TREATMENT OF INFLUENZA — Antiviral treatment is recommended as soon as possible for any patient with suspected or confirmed influenza who is hospitalized, has severe, complicated, or progressive illness, or is at increased risk for complications (see Table 1), even if it is started >48 hours after illness onset.2-4 Such patients should receive antiviral treatment even if they test negative, especially when influenza viruses are known to be circulating in the community; false-negative results can occur with influenza tests, especially with rapid antigen tests and immunofluorescence assays.5

Guidelines for treatment of community-acquired pneumonia (CAP) recommend use of antiviral drugs in patients with CAP and confirmed influenza who are hospitalized, have severe or progressive illness, or are at an increased risk of complications, regardless of the time from illness onset.6

Antiviral treatment can be considered for otherwise healthy symptomatic outpatients with suspected or confirmed influenza who are not at increased risk for complications if it can be started ≤48 hours after illness onset.

Three neuraminidase inhibitors (oral oseltamivir, IV peramivir, and inhaled zanamivir) and the oral cap-dependent endonuclease inhibitor baloxavir marboxil are recommended for treatment of influenza in the US this season (see Table 2).2 Oseltamivir is preferred for treatment of influenza in pregnant women, children, hospitalized patients, and outpatients with severe, complicated, or progressive illness.2-4

Effectiveness – Neuraminidase inhibitors and baloxavir are active against influenza A and B viruses. In adults and children with acute uncomplicated influenza, they shorten the duration of symptoms by about one day.5-11 Randomized trials directly comparing these drugs for treatment of influenza are lacking, but they appear to be similar in efficacy based on available data from observational studies.9,10,12,13 Although most controlled trials of antiviral drugs have not been powered to assess their efficacy in preventing serious influenza complications, experts have generally concluded from the combined results of observational studies, controlled trials, and meta-analyses that early antiviral treatment of influenza in high-risk and hospitalized patients can reduce the risk of complications.7,9-12,14-19 In a randomized trial (available as a preprint, but not yet peer-reviewed) in critically-ill patients with severe influenza illness, use of oseltamivir was associated with a higher rate of mortality at 90 days compared to no antiviral treatment20; formal peer review of the manuscript is needed.

Prompt treatment of an index patient with baloxavir can reduce the risk of influenza transmission to household contacts.21

Timing – Neuraminidase inhibitors are most effective when started ≤48 hours after illness onset, but the results of some observational studies in hospitalized and critically ill patients suggest that treatment started as late as 4-5 days after illness onset can shorten the duration of hospitalization and reduce the risk of pneumonia, respiratory failure, and death.22-24 No data are available on the efficacy of baloxavir when started >48 hours after illness onset.

In a retrospective cohort study of 26,233 hospitalized adults with laboratory-confirmed influenza and pneumonia, delayed initiation of antiviral treatment was associated with a higher risk of death; compared to patients who started antiviral treatment on day 0, the adjusted odds ratio for death was 1.14 (95% CI 1.01-1.27) in those who started treatment on day 1 and 1.40 (95% CI 1.17-1.66) in those who started on days 2-5.25

In an observational study in 840 hospitalized adults with influenza, the risk of disease progression, ICU admission, and in-hospital death was lower with early use of oseltamivir than with no use or late use of the drug.26

View the Comparison Chart: Antiviral Drugs for Seasonal Influenza

POSTEXPOSURE PROPHYLAXIS — Postexposure antiviral prophylaxis can be considered for persons who are at very high risk of developing influenza complications and have not or cannot receive an influenza vaccine for the current season or who are expected to have an inadequate response to vaccination. It may be considered for unvaccinated persons who are household contacts of persons at very high risk of influenza complications. Postexposure antiviral prophylaxis is not recommended for healthy persons exposed to influenza or when >48 hours have elapsed since exposure.2,3

Antiviral prophylaxis with oral oseltamivir or inhaled zanamivir is recommended by the CDC for control of influenza outbreaks in institutional settings.2

Effectiveness – Postexposure prophylaxis of household contacts with oseltamivir, zanamivir, or baloxavir has reduced the risk of symptomatic influenza illness by about 70-90%, compared to placebo.2,27

Timing – Antiviral prophylaxis with oseltamivir, zanamivir, or baloxavir should be started no later than 48 hours after exposure. Oseltamivir and zanamivir should be taken for 7 days after the last known exposure. Baloxavir is taken as a single dose.

