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 (email@example.com).
Clinical Infectious Diseases
? The Author 2011. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
d CID 2011:53 (1 August)