Influenza is estimated to strike between 5% and 10% of adults annually, resulting in billions of dollars in direct and indirect costs. Although antiviral drugs have been available for decades and are indicated for the treatment of uncomplicated influenza,1
these drugs are not widely prescribed. Our decision model, based on data taken from efficacy studies in thousands of patients, demonstrates that the economic impact alone validates the use of antiviral therapy in healthy adults with influenza-like illness. The small benefit of shortening symptoms by an average of 1 day is by no means trivial. If 14 million American workers all return to work 1 day sooner as a result of antiviral therapy, in addition to averting 14 million symptom-days, the annual savings, based on our model, would be $1.5 billion. Even for patients who do not work, treating influenza with amantadine costs only $1200/QALY saved. By comparison, combination therapy for hepatitis C costs $7000 per QALY saved,34
while screening mammography for women aged 69 years or more costs $118,000/QALY saved.35
Previous influenza models,25,27,36–40
which either did not include amantadine or neglected work-related costs, all found antiviral treatment to be cost-effective, but not cost-saving compared to no antiviral therapy, and conclude that its use is justified. Although specific thresholds are offered for probability of influenza infection and prevalence of influenza B, none of these models explores the crucial interaction of these two variables, leaving clinicians to guess as to which drug would be appropriate for a particular patient.
Like other authors, we found that the incremental benefit of using antiviral therapy is small, on the order of 0.0014 QALYs (or 12.2 quality-adjusted hours) gained. Although this benefit may seem small, it is remarkably stable. Only the probability of influenza infection, the proportion of influenza caused by type B, the value of a workday, and the relative efficacy of the drugs have any major impact on the choice of strategy. For example, doubling the incidence of side effects from amantadine would decrease the benefit to 0.0013 QALYs or 11.4 quality-adjusted hours. More importantly, this small benefit does not come at a cost, but actually saves money.
Based on the findings of our study, we offer an algorithmic approach to the management of healthy adults who present with influenza symptoms. The algorithm chooses the most effective strategy with a cost-effectiveness ratio of $50,000/QALY or less (). During the influenza season, such patients have a high probability of influenza infection, and amantadine treatment is cost-saving. In regions where influenza B exceeds 40% of influenza cases (or 20% during a regional epidemic), treatment with a neuraminidase inhibitor offers additional benefit and can be considered cost-effective for working adults (). If more than half of influenza cases are caused by influenza B, then zanamivir is also cost-effective for nonworking adults. In the peri-influenza season, amantadine would still be cost-saving, unless the majority of cases are caused by influenza B, in which case rapid testing followed by treatment with zanamivir is preferred. The proportion of influenza B is reported weekly on the Centers for Disease Control and Prevention's website.17
FIGURE 5 Algorithmic approach to the patient with influenza-like illness. All patients begin in the oval at the top of the diagram. Hexagons are influenza conditions that can be answered either “yes” or “no.” Rectangles represent (more ...)
In years or regions when there is little influenza, or if a patient has received influenza vaccine, the probability of influenza infection will be lower than that used in the algorithm. In that case, the preferred treatment can be found by plotting the clinician's estimate of the probability of influenza infection against the proportion of influenza caused by type B on the graph in .
Our study has limitations. First, for want of comparative data, we assumed that all drugs have equal efficacy. However, if any drug were even 20% more effective than the others in reducing the duration of illness, it would usually be the drug of choice. We also assumed that shortening the duration of fever by 1 day results in patients returning to work 1 day sooner. While several studies found that treatment with neuraminidase inhibitors returned patients to normal activity 1–2 days sooner than did placebo,7,13
no study reported return to work. Because cost-effectiveness of the neuraminidase inhibitors depends on the economic impact of lost work time, future influenza studies should report the effect of the drugs on subjects’ return to work. Amantadine, however, is cost-effective even for nonworking adults.
Other factors, such as the incidence of side effects or whether these drugs prevent influenza complications, did not affect the decision for healthy adults, unless the side effects were so severe that they delayed return to work. Further studies are needed to assess the impact of these drugs on complications in the elderly and the very young, who are disproportionately affected by influenza morbidity and mortality. Indeed, preliminary studies of zanamivir imply that it may have its greatest efficacy in high-risk groups.10
Our analysis did not address vaccinated patients, as there is currently no recommendation for or against vaccination in healthy persons less than 50 years of age. In years when the vaccine is well-matched to circulating strains, vaccinated patients presenting with influenza-like illness should have a significantly lower probability of influenza than unvaccinated patients, making antiviral therapies less cost-effective. However, by estimating the probability of influenza in any given patient, vaccinated or not, the preferred therapy can be chosen based on .
Studies have shown that resistance to amantadine and rimantadine may develop rapidly.1
While there is no evidence that this would lead to resistant strains in subsequent years, effectiveness of these medications may decrease as the influenza season progresses. If so, the neuraminidase inhibitors might become more useful, as they seem less likely to induce resistance.1
All of the cost-effective strategies involve treatment based on clinical diagnosis. We did find a limited role for testing when the probability of influenza infection is low, as in the peri-influenza season, and a majority of cases are caused by influenza B. In this setting, tests with high specificity are most cost-effective. Directigen AB offers the additional benefit of distinguishing between influenza A and B and would be preferred over other tests if the difference in the cost of testing were $5 or less.
Treatment based on clinical diagnosis will surely result in many patients without influenza taking antiviral drugs. Depending on the season and the region, the number-needed-to-treat to shorten the illness by 1 day ranges from 1.25 to 10.0. Anti-influenza drugs have a safety profile similar to or better than antibiotics and nonsteroidal anti-inflammatory agents, which are routinely prescribed for patients with influenza-like illness. Unlike antibiotics, anti-influenza drugs should not induce resistance in patients who do not have influenza. Furthermore, patients offered antivirals would not only benefit from effective treatment, they might be less inclined to request antibiotics.