Anti-influenza treatments are vital particularly when vaccine efficacy is low or unavailable. In several countries, antiviral drugs are given to hospitalized individuals with severe influenza illness, although certain countries such as Japan and China continue to administer it even among healthy individuals presenting uncomplicated influenza. The two classes of influenza antivirals used in several countries are adamantanes and neuraminidase inhibitors (NAIs). The adamantane compounds target the viral M2 protein that is needed for the virus uncoating during its replication. However, the limited effectiveness of the current antiviral drug is that it requires a prompt evaluation for the early initiation of treatment which should be delivered within 48 hours of the onset of symptoms. This then indicates the need for the development of an alternative treatment which can be administered late in the progression of the disease. Here, we briefly take a glimpse into the various aspects of current treatment options, the challenges in the management of the infection, and the emerging trends in the development of novel antiviral drugs.

Current treatment options

Neuraminidase inhibitors (NAIs): There are four neuraminidase inhibitors (NAIs), two are available worldwide for the treatment of influenza since 1999 – 2000 which are oral oseltamivir and inhaled zanamivir. The intravenous peramivir has been approved for the treatment of adults and children in Japan, China and South Korea while inhaled laninamivir octanoate is available for treating adults and children in Japan.

FDA Approved Drugs: Antivirals as the treatment for influenza are used among selected cases to help reduce the symptoms. The three FDA approved antiviral drugs for influenza recommended by the CDC against the currently circulating influenza viruses are; Rapivab (Peraminir), Relenza (Zanamivir), Tamiflu (oseltamivir phosphate). The two older drugs used for the treatments include amantadine and rimantadine which are not recommended by the CDC because of its resistant to several strains of influenza including the 2009 H1N1.

Challenges

The challenges in the past decade include the emergence of pandemic H1N1 in 2009, human infections with avian H7N9 in 2013 and sporadic human cases of avian H5N1 influenza. During the first wave of the 2009 H1N1 pandemic, there was insufficient vaccine to control the infection and therefore antivirals were the first line of defense. Identifying the drug resistance provided important lessons for public health and therefore the global monitoring for antiviral resistance has been critical for the clinical recommendations of treatments. The recent increases in the frequency of oseltamivir-resistant A(H1N1)pmd09 H275Y variants in the USA highlight the potential for global spread. However, one of the factors affecting the effectiveness of antiviral therapy is that only one class of drugs, i.e., NAIs is available currently. As NAIs only pauses the progressions of the infection, it therefore, needs to be administered within 48 hours which poses a great challenge in several countries.

In order to counter the challenge of drug resistance, a combination therapy that affects different viral proteins could be considered. This could also reduce the likelihood of developing a single-drug resistance. However, the challenge associated with developing combination therapy is the lack of approved compounds for different mechanisms of actions. The National Institute of Allergy and Infectious Disease (NIAID) is conducting a double-blinded, randomized phase II study to determine the efficacy of a triple-drug regimen (known as TCAD consisting of oseltamivir, amantadine and ribavirin) against the oseltamivir monotherapy among the infected patients and those at risk of complications.

Emerging Trends in the Influenza Antiviral Landscape

  • Xofluza

Recently, U.S Food and Drug Administration approved Xofluza as a treatment option for acute uncomplicated influenza for individuals older than 12 years and are symptomatic for a duration no longer than 48 hours. The safety and efficacy of the drug were demonstrated in two randomized controlled clinical trials of 1,832 individuals. They were administered Xofluza, a placebo or another antiviral drug within 48 hours of symptoms onset. In both trials, individuals treated with Xofluza had a shorter time to alleviation of symptoms in relation to those who took the placebo.

  • Favipiravir

It selectively inhibits the viral RNA polymerase and illustrated antiviral activity for a broad range of influenza types and subtypes. Favipiravir also illustrates anti-viral activities against other RNA viruses and is potentially a promising drug for untreatable RNA viral infections. Although it is undergoing phase II clinical trials in the United States, it is approved for use in Japan.

  • SiRNA as antiviral

Short interfering RNA (SiRNA) is specific, easy to design which can be used against various strains of viruses by targeting their conserved gene regions. There are reports that innate immune reactions such as Toll-Like Receptor (TLR) could be triggered, however, the novel second generation transfection reagents and nanoparticle technology can bypass this TLR pathway, making it optional for influenza treatment.

  • Nitazoxanide

It is active against a wide range of DNA and RNA viruses and has been approved in the United States for the treatment of Cryptosporidium parvum. Among the influenza viruses, it interferes with the assembly of the haemagglutinin (HA). Although its safety profile has been confirmed by the clinical trials, it is undergoing clinical development for influenza treatment.

  • Fludase

It consists of a bacterial sialidase catalytic domain which is necessary for effective targeting of epithelial cells. Fludase has the antiviral activity against a wide spectrum of influenza A and B viruses. In a phase II study, a group was administered multiple doses of Fludase; individuals treated with uncomplicated cases of influenza infection presented reduced viral load and a significantly shorter time to sustained decreased viral shedding. However, few of the concerns with the use of Fludase include the role of secondary bacterial infection, systemic dissemination and the development of anti-DAS181 antibodies.

  • Immunomodulatory Therapy

Boosting innate immunity can be considered a strategy and one way to enhance it is to stimulate natural killer (NK) cell activity. Passive immunotherapy with convalescent plasma or with hyperimmune globulin could be advantageous as an adjunct therapy for H5N1 and H1N1pdm09 infections that need intensive care support. Individuals with severe H1N1pdm09 infection who were treated with intravenous hyperimmune ƴ-globulin from those who survived the same infection appeared to have lower peak load in the case of treatment initiation within 5 days of symptom onset.

 References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713175/
  2. https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm100228.htm
  3. https://www.ncbi.nlm.nih.gov/pubmed/29656441
  4. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159436/
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865545/
  7. https://www.ncbi.nlm.nih.gov/pubmed/22186145