Influenza prophylaxis and role of oseltamivir

Influenza infection is a priority worldwide and its prevention is the key as it causes massive morbidity and increases mortality risk in a vulnerable population. It is caused by RNA viruses belonging to Orthomyxoviridae. It is an acute viral respiratory infection that affects people of all ages and is linked to significant mortality rates during pandemics, epidemics, and sporadic outbreaks. (1)

Influenza: Lessons Learnt from Past Geographical Burden:

Influenza viruses are of four types-A, B, C, and D. Type A viruses are known to cause pandemics and they are further subdivided based on combinations of the hemagglutinins (HA) and neuraminidases (NA). Type B viruses are also known to cause epidemics and are broken down into lineages of B/Yamagata or B/Victoria. Influenza C viruses cause mild infections, whereas D viruses primarily affect cattle (2). Depending on the climatic and geographical locations, these viruses can cause pandemics, epidemics, and sporadic outbreaks.

In 2009 the Influenza infection which started as an epidemic caused by Influenza A (S-OIV) was later declared a pandemic by WHO. Considering the parameters like case-fatality rates, mortality rates, and basic reproductive rates, it was regarded as a pandemic of moderate severity (3). As analyzed by the Global Influenza Surveillance and Response System in March 2018, 46.8% of cases of Influenza A virus and 53.2% of Influenza virus B were reported. Globally, the reported cases were 3-5 million during epidemics (4). In India, Influenza has been reported every year during winter and the activity caused by these viruses resulted in 38 811 laboratory-confirmed cases and 2266 deaths in 2017 (5).

Why Influenza Prophylaxis is Critical – Antigenic Drift and Antigenic Shift!

Influenza though primarily affecting the respiratory tract has also been associated with other complications. Most of the hospitalized Influenza patients had non-respiratory complications. While pneumonia, is the most common acute respiratory complication, non-respiratory complications included sepsis, acute kidney injury, and acute cardiovascular events (6). The most difficult challenge involved in the management of Influenza is the rapid evolution due to mutation called the Antigenic drift and reassortment of the viral genome called Antigenic shift (7).

Influenza Prophylaxis – Who Likely Needs it the Most?! (8)

It may be clinically relevant to learn the patient profiles who may be likely at higher risk of untoward sequels of influenza and therefore potentially justified considerations for influenza prophylaxis:

• Individuals with chronic medical problems (both adults and children) including pulmonary, cardiac, renal, and metabolic diseases like diabetes mellitus. Also, a reduction in hospitalizations due to vaccinations of diabetes.
• Adults with compromised immunity, including HIV-infected individuals with CD4 levels between 200 and 500 cells/µl. Since the influenza vaccine has been proved to be safe in children who have HIV, its yearly administration should be encouraged. Patients with asplenia and splenic dysfunction fall under the category of immunosuppression.
• Residents of long-term care facilities, rehabilitation centres, and old age homes.
• Healthcare professionals who are in charge of the patients described above.
• Family member of the patients listed above.
• Women who will be expecting during the influenza season and are in their second or third trimester. Women with chronic medical issues are advised to get immunised at any point during their pregnancies.
• Children undergoing long-term aspirin therapy.

Management and Prophylaxis of Influenza Infections:

Infectious Diseases Society of America has put forth a few indications for the chemoprophylaxis of Influenza (9).

• For patients at high risk of complications, post-exposure prophylaxis (PEP) be initiated within 48 hours of initial exposure if unable to vaccinate or vaccine effectiveness is low.
• PEP and vaccination for unvaccinated people should be initiated within 48 hours of initial exposure.
• PEP for people at high risk of complications like transplants should be given during the influenza activity period.
• PEP for unvaccinated and at high risk of complications should be initiated for 14 days or until vaccine effectiveness is achieved.
• PEP for unvaccinated people who are in close contact with people of high risk of complications then should be initiated during the influenza activity period.

CDC has recommended a few drugs for the chemoprophylaxis of Influenza management. They are as follows (10):

• Oral oseltamivir against Influenza A and B in patients who are 3 months and older.
• Inhaled Zanamivir against Influenza A and B in patients 5 years and older.
• Oral Baloxavir against Influenza A and B in patients 12 years and older.

Oseltamivir for Influenza Prophylaxis- Clinical & Pharmacological Review

Oseltamivir is an antiviral prodrug that is used to attenuate the spread of the influenza virus. It is prescribed for acute, uncomplicated illnesses due to influenza A and B infections. Generally prescribed in patients 2 weeks of age and older and those who have been symptomatic for no more than 48 hours.

Oseltamivir is an antiviral neuraminidase inhibitor, which selectively inhibits the enzyme neuraminidase necessary for viral replication. It is available as an inactive prodrug oseltamivir phosphate which when hydrolyzed in vivo converts to active oseltamivir carboxylate. This activated carboxylate form interferes with the release of the progeny virus from the infected host cells and stops the spread to new host cells. Oseltamivir can shorten the duration of shedding of the virus, and viral titer and also reduce the symptoms by 0.5-3 days (11).

