Transcript Influenza A

Treatment and Prophylaxis of Influenza
Masoud Mardani M.D.
Professor of Infectious Diseases
1
Seasonasl Influenza
• Prophylaxis and Treatment
2
Antiviral Therapies for Influenza
Neuraminidase (NA)
NA Inhibitors
• Oseltamivir
• Zanamivir
Matrix protein (M2 )
M2 Inhibitors
• Amantadine
• Rimantadine
3
Antiviral Chemoprophylaxis of Influenza
Efficacy
(vs placebo or no drug)
Strategy
AM/RM
ZNV
OSEL
Seasonal
Non-immunized adults
85%-91% 84%1
84%
Immunized NH elderly
58%-75% ?
92%
Households
3%-100% 82%3
67%-89%2
Nursing homes
Variable
Post-contact/Post-exposure
1. Monto A et al. JAMA. 1999;282:31.
2. Hayden F et al. N Engl J Med. 1999; 341:1336.
3. Hayden F et al. N Engl J Med. 2000;343:12882.
4. Gravenstein S et al. J Am Med Dir Assoc. 2005;6:359.
5. Peters P et al. J Am Gerontol Soc. 2001;404:1025.
61%4
Yes5
4
Approved Antiviral Agents for Influenza
Treatment and Prophylaxis
Amantadine*
Rimantadine*
Zanamivir
Oseltamivir
Protein
target
M2
M2
NA
NA
Activity
A only
A only
A and B
A and B
Therapy
Adults and
children of
1 year
Adults
only
Adults and
children of
5 years
Adults and
children of
1 year
Yes
Adults and
children of
7 years
Yes
Prophylaxis
Yes
*CDC recommends that the previously approved M2 inhibitors amantadine (Symmetrel) and rimantadine
(Flumadine) not be used for the treatment or chemoprophylaxis of influenza A infections in the United
States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006).
Treanor J. Influenza Virus. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious
diseases. 6th ed. New York: Elsevier/Churchill Livingstone; 2005:2072.
http://www.fda.gov/bbs/topics/NEWS/2006/NEW01341.html.
5
Recommended Daily Dosage
Treatment and Prophylaxis of Influenza A and B
Antiviral Agent
Age Groups (years)
1-5
>5
Treatment
By weight
75 mg BID
Prophylaxis
By weight
75 mg QD
Treatment*
10 mg (2 inhalations) QD
10 mg (2 inhalations) QD
Prophylaxis*
10 mg (2 inhalations) QD
10 mg (2 inhalations) QD
Oseltamivir
Zanamivir
*Zanamivir approved for treatment in children >7 years, for prophylaxis in children >5 years
CDC recommends that the previously approved M2 inhibitors amantadine (Symmetrel) and
rimantadine (Flumadine) not be used for the treatment or chemoprophylaxis of influenza A
infections in the United States for the remainder of the 2005-2006 season (CDC. MMWR
Dispatch. January 17, 2006).
http://www.cdc.gov/flu/professionals/antiviralback.htm#table1
6
Oseltamivir: Resolution of All Flu Symptoms
Intent to Treat and Laboratory Documented Influenza Groups
120
Difference = 32 hours*
Difference = 21 hours†
100
Hours
80
60
40
20
0
Influenza Infected
*P < .001
†P = .004
Placebo
Treanor J et al. JAMA. 2000;283:1016-1024.
Intent toTreat
Oseltamivir 75 mg BID
7
Oseltamivir Treatment
Combined RCT Database, Confirmed Influenza
Placebo
Oseltamivir
5/662 (0.8%)
3/982 (0.3%)
% Reduction
Hospitalizations
Healthy adults
High-risk + elderly 13/401 (3.2%)
6/368 (1.6%)
Total
9/1350 (0.7%)
18/1063 (1.7%)
59%*
Lower Respiratory Tract Complications Leading to Antibiotic Use
Healthy adults
35/662 (5.3%)
High-risk + elderly 78/401 (18.5%)
Total
*P
17/982 (1.7%)
45/368 (12.2%)
109/1063 (10.3%) 62/1350 (4.6%)
55%†
= .02; †P < .001
Kaiser L et al. Arch Intern Med. 2003;163:1667.
