The Medical Letter on Drugs and Therapeutics
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1589
Antiviral Drugs for Influenza
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 Select a term to see related articles  Antiviral drugs   baloxavir marboxil   FluMist   influenza   Influenza vaccine   Oseltamivir   Peramivir   Rapivab   Relenza   Tamiflu   Xofluza   Zanamivir 
Summary: Treatment of Influenza
  • Antiviral treatment is recommended for patients with suspected or confirmed influenza who are at high risk for influenza complications, for hospitalized patients, and for outpatients with severe, complicated, or progressive illness.
  • Antiviral treatment should be started as soon as possible; it is most effective when started within 48 hours of illness onset.
  • Antiviral treatment can be considered for previously healthy persons with suspected or confirmed influenza who are not at high risk for influenza complications if it can be started within 48 hours of illness onset.
  • The CDC recommends oral oseltamivir, inhaled zanamivir, IV peramivir, or oral baloxavir for treatment of nonpregnant outpatients with acute uncomplicated influenza.
  • Oseltamivir is the drug of choice for treatment of pregnant women, hospitalized patients, and outpatients with severe, complicated, or progressive influenza illness.

Influenza is generally a self-limited illness, but pneumonia, respiratory failure, and death can occur. FDA-approved antiviral drugs for influenza are listed in Table 2. The neuraminidase inhibitors oseltamivir (Tamiflu, and generics), which is taken orally, and zanamivir (Relenza), which is inhaled, are approved for prophylaxis and treatment of acute uncomplicated influenza. The IV neuraminidase inhibitor peramivir (Rapivab) and the oral polymerase acidic (PA) endonuclease inhibitor baloxavir marboxil (Xofluza) are approved only for treatment.1,2 All of these drugs are active against both influenza A and influenza B viruses. Updated information on influenza activity and antiviral resistance is available from the CDC at www.cdc.gov/flu.

INDICATIONS FOR TREATMENT — Antiviral treatment is recommended as soon as possible for any patient with suspected or confirmed influenza infection who is hospitalized, has severe, complicated, or progressive illness, or is at high risk for influenza complications (see Table 1).3-5 False negative results can occur with some influenza tests; patients with suspected influenza infection who have severe, complicated, or progressive illness or are at high risk for influenza complications should receive antiviral treatment despite a negative test result, especially when influenza is known to be circulating in the community.6

Antiviral treatment can be considered for previously healthy persons with suspected or confirmed influenza who are not at high risk for influenza complications if it can be started within 48 hours of illness onset.

CHOICE OF DRUGS — For treatment of nonpregnant outpatients with acute uncomplicated influenza, the CDC recommends oseltamivir, zanamivir, peramivir, or baloxavir. There are no data suggesting that one drug is more effective than any other in such patients. Oseltamivir is preferred for treatment of pregnant women, hospitalized patients, and outpatients with severe, complicated, or progressive influenza illness.3

PROPHYLAXIS — Antiviral prophylaxis is recommended to help control institutional influenza outbreaks. It can be considered after exposure for persons at high risk for complications who have not received influenza vaccine this season, received it within the previous 2 weeks, or are unlikely to have responded to vaccination, such as those who are immunosuppressed. Prophylaxis is not recommended for healthy persons exposed to influenza or when >48 hours have elapsed since exposure.3

For a more detailed table, click here.

EFFECTIVENESS — Treatment – Use of a neuraminidase inhibitor or baloxavir for treatment of acute uncomplicated influenza in adults shortens the duration of symptoms by about a day.7-9 A meta-analysis of randomized trials in children with influenza found that starting treatment with oseltamivir within 48 hours of symptom onset reduced illness duration by about 18 hours (by 30 hours when trials that enrolled only children with asthma were excluded) and reduced the risk of developing otitis media.10 Although most controlled trials of these drugs have not been powered to assess their efficacy in preventing serious influenza complications, experts have generally interpreted the combined results of controlled trials, observational studies, and meta-analyses as showing that early antiviral treatment of influenza in high-risk patients can reduce the risk of complications.7,11-13

In clinical trials in healthy outpatients ≥12 years old with uncomplicated influenza, administration of baloxavir within 48 hours of symptom onset shortened the duration of influenza symptoms by about a day compared to placebo; the time to alleviation of symptoms was about the same with baloxavir and oseltamivir.9 Similar results were reported in a trial in patients at high risk for influenza complications.14 No controlled trials are available on use of baloxavir for treatment of influenza in immunocompromised or hospitalized patients, or in those with severe influenza.

