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Oseltamivir-resistant influenza A(H1N1) 2009 virus in Greece during the post-pandemic 2010-2011 season
Abstract
Information on the drug susceptibility of influenza epidemic strains is important for antiviral resistance monitoring. In Greece, the 2009-2010 pandemic waves were very mild and seroprevalence rates remained low after this influenza season, resulting in exclusive detection of the pandemic strain during the 2010-2011 influenza season. In the present study during the post-pandemic 2010-2011 season, 50 consecutive influenza A(H1N1) 2009 virus-positive samples from patients hospitalised in Greek hospitals were analysed for resistance to the neuraminidase inhibitor oseltamivir. All patients were hospitalised with severe influenza complications and had previously received oseltamivir. Influenza A(H1N1) 2009 virus detection and testing for oseltamivir resistance were performed with real-time PCR amplification assays. The H275Y substitution associated with resistance to oseltamivir was identified in two immunocompetent patients who received oseltamivir treatment for 3 days and 5 days, respectively. In both cases, patients were discharged in good condition despite development of resistance to antiviral treatment.
... Nowadays, almost all circulating influenza A viruses that recovered from humans are resistant to adamantanes [5]. Although neuraminidase (NA) inhibitors are active against both type A and type B viruses, oseltamivir-resistance occurred in A(H1N1)2009 virus and even in A(H7N9)2013 virus [6][7][8][9]. In addition to drug-resistance, both inhibitors only worked at the early phase of virus infection. ...
... Importantly, almost all the tested medicines displayed significant inhibitory activities against oseltamivir-resistant A/Jinnan/15/2009(H1N1) except Jinzhen oral liquid (1) with IC 50 of 39.82 ± 11.24 L/mL. As for H3N2 viruses, except for Qingkailing oral liquid (7) and Cold liquid (10), all the other medicines inhibited the replication of A/Wuhan/359/1995(H3N2). Of all the tested medicines, Children's Qingre oral liquid (6), Xiaoqinglong mixture (8), and Compound Qinlan oral liquid (9) exhibited strong antiviral activities against amantadineresistant A/Zhuhui/1222/2010(H3N2), with IC 50 values of 7.43 ± 1.44 L/mL, 2.50 ± 0.75 L/mL, and 7.52 ± 3.06 L/mL, (1) Jinzhen oral liquid a >100.00 ± 0 50.00 ± 0 (2) Antiviral oral liquid a >100.00 ± 0 >100.00 ± 0 ...
... TC 50 of drugs against Vero cell and IC 50 against the four EV71 strains were summarized in Table 4. Of all the 10 oral liquids, Xiaoqinglong mixture (8) possessed the best inhibitory activities against EV71 strains with SI > 5. Qingkailing oral liquid (7) and Cold liquid (10) showed no antiviral effect whereas the remaining medicines had relatively weak antiviral activities against the tested strains. ...
Influenza is still a serious threat to human health with significant morbidity and mortality. The emergence of drug-resistant influenza viruses poses a great challenge to existing antiviral drugs. Traditional Chinese medicines (TCMs) may be an alternative to overcome the challenge. Here, 10 oral proprietary Chinese medicines were selected to evaluate their anti-influenza activities. These drugs exhibit potent inhibitory effects against influenza A H1N1, influenza A H3N2, and influenza B virus. Importantly, they demonstrate potent antiviral activities against drug-resistant strains. In the study of mechanisms, we found that Xiaoqinglong mixture could increase antiviral interferon production by activating p38 MAPK, JNK/SAPK pathway, and relative nuclear transcription factors. Lastly, our studies also indicate that some of these medicines show inhibitory activities against EV71 and CVB strains. In conclusion, the 10 traditional Chinese medicines, as kind of compound combination medicines, show broad-spectrum antiviral activities, possibly also including inhibitory activities against strains resistant to available antiviral drugs.
... The 2009-2010 pandemic waves were very mild and the seroprevalence rates remained low after this first new influenza virus season resulting in the exclusive detection of the pandemic strain during the 2010-2011 during the second influenza season. A large number of infected patients were hospitalised with severe influenza complications, presenting a high level increase of resistance towards the antiviral treatment [24,25]. Regarding the antiviral treat ment, during the beginning of the pandemic, all patients re ceived oseltamivir, soon after the confirmation of pandemic H1N1 2009 infection, only but 21% of the cas es were treated from the beginning of the symptoms. ...
