The Guidelines Panel identified the following treatment outcomes as critical for developing recommendations:

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mortality;

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hospitalization;

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complications;

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serious adverse events (drug-related); and

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antiviral drug resistance.

There are no adequate data from head-to-head randomized, controlled trials directly comparing the efficacy of one antiviral medicine against another for treatment of influenza. All treatment recommendations are based on trials that compare active antiviral treatment to placebo among patients with seasonal influenza and, therefore, comparisons between treatments are indirect.

All the recommendations herein are strongly influenced by patterns of antiviral resistance. Resistance prevalence in circulating influenza strains is collated and reported by WHO.⁸ Therefore, these recommendations may need to be modified in light of current or local knowledge of the antiviral susceptibility of circulating viruses.

As of January 2010, the antiviral susceptibilities of circulating viruses are:

The Panel recommends that an antiviral should not be used for treatment where the virus is known or highly likely to be resistant to that antiviral. Since the current epidemiological data indicate an exceptionally low level of prevalence of seasonal H1N1 influenza viruses, amantadine and rimantadine are not currently recommended for use in the treatment of illness from circulating influenza virus strains, except when seasonal H1N1 virus infection is proven or strongly suspected, since all other circulating human influenza virus strains are resistant to these antivirals.

Infections with oseltamivir-resistant pandemic (H1N1) 2009 virus have been documented, comprising both sporadic cases and a limited number of clusters. While limited transmission of these viruses among contacts has been observed, there is no evidence of their wider community level or on-going circulation. WHO's assessment and conclusions on oseltamivir-resistant pandemic (H1N1) 2009 viruses, as set out in the Weekly Epidemiological Record⁹,¹⁰ include:

• All oseltamivir-resistant isolates have the same H275Y mutation that confers resistance to oseltamivir, but not zanamivir.
• No evidence of reassortment between pandemic influenza A (H1N1) 2009 and other seasonal influenza A viruses.
• No association with an altered or unexpected severity of disease, although fatalities have occurred in some severely ill patients.

The largest proportion of cases of oseltamivir resistant pandemic (H1N1) 2009 virus infection has occurred in severely immunocompromised patients. Transplant patients (and especially bone marrow or haemopoetic stem cell transplant recipients) on immunosuppressive chemotherapy have emerged as a particularly vulnerable patient group. A number of cases have also been associated with failure of post-exposure oseltamivir chemoprophylaxis.

Chemoprophylaxis is not generally recommended for the established circulating human influenza viruses, including pandemic (H1N1) 2009, as the opportunity cost and utilization of antiviral drugs that may be needed for treatment is not warranted. With the availability of vaccines for both seasonal influenza and pandemic H1N1 2009 influenza, there should now be less reliance on antiviral chemoprophylaxis for prevention of illness in close community settings and in groups such as health-care workers. The association of post exposure chemoprophylaxis failures (described above) with oseltamivir resistance is an additional consideration in reducing chemoprophylactic use of antiviral medicines. Different considerations however apply to the avian (H5N1) and other zoonotic influenza viruses¹¹.