Data from: Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

PLEASE NOTE, THESE DATA ARE ALSO REFERRED TO IN TWO OTHER ARTICLES. PLEASE
SEE http://dx.doi.org/10.1136/bmj.g2547 AND
http://dx.doi.org/10.1136/bmj.g2545 FOR MORE INFORMATION. Background:
Neuraminidase inhibitors (NIs) are stockpiled and recommended by public
health agencies for treating and preventing seasonal and pandemic
influenza. They are used clinically worldwide. Objectives: To describe the
potential benefits and harms of NIs for influenza in all age groups by
reviewing all clinical study reports of published and unpublished
randomised, placebo-controlled trials and regulatory comments. Search
methods: We searched trial registries, electronic databases (to 22 July
2013) and regulatory archives, and corresponded with manufacturers to
identify all trials. We also requested clinical study reports. We focused
on the primary data sources of manufacturers but we checked that there
were no published randomised controlled trials (RCTs) from
non-manufacturer sources by running electronic searches in the following
databases: the Cochrane Central Register of Controlled Trials (CENTRAL),
MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the
Database of Reviews of Effects, the NHS Economic Evaluation Database and
the Health Economic Evaluations Database. Selection criteria: Randomised,
placebo-controlled trials on adults and children with confirmed or
suspected exposure to naturally occurring influenza. Data collection and
analysis: We extracted clinical study reports and assessed risk of bias
using purpose-built instruments. We analysed the effects of zanamivir and
oseltamivir on time to first alleviation of symptoms, influenza outcomes,
complications, hospitalisations and adverse events in the
intention-to-treat (ITT) population. All trials were sponsored by the
manufacturers. Main results: We obtained 107 clinical study reports from
the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We
accessed comments by the US Food and Drug Administration (FDA), EMA and
Japanese regulator. We included 53 trials in Stage 1 (a judgement of
appropriate study design) and 46 in Stage 2 (formal analysis), including
20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628
participants). Inadequate reporting put most of the zanamivir studies and
half of the oseltamivir studies at a high risk of selection bias. There
were inadequate measures in place to protect 11 studies of oseltamivir
from performance bias due to non-identical presentation of placebo.
Attrition bias was high across the oseltamivir studies and there was also
evidence of selective reporting for both the zanamivir and oseltamivir
studies. The placebo interventions in both sets of trials may have
contained active substances. Time to first symptom alleviation. For the
treatment of adults, oseltamivir reduced the time to first alleviation of
symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P
< 0.0001). This represents a reduction in the time to first
alleviation of symptoms from 7 to 6.3 days. There was no effect in
asthmatic children, but in otherwise healthy children there was (reduction
by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001).
Zanamivir reduced the time to first alleviation of symptoms in adults by
0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a
reduction in the mean duration of symptoms from 6.6 to 6.0 days. The
effect in children was not significant. In subgroup analysis we found no
evidence of a difference in treatment effect for zanamivir on time to
first alleviation of symptoms in adults in the influenza-infected and
non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment
of adults with oseltamivir had no significant effect on hospitalisations:
risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no
significant effect in children or in prophylaxis. Zanamivir
hospitalisation data were unreported. Serious influenza complications or
those leading to study withdrawal. In adult treatment trials, oseltamivir
did not significantly reduce those complications classified as serious or
those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor
in child treatment trials; neither did zanamivir in the treatment of
adults or in prophylaxis. There were insufficient events to compare this
outcome for oseltamivir in prophylaxis or zanamivir in the treatment of
children. Pneumonia. Oseltamivir significantly reduced self reported,
investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to
1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451)
in the treated population. The effect was not significant in the five
trials that used a more detailed diagnostic form for pneumonia. There were
no definitions of pneumonia (or other complications) in any trial. No
oseltamivir treatment studies reported effects on radiologically confirmed
pneumonia. There was no significant effect on unverified pneumonia in
children. There was no significant effect of zanamivir on either self
reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir
significantly reduced the risk of self reported, investigator-mediated,
unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311
(95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and
otitis media. Zanamivir significantly reduced the risk of bronchitis in
adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to
155), but not oseltamivir. Neither NI significantly reduced the risk of
otitis media and sinusitis in both adults and children. Harms of
treatment. Oseltamivir in the treatment of adults increased the risk of
nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm
(NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to
7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold
increases in antibody titre was significantly lower in the treated group
compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I2 statistic
= 0%) (5% absolute difference between arms). Oseltamivir significantly
decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43
(95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB
= 148 (101 to 2509) compared to placebo during the on-treatment period.
There was a dose-response effect on psychiatric events in the two
oseltamivir “pivotal” treatment trials, WV15670 and WV15671, at 150 mg
(standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment
of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to
10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower
proportion of children on oseltamivir with a four-fold increase in
antibodies (RR 0.90, 95% CI 0.80 to 1.00, I2 = 0%). Prophylaxis. In
prophylaxis trials, oseltamivir and zanamivir reduced the risk of
symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83
to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54);
NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI
9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to
16.55); NNTB = 7 (7 to 9)). There was no significant effect on
asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33);
zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like
illness could not be assessed due to data not being fully reported. In
oseltamivir prophylaxis studies, psychiatric adverse events were increased
in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to
2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population.
Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%,
95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on
treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB
> 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to
9.51); NNTH = 25 (95% CI 11 to 116). Authors’ conclusions: Oseltamivir and
zanamivir have small, non-specific effects on reducing the time to
alleviation of influenza symptoms in adults, but not in asthmatic
children. Using either drug as prophylaxis reduces the risk of developing
symptomatic influenza. Treatment trials with oseltamivir or zanamivir do
not settle the question of whether the complications of influenza (such as
pneumonia) are reduced, because of a lack of diagnostic definitions. The
use of oseltamivir increases the risk of adverse effects, such as nausea,
vomiting, psychiatric effects and renal events in adults and vomiting in
children. The lower bioavailability may explain the lower toxicity of
zanamivir compared to oseltamivir. The balance between benefits and harms
should be considered when making decisions about use of both NIs for
either the prophylaxis or treatment of influenza. The influenza
virus-specific mechanism of action proposed by the producers does not fit
the clinical evidence.