Transcript hayden - Flucentre

Epidemic and Pandemic Use of Antivirals
Introduction
15 September 2008
Frederick G. Hayden, M.D.
University of Virginia Health System
Charlottesville, Virginia, USA
Antiviral Agents for Influenza
Class/agent
Brand name
Route
Symmetrel
Flumadine
PO
PO
NA inhibitors
Zanamivir (GG167)
Oseltamivir (GS4104)
Peramivir (RWJ-270201)*
Relenza
Tamiflu
Inhaled/IV*
PO
IV*/IM*
Ribavirin
Virazole
Inhaled*/PO*
/IV*
M2 inhibitors
Amantadine
Rimantadine
*Investigational
Antivirals for Influenza: Overview
• Effective for prophylaxis and early therapy
– Useful in outbreak control
– Rapid antiviral effect
• Differing anti-influenza spectra
– Amantadine/rimantadine: influenza A only
– Oseltamivir/zanamivir: influenza A + B
• Favorable PK characteristics
– Treatment 2X/d; prophylaxis 1X/d
– Few drug interactions
• Differences in dosing routes, PK, tolerance,
efficacy, and resistance profiles
M2 Inhibitor 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 176:S56, 1997
Influenza Prevention In Households: PEP
Antiviral
(Study)
No.
Contacts
(age)
Oseltamivir
955
(Welliver et al, 2000)
(13+ yr)
Oseltamivir*
792
(Hayden et al, 2004)
(1+ yr)
Zanamivir*
837
(Hayden et al, 2000)
(5+ yr)
Zanamivir
1,291
(Monto et al, 2002)
(5+ yr)
*Index case given treatment
Reduction in
2° influenza
illness
89%
73%
Reduction
in influenza
infection
49%
35%
(Index +)
79%
62%
82%
59%
Antiviral Treatment of Acute Influenza
Outcome
M2I
ZNV
OSEL
Symptom relief
Yes
Yes
Yes
?
Yes
Yes
Decrease antibiotic use
?
28%
24-40%
Decrease hospitalization
?
?
~50%
?
?
Yes
~30%
No
Yes
Complications reduction
Treatment of viral
complications
Reduction in transmission
? = No placebo-controlled study or not reported
Oseltamivir Treatment Effects in
A(H5N1) Infection
Virus
Presumed
clade 1
Presumed
clade 2
Total
Survivors/
Treated (%)
Survivors/
Untreated
(%)
Pvalue
45/82 (55%)
6/26 (23%)
0.006
43/106 (41%)
1/30 (3%)
< 0.001
88/188 (47%)
7/56 (12%)
< 0.001
Adapted from Writing Committee of Second WHO Consultation on
Human H5 Infections. N Engl J Med 358: 261, 2008
7
Resistance to M2 Inhibitors (S31N) in
Community Isolates of A/H3N2, 2000-07
100
90
80
70
China
Hong Kong
Australia
Japan
Europe
USA
60
% 50
40
30
20
10
0
2000/1 2001/2 2002/3 2003/4 2004/5 2005/6 2006/7
Bright et al. Lancet 2005, JAMA 2006; Klimov et al. CDC
unpublished; Barr et al. Antiviral Res 2006; R Saito, Niigata Univ,
unpublished
Oseltamivir Resistance in H1N1 (H274Y)
• Rare in community H1N1 isolates, 1996-2007
– 0 to <1% in most surveys
– 2.2% in Japan in 2005-6 (but not in 2006-7 or
early in 2007-8)
• High prevalence in Europe and globally, 2007-8
– Patients without known oseltamivir use or
exposure to those on drug
– Generally no obvious epidemiologic links
• Household contacts, several apparent clusters
– Typical influenza illness; some fatalities
• Efficient person-to-person transmission
Oseltamivir Resistance in H1N1 Viruses
Region
Location
No. isolates
tested
% resistant
AMRO+
(17%)
Canada
USA
508
1026
26%
12%
EURO+
(25%)
France
Norway
496
265
47%
67%
WPRO+
(5%)
China/HK
Japan
666
1652
12%
3%
AFRO*
(85%)
South Africa*
Other*
107
20
100%
45%
Worldwide
4Q07- 1Q08
2Q08-20Aug08
7528
788
16%
31%
+4Q07-
1Q08
*2Q08-20Aug08
http://www.who.int/csr/disease/influenza/h1n1_table/en/index.html; 20 Aug 08
Antivirals for Seasonal, A(H5N1), and
Pandemic Influenza: Efficacy, Resistance,
and New Agents
15 September 2008
Frederick G. Hayden, M.D.
