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Use of Antivirals

Guidance on the Use of Influenza Antiviral Agents

(Current for the 2013-14 Influenza Season)

This page contains excerpts from Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza - Recommendations of the Advisory Committee on Immunization Practices (ACIP). PDF Version [1 MB, 28 pages]

The information on this page should be considered current for clinical practice regarding the use of influenza antiviral medications, along with the current summary of recommendations available at Influenza Antiviral Medications: Summary for Clinicians, and an updated list of references at Antiviral Guide References.

Treatment Efficacy and Effectiveness Studies

Randomized, controlled trials conducted primarily among persons with mild illness in outpatient settings have demonstrated that zanamivir or oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day when administered within 48 hours of illness onset compared with placebo [15, 16, 19--21, 139--142]. One randomized, controlled trial of oseltamivir treatment among 408 children aged 1--3 years reported that when oseltamivir was started within 24 hours of illness onset, the median time to illness resolution was shortened by 3.5 days compared with placebo [143]. Minimal or no benefit was reported in healthy children and adults when antiviral treatment was initiated more than 2 days after onset of uncomplicated influenza. The amount of influenza viral shedding was reduced among those treated, but studies on whether the duration of viral shedding is reduced have been inconsistent [38, 40, 144, 145] and the temporal and causal relationships between changes in influenza viral shedding and clinical outcomes have not been well-established. One evidence review concluded that neuraminidase inhibitors were not effective in reducing the severity or duration of ILI (defined as acute respiratory infection with fever and cough). However, a variety of pathogens can cause ILI besides influenza viruses, and this review did not conclude that neuraminidase inhibitors were ineffective in reducing laboratory-confirmed influenza among adults [146, 147].

Data are limited about the effectiveness of zanamivir and oseltamivir treatment in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). In a study that combined data from 10 clinical trials, the risk for pneumonia among those participants with laboratory-confirmed influenza receiving oseltamivir treatment was approximately 50% lower than among those persons receiving a placebo and 34% lower among patients at risk for complications (p is less than 0.05 for both comparisons) [22]. Although a similar significant reduction also was determined for hospital admissions among the overall group, the 50% reduction in hospitalizations reported in the small subset of high-risk participants was not statistically significant [22]. One randomized, controlled trial found a decreased incidence of otitis media among children treated with oseltamivir [21]. A randomized, controlled trial among children aged 1--3 years found an 85% reduction in acute otitis media when oseltamivir treatment was started within 12 hours of illness onset, but no reduction when treatment was started more than 24 hours from symptom onset [143]. Another randomized, controlled study conducted among influenza virus-infected children with asthma reported greater improvement in lung function and fewer asthma exacerbations among oseltamivir-treated children compared with those who received placebo but did not determine a difference in symptom duration [148]. Insufficient data exist regarding the effectiveness of any of the influenza antiviral drugs for use among children aged younger than 1 year.

Observational studies have determined that oseltamivir reduces severe clinical outcomes in patients hospitalized with influenza. A large prospective observational study assessed clinical outcomes among 327 hospitalized adults with laboratory-confirmed influenza whose health-care provider chose to use oseltamivir treatment compared with untreated influenza patients. The average age of adults in this study was 77 years, and 71% began treatment more than 48 hours after illness onset. In a multivariate analysis, oseltamivir treatment was associated with a significantly decreased risk for death within 15 days of hospitalization (odds ratio [OR] = 0.2; 95% CI = 0.1--0.8). Benefit was observed even among those starting treatment more than 48 hours after symptom onset. However, oseltamivir treatment did not reduce either the duration of hospitalization or 30-day mortality after hospitalization significantly. An additional 185 hospitalized children with laboratory-confirmed influenza were identified during this study, but none received antiviral treatment, and no assessment of outcomes based on receipt of antiviral treatment of hospitalized children could be made [23]. A study in Thailand of patients with laboratory-confirmed influenza also found a significant (OR = 0.13 (95% CI = 0.04--0.40) reduction in mortality among patients who received oseltamivir treatment [149]. A retrospective cohort study of 99 hospitalized persons (median age: 70 years) with laboratory-confirmed influenza who received oseltamivir indicated that persons who received oseltamivir treatment more than 48 hours from illness onset had a median length of stay of 6 days, compared with 4 days for persons who received oseltamivir within 48 hours of symptom onset (p is less than 0.0001) [26], and a subsequent analysis of these data showed benefit for patients who received oseltamivir up to 96 hours after illness onset [27]. A prospective study of 754 hospitalized adults (mean age: 70 years) with laboratory-confirmed seasonal influenza reported that oseltamivir treatment initiated within 2 days was associated with earlier hospital discharge, and improved survival was observed when oseltamivir was administered within 4 days from illness onset [150]. One small observational study found that treatment of persons with leukemia who acquired influenza was associated with a decreased risk for death [151].

