Debate Regarding Oseltamivir use for Seasonal and Pandemic Influenza

Aeron C. Hurt; Heath Kelly


Emerging Infectious Diseases. 2016;22(6):949-955. 

In This Article

Oseltamivir Policies for Seasonal and Pandemic Influenza

The evidence from randomized controlled trials is clear that oseltamivir treatment decreases the duration of symptoms by up to 1 day in adolescent and adult patients with laboratory-confirmed seasonal influenza whose infections are able to be managed in the community. Oseltamivir provides no benefit to patients who have influenza-like illness not caused by influenza virus.[2] Reviews of observational data regarding patients hospitalized with influenza A(H1N1)pdm09 or influenza A(H5N1) infections found that risk for death is cut in half if treatment is initiated within 48 hours of symptom onset.[4,22] Small prepandemic observational studies, although they generally have controlled less for potential biases, also support the conclusion that risk for death is decreased with oseltamivir treatment.[15,23]

These 2 lines of evidence may appear inconsistent. How would an intervention that has a modest effect on symptom duration in patients whose uncomplicated influenza was treated after a visit to a general practitioner be able to cut in half the risk for death among hospitalized patients?

It should not be surprising that treatment for uncomplicated influenza will only produce a modest effect because influenza virus replication precedes symptoms by 1–2 days. This means that the viral load in the patient may have peaked by the time the patient begins antiviral treatment. Given that most antiviral drugs, including oseltamivir, act by reducing viral replication, the effect of treatment will therefore be minimal in otherwise healthy persons when immune responses are already reducing viral titers. It is therefore plausible that community-based randomized controlled trials are not capturing critical information about the mode of action of oseltamivir that is beneficial to severely ill patients.

It is possible that benefit to severely ill patients may be related to the increased duration of viral shedding and higher viral loads found in this group of patients.[26] Elevated cytokine levels, sometimes referred to as a cytokine storm, have been detected for patients infected with highly pathogenic A(H5N1) virus[27] and for severely ill patients infected with influenza A(H1N1)pdm09 and seasonal influenza viruses.[28,29] A randomized controlled trial study of 117 healthy adults experimentally infected with seasonal influenza virus A(H1N1) reported that oseltamivir treatment significantly reduced interleukin-6, interferon-γ, and tumor necrosis factor-α cytokine responses in patients compared with responses in placebo-treated patients.[30] Although these results do not clarify whether the decreased cytokine response was the result of effective viral treatment or a (postulated) immune modulatory effect of oseltamivir, ferret studies conducted in our laboratory suggest that oseltamivir treatment consistently reduces peak temperatures and improves ferret activity/wellness but often does so in the absence of any significant effect on viral load.[31] The difference in outcome for severely infected patients treated with oseltamivir may relate to decreasing the adverse outcome associated with a cytokine storm, which would not be expected in patients with mild disease.