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Neuraminidase Inhibitors in Influenza Treatment and Prevention–Is It Time to Call It a Day?

Neuraminidase inhibitors (NAIs) constitute the primary type of antiviral drugs against influenza... If oseltamivir is used as a therapeutic measure, the delay from the time of infection to the time of treatment initiation leads to the underperformance of the drug. While the efficacy could be increased by increasing dosage, a drug with 99% efficacy administered after 48 hpi yields a negligible effect on influenza virus dynamics and symptoms. If oseltamivir is used as a prophylactic measure, the drug effectiveness is only warranted under limited conditions and should only be considered as an expensive alternative to public health routines in epidemic control.

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 Neuraminidase inhibitors for preventing and treating influenza in adults and children

Oseltamivir and zanamivir have small, non‐specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children.

Articles of Interest

Millions of patients given flu drugs with little or no benefit, study finds

Researchers say benefits of antiviral drugs may have been inflated by studies paid for by pharmaceutical companies.

Antivirals Targeting the Neuraminidase

The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections.

Assessment of adverse events related to anti-influenza neuraminidase inhibitors using the FDA adverse event reporting system and online patient reviews

AEs were more common among those who were younger (<19 years) for zanamivir, while for those who were older (>65 years) for peramivir. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. Psychiatric disorders were most common in younger and older patients, while gastrointestinal disorders were most common in adult given oseltamivir in the WebMD. Adverse symptoms related to NAIs varied and depended on the drugs used and the age of the patient.

Effectiveness of Tamiflu and Relenza questioned

Most experts would agree that the modest benefits of Tamiflu and Relenza, as reported by the review, do not justify the increased adverse risks, let alone the money spent on them by the UK.

Expert Opinion on neuraminidase inhibitors for prevention and treatment of influenza

The neuraminidase inhibitors oseltamivir and zanamivir, currently authorised in the European Union/European Economic Area (EU/EEA) for treatment and prophylaxis of influenza disease (including seasonal, pandemic and zoonotic influenza) have been the subject of debate concerning their effectiveness and safety, as well as the appropriateness of stockpiling these drugs for use in future influenza pandemics.

Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016–2017

This 2016/17 analysis demonstrates that neuraminidase inhibitors remain suitable for treatment and prophylaxis of influenza virus infections, but continued monitoring is important. An expansion of surveillance testing is paramount since several novel influenza antivirals are in late stage clinical trials with some resistance already having been identified

Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity

Despite being a common viral disease, influenza has very negative consequences, causing the death of around half a million people each year. A neuraminidase located on the surface of the virus plays an important role in viral reproduction by contributing to the release of viruses from infected host cells. The treatment of influenza is mainly based on the administration of neuraminidase inhibitors. The neuraminidase inhibitors zanamivir, laninamivir, oseltamivir and peramivir have been commercialized and have been demonstrated to be potent influenza viral neuraminidase inhibitors against most influenza strains.

Influenza Virus Neuraminidase: Structure and Function

The influenza virus NA executes several functions. Firstly, its activity is required at the time of the budding of newly formed viral particles from the surface of the infected cell, to prevent aggregation of viral particles. In addition, NA cleaves neuraminic acid residues from the respiratory tract mucins; by doing so, it facilitates viral movement to the target cell.

Is the Neuraminidase Inhibitor Tamiflu Effective in the Treatment of Influenza?

Influenza is a disease that has caused the deaths of tens of millions people in the last century alone. The influenza neuraminidase protein is essential in the mechanism infection. It enables the virus to leave the infected cell and proliferate. Antiviral neuraminidase inhibitor drugs can be used for treatment. The drug Tamiflu is the standard of care for both treatment and prophylaxis of influenza. The Cochrane reports of 2009 and 2014 conclude that evidence is lacking to support this. Numerous bodies disagree. Cochrane also question the accuracy and credibility of many studies and agencies in support of Tamiflu.

Neuraminidase inhibitors for influenza: a systematic review and meta- analysis of regulatory and mortality data

The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza.

Neuraminidase Is Important for the Initiation of Influenza Virus Infection in Human Airway Epithelium

In summary, we have provided here for the first time direct experimental evidence for the essential role of NA at the stage of virus invasion of the ciliated epithelium of human airways.

