B R I E F R E P O R T
Oseltamivir and Risk of Lower
Respiratory Tract Complications in
Patients With Flu Symptoms: A
Meta-analysis of Eleven Randomized
Miguel A. Herna ´n1,2and Marc Lipsitch1,3
1Department of Epidemiology, Harvard School of Public Health,2Harvard-MIT
Division of Health Sciences and Technology, and3Center for Communicable
Disease Dynamics and Department of Immunology and Infectious Diseases,
Harvard School of Public Health, Boston, Massachusetts
An independent reanalysis of 11 randomized clinical trials
shows that oseltamivir treatment reduces the risk of lower
respiratory tract complications requiring antibiotic treat-
ment by 28% overall (95% confidence interval [CI], 11%–
42%) and by 37% among patients with confirmed influenza
infections (95% CI, 18%–52%).
In a pooled analysis of 10 randomized clinical trials, Kaiser et al
 concluded that oseltamivir reduced the risk of influenza-
related lower respiratory tract complications (LRTCs) requiring
antibiotic therapy by 55%, from 10.3% to 4.6%. All 10 trials had
been funded by Roche, the manufacturer of oseltamivir.
Ina Cochrane reviewonthistopic,Jefferson etal excluded
8 of the 10 studies in the Kaiser paper . Without these 8
studies, they estimated that oseltamivir reduced the risk of in-
fluenza-associated complications (including upper respiratory
complications that may not have required antibiotics) by 45%.
Because the 95% confidence interval included 1, they concluded
that there was no evidence of a benefit of oseltamivir. Several
commentaries on this finding were published [3–7].
After the appearance of these articles, Roche asked us to
perform an independent data analysis. We agreed to do so be-
cause the question is of considerable public health importance,
particularly in the context of a recent influenza pandemic. The
agreement specified that we receive full access to efficacy and
safety data from the 10 trials (we later requested data from
additional trials), assistance from Roche statisticians in
answering data-related questions, and complete freedom to
publish any results. Neither we nor our institution received any
funding for this work from Roche.
Besides the 10 trials in Kaiser et al , we identified another
placebo-controlled, double-blind, randomized trial (WV16277)
funded by Roche. An additional Roche-funded trial in Japan 
in a format compatible with this analysis.
The 11 trials in our analysis (see Supplementary Materials)
included adults and adolescents with flu symptoms during the
1997–2001 influenza seasons. Patients were eligible if they pre-
sented within 36 hours of symptom onset and had fever (tem-
perature $37.8?C if aged ,65 y; $37.5?C if aged $65 y) plus at
least 1 respiratory symptom (cough, sore throat, or coryza) and
1 constitutional symptom (headache, myalgia, chills/sweats, or
fatigue). Patients were randomized toreceive oseltamivir(75 mg
twice daily) or placebo for 5 days.
The primaryendpointof ouranalysiswasanylowerrespiratory
the primary or secondary endpoint in the original trials, but was
reconstructed retrospectively from the database. We focused on
LRTCs treatedwithantibiotics, ratherthanallLRTCs, because the
former is a better surrogate of clinically relevant conditions. An-
tibiotic prescriptions were systematically recorded in the original
trials. Our analyses excluded participants taking antibiotics at
baseline. We also studied the following endpoints: gastrointestinal
(other than headache), and headache.
Our analytic approach differed from that in Kaiser et al  in
First, we computed study-specific risk ratios of LRTC treated
with antibiotics within the first 24 days of follow-up for osel-
tamivir versus placebo, and then we pooled the study-specific
risk ratios using meta-analysis techniques. We used fixed-effect
estimates when the P value for heterogeneity of a bootstrap Q
statistic  was ..10; otherwise, we used random effects. Kaiser
et al  pooled the individual-level data from the studies, which
may lead to confounding because both the distribution of risk
Received 12 November 2010; accepted 17 May 2011.
Correspondence: Miguel Herna ´n, MD, DrPH, Department of Epidemiology, Harvard School of
Public Health, Boston, Massachusetts 02115 (firstname.lastname@example.org).
Clinical Infectious Diseases
? The Author 2011. Published by Oxford University Press on behalf of the Infectious
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d CID 2011:53 (1 August)
factors and the probability of assignment to oseltamivir varied
Second, we included endpoints diagnosed during the first 2
days after randomization. These events were excluded by Kaiser
et al  because they hypothesized that oseltamivir could have
no effect during the first 2 days. Although reasonable, this
approach deviates from the intention-to-treat principle used in
many randomized trials, in which investigators refrain from
all events after randomization in the analysis.
