Amantadine, oseltamivir and zanamivir for the treatment of influenza

The Assessment Group performed a systematic review to identify randomised controlled trials (RCTs) evaluating the clinical effectiveness of amantadine, oseltamivir and zanamivir compared with each other, placebo or with best symptomatic care. Studies included were conducted in people who presented with symptoms typical of influenza, whether influenza was reported as circulating in the community or not. The population was divided into the following categories: otherwise healthy adults; 'at-risk'; older people; children; and 'mixed' populations. Twenty-nine RCTs were identified by the systematic review. There was no new evidence on the clinical effectiveness of amantadine published after the review of the evidence for NICE's technology appraisal guidance on flu treatment. No RCTs that directly compared zanamivir and oseltamivir were included; a Bayesian indirect comparison using placebo as a common comparator was conducted. The trials generally compared zanamivir or oseltamivir with placebo. The background circulating levels of influenza and the influenza vaccination rate in the trials were often not reported clearly. Levels of viral resistance were often not measured, but when reported were low.

In most RCTs, the effectiveness of the antiviral drugs was measured in terms of time to alleviation of symptoms (a composite outcome) and time to return to normal activities. Adverse events and complications were also reported, the latter generally in terms of reductions in antibiotic usage. Analyses were reported for the ITT population (intention to treat; representative of the entire population recruited in the trials) and ITTI population (intention to treat, confirmed as being influenza positive) wherever possible.

Evidence was submitted by consultees that there has been a decline in the rates of GP consultations for acute respiratory illnesses over the past 25 years. This has resulted in the lowering of the threshold levels of the surveillance schemes. In addition, it was stated that the influenza season as defined by the surveillance schemes does not correspond exactly to the period during which the virus is circulating in the community as indicated by virological monitoring. It was also apparent that outbreaks of influenza occur within localised areas, especially in residential care settings, outside of the influenza season.

The Assessment Group identified 21 cost-effectiveness studies that assessed amantadine, oseltamivir or zanamivir for the treatment of influenza. The manufacturer of oseltamivir (Roche Products) also provided a de novo economic model. No cost-effectiveness analyses were submitted by the manufacturers of amantadine or zanamivir. Seven of the identified cost-effectiveness studies were conducted from the perspective of the NHS (including the assessment for the original appraisal of NICE's technology appraisal guidance on flu treatment and the current submission from Roche Products).

The decision-tree model developed by the Assessment Group for NICE's technology appraisal guidance for flu treatment was designed to compare amantadine, oseltamivir and zanamivir with usual care for the treatment and prophylaxis of influenza. The following four separate groups were considered: otherwise healthy adults; high-risk ('at-risk') adults; children; and older people in residential care. For each of the population groups, amantadine compared with usual care had the lowest incremental cost-effectiveness ratios (ICERs), which ranged from £4,535 to £6,190 per quality-adjusted life-year (QALY) gained. However, the Appraisal Committee for the original appraisal for NICE's technology appraisal guidance on flu treatment was unable to accept that the clinical effectiveness of amantadine was sufficiently proven and so it did not recommend amantadine for the treatment of influenza A. The ICERs for oseltamivir compared with usual care ranged from £19,015 to £22,502 per QALY gained. The ICERs for zanamivir compared with usual care ranged from £16,819 to £31,529 per QALY gained.

Of the five other studies conducted from the UK NHS perspective, two compared zanamivir with usual care in both healthy and 'at-risk' adults, two compared oseltamivir with usual care in healthy children and healthy adults, and one compared oseltamivir, zanamivir and usual care in healthy adults. The estimated ICERs for zanamivir compared with usual care ranged from £7,490 to £54,000 per QALY gained for 'at-risk' adults and £65,000 per QALY gained for otherwise healthy adults. The estimated ICERs for oseltamivir compared with usual care ranged from oseltamivir being dominant to £11,173 per QALY gained for healthy children, and £225 to £5,600 for adults per QALY gained. In the only comparison of oseltamivir with zanamivir (in healthy adults), zanamivir was dominated (that is, zanamivir was estimated to be more costly and less effective than oseltamivir).

