Antiviral Drugs For Flu

Influenza (flu) overview

Influenza is a contagious respiratory infection caused by the influenza viruses that infect the nose, throat, and lungs.¹ Influenza (flu) is extremely common with a billion cases globally every year and is present all around the world with most individuals recovering without any treatment.¹ However, in three to five million cases, individuals may become severely ill and will require treatment and influenza is responsible for 290,000 to 650,000 deaths per year.¹

The flu virus is spread easily through tiny droplets released when infected people cough, sneeze or talk.¹ Symptoms of the flu begin after two days of infection and they can include:¹

• High fever
• Cough
• Sore throat
• Runny nose
• Headache
• Muscle and joint pain

The flu symptoms usually make you feel unwell and the cough can last for longer than two months, but most people will recover from the infection within a week and will not require treatments.¹

Antiviral drugs overview

Antiviral drugs are medication developed that targets viruses such as influenza virus and is used to aid the immune system and relieve some of the symptoms of the infection.² Antiviral drugs can also be used to prevent infections and stop you from passing the infection to someone else.²

Each antiviral drug works differently depending on the drug and what virus types they are fighting yet there are several mechanisms where antiviral medications could work:

1. Block receptors that the virus would bind to and prevent them from entering the cells which would in turn inhibit replication inside your cells.²
2. Improve and boost the immune systems which would allow the body to fight off and clear the virus infection.
3. Lower the amount of virus particles in the body, allowing the immune system to clear away the rest.

This article will discuss how antiviral drugs can be used to treat influenza virus and provide treatment. 

Types of influenza viruses

There are four types of influenza virus:¹

• Influenza type A
• Influenza type B
• Influenza type C
• Influenza type D

Influenza Type A and Type B are the most important types of influenza as they are responsible for causing seasonal epidemics of the disease.¹ Type A is more virulent and is more frequent and has been known to cause flu pandemics across the entire globe whilst type B is milder but it still has the potential to cause flu outbreaks.^3,4 Influenza C is a mild or asymptomatic (does not show symptoms) infection and does not cause epidemics.^3,4 Type D viruses infect mainly cattle and do not cause infection or illness in humans.⁴

Influenza type A virus can be further classified into subtypes depending on the proteins present on the surface of the virus.¹ The two proteins it contains are: Hemagglutinin (H) and Neuraminidase (N). There are several subtype combinations of the protein where more than 130 subtypes have been identified in nature but there is a high chance that there are a lot more subtype combinations present now or in the future.⁴ This is due to the influenza virus being able to reshuffle and rearrange its genes in a process called reassortment.⁴ Influenza type A(H1N1) is the subtype that caused the 2009 influenza pandemic.¹

Influenza type B is not split up into subtypes but there are two lineages the virus comes from:⁴

1. Type B/Yamagata,
2. Type B/victoria

Type B virus changes more slowly compared to type A virus and also circulates across the world slower compared to type A. However, type B/Yamagata virus has travelled less frequently compared to type B/Victoria which has travelled globally.⁴ 

Type C causes mild infection and is not a public health importance.¹

Type D affects cattle and has not infected or caused illness in humans.¹

When selecting antiviral drugs, it is important that the doctors know what type of influenza virus you have as many strains of influenza virus have become resistant to these antiviral medications.⁵ 

Antiviral Drug classes

There are three antiviral drug classes known as:

1. Neuraminidase inhibitors (NI),
2. Adamantanes
3. Polymerase inhibitors. 

Neuraminidase Inhibitors (NAI)

NAI is the largest and most common group of drugs prescribed to treat influenza virus.⁶ The mechanism of action of this drug type is to prevent the virus from replicating which prevents transmission.⁶ Examples of NI include:

• Zanamivir, 
• Oseltamivir,
• Peramivir,
• Laniamivir.

