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Wkly Epidemiol Rec. Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 2010
Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 2010 (Wkly Epidemiol Rec., edited)
[Source PDF Document: LINK. EDITED.]
Weekly epidemiological record - 5 february 2010, 85th year - No. 6, 2010, 85, 37?48
Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 2010
Since the first report(1) of oseltamivir-resistant pandemic influenza A (H1N1) 2009 virus in June 2009, >200 cases of resistant virus have been reported worldwide. The purpose of this article is to provide a brief global update on cases of oseltamivir-resistant
pandemic (H1N1) 2009 viruses since the first report published in the Weekly Epidemiological Record(2) in October 2009.
With the exception of the 225 cases summarized here, all clinical samples tested for pandemic (H1N1) 2009 virus lack the H275Y mutation and are therefore assumed to be sensitive to the influenza virus neuraminidase inhibitors oseltamivir and zanamivir.
While this indicates the absence of wider community circulation of oseltamivir-resistant virus, recently reported clusters of cases suggest that such viruses are being transmitted in local settings.
Description of cases of oseltamivir resistance
As of 3 February 2010, a total of 225 oseltamivir-resistant cases had been reported and confirmed worldwide. All these oseltamivir-resistant isolates have the same mutation in the neuraminidase gene (H275Y), conferring resistance to oseltamivir but not to zanamivir. There is also no evidence of reassortment between pandemic (H1N1) 2009 and other seasonal influenza A (H1N1) viruses, which have shown a high prevalence of oseltamivir resistance.
Of the 142 cases of oseltamivir-resistant pandemic influenza virus for which data are available, 56 (40%) have been identified in severely immunocompromised patients, 54 (38%) were associated with the treatment of influenza, 16 (11%) with chemoprophylaxis,(3) and 16 (11%) had no known association with antiviral drug use, including 7 cases occurring as part of a cluster in Viet Nam (described below).
Oseltamivir-resistant viruses have been reported in 20 countries across 4 WHO regions (Table 1); antiviral susceptibility testing has occurred on >20 000 pandemic (H1N1) 2009 specimens isolated from >86 countries. With the exception of the 3 clusters described below, there are few epidemiological links among any of the reported cases. The majority of these cases are sporadic, isolated cases, and there is no evidence yet that oseltamivir-resistant pandemic (H1N1) 2009 viruses are circulating in the community.
Clusters of oseltamivir-resistant viruses in severely immunocompromised patients
Of the 56 cases of oseltamivir-resistant viruses isolated from severely immunocompromised patients, 12 are related to 2 clusters within hospital wards. The first cluster of 4 oseltamivir-resistant pandemic (H1N1) 2009 viruses emerged at Duke University Hospital in Durham, North Carolina, United States.(4) One male and 3 female patients, ranging in age from 43 years to 67 years, with severely immunocompromised status, were admitted to the same ward. The onset of influenza illness occurred in a 2-week period between mid-October and early November. While 3 of the cases were fatal, the role of H1N1 infection in contributing to the deaths is uncertain. In 3 of the 4 cases, the H275Y mutation was identified before oseltamivir was administered.
Table 1 Geographical distribution of oseltamivir-resistant pandemic (H1N1) 2009 viruses, February 2010
[Isolates ? WHO region: Americas ? European ? Eastern Mediterranean ? African ? South-East Asia ? Western Pacific]
(a) Data compiled from information provided by WHO Collaborating Centres for Reference and Research on Influenza, National Influenza Centres and from published reports from national health agencies.
The second known cluster included 8 patients with underlying haematological malignancies at the University Hospital of Wales in Cardiff, Wales, United Kingdom, in November 2009.(5,6) Resistant viruses appeared to have been treatment-induced in 2 cases. At least 4 patients contracted the resistant virus through person-to-person transmission.(7) Two of 8 patients in this cluster had had an interrupted course of oseltamivir treatment before and after the recognition of oseltamivir resistance. None of these cases were fatal.(8)
The observation that severely immunocompromised patients are at a higher risk of developing oseltamivir-resistant virus during treatment has already been highlighted.(2) Following these 2 clusters of cases, WHO issued a briefing note reiterating the importance of monitoring for antiviral resistance in severely immunocompromised patients undergoing antiviral treatment.(3)
Person-to-person transmission of oseltamivir-resistant viruses in healthy adults
In July 2009,9 a cluster of previously unreported cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus infection was identified in 7 healthy young adults travelling on a train from Ho Chi Minh City to Hanoi in Viet Nam. All 7 were shown to have the H275Y mutation in samples taken prior to oseltamivir treatment. The authors concluded that these cases were the result of person-to-person transmission from an unidentified index case. No additional cases have been identified from this cluster subsequently. It is also possible that very limited person-to-person transmission occurred in some of the other 9 cases of the 16 where oseltamivir resistance arose in patients who were not taking the antiviral.
