Medication Summary
Laboratory testing has found the H1N1 influenza A (swine flu) virus susceptible to the prescription antiviral drugs oseltamivir and zanamivir. Other antiviral agents (eg, amantadine, rimantadine) are not recommended because of recent resistance to other influenza strains documented over the past several years. Limited zanamivir resistance was reported for the H1N1 influenza strain in the 2007-2009 pandemic. Oseltamivir resistance was also noted (see below).
Basic supportive care (ie, hydration, analgesics, cough suppressants) should be prescribed. Empiric antiviral treatment should be considered for confirmed, probable, or suspected cases of H1N1 influenza. Treatment of hospitalized patients and patients at higher risk for influenza complications should be prioritized.
WHO guidelines
WHO guidelines recommend treating serious cases immediately. [39] The guidelines represent an international panel of experts who reviewed all available studies regarding antiviral agents (with emphasis on oseltamivir and zanamivir). Evidence indicates that oseltamivir, when properly prescribed, significantly decreases risk of pneumonia (a leading cause of death for both pandemic and seasonal influenza) and the need for hospitalization.
In the 2009 H1N1 pandemic, oseltamivir-resistant strains were observed in a small number of patients (especially among strains bearing the H275Y mutation). Most oseltamivir resistance occurred in severely immunocompromised patients with prior exposure to oseltamivir. [40]
For patients who initially present with severe illness or whose condition begins to deteriorate, initiate oseltamivir as soon as possible. For patients with severe or deteriorating illness, treatment should be provided even if started later. Where oseltamivir is unavailable or cannot be used for any reason, zanamivir may be given. This recommendation applies to all patient groups, including pregnant women, and all age groups, including young children and infants.
For patients with underlying medical conditions that increase the risk of more severe disease, WHO recommends treatment with either oseltamivir or zanamivir. These patients should also receive treatment as soon as possible after symptom onset, without waiting for the results of laboratory tests. Pregnant women are included among groups at increased risk, and WHO recommends that pregnant women receive antiviral treatment as soon as possible after symptom onset.
At the same time, the presence of underlying medical conditions will not reliably predict all or even most cases of severe illness. Worldwide, around 40% of severe cases are now occurring in previously healthy children and adults, usually younger than 50 years. Some of these patients experience a sudden and very rapid deterioration in their clinical condition, usually on day 5 or 6 following the onset of symptoms.
Clinical deterioration is characterized by primary viral pneumonia, which destroys the lung tissue and does not respond to antibiotics, and the failure of multiple organs, including the heart, kidneys, and liver. These patients require management in intensive care units using therapies in addition to antivirals.
Peramivir, an investigational, intravenous neuraminidase inhibitor in Phase 3 clinical trials, has been used successfully in adults and children under an emergency investigational new drug program in the United States. It was well tolerated and associated with recovery in the majority of patients hospitalized with severe H1N1 infection. [41]
Baloxavir marboxil is an antiviral agent approved for the treatment of uncomplicated conventional influenza. Whether it would be an appropriate choice for the 2007-2009 pandemic H1N1 strain is unknown.
Initiate antiviral agents within 48 hours
Prompt initiation of antiviral agents within 48 hours of symptom onset is imperative for providing treatment efficacy against influenza virus. In studies of seasonal influenza, evidence for benefits of treatment is strongest when treatment is started within 48 hours of illness onset. However, some studies of treatment of seasonal influenza have indicated benefit, including reductions in mortality or duration of hospitalization, even in patients in whom treatment was started more than 48 hours after illness onset. The recommended duration of treatment is 5 days. [42, 43]
Prophylaxis with antiviral agents should also be considered in the following individuals (pre-exposure or postexposure):
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Close household contacts of a confirmed or suspected case who are at high risk for complications (eg, chronic medical conditions, persons >65 y or < 5 y, pregnant women)
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School children at high risk for complications who have been in close contact with a confirmed or suspected case
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Travelers to Mexico who are at high risk for complications (eg, chronic medical conditions, persons >65 y or < 5 y, pregnant women)
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Healthcare providers or public health workers who were not using appropriate personal protective equipment during close contact with a confirmed or suspected case
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In September 2009, the CDC updated recommendations concerning the use of antiviral medications for prevention because of reported oseltamivir resistance; antivirals should not be used for postexposure chemoprophylaxis in healthy children or adults to manage outbreaks in the community, school, camp, or other settings. [44]
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Reserve antiviral chemoprophylaxis for persons at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza.
