Oral oseltamivir treatment of influenza in children
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Pediatr Infect Dis J, 2001;20:127–33 Vol. 20, No. 2 Copyright © 2001 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. Oral oseltamivir treatment of influenza in children RICHARD J. WHITLEY, MD, FREDERICK G. HAYDEN, MD, KEITH S. REISINGER, MD, NANCY YOUNG, MD, REGINA DUTKOWSKI, PHD, DAVID IPE, MSC, ROGER G. MILLS, MD AND PENELOPE WARD, MD Background. Oral oseltamivir administration Oseltamivir treatment did not affect the influen- is effective treatment for influenza in adults. za-specific antibody response. This study was conducted to determine the effi- Conclusions. Oral oseltamivir administration cacy, safety and tolerability of oseltamivir in is an efficacious and well-tolerated therapy for children with influenza. influenza in children when given within 48 h of Methods. In this randomized, double blind, pla- onset of illness. cebo-controlled study, children 1 through 12 years with fever [>100°F (>38°C)] and a history INTRODUCTION of cough or coryza
128 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 20, No. 2, Febuary, 2001
METHODS TABLE 1. The Canadian Acute Respiratory Infection and
A double blind, randomized, placebo-controlled, mul- Flu Scale (CARIFS) symptoms
ticenter trial was conducted during the influenza sea- 1 Poor appetite
son of 1998 to 1999 in the United States (70 sites) and 2 Not sleeping well
3 Irritable, cranky, fussy
Canada (10 sites). This study was conducted in accor- 4 Feels unwell
dance with the principles of the Declaration of Helsinki 5 Low energy, tired
6 Not playing well
(amended). Institutional review boards approved the 7 Crying more than usual
protocol at each center. All caregivers provided written 8 Needing extra care
9 Clinginess
informed consent before enrollment. Patients also gave 10 Headache
written consent if they were old enough to understand 11 Sore throat
12 Muscle aches or pains
the risks and benefits of the study. 13 Fever
Study population. When surveillance demon- 14 Cough
15 Nasal congestion, runny nose
strated that influenza was circulating in the commu- 16 Vomiting
nity, children between the ages of 1 and 2 years, 17 Not interested in what’s going on
18 Unable to get out of bed
presenting within 48 h of illness onset and having an
oral/otic temperature ⱖ100°F (37.8°C) and at least
one respiratory symptom (cough or coryza), were
offered enrollment into the study. Study exclusion graded as 0 ⫽ no problem, 1 ⫽ minor, 2 ⫽ moderate,
criteria included: children with respiratory syncytial 3 ⫽ severe or not evaluable. In the computation of the
virus infection (rapid antigen); hospitalized ⬎24 h; total CARIFS at each assessment, a recording of not
evidence of a poorly controlled systemic illness; im- evaluable was not included in the total score. The three
munosuppressed (drugs, transplant recipient, malig- components recorded on the diary card were assessed
nancy or human immunodeficiency virus infection); twice daily (at the same time as drug administration
or history of acetaminophen (paracetamol) allergy. during the treatment period) for the first 10 days and
Influenza therapy (within 4 weeks) and participation once daily thereafter. In addition during the first 3
in a clinical trial with an investigational drug were days, temperature was recorded at a third time,
also exclusion criteria. Influenza immunization was namely midway between the administration of daytime
not an exclusion criterion. doses.
Study design. A physical examination was per- Virologic methods. Nasal and throat swabs were
formed at baseline. A block randomization by site was obtained for detection of influenza virus at enrollment
used. Children were randomized to receive either placebo and on Days 6 and 10. A subset of patients had
or liquid oseltamivir at 2 mg/kg/dose (to a maximum of additional swabs taken on Days 2 and 4 for virus
100 mg/dose) twice daily for 10 doses and were stratified isolation. Swabs were placed in a viral transport me-
for the presence of otitis media at enrollment. All patients dium (Microtest, Atlanta, GA) and shipped by air
were offered acetaminophen for symptomatic relief. express to a central laboratory (Viromed Laboratories,
A physical examination was performed, and blood Inc., Minneapolis, MN). Specimens were inoculated
samples were taken for standard hematologic and onto rhesus monkey kidney cells.18, 19 Isolates were
clinical biochemistry assays at baseline and Day 6. confirmed by immunofluorescence methods with mono-
Tympanometry was performed at enrollment and on clonal antibodies.19 Serum hemagglutination inhibi-
Days 6, 10 and 28. Secondary complications (defined as tion (HAI) antibody titers19 were measured in paired
otitis media, sinusitis, bronchitis or pneumonia requir- acute (enrollment) and convalescent (Day 28) blood
ing physician-prescribed antibiotic intervention that samples. Influenza infection was defined by virus re-
commenced on or after Study Day 3) were recorded. In covery and/or a 4-fold rise in the HAI antibody titers.