In one observational study, oseltamivir treatment of young adults with mild illness from 2009 H1N1 virus infection was reported to reduce the development of radiographically confirmed pneumonia, and initiation of treatment within 2 days of onset reduced the duration of fever and viral RNA shedding [152]. Earlier neuraminidase inhibitor treatment was associated with less severe disease, and any neuraminidase inhibitor treatment had a survival benefit in observational studies of patients hospitalized with 2009 H1N1 virus infection [6, 12, 65, 153, 154]. However, additional data on the impact of antiviral treatment on severe outcomes are needed.

More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A virus infection than for treatment of influenza B virus infection. Data from human clinical studies have indicated that zanamivir and oseltamivir have activity against influenza B viruses [21, 116, 145, 155, 156]. However, an observational study among Japanese children with culture-confirmed influenza and treated with oseltamivir demonstrated that children with influenza A virus infection resolved fever and stopped shedding virus more quickly than children with influenza B, suggesting that oseltamivir might be less effective for the treatment of influenza B [157].

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Treatment Indications

Clinical judgment based on underlying conditions, disease severity, and time since symptom onset are also important factors in treatment decisions. Antiviral treatment is recommended as soon as possible for all persons with suspected or confirmed influenza requiring hospitalization or who have progressive, severe or complicated illness regardless of previous health or vaccination status [28, 51, 105]. In observational studies conducted among severely ill patients, both early initiation of antiviral treatment (less than 2 days from illness onset) and treatment up to less than 5 days after onset were associated with reduced morbidity and mortality, with greater benefit associated with earlier initiation of treatment [6, 7, 51]. Additional research is needed to better assess the impact of treatment, but on the basis of these limited data, treatment of severely ill patients as soon as possible is strongly recommended. Treatment should not be delayed while the results of diagnostic testing are awaited (Table 1). Empiric antiviral treatment is often necessary, and providers should not delay initiation of treatment while awaiting confirmatory diagnostic tests results or if specimens are not obtained. Patients with suspected influenza should complete antiviral treatment for a full treatment course regardless of negative initial test results unless an alternative diagnosis can be established and clinical judgment suggests that influenza is unlikely [28, 51].

Among outpatients, antiviral treatment with a neuraminidase inhibitor is recommended for all persons with suspected or confirmed influenza who are at higher risk for influenza complications because of age or underlying medical conditions (Box). Although all children aged younger than 5 years are considered at higher risk for complications from influenza, the highest risk is for those aged younger than 2 years, with the highest hospitalization and death rates among infants aged younger than 6 months. On the basis of epidemiologic studies of patients with seasonal influenza or 2009 H1N1, persons at higher risk for influenza complications who are recommended for antiviral treatment for suspected or confirmed influenza [11] include:

  • children aged younger than 2 years;
  • adults aged 65 years and older;
  • persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematological (including sickle cell disease), metabolic disorders (including diabetes mellitus) or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury);
  • persons with immunosuppression, including that caused by medications or by HIV infection;
  • women who are pregnant or postpartum (within 2 weeks after delivery);
  • persons aged younger than 19 years who are receiving long-term aspirin therapy;
  • American Indians/Alaska Natives;
  • persons who are morbidly obese (i.e., BMI is 40 or greater); and
  • residents of nursing homes and other chronic-care facilities.

Some treatment recommendations from other expert advisory groups are more definite about the need to treat all persons at higher risk for influenza complications who are suspected of having influenza, especially if the suspected cause is 2009 H1N1 virus infection. The World Health Organization (WHO) has recommended empiric neuraminidase inhibitor treatment for all persons with suspected or confirmed 2009 H1N1 virus infection who are at increased risk for influenza complications [51], and similar recommendations were made by CDC during the 2009 H1N1 pandemic and the subsequent 2009--10 influenza season [28]. IDSA recommends that all persons with laboratory-confirmed or highly suspected influenza virus infection who are at high risk for developing complications receive treatment, when treatment can begin within 48 hours after symptom onset [105]. Clinicians who prefer not to treat empirically should discuss signs and symptoms of worsening illness with such patients and arrange for follow up by telephone or in the clinic. Options for close follow-up should be considered carefully.

Clinicians should monitor local, state, and national recommendations during the influenza season to determine the most appropriate treatment practices and receive updates on antiviral resistance profiles of the circulating viruses (Table 3). A subset of the influenza viruses collected by U.S. WHO collaborating laboratories are sent to CDC for further characterization, including gene sequencing, antiviral resistance testing and antigenic characterization. This information is presented in the antiviral and antigenic characterization sections of the FluView report.