University of Virginia Health System
Charlottesville, Virginia, USA
Do We Need New Anti-Influenza Agents?
• Antiviral resistance
– Global spread of M2 inhibitor resistance in
H3N2 > H1N1
– New emergence of oseltamivir-resistant H1N1
– Dual M2 and NAI resistance in IC hosts
• Antiviral efficacy incomplete in H5N1 disease
– Oseltamivir resistance emergence
• Safety/efficacy ? in risk populations: infants
< 1 yr, pregnancy, hospitalized, IC hosts
• Lack of parenteral agents
Viral Loads and Antiviral Treatments in
Immunocompromised Host with Fatal
Oseltamivir-Resistant H1N1 Illness
Re-intubation 
Extubation 
Intubation 
• 67 yo male with
CLL + recent
chemoRx 
neutropenia
• Fever, cough,
SOB  acute
respiratory
failure
 Oseltamivir resistance (H274Y) 
Amantadine resistance (L26F)
Van der vries et al. NEJM 359:1074, 2008
Medical Needs for Anti-Influenza Antivirals
• Greater antiviral efficacy greater clinical
benefit
• Safety and efficacy in special risk
populations: infants < 1 yr, pregnancy,
hospitalized, immuno-compromised
• Reliable drug delivery in seriously ill patients
• Manage antiviral resistance
• Combinations
Influenza Virus Replication and Sites for
Antiviral Inhibition
De Clercq. Nature Reviews- Drug Discovery 5:1015, 2006
Investigational Anti-Influenza Agents
• Neuraminidase (NA) inhibitors
- Zanamivir (IV), peramivir (IV/IM), A-315675 (oral)
• Long-acting NA inhibitors (LANI)
– CS8958/R-118958 (topical), Flunet (topical)
• Conjugated sialidase- DAS181 (topical)
• HA inhibitors- cyanovirin-N, sialyl-glycopolymer,
arbidol
• Polymerase inhibitors- ribavirin; viramidine;
siRNA; T-705
• Protease inhibitors- aprotinin
• Biologics- antibodies, interferons
Investigational Agents in Clinical
Development
Agent
Target
Sponsor
Route
Development
phase
Zanamivir
NA
GSK
IV
Phase 1, 2a
Peramivir
NA
Biocryst
IV, IM
Phase 2
CS8958
NA
Sankyo,
Biota
Topical Phase 2
T-705
Polymerase
Toyama
Oral
DAS181
HA receptor
Nexbio
Topical Phase 1
Phase 2
Neuraminidase Inhibitors
Peramivir
NA Inhibitor Resistance Profiles
NA
NA
Susceptibility in the NAI assay (fold )
mutation type/
subtype Oselt
Zana
Peram A-315675
E119V
A/N2
R (>50>1000)
S (1)
S (1)
S (1-2)
R292K
A/N2
R (>1000)
S (4-25)
R (40-80)
S (8-13)
H274Y
A/N1
R (>700)
S (1)
R (40-100)
S (3)
R152K
B
R (>30750)
R (10-100)
R (>400)
R (150)
Mishin et al. AAC 49:4516, 2005; Wetherall et al. AAC 41:742, 2003; Abed et
al. Antiviral Res 77: 163, 2008
• IV zanamivir 600 mg or placebo twice daily X 5
days starting 4 hr before virus inoculation
• Highly protective against experimental