addition total antibiotic usage, regardless of diagnosis, Viral isolates from patients were used to investigate
was recorded. Response to therapy was recorded by the the potential for development of resistance based on
caregiver on a diary card with three major components: analysis by neuraminidase inhibition phenotype.20
the patient’s temperature; an assessment of 18 influ- Data analyses. Randomized patients who received
enza symptoms, as shown in Table 1; and the ability of one dose of medication comprised the intent to treat
the child to return to day care/school and/or resump- population (ITT). Patients with laboratory-confirmed
tion of their normal “preillness” daily activity. Diary influenza formed the intent to treat infected (ITTI)
cards also recorded the administration of analgesics/ population. Efficacy analyses were performed on the
antipyretics (acetaminophen) and compliance with the ITTI population, and tolerability was assessed in the
daily regimen of study medication. safety population. All data were recorded on standard-
The 18-influenza symptoms evaluation was assessed ized case record forms
using the validated Canadian Acute Respiratory Infec- The primary endpoint was the time to resolution of
tion and Flu Scale (CARIFS).17 Each symptom was illness. This was defined as the length of time from theVol. 20, No. 2, Febuary, 2001 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL 129
start of the treatment to the first time at which the RESULTS
following conditions were resolved simultaneously and A total of 698 patients from 80 centers in the United
remained so for at least 24 h: (1) cough and nasal States and Canada were enrolled into the study. Three
congestion reported as no or minor problem; (2) return patients withdrew before taking any medication. For 2
to day care/school, or resumption of preillness daily children parental consent was withdrawn for one; for
activity; and (3) temperature ⱕ98.9oF (37.2oC). Data the other phlebotomy was refused. The demographics
from patients who withdrew before resolution of all the of the remaining 695 patients were similar for the
above conditions were censored at the time of the last placebo and oseltamivir recipients (Table 2). Children 2
assessment (i.e. they contributed to the analysis of time years of age or younger accounted for a large proportion
to alleviation of illness until withdrawal from the of both groups (placebo 26%, oseltamivir 23%). Influ-
study). enza was diagnosed in 452 (65%) patients, of whom 235
Other endpoints included time to return to normal received placebo and 217 received oseltamivir (ITTI
health and activity (a component of the primary end- population). The demographic characteristics of the
point), the incidence of secondary illnesses (i.e. otitis ITTI population were similar to that for the ITT popu-
media, etc.), time to alleviation of all CARIFS symp- lation.
The clinical characteristics for the ITTI patients are
toms and the severity of illness [area under the curve
shown in Table 3. Only 3% of children were immunized
(AUC) for the total CARIFS scores]. Other analyses
against influenza. Influenza A, and less often influenza
explored effects on individual symptoms, acetamino-
B, occurred in comparable proportions of the groups.
phen and antibiotic use, viral shedding and hospital-
Otitis media was diagnosed in 15 to 16% at enrollment.
ization rates. Analyses were not adjusted for multiple The median duration of illness before the first dose of
comparisons. medication was similar in both groups. No efficacy
A weighted Mantel-Haenszel test, which accounts information was available from 10 placebo-treated and
for censored data, was used for time to event analyses. 8 oseltamivir-treated patients, and a further 13 place-
The test was stratified for geographic region and the bo-treated and 15 oseltamivir-treated patients data
presence of otitis media at enrollment. Regions were were censored because of missing data points.
