Influenza Treatments - Can you effectively treat the flu? Oseltamivir vs. Zanamivir

Influenza is a disease spread by two subtypes of the influenza virus (A and B), capable of widespread regular epidemics and a high mortality rate. Influenza has been linked to many deaths over centuries, but recorded rates may be unreliable due to unreported cases, and death due to secondary complications such as cardiac or other illness precipitated by influenza infections. Most deaths caused directly by influenza are as a result of acute respiratory distress.

Influenza viruses are commonly characterised by the proteins haemagglutin and neuraminidase, both of which play an important role in cellular infection within the host.

Different forms of these proteins identify different viral strains (e.g. H7N9). Of these two, neuraminidase tends to be highly conserved, i.e. with relatively low incidences of mutation, which would contribute to viral resistance to attack by host immunity or the actions of drugs.

This is why medications that target this protein - or neuraminidase inhibitors - are regarded as the most effective (non-vaccine) anti-influenza drugs.

There are two neuraminidase inhibitors approved for use in the majority of countries, oseltamivir and zanamivir, commonly known by their trade-names, Tamiflu™ and Relenza™ respectively. In this article, these drugs and how they should be used will be discussed.

Oseltamivir

Oseltamivir is a medication that enters the body as a stable precursor of the final active form. The medication is converted to its active form by the liver, and then proceeds to carry out its actions. This 'prodrug' strategy gives more 'working units' of the drug after injection or ingestion. Therefore, Tamiflu™ is available as either an oral or intravenous formulation. The slight drawback of this is that doses must be calculated for each patient based on factors such as weight and age.

Patients and trial subjects of 13 years and older may take a full 75mg dose. Patients who cannot take oral medications, e.g. those on ventilators, are candidates for oseltamivir injection. Oseltamivir is associated with a higher incidence of antiviral resistance in comparison with zanamivir. Oseltamivir is suitable as a treatment for infected patients, and as a preventative (or prophylactic) measure in the event of an epidemic. It may be administered to people aged one year or older.

Oseltamivir has demonstrated efficacy in clinical trials, in comparison with placebo treatments

A recent review of six placebo-controlled trials (including a total of 1709 seasonal influenza patients) found that osteltamivil reduced symptoms and restored normal function more efficently. However, another review of 11 studies found that oseltamivir elicited no significant change in symptom duration or probability of hospitalisation in comparison with placebo. 

A trial comparing 237 transplant patients (who are at a high risk of contracting influenza) given oseltamivir to 238 on placebo found that virus counts were significantly reduced in the oseltamivir group. This indicates a role for oseltamivir in prophylaxis for this and similar patient groups, although there was one case of oseltamivir-resistant influenza observed in this study.

Another systematic review of clinical trials involving adult patients reported that five placebo-controlled trials found a significant effect of oseltamivir on symptom duration, but seven trials found the drug had no effect on hospitalisations.

Eight studies found that the odds of being diagnosed with influenza were significantly reduced by oseltamivir treatment.

Some studies indicate that the efficacy of oseltamivir depends on how soon after infection it is administered. In a small-scale trial, symptom resolution and negative tests of viral infection appeared in 12 patients receiving early treatment, compared to eight given late treatment and seven receiving placebo. A double-blind, randomised, controlled trial running from 2008 to 2010 assigned 598 patients to oseltamivir and 592 to a placebo. Oseltamivir reduced symptom duration, but only in patients treated in 48 hours or less after symptom onset.

Oseltamivir also significantly reduced positive results in tests for the virus from patient samples. A trial of 408 children aged one to three randomised to either oseltamivir or placebo within 24 hours of onset found that symptom duration was significantly reduced in the oseltamivir group.

Zanamivir

Unlike oseltamivir, zanamivir is not a prodrug, and therefore often needs to be administered directly to the lungs via inhalation for optimal efficiency.

Zanamivir may cause breathing difficulties or wheezing in those with lung disorders, and therefore is traditionally not used for this patient population. However, a new, intravenous form of the drug currently in development may allow them to receive zanamivir via this route.

Conventional guidelines for zanamivir administration recommend that patients (seven years or older) inhale a 10mg dose twice daily for five days. Prophylactic (preventative) doses can be taken once a day for ten to 28 days by people five years and older1. Zanamivir has also shown efficacy in placebo-controlled trials.

A review of 28 trials indicated that this drug can reduce the time needed for symptom improvement by over half a day (a very significant difference) in adults.

A review of trials including child patients indicated that zanamivir significantly reduced symptom duration and was significantly effective in providing prophylaxis. A multicentre study randomising 471 patients aged 5-12 years to zanamivir or placebo found that the time to symptom improvement was reduced by the drug by approximately 1.25 days, and also the time taken to restore normal function.

