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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
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
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
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)
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
Palese P. Nature Med 10:S82, 2004
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
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
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
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
Yamashita et al. 43rd ICAAC, abst. no. F-1830, 2003
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
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
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
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
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
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
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