antivirals for pandemic influenza frederick g. hayden, md division of infectious diseases and...
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Antivirals for Pandemic Influenza
Frederick G. Hayden, MDDivision of Infectious Diseases and
International HealthUniversity of Virginia School of Medicine
Charlottesville, Virginia, USA
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Antiviral Agents For Influenza
Class/agent Brand name Route
M2 inhibitors
Amantadine Symmetrel PO
Rimantadine Flumadine PO
NA inhibitors
Zanamivir (GG167) Relenza Inhaled
Oseltamivir (GS4104) Tamiflu PO
Peramivir (BCX-1812)* PO/IV/IM
*Investigational at present in USA.
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Chemoprophylaxis
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Amantadine Prophylaxis During Pandemic Influenza
Hayden. J Infect Dis. 1997;176:S56.
Protective Efficacy
Pandemic Influenza A illness Seroconversion
1968 H3N2 59-100% 28-52%
1977 H1N1 31-71% 19- 39%
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Projected Outbreak of H5N1in Thailand
Red = new cases. Green = areas where the epidemic has finished.Ferguson et al. Nature. Published online. August 2005.
R0 = 1.5
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Projected Outbreak of H5N1 Influenza in Thailand
Left: uncontrolled outbreak. Red = new cases. Green = areas where the epidemic has finished.
Above: Controlled outbreak. Red = areas of infection. Blue = areas where a combination of control measures implemented.
http://www.nigms.nih.gov/news/releases/08032005.html
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Elimination of a Pandemic Virus at its Source?
• Ring chemoprophylaxis feasible if:– Geographically targeted in non-urban setting
– Early intervention within 1-3 weeks
– Virus of low-moderate transmissibility (R0 < 1.8)
– Chemoprophylaxis of 80 - 90% of population
– High compliance
– Movement restrictions; social distancing
• Maximum of 1-3 million courses needed– 300,000 may be sufficient
Ferguson et al. Nature. published online, August 2005.
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Efficiency of Pandemic Antiviral Use
No. persons
Antiviral strategy
Percent on drug
Duration (days)
Total doses
needed
1,000 Prophylaxis 100% 56 56,000
1,000 Treatment 35% 5 3,500
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Efficiency of Pandemic Antiviral Use
No. persons
Antiviral strategy
Percent on drug
Duration (days)
Total doses
needed
1,000 Prophylaxis 100% 56 56,000
1,000 Treatment 35% 5 3,500
16-fold .
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Treatment
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Nasal Aspirate Viral Detection in Hospitalized Children: Effect of NAI Treatment
Influenza virus
Antiviral Tx
No. Duration of fever
(hrs)
Days of Detection
Antigen Culture
A/H3N2 NoneOseltamivirZanamivir
101211
61 + 1541 + 1245 + 14
7.3 + 2.56.2 + 1.65.8 + 2.2
6.8 + 1.76.3 + 1.55.4 + 1.9
B NoneOseltamivirZanamivir
989
62 + 2047 + 1441 + 17
4.6 + 1.04.1 + 1.53.9 + 1.3
6.2 + 1.35.6 + 1.54.3 + 1.3*
*P<0.5 versus no treatment. Mean ages 3.1 – 6.7 years across groupsSato et al. Ped infect Dis J. 2005;24:931.
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Oseltamivir and Complications in ILI: Retrospective Cohort Study, USA, 1999-2004
Outcome < 30 days
Oseltamivir(N = 39,202)
Untreated(N = 136,799)
Adj. Hazard Ratio (95% CI)
Pneumonia 0.9% 1.5% 0.68 (0.63, 0.73)
Myocardial infarction 0.1% 0.3% 0.33 (0.10, 1.07)
Death from any cause
0.003%(N = 1)
0.042%( N = 56) 0.09 (0.01, 0.65)
Nordstrom et al. 2nd Euro Influenza Conf, abst no. S18-2, 2005.
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Estimated Pandemic Mortality, 1918-19
Gani et al. Emerging Infect Dis. 2005;11:1355.
Est
imat
ed D
eath
s pe
r 10
0, 0
00 p
opul
atio
n
No Treatment
20% stockpile – treat all groups
10% stockpile – treat all groups
1918 1919Week no.
