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Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009 (Weekly Epidemiological Record, edited)
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Weekly epidemiological record - 30 october 2009, 84th year - No. 44, 2009, 84, 453?468 -
http://www.who.int/wer
Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009
The earliest isolates of pandemic (H1N1) 2009 influenza virus were shown to be sensitive to the influenza virus neuraminidase inhibitors oseltamivir and zanamivir but resistant to the M2 inhibitors amantadine and rimantadine.1 WHO and other organizations have developed guidelines for the use of antiviral drugs in the clinical management of pandemic (H1N1) 2009 influenza virus infections on the basis of these data.2,3
Since the initial characterization of pandemic (H1N1) 2009 influenza virus in March 2009, laboratories worldwide have been monitoring its susceptibility to neuraminidase inhibitors. The purpose of this article is to summarize current knowledge on oseltamivir-resistant pandemic (H1N1) 2009 influenza viruses and to highlight actions and recommendations that can minimize the emergence and transmission of resistant viruses. The information contained in this report is derived from published case reports, notifications to WHO under the International Health Regulations (2005), and analyses by WHO?s collaborating centres and other laboratories. This information is subject to change as case investigations and epidemiological investigations are completed.
Description of cases of oseltamivir resistance
WHO received the first report of an oseltamivir-resistant pandemic (H1N1) 2009 virus in July 2009. As of 22 October 2009, a total of 39 cases had been described, 7 of which are still under investigation.
In general, cases of oseltamivir resistance have been geographically dispersed, sporadic and not linked to one another. Extensive susceptibility testing of clinical samples and virus isolates suggests that such viruses are not circulating at a community level (Table 1).
The 32 isolates for which information is available share several features:
- all have a mutation in the neuraminidase gene resulting in an amino acid change from histidine to tyrosine at amino acid 275 (referred to as H275Y). Where enzyme-inhibition assays have been undertaken, the viruses have been shown to be resistant to oseltamivir, but they remain sensitive to zanamivir;
- none of these viruses has arisen as a result of reassortment between the pandemic (H1N1) 2009 influenza virus and any other influenza virus, including the seasonal H1N1 strain;
- there has been no evidence of transmission of these viruses beyond the immediate setting in which they were discovered;
- except for cases arising in severely immunosuppressed patients and 2 children who developed pneumonia (discussed below), all the patients with oseltamivir-resistant virus infection had typical influenza-like illness and all have recovered without complication.
Of these 32 reported cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, 16 were associated with the treatment of influenza, including in 7 immunosuppressed patients; 13 with chemoprophylaxis (usually following known exposure to another infected person); and 3 had no history of oseltamivir treatment or prophylaxis.
Immunosuppressed patients
Seven cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus were associated with treatment of immunosuppressed patients. Of these, 4 were in the United States, 2 in the United Kingdom and 1 in Australia. Reports of 2 of the cases from the United States have been published in detail.4 Although both cases were from the same city, the patients were treated in different hospitals and were not epidemiologically linked. Both patients received extended or repeated courses of treatment with oseltamivir; despite this, both continued to shed virus. Virus in samples taken early in the course of the influenza infection was sensitive to oseltamivir, indicating that the resistant viruses emerged during the course of treatment.
The emergence of drug-resistant influenza viruses in severely immunosuppressed or immunocompromised patients undergoing antiviral treatment is not unexpected and has been well documented.5 Virus replication can persist in such patients for prolonged periods of time despite antiviral treatment, creating an environment in which drug-resistant viruses can readily be selected. This phenomenon has been observed for all antiviral drugs for influenza, including zanamivir, to which resistant isolates have not arisen under other clinical circumstances.6
Chemoprophylaxis
Most of the 13 cases associated with prophylaxis have been isolated events with no epidemiological linkages. Two linked cases have been reported in detail.7 Two girls, staying in the same cabin at a summer camp in North Carolina (USA), developed influenzalike illness 3 days apart. The viruses had the H275Y mutation as well as another mutation in the neuraminidase gene (I223V). There are insufficient data to determine whether the resistant virus in these cases arose independently in the 2 individuals, was transmitted from a common source or passed from one girl to the other.