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of amantadine, oseltamivir and zanamivir, having considered evidence on the nature of the condition and the value placed on the benefits of amantadine, oseltamivir and zanamivir by people with influenza, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

The Committee understood that influenza causes a wide spectrum of respiratory illness of varying severity, and can lead to a number of potentially serious complications, especially in certain 'at-risk' groups. The Committee discussed the definition of 'at-risk' groups for whom treatment might be particularly suitable and decided that they would be best defined in the same way as for the current recommendations for vaccination. From the outset the Committee was of the view that vaccination has been established as the first-line intervention to prevent influenza and its complications, and was mindful that the use of antiviral treatments should not in any way detract from efforts to ensure that all eligible people are vaccinated at the beginning of each influenza season.

The Committee noted that the surveillance scheme used in the NHS to determine levels of influenza activity in the community was based on clinical consultations, but that influenza activity as defined by the threshold levels of these consultation rates did not always coincide with laboratory-based virological evidence. The Committee understood that the Health Protection Agency in England and similar organisations in Wales and Northern Ireland use information from a range of clinical, virological and epidemiological influenza surveillance schemes to identify when influenza is circulating in the community. The Committee heard from clinical specialists that the threshold levels are not suitable for defining when antiviral treatments would be most efficacious because they do not accurately identify periods when influenza, as opposed to influenza-like illness, is circulating.

The Committee considered the evidence for effectiveness of amantadine and noted that no new evidence on either the clinical or cost effectiveness of amantadine for the treatment of influenza had been published since the review of the evidence for NICE's technology appraisal guidance on flu treatment. The Committee concluded that it had no basis on which to change the recommendations on the use of amantadine from the original appraisal of NICE's technology appraisal guidance on flu treatment. Therefore amantadine is not recommended for the treatment of influenza.

The Committee then reviewed the evidence on the clinical effectiveness of oseltamivir and zanamivir for the treatment of influenza. The Committee noted that in all of the population subgroups, treatment with either antiviral drug was associated with reductions in the average duration of symptoms compared with placebo, although the difference was not statistically significant in all subgroups. The Committee acknowledged that the reduction in duration of symptoms was generally greater for the 'at-risk' population compared with healthy populations. The Committee heard from clinical experts that this increased reduction in duration of symptoms for the 'at-risk' group was plausible for a number of reasons. It is likely that people in 'at-risk' groups would have a longer duration of illness, and would therefore be more likely to benefit from antiviral treatment. There is also clinical rationale to suggest that people in 'at-risk' groups could also suffer from exacerbations of underlying conditions as a result of influenza. This could increase the duration and severity of influenza symptoms, which would mean an increased potential benefit from antiviral treatments. These exacerbations might also lead to a person not recovering completely, and future influenza infections and subsequent exacerbations being more frequent. The Committee concluded that there is evidence indicating clinical effectiveness of antiviral drugs in a wide range of clinical settings, but that their use is of greatest clinical importance for people in 'at-risk' groups.

The Committee noted that the probabilities for each antiviral drug being the 'best' treatment also differed according to population subgroup. The Committee discussed these results with clinical experts. The Committee was not persuaded that there was any plausible biological explanation for these observed differences. The Committee considered that the data were too sparse and uncertain to allow for any clear distinctions between the antiviral treatments to be made on the basis of clinical efficacy between different populations. The Committee concluded that oseltamivir and zanamivir are both clinically effective treatments for influenza, particularly for those people in 'at-risk' groups.

The Committee considered the evidence on adverse events associated with oseltamivir and zanamivir. The Committee was aware that very sparse adverse event data were reported in the included RCTs. However, it noted that no significant differences between the antiviral treatments compared with placebo were reported.

The Committee considered the structure of the economic models used to generate cost-effectiveness estimates for oseltamivir and zanamivir for the treatment of influenza. The Committee was aware that the models submitted by the manufacturer and the Assessment Group were not dynamic models. That is, the models did not account for effects of influenza treatment in reducing transmission of infection, the development of 'herd immunity', the potential for the development of drug resistance and the effect of treatment of influenza-like illness on attack rates. The Committee appreciated that some aspects of this approach to modelling additional benefits could improve the cost effectiveness of the antiviral agents but that there were potential disadvantages that would make treatment less cost effective. The Committee was also aware that dynamic models were technically complicated and that the current evidence would not have been sufficient to support this modelling approach. The Committee concluded that the evidence available from the submitted models was an appropriate basis on which to make a decision and that on balance an alternative dynamic modelling approach would not change its overall conclusions.

