NPC Archive Item: Oseltamivir▼ (Tamiflu®) in adults: evidence summary

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7th September 2009

A Cochrane review and a systematic review commissioned by NICE suggest that for many adults with seasonal influenza the benefits of oseltamivir▼ are limited, and very sparse data are available relating to possible benefits in people at higher risk of complications.  These relate to effects in seasonal influenza: no data on benefits in H1N1 (swine) influenza are available. The most common adverse effect of oseltamivir▼ is vomiting.

Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria

Health professionals should follow Health Protection Agency advice, but it is important to weigh the likely benefits against possible harms, including side effects. The NPC has produced some patient decision aids may be helpful in some consultations.

What is the background to this?
Oseltamivir▼is licensed for treatment (and prophylxais) of influenza for adults (in July 2009 the Chief Medical Officer said that prophylaxis should not now usually be offered to contacts of cases unless for example, a household member has serious underlying health problems or there are other special circumstances). As with any medicine, it is important to weigh the likely benefits and risks of treatment. The Cochrane review of neuraminidase inhibitors (oseltamivir▼ and zanamivir▼) in adults was last assessed as up to date in May 2008. Very recently, the results of the systematic review and meta-analysis commissioned by NICE to inform the 2009 update of NICE guidance TA058 (updated by TA168, February 2009) have been published. This blog summarises the evidence available at present.

Evidence for benefits
It is important to note that evidence relates to seasonal influenza: no data on benefits in H1N1 (swine) influenza are available. The Cochrane review considered two broad benefits from treatment with oseltamivir▼: reduction of illness duration and reduction in risk of complications (mainly secondary infections).

In otherwise healthy adults, the pooled hazard ratio (HR) for time to alleviation of symptoms with oseltamivir▼compared to placebo was 1.20 (95% confidence interval [CI] 1.06 to 1.35), indicating that patients taking oseltamivir▼ were more likely to have their symptoms alleviated by a given time point.

One of the RCTs included in the Cochrane review gives the best data for the absolute benefits. This trial was in healthy non-immunised adults aged 18 to 65 years with febrile respiratory illness of no more than 36 hours’ duration with temperature of 38°C or more plus at least 1 respiratory symptom and 1 constitutional symptom. 208 patients received placebo and 210 received oseltamivir▼ 75 mg twice daily for 5 days. (Data from the group receiving oseltamivir 150mg twice daily are not included as this dose is not used in routine UK clinical practice). The median illness duration was 97 hours (4 days 1 hour) in the placebo group and 76.3 hours (3 days 4 hours) in the oseltamivir▼ 75mg twice a day group. Oseltamivir▼ shortened the median duration of illness by 21 hours, P<0.004.  Median time to return to normal activities was 230 hours (9 days 14 hours) in the placebo group and 173 hours (7 days 5 hours) in the oseltamivir▼ group. Oseltamivir▼ shortened the median time to resumption of normal activities by 57 hours (2 days 9 hours), P=0.01. These are median values: half of the people in both groups had symptoms for longer or took longer to return to normal activities than the median; and half had symptoms for a shorter time or took less time to return to normal activities.

This result is very similar to the pooled analysis of four trials of 1,410 people included in the NICE review.  Here the difference in the median time to alleviation of symptoms between oseltamivir▼ and placebo groups was 13 hours (95%CI 3 to 23 hours).

Data in the Cochrane review relating to effects on complications in otherwise healthy adults came from one published pooled analysis of subjects with influenza-like illness enrolled in 10 placebo-controlled, double-blind trials of oseltamivir treatment. These included 2,358 otherwise healthy adults aged 13 to 64 years with influenza-like illness, both with (n=1,644) and without (n=714) confirmed influenza infection. Looking at the whole intention to treat (ITT) population, oseltamivir reduced the rate of lower respiratory tract infections leading to antibiotic use (mainly bronchitis) from 4.9% in the placebo group to 2.0% in the oseltamivir▼ group: relative risk (RR) 0.42, absolute risk reduction (ARR) 2.9% (95%CI 1.3% to 4.4%), number needed to treat (NNT) 35 (95%CI 23 to 78).  There were very few episodes of pneumonia and no statistically significant benefit was seen.

The NICE review did not include this pooled analysis, but included two other, smaller studies in their analysis. The pooled odds ratio (OR) for antibiotic use was 0.37 (95%CI 0.29 to 0.48), which is similar to the OR of 0.41 (95%CI 0.25 to 0.65) observed in the analysis referred to above.

With regard to benefits of oseltamivir in at-risk adults (for example, the elderly, the immunocompromised, those with pre-existing lung conditions, etc), data are much more sparse.  The manufacturer’s Summary of Product Characteristics (SPC) states that in people aged 65 years and older with confirmed influenza infection; and in adults with chronic cardiac and/or respiratory disease with confirmed influenza infection, oseltamivir▼ 75 mg twice daily for 5 days did not reduce the median duration of influenza illness significantly. The total duration of fever was reduced by one day in the groups treated with oseltamivir▼.

The pooled analysis (prepared for NICE) included 1,206 at-risk adults, defined as immunised or unimmunised community living people aged 65 years or older and adults and adolescents with chronic obstructive airways disease, asthma, and/or cardiac disease of sufficient severity to require regular outpatient medical care. There was no significant reduction in risk of lower respiratory tract infections leading to antibiotic use in the at-risk ITT population, although it was significant in those at-risk adults with confirmed influenza (12.2% vs 18.5%, NNT=16 [95%CI 9 to 89], P=0.02)

Data in the SPC indicates that in influenza-positive patients with chronic cardiac and/or respiratory disease, the combined incidence of lower respiratory tract complications (mainly bronchitis) treated with antibiotics was 17% in the placebo group and 14% in the oseltamivir▼ treated population, but this reduction was not statistically significant (P = 0.6).  The SPC also says that in the influenza-positive elderly, oseltamivir▼ significantly reduced the incidence of specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics from 19 % in the placebo group to 12 % in the oseltamivir treated population (P=0.02).

Evidence of harms
The SPC states that the incidence of nausea without vomiting is 11% in adults taking oseltamivir▼and 7% taking placebo (NNT=25). The incidence of vomiting is given as 8% and 3% respectively (NNT=20). Insufficient data are available on the relative incidence of other side effects.

So what?
As with any medicine, it is important to weigh the likely benefits and risks of treatment. This is made more difficult by the limited data available: no published data relates to the effectiveness of oseltamivir▼ in H1N1 (pandemic) influenza and the evidence for effectiveness in seasonal influenza in higher-risk adults is extremely sparse. For most people, H1N1 (pandemic) influenza seems to be relatively mild, although unpleasant.  People with co-morbidities such as asthma may well be at greater risk of complications but the likely benefit from oseltamivir▼in such people is difficult to quantify: the only data available did not show a statistically significant benefit.

The NPC has produced some patient decision aids may be helpful in some consultations.

Study details

Cochrane review
Jefferson T, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001265. DOI: 10.1002/14651858.CD001265.pub2. Last reviewed as up to date 19th May 2008

NICE review
Burch J et al Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis The Lancet Infectious Diseases, Early Online Publication, 8 August 2009 doi:10.1016/S1473-3099(09)70199-9

Trial in otherwise healthy adults
Treanor J et al. Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza JAMA 2000;283:1016-24

Published pooled analysis
Kaiser L et al Impact of Oseltamivir Treatment on Influenza-Related Lower Respiratory Tract Complications and Hospitalizations. Arch Intern Med. 2003;163:1667-72

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