60
50
40
30
20
10
024 26 28 30 32 34 36 38 40 42 44 46 48 50 2 4 6 8 10 12 14 1622 52 18
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H5N1 Virus
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Oseltamivir in Experimental A/HK/156/97 (H5N1) Infection of Mice
Leneva et al. Antiviral Res. 2000;48:101.
Dose: 1mg/kg/d
100
80
60
40
20
0
Per
cent
of
Sur
vivo
rs
Days After Infection
7 8 9 11 12 141310
4 hours before infection
24 hours delay
36 hours delay
48 hours delay
72 hours delay
control
x
x
xx
x
xx
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Oseltamivir for A/Vietnam/1203/04 Virus in Mice
Days After Inoculation
0.25
0
0.5
0.75
1
5 15 20 25100
10 mg/kg/day
1 mg/kg/day
0.1 mg/kg/dayplacebo
B8-Day Treatment
Sur
viva
l Dis
trib
utio
n F
unct
ion
Days After Inoculation
0.25
05 15 20 25100
0.5
0.75
1A
5-Day Treatment
Yen et al. JID. 2005;192:665.
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Yen et al. JID. 2005;192:665.
Sensitivity of Reverse Genetic-Derived Influenza Viruses to Neuraminidase (NA) inhibitors (NAIs) in
NA-inhibition and Virus-reduction Assays
IC50, nmol/L EC50, µmol/L
Reverse-genetics virus Zanamivir
Oseltamivir
carboxylate Zanamivir
Oseltamivir
carboxylate
VN1203 x PR8 (H1N1) 0.8 ± 0.1 0.4 ± 0.1 0.9 ± 0.1 0.1 ± 0.1
HK 156 PR8 (H1N1) 0.7 ± 0.1 4.1 ± 0.2 0.5 ± 0.1 1.0 ± 0.1
PR/8/34 (H1N1) 0.7 ± 0.1 4.5 ± 0.2 1.1 ± 0.1 4.6 ± 1.2
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Oseltamivir Therapy in H5N1: Thailand and Vietnam, 2004-5
Oseltamivir Treatment No. Patients No. (%)
Survivors
Yes 25 6 (24%)
No 12 3 (25%)
Writing Committee. NEJM. 2005;353:1374.
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Oseltamivir Treatment Failure in H5N1
• Late initiation- pulmonary injury
• Primary infection → sustained replication
• Altered pathogenesis– Viral virulence factors
– Extra-pulmonary dissemination
– Pro-inflammatory host immune responses
• Inadequate dose regimen– Inadequate absorption (diarrhea, GI dysfunction)
• Antiviral resistance emergence
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Amantadine Therapy in H5N1:Hong Kong, 1997
Amantadine treatment
No.patients
No. (%) survivors
Yes
< 5 days
> 6 days
10
4
6
6 (60%)
4 (100%)
2 (33%)
No 8 6 (75%)
K-Y Yuen, personal communication.
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Pharyngeal Viral Loads during Oseltamivir Treatment of H5N1
de Jong et al. NEJM. 2005;353:25.
Com
plem
enta
ry D
NA
(log
copi
es/m
l of
vira
l-tra
n sp
ort
med
ium
)
Days Since Admission
Patient 1, died
Patient 2, died
Patient 3, died
Patient 4, died
Patient 5, survived
Patient 6, survived
Patient 7, survived
Patient 8, survived
Oseltamivir-resistant
Oseltamivir-resistant
Oseltamivir-resistant
Oseltamivir-therapy
8
7
6
5
4
3
087654321 9 10 11
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Antiviral Resistance
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Antiviral Resistance to M2 Inhibitors in Community Isolates of A/H3N2, 1995-2005
Bright et al. 2nd Euro Influenza Conf 2005. Lancet. pub online Sept 22, 2005.
%
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Antiviral Research 49 (2001) 147-156
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Oseltamivir Resistance, Japan, 2003-4
• Single season survey of NAI resistance– ~ 6M treatment courses (or ~5% of population) – Outpatient isolates from 74 public health labs– Phenotypic susceptibility by NAI assay
• 3/1,180 (0.3%) of influenza A (H3N2) isolates resistant– 2 E119V, 1 A292K
• Very low frequency of resistance in community isolates despite substantial oseltamivir use– Likely due to low-level transmission of resistant
variants and not primary NA inhibitor resistanceNeuraminidase Inhibitor Susceptibility Network. WHO Weekly Epi Record. April 29, 2005.
