Debate Regarding Oseltamivir use for Seasonal and Pandemic Influenza

Aeron C. Hurt; Heath Kelly

Disclosures

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

In This Article

Abstract and Introduction

Abstract

A debate about the market-leading influenza antiviral medication, oseltamivir, which initially focused on treatment for generally mild illness, has been expanded to question the wisdom of stockpiling for use in future influenza pandemics. Although randomized controlled trial evidence confirms that oseltamivir will reduce symptom duration by 17–25 hours among otherwise healthy adolescents and adults with community-managed disease, no randomized controlled trials have examined the effectiveness of oseltamivir against more serious outcomes. Observational studies, although criticized on methodologic grounds, suggest that oseltamivir given early can reduce the risk for death by half among persons hospitalized with confirmed infection caused by influenza A(H1N1)pdm09 and influenza A(H5N1) viruses. However, available randomized controlled trial data may not be able to capture the effect of oseltamivir use among hospitalized patients with severe disease. We assert that data on outpatients with relatively mild disease should not form the basis for policies on the management of more severe disease.

Introduction

A lively, and sometimes heated, debate has recently been conducted in the popular press[1] and medical literature[2–4] about the effectiveness of oseltamivir, its usefulness in treating seasonal influenza, and the need for it to be stockpiled for use in a future influenza pandemic. Oseltamivir, manufactured by F. Hoffmann-La Roche (Roche) (Indianapolis, IN, USA), is the market leader of the neuraminidase inhibitors (NAI), the first class of antiviral drugs designed specifically to treat influenza.

Oseltamivir came on the market in many countries in 2000 after clinical studies had been conducted among influenza virus–infected patients with uncomplicated illness. Trial data from outpatient studies have been summarized in a recent meta-analysis of individual patient data, including published and unpublished studies, which confirms that oseltamivir will reduce the duration of symptomatic laboratory-confirmed influenza in otherwise healthy adults from 5 days to 4 days,[2] a result consistent with those of a previous systematic review by the Cochrane group.[3]

After the drug's market release, oseltamivir use for treatment of seasonal influenza was modest in most countries, except for Japan, where widespread use of the drug was adopted. However, governments began to consider antiviral drug administration as a key component of their planned pandemic response after human infections with avian influenza A(H5N1) virus increased in 2003 and were associated with a case-fatality risk of >50%.[5] Suitable vaccines would not be available at the start of a pandemic; thus, use of antiviral agents was seen as a critical part of a pandemic response.

Because the mode of administration for oseltamivir was simpler (oral) than that for zanamivir (inhalation) and because the systemic effect of oseltamivir was expected to be appropriate for treatment of highly pathogenic viruses, oseltamivir was suddenly in high demand, apparently driven by warnings from Roche that preemptive stockpiling was the only way that governments could be assured of drug availability.[6] Since 2005, governments of middle-income and high-income countries around the world have spent billions of dollars (estimated) stockpiling oseltamivir.[7] However, by November 2015, the influenza A(H5N1) virus that initiated stockpiling had caused only 844 human cases of infection and 449 deaths (case-fatality risk 53.2%) across 16 countries worldwide, with only 7 countries reporting >10 cases.[8]

The first pandemic of the 21st century occurred unexpectedly in 2009 after the global spread of a novel virus—influenza A(H1N1)pdm09—of swine (rather than avian) origin. In response, many countries activated their stockpiles of antiviral agents or accessed existing community supplies. This was the first time that specific antiviral drugs were available in a pandemic. In the United States during 2009, 8.7 million oseltamivir prescriptions (28.4 prescriptions/1,000 persons) were dispensed from community pharmacies, not from the stockpile, at a cost of US $905 million.[9]

Although the number of deaths due to the 2009 pandemic was lower than initially anticipated, a unique opportunity was provided to review the effectiveness of oseltamivir in the pandemic setting and to determine the benefit of oseltamivir for patients who were hospitalized with confirmed influenza A(H1N1)pdm09 virus infection. Such observational data were valuable to ascertain the effect of oseltamivir in severely ill or hospitalized patients given the continued absence of data from placebo-controlled, randomized controlled trials.

Questioning whether oseltamivir is useful for treating serious illness and whether it should be stockpiled has extended the debate on the effectiveness of oseltamivir in the community. We believe that these issues should be considered separately.

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