infection (14% vs 100%), virus shedding (0 vs
100%), and illness
Pharmacokinetic Profiles of Intravenous and
Intramuscular Peramivir
Intravenous
Intramuscular
• Linear PK; prolonged plasma T1/2elim (18 – 20 hr)
Kilpatrick JM, et al. Pharmacokinetics and Safety of Peramivir by Intramuscular
Administration, Options for the Control of Influenza VI, Toronto, 2007
21
IM Peramivir: Time to Alleviation of Illness
J Alexander, BioCryst Pharmaceuticals, unpublished data
Long Acting Neuraminidase
Inhibitors (LANI)- 2 Strategies
CS-8958
FLUNET
OMe
O
O
CH3(CH2)6
O
CO2H
OH
HN
O
HO
HO
OMe
O
R-125489
CO2H
O
HN
HN
O
OH
O
N
H
HO
HO
NH2
NH
OH
HN
O
X
N
H O
O
NH
HO
O
NH2
HN
HN
NH2
NH
Pro-drug
Clinical
Dimer
Preclinical
COMMERCIAL IN CONFIDENCE
O
HN
O
O
O
HN
OH
NH2
NH
23
Yamashita et al. 43rd ICAAC, Abstract no. F-1830, 2003
• Double-blinded trial found that inhaled CS-8958
administered once only was not statistically
different than standard oseltamivir regimen.
T-705: Summary of Pre-Clinical Findings
F
N
OH
N
CONH2
T-705
6-fluoro-3-hydroxy-2pyrazinecarboxamide
Furuta et al. AAC
46:977, 2002; AAC
49:981, 2005
• Inhibitory for influenza A, B, C
viruses: EC50s 0.01 - 0.5 µg/ml
• Active against flavi, arena,
bunya, picorna, alpha, and
paramyxo viruses
• Cytotoxicity for mammalian
cell > 1,000 µg/ml
• Triphosphate is inhibitor of
influenza RNA polymerase.
• Active orally in murine models
T-705: In Vitro Activity vs Ribavirin
IC50(μM) ± SD
(A PR/8/34 H1N1
influenza)
CC50(μM) ± SD
(MDCK cells)
T-705
1.0 ± 0.9
> 6,370
Ribavirin
31.6 ± 9.2
94.3 ± 47.6
Compound
Furuta Y, et al. Antimicrob Agents Chemother. 2005;49:981-986.
Effect of a T-705 Treatment in Mice
Exposed to Lethal A/Duck/N/1525/81
(H5N1) Virus
Control
T-705, 300 mg/kg
* *
100
*
* *
*P < .01 relative to control
*
80
Survival (%)
T-705, 600 mg/kg
*
*
60
40
20
0
4
12
24
48
60
Delay before starting treatment following viral exposure, hours
Sidwell RW, et al. Antimicrob Agent Chemother. 2007;51:845-851.
Pharmacokinetics of Oral T-705
– Mainly excreted as T705M1 in urine
• Single doses up to
1,600 mg or multiple
up to 400 mg tid for 7
days well tolerated
90 mg (n=6)
200 mg (n=6)
100
T-705 Plasma Concentration (μg/mL)
• Bioavailability > 97%
in mouse
• Rapid absorption in
humans (Tmax < 1 hr)
• Plasma T1/2elim from
1.3 to 3.9 hr
30 mg (n=6)
400 mg (n=6)
800 mg (n=6)
1600 mg (n=6)
10
1
0.1
0.01
0.001
0
3
6
9
12
15
18
21
24
Time after dose (hr)
Single oral doses of T-705 over
a range of 30 to 1600 mg
Toyama Chemical Co, unpublished
Molecular Model of DAS181 (Fludase®)
• Fusion construct with
catalytic domain of A.