Prophylaxis – Neuraminidase inhibitors have generally been about 70-90% effective when used for prophylaxis against susceptible strains of influenza A or B viruses.3 In one trial (BLOCKSTONE; available only as a press release), a single dose of baloxavir was effective when used for prophylaxis, but it is not approved by the FDA for such use.

TIMING — Treatment – Neuraminidase inhibitors are most effective when started within 48 hours of illness onset, but complications of influenza can occur >48 hours after illness onset. 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 reduce the risk of complications such as pneumonia, respiratory failure, and death.15-17 Adults (outpatient or hospitalized) with community-acquired pneumonia (CAP) who test positive for influenza should receive antiviral treatment regardless of the duration of illness.18 No data are available on the efficacy of baloxavir started >48 hours after symptom onset.

Prophylaxis – When indicated, prophylaxis with oseltamivir or zanamivir should be started within 48 hours after exposure to the influenza virus and continued for 7 days after the last known exposure. For institutional outbreaks, the CDC recommends prophylaxis be given for at least 2 weeks and continued for up to 1 week after the end of the outbreak.

PREGNANCY AND LACTATION — Pregnant women are at increased risk for severe complications of influenza, including death. Oseltamivir and zanamivir appear to be safe for use during pregnancy.19,20 Prompt treatment with oseltamivir is recommended for women with suspected or confirmed influenza who are pregnant or ≤2 weeks postpartum.21-23 Oseltamivir, which is minimally excreted in breast milk, is also preferred for treatment of women who are breastfeeding. No data are available on use of baloxavir during pregnancy or while breastfeeding.

Antiviral prophylaxis can be considered for pregnant women who have had close contact with someone likely to have been infected with influenza. Zanamivir may be preferred for prophylaxis because of its limited systemic absorption, but oseltamivir is a reasonable alternative, especially in women at increased risk for respiratory problems.

RESISTANCE — Nearly all (>99%) of the recently circulating influenza virus strains tested by the World Health Organization (WHO) have been susceptible to neuraminidase inhibitors.24 Reduced susceptibility of some influenza strains, particularly influenza A(H1N1), to oseltamivir or peramivir can emerge during or after treatment, especially in immunocompromised patients with prolonged viral shedding and in young children.25-28 Resistant isolates have usually remained susceptible to zanamivir, but reduced susceptibility to zanamivir has been reported.29,30 In immunocompromised patients, use of a double dose of oseltamivir reduced the incidence of oseltamivir resistance compared to standard dosing, but it can cause more adverse effects.31

Baloxavir is active against neuraminidase inhibitor-resistant strains of influenza A and B viruses, including A(H1N1), A(H5N1), and A(H3N2). Amino acid substitutions associated with reduced susceptibility to baloxavir have occurred following treatment with a single dose.9 Reduced susceptibility to baloxavir appears to be more frequent in influenza A(H3N2) viruses and in children, and person-to-person transmission of resistant strains may occur.32,33 Baloxavir is not recommended for severely immunosuppressed patients because of concerns that prolonged replication of the influenza virus in these patients could lead to emergence of resistance. Oseltamivir and peramivir may be active against influenza strains with reduced susceptibility to baloxavir.34

ADVERSE EFFECTS — Nausea, vomiting, and headache are the most common adverse effects of oseltamivir; taking the drug with food may minimize GI adverse effects. Diarrhea, nausea, sinusitis, fever, and arthralgia have been reported with zanamivir. Inhalation of zanamivir can cause bronchospasm; the drug should not be used in patients with underlying airway disease. Diarrhea and neutropenia have occurred with peramivir. Neuropsychiatric events, including self-injury and delirium, have been reported in patients taking neuraminidase inhibitors, but a causal relationship has not been established, and neuropsychiatric dysfunction can be a complication of influenza illness.35

Baloxavir was well tolerated in clinical trials. It appears to cause less nausea and vomiting than oseltamivir.2

DRUG INTERACTIONS — Use of a neuraminidase inhibitor or baloxavir within 48 hours before or <2 weeks after administration of the intranasal live-attenuated influenza vaccine (FluMist Quadrivalent) could inhibit replication of the vaccine virus, reducing the vaccine's efficacy.

Coadministration of antacids, laxatives, multivitamins, or other products containing polyvalent cations such as calcium, aluminum, iron, magnesium, selenium, or zinc can reduce serum concentrations of baloxavir and should be avoided.

