Dr Masoud Mardani Prof of Infectious Diseases Shahid Beheshti University

updated its recommendations for the use

of influenza antiviral medicines

September 8, 2009 CDC

It is to prioritize use of these drugs for those patients

who are severely ill (hospitalized) and those patients with influenza-like illness and who are at high risk for influenza related complications.

limited situations in which antiviral medications should be used for chemoprophylaxis (prevention) this season.

The antiviral drugs should not be used for prevention in healthy persons based on community exposures.

Most people ill with influenza will recover without complications.

Some people are at increased risk of influenza complications and are prioritized for treatment with influenza antiviral drugs this season. They include:

People hospitalized with suspected or confirmed influenza

People with suspected or confirmed influenza who are at higher risk for complications • Children younger than 5 years old (children under 2

years old are at higher risk for complications than older children)

• Adults 65 years and older

• Pregnant women

• People with certain chronic medical or immunosuppressive conditions

People younger than 19 years of age who are receiving long-term aspirin therapy .

Treatment with influenza antiviral drugs is generally not needed for people who are not at higher risk for complications or do not have severe influenza, such as those requiring hospitalization.

However, any suspected influenza patient who presents with emergency warning signs (for example, difficulty breathing or shortness of breath) or signs of lower respiratory tract illness should promptly receive antiviral therapy

oseltamivir (trade name Tamiflu®)

or zanamivir (trade name Relenza®)

Or Peramivir which recently authorized

for IV use in emergency set up

is recommended for all people with

suspected or confirmed flu who require

hospitalization.

antiviral drugs should be started within 2 days after becoming sick.

These drugs can reduce the severity of flu symptoms and shorten the time you are sick by 1 or 2 days.

They may also prevent serious flu

complications.

Antiviral drugs may be especially important for people who are very sick (hospitalized) with the flu and who are at increased risk of serious flu complications, such as pregnant women, young children and those with chronic health conditions.

antiviral drugs are about 70% to 90%

effective against susceptible viruses (i.e.,

viruses that are not resistant to the

antiviral medication).

It’s important to remember that flu

antiviral drugs are not a substitute for

getting a flu vaccine

Even for patients whose treatment was started

more than 48 hours after illness onset.

When treatment is indicated, health care providers

generally should not wait for laboratory

confirmation of influenza to begin treatment with

antiviral drugs because laboratory testing can

delay treatment and because a negative rapid test

for influenza does not rule out influenza.

The sensitivity of rapid influenza diagnostic tests

can range from 10-70% for 2009 H1N1 virus.

Groups at higher risk for influenza related complications are similar to those at higher risk for seasonal influenza complications and include: children younger than 5 years old;

adults 65 years of age and older, pregnant women, people of any age with certain chronic medical

conditions (for example, asthma, diabetes, lung disease, people with weakened immune systems, etc.) and people younger than 19 years of age who are receiving long-term aspirin therapy.

The recommended duration of treatment

is five days.

However, hospitalized patients with

severe infections might require longer

treatment courses.

occupational risk for exposure (health care personnel, public health workers, or first responders who are working in communities with influenza A H1N1 outbreak), especially those at higher risk for complications of influenza, should carefully follow guidelines for appropriate personal protective equipment to prevent influenza exposure to influenza.

Antiviral chemoprophylaxis generally

should be reserved for people at higher

risk for influenza-related complications

who have had contact with someone

likely to have been infected with

influenza.

health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period.

However, use of recommended PPE and other administrative controls (e.g. having health care personnel stay home from work when ill, and triaging for identification of potentially infectious patients) should be used

there are no safety data regarding long

term or frequent use of antiviral agents in

children, and limited data for healthy

adults

Duration of antiviral chemoprophylaxis

post-exposure is 10 days after the last

known exposure

The preferred treatment of pregnant women, Oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women.

Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because of its systemic activity.

Side effects differ for each drug.

If an antiviral drug has been prescribed

for you, ask your doctor to explain how to

use the drug and any possible side

effects.

Health care professionals prescribing flu

antiviral drugs should alert patients

about adverse events that can occur.

