Emergence of intratreatment resistance to oseltamivir in pandemic influenza a H1N1 2009 virus

Valinotto, Laura; Díez, Roberto A.; Barrero, Paola Roxana; Farías, Julio A; López, Eduardo; Mistchenko, Alicia

doi:10.3851/imp1635

Cited by 17 publications

(13 citation statements)

References 14 publications

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“…It is noteworthy that we found that five patients presented with oseltamivir-resistant variant H275Y and that one patient presented with the N295S mutation. These mutants might have been favored by the high degree of selective pressure and thus resulted in virus more fit to survive in this modified environment over a short period (32). However, to the best of our knowledge, these resistant strains did not show person-to-person transmission; therefore, compensating mutations occurring elsewhere in their genomes that might improve their fitness and transmissibility need further study.…”

Section: Discussionmentioning

confidence: 88%

Genetic and Phylogenetic Analyses of Influenza A H1N1pdm Virus in Buenos Aires, Argentina

Barrero

Viegas

Valinotto

et al. 2011

J Virol

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Section: Discussionmentioning

confidence: 88%

Genetic and Phylogenetic Analyses of Influenza A H1N1pdm Virus in Buenos Aires, Argentina

Barrero

Viegas

Valinotto

et al. 2011

J Virol

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“…The use of antibiotic and/or neuraminidase inhibitors in the treatment of patients with influenza was reported in three studies 2,71,72 . Oseltamivir resistance of influenza A (H1N1) 2009 virus was reported in two studies in Argentina 85,86 …”

Section: Resultsmentioning

confidence: 99%

Burden of influenza in Latin America and the Caribbean: a systematic review and meta‐analysis

Savy

Ciapponi

Bardach

et al. 2012

Influenza Resp Viruses

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Please cite this paper as: Savy et al. (2012) Burden of influenza in Latin America and the Caribbean: a systematic review and meta‐analysis. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12036. Objective Influenza causes severe morbidity and mortality. This systematic review aimed to assess the incidence, etiology, and resource usage for influenza in Latin America and the Caribbean. Design Meta‐analytic systematic review. Arcsine transformations and DerSimonian Laird random effects model were used for meta‐analyses. Setting A literature search from 1980 to 2008 in MEDLINE, Cochrane Library, EMBASE, LILACS, Ministries of Health, PAHO, proceedings, reference lists, and consulting experts. Sample We identified 1092 references, of which 31 were finally included, in addition to influenza surveillance reports. We also used information from the 10 reports from the collaborative group for epidemiological surveillance of influenza and other respiratory virus (GROG), and information retrieved from the WHO global flu database FLUNET. Main outcome measures Incidence, percentage of influenza specimens out of the total received by influenza centers and resource‐use outcomes. Results A total of 483 130 specimens of patients with influenza were analyzed. Meta‐analysis showed an annual rate of 36 080 (95%CI 28 550 43 610) influenza‐like illness per 100 000 persons‐years. The percentage of influenza out of total specimens received by influenza centers ranged between 4.66% and 15.42%, with type A the most prevalent, and A subtype H3 predominating. The mean length of stay at hospital due to influenza ranged between 5.8 12.9 days, total workdays lost due to influenza‐like illnesses were 17 150 days, and the mean direct cost of hospitalization was US$575 per laboratory‐confirmed influenza case. Conclusions Our data show that seasonal influenza imposes a high morbidity and economic burden to the region. However, the vaccine‐uptake rate has been low in this region. Population‐based cohort studies are required to improve the knowledge about incidence and resource utilization, which would inform healthcare authorities for decision making.

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“…Population sequencing can identify minority species only down to 25% of the population, which is a major deficiency of this technique and may result in minority species not being identified. In studies with oseltamivir, resistant virus has generally been detected among viruses isolated on or after day 4 (43,44). Clonal analysis of virus samples obtained on day 4 or beyond was therefore carried out in this study.…”

Section: Discussionmentioning

confidence: 99%

Virus Susceptibility Analyses from a Phase IV Clinical Trial of Inhaled Zanamivir Treatment in Children Infected with Influenza

Yates

Mehta

Horton

et al. 2013

Antimicrob Agents Chemother

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A zanamivir postapproval efficacy study was conducted in children (n ‫؍‬ 279) in Japan during three influenza seasons. Pharyngeal swab specimens (n ‫؍‬ 714) were obtained for detailed resistance analysis. From 371 cultured viruses, 3 viruses (A/H1N1) from two subjects showed reduced susceptibility to zanamivir at day 1 (before treatment), 1 had an N74S amino acid substitution (fold shift, 46), and 2 (day 1 and day 2) had a Q136K amino acid substitution (fold shifts, 292 and 301). Q136K was detected only in cultured virus and not in the swab. From the remaining 118 cultured viruses obtained during or after treatment with zanamivir, no shifts in virus susceptibility were detected. Neuraminidase (NA) population sequencing showed that viruses from 12 subjects had emergent amino acid substitutions, but 3 with susceptibility data were not zanamivir resistant. The remainder may be natural variants. Further analysis is planned. Hemagglutinin (HA) sequencing showed that viruses from 20 subjects had 9 HA amino acid substitutions that were previously implicated in resistance to neuraminidase inhibitors in in vitro assays or that were close to the receptor binding site. Their role in in vivo resistance appears to be less important but is not well understood. NA clonal sequence analysis was undertaken to determine if minority species of resistant viruses were present. A total of 1,682 clones from 90 subjects were analyzed. Single clones from 12 subjects contained amino acid substitutions close to the NA active site. It is unclear whether these single amino acid substitutions could have been amplified after drug pressure or are just chance mutations introduced during PCR.

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Emergence of intratreatment resistance to oseltamivir in pandemic influenza a H1N1 2009 virus

Abstract: We describe the intratreatment emergence of oseltamivir resistance in two paediatric patients. Pyrosequencing allowed us to detect variant mixtures, showing the transition of the viral population from sensitive to resistant.

Cited by 17 publications

References 14 publications

Genetic and Phylogenetic Analyses of Influenza A H1N1pdm Virus in Buenos Aires, Argentina

Genetic and Phylogenetic Analyses of Influenza A H1N1pdm Virus in Buenos Aires, Argentina

Burden of influenza in Latin America and the Caribbean: a systematic review and meta‐analysis

Virus Susceptibility Analyses from a Phase IV Clinical Trial of Inhaled Zanamivir Treatment in Children Infected with Influenza

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