Next Generation Neuraminidase Inhibitors for Treatment and Prophylaxis of the Flu

The influenza neuraminidase (also known as a sialidase) is a validated enzyme target for the control of influenza infections. Four drugs that target this enzyme are currently in clinical use: laninamivir/Inavir®, oseltamivir/Tamiflu®, peramivir/Rapivab®, zanamivir/Relenza®. However, emerging resistances against these drugs as well as the ongoing Covid-19 pandemic create a need for new neuraminidase inhibitors (NAIs).

Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections

Peramivir is a highly potent inhibitor against influenza A and B viruses with a well-demonstrated safety profile. Administration via IV route provides an alternative for patients who cannot use oral drugs. Common side effects include gastrointestinal disorders and decreased neutrophil count and are self-limiting

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

Neuraminidase inhibitors are reagents used to block the enzyme called neuraminidase to prevent the influenza infection from spreading. Neuraminidase inhibitors are widely used in the treatment of influenza infection, but still there is a need to develop more potent agents for the more effective treatment of influenza.

Tamiflu and Relenza for treatment and prevention of influenza

The Cochrane Collaboration published an evidence review of Tamiflu (the antiviral drug oseltamivir) and Relenza (zanamivir) trials, reporting that Tamiflu shortens symptoms of influenza but other claims made for the drugs were not well supported by evidence from clinical study reports.

Tamiflu and Relenza: getting the full evidence picture

It is believed that the major function of viral neuraminidase (NA) is at the final stage of infection when NA cleaves sialic acid from cell surface and progeny virions facilitating virus release from infected cells. Less is known about NA functions during virus entry into the cell. It has long been assumed that NA promotes virus access to target cells in airways by mucus degradation. However, this concept has never been formally proven due to the lack of an adequate experimental system.

Resources

Rapivab (Peramivir)

The usefulness of neuraminidase inhibitors is limited by the need to give them within 48 hours of symptoms developing. In otherwise healthy people an infusion of peramivir will alleviate symptoms about a day faster than placebo.2 Its efficacy is similar to oral oseltamivir, but it may reduce fever more rapidly in adults.3 There is insufficient evidence to show that peramivir is effective for serious cases of influenza requiring hospitalisation. Its efficacy and safety in pregnancy are also unknown. Although the 300 mg dose had similar efficacy, the recommended adult dose is 600 mg as the higher dose reduces viral shedding. As with other neuraminidase inhibitors, the influenza virus may develop resistance to peramivir.

Relenza (Zanamivir)

Relenza (zanamivir) is an antiviral medication. It can help ease flu symptoms and prevent the flu in certain adults and children. But it doesn't replace the seasonal flu vaccine. Relenza (zanamivir) comes as an inhaler that's inhaled by mouth twice daily for flu treatment or once daily for flu prevention. Because of the rare risk of bronchospasm, people who have asthma or chronic obstructive pulmonary disease (COPD) aren't recommended to use this medication. Common side effects include runny nose and dizziness. Relenza (zanamivir) is brand name only and not available as a generic medication.

Tamiflu (Oseltamivir)

Tamiflu (oseltamivir) works well to treat the flu, but you have to take your first dose within 48 hours of the start of your flu symptoms. It can also help prevent the flu if you've recently been in close contact with someone who has the flu. Kids as young as 2 weeks old can take Tamiflu (oseltamivir), but keep in mind that the pediatric dosing is different than adult dosing. It's only available with a prescription (not available over the counter), so don't wait to see your provider if you start feeling sick. This medication comes as a brand or generic capsule or fruit-flavored liquid. Tamiflu (oseltamivir) can cause side effects like nausea and vomiting.

CDC

Antiviral treatment is recommended as soon as possible for any patient with suspected or confirmed influenza who: is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications.

theNNT

May reduce duration of symptoms by <1 day but associated with adverse events. In summary, the existing data indicate that NAIs reduce the duration of symptoms by less than a day in patients with confirmed or suspected influenza. The use of NAIs to treat influenza does not prevent hospitalization and is associated with adverse events. Therefore, we have assigned a color recommendation of yellow (unclear if it provides benefit, more data needed) to this treatment.

Virology Blog

In the wake of a British Medical Journal article which concludes that Tamiflu has at best a modest effect, many readers have asked if influenza neuraminidase inhibitors function at all. If you’d like a good critique of this study, I suggest reading Paul Revere’s analysis at Effect Measure. For our part, we’ll examine some of the virological evidence for the effectiveness of Tamiflu.