The 2009 influenza A - subtype H1N1 pandemic tested the public health care systems all around the globe, infecting millions and leading to thousands of deaths. Greece became the epidemic centre of the 2009 flu pandemic due to the low compliance of the general population towards the vaccination programme, the resistance acquired against antiviral drugs and the economic scenario at the time. Our study, after a thorough research in the “Medline/PubMed, Scopus, Google Scholars” medical databases, accompanied by a wide range search of medical literature from Greece, sought to have a closer look at the pandemic from a Greek perspective. Finally, we used as key words the terms: “2009, flu, influenza A - H1N1 virus, vaccine, pandemic, Greece”. © 2016, EDIMES Edizioni Medico Scientifiche. All rights reserved.
... Europe the manufacturer claims that oseltamivir reduces complications while in the US, it was not allowed to do so due to insufficient evidence on complications [12]. Few data are available regarding influenza in Greece [13][14][15][16]. In a previous study, using the SOS network (a network of physicians who perform house-call visits) in Attica, it was shown that physicians prescribed oseltamivir instead of antibiotics when a rapid influenza test was positive [17]. ...
To evaluate the factors associated with oseltamivir prescription and to study the effectiveness of oseltamivir in reducing influenza-related complications. A prospective cohort study using the SOS Doctors (a network of physicians who perform house-call visits in Attica, Greece). Patients with confirmed or clinically suspected influenza were followed up to 14 days during the 2011-2012 influenza period. 410 patients with confirmed or suspected influenza were included. Healthy adults were mainly enrolled, with a median age of 44 years. Influenza diagnosis was mainly based on clinical criteria (65.8 % of patients). Oseltamivir was prescribed for 45.4 % of them. In a multivariate analysis, prescription of oseltamivir was associated with the attending physician (p < 0.001), positive influenza test (p < 0.001) and diabetes (p = 0.027). Data on complications were available for 351 patients, and 50 (15.8 %) of them reported at least one. Seven patients required hospitalization. Types of complications (pneumonia, bronchitis, etc.) were not significantly different between patients receiving and those not receiving oseltamivir. In the multivariate analysis, higher oseltamivir prescription rate was associated with fewer complications (p < 0.001). Bearing in mind the limitations of a non-randomized study, in a real-life setting, oseltamivir prescription and the rate of complications in patients with influenza were associated with the attending physician, underlying diseases and diagnostic tests. Overall, when the frequency of oseltamivir prescription increased, the influenza-related complications decreased.
... Potential hypersensitivity reactions often associated with administration of whole antibody are considerably reduced by using these Fab fragments or their divalent counterpart F(ab) 2 . Hence, this type of treatment has the potential to be readily transferable to infectious disease management, particularly in light of the increased incidence of drug resistance to circulating pathogens [6,7] and the medley of undesirable side effects often associated with conventional drug treatments [8,9,10]. Of particular interest here is the applicability of this approach to infections with viral pathogens such as influenza, as natural immunity to many such viruses is facilitated through the action of neutralising antibodies [3,11,12]. ...
Passive immunotherapies utilising polyclonal antibodies could have a valuable role in preventing and treating infectious diseases such as influenza, particularly in pandemic situations but also in immunocompromised populations such as the elderly, the chronically immunosuppressed, pregnant women, infants and those with chronic diseases. The aim of this study was to optimise current methods used to generate ovine polyclonal antibodies. Polyclonal antibodies to baculovirus-expressed recombinant influenza haemagglutinin from A/Puerto Rico/8/1934 H1N1 (PR8) were elicited in sheep using various immunisation regimens designed to investigate the priming immunisation route, adjuvant formulation, sheep age, and antigen dose, and to empirically ascertain which combination maximised antibody output. The novel adjuvant CoVaccine HT™ was compared to Freund’s adjuvant which is currently the adjuvant of choice for commercial production of ovine polyclonal Fab therapies. CoVaccine HT™ induced significantly higher titres of functional ovine anti-haemagglutinin IgG than Freund’s adjuvant but with fewer side effects, including reduced site reactions. Polyclonal hyperimmune sheep sera effectively neutralised influenza virus in vitro and, when given before or after influenza virus challenge, prevented the death of infected mice. Neither the age of the sheep nor the route of antigen administration appeared to influence antibody titre. Moreover, reducing the administrated dose of haemagglutinin antigen minimally affected antibody titre. Together, these results suggest a cost effective way of producing high and sustained yields of functional ovine polyclonal antibodies specifically for the prevention and treatment of globally significant diseases.
