Neuraminidase Inhibitors, Endonuclease Inhibitors Significant for Influenza Pandemics, Foundational for Further Antiviral Support

Due to the immeasurable qualities of viral spread (e.g., viral strain, time of onset, or geographic origin) at the start of influenza pandemics, they can be difficult to predict. When implemented properly, effective antiviral drugs that target the conserved viral proteins can serve as first-line treatments acting against emerging influenza strains, according to a study published by Antiviral Research. The study authors noted that these treatment methods can reduce viral loads, limit transmission, and help reduce the severity of infections, which reduce morbidity and mortality until more effective and antigenically matched vaccines are available.

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Due to their lower costs, longer clinical use, and availability, neuraminidase (NA) inhibitors (NAIs) are used more widely than the cap-dependent endonuclease inhibitor (CENI) baloxavir marboxil (BXM). In the near future, these 2 drug classes could be the foundation for antiviral support during influenza pandemics, according to the study authors.

NAIs target NA glycoprotein—the abundant surface glycoprotein behind hemagglutinin (HA)—by preventing the spread of viruses by hindering the enzymatic activity that is necessary for new virions from host cells. Multiple NAIs (oseltamivir, zanamivir, peramivir, and laninamivir) show different therapeutic benefits and efficacy depending on the influenza strain infecting the patient. Treatments should be administered within 48 hours of the patient’s initial symptom onset.

In a meta-analysis of 9 randomized control trial (RCTs), oseltamivir-treated groups showed a reduced risk of lower respiratory tract complications and hospital admission, compared to placebo-treated groups. Further, another meta-analysis of 20 RCTs examining oseltamivir and zanamivir in healthy adults who were exposed to naturally occurring influenza showed modest efficacy against influenza symptoms. Different research shows that NAI treatment significantly reduced the mortality risk of patients who were hospitalized, with early treatment (within 48 hours) showing the greatest reductions in mortality.

According to the authors, clinical outcomes of antiviral therapy can be compromised by the development of influenza viruses with reduced resistance to NAIs and with resistant profiles differing for the various NAI and NA subtypes. Currently, 2 novel NAIs and an NA blocker are in phase 1 and 2 development, with the NAI showing good safety and tolerability profiles while preventing and treating various strains of influenza, and the NA delivering universal protection against various influenza strains.

According to the authors, BXM is a relatively new drug without a generic equivalent, making it difficult to compare the demand to NAIs. Compared to oseltamivir, BMX has demonstrated similar time to alleviation of symptoms (TTAS) and greater reductions in viral load in healthy adults, with similar TTAS to oseltamivir in high-risk adults.

Further, a study demonstrated possible reductions in hospitalizations for those who received BMX versus those who received NAIs; however, a different trial showed that BXM efficacy was low and had the possibility of viral rebound when used with different medications. Despite the low barrier to resistance, BXM is highly effective and could be used in a pandemic due to its efficacy against influenza, according to the study authors.

Currently, early studies involving NAI combinations were inconclusive or did not show superiority over the use of a single NAI. A study that used a combination of oseltamivir and peramivir showed that the combination treatment did not properly treat adults with influenza infection; however, oseltamivir on its own was more effective. Further, a trial that used a combination of oseltamivir, rimantadine, and ribavirin had significantly reduced viral loads, but did not provide other significant clinical outcomes. Combination NAI therapy has presented limited clinical benefits, and additional trials are needed to investigate further while taking dosing, timing of administration, target population (high risk versus uncomplicated infections), and different combinations (including CENIs) into consideration.

The widespread morbidity and mortality in the early months of the COVID-19 pandemic emphasized the consequences of combating a viral pandemic without readily available vaccines and antivirals targeted toward viruses; however, this is not the case for influenza as there are 2 available classes of antivirals with different mechanisms. The authors note that beginning investigations prior to the next influenza pandemic rather than in reaction to it will not only benefit the response but will help reduce the mortality and morbidity that is associated with it.

Reference

Jones JC, Yen H, Adams P, Armstrong K, Govorkova EA. Influenza antivirals and their role in pandemic preparedness. Antiviral Res. 2023;210:105499. doi:10.1016/j.antiviral.2022.105499