viscosus sialidase and
an epitheliumanchoring domain
(human amphiregulin)
– Active against both α2,6and α2,3-linked sialic
Malakhov et al. AAC 50:1470,
2006
acid receptors
Preclinical Features of DAS181
• Inhibitory for range of influenza A and B
viruses
– In vitro EC90 values: 1-14 nM
– Epithelial tag increases activity 5-30 fold
– Pretreatment (24 hr) effective
• Intranasal dosing shows
– Prophylactic and therapeutic activities in mice
– Antiviral effects with reduced inflammatory
responses in ferrets
Malakhov et al. Antimicrob Agent Chemother 50:1470, 2006
Effect of DAS181 on S. pneumo Binding
to Human Airway Epithelium (HAE) Cells
• DAS181 treatment had no significant effect on
adherence.
Nicholls et al. J Antimicrob Chemother 62:426, 2008
DAS181 Treatment in Mice with H5N1
• Dose of 1
mg/kg/d for
7-8 d
• Inoculum of
3 MLD50
• Time-totreatment
effects on
survival and
lung titers on
day 3 and 6.
Belser et al. JID 196:1439, 2007
Potential Role of Combination Antiviral
Therapy in Influenza Treatment
• Combinations evaluated in animal models
– Amantadine + interferon
– M2 inhibitors + ribavirin
– M2 inhibitors + oseltamivir
– Oseltamivir + ribavirin
• Combinations evaluated in humans
– Oral rimantadine + nebulized zanamivir
• Future
considerations
– Dual NAIs
– Triple therapy: M2 inhibitor + ribavirin (or other
transcriptase inhibitor) + IFN-α or NAI
– Inclusion of other novel agents
Ong and Hayden. J Infect Dis 196:181, 2007; Hayden FG. Antivir Res 71:372, 2006
CASG* Trial of Nebulized Zanamivir +
Rimantadine in Hospitalized Adults
Measure
Zanamivir + Rimantadine P value
Rimantadine
alone
No or mild
cough,
day 3
15/16 (94%)
11/20 (55%)
.01
4.7 ± 2.3
5.2 ± 2.3
.52
0
3
ND
Days of
hospitalization
Frequency of
rimantadine
resistance
*CASG = Collaborative Antiviral Study Group.
Ison et al. Antiviral Ther. 2003;8:183-190.
Survival of mice inoculated with rg VN-1203/04 –
Amantadine susceptible
Combination therapy
1
0.75
AM 30
0.5
AM 15
OS 10
0.25
AS 1.5
Control
0
0
5
10
OS 1
15
Days after inoculation
20
Survival distribution function
Survival distribution function
Single-drug therapy
1
AM 30 + OS 10
0.75
AM 15 + OS 10
0.5
0.25
Control
0
0
5
10
15
20
Days after inoculation
Ilyushina et al. Antiviral Therapy 12;363, 2007
39
• Comparison of monotherapy with i.p.
zanamivir (ZNV), celecoxib, mesalazine, or
gemfibrizol to triple regimen of ZNV +
celecoxib + mesalazine in mice
– High inoculum of A/Vietnam/1194/04 (103 LD50)
– Therapy initiated at 48 hrs post-inoculation
– No survival benefit of early therapy (4 hrs) with
single agents except ZNV
Zheng et al. PNAS, on line 6/2008
Antiviral + Immunomodulator Therapy for
H5N1 in Mice
•  survival with ZNV + celecoxib + mesalazine
• 2/8 surviving mice in triple therapy group had
detectable titers at day 21.