8
Oseltamivir Resistance
Emergence During Treatment
Resistance Reported/
Number Patients
Rate of
Emergence
Adult trials
1/350
<<1%
US pediatric trial
5/147
4%
Japanese children
7/43
16%
Japanese children
9/50
18%
Setting
Kaiser L et al. Arch Intern Med. 2003;163:1667-1672.
Whitley R et al. Pediatr Infect Dis J. 2001;20:127-133.
Kiso M et al. Lancet. 2004;364:759-765.
9
Oseltamivir: Time to Return to Normal
Important Quality of Life Assessments
12
Days
10
Health Status
Activity Level
Difference = 1.9 days*
Difference = 2.8 days†
8
6
4
2
0
*P < .001
†P = .02
Placebo
(n = 129)
Oseltamivir
75 mg BID
(n = 124)
Treanor J et al. JAMA. 2000;283:1016-1024.
Placebo
(n = 129)
Oseltamivir
75 mg BID
(n = 124)
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Zanamivir Resistance
• Resistance not recorded in results from clinical trials1, 2, 3
• The only zanamivir-resistant mutant identified was in a virus from
an immunocompromised child4
• Particular binding mechanisms may account for low levels of
resistance to zanamivir5, 6
• Particular mutants are resistant to zanamivir in vitro7, 8
1. Monto A et al. Antimicrob Agents Chemother. 2006;50:2395-2402.
2. Ambrozaitis A et al. J Am Med Dir Assoc. 2005;6:367-374.
3. Herlocher M et al. J Infect Dis. 2003;188:1355-1361.
4. Gubareva L et al. J Infect Dis. 1998;178:1257-1262.
5. Moscona A. N Engl J Med. 2005;353:2633-2636.
6. Gupta R and Nguyen-Van-Tam J. N Engl J Med. 2006;354:1423-1424.
7. Yen H et al. Antimicrob Agents Chemother. 2005;49:4075-4084.
8. Mishin V et al. Antimicrob Agents Chemother. 2005;49:4515-4520.
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Influenza in Children
Overview
• Flu symptoms in school-age children and adolescents are
similar to those in adults
– Temperature of 101°F or above, cough, muscle ache,
headache, sore throat, chills, fatigue, general malaise
– Public advised to contact physician for these symptoms
• Children tend to have higher temperatures than adults,
ranging from 103°F to 105°F
• Flu in preschool children and infants is hard to pinpoint,
since its symptoms are so similar to infections caused by
other viruses
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Influenza in Immunocompromised Patients
• Immunocompromised patients suffer more complications
and have higher morbidity and mortality from influenza
infection
– High rate of hospitalization and ICU admissions
– Higher rate of pulmonary complications
• 50% of BMT and 13% renal transplant patients had lower
respiratory tract infections
• 50% of BMT and 7% of renal transplant patients with influenza
complicated by pneumonia
• 63% progressed to pneumonia
– 43% mortality
http://www.shea-online.org/Assets/files/W_-_Seasonal_and_Pandemic_Influenza__Children__Immunocompromised_Hosts__Pregnant_Women__and_Nursing_Home_Residents.ppt.
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Influenza In Pregnant Women
Adjusted Incidence Rates of Acute Cardiopulmonary
Events per 10,000 Women-Months for High Risk Women
Events per 10,000
women-months
120
Non-influenza
Peri-influenza *
Influenza
100
80
60
40
20
0
Not
Pregnant
1 to 13
14 to 26
27 to 42
Pregnancy Status (Weeks)
Neuzil K et al. Am J Epidemiol. 1998;148:1094-1102.