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Oseltamivir Resistance In N1 Neuraminidase
• Single nucleotide substitution (His274Tyr) →↓oseltamivir susceptibility (≥ 400–fold)
• Frequency drug therapy of H1N1: – H1N1: children 16% (7/43), adults 4% (2/50)
– H5N1: 2/8 (25%)
• Reduced replication in cell culture (> 2.0 log10)– ↓infectivity in mouse (1,000-fold) and ferret
(>10-fold)
– Variable ↓ pathogenicity in ferret
• Transmissible in ferret modelIves et al. Antiviral Res. 2002;5:307.Herlocher et al. JID. 2004;190:1627.
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Oseltamivir-Susceptible and Resistant H5N1 in Ferrets: Effect of His274Tyr Mutation
Le et al. Nature. 2005.
-1
-0.5
0
0.5
1
1.5
2
2.5
3
1 2 3 4 5 6 7 8 9
R contS cont
Cha
nges
in B
ody
Tem
pera
ture
(ºC
)Days Postinfection
Oseltamivir – resistant
Oseltamivir – sensitive
Viru
s T
iter
(Log
10 P
FU
/ml)
Oseltamivir – resistant, mock treated
Oseltamivir – sensitive, mock treated
Days Postinfection
0
≤1
2
3
4
5
6
1 3 5 7 9
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NA Inhibitor Resistance Profiles
NA mutation
NA type/ subtype
Susceptibility in the NAI assay (fold )
Oselt Zana Peram A-315675
E119V A/N2 R (>50) S (1) S (1) S (1)
R292K A/N2 R (>1000) S (4-25) R (40-80) S (8)
H274Y A/N1 R (>700) S (1) R (40-100) S (3)
R152K B R (>30-750) R (10-100) R (>400) R (150)
Mishin et al. AAC. 2005;49:4516. Wetherall et al. AAC. 2003;41:742.
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Oseltamivir-Rimantadine for A/Qa/HK/G1/97 (H9N2) in Mice
Per
cent
Sur
viva
l (da
y 14
)
Oseltamivir dose (mg/kg/d)
Leneva et al. Antiviral Research. 2000;48:101.
0
20
40
60
80
100
0 0.1 1 10
Oseltamivir + Rimantadine 10 mg/kg/d
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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; viramidine
• Protease inhibitors– Aprotinin
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IV Peramivir in Influenza A/duck/MN/1525/81(H5N1) Infection in Mice
Drug Route Dose(mg/kg)
Survival (N=10)
Days to death (mean + SD)
Peramivir IV 30 x 1 100%* >21*
IV 10 x 1 100%* >21*
IV 3 x 1 50% 9.6 + 1.3
Oseltamivir Car IV 20 x 1 60% 8.0 + 1.8
Oseltamivir PO 10 bid x 5 d 70% 7.7 + 2.1
Saline IV -- 45% 9.1 + 1.4
* P<0.01 compared to saline controls Barnard et al. Presented at Second International Conference on Community Acquired Pneumonia, Montreal, Sept 17-19, 2005.
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Antivirals for Pandemic Influenza: Conclusions
• M2 inhibitors have proven efficacy in pandemic influenza and are a less costly option for prophylaxis if virus is susceptible
• Targeted geographic NAI prophylaxis might succeed in containing the emergence of a pandemic under certain conditions
• If available in sufficient time (rapid distribution) and quantities (stockpiling), NA inhibitors could provide substantial benefits in pandemic influenza
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Antivirals for Pandemic Influenza: Conclusions
• Oseltamivir-resistant N1 variants due to H274Y emerge during Rx but are less fit and retain susceptibility to zanamivir
• Concerns about NA inhibitor resistance should not be a deterrent to stockpiling decisions
• Need exists for alternative agents/approaches– An injectable NAI is needed, especially one with
activity for oseltamivir-resistant variants
– Combinations of antivirals and of antivirals and host immune response modifiers warrant study
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