defined on a geographic basis to give ⬃40 subjects per Clinical efficacy. Among influenza-infected chil-
treatment group in the ITTI population and identified dren oseltamivir therapy reduced the median time to
before unblinding. The weighting scheme used the resolution of illness by 36 h (26%; P ⬍ 0.0001) com-
generalized Gehan-Wilcoxon weights for which the pared with placebo (Table 4). A difference in the pro-
weighting is equal to the number in the risk group. The portion of children who improved was apparent within
results are reported for median duration for each 24 h after initiating therapy and persisted until ⬃480
treatment group with 95% confidence intervals. Esti- h (Day 20), at which point the two groups were compa-
mates of the difference in median duration were ob- rable, as shown in Figure 1. The time to resolution of
tained from the Kaplan-Meier curves. Estimates of the illness was shorter in oseltamivir than in placebo
intergroup variability were obtained through boot- recipients for all age groups analyzed, as shown in
strapping21 to provide a 95% confidence interval. For Table 4. The individual components for alleviation of
the severity of illness endpoint AUC for total CARIFS illness were all achieved earlier in oseltamivir than in
symptoms was analyzed by an extended Wilcoxon rank placebo recipients (Table 4).
sum (van Elteren) test, stratified for region, presence of For the entire ITT population (all randomized chil-
otitis media at baseline and age (ⱕ2, 3 to 5, 6 to 12). dren) oseltamivir treatment also significantly reduced
The relative risk (and 95% confidence interval) of the median time to resolution of illness by 21 h (17%,
developing otitis media was computed by comparison of
proportions. All analyses were performed with SAS
(Version 6.12) systems and procedures (SAS Institute, TABLE 2. Demographic characteristics of the intent to
treat population
Cary, NC).
Sample size. The sample size calculation was based Demographic Characteristic
Placebo Oseltamivir
(n ⫽ 351) (n ⫽ 344)
on adult treatment studies, assuming an estimated
treatment difference of 1.25 days (SD, 4 days). A cohort Sex (males) 179 (51)* 171 (50)
Median age, yr (range) 5 (1–12) 5 (1–12)
of 170 infected patients per treatment group was re- Median wt, kg (range) 20 (8 – 85) 20 (8 – 69)
quired to detect this treatment difference with a two Race
Caucasian 229 (65) 222 (65)
group t test at the 5% level of significance and an 80% Hispanic 61 (17) 62 (18)
power. On the basis of an influenza infection rate of Black 39 (11) 37 (11)
Oriental 6 (2) 7 (2)
⬃50%, this study was designed to recruit ⬃680 pa- Other 16 (5) 16 (5)
tients. * Numbers in parentheses, percent unless otherwise stated.130 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 20, No. 2, Febuary, 2001
TABLE 3. Clinical characteristics of the intent to treat prescribed antibiotic treatment was also significantly
infected population lower in the oseltamivir group (68 of 217, 31%) com-
Clinical Characteristic Placebo Oseltamivir pared with placebo recipients (97 of 235, 41%; P ⫽
Influenza-infected 235 217
0.03).
Influenza A 153 (65) 150 (69) No patient in the oseltamivir group and two patients
Influenza B 82 (35) 66 (31)
Influenza A and B 0 1 (0)
in the placebo group required hospitalization during
Median duration of illness 28.0 26.7 this study. One child was hospitalized for dehydration
before study start (h)
Symptom onset ⬎48 h 7 (3) 6 (3) and one for ingestion of a caustic substance.
Immunized 6 (3) 4 (2) Virologic measures. The shortened clinical course
Otitis media at baseline 35 (15) 34 (16)
Median baseline symptom 30 (5–51) 32 (0 –52) of influenza was accompanied by an accelerated decline
score (range) in virus recovery from the upper respiratory tract.
Median baseline temperature, 101.8 (97.8 –106.8) 102.0 (96.8 –106.3)
°F (range) More than 90% of patients in each group shed virus at
* Numbers in parentheses, percent unless otherwise stated. enrollment (placebo 207 of 231, oseltamivir 191 of 213).
The majority of patients had nose/throat swabs taken
on Days 2, 4 and 6 of the study. In this population, by
105 h, 95% confidence interval, 91 to 112, vs. 126 h,
95% confidence interval, 117 to 137; P ⫽ 0.0002). Day 4 only 51 of 93 (55%) of patients receiving oselta-
Influenza-infected children who received oseltamivir mivir shed virus compared with 72 of 105 (69%) of
had a significant reduction in the median duration of placebo recipients. Oseltamivir treatment significantly
total CARIFS symptoms compared with placebo recip- reduced viral titers compared with placebo (median
ients (P ⬍ 0.0001) (Table 4). Similarly the extent and AUC virus titers, in which TCID50 is 50% tissue
severity of illness, measured by the AUC of the total culture-infective dose: placebo, 303 log10 TCID50 ⫻
CARIFS symptoms, was reduced by 29% in oseltamivir hours/ml; oseltamivir: 243 log10 TCID50 ⫻ hours/ml;
compared with placebo recipients (P ⫽ 0.002), as shown P ⫽ 0. 04) (Fig. 2).