Pre-exposure prophylaxis can be considered in the following persons:
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Any health care provider who is at high risk for complications (eg, persons with chronic medical conditions, adults >65 y, pregnant women)
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Individuals not considered to be at high risk but who are nonetheless traveling to Mexico, first responders, or border workers who are working in areas with confirmed cases
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Oseltamivir ring prophylaxis can be considered for outbreaks of pandemic H1N1 influenza A, especially among closed populations such as military personnel; ring prophylaxis involved the use of oseltamivir 75 mg once daily to members of the same military unit where contact opportunities were substantial. [45]
Pediatric considerations
Aspirin or aspirin-containing products (eg, bismuth subsalicylate [Pepto Bismol]) should not be included in the treatment of confirmed or suspected viral infection in persons aged 18 years or younger because of the risk of Reye syndrome. For relief of fever, other antipyretic medications (eg, acetaminophen, nonsteroidal anti-inflammatory drugs) are recommended.
Pregnant women
Oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinical studies have been conducted to assess the safety of these medications in pregnant women.
Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, oseltamivir or zanamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the embryo or fetus; the manufacturers' package inserts should be consulted. However, no adverse effects have been reported among women who received oseltamivir or zanamivir during pregnancy or among infants born to women who have received oseltamivir or zanamivir.
Prompt use of antiviral drugs during the 2009 H1N1 influenza pandemic improved survival among severely ill pregnant women. The CDC examined reports of severe flu (resulting in death or ICU admission) in 347 pregnant women during the pandemic, including 272 who were admitted to the ICU and survived and 75 who died. Severely ill postpartum women (n=15), including 9 who died, also were reported.
Of the 307 pregnant women for whom information regarding the presence of underlying medical conditions was available, half had underlying conditions such as asthma, diabetes, or hypertension. Among those who died, 86.1% received antiviral treatment with oseltamivir or zanamivir, compared with 94.8% of survivors. Time to initiate treatment from symptom onset was significantly different for women who died, compared with those who survived (P< .01). Only 4 women (7%) of those who died received an antiviral within 2 days of symptom onset, compared with 41% of survivors.
This analysis reaffirms the importance of prevention (ie, vaccination of pregnant women regardless of trimester) and prompt treatment with a neuraminidase inhibitor (ie, within 2 d of symptom onset) if influenza occurs during pregnancy. [33]
Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because zanamivir is an inhaled medication and has less systemic absorption, some experts prefer zanamivir over oseltamivir for use in pregnant women, when feasible. [42, 46] Others recommend that, because pregnant women may have a decreased ability to inhale zanamivir, they should be given oseltamivir.
Prevention
A systematic review and meta-analysis has reported on the immunogenicity and safety of the 2009 influenza A (H1N1) vaccine. No death or case report of Guillain-Barre syndrome was reported, and the vaccine, with or without adjuvant, appeared to be generally seroprotective after one dose among patients older than 36 months. [47]
After the initial year H1N1 influenza reappeared in 2009, the A/California/7/2009 (H1N1)pdm09-like strain has been incorporated into seasonal influenza vaccines. All persons aged 6 months or older should receive influenza vaccine annually.
Influenza vaccines are discussed more broadly in other reviews.
Antiviral Agent
Class Summary
Drugs indicated for treatment of H1N1 influenza A virus include neuraminidase inhibitors (ie, oseltamivir and zanamivir).
Oseltamivir and zanamivir inhibit neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, these agents decrease the release of viruses from infected cells and, thus, viral spread.
These antivirals are effective in the treatment of influenza A or B and must be administered within 48 hours of symptom onset to provide optimal treatment. The sooner the drug is administered after symptom onset, the better the likelihood of a good outcome. However, some studies of treatment of seasonal influenza have indicated benefit, including reductions in mortality or duration of hospitalization even for patients whose treatment was started more than 48 hours after illness onset. [42] Antivirals reduce the length of illness by an average of 1.5 days. (In a subgroup of high-risk patients, illness was reduced by 2.5 d.) In addition, the severity of symptoms is also reduced.
On October 23, 2009, the FDA announced emergency-use authorization of the investigational intravenous neuraminidase inhibitor, peramivir. In an observational study of 31 patients, intravenous peramivir was administered to patients with progressive H1N1 pneumonia despite treatment with oseltamivir. [41] Peramivir was well-tolerated, and the 56-day survival rate was 59%. Peramivir gained full FDA approval in 2014 for treatment of acute uncomplicated influenza in patients who have been symptomatic for less than 2 days.
Oseltamivir (Tamiflu)
Inhibits neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, decreases release of viruses from infected cells and thus viral spread. Effective to treat influenza A or B. Start within 40 h of symptom onset. Available as 30-mg, 45-mg, and 75-mg oral capsules and as a powder for suspension that contains 12 mg/mL after reconstitution.
