Transcript Antivirals for Pandemic Influenza (Slide Show)

Antivirals for Pandemic
Influenza
Frederick G. Hayden, MD
Division of Infectious Diseases and
International Health
University of Virginia School of Medicine
Charlottesville, Virginia, USA
Antiviral Agents For Influenza
Class/agent
Brand name
Route
Amantadine
Symmetrel
PO
Rimantadine
Flumadine
PO
Zanamivir (GG167)
Relenza
Inhaled
Oseltamivir (GS4104)
Tamiflu
PO
M2 inhibitors
NA inhibitors
Peramivir (BCX-1812)*
*Investigational at present in USA.
PO/IV/IM
Chemoprophylaxis
Amantadine Prophylaxis During
Pandemic Influenza
Protective Efficacy
Pandemic
Influenza A illness
Seroconversion
1968 H3N2
59-100%
28-52%
1977 H1N1
31-71%
19- 39%
Hayden. J Infect Dis. 1997;176:S56.
Projected Outbreak of H5N1
in Thailand
R0 = 1.5
Red = new cases.
Green = areas where the epidemic has finished.
Ferguson et al. Nature. Published online. August 2005.
Projected Outbreak of H5N1
Influenza in Thailand
Above: Controlled outbreak. Red = areas
of infection. Blue = areas where a combination
of control measures implemented.
Left: uncontrolled outbreak. Red = new cases.
Green = areas where the epidemic has finished.
http://www.nigms.nih.gov/news/releases/08032005.html
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.
Efficiency of Pandemic Antiviral Use
No.
Antiviral
persons strategy
Total
Percent Duration doses
on drug (days)
needed
1,000
Prophylaxis
100%
56
56,000
1,000
Treatment
35%
5
3,500
Efficiency of Pandemic Antiviral Use
No.
Antiviral
persons strategy
Total
Percent Duration doses
on drug (days)
needed
1,000
Prophylaxis
100%
56
56,000
1,000
Treatment
35%
5
3,500
16-fold .
Treatment
Nasal Aspirate Viral Detection in Hospitalized
Children: Effect of NAI Treatment
Influenza
virus
Antiviral
Tx
No. Duration Days of Detection
of fever
(hrs)
Antigen Culture
A/H3N2
None
Oseltamivir
Zanamivir
10
12
11
61 + 15
41 + 12
45 + 14
7.3 + 2.5 6.8 + 1.7
6.2 + 1.6 6.3 + 1.5
5.8 + 2.2 5.4 + 1.9
B
None
Oseltamivir
Zanamivir
9
8
9
62 + 20
47 + 14
41 + 17
4.6 + 1.0 6.2 + 1.3
4.1 + 1.5 5.6 + 1.5
3.9 + 1.3 4.3 + 1.3*
*P<0.5 versus no treatment.
Mean ages 3.1 – 6.7 years across groups
Sato et al. Ped infect Dis J. 2005;24:931.
Oseltamivir and Complications in ILI:
Retrospective Cohort Study, USA, 1999-2004
Outcome
< 30 days
Oseltamivir
Untreated
Adj. Hazard
(N = 39,202) (N = 136,799) 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%
0.042%
(N = 1)
( N = 56)
0.09 (0.01, 0.65)
Nordstrom et al. 2nd Euro Influenza Conf, abst no. S18-2, 2005.
Estimated Deaths per 100, 000 population
Estimated Pandemic Mortality, 1918-19
60
No Treatment
20% stockpile – treat all groups
50
10% stockpile – treat all groups
40
30
20
10
0
22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 2 4
1918
6 8 10 12 14 16 18
1919
Week no.
Gani et al. Emerging Infect Dis. 2005;11:1355.
H5N1 Virus
Oseltamivir in Experimental
A/HK/156/97 (H5N1) Infection of Mice
100
4 hours before infection
x
Percent of Survivors
80
24 hours delay
x
36 hours delay
x
60
48 hours delay
72 hours delay
control
40
Dose: 1mg/kg/d
x
20
x
0
7
8
9
10
x
x
11 12 13 14
Days After Infection
Leneva et al. Antiviral Res. 2000;48:101.