Third, Kaiser et al  excluded patients who deviated from
protocol (eg, did not take the assigned treatment), and included
patients whowithdrewfromthestudy onlyuptothe withdrawal
date. A true intention-to-treat analysis would include the
complete follow-up of all randomized patients. We explored the
sensitivity of the estimates to these exclusions.
Finally, we conducted subset analyses by influenza infection
status, for comparability with themeta-analysis by Jefferson et al
pool individual-level data of small studies with zero cells. Other
subset analyses could not be conducted because of insufficient
sample sizes in several of the trials.
The analysisincluded3908patients: 2188intheoseltamivirarms
and 1720 in the placebo arms. 291 patients (130 oseltamivir, 161
placebo) had an LRTC treated with antibiotics within the first 24
days of follow-up; 28 cases (21.5%) occurred for oseltamivir and
20 (12.4%) for placebo in the first 2 days. The meta-analytic risk
ratio of LRTC treated with antibiotics was .72 (95% confidence
interval [CI], .58–.89; P value for heterogeneity 5 .30) for
oseltamivir versus placebo (see Figure 1). Had we pooled in-
dividual-level data rather than meta-analyzed the study-specific
risk ratios, the risk ratio would have been .63 (95% CI, .51–.79).
Had we further ignored events during the first 2 days of follow-
up, the risk ratio would have been .57 (95% CI, .44–.73).
The risk ratio (95% CI; P value for heterogeneity) was 1.46
(.66–1.04; .44) for diarrhea, 1.47 (1.05–2.04; .36) for headache,
and 1.02 (.72–1.44; .83) for other neuropsychiatric disorders.
Of the 3908 patients, 2570 were infected with influenza at
baseline (1429 oseltamivir, 1141 placebo). Of these 2570
patients, 201 (79 oseltamivir, 122 placebo) had an LRTC treated
with antibiotics within the first 24 days of follow-up; 16 cases
(20.3%) for oseltamivir and 15 (12.3%) for placebo occurred in
the first 2 days. Among influenza-infected patients, the risk ratio
of LRTC treated with antibiotics was .63 (95% CI, .48, –.82;
P value for heterogeneity 5 .18) for oseltamivir versus placebo.
A pooled analysis would have estimated a risk ratio of .52
(95% CI, .39–.68). If we had further ignored events during the
first 2 daysof follow-up, the riskratio would havebeen.47(95%
CI, .35–.64), similar to the findings of Kaiser et al . An
analysis of the 10 studies reported by Kaiser et al  reproduced
their finding precisely.
Of the remaining 1338 patients (759 oseltamivir, 579 placebo)
who were not infected with influenza, 90 (51 oseltamivir, 39
placebo) had an LRTC treated with antibiotics within the first 24
Oseltamivir and the risk of lower respiratory tract complications requiring antibiotics.
d CID 2011:53 (1 August)
d BRIEF REPORT
was 1.06 (95% CI, .71–1.58; P value for heterogeneity 5 .97) for
oseltamivir versus placebo.
Kaiser et al  excluded 24 patients (14 oseltamivir, 10
placebo) who were randomized. We repeated the analyses under
half of the oseltamivir patients but no placebo patients developed
the outcome. The risk ratio was .75 (95% CI, .60, .93; P value for
heterogeneity 5 .45).
A total of 159 patients (96 oseltamivir, 63 placebo) withdrew
before the endpoint or 24 days of follow-up. We repeated the
analyses under an unrealistic scenario that was unfavorable to
oseltamivir: among those who withdrew, a quarter of oseltamivir
ratio was .82 (95%CI, .67–1.01; P value forheterogeneity 5 .50).
For LRTC in general, the risk ratio (95% CI; P value for het-
erogeneity) for oseltamivir versus placebo was .76 (.62–.93; .19)
in all patients, .71 (.56–.90; .35) in influenza-infected patients,
and .96 (.66–1.39; .95) in non–influenza-infected patients.
Our reanalysis confirms that oseltamivir reduces the risk of
LRTC treated with antibiotics among patients with flu symp-
about 28% overall and 37% in patients with influenza infection.
No reduction was observed in patients without influenza. The
effect estimates changed little even under rigorous sensitivity
analyses. We also confirmed previous reports of increased risk of
nausea and vomiting [2, 10], but found no evidence of increased
risk of neuropsychiatric disorders, except for headache, among
those assigned to oseltamivir.