in Table 4. Individual symptoms such as fever, cough Fourfold or greater rises in serum HAI antibody titer
and coryza also resolved faster in patients who received occurred in 97% of placebo and 92% of oseltamivir
oseltamivir, with median reductions in duration of 36% recipients. There were no differences in convalescent
(P ⬍ 0.0001), 45% (P ⫽ 0.0008) and 34% (P ⫽ 0.09), geometric mean titer as indicated in Table 4. Oselta-
respectively, as shown in Table 4. Median total acet- mivir treatment therefore did not inhibit the antibody
aminophen consumption was 31% less for subjects in response to naturally acquired influenza infection.
the oseltamivir (40 mg/kg) compared with the placebo No evidence of influenza virus resistant to oseltami-
(59 mg/kg) groups (P ⫽ 0.002). vir was detected at baseline (n ⫽ 385) based on sensi-
Among 144 (32%) children infected with influenza B, tivity of the viral neuraminidase to inhibition by Ro
subgroup analyses showed a significant reduction in 64-0802, the active metabolite of oseltamivir. Similarly
the median durations of fever, cough and coryza (pla- no evidence of resistance was found in placebo recipi-
cebo 100 h, oseltamivir 73 h; P ⫽ 0.01) and of the 18 ents at any time during the study (n ⫽ 217). In
symptoms reported on the CARIFS (placebo 96 h, oseltamivir recipients 10 posttreatment influenza iso-
oseltamivir 56 h; P ⫽ 0.008). lates had a 50% inhibitory concentration for neuramin-
The incidence of physician-diagnosed complications idase inhibition higher than pretreatment values, in-
requiring antibiotic treatment developing after Study
dicating in vitro resistance. The overall incidence was
Day 2 was reduced by 40% in the oseltamivir treatment
10 of 182 (5.5%) of oseltamivir-treated patients who
group (36 of 217, 17%) compared with placebo recipi-
were culture-positive and for whom satisfactory viral
ents (65 of 235, 28%; P ⫽ 0.005). The relative risk of
neuraminidase sensitivity assay data were obtained.
developing otitis media, the most common secondary
illness in both groups, was 0.56 (95% confidence inter- Analysis of these samples confirmed the associated
val, 0.36 to 0.87), a 44% reduction for oseltamivir genotypic mutations to be those previously described
recipients (26 of 217, 12%) compared with those taking from in vitro studies and in adults.22, 23 The mutations
placebo (50 of 235, 21%). Otitis media was confirmed by identified in this study were the arginine to lysine
tympanometry in a proportion of patients; the overall mutation at p292 (R292K) in 8 children, a glutamate to
concordance between clinical diagnosis and tympano- valine mutation at p119 (E119V) in 1 child and a
metric confirmation of otitis media was 93% (100% in histidine to tyrosine mutation at p274 (H274Y) in 1
the placebo group and 81% in oseltamivir group). The child. The variants were identified on Study Day 6 in 9
incidence of tympanometrically confirmed otitis media cases and Day 4 of treatment in one case. No variants
was 37 of 200 (18.5%) placebo recipients and 17 of 183 were detectable by Study Day 10. The clinical course of
(9.3%) oseltamivir recipients, a relative risk reduction disease in these patients was no different than that of
of 50%. The proportion of patients receiving physician- children with isolates, which remained susceptible toVol. 20, No. 2, Febuary, 2001 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL 131
TABLE 4. Clinical outcomes in the intent to treat infected population
Clinical Outcome Placebo (n ⫽ 235) Oseltamivir (n ⫽ 217) Difference (h)
Median duration of illness (h) 137 (125–150)* 101 (89 –118) 36 (26)
P ⬍ 0.0001†
ⱕ2 yr 161 (139 –171) 139 (103–160) 23 (14)
(n ⫽ 55) (n ⫽ 39)
2–ⱕ5 yr 137 (98 –153) 99 (85–124) 38 (28)
(n ⫽ 56) (n ⫽ 68)
⬎5 yr 125 (114 –141) 90 (76 –109) 35 (28)
(n ⫽ 114) (n ⫽ 102)
Median duration of individual CARIFS symptoms (h)
Fever‡ 68 (55–78) 44 (40 – 48) 25 (36)
P ⬍ 0.0001
Cough 71 (63– 81) 39 (32–51) 32 (45)
P ⫽ 0.0008
Coryza 66 (43–77) 43 (31–53) 23 (34)
P ⫽ 0.09
CARIFS symptoms
Median duration (h) 100 (80 –110) 63 (50 –74) 36 (36)
P ⬍ 0.0001
Median AUC symptom scores, score 䡠 h (range 1358 (0 –18824 960 (0 –7078)
P ⫽ 0.002
Median AUC virus titer, log10 TCID50 䡠 h/ml (range) 303 (7–933) 243 (10 – 867)
P ⫽ 0.04
Geometric mean fold change in antibody titer 24.9 ⫾ 7.26§ 16.6 ⫾ 4.07
* Numbers in parentheses, 95% confidence interval unless otherwise stated.
