Neuraminidase Inhibitor, Polymerase Inhibitor Use for Influenza Treatment Continues, Other Methods Considered


While monitoring influenza virus resistance as it develops, researchers are prioritizing further investigations to decrease the risk of resistant strains.

Influenza A virus (IAV) is one of the most rapidly changing microorganisms because its genetic instability allows it to change its biologic properties (e.g., virulence, adaptation to new hosts). Because of the virus’s genetic variability, it is difficult to properly implement effective prophylactic programs, such as vaccinations, according to a study published in International Journal of Molecular Sciences.

Health care worker giving patient an influenza vaccine

Image credit: arcyto |

A single variant of influenza has the ability to cause a public health threat. Although currently available antiviral drugs can reduce the symptoms of influenza and limit virus transmission, the possibility of selecting resistant strains still exists, meaning influenza treatment continues to be a challenge. The study authors reviewed prior research to describe the evolution of influenza, as well as the consequences of the virus’s variability, mutations, and recombination.

Previously, the M2 protein inhibitors (M2Is) amantadine and rimantadine were effective in treating and preventing infection caused by IAV, with efficacy rates of up to 90%; however, M2Is could not be used to treat influenza B infection (IBI) due to the lack of M2 protein on its surface. The success of treatment with M2Is is dependent on the early administration (within 48 hours) from the onset of influenza symptoms, according to the study.

The virus’s first resistance to amantadine was initially observed during the 1980 epidemic; however, it remained at a low level (1% to 2%) until the year 2000. From 2000 to 2004, amantadine resistance among the A/H3N2 subtype increased from 1.1% to 27% in Asia, and to 4.7%, 3.9%, and 4.3% in Europe, North America, and South America, respectively. Further, there was a dramatic increase of amantadine-resistant strains worldwide (90.6% for the A/H3N2 strain; 15.6% for the A/H1N1 strain) during the 2005/2006 influenza season. By 2013, approximately 45% of all IAV subtypes were resistant to amantadine.

Neuraminidase inhibitors (NIs) were used as an antiviral agent because neuraminidase can facilitate the release of viral particles by severing the sialic acid groups hemagglutinin—a surface protein influenza uses—is bound to. Zanamivir and oseltamivir, which are prodrugs processed in vivo to their active form, can inhibit both IAV and IBV replication, reducing the duration time of virus release. Prior studies have shown that NIs can decrease the duration of illness by approximately 40% if they are administered within 36 hours of symptom onset. Further, they can reduce the risk of incidence of influenza complications (e.g., otitis media, sinusitis, pneumonia). If administered shortly after exposure to IAV and IBV, both zanamivir and oseltamivir can decrease the risk of influenza infection by approximately 70% to 90%.

Prior studies have shown that treatment-related oseltamivir resistance is more frequent in the influenza A/H1N1 strain than in the A/H3N2 strain. Both in vitro and in vivo studies have presented that influenza A/H3N2 strains and influenza B strains—which show a resistance to NIs—have a lower capacity for replication and transmission ability. Multiple cases have indicated that resistance is able to occur after prolonged treatment (>10 days), and in some cases, can take more than a month to appear. Additionally, mutations decreasing the efficacy of laninamivir and peramivir, 2 other NIs, were detected in IBV.

Currently, 2 viral polymerase inhibitors (PIs)—favipiravir and baloxavir—are in use. PIs act by targeting the viral polymerase subunits that make up influenza. The 2 therapeutic agents inhibit a process necessary for the virus’s life cycle, with favipiravir inhibiting the subunit PB1 and baloxavir blocking the subunit PA. However, some influenza strains—particularly IAV—have shown resistance to baloxavir. Prior research shows the emergence of baloxavir-resistant viruses in up to 9.7% of adult clinical trial participants, and 23.4% of children who receive baloxavir. Further, favipiravir’s bioavailability after oral administration reaches over 97%, with reduced susceptibility not yet reported in clinical studies.

Due to the emergence of antiviral drug-resistant influenza strains, there is a need for alternative treatments. Prior research shows that the anti-influenza drugs VIS410 and Ro-3306 are potential candidates. According to the current study authors, natural therapies, such as herbal remedies, are in consideration due to the anti-inflammatory, respiratory, and probiotic effects they can have.

Since the last significant influenza pandemic and the replacement of M2 protein inhibitors, several antiviral drugs in the class of NIs and viral PIs have been created, tested, and approved. According to the current study authors, the priority in the future is to continue conducting rational antiviral therapy to decrease the risk of resistant strains while monitoring influenza virus resistance as it develops.


Smyk JM, Szydłowska N, Szulc W, Majewska A. Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects. International Journal of Molecular Sciences. 2022; 23(20):12244.

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