Oseltamivir for A/Vietnam/1203/04
Virus in Mice
5-Day Treatment
Survival Distribution Function
A
8-Day Treatment
B
1
1
10 mg/kg/day
0.75
0.75
1 mg/kg/day
0.5
0.5
0.25
0.25
0.1 mg/kg/day
placebo
0
0
0
5
10
15
20
Days After Inoculation
Yen et al. JID. 2005;192:665.
25
0
5
10
15
20
Days After Inoculation
25
Sensitivity of Reverse Genetic-Derived Influenza
Viruses to Neuraminidase (NA) inhibitors (NAIs) in
NA-inhibition and Virus-reduction Assays
IC50, nmol/L
Reverse-genetics virus
Zanamivir
EC50, µmol/L
Oseltamivir
Oseltamivir
carboxylate Zanamivir 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
Yen et al. JID. 2005;192:665.
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.
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
Amantadine Therapy in H5N1:
Hong Kong, 1997
Amantadine
treatment
No.
patients
No. (%)
survivors
10
6 (60%)
< 5 days
4
4 (100%)
> 6 days
6
2 (33%)
8
6 (75%)
Yes
No
K-Y Yuen, personal communication.
Complementary DNA
(log copies/ml of viral-tran sport medium)
Pharyngeal Viral Loads during
Oseltamivir Treatment of H5N1
8
Patient 1, died
Oseltamivirresistant
7
Patient 2, died
Patient 3, died
Oseltamivirresistant
Oseltamivirresistant
Patient 4, died
Patient 5, survived
6
Patient 6, survived
Patient 7, survived
5
Patient 8, survived
4
3
Oseltamivir-therapy
0
1
2
3
4
5
6
7
8
Days Since Admission
de Jong et al. NEJM. 2005;353:25.
9
10
11
Antiviral Resistance
Antiviral Resistance to M2 Inhibitors in
Community Isolates of A/H3N2, 1995-2005
80
70
China
Hong Kong
Japan
S Korea
Europe
USA
60
50
% 40
30
20
10
0
1995
1998
2000/1
2002
2003
2004
Bright et al. 2nd Euro Influenza Conf 2005. Lancet. pub online Sept 22, 2005.
2005
Antiviral Research 49 (2001) 147-156
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 resistance
Neuraminidase Inhibitor Susceptibility Network.
WHO Weekly Epi Record. April 29, 2005.
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 model
Ives et al. Antiviral Res. 2002;5:307.
Herlocher et al. JID. 2004;190:1627.
6
5
4
3
2
≤1
0
1
3
5
7
9
Days Postinfection
Changes in Body Temperature (ºC)
Virus Titer (Log10 PFU/ml)
Oseltamivir-Susceptible and Resistant H5N1
in Ferrets: Effect of His274Tyr Mutation
3
2.5
R cont
S cont
2
1.5
1
0.5
0
-0.5 1 2 3 4 5 6 7 8 9
-1
Days Postinfection
Oseltamivir – sensitive, mock treated
Oseltamivir – sensitive
Oseltamivir – resistant, mock treated
Oseltamivir – resistant
Le et al. Nature. 2005.
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.
Oseltamivir-Rimantadine for
A/Qa/HK/G1/97 (H9N2) in Mice
Oseltamivir
+ Rimantadine 10 mg/kg/d
Percent Survival (day 14)
100
80
60
40
20
0
0
0.1
1
Oseltamivir dose (mg/kg/d)
Leneva et al. Antiviral Research. 2000;48:101.
10
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
IV Peramivir in Influenza
A/duck/MN/1525/81(H5N1) Infection in Mice
Drug
Peramivir
Route
Dose Survival Days to death
(mg/kg) (N=10) (mean + SD)
IV
30 x 1
100%*
>21*
IV
10 x 1
100%*
>21*
IV
3x1
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.
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
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