† P values computed using the weighted Mantel-Haenszel test.
‡ Individual component of fever used in the primary endpoint is not taken from the CARIFS score, but is temperature ⱕ98.9°F (37.2°C).
§ Mean ⫾ SE.
FIG. 2. Median viral titers over time for intent to treat in-
fected population [patients with more frequent (positive culture
at baseline and swab samples available at Days 2, 4 and 6)
FIG. 1. Time (hours) to alleviation of all symptoms in influen-
throat/nasal swabs patients] treated with placebo (n ⫽ 89) or
za-infected children. C, censoring for patients for whom no
oseltamivir 2 mg per kg (n ⫽ 80) twice daily for 5 days. For those
subsequent efficacy information was available.
with negative swabs a value of zero was substituted for that titer.
oseltamivir. There was no evidence of resistance in serious adverse events during treatment (placebo:
influenza B isolates. pneumonia, one; dehydration, one; oseltamivir: pneu-
Safety and tolerability. Oseltamivir treatment monia, two; dehydration, one); none of these events
was generally well-tolerated with an incidence of ad- were considered to be related to the study drug and all
verse events comparable with those of the placebo resolved without sequelae. The overall discontinuation
recipients. No differences were seen in laboratory pa- rate as a result of an adverse event was low and
rameters and vital signs between the groups. More comparable in both groups: four (1.1%) for placebo and
than 90% of children took all scheduled doses, regard- six (1.8%) for oseltamivir recipients.
less of randomization group. The most common adverse
events were those involving the gastrointestinal sys- DISCUSSION
tem: emesis was reported in 14.3% of patients receiving The severity of influenza is illustrated by the out-
oseltamivir compared with 8.5% receiving placebo; come of the placebo recipients. Children in the placebo
however, ⬃1% of children discontinued the study be- group in this study experienced influenza symptoms
cause of this adverse event. The incidence of diarrhea for a median of 5.7 days after enrollment. Because the
was higher in placebo (10.5%) compared with oseltami- median duration of disease was slightly greater than 1
vir recipients (8.8%). Five patients (0.7%) reported day before entry, disease in these children lasts for 1132 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 20, No. 2, Febuary, 2001
week. Complications in children are common and in- In vivo data from animal studies of influenza viruses
clude pneumonia and otitis media.3 Indeed in this resistant to the class of neuraminidase inhibitors have
study nearly 30% of placebo recipients had physician- previously documented that these strains are less in-
diagnosed complications, with otitis media developing fectious and less pathogenic than wild-type influenza
in ⬎20%, all of whom received antibiotic therapy. virus.22 Consistent with these observations children
Furthermore the placebo recipients excreted large excreting these viruses did not have protracted disease.
quantities of virus for at least 4 days, providing a Children who excreted resistant virus did so only at the
reservoir for spread within the community. Because end of the treatment period and were uniformly cul-
influenza infections are an important cause of illness ture-negative at the next time point (Day 10). Thus
during the winter months and increase the burden of resistance appears to be a short lived phenomenon with
the primary health care provider,1 attempts at both no apparent clinical sequelae in this clinical trial. The
prevention and treatment would be of significant value nature of the virus strains that emerge during treat-
to the health care system. To this end oseltamivir ment suggests that the potential for transmission of
therapy significantly improved outcome. resistant virus is very low, although this requires
This is the first study to demonstrate the efficacy further investigation in clinical practice. Future inves-
and tolerability of an antiviral for the therapy of tigations with neuraminidase inhibitors, as with other
influenza A or B illness in children. Oseltamivir, when antiviral agents, must assess the potential for the
given within 48 h of the onset of symptoms, decreased development of resistance and the potential clinical
the time to resolution of illness by 26% (1.5 days) and implications.