A trial of 3363 older adults or adolescents at high risk of influenza-related complications due to pre-existing conditions randomised to zanamivir or placebo (once daily for 28 days) demonstrated that the drug was significantly effective in preventing influenza infections and complications. However, a trial randomising 494 long-term care patients (91% of whom were unvaccinated against influenza) to zanamivir or placebo found no significant prophylactic effect for either group, although the drug did reduce influenza-associated fever to a moderately significant extent.

Combination Therapy

Another viable strategy in influenza treatments is combination therapy, i.e. the administration of both zanamivir and oseltamivir, to reduce the risks associated with antiviral resistance and secondary infection.

A study was conducted to compare the efficacy of combination therapy with that of the standalone treatments in preventing transmission within the households of patients. It found that the combination therapy significantly reduced these secondary infections, but only when the patient received it in the first 24 hours, compared to either individual treatment administered in the same timeframe. Therefore, an oseltamivir/zanamivir multidrug, given as soon as possible after diagnosis, to patients that are in good health otherwise, may be the best option to prevent the spread of influenza.

On the other hand, a study of 145 centres randomising 447 patients to either oseltamivir, zanamivir or their combination found that the combination therapy was not effective in comparison with oseltamivir, and was more effective than zanamivir, but not to a significant degree. In addition, the combination therapy tended to cause more side-effects than the stand-alone drugs. A further drawback of combination therapy may be the probability of its high cost to most consumers.

References

1. Kamali A, Holodniy M. Influenza treatment and prophylaxis with neuraminidase inhibitors: a review. Infection and drug resistance.2013;6:187-198.
2. Burmeister WP, Ruigrok RW, Cusack S. The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid. The EMBO journal.1992;11(1):49-56.
3. Duval X, van der Werf S, Blanchon T, et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS medicine.2010;7(11):e1000362.
4. Kim CU, Lew W, Williams MA, et al. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. Journal of the American Chemical Society.1997;119(4):681-690.
5. Cheng VC, To KK, Tse H, Hung IF, Yuen KY. Two years after pandemic influenza A/2009/H1N1: what have we learned? Clinical microbiology reviews.2012;25(2):223-263.
6. Samson M, Pizzorno A, Abed Y, Boivin G. Influenza virus resistance to neuraminidase inhibitors. Antiviral research.2013;98(2):174-185.
7. Toovey S, Dutkowski R, Smith P, Smith JR. Oseltamivir effectiveness in seasonal influenza patients taking symptomatic therapy: retrospective analysis of RCT data. International journal of clinical pharmacology and therapeutics.2013;51(12):932-941.
8. Ebell MH, Call M, Shinholser J. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials. Family practice.2013;30(2):125-133.
9. Ison MG, Szakaly P, Shapira MY, Krivan G, Nist A, Dutkowski R. Efficacy and safety of oral oseltamivir for influenza prophylaxis in transplant recipients. Antiviral therapy.2012;17(6):955-964.
10. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. The Cochrane database of systematic reviews.2012;1:Cd008965.
11. Dharan NJ, Fry AM, Kieke BA, et al. Clinical and virologic outcomes in patients with oseltamivir-resistant seasonal influenza A (H1N1) infections: results from a clinical trial. Influenza and other respiratory viruses.2012;6(3):153-158.
12. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. The Lancet. Infectious diseases.2014;14(2):109-118.
13. Heinonen S, Silvennoinen H, Lehtinen P, et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.2010;51(8):887-894.
14. McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza and other respiratory viruses.2013;7 Suppl 1:25-36.
15. Heneghan CJ, Onakpoya I, Thompson M, Spencer EA, Jones M, Jefferson T. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ (Clinical research ed.).2014;348:g2547.
16. Wang K, Shun-Shin M, Gill P, Perera R, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children (published trials only). The Cochrane database of systematic reviews.2012;4:Cd002744.
17. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. The Pediatric infectious disease journal.2000;19(5):410-417.
18. LaForce C, Man CY, Henderson FW, et al. Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial. Clinical therapeutics.2007;29(8):1579-1590; discussion 1577-1578.
19. Ambrozaitis A, Gravenstein S, van Essen GA, et al. Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population. Journal of the American Medical Directors Association.2005;6(6):367-374.
20. Carrat F, Duval X, Tubach F, et al. Effect of oseltamivir, zanamivir or oseltamivir-zanamivir combination treatments on transmission of influenza in households. Antiviral therapy.2012;17(6):1085-1090.