Postpartum
*November 1-April 30
period with no influenza
activity
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Seasonal Influenza
Prophylaxis and Treatment: Summary
• Efficacious and well-tolerated medications are available
for prophylaxis and treatment of seasonal influenza
• Neuraminidase inhibitors are useful to limit duration
and severity of influenza if taken early
– Use of M2 inhibitors is limited by widespread resistance
• Influenza prevention and treatment remain challenging
in special populations such as children, pregnant
women, and immunocompromised individuals like
transplant recipients
15
Pandemic Influenza
Avian Influenza in Humans
Avian H5N1
Swelling of the head and face in an affected bird
http://www.aphis.usda.gov/vs/birdbiosecurity/photos.html
17
Avian H5N1
Purple discoloration of the comb in the affected bird
http://www.aphis.usda.gov/vs/birdbiosecurity/photos.html
18
Nations with Confirmed Cases
H5N1 Avian Influenza (May 19, 2006)
http://pandemicflu.gov/
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H5N1 Antiviral Treatment
• Most H5N1 viruses sensitive to oseltamivir and
zanamivir: 3 H5N1 virus isolates reported resistant
to oseltamivir
• Most clade 1 H5N1 viruses resistant to
amantadine and rimantadine (most clade 2 viruses
sensitive to amantadine and rimantadine)
• Neuraminidase inhibitor treatment recommended
(oseltamivir)
http://www.who.int/csr/disease/avian_influenza/guidelines/protocolfinal30_05_06a.pdf.
http://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.html.
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Pandemic Influenza
Potential Antiviral Agents
Class/Agent
M2 inhibitors
Amantadine
Rimantadine
NA inhibitors
Zanamivir (GG167)
Oseltamivir (GS4104)
Peramivir (BCX-1812)*
Brand Name
Route
Symmetrel
Flumadine
PO
PO
Relenza
Tamiflu
Inhaled
PO
PO/IV/IM
*Investigational in US
CDC recommends that the previously approved M2 inhibitors amantadine and rimantadine
not be used for the treatment or chemoprophylaxis of influenza A infections in the United
States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17,
2006).
21
Oseltamivir Therapy in H5N1
Thailand and Vietnam, 2004-2005
Oseltamivir
Treatment
Number Patients
Number (%)
Survivors
Yes
25
6 (24%)
No
12
3 (25%)
Writing Committee. N Engl J Med. 2005;353:1374-1385.
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Oseltamivir Resistance
N1 Neuraminidase
• Frequency of drug therapy in humans
– H1N1: children 16% (7/43), adults 4% (2/50)
– H5N1: 2/8 (25%)
• Single nucleotide substitution (His274Tyr), leads to
– ↓ oseltamivir susceptibility (400–fold)
• Reduced replication in cell culture (>2.0 log10), leads to
– ↓ infectivity in mouse (1000-fold) and ferret (>10-fold)
– Variable ↓ pathogenicity in ferret
• Transmissible in ferret model
Ives J et al. Antiviral Res. 2002;55:307-317.
Herlocher M et al. J Infect Dis. 2004;190:1627-1630.
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Management
• Most hospitalized patients with avian influenza A
(H5N1) have required ventilatory support within 48
hours after admission,
• Empirical treatment with broad-spectrum antibiotics,
antiviral agents, alone or with corticosteroids ,have
been used in most patients
• Cultivable virus generally disappears within two or
three days after the initiation of oseltamivir among
survivors.
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Influenza A (H5N1) Pneumonia
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Case Detection and Management
• Hospitalization: in isolation whenever possible
• Antiviral Agents
• These viruses are susceptible in vitro to oseltamivir.
• Early treatment will provide the greatest clinical benefit.
– oseltamivir
• 75 mg twice daily for five days in adults weight-adjusted
twice-daily doses for five days in children older than
one year of age — twice-daily doses of 30 mg for those
weighing 15 kg or less, 45 mg for those weighing more
than 15 to 23 kg, 60 mg for those weighing more than
23 to 40 kg, and 75 mg for those weighing more than
40 kg) are reasonable for treating early, mild cases of
influenza A (H5N1)
26
• Higher doses (150 mg twice daily in adults) and
treatment for 7 to 10 days are considerations in treating
severe infections, but prospective studies are needed.