The CDC recommends postexposure prophylaxis with oral oseltamivir or inhaled zanamivir for at least 2 weeks for institutional influenza outbreaks; it should be continued for up to 1 week after the end of the outbreak.

PREGNANCY AND LACTATION — Pregnant and postpartum women are at increased risk for complications of influenza. Empiric antiviral treatment should be started as soon as possible in those with suspected or confirmed influenza. Oseltamivir is preferred for women who are pregnant, postpartum (≤2 weeks), or breastfeeding. Zanamivir and peramivir are alternatives. Baloxavir is not recommended for use in pregnant or breastfeeding women because of a lack of data.28-32

Antiviral postexposure prophylaxis can be considered for pregnant women and those who are ≤2 weeks postpartum who cannot receive an influenza vaccine or are unlikely to respond to influenza vaccination. Oseltamivir is preferred.30,31

RESISTANCE — Over 99% of recently circulating influenza virus strains tested by the World Health Organization have been susceptible to neuraminidase inhibitors and baloxavir.33 Reduced susceptibility of some influenza virus strains, particularly influenza A(H1N1) viruses, to oseltamivir or peramivir can emerge during or after treatment, especially in young children and immunocompromised patients with prolonged viral shedding.34-39 Resistant isolates have usually remained susceptible to zanamivir, but reduced susceptibility to the drug has been reported.40 In immunocompromised patients, a double dose of oseltamivir reduced the incidence of oseltamivir resistance compared to standard dosing, but it did not improve efficacy and caused more adverse effects.41

Amino acid substitutions associated with reduced susceptibility to baloxavir have occurred following treatment with a single dose of the drug.8,21,42 Reduced susceptibility to baloxavir appears to be more frequent in persons infected with influenza A(H3N2) or A(H1N1)pdm09 viruses, particularly children.33,43,44 Baloxavir monotherapy is not recommended for use in severely immunocompromised patients because of concerns that prolonged viral replication in such patients could lead to emergence of resistance.2 Oseltamivir and peramivir may be active against influenza virus strains with reduced susceptibility to baloxavir.45 Baloxavir is active against neuraminidase inhibitor-resistant strains of influenza A and B viruses, including A(H1N1), A(H5N1), A(H3N2), and A(H7N9).

ADVERSE EFFECTS — Nausea, vomiting, and headache are the most common adverse effects of oseltamivir; taking the drug with food may minimize GI adverse effects. Oseltamivir has been associated with bradycardia in critically ill patients.46 Headache, diarrhea, nausea, vomiting, bronchitis, cough, sinusitis, and ear, nose, and throat infections have been reported with zanamivir. Inhalation of zanamivir can cause bronchospasm; the drug should not be used in patients with underlying airway disease. Diarrhea, vomiting, and neutropenia have occurred with peramivir.47 Baloxavir appears to cause less nausea and vomiting than oseltamivir.48

Neuropsychiatric events, including self-injury and delirium, have been reported in patients taking neuraminidase inhibitors or baloxavir, but a causal relationship has not been established, and neuropsychiatric dysfunction can be a complication of influenza itself. In a retrospective cohort study of children 5-17 years old enrolled in Tennessee Medicaid during the 2016-2017 and 2019-2020 influenza seasons, oseltamivir use was associated with lower rates of neuropsychiatric events than untreated influenza (34.8% vs 59.9%; adjusted risk ratio 0.53, 95% CI 0.33-0.88).49

Hypersensitivity reactions, including anaphylaxis, have been reported with all of these drugs.

DRUG INTERACTIONS — Coadministration of dairy products, beverages, antacids, laxatives, multivitamins, or other products containing polyvalent cations (e.g., calcium, aluminum, iron, magnesium, selenium, zinc) can reduce serum concentrations of baloxavir and should be avoided.

USE WITH THE LIVE-ATTENUATED VACCINE — Use of oseltamivir or zanamivir within 48 hours before, peramivir within 5 days before, or baloxavir within 17 days before administration of the live-attenuated intranasal influenza vaccine (FluMist, FluMist Home) could inhibit replication of the vaccine virus, reducing the vaccine's effectiveness, and is not recommended.1 Persons who receive any of these antiviral drugs during these specified times or within 2 weeks after receiving the live-attenuated vaccine should be revaccinated with an injectable influenza vaccine.50,51

View the Comparison Chart: Antiviral Drugs for Seasonal Influenza

REFERENCES