Avian influenza A (H5N1) virus infection

There is no standardized approach for the clinical management of humans with highly pathogenic avian influenza (HPAI) A(H5N1) virus infection. Optimal supportive care and prompt initiation of antiviral therapy are considered the mainstays of treatment.

Patients with severe illness due to HPAI A(H5N1) virus infection can present with clinical findings similar to those of pneumonia caused by other infectious etiologies. Given that human infection with HPAI A(H5N1) virus is rare (even among people with high-risk exposures), diagnostic evaluation and therapy should also consider alternative etiologies.

Avian influenza A virus infection of humans is a notifiable disease. Local or national public health departments should be contacted for guidance. Many local health departments can directly assist clinicians to determine which people need testing, to facilitate testing, and to assist with case management.

Antiviral postexposure prophylaxis for close contacts

The decision to start antiviral postexposure prophylaxis should be considered on a case-by-case basis and guided by the nature of HPAI A(H5N1) virus exposure and subsequent risk of developing infection. Local or national public health departments should be contacted for guidance.

The Centers for Disease Control and Prevention (CDC) recommends postexposure prophylaxis for asymptomatic close contacts of human cases, according to their risk of exposure (see below for categories).[131]Centers for Disease Control and Prevention. Interim guidance for follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease or with potential to cause severe human disease, and use of antiviral medications for post-exposure prophylaxis. Aug 2024 [internet publication]. https://www.cdc.gov/bird-flu/php/novel-av-chemoprophylaxis-guidance ​

• A close contact is defined as a person with close contact (within 6 feet [2 meters]) within a room or care area or other enclosed space, who had unprotected (i.e., without use of recommended personal protective equipment) exposure to a person who is a symptomatic confirmed or probable human case of novel influenza A virus infection for a prolonged period of time, or who had direct contact with infectious secretions while the case was likely to be infectious (beginning 1 day prior to illness onset and continuing until resolution of illness).

Highest-risk exposure groups

• Includes household members or other persons, including healthcare personnel, with unprotected, prolonged close contact to a symptomatic confirmed or probable case in a room or other enclosed space, including a healthcare setting.

• These people have a recognized risk of transmission, and postexposure prophylaxis is recommended.

Moderate-risk exposure groups

• Includes people with unprotected, prolonged close contact to a symptomatic confirmed or probable case outside of a room or other enclosed space. It also includes laboratory personnel with unprotected direct or close exposure to a novel influenza A virus.

• These people have a variable risk of transmission, and postexposure prophylaxis may be considered on a case-by-case basis.

Low-risk exposure groups

• Includes people and healthcare personnel wearing all recommended personal protective equipment, with prolonged close contact to a symptomatic confirmed, probable, or suspected case in a room or other enclosed space, including healthcare settings. It also includes people who are not household members (e.g., work, school, or social contacts) with a short duration of unprotected close contact to a symptomatic confirmed or probable case in a nonhospital setting outside of the home.

• Transmission is unlikely in these people, and postexposure prophylaxis is not routinely recommended.

Postexposure prophylaxis can be considered for any person who meets epidemiologic exposure criteria. The decision to start postexposure prophylaxis in low- or moderate-risk groups should be based on clinical judgment, consideration of the type of exposure, and whether the contact is at high risk for complications.[131]Centers for Disease Control and Prevention. Interim guidance for follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease or with potential to cause severe human disease, and use of antiviral medications for post-exposure prophylaxis. Aug 2024 [internet publication]. https://www.cdc.gov/bird-flu/php/novel-av-chemoprophylaxis-guidance

The CDC does not routinely recommend postexposure prophylaxis for people handling sick or potentially infected birds or other sick or dead animals or decontaminating infected environments who properly use (including removing) the recommended personal protective equipment, provided there are no breaches. However, postexposure prophylaxis and influenza A(H5) testing can be offered to asymptomatic people who experience a high risk of exposure to animals confirmed or highly suspected to be infected with HPAI A(H5N1) virus without using the recommended personal protective equipment (or if there are breaches in or failures of the recommended personal protective equipment).[41]Centers for Disease Control and Prevention. Highly pathogenic avian influenza A(H5N1) virus: interim recommendations for prevention, monitoring, and public health investigations. Dec 2024 [internet publication]. https://www.cdc.gov/bird-flu/prevention/hpai-interim-recommendations.html