Of the 11 remaining cases associated with oseltamivir prophylaxis, 5 were isolated in Japan, 2 from the United States and 1 each from Canada, China and the Special Administrative Region (SAR) of Hong Kong, and Denmark. The association of oseltamivir- resistant influenza viruses with chemoprophylaxis has not been documented previously and, although these cases are few in number, this is a concern. In 2 clinical studies of oseltamivir?s effectiveness in preventing influenza among household contacts, no oseltamivir-resistant variants were detected.8,9
The number of cases of influenza infection occurring during prophylaxis in these studies was 338 and 11.9
There are 2 possible mechanisms for emergence and detection of resistance during prophylaxis. First, a resistant virus may be transmitted from a prior contact, especially if that contact was being treated with oseltamivir. This phenomenon has been well documented for the M2 inhibitor rimantadine, where the emergence of a drug-resistant virus in treated index cases and its subsequent onward transmission contributed to the failure of prophylaxis in contacts.10 However, such a scenario does not account for all 13 cases associated with post-exposure prophylaxis. In 1 case, the prior contact had been treated with zanamivir, not oseltamivir, while in some of the other cases there is no recorded use of oseltamivir in the presumed prior contacts. In contrast to the situation described for rimantadine,10 treating index cases with oseltamivir did not result in the emergence or transmission of oseltamivir-resistant virus during household studies.9
The second possible mechanism is for the mutated virus to originate during low-level replication in the individual taking oseltamivir prophylaxis (either prior to, or during use of, the antiviral). The lower frequency of administration of oseltamivir for prophylaxis (once per day versus twice daily for treatment) may be a contributing factor, as has been suggested previously.5
In all cases where samples have been available from the prior contact case (n=6), they have been shown to comprise oseltamivir-sensitive virus, indicating that the resistant virus has likely arisen within the case cluster.
In all of these prophylaxis-associated cases, the illness was typical influenza that resolved without complication.
Some patients received no further treatment, while others started a new treatment course of oseltamivir.
Two were treated with zanamivir.
Treatment
Of the 32 cases, 9 emerged during oseltamivir treatment in immunocompetent patients, 3 of whom were in Japan, 3 in Viet Nam11 and 1 each in Canada and Singapore. The point of contact in Taipei also reported 1 case. Where data are available, (n=6) the virus present in samples taken before the start of treatment was sensitive to oseltamivir.
In 2 cases, the oseltamivir-resistant viruses were discovered as a result of repeated sampling due to prolonged illness. One patient was being treated for bacterial pneumonia, which responded to antibiotics, and the second had viral pneumonia, which resolved following a second course of oseltamivir.
No association with antiviral use
Three cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus were detected in patients who had not taken oseltamivir for treatment or prophylaxis. One case was reported from Japan and 2 from Hong Kong SAR, although there is no epidemiological link between them. The first was in a traveller returning from San Francisco (USA).12 The source of infection in this case remains unknown. The second was from 1 of 3 contacts of a patient being treated with oseltamivir. Viruses from the other 2 contacts who developed influenza-like illness before and after the index case remained sensitive to oseltamivir.
Implications
Detection and investigation of cases
The risk of resistance is considered higher in patients who have prolonged illness (particularly those with severely compromised or suppressed immune systems) and who have received antiviral treatment for an extended duration and still test positive for the virus. The risk of resistance is also considered higher in people who receive oseltamivir for post-exposure prophylaxis following exposure to another person with influenza and who then develop illness despite taking oseltamivir. In both of these clinical situations (prolonged influenza illness and chemoprophylaxis failure), health-care staff should have a high level of suspicion that oseltamivir resistance has developed. A laboratory investigation should be undertaken to determine whether resistant virus is present. Clinical specimens or virus isolates for virological investigation should be sent to a specialized laboratory capable of performing antiviral susceptibility testing, such as one of the WHO collaborating centres for influenza13 or a national influenza centre.14
Samples that should be considered for testing include those from patients who have had >5 days of antiviral treatment and still have unresolved or complicated illness, and patients who present with influenza-like illness despite taking antiviral chemoprophylaxis.
When a drug-resistant virus is detected, WHO recommends that an epidemiological investigation be undertaken to determine the source of infection and whether onward transmission of the resistant virus has occurred.
This investigation should include contact tracing and virological investigation. In addition, community surveillance for oseltamivir-resistant pandemic (H1N1) 2009 influenza virus strains should be enhanced.
The detection of oseltamivir-resistant viruses to date has been strongly biased by the sampling strategies used for pandemic surveillance. The overwhelming majority of samples are taken on initial clinical presentation; relatively few examples of post-treatment specimens have been collected. More data need to be collected on a case-by-case basis and through prospective studies to better assess the risk of oseltamivir-resistant virus developing during treatment of both severe, prolonged illness and uncomplicated illness in the community.
Clinical case management
In general, WHO does not recommend using antiviral drugs for prophylaxis against pandemic (H1N1) 2009 influenza. For people who have been exposed to an infected person and who are at a higher risk of developing severe or complicated illness, an alternative option is to closely monitor them for symptoms and promptly administer antiviral treatment if symptoms develop. This option has 2 potential benefits. First, it reduces the risk that a suboptimal dose may be used in patients already infected at the time chemoprophylaxis starts (as may have been the case for at least 1 of the patients described here).5 Second, it ensures that treatment is administered only when needed.