Yes. CDC and ACIP recommend use of

antiviral drugs for people allergic to

eggs (which can cause them to have an

allergic reaction to the vaccine)

or for people who previously have

encountered complications from

Guillain-Barre syndrome (GBS)

associated with influenza vaccination.

The seasonal flu vaccine is unlikely to

provide protection against 2009 H1N1

influenza.

However a 2009 H1N1 vaccine is

currently in production and it is ready

for the public in the fall.

The 2009 H1N1 vaccine is not intended to

replace the seasonal flu vaccine – it is

intended to be used along-side seasonal

flu vaccine.

Pregnant women because they are at higher risk of complications and can potentially provide protection to infants who cannot be vaccinated;

Household contacts and caregivers for children younger than 6 months of age because younger infants are at higher risk of influenza-related complications and cannot be vaccinated. Vaccination of those in close contact with infants younger than 6 months old might help protect infants by “cocooning” them from the virus;

Healthcare and emergency medical

services personnel because infections

among healthcare workers have been

reported and this can be a potential

source of infection for vulnerable

patients. Also, increased absenteeism in

this population could reduce healthcare

system capacity;

All people from 6 months through 24 years of age • Children from 6 months through 18 years of age

because cases of 2009 H1N1 influenza have been seen in children who are in close contact with each other in school and day care settings, which increases the likelihood of disease spread, and

• Young adults 19 through 24 years of age because many cases of 2009 H1N1 influenza have been seen in these healthy young adults and they often live, work, and study in close proximity, and they are a frequently mobile population; and,

Once the demand for vaccine for the

prioritized groups has been met at the local

level, programs and providers should also

begin vaccinating everyone from the ages of 25

through 64 years.

Persons aged 25 through 64 years who have

health conditions associated with higher

risk of medical complications from

influenza

Current studies indicate that the risk for

infection among persons age 65 or older is less than the risk for younger age groups.

However, once vaccine demand among younger age groups has been met, programs and providers should offer vaccination to people 65 or older.

Swine Influenza (swine flu) is a respiratory disease of pigs caused by type A influenza virus that regularly causes outbreaks of influenza in pigs .

most outbreaks occur during the late fall and winter months similar to outbreaks in humans .

The classical swine flu virus (an influenza type A H1N1 virus) was first isolated from a pig in 1930

25%-30% of world’s

population (~500

million people) fell ill

>40 million deaths

worldwide; ~60% in

people ages 20-45

>500,000 deaths in

United States; 196,000

in October, 1918

alone

Influenza

Pandemic

of 1918-19

Hemagglutinin

Neuraminidase

Influenza Virus

Drift

Shift

Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. N Engl J Med 2009;10.1056/NEJMoa0903810

Comparison of H1N1 Swine Genotypes in Recent Cases in the United States

like seasonal flu, symptoms of swine flu infections can include:

fever, which is usually high, but unlike seasonal flu, is sometimes absent

cough runny nose or stuffy nose sore throat body aches headache chills fatigue or tiredness, which can be extreme diarrhea and vomiting, sometimes, but more commonly seen

than with seasonal flu

Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. N Engl J Med 2009;10.1056/NEJMoa0903810

Characteristics and Symptoms of the 642 Patients with Confirmed Swine-Origin Influenza A (H1N1)

Signs of a more serious swine flu

infection might include;

pneumonia and

Rapidly Progressive Pneumonia

respiratory failure.

With regular seasonal flu, infants and the

elderly are usually thought to be most at

risk for serious infections, in addition to

people with chronic medical problems.

Swine flu high risk groups, people who

are thought to be at risk for serious, life-

threatening infections, are a little

different and can include:

pregnant women

people with chronic medical problems,

such as chronic lung disease, like asthma,

cardiovascular disease, diabetes, and

immunosuppression

children and adults with obesity

More serious symptoms that

would indicate that a child with

swine flu would need urgent

medical attention

Fast breathing or trouble breathing

Bluish or gray skin color

Not drinking enough fluids

Severe or persistent vomiting

Not waking up or not interacting

Being so irritable that the child does not

want to be held

Flu-like symptoms improve but then

return with fever and worse cough

spring allergies - runny nose, congestion, and cough

common cold - runny nose, cough, and low grade fever

sinus infections - lingering runny nose, cough, and fever

strep throat - sore throat, fever, and a positive strep test

A respiratory specimen would generally need to be

collected within the first 4 to 5 days of illness (when an

infected person is most likely to be shedding virus .)