The benefits of antiviral treatment are likely to be greatest if treatment is started as soon as possible after illness onset, and evidence for benefit is strongest in studies in which treatment was started within 48 hours of illness onset. However, treatment of any person with confirmed or suspected influenza who requires hospitalization is recommended, even if the patient presents more than 48 hours after illness onset [12, 28, 51, 105]. Patients with influenza are at high risk for such secondary bacterial complications as bacterial pneumonia. Antibacterial therapy plus antiviral treatment are recommended for patients with community-acquired pneumonia when influenza also is suspected. Antibiotic treatment should be directed at likely bacterial pathogens associated with influenza such as S. pneumoniae, S. pyogenes, and S. aureus, including methicillin-resistant (MRSA), especially for hospitalized patients [158, 159]. Clinicians should consider influenza virus infection as the possible cause of any febrile respiratory illness requiring hospitalization during influenza season and consider testing for influenza and starting empiric antiviral therapy (159).

Treatment also can be considered, on the basis of clinical judgment, for outpatients with uncomplicated, suspected, or confirmed influenza who are not known to be at increased risk for developing severe or complicated illness if antiviral treatment can be initiated within 48 hours of illness onset. Persons with influenza who present with an uncomplicated febrile illness typically do not require treatment unless they are at higher risk for influenza complications, but early empiric antiviral treatment of these patients also might provide benefit (e.g., a shortened duration of illness). Persons with influenza who are already beginning to recover do not need to start treatment. Treatment decisions, especially those involving empiric treatment, should be informed by knowledge of influenza activity in the community. Empiric treatment for febrile respiratory illness when influenza activity in the community is low is likely to result in a large proportion of persons without influenza receiving unnecessary influenza antivirals. In addition, patients not at increased risk for developing severe or complicated illness and who have mild, uncomplicated illness are less likely to benefit from treatment if initiated more than 48 hours after illness onset.

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Treatment Issues for Patients Hospitalized with Suspected or Confirmed Influenza

Treatment of patients with severe influenza (e.g., those requiring hospitalization) presents multiple challenges. The effect of specific antiviral strategies in serious or life-threatening influenza is not established from clinical trials conducted to support licensure of oseltamivir and zanamivir, as those studies were conducted primarily among previously healthy outpatients with uncomplicated illness. However, a number of more recent observational studies have reported that oseltamivir treatment up to 96 hours after illness onset of patients hospitalized with suspected or confirmed influenza is associated with lower risk for severe outcomes [12, 23, 27, 65, 150]. For this reason, recommendations in this report do not necessarily represent FDA-approved uses of antiviral products but are based on published expert opinion and observational studies and are subject to change as the developmental status of investigational products and the epidemiologic and virologic features of influenza change over time.

Initiation of antiviral treatment as early as possible is recommended for hospitalized patients. However, antiviral treatment might be effective in reducing morbidity and mortality in hospitalized patients even if treatment is not started until more than 48 hours after onset of illness. Data from observational studies indicates the benefit of antiviral treatment for hospitalized persons even when treatment is delayed [12, 23, 26--28, 150]. Careful attention to ventilator and fluid management and to the prevention and treatment of secondary bacterial pneumonia (e.g., S. pneumoniae, S. pyogenes, and S. aureus, including MRSA) also is critical for severely ill patients [66, 158--161].

Treatment regimens might need to be altered to fit the clinical circumstances. For example, clinical judgment should be the guide regarding the need to extend treatment regimens longer than 5 days for patients whose illness is prolonged. No data are available to evaluate the effectiveness of larger doses of antivirals to treat severe influenza illness (e.g., viral pneumonia requiring admission to an intensive care unit), and one study indicated that enteric absorption among critically ill patients was adequate [162]. However, doubling the dose of oseltamivir (e.g., 150 mg twice daily in adults) has been advocated as an appropriate strategy in the treatment of severely ill patients with influenza A (H5N1), and limited data suggest this dosage is well tolerated [163] and might be beneficial [164].

Limited data indicate that administering oseltamivir via a gastric tube can provide systemic absorption in some critically ill patients with 2009 H1N1 or H5N1 [162, 165, 166], and these findings might be applicable to severe illness with other influenza virus infections. However, gastric stasis or bleeding can make this administration route problematic because of the potential for reduced absorption of medication [165, 167]. For these patients, parenteral medications might be preferable, but no clinical trials have demonstrated increased benefit, and none are FDA-approved. Clinical trials are needed to better understand optimal treatment approaches, and clinicians interested in enrolling patients in clinical trials of experimental intravenous antivirals and combination antiviral treatment should consult the National Institutes of Health (available at http://www.clinicaltrials.gov). For patients who are not eligible for clinical trial enrollment, physicians might wish in some instances to pursue single-patient emergency Investigational New Drug (IND) protocols for antivirals that are not licensed. Clinicians may contact the study sponsor or manufacturer to explore this possibility and obtain information about implementing an IND protocol; contact information is available at http://www.clinicaltrials.gov.