Implications for clinical management
WHO published guidelines for antiviral treatment of pandemic (H1N1) 2009 influenza virus infection in August 2009.(10) These recommendations took into account the possibility of the emergence of antiviral resistance. WHO and other organizations(11,12) also published further briefing notes and guidance as new information became available during the past several months.(13) These guidelines recommend not using a particular antiviral in cases in which the virus is known to be or is highly likely to be resistant to it. All of the oseltamivir-resistant viruses characterized to date remain sensitive to zanamivir. Zanamivir remains a therapeutic alternative for all patients with serious illness caused by pandemic (H1N1) 2009 influenza virus infection that is known to be resistant to oseltamivir. This is particularly true for patients with severely compromised or suppressed immune systems; they are recognized to be at higher risk of developing resistance to oseltamivir during treatment.
Although almost one third of all known cases of resistance have occurred in the group of patients discussed in this article, the lack of information on the total population of immunocompromised people being treated (as the denominator) has hampered the calculation of the true rate. In view of this, the development of resistance in such patients is assumed to be an event with a high probability, and prevention of infection in this group of patients should have a high priority.
Conclusions
The number of reported cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus remains low despite the large scale of the pandemic, widespread use of oseltamivir and extensive monitoring of susceptibility. Although there is no evidence of general community circulation of such resistant viruses, there is clear evidence of limited person-to-person transmission in several epidemiological settings. Active surveillance for antiviral resistance in pandemic (H1N1) 2009 virus needs to be maintained by clinicians, laboratories and agencies. All cases of oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus should be investigated and promptly notified to relevant agencies including WHO.
(1) First isolation of a secondary oseltamivir-resistant A (H1N1)v strain in Denmark. Stockholm, Sweden, European Centre for Disease Prevention and Control, 2009 (LINK, accessed January 2010).
(2) Oseltamivir resistance in immunocompromised hospital patients: pandemic (H1N1) 2009 briefing note 18. Geneva, World Health Organization, 2009 (LINK, accessed January 2010).
(3) Baz M et al. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. New England Journal of Medicine, 2009, 361:2296?2297 (also available at: LINK).
(4) CDC confirms four new cases of oseltamivir (Tamiflu)-resistant H1N1. Durham, NC, DukeHealth.org, 2009 (LINK, accessed January 2010).
(5) HPA statement on possible transmission. London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(6) Oseltamivir-resistant pandemic (H1N1) 2009 influenza case and cluster investigation. London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(7) HPA weekly national influenza report: 26 November 2009 (week 48). London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(8) Oseltamivir-resistant novel influenza A(H1N1) virus infection in two immunosuppressed patients. Morbidity and Mortality Weekly Report, 2009, 58:893?896 (also available at: LINK).
(9) Mai, LQ et al. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. New England Journal of Medicine, 2009, 362:86?87 (also available at: LINK).
(10) WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Geneva, World Health Organization, 2009 (LINK, accessed January 2010).
(11) Updated interim recommendations: special considerations for clinicians regarding 2009 H1N1 influenza in severely immunosuppressed patients. Atlanta, Georgia, United States Centers for Disease Control and Prevention, 2009 (LINK, accessed January 2010).
(12) Inpatient clinical management issues relating to oseltamivir-resistant pandemic (H1N1) 2009 influenza virus. London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(13) Antiviral use and the risk of drug resistance: pandemic (H1N1) 2009 briefing note 12. Geneva, World Health Organization, 2009 (LINK, accessed January 2010).
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[Source PDF Document: LINK. EDITED.]