Influenza human infections are considered as a persistent global public health issue. Whereas vaccination is important for prevention, given its limitations, antiviral therapy is at the forefront of treatment, while it also plays a significant role in prevention. Currently, two classes of drugs, adamantanes (M2 blockers) and neuraminidase inhibitors (NAIs), are available for treatment and chemoprophylaxis of influenza infections. Given the resistance patterns of circulating influenza strains, adamantanes are not currently recommended. The current review mainly focuses on the development of resistance to NAIs among A and B subtypes of influenza virus strains over the last 5 years. 'Permissive' drift mutations and reassortment of viral gene segments have resulted in NAI oseltamivir-resistant A/(H1N1) variants that rapidly became predominant worldwide in the period 2007-2009. However, the prevalence of antiviral resistance to NAI zanamivir remains relatively low. In addition, the recently developed NAIs, peramivir and laninamivir, while licensed in certain countries, are still under evaluation and only a few reports have described resistance to peramivir. Although in 2014, the majority of circulating human influenza viruses remains susceptible to all NAIs, the emergence of oseltamivir-resistant influenza variants that could retain viral transmissibility, highlights the necessity for enhanced epidemiological and microbiological surveillance and clinical assessment of antiviral resistance.
Neuraminidase inhibitors (NAIs), such as oseltamivir and zanamivir, are the medicines of choice against influenza A or B. Oseltamivir resistance can be conferred by a single point missense mutation from histidine to tyrosine at position 275 (H275Y). Oseltamivir resistance in seasonal influenza A strains rose markedly during the 2007-2008 season. Furthermore, oseltamivir resistant (OsR) strains of pandemic influenza A/ H1N1 2009 (influenza A(H1N1)pdm09) have been increasingly isolated, although the majority remain sensitive. These OsR strains retain virulence, replicative fitness and transmissibility from person to person, with outbreaks reported. Treatment options in those at risk of severe or complicated disease are limited to zanamivir which is only licenced in those over the age of 5 years; of further concern, strains demonstrating low level resistance to both oseltamivir and zanamivir have been reported. Strategies to reduce emergence of resistant strains, such as higher dose oseltamivir regimens, need further examination.
In Europe, the 2007-08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward. Oseltami-vir-resistant influenza viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use. By country, the proportion of ORVs ranged from 0% to 68%, with the highest proportion in Norway. The average weighted prevalence of ORVs across Europe increased gradually over time, from near 0 in week 40 of 2007 to 56% in week 19 of 2008 (mean 20%). Neuraminidase genes of ORVs possessing the H275Y substitution formed a homogeneous subgroup closely related to, but distinguishable from, those of oseltamivir-sensitive influenza viruses A (H1N1). Minor variants of ORVs emerged independently, indicating multiclonal ORVs. Overall, the clinical effect of ORVs in Europe, measured by influenza-like illness or acute respiratory infection, was unremarkable and consistent with normal seasonal activity.
In this manuscript, we summarise the experience of Greece during the post-pandemic influenza season 2010/11 from 04 October 2010 to 22 May 2011. The spread of the disease and its impact were monitored using multiple surveillance systems, such as sentinel surveillance, virological surveillance and all-cause mortality surveillance. We also focus on the characteristics of laboratory-confirmed severe influenza cases who required admission to an intensive care unit (ICU) (n=368), and/or with a fatal outcome (n=180). The influenza-like illness rate reported from sentinel surveillance started rising in early January 2011 and peaked between 31 January and 6 February 2011. The total number of ICU admissions was higher in the post-pandemic influenza season than during the pandemic period causing a lot of pressure on ICUs. The overall population mortality rate due to influenza A(H1N1)2009 was higher than during the pandemic period (15.9 vs 13.2 fatal cases per million, p=0.087). Our data suggest that the severity of clinical illness in the first post-pandemic influenza season was comparable or even higher than during the pandemic.
Resistance to oseltamivir was observed in influenza A pandemic (H1N1) 2009 virus isolated from an untreated person in Hong Kong, China. Investigations showed a resistant virus with the neuraminidase (NA) 274Y genotype in quasi-species from a nasopharyngeal aspirate. Monitoring for the naturally occurring NA 274Y mutation in this virus is necessary.
Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North
American and Eurasian swine lineages has continued to circulate in humans. The lack of similarity between the 2009 A(H1N1)
virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period.
Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses.
Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously
unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are
homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1).
In Europe, the 2007-08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward. Oseltamivir-resistant influenza viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use. By country, the proportion of ORVs ranged from 0% to 68%, with the highest proportion in Norway. The average weighted prevalence of ORVs across Europe increased gradually over time, from near 0 in week 40 of 2007 to 56% in week 19 of 2008 (mean 20%). Neuraminidase genes of ORVs possessing the H275Y substitution formed a homogeneous subgroup closely related to, but distinguishable from, those of oseltamivir-sensitive influenza viruses A (H1N1). Minor variants of ORVs emerged independently, indicating multiclonal ORVs. Overall, the clinical effect of ORVs in Europe, measured by influenza-like illness or acute respiratory infection, was unremarkable and consistent with normal seasonal activity.
During the 2007-2008 influenza season, oseltamivir resistance among influenza A(H1N1) viruses increased significantly for the first time worldwide. Early surveillance data suggest that the prevalence of oseltamivir resistance among A(H1N1) viruses will most likely be higher during the 2008-2009 season.
To describe patients infected with oseltamivir-resistant influenza A(H1N1) virus and to determine whether there were any differences between these patients and patients infected with oseltamivir-susceptible A(H1N1) virus in demographic or epidemiological characteristics, clinical symptoms, severity of illness, or clinical outcomes.
Influenza A(H1N1) viruses that were identified and submitted to the Centers for Disease Control and Prevention by US public health laboratories between September 30, 2007, and May 17, 2008, and between September 28, 2008, and February 19, 2009, were tested as part of ongoing surveillance. Oseltamivir resistance was determined by neuraminidase inhibition assay and pyrosequencing analysis. Information was collected using a standardized case form from patients with oseltamivir-resistant A(H1N1) infections and a comparison group of patients with oseltamivir-susceptible A(H1N1) infections during 2007-2008.
Demographic and epidemiological information as well as clinical information, including symptoms, severity of illness, and clinical outcomes.
During the 2007-2008 season, influenza A(H1N1) accounted for an estimated 19% of circulating influenza viruses in the United States. Among 1155 influenza A(H1N1) viruses tested from 45 states, 142 (12.3%) from 24 states were resistant to oseltamivir. Data were available for 99 oseltamivir-resistant cases and 182 oseltamivir-susceptible cases from this period. Among resistant cases, median age was 19 years (range, 1 month to 62 years), 5 patients (5%) were hospitalized, and 4 patients (4%) died. None reported oseltamivir exposure before influenza diagnostic sample collection. No significant differences were found between cases of oseltamivir-resistant and oseltamivir-susceptible influenza in demographic characteristics, underlying medical illness, or clinical symptoms. Preliminary data from the 2008-2009 influenza season identified resistance to oseltamivir among 264 of 268 influenza A(H1N1) viruses (98.5%) tested.
Oseltamivir-resistant A(H1N1) viruses circulated widely in the United States during the 2007-2008 influenza season, appeared to be unrelated to oseltamivir use, and appeared to cause illness similar to oseltamivir-susceptible A(H1N1) viruses. Circulation of oseltamivir-resistant A(H1N1) viruses will continue, with a higher prevalence of resistance, during the 2008-2009 season.
Variable levels of oseltamivir resistance among seasonal influenza A(H1N1) isolates have been reported in Europe during the 2007-8 northern Hemisphere influenza season. It has been questioned whether oseltamivir use could have driven the emergence and predominance of resistant viruses. This study aimed at describing the levels of use of oseltamivir in 12 European Union (EU) Member States and European Economic Area (EEA)/European Free Trade Area (EFTA) countries. The data were converted into prescription rates and compared with the national proportions of resistant influenza A(H1N1) viruses through regression analysis. Overall use of oseltamivir in European countries between 2002 and 2007 was low compared to e.g. the use in Japan. High variability between the countries and over time was observed. In eight of the 12 countries, there was a peak of prescriptions in 2005, coinciding with concerns about a perceived threat from an influenza pandemic which might have lead to personal stockpiling. Ecological comparison between national levels of use of oseltamivir in 2007 and the proportions of A(H1N1) viruses that were resistant to oseltamivir showed no statistical association. In conclusion, our results do not support the hypothesis that the emergence and persistence of these viruses in 2007-8 was related to the levels of use of oseltamivir in Europe. Further investigation is needed to elucidate the reasons for different level of use between the countries.