Patients receiving antiviral medications who do not respond to treatment might have an infection with an antiviral-resistant influenza virus. Oseltamivir resistance, sometimes within 1 week of treatment initiation, has been reported particularly among immunocompromised patients with 2009 H1N1 virus infection who were receiving treatment with oseltamivir [114, 168--170]. Infection-control measures are especially important for patients who are immunocompromised to reduce the risk for transmission of oseltamivir-resistant viruses [104, 105].

Investigational parenterally administered products that can be obtained via IND or other protocols in clinical trials include peramivir and zanamivir. Peramivir is an investigational neuraminidase inhibitor medication that has variable activity against influenza A and B viruses as reported in human and animal studies with small sample sizes [171, 172]. Investigational preparations of zanamivir that can be administered parenterally have been reported to reduce the likelihood of infection in a challenge model of experimental infection with influenza A virus [171, 173]. Intravenous zanamivir has been used with success in clinical settings [169, 170]. Intravenous zanamivir is the recommended antiviral treatment for severely ill patients with highly suspected or confirmed oseltamivir-resistant 2009 H1N1 virus infection [51, 169, 174].

For patients who are intubated, use of the zanamivir disc inhaler is not possible. Suboptimal delivery to sites of infection in patients with pneumonic or extrapulmonary disease is also of concern for patients with severe respiratory illness [171]. Limited experimental use of an unlicensed nebulized formulation of zanamivir has been well tolerated [175], but use of the nebulized preparation of the licensed powder formulation contained in the disc inhaler is not recommended because it has been demonstrated to clog ventilator tubing [176].

Concerns about influenza viruses with pandemic potential, the appearance and widespread transmission of 2009 pandemic influenza A (H1N1), and the limited treatment options available for severely ill patients has prompted renewed interest in development of additional antiviral drugs with activity against influenza viruses [171, 177]. Clinicians should be alert to the future availability of new therapeutic options and recommendations. In addition, careful attention to infection-control measures is recommended [104, 105], particularly in hospital areas that house immunocompromised patients.

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Postexposure Chemoprophylaxis Effectiveness

In randomized, placebo-controlled trials, both oseltamivir and zanamivir were efficacious in the prevention of influenza illness among persons administered chemoprophylaxis after a household member or other close contact had laboratory-confirmed influenza (zanamivir: 72%--82%; oseltamivir: 68%--89%) [13, 14, 17, 18, 141, 178, 179]. Postexposure chemoprophylaxis with neuraminidase inhibitors generally should be reserved for those who have had recent close contact with a person with influenza. Persons who can be considered for antiviral chemoprophylaxis include family or other close contacts of a person with a suspected or confirmed case who are at higher risk for influenza complications but have not been vaccinated against the influenza virus strains circulating at the time of exposure [28, 105]. Unvaccinated health-care workers who have occupational exposures and who did not use adequate personal protective equipment at the time of exposure are also potential candidates for chemoprophylaxis [28]. Because of widespread resistance among currently circulating influenza A virus strains and inherent nonsusceptibility among influenza B viruses, adamantanes have limited use in the prevention of influenza. Persons who receive an antiviral medication for chemoprophylaxis might still acquire influenza virus infection and be potentially able to transmit influenza virus, even if clinical illness is prevented [180, 181]. Development of illness caused by oseltamivir resistant 2009 H1N1 virus infection has been reported among persons receiving oseltamivir chemoprophylaxis [115], and one report of a small community cluster indicates that person-to-person transmission is possible among healthy persons who are not receiving oseltamivir [112].

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Postexposure Chemoprophylaxis Indications

Clinical judgment and advice from local authorities are important factors in making postexposure chemoprophylaxis decisions. Decisions on whether to administer antivirals for chemoprophylaxis should take into account the exposed person's risk for influenza complications, the type and duration of contact, recommendations from local or public health authorities, and clinical judgment. Generally, postexposure chemoprophylaxis for persons should be only used when antivirals can be started within 48 hours of the most recent exposure [28]. In areas with limited antiviral medication availability, local public health authorities might provide additional guidance about prioritizing chemoprophylaxis within groups at higher risk for complications. In certain situations, CDC or local public health authorities might recommend that antiviral medication resources be primarily directed at treatment and that antiviral chemoprophylaxis be used only in certain limited situations [28].

Chemoprophylaxis with antiviral medications is not a substitute for influenza vaccination when influenza vaccine is available. Adverse events associated with antiviral medications are generally mild and self-limited (see Adverse Events) but might result in morbidity resulting from medication side effects that outweigh the potential benefit of antiviral chemoprophylaxis [182, 183]. In addition, indiscriminate use of chemoprophylaxis might promote resistance to antiviral medications [115, 184] or reduce antiviral medication availability for treatment of persons at higher risk for influenza complications or who are severely ill [28].