Zanamivir (Relenza)
Inhibitor of neuraminidase, which is a glycoprotein on the surface of the influenza virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, release of viruses from infected cells and viral spread are decreased. Effective against both influenza A and B. Inhaled through Diskhaler oral inhalation device. Circular foil discs containing 5-mg blisters of drug are inserted into supplied inhalation device.
Individuals with asthma or other respiratory conditions that may decrease ability to inhale the drug should be given oseltamivir (eg, asthma, pregnancy). Severe respiratory failure caused by H1N1 influenza has been reported in the southern hemisphere during July and August 2009; therefore, in severely ill patients, the ability to inhale zanamivir may be impaired.
Peramivir (Rapivab)
Elicits antiviral activity by inhibiting influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. It is indicated for treatment of acute uncomplicated influenza in patients aged 6 months and older who have been symptomatic for less than 2 days.
Vaccines
Class Summary
Influenza vaccine is administered each year before flu season. The vaccines may contain either 3 virus strains (2 influenza A and 1 influenza B) or 4 virus strains (2 influenza A strains and 2 influenza B strains), which antigenically represent the influenza strains likely to circulate the next flu season, in the formulation each year. The US Food and Drug Administration (FDA) makes the final decision about vaccine strains for influenza vaccines to be sold in the United States, based on year-round surveillance conducted by the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).
Influenza virus vaccine trivalent (Fluzone, Agriflu, Flucelvax, Fluarix, Fluvirin, Fluzone High-Dose, Fluzone Intradermal)
Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The FDA determines influenza vaccine contents annually. Carefully check the indications and age ranges for various brands of influenza vaccine. For example, Fluzone is approved for children as young as 6 months, whereas Fluvirin is approved for children aged 4 years or older. Fluzone High-Dose is specifically formulated to provide a higher antigen content to evoke a stronger immune response in patients aged ≥65 years.
Influenza virus vaccine quadrivalent (Afluria Quadrivalent, Fluarix Quadrivalent, Flucelvax Quadrivalent)
Quadrivalent vaccines contain 2 strains of influenza A and 2 strains of influenza B. The vaccine induces antibodies specific to virus strains contained in the vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season. It is administered as an IM injection and approved for adults and children 3 years or older.
Influenza virus vaccine trivalent, recombinant (Flublok)
This vaccine is made from recombinant hemagglutinin proteins that are not derived from egg or chick embryo. Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The US Public Health Service determines influenza vaccine contents annually. Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year. It is administered as an IM injection and approved for adults aged 18-49 years.
Influenza virus vaccine quadrivalent, recombinant (Flublok Quadrivalent)
This vaccine is made from recombinant hemagglutinin proteins that are not derived from egg or chick embryo. Contains 4 viral strains (2 influenza A strains and 2 influenza B strains), which antigenically represent the influenza strains likely to circulate the next flu season.
Influenza virus vaccine trivalent, adjuvanted (Fluad)
Contains 3 viral strains (2 influenza A and 1 influenza B) which antigenically represent the influenza strains likely to circulate the next flu season, in the formulation each year.
Influenza virus vaccine quadrivalent, intranasal (FluMist Quadrivalent)
Discontinued for 2016/2017 Northern Hemisphere season because of low efficacy during several preceding years. The intranasal influenza vaccine is indicated for active immunization to prevent influenza A and B viruses in healthy children, adolescents, and adults. Quadrivalent vaccines contain 2 strains of influenza A and 2 strains of influenza B. The vaccine induces antibodies specific to virus strains contained in the vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season.
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This preliminary negative stained transmission electron micrograph depicts some of the ultrastructural morphology of the A/CA/4/09 swine flu virus. Courtesy of CDC/ C. S. Goldsmith and A. Balish.
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Swine influenza virus. Colorized transmission electron micrograph (37,800X) of the A/New Jersey/76 (Hsw1N1) virus under plate magnification. Image taken during the virus' first developmental passage through a chicken egg. Courtesy of the CDC/Dr. E. Palmer; R.E. Bates.
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Phase 6 criteria: In addition to the criteria defined in Phase 5, the same virus has caused sustained community-level outbreaks in at least one other country in another WHO region. Courtesy of the WHO.
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Negative stained transmission electron micrograph of recreated 1918 influenza virions. Courtesy of CDC/ Dr. Terrence Tumpey.
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This preliminary negative stained transmission electron micrograph depicts some of the ultrastructural morphology of the A/CA/4/09 swine flu virus. Courtesy of CDC/ C. S. Goldsmith and A. Balish.