REFERENCES

  1. Peramivir (Rapivab): an IV neuraminidase inhibitor for treatment of influenza. Med Lett Drugs Ther 2015; 57:17.
  2. Baloxavir marboxil (Xofluza) for treatment of influenza. Med Lett Drugs Ther 2018; 60:193.
  3. CDC. Influenza antiviral medications: summary for clinicians. Available at: www.cdc.gov/flu. Accessed December 20, 2019.
  4. T Uyeki et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on diagnosis, treatment, chemo-prophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis 2019; 68:e1.
  5. Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2019-2020. Pediatrics 2019; 144:e20192478.
  6. CDC. Information for clinicians on influenza virus testing. Available at: www.cdc.gov. Accessed December 20, 2019.
  7. J Dobson et al. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 2015; 385:1729.
  8. IDSA. IDSA statement on neuraminidase inhibitors. Available at: http://bit.ly/34AdhEU. Accessed December 20, 2019.
  9. FG Hayden et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018; 379:913.
  10. RE Malosh et al. Efficacy and safety of oseltamivir in children: systematic review and individual patient data meta-analysis of randomized controlled trials. Clin Infect Dis 2018; 66:1492.
  11. In brief: concerns about oseltamivir (Tamiflu). Med Lett Drugs Ther 2015; 57:14.
  12. MK Doll et al. Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses. J Antimicrob Chemother 2017; 72:2990.
  13. J Katzen et al. Early oseltamivir after hospital admission is associated with shortened hospitalization: a 5-year analysis of oseltamivir timing and clinical outcomes. Clin Infect Dis 2019; 69:52.
  14. MG Ison et al. Phase 3 trial of baloxavir marboxil in high risk influenza patients (CAPSTONE-2 Study). Presented at ID Week, San Francisco, CA, Oct 3-7, 2018. Abstract LB16. Available at: http://bit.ly/2PCO3Bh. Accessed December 20, 2018.
  15. JK Louie et al. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics 2013; 132:e1539.
  16. SG Muthuri et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014; 2:395.
  17. JK Louie et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 2012; 55:1198.
  18. JP Metlay et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019; 200:e45.
  19. S Graner et al. Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study. BMJ 2017; 356:j629.
  20. V Ehrenstein et al. Oseltamivir in pregnancy and birth outcomes. BMC Infect Dis 2018; 18:519.
  21. ACOG Committee Opinion No. 753: assessment and treatment of pregnant women with suspected or confirmed influenza. Obstet Gynecol 2018; 132:e169.
  22. IK Oboho et al. Benefit of early initiation of influenza antiviral treatment to pregnant women hospitalized with laboratory-confirmed influenza. J Infect Dis 2016; 214:507.
  23. CDC. Recommendations for obstetric health care providers related to use of antiviral medications in the treatment and prevention of influenza. Available at: www.cdc.gov. Accessed December 20, 2019.
  24. A Lackenby et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016-2017. Antiviral Res 2018; 157:38.
  25. AC Hurt et al. Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J Infect Dis 2012; 206:148.
  26. C Renaud et al. H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients. Emerg Infect Dis 2011; 17:653.
  27. JW Tang et al. Transmitted and acquired oseltamivir resistance during the 2018-2019 influenza season. J Infec 2019; 79:612.
  28. R Roosenhoff et al. Viral kinetics and resistance development in children treated with neuraminidase inhibitors: the Influenza Resistance Information Study (IRIS). Clin Infec Dis 2019 Sep 27 (epub).
  29. E Takashita et al. Influenza A(H1N1)pdm09 virus exhibiting enhanced cross-resistance to oseltamivir and peramivir due to a dual H275Y/G147R substitution, Japan, March 2016. Euro Surveill 2016; 21:pii=30258.
  30. R Trebbien et al. Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, 2014. Euro Surveill 2017; 22:pii=30445.
  31. E Mitha et al. Safety, resistance, and efficacy results from a phase IIIb study of conventional- and double-dose oseltamivir regimens for treatment of influenza in immunocompromised patients. Infect Dis Ther 2019; 8:613.
  32. E Takashita et al. Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit 138T substitution detected from a hospitalized child without prior baloxavir treatment, Japan, January 2019. Euro Surveill 2019; 24:pii=1900170.
  33. E Takashita et al. Human-to-human transmission of influenza A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019. Emerging Infectious Diseases 2019; 25:2108.
  34. M Seki et al. Adult influenza A (H3N2) with reduced susceptibility to baloxavir or peramivir cured after switching anti-influenza agents. ID Cases 2019; 18:e00650.
  35. S Toovey et al. Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review. Adv Ther 2012; 29:826.
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