Weekly epidemiological record - 5 february 2010, 85th year - No. 6, 2010, 85, 37?48
Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 2010
Since the first report(1) of oseltamivir-resistant pandemic influenza A (H1N1) 2009 virus in June 2009, >200 cases of resistant virus have been reported worldwide. The purpose of this article is to provide a brief global update on cases of oseltamivir-resistant
pandemic (H1N1) 2009 viruses since the first report published in the Weekly Epidemiological Record(2) in October 2009.
With the exception of the 225 cases summarized here, all clinical samples tested for pandemic (H1N1) 2009 virus lack the H275Y mutation and are therefore assumed to be sensitive to the influenza virus neuraminidase inhibitors oseltamivir and zanamivir.
While this indicates the absence of wider community circulation of oseltamivir-resistant virus, recently reported clusters of cases suggest that such viruses are being transmitted in local settings.
Description of cases of oseltamivir resistance
As of 3 February 2010, a total of 225 oseltamivir-resistant cases had been reported and confirmed worldwide. All these oseltamivir-resistant isolates have the same mutation in the neuraminidase gene (H275Y), conferring resistance to oseltamivir but not to zanamivir. There is also no evidence of reassortment between pandemic (H1N1) 2009 and other seasonal influenza A (H1N1) viruses, which have shown a high prevalence of oseltamivir resistance.
Of the 142 cases of oseltamivir-resistant pandemic influenza virus for which data are available, 56 (40%) have been identified in severely immunocompromised patients, 54 (38%) were associated with the treatment of influenza, 16 (11%) with chemoprophylaxis,(3) and 16 (11%) had no known association with antiviral drug use, including 7 cases occurring as part of a cluster in Viet Nam (described below).
Oseltamivir-resistant viruses have been reported in 20 countries across 4 WHO regions (Table 1); antiviral susceptibility testing has occurred on >20 000 pandemic (H1N1) 2009 specimens isolated from >86 countries. With the exception of the 3 clusters described below, there are few epidemiological links among any of the reported cases. The majority of these cases are sporadic, isolated cases, and there is no evidence yet that oseltamivir-resistant pandemic (H1N1) 2009 viruses are circulating in the community.
Clusters of oseltamivir-resistant viruses in severely immunocompromised patients
Of the 56 cases of oseltamivir-resistant viruses isolated from severely immunocompromised patients, 12 are related to 2 clusters within hospital wards. The first cluster of 4 oseltamivir-resistant pandemic (H1N1) 2009 viruses emerged at Duke University Hospital in Durham, North Carolina, United States.(4) One male and 3 female patients, ranging in age from 43 years to 67 years, with severely immunocompromised status, were admitted to the same ward. The onset of influenza illness occurred in a 2-week period between mid-October and early November. While 3 of the cases were fatal, the role of H1N1 infection in contributing to the deaths is uncertain. In 3 of the 4 cases, the H275Y mutation was identified before oseltamivir was administered.
Table 1 Geographical distribution of oseltamivir-resistant pandemic (H1N1) 2009 viruses, February 2010
[Isolates ? WHO region: Americas ? European ? Eastern Mediterranean ? African ? South-East Asia ? Western Pacific]
- No. of isolates tested for antiviral susceptibility(a) - >8000 - >7500 - 50 - 66 - 20 - >7500
- No. of oseltamivir-resistant isolates reported ? 65 - 77 - 1 - 0 - 0 - 82
(a) Data compiled from information provided by WHO Collaborating Centres for Reference and Research on Influenza, National Influenza Centres and from published reports from national health agencies.
The second known cluster included 8 patients with underlying haematological malignancies at the University Hospital of Wales in Cardiff, Wales, United Kingdom, in November 2009.(5,6) Resistant viruses appeared to have been treatment-induced in 2 cases. At least 4 patients contracted the resistant virus through person-to-person transmission.(7) Two of 8 patients in this cluster had had an interrupted course of oseltamivir treatment before and after the recognition of oseltamivir resistance. None of these cases were fatal.(8)
The observation that severely immunocompromised patients are at a higher risk of developing oseltamivir-resistant virus during treatment has already been highlighted.(2) Following these 2 clusters of cases, WHO issued a briefing note reiterating the importance of monitoring for antiviral resistance in severely immunocompromised patients undergoing antiviral treatment.(3)
Person-to-person transmission of oseltamivir-resistant viruses in healthy adults
In July 2009,9 a cluster of previously unreported cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus infection was identified in 7 healthy young adults travelling on a train from Ho Chi Minh City to Hanoi in Viet Nam. All 7 were shown to have the H275Y mutation in samples taken prior to oseltamivir treatment. The authors concluded that these cases were the result of person-to-person transmission from an unidentified index case. No additional cases have been identified from this cluster subsequently. It is also possible that very limited person-to-person transmission occurred in some of the other 9 cases of the 16 where oseltamivir resistance arose in patients who were not taking the antiviral.
