Antiviral drugs are shown to be effective in prophylaxis and therapy for influenza and are likely to be active against a potential new pandemic strain. Several studies have demonstrated the efficiency of the neuraminidase inhibitor oseltamivir (known under a brand name Tamiflu) in reducing influenza viral titer and symptom intensity; nevertheless, its usefulness can be compromised by the emergence and spread of drug-resistant virus.
While resistance has been a longstanding problem with the use of the “old” influenza drugs amantadine and rimantadine, during the 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 pursue continuous monitoring of antiviral susceptibility, as well as 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: genotypic resistance (detected via sequencing of the viral genome and identification of mutations associated with drug resistance), phenotypic resistance (measured by viral replication at a different drug concentrations in vitro), as well as clinical resistance (based on real-life response to the treatment).
Mutations associated with amino acid changes in the viral neuraminidase or 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 (another important neuraminidase inhibitor), whereas mutations in neuraminidase may 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 neuraminidase gene has also been shown to reduce susceptibility to oseltamivir, but zanamivir as well.
Changes at residues E119, V116, I117, Q136, I223 (I222) and D199 (D198) around neuraminidase active site are associated with reduced susceptibility to oseltamivir in both seasonal and H5N1 (i.e. avian influenza) viruses. 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 incidence of development of resistant strains of seasonal H1N1 and H3N2 influenza has been low among adults and adolescents (0.3%), but pediatric patients have demonstrated higher rates (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 patients infected with resistant strains my 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, but also in instances in which patients have had contact with immunocompromised hosts undergoing treatment.
For practical purposes, if 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 we encounter the greatest risk of generating resistance.
In short, the global occurrence of influenza virus resistance connected with the seasonal use of oseltamivir is presently small and 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 uttermost importance.