Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance

Bloom, Jesse D.; Gong, Lizhi Ian; Baltimore, David

doi:10.1126/science.1187816

Cited by 628 publications

(676 citation statements)

References 32 publications

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“…In our study, the frequency of detection of resistance due to a 275Y substitution gradually increased during the surveillance, but the limited number of cases makes any interpretation difficult. According to the studies performed recently, it seems that this path to a sustained 275Y virus in H1N1pdm09 as observed in 2008 for the Brisbane‐like H1N1 has not started, but should be monitored 26, 27…”

Section: Discussionmentioning

confidence: 99%

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Lina

Boucher

Osterhaus

et al. 2018

Influenza Resp Viruses

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Background and objectivesThe Influenza Resistance Information Study (IRIS) was initiated in 2008 to study the emergence of neuraminidase inhibitor (NAI) resistance and the clinical course of influenza in immunocompetent treated and untreated patients.MethodsPatients had throat/nose swabs collected on days 1, 3, 6 and 10 for analyses of influenza type, subtype and virus susceptibility to NAIs. RT‐PCR‐positive samples were cultured and tested for NAI resistance by specific RT‐PCR and phenotypic testing. Scores for influenza symptoms were recorded on diary cards (Days 1‐10). This study focuses on influenza A‐infected cases only.ResultsAmong 3230 RT‐PCR‐positive patients, 2316 had influenza A of whom 1216 received oseltamivir monotherapy within 2 days of symptom onset (9 seasonal H1N1; 662 H3N2; 545 H1N1pdm2009). Except for 9 patients with naturally resistant seasonal H1N1 (2008/9), no resistance was detected in Day 1 samples. Emergence of resistance (post‐Day 1) was detected in 43/1207 (3.56%) oseltamivir‐treated influenza A‐infected patients, with a higher frequency in 1‐ to 5‐year‐olds (11.8%) vs >5‐year‐olds (1.4%). All N1‐ and N2‐resistant viruses had H275Y (n = 27) or R292K (n = 16) substitutions, respectively. For 43 patients, virus clearance was significantly delayed vs treated patients with susceptible viruses (8.1 vs 10.9 days; P < .0001), and 11 (23.2%) remained RT‐PCR positive for influenza at Day 10. However, their symptoms resolved by Day 6 or earlier.ConclusionsOseltamivir resistance was only detected during antiviral treatment, with the highest incidence occurring among 1‐ to 5‐year‐olds. Resistance delayed viral clearance, but had no impact on symptom resolution.

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Section: Discussionmentioning

confidence: 99%

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Lina

Boucher

Osterhaus

et al. 2018

Influenza Resp Viruses

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“…Permissive or compensatory mutations in an IAV are clearly important for the ability of a virus to harbor a selected resistance mutation (15,31,32). Several amino acid variants at NA position 222 can have both permissive and additive effects with NA-H274Y in human influenza A (H1N1) virus (31,33,34), and it is possible that the NA-N222 variant in this avian influenza A (H1N1) virus might have had a permissive function for the acquisition and retention of NA-H274Y.…”

Section: Discussionmentioning

confidence: 99%

Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards

Gillman

Muradrasoli

Söderström

et al. 2015

Appl Environ Microbiol

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Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo mallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.

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“…Resistance in natural isolates is associated with mutations in the NA, but mostly these resistant viruses are less fit, only appear sporadically, and do not spread 72 . However, seasonal H1N1 viruses with the H275Y (N1 numbering; H274Y in N2) mutation spread throughout the world in 2008, apparently because a compensating mutation had increased their fitness and transmissibility 73 . However, this lineage of H1N1 viruses rapidly disappeared in the face of the swine-origin H1N1 virus that appeared in 2009, so their fitness may have been marginal.…”

Section: Na Inhibitors and Resistance Mutationsmentioning

confidence: 99%

Influenza neuraminidase

Air

2011

Influenza Resp Viruses

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216

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Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been largely ignored as a vaccine target despite evidence that inclusion of neuraminidase in the subunit vaccine gives increased protection. This article describes current knowledge on the structure, enzyme activity and antigenic significance of neuraminidase.

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Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance

Cited by 628 publications

References 32 publications

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards

Influenza neuraminidase

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