Implications for clinical management
WHO published guidelines for antiviral treatment of pandemic (H1N1) 2009 influenza virus infection in August 2009.(10) These recommendations took into account the possibility of the emergence of antiviral resistance. WHO and other organizations(11,12) also published further briefing notes and guidance as new information became available during the past several months.(13) These guidelines recommend not using a particular antiviral in cases in which the virus is known to be or is highly likely to be resistant to it. All of the oseltamivir-resistant viruses characterized to date remain sensitive to zanamivir. Zanamivir remains a therapeutic alternative for all patients with serious illness caused by pandemic (H1N1) 2009 influenza virus infection that is known to be resistant to oseltamivir. This is particularly true for patients with severely compromised or suppressed immune systems; they are recognized to be at higher risk of developing resistance to oseltamivir during treatment.
Although almost one third of all known cases of resistance have occurred in the group of patients discussed in this article, the lack of information on the total population of immunocompromised people being treated (as the denominator) has hampered the calculation of the true rate. In view of this, the development of resistance in such patients is assumed to be an event with a high probability, and prevention of infection in this group of patients should have a high priority.
Conclusions
The number of reported cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus remains low despite the large scale of the pandemic, widespread use of oseltamivir and extensive monitoring of susceptibility. Although there is no evidence of general community circulation of such resistant viruses, there is clear evidence of limited person-to-person transmission in several epidemiological settings. Active surveillance for antiviral resistance in pandemic (H1N1) 2009 virus needs to be maintained by clinicians, laboratories and agencies. All cases of oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus should be investigated and promptly notified to relevant agencies including WHO.
(1) First isolation of a secondary oseltamivir-resistant A (H1N1)v strain in Denmark. Stockholm, Sweden, European Centre for Disease Prevention and Control, 2009 (LINK, accessed January 2010).
(2) Oseltamivir resistance in immunocompromised hospital patients: pandemic (H1N1) 2009 briefing note 18. Geneva, World Health Organization, 2009 (LINK, accessed January 2010).
(3) Baz M et al. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. New England Journal of Medicine, 2009, 361:2296?2297 (also available at: LINK).
(4) CDC confirms four new cases of oseltamivir (Tamiflu)-resistant H1N1. Durham, NC, DukeHealth.org, 2009 (LINK, accessed January 2010).
(5) HPA statement on possible transmission. London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(6) Oseltamivir-resistant pandemic (H1N1) 2009 influenza case and cluster investigation. London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(7) HPA weekly national influenza report: 26 November 2009 (week 48). London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(8) Oseltamivir-resistant novel influenza A(H1N1) virus infection in two immunosuppressed patients. Morbidity and Mortality Weekly Report, 2009, 58:893?896 (also available at: LINK).
(9) Mai, LQ et al. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. New England Journal of Medicine, 2009, 362:86?87 (also available at: LINK).
(10) WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Geneva, World Health Organization, 2009 (LINK, accessed January 2010).
(11) Updated interim recommendations: special considerations for clinicians regarding 2009 H1N1 influenza in severely immunosuppressed patients. Atlanta, Georgia, United States Centers for Disease Control and Prevention, 2009 (LINK, accessed January 2010).
(12) Inpatient clinical management issues relating to oseltamivir-resistant pandemic (H1N1) 2009 influenza virus. London, England, Health Protection Agency, 2009 (LINK, accessed January 2010).
(13) Antiviral use and the risk of drug resistance: pandemic (H1N1) 2009 briefing note 12. Geneva, World Health Organization, 2009 (LINK, accessed January 2010).
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