Patients receiving postexposure antiviral chemoprophylaxis should be informed that chemoprophylaxis lowers but does not eliminate the risk for influenza, that susceptibility to influenza returns once the antiviral medication is stopped, and that influenza vaccination is recommended if available. Patients receiving chemoprophylaxis should be encouraged to seek medical evaluation as soon as they develop a febrile respiratory illness suggestive of influenza because influenza virus infection still can occur while a patient is on chemoprophylaxis and might indicate infection with a virus resistant to the antiviral medication used. Either oseltamivir or zanamivir is recommended for antiviral chemoprophylaxis of 2009 H1N1, influenza A (H3N2), or influenza B influenza virus infection (Table 1).

An emphasis on early treatment is an alternative to chemoprophylaxis in managing certain persons who have had a suspected exposure to influenza virus [28]. Persons with risk factors for influenza complications who are household or close contacts of persons with confirmed or suspected cases and health-care personnel who have occupational exposures can be counseled about the early signs and symptoms of influenza and advised to contact their health-care provider immediately for evaluation and possible early treatment if clinical signs or symptoms develop. Health-care providers should use clinical judgment regarding situations in which early recognition of illness and treatment might be an appropriate alternative. In some exposure circumstances (e.g., when the person exposed is at higher risk for complications of influenza virus infection), health-care providers might choose to give the exposed patient a prescription for an influenza antiviral. Providers may request that the patient contact the provider if signs or symptoms of influenza develop, obtain an antiviral medication as quickly as possible, and initiate treatment. These patients also should be counseled about influenza antiviral medication adverse events and informed that they remain susceptible to influenza virus infection after the antiviral medications are stopped.

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Preexposure Chemoprophylaxis

In community studies of healthy adults administered antiviral medications during influenza virus activity, both oseltamivir and zanamivir had similar efficacy in preventing febrile, laboratory-confirmed influenza illness (zanamivir: 84%; oseltamivir: 82%) [13, 17]. Studies also have demonstrated efficacy for prevention of influenza among patients in institutional settings [179, 185--187]. For example, a 6-week study of oseltamivir chemoprophylaxis among nursing home residents demonstrated a 92% reduction in influenza illness (185). A 4-week study among community-dwelling persons at higher risk for influenza complications (median age: 60 years) demonstrated that zanamivir had an 83% effectiveness in preventing symptomatic laboratory-confirmed influenza [188]. The efficacy of antiviral agents in preventing influenza among severely immunocompromised persons is unknown. A small nonrandomized study conducted in a stem cell transplant unit suggested that oseltamivir can prevent progression to pneumonia among influenza virus-infected patients and that therefore prevention of severe illness might be achievable with chemoprophylaxis [189].

When used, preexposure chemoprophylaxis must be administered for the duration of time when exposure might occur. The adverse events associated with long-term use are uncertain [181], and prolonged use of antivirals might select for resistance to antiviral medications. Therefore, preexposure antiviral chemoprophylaxis should be used only for persons who are at very high risk (e.g., severely immunosuppressed patients) for influenza-related complications who cannot otherwise be protected during times when a high risk for exposure exists. In the event of concern about potential shortage of antiviral medications, CDC or other health authorities might recommend prioritizing treatment of persons at higher risk for complications or who have severe influenza illness.

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Duration of Chemoprophylaxis

Postexposure chemoprophylaxis is typically administered for a total of no more than 10 days after the most recent known exposure to a close contact known to have influenza [105]. The likelihood of compliance and adverse events should be considered when determining the timing and duration for administering influenza antiviral medications for chemoprophylaxis. Failure to complete a course of oseltamivir for chemoprophylaxis because of gastrointestinal adverse events is common and might lead to antiviral resistance. In one study, only 15 (48%) of 31 primary school children and 41 (76%) of 54 secondary school children who started oseltamivir chemoprophylaxis completed a full course. Gastrointestinal adverse events (e.g., nausea and stomach discomfort) were cited as the most common reason for stopping medications before the recommended course was completed [190].

The duration of pre-exposure chemoprophylaxis based on potential exposure in the community depends on the duration of community influenza activity. Regimens as long as 28 days for zanamivir, and 42 days for oseltamivir, have been well tolerated, but no published data are available regarding use of regimens lasting more than 6 weeks (181). To be maximally effective as pre-exposure chemoprophylaxis, the drug must be taken each day for the duration of influenza activity in the community. During periods of widespread community activity and limited or no influenza vaccine availability, such as during the 2009 H1N1 pandemic, pre-exposure chemoprophylaxis has a very limited role because of concerns about antiviral medication supply, need for long-term use, and the potential for adverse events and selection for antiviral resistance.