The Committee then reviewed the cost-effectiveness estimates of oseltamivir and zanamivir as submitted by the manufacturer of oseltamivir and the Assessment Group. In particular, the Committee considered the key inputs in the models were the probability that an influenza-like illness is true influenza and complication rates following influenza infection and subsequent related hospitalisation and mortality.

The Committee first considered the different estimates of the probability that an influenza-like illness is true influenza. The Committee noted that the probability used in the manufacturer's model was lower than that used in the Assessment Group model (for which different probabilities were used according to age group). The Committee was aware that the confidence intervals surrounding the probability estimates for different population subgroups used in the Assessment Group model were wide and overlapped with one another. The Committee heard from clinical experts that the probability of an influenza-like illness being true influenza in children was likely to be lower than that assumed in the Assessment Group model because of increased difficulties in diagnosis in children and the probability of other conditions such as respiratory syncytial virus, which can present as influenza-like illness. The Committee thought that this was particularly likely for otherwise healthy children and concluded that the estimate of 56% (influenza-like illness is true influenza) was too high and should be more closely aligned to that of adults (that is, 41%).

The Committee considered whether the vaccination status would affect the probability that a person presenting with an influenza-like illness would have true influenza. The Committee considered that this would depend on a number of factors, including whether the vaccine was appropriately matched to the currently circulating strain of influenza virus and whether sufficient time had elapsed since vaccination to ensure it was effective. The Committee noted that there were insufficient data on which to inform differential considerations on the basis of vaccination status. Therefore the Committee concluded that any recommendation on the use of antiviral drugs would not distinguish between vaccinated and non-vaccinated people.

The Committee then discussed whether increases in GP consultation rates (for example, as a result of a positive recommendation for the use of antiviral drugs) could result in more people presenting to a healthcare provider with an influenza-like illness that was not true influenza. The Committee heard from clinical experts that this was plausible. The Committee was also aware that current surveillance schemes are based in part on the number of GP consultations, and increases in consultation rates could lead to an apparent increase in influenza prevalence and thus reduction in the positive predictive value of influenza diagnoses. The Committee considered that such a scenario was more probable in healthy populations. The Committee concluded that for healthy populations increases in GP consultation rates would lead to decreases in the probabilities that an influenza-like illness was true influenza. The Committee was also aware that there would be extra costs associated with an increase in GP consultation rates. Therefore the Committee concluded that the base-case ICERs for these groups would be underestimates if a positive recommendation were given.

The Committee considered the effects of oseltamivir and zanamivir treatment on complication rates associated with influenza. The Committee noted that the economic model provided by the Assessment Group included complication rates based only on reductions in antibiotic use in the absence of more direct data. The Committee was aware that there may be additional, alternative, approaches to measuring complication rates and that there were wide confidence intervals and uncertainty in the relative reduction rates in antibiotic use, particularly for healthy adults and children. The Committee also considered that the lower severity and duration of influenza symptoms, as may occur in healthy populations compared with 'at-risk' populations as discussed in section 4.3.5, could lead to a lower incidence of complications and subsequent hospitalisations.

The Committee considered the effects of influenza on health-related quality of life. In the Assessment Group base case, an average quality of life decrement had been applied across the duration of an episode of influenza illness. The Committee noted that influenza is generally associated with worse disutility at the beginning rather than at the end of the illness. The Committee considered that it is more plausible that a reduction in symptoms arising from treatment would occur at the end of the illness. This would result in a lower impact on health-related quality of life, with an overall lower average quality of life decrement, compared with a reduction in symptoms at the beginning of the illness. The Committee noted that the Assessment Group estimated that in such a circumstance the average decrement in quality of life should be reduced to between 0.22 and 0.23 for healthy populations. The Committee considered that people in the 'at risk' population would be expected to have more severe symptoms for a longer period and that it is plausible that having to visit their GP to obtain treatment in the early phase of the illness might in itself cause additional impact on health-related quality of life. Therefore, taking all of these factors into account, the Committee accepted the average base-case decrement in quality of life for 'at risk' populations used in the Assessment Group base case (that is, between 0.5 and 0.6).

