Antiviral drugs are shown to be effective in both the prophylaxis and treatment for influenza. Furthermore, these drugs are also likely to be active against a potential new pandemic strain. Several studies have demonstrated the efficiency of the neuraminidase inhibitor oseltamivir, which is known under the brand name Tamiflu, in reducing influenza viral titer values and symptom intensity. Nevertheless, its usefulness can be compromised by the emergence and spread of a drug-resistant virus.
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While resistance has been a longstanding problem with the use of the “old” influenza drugs amantadine and rimantadine, during winter 2007/2008, researchers and clinicians became aware of virus-acquired resistance against oseltamivir. The current situation with an increasing resistance problem strengthens the need to continuously monitor antiviral susceptibility, as well as the promote the development of new antiviral drugs and treatment regimes.
Principles of oseltamivir resistance
Generally, there are three levels of resistance to oseltamivir and other neuraminidase inhibitors. These resistance levels include genotypic resistance, phenotypic resistance, and clinical resistance.
Genotypic resistance can be detected via the sequencing of the viral genome and identification of mutations associated with drug resistance. Comparatively, phenotypic resistance is measured by viral replication at different drug concentrations in vitro. Thirdly, clinical resistance is based on the real-life response to the treatment.
Mutations associated with amino acid changes in the viral neuraminidase, hemagglutinin, or both, can cause resistance to oseltamivir. The principal difference is that mutations in hemagglutinin confer resistance not only to oseltamivir, but zanamivir as well, which is another important neuraminidase inhibitor. This is comparable to mutations in neuraminidase, which may instead render oseltamivir ineffective, but retain susceptibility to zanamivir.
Oseltamivir resistance can be conferred by a single point missense mutation from histidine to tyrosine at position 275 (H275Y) of the neuraminidase gene, which is the most commonly reported mutation. The amino acid replacement N295S (N294S) in the neuraminidase gene has also been shown to reduce susceptibility to both oseltamivir and zanamivir.
Changes at residues E119, V116, I117, Q136, I223 (I222), and D199 (D198) around neuraminidase active sites are associated with reduced susceptibility to oseltamivir in both seasonal influenzas and H5N1, which is the avian influenza virus. Furthermore, crystal structure studies of H1N1 and H5N1 viruses hinted that mutations at amino acids K150, Q136, and D151 may affect susceptibility to this drug.
The development of resistant strains of seasonal H1N1 and H3N2 influenza has had a low recorded incidence among adults and adolescents of approximately 0.3%. However, pediatric patients have demonstrated higher rates of up to 8.6%. Whether higher doses of oseltamivir needs to be used in such cases, or over longer periods of time than currently recommended, is still subject to debate.
It must be emphasized that oseltamivir resistance in influenza viruses is relative, which means that patients infected with resistant strains may still benefit from receiving this drug. Therefore, the clinical response to treatment with oseltamivir remains the most important proof of antiviral effectiveness.
Predicting and minimizing resistance
It is very cumbersome to predict when drug resistance will develop. Clinicians should suspect resistance to this antiviral medication when influenza is detected in patients who receive prophylaxis, in individuals whose condition fails to improve despite oseltamivir therapy, in cases when infection persists in immunocompromised hosts, as well as in instances in which patients have had contact with immunocompromised hosts undergoing treatment.
For practical purposes, if the patient’s condition continues to deteriorate with no other identifiable causes despite 10 days of oseltamivir treatment, active testing for resistance should be pursued. Protocols to provincial public health laboratories should be provided in order to facilitate rapid testing for H275Y mutation.
To minimize the risk of development of resistance, oseltamivir should be used appropriately and at sufficient doses according to published guidelines. This recommendation is particularly relevant for pediatric and immunocompromised populations, where the greatest risk of generating resistance is often encountered.
In short, the global occurrence of influenza virus resistance connected with the seasonal use of oseltamivir is presently small. Therefore, resistant viruses might be of little clinical significance, excluding perhaps in immunocompromised patients. However, continued attention, especially of evolving avian H5N1 strains, combined with alert, thorough laboratory-based monitoring, is of the uttermost importance.
- Tisdale M. Influenza M2 Ion-Channel and Neuraminidase Inhibitors. In: Mayers D, editor. Antimicrobial Drug Resistance: Mechanisms of Drug Resistance, Volume 1. Springer Science & Business Media, 2009; pp. 421-447.