Antiviral Therapy in Influenza: Decoding the Scope of Oseltamivir

Influenza viruses are members of the "Orthomyxoviridae" family, an RNA virus with various antigenic properties.[1] These annual epidemics are predicted to cause 3 to 5 million episodes of severe disease and 290 000 to 650 000 respiratory deaths worldwide. Influenza can cause significant work/school absenteeism and a dip in productivity. During peak disease seasons, clinics and hospitals might become overburdened.

Seasonal influenza viruses are classified into four types: A, B, C, and D. The influenza A and B viruses spread and produce seasonal outbreaks of sickness.

Influenza A viruses are further categorised into subtypes based on the combinations of the proteins on the virus's surface, hemagglutinin (HA) and neuraminidase (NA). Subtypes A(H1N1) and A(H3N2) influenza viruses circulate in humans. The A (H1N1) virus is also known as A(H1N1) pdm09 since it caused the 2009 pandemic. Only Influenza A viruses have been linked to pandemics.

There are no subtypes of Influenza B viruses. However, they can be divided into lineages. The influenza type B viruses that are currently circulating are either B/Yamagata or B/Victoria.

Influenza C virus is identified less frequently and usually produces minor infections. Therefore, it is of no significant public health concern.

Influenza D viruses typically affect cattle and are not known to affect humans.[2]

Influenza Transmission and Clinical Presentation

The virus spreads from person to person via respiratory droplets produced by coughing or sneezing. Close contact (<1 m) with infected individuals makes infection contagious. Individuals usually recover within a few days, but Influenza can cause complications and even death, particularly in high-risk groups such as pregnant women and those with underlying immunodeficiency. High fever, body soreness, headache, severe malaise, dry cough, sore throat, and runny nose are among the symptoms of influenza. Clinical manifestations should be used to distinguish it from the common cold.[1]

Influenza Infections: Pathophysiology

Influenza is an acute respiratory disease that causes upper respiratory tract and trachea inflammation [3]. The influenza virus directly infects the respiratory tract or damages the immune system response. Only the respiratory epithelium in humans successfully cleaves the hemagglutinin (HA) molecule, resulting in infectious virus particles. Virus transmission occurs through a susceptible individual’s contact with aerosols or respiratory fomites from an infected individual.[4]. Both neuraminidase and hemagglutinin are essential for virulence since they are the primary targets of neutralising antibodies. Hemagglutinin binds to epithelial cells in the respiratory tract, and Neuraminidase breaks the bond that holds the virus together, allowing the infection to spread. Their H and N proteins are responsible for identifying influenza viruses. Influenza A virus is a genetically labile virus with a high mutation rate. This causes significant alterations in antigenic and functional proteins.[3]

Various factors, including airway blockage, loss of alveolar structure, loss of lung epithelial integrity due to direct epithelial cell death, and degradation of the essential extracellular matrix, can cause the lung's failure to fulfil its fundamental gas exchange function.[4]

Decoding the Role of Oseltamivir in Influenza

Oseltamivir is a prodrug of oseltamivir carboxylate, a sialic acid transition state analogue. It is a potent, selective inhibitor of neuraminidases of the Influenza A and Influenza B viruses. It has an antiviral spectrum and potency similar to Zanamivir. It inhibits amantadine and rimantadine-resistant influenza A viruses and can be helpful against some zanamivir-resistant variants. [5]

Oseltamivir: Clinical Pharmacological Profile

Influenza neuraminidase cleaves terminal sialic acid residues and destroys the receptors recognised by viral hemagglutinin, which are present on the cell surface, in progeny virions, and respiratory secretions. The enzymatic action is essential for the release of viruses from infected cells. Interaction of oseltamivir carboxylate with neuraminidase causes a conformational change within the enzyme's active site and inhibits its activity. Inhibition of neuraminidase activity leads to viral aggregation at the cell surface and reduces virus spread within the respiratory tract.[5]

Oseltamivir carboxylate plasma concentrations were identified in volunteers within 30 minutes of oral oseltamivir treatment and peaked within 3 to 4 hours at a steady state. Oseltamivir has a high oral bioavailability (79%) compared to an intravenous dose of oseltamivir carboxylate, and food seems not to influence absorption.[6]

Therapeutic Efficacy of Oseltamivir: Review of Clinical Evidence

Several randomised, double-blind, placebo-controlled trials have explored the use of Oseltamivir for the prophylaxis and treatment of febrile Influenza.

For prophylaxis [6]

Many studies have shown that oral administration of Oseltamivir 75 mg can act as a prophylaxis and significantly reduces the development of naturally acquired Influenza.