The CDC recommends oral oseltamivir for postexposure prophylaxis. It is recommended for people of any age, including newborn infants, and pregnant women. Administration should begin as soon as possible, ideally within 48 hours after first exposure.[131]Centers for Disease Control and Prevention. Interim guidance for follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease or with potential to cause severe human disease, and use of antiviral medications for post-exposure prophylaxis. Aug 2024 [internet publication]. https://www.cdc.gov/bird-flu/php/novel-av-chemoprophylaxis-guidance

• Treatment should continue for 5 or 10 days. If exposure was time-limited and not ongoing, postexposure prophylaxis is recommended for 5 days from the last known exposure. If exposure is likely to be ongoing (e.g., household setting), 10 days is recommended.

• The CDC recommends that postexposure prophylaxis should be given twice daily (i.e., the treatment dosing frequency) rather than once daily (i.e., the typical seasonal influenza antiviral postexposure prophylaxis dose) because of the potential that HPAI A(H5N1) virus infection may have already occurred. However, the dose may vary depending on location, and local guidelines should be consulted.

Contacts of symptomatic confirmed or probable cases should be monitored closely for signs and symptoms of illness for up to 10 days following the date of last exposure.[131]Centers for Disease Control and Prevention. Interim guidance for follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease or with potential to cause severe human disease, and use of antiviral medications for post-exposure prophylaxis. Aug 2024 [internet publication]. https://www.cdc.gov/bird-flu/php/novel-av-chemoprophylaxis-guidance

• This includes daily assessment for acute respiratory symptoms and temperature measurement.

• Close contacts of suspected cases may also be monitored until test results are available, if resources are available to do this.

If the person develops a compatible illness during this time, the person should be referred for prompt medical evaluation and testing, and treated as a suspected case (including isolation and starting antiviral postexposure prophylaxis if not already on it).[131]Centers for Disease Control and Prevention. Interim guidance for follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease or with potential to cause severe human disease, and use of antiviral medications for post-exposure prophylaxis. Aug 2024 [internet publication]. https://www.cdc.gov/bird-flu/php/novel-av-chemoprophylaxis-guidance

• If a close contact becomes symptomatic or has worsening of symptoms during or after use of postexposure prophylaxis, appropriate infection prevention and control measures should be instituted and respiratory specimens collected for testing as soon as possible.

• If a close contact tests positive and has been taking oseltamivir postexposure prophylaxis for ≥3 days before becoming symptomatic, oseltamivir should be stopped and inhaled zanamivir or oral baloxavir initiated, as some novel influenza A viruses may rapidly become oseltamivir-resistant.

Postexposure prophylaxis may also be considered for people with recent close exposure (within approximately 6 feet [2 meters]) to A(H5) virus-infected animals.

• An exposure may include animals or animal parts, food products, contaminated surfaces, or environments (e.g., farms).

• The decision to initiate postexposure prophylaxis in these people should be based on clinical judgment, with consideration given to the type (e.g., without use or personal protective equipment) and duration of exposure, time since exposure, known infection status of bird(s) or other animals, and whether the exposed person is at higher risk for complications.

The World Health Organization (WHO) conditionally recommends using oseltamivir for asymptomatic people exposed to zoonotic influenza viruses associated with high mortality in humans or with an unknown risk of causing severe disease in the prior 2 days (based on low-quality evidence).[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759 ​ The WHO also conditionally recommends zanamivir, baloxavir, or laninamivir as other options, but the CDC does not currently recommend these agents.[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759 [131]Centers for Disease Control and Prevention. Interim guidance for follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease or with potential to cause severe human disease, and use of antiviral medications for post-exposure prophylaxis. Aug 2024 [internet publication]. https://www.cdc.gov/bird-flu/php/novel-av-chemoprophylaxis-guidance

Infection prevention and control

Patients with suspected, probable, or confirmed HPAI A(H5N1) virus infection should be isolated and local infection control recommendations should be followed. If an airborne infection isolation room (e.g., with negative pressure and HEPA filtration) is not available, the patient should be isolated in a private room.[125]Centers for Disease Control and Prevention. Interim guidance for infection control within healthcare settings when caring for confirmed cases, probable cases, and cases under investigation for infection with novel influenza A viruses associated with severe disease. Mar 2022 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-flu-infection-control/index.html

