Use of Flu Antivirals

Background and Guidance on the Use of Influenza Antiviral Agents

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 hospital 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. 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. 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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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.

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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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].

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].

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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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