• Hayden et al. compared the efficacy of Oseltamivir with the placebo in healthy unvaccinated adults(18-65y). The study included 1559 patients, of which 519 patients were placed in the placebo group, 520 patients were given oseltamivir 75 mg OD for six weeks, and 520 patients were given oseltamivir 75 mg bid for 6 weeks. After six weeks, the protective efficacy (protection from influenza-associated bronchitis, pneumonia or sinusitis) in the oseltamivir group (75 mg OD and 75 mg bid) was 76% and 72% better than the placebo group, respectively.
• Peters et al. studied high-risk elderly people (>65 years), where 272 patients were included in the placebo group, and 276 were given oseltamivir 75 mg OD for six weeks. After six weeks, the protective efficacy (protection from influenza-associated bronchitis, pneumonia or sinusitis) was 92% in the elderly who received Oseltamivir.

For treatment

Adults: Several studies have claimed that oral Oseltamivir reduces the duration and severity of naturally acquired Influenza in patients when initiated at the early stage of infection and lowers the likelihood of secondary complications compared with a placebo.[6]

• Treanor et al. studied 629 healthy non-immunized adults aged 18-65 with febrile respiratory illness of no more than 36 hours. They included 129 subjects in the placebo group, 124 were given Oseltamivir 75 mg bid, and 121 patients were given Oseltamivir 150 mg bid for five days. The primary endpoints were the duration of the illness and the severity of the illness. The study concluded that the duration of illness was reduced by 30% in both the oseltamivir group of 75 mg bid and 150 mg bid (median, 71.5 hours; P < .001, median 69.9 hours; P= 0.006, respectively) than the placebo group (median, 103.3 hours). The severity of illness was also reduced by 38% (median score, 597 score-hours; P < .001) with Oseltamivir 75 mg bid and by 35% (median score, 626 score hours; P< .001) with Oseltamivir 150 mg bid when compared to placebo (median score, 963 score-hours).[7]
• Nicholson et al. conducted a randomised controlled trial of 726 previously healthy non-immunised adults with a febrile influenza-like illness of up to 36 h duration. They included 238 subjects in the placebo group, 243 subjects were given oseltamivir 75 mg bid and 245 subjects were given oseltamivir 150 mg bid. The primary endpoint of the study was the duration of illness. The study concluded that the duration of illness was significantly shorter by 29 h (25% reduction, median duration 87·4 h [95% Cl 73·3–104·7], p=0·02) with Oseltamivir 75 mg and by 35 h (30%, 81·8 h [68·2–100·0], p=0·01) with oseltamivir 150 mg compared with placebo (116·5 h [101·5–137·8]). [8]

Children: Evidence has demonstrated that Oseltamivir also effectively treats children suffering from Influenza.

• In a randomised, double-blind study of 452 children aged 1 to 12 years infected with influenza A (67%) or B (33%), a liquid formulation of Oseltamivir (2 mg/kg twice daily for five days) reduced the median duration of illness by 1.5 days (p <0.0001) and severity of illness by 29% (AUC 960 vs 1358 score; p <0.002). [6]

Points to remember

• Influenza is a viral disease that primarily affects the respiratory system and significantly decreases the quality of life and productivity.
• Influenza A and B subtypes are prevalent and produce seasonal outbreaks of illness
• Oseltamivir is a potent drug that could produce beneficial effects if given within 48 hrs of the onset of the flu.
• Many clinical trials and studies have proved the patient benefit (adults and children) of oseltamivir in influenza. hence it can be used as both prophylactic and treatment options in susceptible or infected patients.
• When administered early in the course of an infection, oseltamivir reduces the duration and severity of naturally acquired influenza in patients and the likelihood of secondary complications.

References

1. Moghadami M. A Narrative Review of Influenza: A Seasonal and Pandemic Disease. Iran J Med Sci. 2017 Jan;42(1):2-13. PMID: 28293045; PMCID: PMC5337761.

2. World Health Organization. (2023). Influenza (Seasonal). Retrieved 2nd March 2023 from https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal)

3. Boktor SW, Hafner JW. Influenza. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459363/

4. Kalil AC, Thomas PG. Influenza virus-related critical illness: pathophysiology and epidemiology. Crit Care. 2019 Jul 19;23(1):258. doi: 10.1186/s13054-019-2539-x. PMID: 31324202; PMCID: PMC6642581.

5. Goodman, L. S., Gilman, A., Hardman, J. G., Gilman, A. G., & Limbird, L. E. (1996). Goodman & Gilman's the pharmacological basis of therapeutics (9th ed.). New York: McGraw-Hill, Health Professions Division.

6. McClellan, K., Perry, C.M. Oseltamivir. Drugs 61, 263–283 (2001). https://doi.org/10.2165/00003495-200161020-00011

7. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000 Feb 23;283(8):1016-24. doi: 10.1001/jama.283.8.1016. PMID: 10697061.

8. KG Nicholson, FY Aoki, ADME Osterhaus, S Trottier, O Carewicz, CH Mercier, A Rode, N Kinnersley, P Ward, Efficacy and safety of oseltamivir in treatment of acute influenza: a randomized controlled trial, The Lancet, Volume 355, Issue 9218, 2000, Pages 1845-1850, ISSN 0140-6736