Given the potential infectiousness and virulence of HPAI A(H5N1) virus, enhanced infection control precautions are recommended, including airborne and contact precautions (with the use of eye protection), in addition to standard precautions.[125]Centers for Disease Control and Prevention. Interim guidance for infection control within healthcare settings when caring for confirmed cases, probable cases, and cases under investigation for infection with novel influenza A viruses associated with severe disease. Mar 2022 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-flu-infection-control/index.html  

There may be slight infection control recommendation differences between national public health organizations; therefore, if HPAI A(H5N1) virus infection is considered in a patient, it is recommended that clinicians consult national infection control guidelines.

Patients may be treated as outpatients or in hospital depending on disease severity and clinical presentation.

Antiviral treatment

Antiviral treatment is recommended as soon as possible for outpatients and hospitalized patients who are suspected, probable, or confirmed cases of HPAI A(H5N1) virus infection. Antiviral treatment should not be delayed by diagnostic specimen collection or laboratory testing.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​ Available evidence suggests that early diagnosis is associated with improved clinical outcomes.[132]Patel RB, Mathur MB, Gould M, et al. Demographic and clinical predictors of mortality from highly pathogenic avian influenza A (H5N1) virus infection: CART analysis of international cases. PLoS One. 2014 Mar 25;9(3):e91630. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965392 http://www.ncbi.nlm.nih.gov/pubmed/24667532?tool=bestpractice.com Antiviral therapy can be discontinued in patients who are not hospitalized and who test negative for HPAI A(H5N1) virus infection (or other influenza viruses). 

People who are asymptomatic but test positive for influenza A (H5) infection after exposure to infected animals (and who report not wearing or a breach in the recommended personal protective equipment) should be offered antiviral treatment, unless they are already receiving postexposure prophylaxis, and actively monitored for the development of signs and symptoms for 10 days after the last known exposure.[41]Centers for Disease Control and Prevention. Highly pathogenic avian influenza A(H5N1) virus: interim recommendations for prevention, monitoring, and public health investigations. Dec 2024 [internet publication]. https://www.cdc.gov/bird-flu/prevention/hpai-interim-recommendations.html

Neuraminidase inhibitors are widely available and active against all currently circulating zoonotic influenza A viruses. There are four commercially available neuraminidase inhibitors (depending on location), and they vary by route of administration, dosing and duration of treatment, contraindications, and adverse effects:

• Oseltamivir

• Zanamivir

• Peramivir

• Laninamivir.

Oral or enterically administered oseltamivir is the most widely studied and available, and it is recommended first-line in all patients with suspected, probable, or confirmed HPAI A(H5N1) virus infection.

• The WHO conditionally recommends oseltamivir for people with suspected or confirmed severe influenza virus infection, based on very low-quality evidence. This includes patients with novel influenza A virus infection associated with high mortality, or with an unknown risk of severe disease, even if they do not otherwise fulfill criteria for severe infection. Treatment should be administered as early as possible and within 2 days of onset of symptoms.[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759  

• The CDC recommends oseltamivir treatment for all hospitalized patients regardless of time since onset of illness, and all symptomatic outpatients. Oseltamivir is recommended for all patients with conjunctivitis or acute respiratory illness due to the potential for progression to severe disease, but clinical judgment may be used to decide whether to initiate treatment in untreated patients with uncomplicated disease in whom symptoms are nearly resolved and there is an absence of fever.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​ 

• Oseltamivir is recommended for people of any age, including newborn infants. It is the preferred option in pregnant women.[133]Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. Dec 2023 [internet publication]. https://www.cdc.gov/flu/hcp/antivirals/summary-clinicians.html