– long-acting topical neuraminidase inhibitors, ribavirin and
possibly, interferon alfa.
• Immunomodulators
– Corticosteroids have been used frequently in treating patients
with influenza A (H5N1), with uncertain effects.
27
–QUESTIONS ?
28
• Should oseltamivir, zanamivir, amantadine, and/or
rimantadine be used for treatment or prophylaxis?
• Should ribavirin, corticosteroids, immunoglobulin,
and/or interferon be used for treatment?
• Should broad-spectrum antibiotics be used for the
prevention of secondary pneumonia?
29
• To answer these questions, the guidelines include a
table with the recommended dose and duration of
treatment and chemoprophylaxis for management of
human infection with avian influenza A (H5N1) virus
in different age groups.
• Recommended agents include oseltamivir,
zanamivir, amantadine, and rimantadine for
treatment and prophylaxis.
30
•
• Groups at moderate-risk exposure are defined
as those with unprotected and very close
direct exposure to sick or dead H5N1 infected
animals or to poultry implicated directly in
human cases,
• Those involved in handling sick animals or
decontaminating known infected animals or
environments without proper use of personal
protective equipment,
• and healthcare personnel in close contact with
strongly suspected or confirmed H5N1
patients or virus-containing samples
31
• To determine who should receive
chemoprophylaxis:
• We defined high-risk exposure groups as
household or close family contacts of a strongly
suspected or confirmed H5N1 patient
• Because of potential exposure to a common
environmental or poultry source as well as
exposure to the index case.
32
• In a nonpandemic situation, recommendations for
treatment of patients with confirmed or strongly
suspected infection with avian influenza A (H5N1)
• are as follows:
33
• Patients should receive oseltamivir treatment as soon as
possible (strong recommendation).
• Clinicians might administer zanamivir (weak recommendation).
• If neuraminidase inhibitors are available, clinicians should not
administer amantadine alone as a first-line treatment (strong
recommendation).
• If neuraminidase inhibitors are not available and especially if
the virus is known or likely to be susceptible, clinicians might
administer amantadine as a first-line treatment (weak
recommendation).
34
• If neuraminidase inhibitors are available, clinicians
should not administer rimantadine alone as a first-line
treatment (strong recommendation).
• If neuraminidase inhibitors are not available and
especially if the virus is known or likely to be
susceptible, clinicians might administer rimantadine as
a first-line treatment (weak recommendation).
• If neuraminidase inhibitors are available and especially
if the virus is known or likely to be susceptible,
clinicians might administer a combination of
neuraminidase inhibitor and M2 inhibitor (weak
recommendation). This should only be done in the
context of prospective data collection.
35
• High-risk exposure groups should receive
oseltamivir as chemoprophylaxis continuing for 7 to
10 days after the last known exposure (strong
recommendation).
• In moderate-risk exposure groups, oseltamivir may
be administered as chemoprophylaxis, continuing
for 7 to 10 days after the last known exposure (weak
recommendation).
• Low-risk exposure groups should probably not
receive oseltamivir for chemoprophylaxis (weak
recommendation).
36
Pandemic Influenza
Prophylaxis and Treatment Summary
• Combating an influenza pandemic includes seasonal
influenza vaccination, social distancing techniques,
possible ring chemoprophylaxis
• Current antiviral possibilities for both prophylaxis and
treatment include NA inhibitors and M2 inhibitors
– NA inhibitors in limited supply and must be administered
within 48 hours from symptom onset
– M2 inhibitors could be useful against pandemic influenza,
but resistance to M2 inhibitors may develop rapidly
• Combinations of antivirals and of antivirals plus host
immune response modifiers warrant study
37
Seasonal
Influenza
Preparedness
Pandemic
Influenza
Preparedness
38