Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection

Abstract

Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.

Rimantadine and Oseltamivir Demonstrate Synergistic Combination Effect in an Experimental Infection with Type a (H3N2) Influenza Virus in Mice

“…An additive or synergistic effect of the combination as considered against H1N1 and H3N2 variants of influenza A virus was established in another previous study (Govorkova et al, 2004) (Bright et al, 2005), and to a lesser but gradually increasing degree towards NA inhibitors (de Jong et al, 2005).…”

Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

“…However, both drug resistance and vaccine development and production problems pose difficulties for influenza control programs. For example, the very stable antiviral drug oseltamivir (Tamiflu) has been found in watercourses in Japan where ducks that harbor influenza A viruses come into direct contact with the drug, potentially leading to the selection of oseltamivir-resistant strains of influenza virus (2). In addition, vaccine production can be problematic, due to the difficulty of working with highly pathogenic avian influenza (HPAI) viruses, the relatively low immunogenicity of some strains, and the need to protect against the large number of strains of H5N1, H7N1, H9N3, etc., circulating in the environment.…”

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

“…Although the H274Y mutation in infl uenza A H1N1 neuraminidase had been previously reported, 61,62 its occurrence in infl uenza A (H5N1) infection raised concern because it was associated with death in two of the eight infl uenza A (H5N1) virus -infected patients. 63 Whether there was a causal relationship between the emergence of the H274Y mutation and the lethal outcome could not be ascertained, however. 63 The effi cacy of oseltamivir in the treatment of H5N1 infection in humans could, because of its anecdotal use, not been unequivocally demonstrated.…”

“…63 Whether there was a causal relationship between the emergence of the H274Y mutation and the lethal outcome could not be ascertained, however. 63 The effi cacy of oseltamivir in the treatment of H5N1 infection in humans could, because of its anecdotal use, not been unequivocally demonstrated. Yet, it should be pointed out that oseltamivir has been shown to protect ferrets against lethal infl uenza H5N1 infection: Treatment with oseltamivir at 5 mg/kg/day for 5 days twice daily (orally) resulted in complete inhibition of virus replication in the lungs and small intestine on day 5 p.i.…”

“…132 Zanamivir remains an attractive antiviral drug for combination with oseltamivir because of a non -overlapping resistance pattern, but then the route of administration will need to be reconsidered, since, if administered by inhalation, it does not reach the sites (lower respiratory tract and extrapulmonary) where avian infl uenza H5N1 replicates. 133 Some authors have questioned the effectiveness of neuraminidase inhibitors in interrupting viral spread and argued that their use in a serious epidemic or pandemic should not be considered without concomitant public -health measures such as barriers, distance, and personal hygiene. 134 The same authors also argued against the use of amantadine and rimantadine.…”