• No completed randomized, placebo-controlled trials exist for oseltamivir in hospitalized influenza patients. However, observational uncontrolled studies have suggested a survival benefit to early oseltamivir therapy in these patients, especially when antivirals are started early in the clinical course, or before the onset of acute respiratory distress syndrome (ARDS).​[30]Kandeel A, Manoncourt S, Abd el Kareem E, et al. Zoonotic transmission of avian influenza virus (H5N1), Egypt, 2006-2009. Emerg Infect Dis. 2010 Jul;16(7):1101-7. https://wwwnc.cdc.gov/eid/article/16/7/09-1695_article http://www.ncbi.nlm.nih.gov/pubmed/20587181?tool=bestpractice.com [32]Oner AF, Dogan N, Gasimov V, et al. H5N1 avian influenza in children. Clin Infect Dis. 2012 Jul;55(1):26-32. https://academic.oup.com/cid/article/55/1/26/317646/H5N1-Avian-Influenza-in-Children http://www.ncbi.nlm.nih.gov/pubmed/22423125?tool=bestpractice.com [82]Kandun IN, Tresnaningsih E, Purba WH, et al. Factors associated with case fatality of human H5N1 virus infections in Indonesia: a case series. Lancet. 2008 Aug 30;372(9640):744-9. http://www.ncbi.nlm.nih.gov/pubmed/18706688?tool=bestpractice.com [105]de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006 Oct;12(10):1203-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333202 http://www.ncbi.nlm.nih.gov/pubmed/16964257?tool=bestpractice.com [134]Adisasmito W, Chan PK, Lee N, et al. Effectiveness of antiviral treatment in human influenza A (H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. 2010 Oct 15;202(8):1154-60. https://academic.oup.com/jid/article/202/8/1154/926337 http://www.ncbi.nlm.nih.gov/pubmed/20831384?tool=bestpractice.com [135]Chan PK, Lee N, Zaman M, et al. Determinants of antiviral effectiveness in influenza virus A subtype H5N1. J Infect Dis. 2012 Nov;206(9):1359-66. http://www.ncbi.nlm.nih.gov/pubmed/22927451?tool=bestpractice.com

Inhaled zanamivir may be an alternative option in nonintubated patients who do not have underlying airway disease (e.g., COPD, asthma).

• The WHO suggests not administering inhaled zanamivir to people with suspected or confirmed severe influenza virus infection, based on very low-quality evidence. The recommendation is based on the very low certainty of benefit on critical outcomes of mortality, hospitalization, or intensive care unit admission, rather than on evidence of harm. The WHO acknowledges that this recommendation does not apply to situations where the causative strain is known or at high risk of being resistant to oseltamivir.[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759

• The CDC does not currently recommend inhaled zanamivir in outpatients or hospitalized patients due to a lack of data in these patients.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​ 

Other neuraminidase inhibitors may be available in certain jurisdictions.

• The WHO suggests not administering intravenous peramivir or inhaled laninamivir to patients with suspected or confirmed severe influenza virus infection, based on very low-quality evidence.[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759

• The CDC recommends intravenous peramivir as an alternative to oseltamivir only in hospitalized patients who cannot tolerate or absorb oral or enterically administered oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding. If used, a minimum of 5 days of treatment is recommended.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​ 

• Intravenous zanamivir may be available in some countries for hospitalized patients with severe or critical illness, especially if oseltamivir-resistant virus infection is suspected.

• Combination therapy with more than one neuraminidase inhibitor is not recommended because of the potential for antagonism.[136]Duval X, van der Werf S, Blanchon T, et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Med. 2010 Nov 2;7(11):e1000362. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970549 http://www.ncbi.nlm.nih.gov/pubmed/21072246?tool=bestpractice.com

Oral baloxavir is a newer antiviral agent with a different mechanism of action to neuraminidase inhibitors (selective inhibitor of influenza cap-dependent endonuclease).

• The WHO recommends considering baloxavir as an alternative to oseltamivir when oseltamivir is not available for patients with suspected or confirmed severe influenza virus infection. However, this recommendation is based on indirect evidence from nonsevere seasonal influenza and is of very low certainty.[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759

• The CDC does not currently recommend baloxavir monotherapy in outpatients or hospitalized patients due to a lack of data in these patients.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance

Recommendations for antiviral therapy are based on observational studies and indirect evidence from studies of antiviral treatment of seasonal influenza. There are no data from randomized trials in patients with novel influenza A virus infections.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance

Children may experience unique cutaneous, behavioral, and neurologic adverse events with neuraminidase inhibitors; therefore, extra caution should be used in this population.