The Committee then considered the cost-effectiveness estimates for oseltamivir and zanamivir treatment in otherwise healthy populations. It considered that the most plausible presented ICERs in this group were from the scenarios exploring the combined effect of excluding hospitalisation and mortality benefits, increased GP consultation rates with a subsequent reduction in the probability that an influenza-like illness is true influenza and a reduced decrement in quality of life of 0.2. The point estimate ICERs resulting from these scenarios ranged from £21,000 to £31,500 per QALY gained in healthy children and from £39,900 to £65,600 per QALY gained for healthy adults. The Committee was also mindful of its conclusion that in children 56% is an overestimate of the probability that influenza-like illness is influenza, and that the estimate should be more closely aligned with that for adults (that is, 41%). Hence it considered that the ICERs of £21,000 to £31,500 per QALY gained in healthy children were underestimates of the true ICERs within the preferred set of assumptions accepted by the Committee. The Committee was also aware that the ICERs presented assumed treatment with oseltamivir in all cases, because oseltamivir dominated zanamivir in healthy populations. The Committee was mindful that if both oseltamivir and zanamivir were recommended, then the true ICERs for healthy populations would be higher. Therefore, the Committee concluded that oseltamivir and zanamivir for the treatment of influenza in otherwise healthy children and adults would not be a cost-effective use of NHS resources.

The Committee further considered the cost-effectiveness estimates of oseltamivir and zanamivir in 'at-risk' populations. Having reviewed a number of the key parameters from the economic models, the Committee concluded that for 'at-risk' populations the economic estimates submitted by the Assessment Group and the manufacturer of oseltamivir were plausible. The Committee concluded that because the base-case estimates were all less than £20,000 per QALY gained for these population subgroups, then oseltamivir and zanamivir, within their licensed indications, could be recommended as cost-effective uses of NHS resources.

The Committee then discussed whether both oseltamivir and zanamivir should be recommended for the treatment of influenza. The Committee was aware of the limitations in the evidence base for comparative efficacy of the two drugs and it was not persuaded that there was evidence of differential effectiveness. However, the Committee noted that the drugs were administered differently and that zanamivir was not licensed for children aged 5 years or younger. The Committee concluded that it was therefore preferable not to give specific recommendations for oseltamivir or zanamivir, and that the decision as to which to prescribe should be made after consultation between the healthcare professional, the patient and carers on a case-by-case basis, taking into account the patient's preferences regarding drug delivery and potential adverse effects and contraindications. However, the Committee considered that if all other considerations are equal, the choice should be based on the less costly option within the marketing authorisations of the products.

The Committee considered the need for managing outbreaks that occur outside the influenza season as defined by the surveillance threshold. It noted that such outbreaks often occurred in residential care establishments and were frequently associated with poor outcomes and complications in vulnerable populations. The Committee noted that the population in residential care was most likely to be older people or people otherwise at risk of influenza complications. It was mindful that, because oseltamivir and zanamivir are effective only against true influenza, the cost effectiveness of treatment in such situations would depend on the probability that the influenza-like illness was influenza. The Committee noted that this probability was low in the absence of wider circulation of influenza. Therefore, the Committee considered it important that in such situations there should be firmer evidence that the influenza-like illness was influenza. Such evidence could be supplied by virological testing. The Committee considered other people who lived together in a residential setting, such as a prison or boarding school. It noted that such populations would comprise mostly healthy people for whom the consequences of influenza infection would be minor. The Committee agreed that such populations would not be exceptions and treatment during outbreaks outside the influenza season would not be cost effective unless people in those populations were in an 'at-risk' group. Therefore the Committee recommended that outside the periods when national surveillance indicates that influenza virus is circulating, oseltamivir and zanamivir could be recommended for treatment of influenza in 'at-risk' people living in long-term residential or nursing homes, but only if there is a high level of certainty that a localised outbreak is occurring, usually based on virological evidence of infection with influenza in the incident case or cases.