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Transcript of ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA IOM Briefing April 4, 2005 Frederick G. Hayden,...
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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
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Antiviral Agents for Influenza
Class/agent Brand name Route
M2 inhibitors Amantadine Rimantadine
Symmetrel Flumadine
PO PO
NA inhibitors Zanamivir (GG167) Oseltamivir (GS4104) Permavir (RWJ-270201)*
Relenza Tamiflu
Inhaled
PO PO
*Investigational in USA
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Amantadine Prophylaxis During Pandemic Influenza
Protective efficacy
Pandemic Influenza A illness
Seroconversion
1968 H3N2
1977 H1N1
59-100%
31-71%
28-52%
19-39%
Hayden. J Infect Dis 176:S56, 1997
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Chemoprophylaxis of Epidemic Influenza
Strategy AM/RM ZNV OSEL
Seasonal Non-immunized adults 85-91% 84% 84% Immunized NH elderly 58-75% ? 92% Post-contact / post-exposure Households 3-100% 82% 67-89% Nursing homes Variable Yes Yes
?= No placebo-controlled study or not reported
Efficacy (vs placebo or no drug)
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Oseltamivir PEP in Households: Reduction in Influenza Illness, 2000-01
Contact Age
No. Observa-tion
Osel PEP
Efficacy
(95% CI)
13+ 373 8% 2% 74%
1-5 yrs 20 36% 22% 39% (-211%, 88%)
6-12 yrs 109 22% 9% 61%(-19%, 87%)
Note: All index cases influenza-positive and treated with oseltamivir (ITTI)
Hayden et al. JID 189:440, 2004
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Antiviral Treatment of Influenza
Outcome AM/RM ZNV OSEL
Symptom relief Yes Yes Yes
Prevention of complications ? Yes Yes
Decrease antibiotic use ? 28% 24-40%
Decrease hospitalizations ? ? ~50%
Treatment of viral complications
? ? ?
Reduction in transmission ? (30%) ? ?
?= No placebo-controlled study or not reported
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Oseltamivir Treatment: Effect on Hospitalizations
Hospitalizations % Reduction
Placebo Oseltamivir
Healthy adults 5/662 (0.8%) 3/982 (0.3%) 60%
High-risk + elderly
13/401 (3.2%) 6/368 (1.6%) 50%
Total 18/1063 (1.7%) 9/1350 (0.7%) 59% (P=0.019)
Kaiser et al. Arch Intern Med 163:1667, 2003
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Oseltamivir and Complications: Retrospective Cohort Study, USA
Outcome Exposed Unexposed Adj. Hazard Ratio (95% CI)
Age 1-12
Pneumonia
Hosp.
(n=586)
4 (0.7%)
1 (0.2%)
(n=17,886)
453 (2.5%)
120 (0.7%)
0.34 (0.13, 0.90)
0.29 (0.04, 2.07)
Age 13-59
Pneumonia
Hosp.
(n=10,649)
138 (1.3%)
99 (0.9%)
(n=41,007)
885 (2.1%)
510 (1.2%)
0.81 (0.68, 0.97)
0.75 (0.60, 0.93)
Age 60+
Pneumonia
Hosp.
(n=463)
8 (1.7%)
10 (2.2%)
(n=3,298)
290 (8.8%)
163 (4.9%)
0.41 (0.20, 0.82)
0.55 (0.29, 1.05)
Nordstrom et al. 44th ICAAC, abst no. V-1260, 2004
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Anti-Influenza Agents: Adverse Drug Reaction Profiles
Agent ADR Severity Freq Dose-related
Amantadine CNS
GI
Mild- severe
Mild
10-30%
Common
Yes
Yes
Rimantadine CNS
GI
Mild- moderate
Mild
<10%
Common
Yes
Yes
Zanamivir Broncho-spasm
Mild- severe Very un-common
No
Oseltamivir GI Mild Common Yes
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Influenza Antivirals: Pregnancy Risks
Drug Embryo-toxicity*
Terato-genicity*
Pregnancy category
Breast milk excretion
Amantadine Yes Yes+ C Yes
Rimantadine Yes Yes C Yes
Oseltamivir No No C Yes+
Zanamivir No No C Yes+
Ribavirin Yes Yes X ?
* Animal models+ Case reports in humans
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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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Detection Of Antiviral Resistant Influenza During Treatment
Frequency of resistance
Oseltamivir M2 inhibitor
Out-patient adults
Out-patient children
0.4%
5.5%
~30%
~30%
Inpatient children 18% 80%
Immunocompromised
? >33%
Roberts N. Phil Trans R Soc Lond 356:1895, 2001
Kiso et al. Lancet 364: 759, 2004
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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
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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
NA mutation
NA type/ subtype
Susceptibility in the NAI assay (fold )
Oseltamr Zanamivir Peramivir A-315675
E119V A/N2 R (>50) S (1) S S
R292K A/N2 R (>1000) S (4-25) R (30) S (8)
H274Y A/N1 R (900) S (1) R (40) S (3)
R152K B R (>30-750) R (10-100) R (>500) R (150)
Gubareva LV. Virus Res 103:199, 2004; Wetherall et al. AAC 41:742, 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 (>48 hr)
• Parenteral route of administration• Resistance prevention and management• Combinations of antivirals• New antiviral targets
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Oseltamivir Treatment in Adults: Antiviral Effects
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0 2 4 6 8
Day
Placebo
Oseltamivir 75 BID
Oseltamivir 150 BID
Median viral titer, log10 TCID50/ml
Treanor et al. JAMA 283:1016, 2000
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Oseltamivir Treatment in Children:Antiviral Effects
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
0 2 4 6 8 10
PlaceboOseltamivir
p<0.05
Viral titer log10 TCID/mL
DaysWhitley et al. PIDJ 20:127, 2001
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Palese P. Nature Med 10:S82, 2004
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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
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0
50
100
150
200
250
0 2 4 6 8 10 12 14 16 18 20 22 24
0.5 mg/kg 1 mg/kg 1.5 mg/kg 2 mg/kg 5 mg/kg 10 mg/kg
Peramivir Single-Dose PharmacokineticsPeramivir 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
Treatment Group
Days·log TCID50/ml
P Value
Placebo 5.61
Peramivir 800/400
-1.38 P=0.0003
Peramivir 800 -1.92 P<0.0001
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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)• Protease inhibitors
–Aprotinin
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Yamashita et al. 43rd ICAAC, abst. no. F-1830, 2003
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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.
Absence of Interferon in Lungsfrom Fatal Cases of Influenza
National Institute for Medical Research, Mill Hill, LondonInterferon and Influenza, S Baron and A Isaacs, January 1962
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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 > 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
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Time, h
* p0.01† p0.001‡ p0.05
PlaceboOseltamivir
Hayden et al.JAMA 1999
Oseltamivir reduces cytokine levels
-36-24
-120
1224
3648
6072
8496
108120
132144
156
0
3
6
9
12
‡
0.0
0.2
0.4
0.6 *
0
3
6
9
12 *
†
IL-6
TNF
IFN
Drug administration
Med
ian
co
nce
ntr
atio
n p
g/m
L
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 <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
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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