However, some persons, especially children, may shed virus

for 10 days or longer .

Identification as a swine flu influenza A virus requires

sending the specimen to Refference laboratory testing .

A respiratory specimen would generally need to be

collected within the first 4 to 5 days of illness (when an

infected person is most likely to be shedding virus .)

However, some persons, especially children, may shed virus

for 10 days or longer .

Identification as a swine flu influenza A virus requires

sending the specimen to Refference laboratory testing .

There are four different antiviral drugs that are licensed for use for the treatment of influenza: amantadine, rimantadine, oseltamivir and zanamivir .

The most recent swine influenza viruses isolated from humans are resistant to amantadine and rimantadine.

At this time, CDC recommends the use of oseltamivir or zanamivir for the treatment and/or prevention of infection with swine influenza viruses.

Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. N Engl J Med 2009;10.1056/NEJMoa0903810

Characteristics and Symptoms of the 642 Patients with Confirmed Swine-Origin Influenza A (H1N1)

Neuraminidase (NA)

Matrix protein (M2 )

M2 Inhibitors

• Amantadine

• Rimantadine

NA Inhibitors

• Oseltamivir

• Zanamivir

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%

Post-contact/Post-exposure

Households 3%-100% 82%3 67%-89%2

Nursing homes Variable 61%4 Yes5

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.

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

Prophylaxis Yes Yes

Adults and

children of

7 years

Yes

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.

*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).

Antiviral Agent Age Groups (years)

1-5

>5

Oseltamivir

Treatment By weight 75 mg BID

Prophylaxis By weight 75 mg QD

Zanamivir

Treatment* 10 mg (2 inhalations) QD 10 mg (2 inhalations)

QD

Prophylaxis* 10 mg (2 inhalations) QD 10 mg (2 inhalations)

QD

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

*Zanamivir approved for treatment in children >7 years, for prophylaxis in children >5 years

0

20

40

60

80

100

120

Influenza Infected Intent toTreat

Ho

urs

Placebo Oseltamivir 75 mg BID

Difference = 32 hours*

*P < .001 †P = .004

Treanor J et al. JAMA. 2000;283:1016-1024.

Difference = 21 hours†

Placebo Oseltamivir % Reduction

Hospitalizations

Healthy adults 5/662 (0.8%) 3/982 (0.3%)

High-risk + elderly 13/401 (3.2%) 6/368 (1.6%)

Total 18/1063 (1.7%) 9/1350 (0.7%) 59%*

Lower Respiratory Tract Complications Leading to Antibiotic Use

Healthy adults 35/662 (5.3%) 17/982 (1.7%)

High-risk + elderly 78/401 (18.5%) 45/368 (12.2%)

Total 109/1063 (10.3%) 62/1350 (4.6%) 55%†

*P = .02; †P < .001

Setting 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%

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.

Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. N Engl J Med 2009;10.1056/NEJMoa0903810

Susceptibility of 37 Isolates of Swine-Origin Influenza A (H1N1) Virus to Neuraminidase Inhibitors

Health Status Activity Level

0

12

8

6

4

2

Placebo (n = 129)

Oseltamivir 75 mg BID (n = 124)

10

Placebo (n = 129)

Oseltamivir 75 mg BID (n = 124)

Days

*P < .001 †P = .02

Treanor J et al. JAMA. 2000;283:1016-1024.

Difference = 1.9 days* Difference = 2.8 days†

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.

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

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.

0

20

40

60

80

100

120

Not

Pregnant

1 to 13 14 to 26 27 to 42 Postpartum

Non-influenza Peri-influenza Influenza

Neuzil K et al. Am J Epidemiol. 1998;148:1094-1102.

Influenza In Pregnant Women E

vents

per

10,0

00

wom

en-m

onth

s

Pregnancy Status (Weeks) *November 1-April 30

period with no influenza

activity

*

Seasonal

Influenza

Preparedness

Pandemic

Influenza

Preparedness