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Considerations for Antiviral Use if Oseltamivir-Resistant Virus Strains Are Circulating

During the 2008--09 influenza season, oseltamivir resistance among circulating seasonal influenza A (H1N1) virus strains affected clinical practice by 1) presenting challenges for the selection of antiviral medications for treatment and chemoprophylaxis of influenza and 2) providing additional reasons for clinicians to test patients for influenza virus infection and to consult available influenza viral surveillance data when evaluating persons with acute respiratory illness. However, since September 2009, almost all (99%) circulating influenza A and B viruses have been susceptible to oseltamivir (seasonal influenza A [H1N1] viruses have not been detected in the United States since 2009) [191]. Information about antiviral treatment options has been outlined according to the results of influenza diagnostic testing (Table 3). Testing for antiviral resistance of influenza viruses is not routinely available in clinical settings, and many settings will not have access to influenza A virus subtyping information. CDC provides weekly updates on influenza virus surveillance at the national level. If oseltamivir-resistant viruses are not circulating, antiviral treatment for influenza should consist of either oseltamivir or zanamivir. However, continued changes in antiviral resistance are likely among influenza viruses, and clinicians should remain attentive to updates in antiviral treatment guidance.

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Considerations for Antiviral Use When Antiviral Supplies Are Limited

During widespread illness or a pandemic, demand for antivirals might exceed available supplies. When antiviral supplies are limited, recommendations for antiviral treatment and chemoprophylaxis might differ according to disease incidence, severity of illness, and likelihood for influenza-related complications. Conservation of antiviral supplies to prioritize use for those with higher risk for complications or severe illness might be necessary. Updated information on the most recent guidance for antiviral use from CDC and local public health officials should be sought during widespread illness or a pandemic, and medications should be reserved as much as possible for use in patients who are severely ill or at higher risk for complications.

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Control of Influenza Outbreaks in Institutions

Use of antiviral drugs for treatment and chemoprophylaxis of influenza is a key component of influenza outbreak control in institutions that house patients at higher risk for influenza complications. In addition to antiviral medications, other outbreak-control measures include instituting droplet and contact precautions and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccination (if available) to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients [105, 192--194]. Both adamantanes and neuraminidase inhibitors have been used successfully to control outbreaks caused by susceptible strains when antiviral medications are combined with other infection-control measures [104, 105, 192--197].

Persons who are candidates for chemoprophylaxis should be provided with medications most likely to be effective against the influenza virus that is the cause of the outbreak, if known. Respiratory specimens should be obtained from ill persons during institutional outbreaks and sent for testing to determine the virus type or subtype of influenza A virus associated with the outbreak and to guide antiviral therapy decisions. Persons whose need for chemoprophylaxis is attributed to potential exposure to a person with laboratory-confirmed 2009 H1N1, influenza A (H3N2), or influenza B should receive oseltamivir or zanamivir. Zanamivir should be used when persons require chemoprophylaxis as a result of exposure to influenza virus strains that are suspected of being oseltamivir-resistant [108].

When chemoprophylaxis is indicated, a neuraminidase inhibitor medication should be started as early as possible to reduce the spread of the virus [105]. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications. Specimens should be collected from ill persons for influenza typing, influenza A virus subtyping, or viral culture to assess antiviral resistance and provide data on the outbreak etiology. Chemoprophylaxis should be administered to all eligible residents, regardless of whether they received influenza vaccination during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 10 days after illness onset in the last patient [105]. During institutional outbreaks, chemoprophylaxis also can be offered to unvaccinated staff members who provide care to persons at high risk of complications. Chemoprophylaxis should be considered for all employees, regardless of their influenza vaccination status, if indications exist that the outbreak is caused by a strain of influenza virus that is not well matched by the vaccine. Such indications might include multiple documented breakthrough influenza-virus infections among vaccinated persons who otherwise would be expected to respond to vaccination, studies indicating low vaccine effectiveness, or circulation in the surrounding community of suspected index case(s) of strains not contained in the vaccine.

To limit the potential transmission of antiviral drug-resistant influenza virus during outbreaks in institutions, whether in chronic or acute-care settings or other closed settings, measures should be taken to reduce contact between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis. Guidelines recently published by IDSA provide a summary of the prevention and management of influenza outbreaks in institutional settings [105].

TABLE 1. Recommended dosage and schedule of influenza antiviral medications* for treatment and chemoprophylaxis§

 

Antiviral agent

Age group (yrs)

