Antivirals for Pandemic Influenza

Frederick G. Hayden, MDDivision of Infectious Diseases and

International HealthUniversity of Virginia School of Medicine

Charlottesville, Virginia, USA

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.

Chemoprophylaxis

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%

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

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

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. 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

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 .

Treatment

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.

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.

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

H5N1 Virus

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

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.

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

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

Yes

< 5 days

> 6 days

10

4

6

6 (60%)

4 (100%)

2 (33%)

No 8 6 (75%)

K-Y Yuen, personal communication.

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

Antiviral Resistance

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.

%

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 resistanceNeuraminidase 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 modelIves et al. Antiviral Res. 2002;5:307.Herlocher et al. JID. 2004;190:1627.

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

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

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

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 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.

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