Influenza Antivirals: Future Directions
• Goal: Rapid inhibition of influenza viral
replication at all affected sites
• Near-term: parenteral NAIs
– IV zanamivir or IV/IM peramivir
• Next: antiviral combinations
– NAI plus M2 inhibitors, polymerase inhibitor
(T-705 or ribavirin), or neutralizing antibodies
• Longer-term:
– Antivirals with immunomodulators
– Host function-targeted agents
Forthcoming Book from ASM Press
• Third edition
• Updates 2002
version
• Available first
quarter 2009
44
Back-up Slides
• Pre-clinical assessment of arbidol toxicity and
antiviral activity
– Ethyl-6-bromo-4-[(dimethylamino)-methyl]-5hydroxy-1-methyl-2-[(phenylthio)methyl]-indole3-carboxylate hydrochloride monohydrate
– Previous reports of activity for influenza,
hepatitis B and C viruses
Shi et al. Arch Virol 152:1447, 2007
• Influenza testing by CPE inhibition in MDCK cells
• Arbidol causes overt cytotoxicity at >16 ug/ml
• Broad spectrum; narrow therapeutic index
Shi et al. Arch Virol 152:1447, 2007
In Vivo Activity of Arbidol
• Murine model of
A/PR/8/34(H1N1)
• Drugs by oral
gavage X 6 d
starting 24 hr previrus
• Up to ~3 log10 
lung virus titers
• LD50 of 314
mg/kg/d for arbidol
• Narrow TI
Shi et al. Arch Virol 152:1447, 2007
• Kinetic analysis of NA (sialidase) activity
– Whole virus suspensions of isolates from
2007-8 and prior seasons
• Vm (reflecting enzyme activity) similar in
susceptible and resistant isolates from 2007-8
but both ~3X  than in earlier H1N1 viruses
• Km (reflects substrate affinity) ~2X  in
susceptible H1N1 from 2007-8 than earlier;
intermediate for oseltamivir-resistant isolates
Rameix-Welti et al. PLoS Pathogens 4:e1000103, 2008
Growth of H1N1 Viruses from 2007-8 in
MDCK SIAT-1 Cells
• Replication of
oseltamivirresistant H1N1
(H274Y) isolates
not impaired in
vitro compared
to susceptible
H1N1 viruses
from 2007-8 or
earlier.
Rameix-Welti et al. PLoS Pathogens 4:e1000103, 2008
S
R
S
R
NA Gene
Phylogeny
• NA substitutions
found in majority
of H1N1 from 20078 include 3 near
catalytic site (222,
249, 344).
•  NA affinity for
substrate and NAIs
may have altered
HA-NA balance to
 fitness ?
Rameix-Welti et al. PLoS
Pathogens 4:e1000103, 2008
Clinical Experience Suggests No Role for
Corticosteroids in A(H5N1) Treatment
•Vietnam
Survival
Steroid Rx
No steroids
Pvalue
Hanoia
12/29 (41%)
29/38 (76%)
0.008
Published
casesb
3/19 (16%)
10/15 (66%)
0.007
a Cao
T, Liem NT. N Engl J Med 2008; 358: 261
b Emerg Infect Dis 2005; 11: 201; N Engl J Med 2004; 350: 1179;
N Engl J Med 2006; 355: 2186-94.
Convalescent Plasma Therapy in H5N1
Disease
• Case report of 31 yo male who presented
with 4 day Hx of fever, cough, and sputum
– CXR on day 6 showed LLL pneumonia
– Tracheal aspirate + H5N1 by RT-PCR and
culture
– Oseltamivir 150 mg bid started day 9 of
illness but progressive bilateral pneumonia
– Convalescent plasma infusions from H5
survivor (200 ml X 3) on days 12-13
• Plasma neutralizing ab titer of 1:80
– Hospital discharge on day 30
Zhou et al. NEJM 357:1450, 2007
Convalescent Plasma Therapy in H5N1
Disease
• Relative contributions of exogenous plasma, endogenous
immune responses, and oseltamivir ?
Zhou et al. NEJM 357:1450, 2007
• H5N1 hyperinduces COX-2 and proinflammatory cytokine RNAs in macrophages but
not type 2 alveolar epi cells, compared to
H1N1.
• COX-2 expressed in epithelial cells of
autopsy lung tissue of H5N1 patients