As for any meta-analysis, the quality of our estimates depends
on the quality of the individual studies. Of the 11 trials included
in the meta-analysis, only 2 have been published in peer-
reviewed journals [11, 12]. The other 9 were either unpublished
or published only in abstract form until their findings were re-
ported by Kaiser et al. Jefferson et al considered the unpublished
trials analyzed by Kaiser et al as ‘‘inaccessible to proper scrutiny’’
and excluded them from their Cochrane meta-analysis. How-
ever, the unpublished trials are no more favorable to oseltamivir
than the published ones. Using only the 2 published trials, the
reduction in the 24-day risk of LRTC treated with antibiotics is
65% (risk ratio, .35; 95% CI, .15–.82) in the oseltamivir arms.
Our reanalysis has at least 2 limitations. First, it was not
possible to assess the potential benefit for high-risk participants
who are hospitalized , because the sample size of most
studies was too small to consider hospitalization as an outcome.
Second, the datain thesestudies were collected in anera without
viral resistance to oseltamivir. The effectiveness of oseltamivir
may be different now.
Supplementary materials are available at Clinical Infectious
Diseases online (http://www.oxfordjournals.org/our_journals/
cid/). Supplementary materials consist of data provided by
the author that are published to benefit the reader. The posted
materials are not copyedited. The contents of all supplementary
data are the sole responsibility of the authors. Questions or
messages regarding errors should be addressed to the author.
The authors thank Laurent Kaiser and Fred Hayden for helpful com-
ments and clarifications.
Financial support.This work was supported by the Models of In-
fectious Disease Agent Study program of the National Institute of General
Medical Sciences (grant 1U54GM088558 to M. L.). The content is solely the
responsibility of the authors and does not necessarily represent the official
views of the National Institute Of General Medical Sciences or the National
Institutes of Health.
Potential conflicts of interest.M. L. received consulting income in
2007–2008 from the Avian/Pandemic Flu Registry, a project of Outcome
Sciences (Cambridge, MA), which was sponsored by Roche, and has re-
ceived consulting income or honoraria from Novartis and Pfizer. M. A. H;
1. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of
oseltamivir treatment on influenza-related lower respiratory tract com-
plications and hospitalizations. Arch Intern Med 2003; 163:1667–72.
2. JeffersonT, JonesM,DoshiP, DelMarC. Neuraminidase inhibitorsfor
preventing and treating influenza in healthy adults: Systematic review
and meta-analysis. BMJ 2009; 339:b5106.
3. Godlee F, ClarkeM. Why don’t we haveall the evidenceonoseltamivir?
BMJ 2009; 339:b5351.
4. Doshi P. Neuraminidase inhibitors—The story behind the Cochrane
review. BMJ 2009; 339:b5164.
5. Cohen D. Complications: Tracking down the data on oseltamivir. BMJ
6. Smith J. Roche replies to the authors of the Cochrane review on
oseltamivir. BMJ 2009; 339:b5364.
7. Smieja M. ACP Journal Club. Review: Neuraminidase inhibitors relieve
influenza symptoms and reduce laboratory-confirmed influenza in
healthy adults. Ann Intern Med 2010; 152:JC-211.
8. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. Clinical efficacy and
safety of the selective oral neuraminidase inhibitor oseltamivir in
treating acute influenza—Placebo-controlled double-blind multicenter
phase III trial [in Japanese]. Kansenshogaku Zasshi. [Jpn J Infect Dis]
9. Costa-Bouzas J, Takkouche B, Cadarso-Sua ´rez C, Spiegelman D.
HEpiMA: A software for the identification of heterogeneity in meta-
analysis. Comput Methods Programs Biomed 2001; 64:101–7.
10. Dutkowski R, Thakrar B, Froehlich E, Suter P, Oo C, Ward P. Safety and
pharmacology of oseltamivir in clinical use. Drug Saf 2003; 26:787–801.
11. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of
oseltamivir in treatment of acute influenza: A randomised controlled
trial. Neuraminidase Inhibitor Flu Treatment Investigator Group.
Lancet 2000; 355:1845–50.
12. Treanor JJ, Hayden FG, Vrooman PS, et al. U.S. Oral Neuraminidase
Study Group. Efficacy and safety of the oral neuraminidase inhibitor
oseltamivir in treating acute influenza: a randomized controlled trial.
JAMA 2000; 283:1016–24.
13. Kaiser L. Influenza will not miss opportunities. Clin Infect Dis 2006;
d CID 2011:53 (1 August)