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Zanamivir is Efficacious in the Adolescent Population

Question

  • In an adolescent with signs and symptoms of acute influenza infection less than 48 hrs in duration, would treatment with zanamivir significantly decrease the duration/course of disease permitting earlier return to normal daily activities?

Clinical Bottom Lines

  1. Patients with influenza have a earlier alleviation of symptoms when receiving inhaled zanamivir by median times of 1 to 1.5 days with a mean of 0.7 days.1
  2. In patients with influenza, initiating use of zanamivir while febrile or starting within 30 hrs of onset of symptoms will result in the greatest benefit with alleviation of symptoms by 2-3 days median time and 3 days median time.
  3. Patients starting treatment with inhaled zanamivir within 30 hrs of symptom onset return to usual activities 1 day (median) and 1.3 day (mean) sooner than those receiving placebo.


Summary of Key Evidence

  1. Published in 1997, Hayden et al 1 describes randomization to placebo, inhaled zanamivir, or inhaled/intranasal zanamivir of 417 patients in North American and Europe, ages 13 to 46 yrs of age.  Each had suspected influenza with symptoms less than 48 hrs duration.  Treatment was for 5 days.  Results as in Table 1.
  2. The MIST, Management of Influenza in Southern Hemisphere) group published in 1998 results of randomization of 455 patients with suspected influenza, ages 12 and older.2  Each patient had symptoms less than 36 hours.  Each received five days of treatment with inhaled zanamivir or placebo.  Table 1 summarizes results.
  3. In Hayden et al, the time for return to usual activities was measured in both placebo and zanamivir-receiving groups as summarized in Table 2.
  4. In Hayden et al (1), 31% of intention to treat placebo group were asymptomatic at 5 days vs 40 % of inhaled zanamivir (AAR=9%; NNT=11)1.  In flu positive groups, 50% of placebo were asymptomatic at 5 days vs 62% in inhaled zanamivir (AAR = 12%; NNT = 8).   In those flu positive and symptomatic < 30 hrs, 42% of  placebo were asymptomatic at 5 days vs 68% of those treated with inhaled zanamivir (AAR = 26%; NNT =4).
  5. In MIST (2) high risk participants,  46% of the placebo group vs 14% of the zanamivir group had complications with bronchitis (8%), pneumonia (4%), and other chest infections (7%) (p=0.004; ARR = 32%; NNT = 3); 38% of placebo vs 14 % of zanamivir groups needed antibiotics (p= 0.025; ARR =24%; NNT =4).  NOTE THAT THE METHODS DID NOT INDICATE WHAT PROPORTION OF THESE GROUPS WERE PEDIATRIC PATIENTS.

Table 1: Time to Alleviation of Major Symptoms

Study
Group
Zanamivir Median (Mean)
Placebo Median (Mean)
Difference Median (Mean)
p-value (median difference)
Hayden et al, 1997
All intention to treat
5 (5.3)
5 (6.0)
-0 (-0.7)
0.05
 
Fever at Enrollment (>37.8)
4 (5.3)
7 (6.8)
-3 (-1.5)
0.01
 
No Fever at Enrollment
4 (5.5)
4 (5.5)
0 (0)
0.93
 
<30 hr symptoms
4 (5.1)
7 (7)
-3 (-2.9)
0.001
 
30-48 hr symptoms
5 (5.8)
4 (5.5)
-1 (-0.3)
0.68
MIST, 1998
All intention to treat
4.5
6.0
-1.5
0.004
 
Fever at Enrollment (>37.8)
4.5
6.5
-2.0
<0.001
 
No Fever at Enrollment
6.0
5.5
0.5
0.93
 
High Risk, flu-positive*
5.0
8.25
-3.25
0.161

* High risk defined as chronic respiratory disease, cardiac disease, metabolic disorders, immunocompromised, and age >65.

Table 2: Time to Resumption of Usual Activities in Days
 

Study
Group
Zanamivir Median (Mean)
Placebo Median (Mean)
Difference Median (Mean)
p-value (mean difference)
Hayden et al, 1997
Confirmed flu infection
4 (4.6)
4 (4.9)
0 (-3)
0.41
 
Fever at enrollment (>37.8)
4 (4.5)
5 (5.1)
-1 (-0.6)
0.23
 
No Fever at enrollment
4 (4.7)
3 (4.5)
1 (0.1)
0.81
 
<30 hr symptoms
4 (4.1)
5 (5.4)
-1 (-1.3)
0.02
 
30-48 hr symptoms
5 (5.1)
4 (4.4)
1 (0.7)
0.26

Additional Comments

  • Studies were conducted during influenza season and defined influenza-like illness (inclusion criteria) as fever/feverishness and two or more of the following: cough, headache, myalgia, sore throat.  Each patient was tested for influenza via nasal/throat swabs for culture and/or antigen detection and/or a four-fold increase in specific antibody production.
  • In the study by Hayden 63% of symptomatic enrollees were influenza positive w/ 56% type A, 44% type B.1  In MIST  71% of patients were influenza positive w/ 67% type A, 33% type B.2  Both studies reported equal efficacy among A and B types w/ no appreciable efficacy in non-influenza positive patients.
  • Zanamivir is well tolerated with adverse effects of GI and respiratory irritation; however these are poorly distinguished from influenza illness itself.
  • Cost of treatment is generally approximately $50 for a 5 day course during the 1999-2000 season.
  • Rapid detection (Directigen Flu A) has been developed requiring 20 min with sensitivity and specificity of 70% and 99% respectively.

Citation

  1. Hayden FG, et al.  Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. New England Journal of Medicine.  1997; 337:874-80.
  2. MIST Study Group.  Randomized trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet.  1998; 352:1877-81.

CAT Author: Pat Seed, MD, Ph.D

CAT Appraisers: John G. Frohna, MD

Date appraised: January 17, 2000

Last updated June 14, 2003
Department of Pediatrics and Communicable Diseases
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