Global Alert and Response (GAR)

Oseltamivir resistance in immunocompromised hospital patients

Pandemic (H1N1) 2009 briefing note 18

WHO has been informed of two recent clusters of patients infected with oseltamivir-resistant H1N1 viruses. Both clusters, detected in Wales, UK and North Carolina, USA, occurred in a single ward in a hospital, and both involved patients whose immune systems were severely compromised or suppressed. Transmission of resistant virus from one patient to another is suspected in both outbreaks.

The emergence of drug-resistant influenza viruses in severely immunosuppressed or immunocompromised patients undergoing antiviral treatment is not unexpected and has been well documented during seasonal influenza. 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 also been observed for the pandemic (H1N1) 2009.

Upon receipt of the reports, WHO organized a telephone conference with officials and staff from the hospitals and experts in clinical medicine, epidemiology, and virology to discuss the two outbreaks. Particular attention is being given to the best treatment options for immunocompromised patients who become infected with the pandemic virus.

The outbreaks

The Wales outbreak, which was detected in late October, involved eight patients. All of these patients were hospitalized because of severe haematological disorders. No deaths occurred. Three of these patients remain in hospital, with one being treated in intensive care.

In the USA outbreak, which involved four severely immunocompromised patients, cases occurred in a two-week period between mid-October and early November. Three of the four cases were fatal, but the role of H1N1 infection in contributing to these deaths is uncertain.

All of the resistant viruses carried the same H275Y mutation, indicating resistance to oseltamivir but susceptibility to the second antiviral drug, zanamivir.

Ongoing investigation

The outbreaks are being further investigated to determine the mode of transmission within the wards and to ensure that resistant viruses have not spread to staff, other patients in the hospitals, or into the wider community. Results to date are reassuring.

No illness in staff caring for these patients has been detected, suggesting that the resistant virus does not spread easily to otherwise healthy people, especially when good measures for infection control are in place. Moreover, intensified surveillance has found no spread to other wards within the two hospitals or into the wider community.

Modified treatment recommendations

The experts agreed that severely immunocompromised patients need to be regarded as an especially vulnerable group. These patients are highly susceptible to infection, particularly difficult to treat, and especially likely to develop resistance.

As early signs of influenza may be masked by symptoms associated with underlying disorders or their treatment, the experts further agreed that doctors treating such patients should operate with a high level of suspicion for influenza virus infection and be especially vigilant for the rapid development of oseltamivir resistance.

In these patients, standard treatment doses and duration for treatment with oseltamivir are unlikely to be sufficient. Though clinical judgement is important, doses may need to be increased and continued, without interruption, for the duration of acute illness. Zanamivir should be considered as the treatment of choice for patients who develop prolonged influenza illness despite treatment with oseltamivir.

Once oseltamivir resistant virus has been detected in a ward treating severely immunocompromised patients, doctors should consider switching to zanamivir as the antiviral drug of first choice for treatment and when considering post exposure prophylactic treatment of other patients on the ward.

The experts were emphatic in their recommendation that health care staff, carers and family contacts of patients be vaccinated against pandemic influenza.

Vigilant monitoring needed

WHO recommends vigilant monitoring for the development of oseltamivir-resistant viruses and for any changes in the transmissibility or pathogenicity of these viruses. Experience with seasonal influenza viruses shows that resistant viruses can quickly spread within the general population and become established, rendering one or more antiviral drugs ineffective.

Experience acquired since the initial characterization of the H1N1 pandemic virus in March shows that the neuraminidase inhibitors, oseltamivir and zanamivir, when administered early, reduce the risk of complications and may also improve the clinical outcome in patients with severe disease. This experience underscores the need to protect the effectiveness of these drugs by minimizing the occurrence and impact of drug resistance.

WHO received the first report of an oseltamivir-resistant pandemic virus in July. In general, cases of oseltamivir resistance have been geographically dispersed, sporadic and not linked to one another. The number of these events has been steadily increasing, in line with recent increases in influenza activity in many parts of the world and a corresponding increase in the administration of antiviral drugs.

Within the past two weeks, the number of documented cases of oseltamivir resistance in H1N1 viruses has risen from 57 to 96. Around one third of these cases occurred in patients whose immune systems were severely suppressed by haematological malignancy, aggressive chemotherapy for cancer, or post-transplant treatment. The clusters in the two hospital wards should be viewed in the context of these overall trends. Although all incidents of oseltamivir resistance merit investigation, no evidence suggests that events to date constitute a public health threat.

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