0--6

7--9

10--12

13--64

65 and older

Zanamivir

Treatment, influenza A and B

NA

10 mg (2 inhalations) twice daily

10 mg (2 inhalations) twice daily

10 mg (2 inhalations) twice daily

10 mg (2 inhalations) twice daily

Chemoprophylaxis, influenza A and B

NA for ages 1--4

Ages 5--9
10 mg (2 inhalations) once daily

10 mg (2 inhalations) once daily

10 mg (2 inhalations) once daily

10 mg (2 inhalations) once daily

Oseltamivir

Treatment,** influenza A and B

Dose varies by child's weight**

Dose varies by child's weight**

Dose varies by child's weight**

More than 40 kg = adult dose

75 mg twice daily

75 mg twice daily

Chemoprophylaxis, influenza A and B

Dose varies by child's weight††

Dose varies by child's weight††

Dose varies by child's weight††

More than 40 kg = adult dose

75 mg once daily

75 mg once daily

Abbreviation: NA = not approved

* Zanamivir is manufactured by GlaxoSmithKline (Relenza --- inhaled powder). Zanamivir is approved for treatment of persons aged 7 years and older and approved for chemoprophylaxis of persons aged 5 years and older. Zanamivir is administered through oral inhalation by using a plastic device included in the medication package. Patients will benefit from instruction and demonstration of the correct use of the device. Zanamivir is not recommended for those persons with underlying airway disease. Oseltamivir is manufactured by Roche Pharmaceuticals (Tamiflu --- tablet). Oseltamivir is approved for treatment of persons aged 2 weeks and older and for chemoprophylaxis of persons aged 1 year and older. Oseltamivir is available for oral administration in 30 mg, 45 mg, and 75 mg capsules and liquid suspension. This information is based on data published by the Food and Drug Administration (FDA).

† Recommended duration for antiviral treatment is 5 days. Longer treatment courses can be considered for patients who remain severely ill after 5 days of treatment.

§ Recommended duration of post-exposure chemoprophylaxis for high-risk patients is 7 days after the most recent known exposure if chemoprophylaxis can be started within 48 hours of exposure; however, early treatment if symptomatic is preferred. For control of outbreaks in long-term care facilities and hospitals, CDC recommends antiviral chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the most recent known case was identified

¶ See Table 4 for information about use of oseltamivir for infants aged younger than 1 year. A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance less than 30 mL/min.

** The treatment dosing recommendation for oseltamivir for children aged 2 weeks to younger than one year is 3mg/kg twice a day. The treatment dosing recommendation for oseltamivir for children aged 1 year and older who weigh 15 kg or less is 30 mg twice a day. For children who weigh more than 15 kg and up to 23 kg, the dose is 45 mg twice a day. For children who weigh more than 23 kg and up to 40 kg, the dose is 60 mg twice a day. For children who weigh more than 40 kg, the dose is 75 mg twice a day.

†† The chemoprophylaxis dosing recommendation for oseltamivir for children aged 1 year and older who weigh 15 kg or less is 30 mg once a day. For children who weigh more than 15 kg and up to 23 kg, the dose is 45 mg once a day. For children who weigh more than 23 kg and up to 40 kg, the dose is 60 mg once a day. For children who weigh more than 40 kg, the dose is 75 mg once a day.

 

TABLE 3. Recommendations for the selection of antiviral treatment using laboratory test results and viral surveillance data*

Rapid antigen, RT-PCR or other laboratory test

Preferred medication(s)†

Alternative (combination antiviral treatment)

Not performed or negative but clinical suspicion for influenza†

Oseltamivir or zanamivir

None

Positive A or positive A+B§

Oseltamivir or zanamivir

None

Positive 2009 influenza A(H1N1)

Oseltamivir or zanamivir

None

Positive A(H3N2), or B

Oseltamivir or zanamivir

None

Abbreviation: RT-PCR = reverse transcription-polymerase chain reaction.

* Antiviral recommendations might change over time. Influenza antiviral medications used for treatment are most beneficial when initiated within the first 2 days of illness. Clinicians should consult the package insert of each antiviral medication for specific dosing information, approved indications and ages, contraindications/warnings/precautions, and adverse effects.

† Influenza viral surveillance data might help guide antiviral choices if oseltamivir resistance becomes more prevalent among circulating influenza viruses. Consult guidance from local or state public health laboratories or CDC for further information regarding currently circulating viruses. CDC viral surveillance data are updated weekly during the influenza season and is available at FluView.

§ Positive A+B indicates a rapid antigen test that cannot distinguish between influenza A and influenza B viruses.

 

TABLE 4. Dosing recommendations for treatment or chemoprophylaxis of children aged younger than 1 year using oseltamivir*

Age

Recommended treatment dose for 5 days†

Recommended chemoprophylaxis†

Younger than 3 mos

3 mg/kg/dose twice daily

Not recommended unless situation judged critical because of limited data on use in this age group

3--11 mos

3 mg/kg/dose twice daily

3 mg/kg/dose once daily

* An Emergency Use Authorization (EUA) was issued by the FDA on April 28, 2009, and expired on June 23, 2010. This EUA allowed use of oseltamivir for treatment or chemoprophylaxis of 2009 pandemic influenza A (H1N1) virus infection during the pandemic in infants aged younger than 1 year. Currently circulating 2009 H1N1, seasonal influenza A (H3N2), and B viruses are susceptible to oseltamivir.