Each NAI drug has a different molecular shape but they all bind specifically to the active site of the surface protein neuraminidase and once bound, it will cause a blockage in the enzymatic activity of the virus, which prevents viral replication.⁶ NI drugs are given to patient 48 hours after symptoms have begun and have been shown to decrease the hospitalisation time of severely sick patients.⁶

NAI drugs are 68-90% effective in preventing infection and reducing the time taken for symptoms to be relieved.⁷ NAI are effective and have been approved for use for both type A and type B influenza virus.⁸ However, despite the use of NAI drugs, there have been reports that the influenza virus is becoming resistant to the drugs, especially within the type A H1N1 subtype.⁸ This is due to the active site surrounding the neuraminidase protein undergoes mutations and the genetic changes which mean the NAI drugs can’t bind to the protein’s active site anymore.⁸ 

Adamantanes

Adamantanes is an inhibitor of the Matrix-2 (M2) ion channel.⁹ These drugs work by blocking the ion channel formed by the M2 protein and this prevents early stage viral replication and is thus given to patients within 48 hours after infection to reduce the illness by 1.5 days.⁸ Adamantanes drugs are readily available and at low cost and have been used for nearly 50 years to treat the influenza virus.⁸

There are two drugs available within the adamantanes drug class:

1. Amantadine 
2. Rimantadine

Both of these drugs work by targeting and blocking the virus’s coating and preventing it from entering the host (human) cells, which prevents infection.⁸ 

Adamantanes drugs are used to treat influenza type A but are not effective for influenza type B. However, despite them being used for decades, they are no longer recommended to treat influenza viruses due to an increasing level of influenza A becoming resistant to them.⁸ M2-resistant influenza virus can spread between people and can cause infection. An increase in antiviral resistance is a major challenge in treating influenza. 

Polymerase Inhibitor

The polymerase inhibitor drug class works by inhibiting RNA synthesis which prevents the virus from replicating.⁸ There are two types of polymerase inhibitors:

1. RNA-dependent RNA Polymerase inhibitors, for example, favipiravir.
2. Polymerase Acidic Endonuclease inhibitor, for example, baloxavir marboxil.

The mechanism of action for favipiravir is to directly inhibit RNA production and stop the transmission of the infection.⁸ Baloxavir marboxil is the only FDA-approved polymerase inhibitor and it works by inhibiting and blocking the endonuclease of the virus's RNA complex.⁸ Once the complex is blocked, the mRNA synthesis fails and there is no viral protein synthesis, leading to the virus being unable to replicate and transmit the disease.⁸ 

Favipiravir is not used as commonly as other antiviral drugs and is therefore unlikely to become resistant. There is, however, research showing that favipiravir can increase the risk of embryotoxicity (risk to normal fetus growth) and mitochondrial toxicity (where the mitochondria become damaged).⁸

Treatment guidelines

Influenza outbreaks do occur every year and in most individuals, influenza is uncomplicated and they recover without any antiviral treatment.⁵ Antiviral treatment is given to specific high-risk individuals who¹⁰:

• Are hospitalized due to influenza - this could be due to symptoms become worse like high fever or bad cough,
• Already has severe and complicated or progressive illness such as diabetes, asthma or heart disease,
• Or has a higher risk for influenza complications such as AIDS patients, cancer patients or those who are immunocompromised.

Antiviral drugs are given to patients who are suspected to have influenza and waiting for laboratory results is not necessary.¹⁰ When patients are hospitalized due to influenza virus, they are given NAI drug oseltamivir and this is the same for patients with underlying disease where oral oseltamivir is given as soon as possible.¹⁰ For patients who have confirmed influenza and are not hospitalized, oral oseltamivir, zanamivir, peramivir or oral baloxavir are given to treat the virus and lower the symptoms.¹⁰

Antiviral resistance

Antiviral resistance is a major issue. Currently, antiviral resistance to neuraminidase inhibitors and to baloxavir marboxil virus is circulating at a low level but this can change depending on the season and which strain of influenza virus is spreading the most.¹⁰  The problem with antiviral-resistant influenza virus is that it can appear randomly and can appear after antiviral treatment in immunocompromised patients.¹⁰ Another complication with antiviral resistance influenza is that the resistant virus can spread between people, allowing the resistant virus to spread to more people.