Combination antiviral treatment with oseltamivir plus baloxavir (drugs from two different classes of medications) may be considered in immunocompromised patients and hospitalized patients due to concerns about resistance. Seek guidance from your local public health authority for antiviral treatment in patients who are immunocompromised.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​​

Most avian influenza viruses, including HPAI A(H5N1), are susceptible to neuraminidase inhibitors and baloxavir. M2 inhibitors (amantadine or rimantadine) are not recommended for the treatment of novel influenza A virus infections, including HPAI A(H5N1) virus infection, due to the high prevalence of resistance to this class of antivirals in viruses circulating among wild birds and poultry.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​​

Supportive care

Most patients admitted to the hospital with HPAI A(H5N1) virus infection have rapidly progressive viral pneumonia leading to ARDS and multi-organ failure. Patients with early recognition of disease and initiation of antiviral and supportive therapies may have improved clinical outcomes.[137]Kayali G, Webby RJ, Ducatez MF, et al. The epidemiological and molecular aspects of influenza H5N1 viruses at the human-animal interface in Egypt. PLoS One. 2011 Mar 21;6(3):e17730. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061862 http://www.ncbi.nlm.nih.gov/pubmed/21445292?tool=bestpractice.com [138]Fiebig L, Soyka J, Buda S, et al. Avian influenza A(H5N1) in humans: new insights from a line list of World Health Organization confirmed cases, September 2006 to August 2010. Euro Surveill. 2011 Aug 11;16(32):19941. https://www.eurosurveillance.org/content/10.2807/ese.16.32.19941-en http://www.ncbi.nlm.nih.gov/pubmed/21871222?tool=bestpractice.com

While there is no standardized approach for the clinical management of humans with HPAI A(H5N1) virus infection, the WHO recommends that supportive care follow published evidence-based guidelines for the clinical syndrome present (e.g., septic shock, respiratory failure, and ARDS).​[139]Arabi Y, Gomersall CD, Ahmed QA, et al. The critically ill avian influenza A (H5N1) patient. Crit Care Med. 2007 May;35(5):1397-403. http://www.ncbi.nlm.nih.gov/pubmed/17414089?tool=bestpractice.com ​

The WHO suggests not administering corticosteroids to patients with suspected or confirmed severe influenza virus infection, based on very low-quality evidence. However, there is a possibility of important benefit, especially where the clinical diagnosis overlaps with acute respiratory distress syndrome (ARDS). Corticosteroids possibly decrease mortality in the late phase of ARDS, but there was no direct evidence for patients with ARDS caused by influenza virus. The WHO also suggests not administering other adjunctive immunomodulatory therapies (macrolides, nonsteroidal anti-inflammatory drugs [NSAIDs], mTOR inhibitors, or passive immune therapy).[123]World Health Organization. Clinical practice guidelines for influenza. Sep 2024 [internet publication]. https://www.who.int/publications/i/item/9789240097759

Antiviral resistance

Where the clinical course remains severe or progressive, investigations for antiviral resistance should be performed, if possible. Emergence of oseltamivir and peramivir resistance during treatment of patients with HPAI A(H5N1) virus infection has been reported.[112]Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Sep 2024 [internet publication]. https://www.cdc.gov/bird-flu/hcp/novel-av-treatment-guidance ​​[140]de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353:2667-2672. http://www.nejm.org/doi/full/10.1056/NEJMoa054512#t=article http://www.ncbi.nlm.nih.gov/pubmed/16371632?tool=bestpractice.com [141]Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005 Oct 20;437(7062):1108. http://www.ncbi.nlm.nih.gov/pubmed/16228009?tool=bestpractice.com ​ Additionally, HPAI A(H5N1) virus infection with de novo reduced susceptibility to oseltamivir (before oseltamivir exposure) has been reported.[142]Le MT, Wertheim HF, Nguyen HD, et al. Influenza A H5N1 clade 2.3.4 virus with a different antiviral susceptibility profile replaced clade 1 virus in humans in northern Vietnam. PLoS One. 2008 Oct 6;3(10):e3339. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556101 http://www.ncbi.nlm.nih.gov/pubmed/18836532?tool=bestpractice.com Contacting local or national public health departments for information about antiviral resistance and antiviral treatment guidance is highly recommended.