† Current weight-based dosing recommendations are not appropriate for premature infants. Premature infants might have slower clearance of oseltamivir because of immature renal function, and doses recommended for full-term infants might lead to very high drug concentrations in this age group. Very limited data from a small cohort of premature infants suggested that oseltamivir concentrations among premature infants administered oseltamivir 1 mg/kg twice daily would be similar to those observed with the recommended treatment dose in term infants (3 mg/kg twice daily). Observed drug concentrations were highly variable among premature infants. These data are insufficient to recommend a specific dose of oseltamivir for premature infants [202].

 

BOX. Summary of influenza vaccination recommendations

  • All persons aged 6 months and older should be vaccinated annually.
  • Protection of persons at higher risk for influenza-related complications should continue to be a focus of vaccination efforts.
  • When vaccine supply is limited, vaccination efforts should focus on delivering vaccination to persons who:
    • are aged 6 months--4 years (59 months);
    • are aged 50 years and older;
    • have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus);
    • are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus);
    • are or will be pregnant during the influenza season;
    • are aged 6 months--18 years and receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye syndrome after influenza virus infection;
    • are residents of nursing homes and other chronic-care facilities;
    • are American Indians/Alaska Natives;
    • are morbidly obese (body-mass index is 40 or greater);
    • are health-care personnel;
    • are household contacts and caregivers of children aged younger than 5 years and adults aged 50 years and older, with particular emphasis on vaccinating contacts of children aged younger than 6 months; and
    • are household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza.
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Selected References

Booy R, Lindley RI, Dwyer DE, Yin JK, Heron LG, Moffatt CR, Chiu CK, Rosewell AE, Dean AS, Dobbins T, Philp DJ, Gao Z, Macintyre CR. Treating and preventing influenza in aged care facilities: a cluster randomised controlled trial. PLoS One. 2012;7(10):e46509.

Chartrand C, Leeflang MM, Minion J, Brewer T, Pai M. Accuracy of rapid influenza diagnostic tests: a meta-analysis. Ann Intern Med. 2012 Apr 3;156(7):500-11.

Hsu J, Santesso N, Mustafa R, Brozek J, Chen YL, Hopkins JP, Cheung A, Hovhannisyan G, Ivanova L, Flottorp SA, Saeterdal I, Wong AD, Tian J, Uyeki TM, Akl EA, Alonso-Coello P, Smaill F, Schünemann HJ. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012 Apr 3;156(7):512-24.

Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008965.

Kimberlin DW et al., Oseltamivir pharmacokinetics, dosing, and resistance in children from birth to two years of age with influenza. Journal of Infectious Diseases 2012;epublished ahead of print.

Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, Guevara H, Uyeki TM. Treatment With Neuraminidase Inhibitors for Critically Ill Patients With Influenza A (H1N1)pdm09. Clin Infect Dis. 2012 Nov;55(9):1198-204.

Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, Louie J, Doyle TJ, Crockett M, Lynfield R, Moore Z, Wiedeman C, Anand M, Tabony L, Nielsen CF, Waller K, Page S, Thompson JM, Avery C, Springs CB, Jones T, Williams JL, Newsome K, Finelli L, Jamieson DJ; Pandemic H1N1 Influenza in Pregnancy Working Group. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. 2010 Apr 21;303(15):1517-25.

Viasus D, Paño-Pardo JR, Pachón J, Riera M, López-Medrano F, Payeras A, Fariñas MC, Moreno A, Rodríguez-Baño J, Oteo JA, Ortega L, Torre-Cisneros J, Segura F, Carratalà J; Novel Influenza A(H1N1) Study Group of the Spanish Network for Research in Infectious Diseases (REIPI). Timing of oseltamivir administration and outcomes in hospitalized adults with pandemic 2009 influenza A(H1N1) virus infection. Chest. 2011 Oct;140(4):1025-32.

Yang SG, Cao B, Liang LR, Li XL, Xiao YH, Cao ZX, Jia HY, Yu HJ, Xu Z, Gu L, Yang YD, Chen Y, Du WB, Yan XX, Liang ZA, Zhang W, Zhang CL, Chen W, Guo CP, Jiang XL, Yang M, Deng GM, Yu KJ, Hu K, Zou Q, Li LJ, Wang C; National Influenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China. Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus. PLoS One. 2012;7(1):e29652.

Yu H, Feng Z, Uyeki TM, Liao Q, Zhou L, Feng L, Ye M, Xiang N, Huai Y, Yuan Y, Jiang H, Zheng Y, Gargiullo P, Peng Z, Feng Y, Zheng J, Xu C, Zhang Y, Shu Y, Gao Z, Yang W, Wang Y. Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China. Clin Infect Dis. 2011 Feb 15;52(4):457-65.

Review the additional references cited in this guidance.

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