overall severity of illness by 29% for influenza-infected. Oseltamivir was well-tolerated in this study. Al-
Consistent with this effect the use of acetaminophen though emesis of mild or moderate intensity and that of
was significantly reduced in oseltamivir-treated pa- short duration was reported more frequently in chil-
tients. dren taking oseltamivir, fewer than 1% of children
Oseltamivir significantly reduced the occurrence of withdrew from the study for this adverse event. Inter-
estingly oseltamivir recipients experienced a lower
secondary complications during the study, notably oti-
incidence of diarrhea compared with placebo. Gastro-
tis media. The 44% reduction observed in the incidence
intestinal disturbances such as emesis, nausea and
of otitis media is medically significant and was associ-
diarrhea occur in as many as 40% of children with
ated with reduced antibiotic usage. This benefit is of
influenza.25 Finally the development of natural protec-
great value in the era of increasing antimicrobial
tive serum antibodies postexposure in oseltamivir re-
resistance. The proportion of adult patients with influ-
cipients demonstrated that the humoral immune re-
enza-related complications requiring antibiotic treat-
sponse to infection was not affected by treatment.
ment was reduced by 50% in oseltamivir recipients.13
In conclusion oseltamivir given within 48 h of onset
In our study the hospitalization rate was very low, with
of illness is an effective and well-tolerated therapy for
no oseltamivir recipients requiring hospitalization dur- acute influenza A and B illness in previously healthy
ing the study. This observation should be expected in children. Furthermore, and importantly, secondary
otherwise healthy children. complications were significantly decreased.
Treatment with oseltamivir shortened the duration
and severity of symptoms, such as cough or coryza, and
ACKNOWLEDGMENTS
caused a rapid decline in viral shedding. Hypotheti-
The study was funded by F. Hoffmann-La Roche Ltd., Basel,
cally oseltamivir treatment might reduce the likelihood Switzerland.
of spread of influenza to close contacts; this possibility We thank the patients and their families, without whose
requires specific study. In an earlier study amantadine cooperation this study would not have been possible. We thank
Viromed Laboratories Inc., for virology testing: Dr. F. Pistoor and
and rimantadine antiviral therapy of the index case in coworkers at Erasmus University, Rotterdam for virus titer
families decreased the likelihood of infection in con- assays; Dr. E. Covington and Dr. N. Roberts, Roche, Welwyn, UK,
for neuraminidase phenotyping; Dr. K. Soderbarg, Professional
tacts by 30%.24 Genetics Laboratory, Uppsala, Sweden, for neuraminidase/
Because oseltamivir carboxylate is primarily elimi- hemagglutinin genotyping; and Dr. Mark M. Blatter of Primary
nated by renal excretion and because the glomerular Physicians Research, PA, and Pediatric Associates of Charlottes-
ville, VA, for their invaluable help with this study.
filtration rate is higher in children than in adults, a We also thank the following study investigators: Canada: F.
larger dose of oseltamivir on a milligrams per kg basis Boucher, Centre Hospitalier de l’Université du Quebec, Sainte-
is required in the pediatric population. The 2-mg/kg Foy, Quebec; F. Diaz-Mitoma, Herridge Community Health Cen-
tre, Ottawa, Ontario; J. Janzen, Kells Medical Research Group
dose of oseltamivir used in this study provides expo- Inc., Pointe-Claire, Quebec; J. Leroux, ZOOM International,
sure to the active metabolite oseltamivir carboxylate St.-Jerome, Quebec; M. Luterman, Group North Windsor, Wind-
equivalent to that previously shown to be effective for sor, Ontario; S. Mehra, Oshawa Clinic, Oshawa, Ontario; V.
Senikas, Clinical Research Consultant Group, Montreal, Quebec;
the treatment of influenza in adults (75 mg twice a D. Shu, Gain Medical Centre, Coquitlam, British Columbia; P.
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