Oseltamivir is administered as the prodrug oseltamivir phosphate orally. The recommended dose of Oseltamivir for influenza infection is 75 mg twice daily for 5 days and 75mg orally daily for 1-6 weeks as a prophylactic drug. It is available in both capsule and powder forms (12). Treatment with this drug should be initiated as early as 48 hours within the onset for optimal benefit. It is generally a well-tolerated drug and has few drug interactions. The common side effects are nausea, vomiting, abdominal pain, diarrhea, headache, insomnia, and vertigo. Occasionally respiratory suppression resulting from central nervous system suppression, hypothermia, hypoactivity, and sudden death due to sudden-onset type neuropsychiatric reactions have been reported (11). The plasma half-life is 6 – 10 h. Sixty to eight percent of oseltamivir phosphate and carboxylate are eliminated by glomerular filtration and tubular secretion through the renal tubule organic anion transporter system and the remaining 20% by feces. No significant interactions between liver enzymes are seen. It belongs to pregnancy class C of medications (12)

Oseltamivir: Review of Evidence of Clinical Efficacy:

• Doll et al conducted a systematic review of the systematic reviews/meta-analysis for influenza treatment, prophylaxis, and outbreak control. They found that pre-or post-exposure prophylaxis of oseltamivir has considerably lowered the rate of secondary transmission of symptomatic influenza infections. (13)
• Another systematic review and meta-analysis on Neuraminidase inhibitors for influenza treatment concluded that oseltamivir prophylaxis reduced symptomatic influenza in individuals and households. (14)
• Ison et al carried-out research on the efficacy and safety of oseltamivir for influenza prophylaxis in Haematopoietic stem cell transplant (HSCT) and solid organ transplant patients. They found that Oseltamivir prophylaxis was generally well-tolerated and reduced culture- or PCR-confirmed influenza incidence in transplant recipients. (15)

Using Oseltamivir: CDC Recommendations

CDC recommends a chemoprophylaxis duration of 7 days after the last known exposure. Oral oseltamivir for 2 weeks and continuing up to 1 week is recommended after the last known case was identified. Antiviral chemoprophylaxis is recommended for all those who have taken vaccination too (10).

The use of oseltamivir as a chemoprophylaxis is not recommended for children below 3 months old, unless the situation is judged critical.

For patients > 3 months and < 1 year old - 3 mg/kg/dose once daily.

For patients >1 year, the dosing regimen depends upon the child’s weight:

• ≤15 kg, dose is 30 mg once a day
• >15 to 23 kg, the dose is 45 mg once a day
• >23 to 40 kg, the dose is 60 mg once a day
• >40 kg and adults, the dose is 75 mg once a day.

Take-Home Messages:

• Oseltamivir is a potent and selective inhibitor of the neuraminidase glycoprotein essential for the replication of influenza A and B viruses.
• It is well tolerated orally and is available in both capsule and powder forms.
• Administration of oseltamivir at 75mg twice a day dosing reduced the risk of illness in healthy as well as high-risk individuals.
• The rationale use of the drug oseltamivir interrupts the transmission of Influenza infection from person to person. Despite the regular use of vaccinations, Oseltamivir can be used for prophylaxis in high-risk vaccinated individuals as it significantly reduces the symptoms and the risk of hospitalization in infected individuals and hastens their recovery towards a return to daily activities.

References:

1. Javanian M, Barary M, Ghebrehewet S, Koppolu V, Vasigala V, Ebrahimpour S. A brief review of influenza virus infection. J Med Virol. 2021;93(8):4638-4646. doi:10.1002/jmv.26990.

2. Influenza. WHO. https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal). Published 2018. Accessed June 5, 2022.

3. Preziosi, P. (2011). Influenza pharmacotherapy: present situation, strategies, and hopes. Expert Opinion on Pharmacotherapy, 12(10), 1523–1549.

4. Saxena SK, Haikerwal A, Kumar S, Bhatt ML. Introductory Chapter: Human Influenza A Virus Infection-Global Prevalence, Prevention, Therapeutics, and Challenges. Influenza: Therapeutics and Challenges. 2018 Sep 19;1.

5. Kulkarni SV, Narain JP, Gupta S, Dhariwal AC, Singh SK, Macintyre C R. Influenza A (H1N1) in India: Changing epidemiology and its implications. Natl Med J India 2019;32:107-108.

6. Influenza. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/spotlights/2019-2020/study-flu-complications.html

7. Kandel R, Hartshorn KL. Prophylaxis and treatment of influenza virus infection. BioDrugs. 2001;15(5):303-323. doi:10.2165/00063030-200115050-00003

8. Jones s, Jones R. Influenza: prevention, prophylaxis, and treatment. SA Fam Pract 2008;50(2):38-4.

9. Gaitonde DY, Moore FC, Morgan MK. Influenza: Diagnosis and Treatment. Am Fam Physician. 2019;100(12):751-758.

10. Influenza Antiviral Medications: Summary for Clinicians | CDC https:// www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

11. Sur M, Lopez MJ, Baker MB. Oseltamivir. [Updated 2022 May 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539909/

12. Schirmer, P., & Holodniy, M. (2009). Oseltamivir for treatment and prophylaxis of influenza infection. Expert Opinion on Drug Safety, 8(3), 357–371.

13. Doll MK, Winters N, Boikos C, Kraicer-Melamed H, Gore G, Quach C. Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses. J Antimicrob Chemother. 2017;72(11):2990-3007. doi:10.1093/jac/dkx271

14. Heneghan CJ, Onakpoya I, Jones MA, et al. Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technol Assess. 2016;20(42):1-242. doi:10.3310/hta20420

15. Ison MG, Szakaly P, Shapira MY, Kriván G, Nist A, Dutkowski R. Efficacy and safety of oral oseltamivir for influenza prophylaxis in transplant recipients. Antivir Ther. 2012;17(6):955-964. doi:10.3851/IMP2192.