infect Dis 176S56, 1997
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Chemoprophylaxis of Epidemic Influenza
Efficacy (vs placebo or no drug)
? No placebo-controlled study or not reported
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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 189440, 2004
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Relenza (zanamivir for inhalation)Rotadisk and
Diskhaler
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Epidemic Curve of Influenza A Outbreak in a
Long-term Care Facility
Lee et al. Infect Control Hosp Epidemiol 21 700,
2000
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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

Gravenstein et al. 40th ICAAC, Abst 1155, 2000
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ZANAMIVIR COMPARED WITH RIMANTADINE
Distribution of influenza cases
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INFLUENZA PROPHYLAXIS IN NURSING HOMES Zanamivir
vs Rimantadine Outcomes

• 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

Gravenstein et al. 40th ICAAC, Abst 1155, 2000
Daly et al. 40th ICAAC, Abst 181, 2000
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Antiviral Treatment of Influenza
? No placebo-controlled study or not reported
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AMANTADINE TREATMENT OF INFLUENZA A/HONG KONG/68
ILLNESS
Amantadine dose 100 mg q12h for 7 days
Galbraith et al. Lancet II113, July 17, 1971
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Indirect Effects of Amantadine Treatment
Glezen et al. Proceedings of the 16th
International Congress of Chemotherapy, Israel,
1989
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INFLUENZA A2/ MARYLAND/1/68 VIRUS
SHEDDING IN ADULTS
Togo et al. JAMA, 1970, 2111154
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Oseltamivir Treatment in Adults Antiviral Effects
Median viral titer, log10 TCID50/ml
Treanor et al. JAMA 2831016, 2000
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Oseltamivir Treatment in ChildrenAntiviral
Effects
Viral titer log10 TCID/mL
Days
Whitley et al. PIDJ 20127, 2001
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EFFECTS OF OSELTAMIVIR TREATMENT ON RETURN TO
NORMAL ACTIVITIES
Time to return to normalhealth and activity
(days)
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Health status
Activity

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2.8d

8
1.9d
6
4
2
0
Placebo(n129)
Oseltamivir75mg bid(n124)
Placebo(n129)
Oseltamivir75mg bid(n124)
plt0.001 p0.02
Treanor et al. JAMA 283 2000
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OSELTAMIVIR Effect of Time to Treatment
Aoki et al. J Antimicrob Chemo 51123, 2003
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Oseltamivir Treatment Effect on
Hospitalizations
Kaiser et al. Arch Intern Med 1631667, 2003
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Impact of Antiviral Therapy on Influenza
Complications in Nursing Home Residents, Canada
Percent
Bowles et al. J Am Geriat Soc 2002
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Oseltamivir and Complications Retrospective
Cohort Study, USA
Nordstrom et al. 44th ICAAC, abst no. V-1260,
2004
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Treatment of Influenza in Immunocompromised
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Pneumococcal Adherence To Human Lung Cells
Peltola and McCullers. Pediatr Infect Dis J
23S87 2004
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Influenza - Pneumococcal Pneumonia
McCullers JA. JID 190519-26 2004
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INHALED ZANAMIVIR TREATMENT Effect on
Complications and Antibiotic Use
Placebo (n765) 18 8 9 7 2 0.4
Risk Reduction 28 10 40
Respiratory events leading to antibiotics Any
event Upper respiratory Lower
respiratory Acute bronchitis Pneumonia Hospital
izations
Zanamivir (n807) 13 7 5 5 1 0.4
Kaiser et al. Arch Intern Med 160 3234,
2000 plt0.05
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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
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Influenza A/H5N1 In Humans
Confirmed (suspect) M2 inhibitor-resistant due
to S31N mutation
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EFFECT OF WILD-TYPE AND DRUG-RESISTANT HUMAN
INFLUENZA A VIRUSES IN FERRETS
Viral titers
Nasal cells
Temperature

• Rimantadine-resistant variant (Ser31Asp)
• Wild-type sensitive isolate

Sweet et al. J Infect Dis. 164969, 1991
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TRANSMISSION OF M2-RESISTANT H5N2 IN
EXPERIMENTALLY INFECTED BIRDS
Bean WJ et al. JID 1591050, 1989
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Influenza Prevention In HouseholdsPEP without
index treatment
Laboratory proven influenza illness in
contacts Clinical influenza
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Influenza Prevention In HouseholdsCombined
index treatment and PEP
Ages 5 years and older Excludes contacts
positive for influenza prior to prophylaxis
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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

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Detection Of Antiviral Resistant Influenza
During Treatment
Roberts N. Phil Trans R Soc Lond 3561895,
2001 Kiso et al. Lancet 364 759, 2004
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Oseltamivir Resistance In N1 Neuraminidase

• Single nucleotide substitution (His274Tyr)
• ? ?oseltamivir susceptibility ( 400fold)
• Frequency drug therapy
• Children 16 (7/43)
• Adults 4 (2/50)
• Reduced replication in cell culture (gt 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 5307, 2002 Herlocher
et al. JID 1901627, 2004
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TRANSMISSION OF OSELTAMIVIR-RESISTANT VIRUSES IN
FERRETS
Herlocher et al. JID 1901627, 2004 Herlocher
et al. Antiviral Res 5499, 2002
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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.

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NA Inhibitor Resistance Profiles
Gubareva LV. Virus Res 103199, 2004 Wetherall
et al. AAC 41742, 2003
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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 (gt48 hr)
• Parenteral route of administration
• Resistance prevention and management
• Combinations of antivirals
• New antiviral targets

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Oseltamivir Inhibition of Avian Influenza Viruses
Leneva et al. Antiviral Res 48101, 2000
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Oseltamivir in Experimental A/HK/156/97 (H5N1)
Infection of Mice
Dose 1mg/kg/d
Leneva et al. Antiviral Res 48101, 2000
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Palese P. Nature Med 10S82, 2004
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IV Zanamivir in Experimental Influenza A

• Double-blind, randomized, placebo-controlled
• Healthy adults with serum HAI titers lt 18
• 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 n8 vs ZNV n7)
• Infection- 100 vs 14, Plt0.005
• Virus shedding- 100 vs 0, Plt0.005
• URI- 100 vs 0, Plt0.005

Calfee et al. Antimicrob Agents Chemother
431616, 1999
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NW Viral Titer
Intravenous Zanamivir in Experimental Influenza
A/H1N1
Symptom Score
Calfee et al. AAC 431616 1999
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Peramivir Single-Dose Pharmacokinetics
Mean plasma concentrations in healthy males oral
solution
ng/ml
Time
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Peramivir Phase 3 Treatment Quantity of Viral
Shedding
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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

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Yamashita et al. 43rd ICAAC, abst. no. F-1830,
2003
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siRNA Treatment of Influenza A in Mice
siNP siPA siGFP Plt0.05
Tompkins SM, et al. Proc Natl Acad Sci USA.
20041018682
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20 JAN. 6, 1962
INTERFERON AND INFLUENZA
BRITISH MEDICAL JOURNAL
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.
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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
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Effect of Prior Statin Therapy on Sepsis

• Prospective, observational cohort study
• 361 hospitalized pts with proven/suspected acute
  bacterial infection
• Statin therapy gt 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 110880, 2004
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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
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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 lt1 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

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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

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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