WHO does not recommend using a particular antiviral in cases in whom the virus is known to be or is highly likely to be resistant to it.2 For this reason, zanamivir is the treatment of choice for patients who become ill while on oseltamivir prophylaxis, and it should also be considered for patients who develop prolonged viral illness despite treatment with oseltamivir. Since all of the oseltamivir-resistant pandemic (H1N1) 2009 influenza viruses characterized to date remain sensitive to zanamivir, it remains a therapeutic alternative for all patients with serious illness caused by oseltamivir-resistant pandemic (H1N1) 2009 influenza virus.
So far, there is no evidence of sustained transmission of these oseltamivir-resistant pandemic (H1N1) 2009 viruses; there is, however, strong suspicion that very limited transmission occured among close contacts in some of these cases. Where drug-resistant virus is suspected, appropriate infection-control measures should be reinforced to prevent spread.15
Conclusions
Growing international experience in the treatment of pandemic (H1N1) 2009 influenza virus infections underscores the importance of early treatment with the antiviral drugs oseltamivir or zanamivir. The experience of clinicians (including those who have treated severe cases of pandemic influenza) and national authorities suggests that prompt administration of these drugs following the onset of symptoms reduces the risk of complications and may also improve the clinical outcome in patients with severe disease.
This underscores the need to protect the effectiveness of these drugs by minimizing the occurrence and impact of drug resistance. WHO expects that these medicines will, and should continue to, be used in accordance with their respective guidelines,10 but urges clinicians and public health authorities to be alert to the emergence of oseltamivir-resistant viruses that might have an impact on patient care and public health.
The relatively small number of sporadic cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus recorded so far merits close monitoring but does not constitute a public health threat at this time. There is no evidence that such viruses are circulating at a community level, nor have they been associated with altered or unexpected severity of disease. There is, however, a need to monitor vigilantly for changes in transmissibility or pathogenicity, which may not be evident on a case-by-case basis. For this reason, WHO urges all clinicians, laboratories and agencies to promptly notify WHO of all cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza virus and to provide the relevant clinical and epidemiological data.
Acknowledgements
WHO thanks the collaborating centres for influenza and other national influenza centres for providing information on oseltamivir-resistant viruses.
[Table 1 Geographical distribution of oseltamivir-resistant pandemic (H1N1) 2009 influenza viruses, 22 October 2009]
[Isolates ? WHO Region - Number of oseltamivir-resistant isolates reported - Number of isolates or clinical specimens tested for antiviral susceptibility (a)]
- African 0 -71
- Eastern Mediterranean 0 - 45
- European 4 - 2313
- Americas 16 - 6160
- South-East Asia 0 - 20
- Western Pacific 19 - 3900
(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.
Reference:
- Drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009. Morbidity and Mortality Weekly Report, 2009, 58:433?435 (LINK, accessed October 2009).
- WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Geneva, World Health Organization, 2009 (LINK, accessed October 2009).
- Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009?2010 season. Atlanta, GA, 2009 (LINK, accessed October 2009).
- Oseltamivir-resistant novel influenza A(H1N1) virus infection in two immunosuppressed patients. Morbidity and Mortality Weekly Report, 2009, 58:893?896 (LINK, accessed October 2009).
- Hayden FG. Antiviral resistance in influenza viruses: clinical and epidemiological aspects. In: Mayers DL, ed. Antimicrobial drug resistance. New York, Humana Press, 2009:1011?1034.
- Gubareva LV et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. Journal of Infectious Diseases, 1998, 178:1257?1262.
- Oseltamivir-resistant 2009 pandemic influenza (H1N1) virus infection in two summer campers receiving prophylaxis ? North Carolina, 2009. Morbidity and Mortality Weekly Report, 2009, 58:969?972 (LINK, accessed October 2009).
- Welliver R et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. Journal of the American Medical Association, 2001, 285:748?754.
- Hayden, FG et al. Management of influenza in households: a prospective randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. Journal of Infectious Diseases, 2004, 189:440?449.
- Hayden FG et al. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. New England Journal of Medicine, 1989, 321:1696?1702.
- Van Doorn R. Influenza pandemic (H1N1) 2009 (68): Viet Nam, virus clearance. Pro-Med mail (Archive number 20091011.3519 11 October 2009 (available from LINK, accessed October 2009).
- Leung TWC et al. Detection of an oseltamivir-resistant pandemic influenza A/H1N1 virus in Hong Kong. Journal of Clinical Virology, 2009, 46:298?299.
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