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Knowledge of seroprevalence rates against 2009 pandemic H1N1 virus will assist vaccination recommendations and the preparation of the health-care system during subsequent years. This study was conducted in Greece during June-August 2010 to estimate the seroprevalence rate against pandemic H1N1 virus. Persons presenting in 29 health-care facilities across the country were studied. Seroprevalence was estimated employing a virus-free ELISA that specifically recognizes 2009 H1N1 virus antibodies in human sera. Sera collected from 2005 to April 2009 were also used to estimate pre-pandemic seroprevalence rates. A total of 954 persons were studied. The overall seroprevalence rate was 28.5% (95% confidence interval=25.6-31.3%). Age-specific rates were 34.2% in persons 0-4 years, 36.3% in persons 5-19 years, 25.0% in persons 20-39 years, 23.4% in persons 40-59 years, and 31.8% in persons ≥ 60 years. The highest rates were recorded in the Regions of Ionian Islands (67%) and Epirus (42.9%), while the lowest (8.4%) in the Region of Thessaly. Age-specific attack rates of infection during 2009-2010 were 28.8% in persons 0-4 years, 32.5% in persons 5-19 years, 14.3% in persons 20-39 years, 19.1% in persons 40-59 years, and 14.4% in persons ≥ 60 years. Multivariate analysis revealed that Region of residence and caring for children <5 years were associated with increased risk for seropositivity. Urbanity, personal and family characteristics, working in a health-care facility or in a school, history of pandemic H1N1 vaccination or history of influenza-like illness during 2009-2010 were not associated with increased risk for seropositivity.
N. Adriaenssens, S. Coenen, A. C. M. Kroes, A. Versporten, V. Vankerckhoven, A. Muller, H. S. Blix, H. Goossens, , H. Mittermayer, S. Vaerenberg, B. Markova, A. Andrasevic, A. Kontemeniotis, J. Vlcek, N. Frimodt-Moller, L. Rootslane, J. Vuopio-Varkila, P. Cavalie, W. Kern, H. Giamarellou, G. Ternak, H. Briem, R. Cunney, R. Raz, P. Folino, U. Dumpis, R. Valinteliene, M. Bruch, M. Borg, S. Natsch, H. S. Blix, W. Hryniewicz, M. Ribeirinho, A. Baicus, S. Ratchina, V. Foltan, M. Cizman, J. Campos, G. Skoog, G. Zanetti, S. Unal, P. Davey. (2011) European Surveillance of Antimicrobial Consumption (ESAC): systemic antiviral use in Europe. Journal of Antimicrobial Chemotherapy 66, 1897-1905
CrossRef
The first cases in the world of person to person transmission of a strain of swine flu that is resistant to oseltamivir (Tamiflu) seem to have emerged in a Welsh hospital.
The UK Health Protection Agency said on 20 November that five people with serious underlying health conditions at the University Hospital of Wales in Cardiff were known to be infected with a strain of oseltamivir resistant swine flu. Three other cases were being investigated.
Officials said it seemed likely that transmission of the resistant strain had taken place, the first documented cases of person to person transmission in the world. The World Health Organization has received reports of 57 incidences of oseltamivir resistance worldwide, but no previous instances of spread between patients have been reported.
They said that the virus remains sensitive to zanamivir (Relenza) and …
To the Editor: Neuraminidase inhibitors (oseltamivir and zanamivir) are recommended for treatment of severe illness caused by the 2009 pandemic influenza A (H1N1) virus, and their use has also been advocated for postexposure prophylaxis in high-risk persons.1 We report the emergence of an oseltamivir-resistant virus in a familial cluster of infections with the 2009 H1N1 virus. In a 13-year-old boy with asthma, infection with the 2009 H1N1 virus developed and was confirmed by reverse-transcriptase polymerase-chain-reaction (RT-PCR) testing of a nasopharyngeal aspirate. Administration of oseltamivir (60 mg twice a day for 5 days for this boy who weighed 32 kg) was . . .
Oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus
- Chen H Cheung
- Tai H Cl
- Chan P Jf Zhao
- Cheng
- Vc
Chen H, Cheung CL, Tai H, Zhao P, Chan JF, Cheng VC, et al. Oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus, Hong Kong China. Emerg Infect Dis 2009;15:1970–2.