Antimicrobial Resistance Series Part 1: Antiviral Resistance

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Antiviral Resistance

“Antimicrobial resistance happens when micro-organisms (such as bacteria, fungi, viruses, and parasites) change when they are exposed to antimicrobial drugs (such as antibiotics, antifungals, antivirals and antiparasitics). Microorganisms that develop antimicrobial resistance are sometimes referred to as ‘superbugs’.” – World Health Organization (WHO)

Microbes and Antimicrobial Resistance

Microbes are:

  • Bacteria
  • Fungi
  • Viruses
  • Parasites

Antimicrobial drugs are:

  • Antibiotics to fight bacterial infections
  • Antifungals to target fungal infections
  • Antivirals against viral infections
  • Antiparasitics for parasitic infections

Antimicrobial Resistance Concerns

When antimicrobial resistance occurs, the consequences are:

  • The inability to treat common infectious diseases, which results in prolonged illness, disability and even death.
  • Reliance on more potent antimicrobials that can cause serious side effects.
  • Medical procedures such as chemotherapy, organ transplant, surgery, and diabetes management that becomes high risk.

Antimicrobial Confusion

Most of the attention has been paid to antibiotic resistance for a variety of reasons, such as:

  • More commonly prescribed than antifungals, antivirals, and antiparasitics.
  • Medical professionals inadvertently prescribed the wrong antibiotic to treat a bacterial infection.
  • Medical professionals misdiagnosed a fungal, parasitic or viral infection as a bacterial infection.
  • Sometimes antibiotics can be used to treat parasitic infections like malaria.
  • Antibiotics are used widely in livestock production for control, prevention, and treatment of disease, and for “production purposes” such as growth promotion in agribusiness.

Organizations like the federal Centers for Disease Control and Prevention (CDC) have been using the terms antimicrobial resistance and antibiotic resistance interchangeably.

But, this interchanging is confusing and needs to stop.

Think about it: with the correct knowledge you could be more in control of your household’s healthcare by making sure you and your pets are receiving the right medication, as needed.

While WHO considers antibiotic resistance the greatest urgency of the four global antimicrobial resistant health risks, we should not neglect or forget the other three: antifungal, antiviral and antiparasitic resistance.

In the first part of this series, we will be discussing antiviral resistance.

Well Known Viruses

  • HIV/AIDS
  • Influenza
  • Hepatitis
  • Herpes

Virus Particles

Viruses are intracellular pathogens that contain RNA/DNA, which need help from host cells to replicate.

Viruses seem so amorphous compared to other microbes. You can see a bacterial infection on your skin. You can see fungi in the woods. You can see parasitic worms in feces.

Virus particles do exist. They are tiny (microscopic) – in fact, about one thousand times smaller than bacteria.

What Antiviral Medications Do

An antiviral medication inhibits a virus from replicating.

There are two broad categories of antivirals:

  • Directly acting antivirals target either the protein or the RNA/DNA of a specific virus. While these antivirals are considered less toxic, viruses are more likely to become resistant to them.
  • Host-acting antivirals modify the cells of the hosts or arouse an immune response that affects virus life cycles. They are less likely to develop resistance, but are considered more toxic.

Antiviral Resistance

Antiviral resistance occurs when a virus mutates to survive.

Additionally, antiviral resistance depends on many factors such as:

  • an already immunocompromised patient
  • a co-infection with another disease
  • the presence of any preexisting conditions
  • how long the patient had the disease prior to diagnosis
  • the strain of the virus

We should view individuals who have one or more of these factors as having a drug resistant mutation which serves as a sentinel, because that viral resistance will likely spread to others and could become a pandemic.

All of the aforementioned viruses – HIV/AIDS, herpes, influenza, and hepatitis – have become or are becoming resistant to some of the available antivirals meant to target them. The most documented resistance concerns the ever-mutating strains of the human, swine, avian and equine influenza viruses.

Influenza A

There are three main types of human influenza: A, B, and C. To make it more confusing, there are subtypes like H1N1 or H3N2 and all of the subtypes have mutations. Resistant mutations of the flu can be passed through contact or be caused by selective pressure of the drug.

