Understanding the Impact of Resistance to Influenza Antivirals

Abstract

Influenza poses a significant burden on society and health care systems. Although antivirals are an integral tool in effective influenza management, the potential for the emergence of antiviral-resistant viruses can lead to uncertainty and hesitation among front-line prescribers and policy makers. Here, we provide an overview of influenza antiviral resistance in context, exploring the key concepts underlying its development and clinical impact. Due to the acute nature of influenza in immunocompetent patients, resistant viruses that develop during antiviral treatment of a single patient ("treatment-emergent resistance") are usually cleared in a relatively short time, with no impact on future antiviral efficacy. In addition, although available data are limited by small numbers of patients, they show that antiviral treatment still provides clinical benefit to the patient within whom resistance emerges. In contrast, the sustained community transmission of resistant variants in the absence of treatment ("acquired resistance") is of greater concern and can potentially render front-line antivirals ineffective. Importantly, however, resistant viruses are usually associated with reduced fitness such that their widespread transmission is relatively rare. Influenza antivirals are an essential part of effective influenza management due to their ability to reduce the risk of complications and death in infected patients. Although antiviral resistance should be taken seriously and requires continuous careful monitoring, it is not comparable to antibiotic resistance in bacteria, which can become permanent and widespread, with far-reaching medical consequences. The benefits of antiviral treatment far outweigh concerns of potential resistance, which in the vast majority of cases does not have a significant clinical impact.

Keywords: antiviral agents; drug resistance evolution; influenza.

FIG 1

Two types of influenza antiviral resistance can be distinguished. Resistance to influenza antivirals is referred to as either “treatment emergent” or “acquired.” Treatment-emergent resistance refers to that which emerges de novo in an individual patient in response to the selection pressure of antiviral treatment, for example, during a clinical trial. In contrast, acquired resistance occurs without the selection pressure of antiviral treatment because the virus is already resistant before it is transmitted to the new host.

FIG 2

Currently used approaches for calculating antiviral resistance can result in overestimation of resistance rates. Rates of treatment-emergent resistance are estimated from clinical trial data and include only patients with detectable virus within the posttreatment sample. This means that resistance rates will be overestimated, as in most cases, the patients without detectable posttreatment virus will be excluded from the denominator but would most likely not have developed resistant virus. This is illustrated in the example from the miniSTONE-2 trial (54).