Factors that contribute to resistance

• Random mutation of the virus occurs during viral replication and this can change the genetic makeup of the virus, making the antiviral unable to recognise the mutated virus.²
• Sometimes the virus stops responding to the antiviral drugs and the reason for this is not known. This process is called spontaneous resistance.¹
• Prolonged antiviral medication intake can lead to genetic mutation during viral replication.
• The misuse of antiviral drugs is a major factor that leads to resistance; if a patient misses a dose of antivirals, or does not take the full course of medication, this can lead to the virus mutating and becoming resistant.

Side effects and adverse reactions

Before antiviral drugs are given to patients, doctors will need to consider a few factors before deciding the best treatment.¹⁰ These are:

• Patient age
• Patient weight
• Any medical conditions
• Would the antiviral medication react with other medication they may take

Antiviral drugs are effective at curing viral infections by easing the symptoms, decreasing how long you are sick and preventing the spread of infection.² But there are some common side effects individuals may have depending on the drug type and its dosage:

• Cough
• Dry mouth
• Diarrhea
• Dizziness
• Headaches
• Vomiting and nausea
• Insomnia
• Skin rashes
• Fatigue

Antiviral drugs are relatively safe drugs and pregnant women, elderly and young children can be given specific antiviral medication but the type of medication and the dosage will vary.²

Current research and future developments

Antiviral medication is an exciting new field in biology where there is much research in developing treatments against viruses. Considering that the influenza virus poses a threat to global public health, antiviral medication for influenza is being researched. The current antiviral drugs are limited in their effectiveness depending on the stage of infection and the rising levels of antiviral resistance influenza virus. 

Current research includes a new inhibitor (D715-2441) that inhibits influenza type A and targets viral replication.⁶ Another novel drug is FA-6005 which targets both influenza type A and type B by preventing virus replication and interrupts cellular transport.⁶

Future developments include:

1. Phytochemicals (plant compounds) are being investigated. An example is catechin and gallic acid from the Toona sinensis leaves inhibiting viral replication and preventing the virus from adhering to the host cells.⁶
2. Drug combination: is a therapeutic approach where influenza is treated by more than 1 drug. This can allow for higher effectiveness and lower dosages which would prevent resistance from occurring.¹⁰

Summary

Influenza is a contagious respiratory illness and has been a global health threat for years. Influenza virus is around and spreads the entire year but its major peaks are during the winter between December and February.¹ Most people recover from the influenza virus without any treatment but for some individuals, influenza can cause severe illness and can even cause death. Thus antiviral drugs are needed to fight against the infection. Antiviral drugs are a group of medications that target the virus and clear it away - similar to how antibiotics work against bacterial infection. There are four FDA-approved antiviral drugs for influenza virus:

1. Zanamivir,
2. Peramivir,
3. Oseltamivir,
4. Baloxavir marboxil.

Antiviral drugs are useful medications that can clear away the viral infection, reduce how long you are sick and prevent transmission of the infection to other people. However, certain strains of the influenza virus have started to become resistant to these antiviral drugs, very similar to how certain bacteria are becoming antibiotic-resistant. This is a major problem that can lead to devastating effects, if the viruses have become resistant to all antiviral drugs, there would be nothing to combat the virus if the patient is severely ill. There are steps we can take, as individuals taking the medicine to prevent the virus from becoming resistant:

• Make sure we complete the medicine treatment prescribed to us - if the doctors say we need to take this medicine for 7 days, we need to finish the entire course for 7 days - not to finish early or to continue using the medicine.
• Do not skip taking the medication, even if you feel better as this will create an environment for the virus to mutate and become resistant.

Antiviral drugs are a developing area in biomedicine and there is research in this area to increase the efficiency of the medicine, reducing the dosage required and to prevent resistance. In the future, we may have even more antiviral medication in our arsenal to fight against influenza virus and other dangerous viruses too.