Most of us have heard of Tamiflu (oseltamivir), Relenza (zanamivir), Rapivab (peramivir),or Xofluza (baloxavir marboxil). Resistance has cropped up to all three medications.

Xofluza was approved by the Japanese Ministry of Health in February 2018 and in October 2018 by the U.S. Food and Drug Administration. By December 2018, Japanese researchers identified H3N2 viruses carrying the PA138T baloxavir resistance mutation in two children who had been treated with the drug. Genetic sequencing revealed that the two mutated viruses originated from different lineages, which means human-to-human transmission was not involved. In essence, their findings indicate that these virus mutations emerged under the selective pressure of baloxavir marboxil.

Then, everything can flip on its head. In April 2009, a novel swine-origin H1N1 subtype emerged that caused a pandemic and was sensitive to oseltamivir. That strain of H1N1 replaced other H1N1 strains that were resistant to oseltamivir. In fact, the CDC stated that over 99% of the H1N1 isolates were resistant to oseltamivir prior to the pandemic, although all were still sensitive to zanamivir.

You might be thinking that at least we have four options for the flu, that if one antiviral fails another will work, and that only two people had resistant mutations thus far to baloxavir. The reality is that the arsenal of three is small, and there are already documented incidences of resistance to peramivir, oseltamivir and zanamivir.

Adamantane is another class of antiviral medication. Amantadine was the first drug of the class to be approved for clinical use in 1966 followed by rimantadine in 1993. At first, both were successful at inhibiting and preventing influenza A up to 90% of the time.

Resistance of influenza A to amantadine was first detected during the 1980 epidemic, but the resistance to both drugs in seasonal influenza A subtypes was rare with only 1–2% frequency until 2000. Since then, it has risen sharply.

2000-2004 Resistance

The overall resistance to adamantanes among H3N2 avian influenza subtypes rose to 12.3% globally.

  • Asia – increase from 1.1% to 27%
  • Europe – 4.7%
  • North America – 3.9%
  • South America – 4.3%
  • Oceania region – No detection

2004 – 2005

Only 15% of the H3N2 strain and 4.1% of the H1N1 global isolates were resistant to adamantanes.

2005-2006

90.6% of the H3N2 strain and 15.6% of the H1N1 global isolates were adamantane resistant with all aforementioned regions contributing equally.

  • 100% of the H3N2 strain isolates from South Korea, Taiwan, Japan, Hong Kong, and China were resistant to adamantanes.
  • USA – up to 96.4% of the H3N2 strain isolates and up to 25% of the H1N1 isolates were adamantane resistant.

At this time, the CDC advised against the use of adamantanes to treat influenza A infections.

2013

45% of all influenza subtypes circulating in the world were resistant to adamantanes.

  • 69% of the H1 subtype
  • 43% of the H3
  • 28% of the H5
  • 12% of the H7
  • 23% of the H9

Adamantane-resistant mutations were rare in influenza strains:

  • H2
  • H4
  • H6
  • H10
  • H11

No mutations were identified in the H8 and H12–16 influenza subtypes.

More than likely, the increase of influenza A resistance to adamantanes is from its widespread use. Yet, an increase in resistance has also been noted in countries where adamantanes use was low. This likely reflects circulation of the mutant viruses, which may have emerged without drug pressure and have replication potential and virulence.

Finally, please remember that the ubiquitous, highly contagious strains of canine influenza viruses arose in the 2000s as mutations of the H3N2 strain of avian influenza origin and H3N8 strain of equine origin.

References

“Antimicrobial Resistance.” World Health Organization, 15 Feb. 2018, www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance.

Hussain, Mazhar et al. “Drug resistance in influenza A virus: the epidemiology and management.” Infection and Drug Resistance, vol. 10 121-134. 20 Apr. 2017, doi:10.2147/IDR.S105473. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404498/.

Schnirring, Lisa. “Experts on Watch for Resistance to New Flu Drug.” University of Minnesota Center for Infectious Disease Research and Policy, 18 Jan. 2019, www.cidrap.umn.edu/news-perspective/2019/01/experts-watch-resistance-new-flu-drug.

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