Influenza cost-effectiveness of therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2] Rebecca Cohen

Overview

Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. However, the economic impact of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.[1] Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease gross domestic product by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion.[2] Medications are available for prevaccination, chemoprophylaxis, and treatment. Vaccines range in cost per quality adjusted life year, or QALY, depending on the age and risk factors of patient from -$10,000 per QALY (cost-saving) for high-risk children up to around $100,000 per QALY for older, healthy children. [3] Vaccination and prevention of influenza cases is generally considered to be the most cost-effective manner of combating influenza. Chemoprophylaxis costs around $10,000 per QALY, though this figure varies for adamantanes and neuraminidase inhibitors. Treatment using antiviral medications can cost anywhere from $1,000 per QALY for amantadine up to around $50,000 per QALY to administer zanamivir to healthy adults. Most treatment options are still considered cost-effective when compared to no treatment.[4]

Cost-Effectiveness of Therapy Adapted from CDC [5][6]

Vaccination

  • Influenza vaccines are available in trivalent inactivated influenza forms, which protect against two strains of type A influenza virus and one type B influenza lineage, and in quadrivalent inactivated influenza forms that protect against two type A strains and both type B influenza lineages.
  • Two forms of influenza vaccines include the inactivated influenza vaccine (IIV) and the live attenuated influenza vaccine (LAIV)
  • Though quadrivalent vaccines tend to be more expensive than their trivalent counterparts, quadrivalent vaccinations will protect more people from the influenza virus inflection.
  • One study found that society could save an average of $3.1 billion if quadrivalent vaccines were used for mass vaccination instead of trivalent vaccines and the pricing of the two vaccines was the same [7].
  • If the price of quadrivalent vaccines rises, they are still cost-saving up until premiums reach about $105[7].
  • In a lifetime multi-cohort model, the quadrivalent vaccine was found to be cost-effective when compared to the trivalent vaccine, and this finding was robust even with increases in the cost of the quadrivalent vaccination [8].
  • Mathematical modeling study found that it is cost-effective to vaccinate young children, regardless of risk, and all high-risk children with influenza vaccination [3]. The health benefits derived from vaccinating high-risk children are greater than the possible adverse events in terms of QALYs for both LAIV and IIV. Risk status was found to be more important than age in determining the cost-effectiveness of vaccination.
  • In the elderly who have weaker immune systems and are at higher risk of complications or morbidity due to influenza, it is still considered to be cost saving to vaccinate against influenza[9].
  • In the event of an influenza pandemic, one mathematical modeling study examining cost-effective vaccination strategies found that the most cost-effective strategy for vaccination was variable depending on a country’s demographic characteristics or pre-existing immunity [10].
  • For example, in a nation with an aging population it may be cost-effective to vaccinate the elderly over the children who tend to transmit the virus. In general, there was evidence that vaccinating the young high-transmitters (children ages 2-19) is a cost-effective vaccination strategy. Ultimately all influenza vaccines were found to be cost-effective options compared to no vaccination.
  • Another study using a dynamic linear model found that in the case of an influenza pandemic, that prevaccination (70% of the population with a low-efficacy vaccine) or full targeted antiviral prophylaxsis (with oseltamavir) are both cost-saving strategies in the event of an influenza pandemic [11].
  • Prophylaxsis is the most cost-effective strategy to combat and influenza pandemic because it saves in medical costs and in social costs resulting from a loss of productivity.

Inactivated Influenza Vaccine

  • Using mathematical modeling, one study found administering IIVs to not high-risk children had a cost that ranged from about $12,000 per QALY for 6 month-olds to about $119,000 per QALY for 12-17 year olds [3].
  • IIV in high-risk children ranged from about -$10,000 (cost-saving) per QALY for children 6-23 months old to $1,000-$10,000 per QALY for 3-17 year olds. In not high-risk children, the benefits of this vaccine decrease with age.
  • IIVs are less effective than LAIV
  • In a randomized study of 2,229 children aged 6–17 years with asthma, 4.1% of LAIV and 6.2% of trivalent IIV recipients developed influenza, for a relative reduction of 34.7%.[12]
  • In 2004-2005 a multinational RCT was conducted among 8,352 children aged 6–59 months. For the primary endpoint in this trial, culture-confirmed influenza-like illness, there were 45% fewer cases of influenza for well-matched influenza strains and 58% fewer for mismatched strains among live versus inactivated vaccine recipients.[13]
  • One study included 2,187 children aged 6–71 months who had recurrent respiratory tract infections[14] and found overall influenza rates of 2.3% among LAIV recipients and 4.8% for trivalent IIV recipients, for a 52.7% decrease in children receiving LAIV compared to those receiving the IIV.

Live Attenuated Influenza Vaccine

  • LAIV is more expensive to produce and distribute than IIVs, but because their intranasal administration, they can be issued in more cost-effective manner, like by an authorized school nurse or employee health office instead of a primary care physician [9].
  • A study modeling the cost-effectiveness of the LAIV found that vaccination children ages 2-18 had a cost of $392 (£251) per QALY and is therefore within the threshold of cost-effective vaccinations [9].
  • Vaccinating children with LAIV is cost-effective due in part to herd immunity to individuals who are at-risk of infection and due to hospitalizations averted because children are the primary vectors transmitting the virus to high-risk individuals.
  • Even with rates of vaccination of children as low as 10%, the policy was still found to be cost-effective and with vaccination rates as high as 90%, the policy was still found to be cost saving.
  • Another study found LAIV had a cost between $8,648 per QALY for 6 month olds to $109,000 per QALY for 12-17 year olds [3]
  • LAIV is more expensive than trivalent vaccines, but is a more cost-effective vaccine because it is more effective at preventing people from contracting the virus and thus reduces physician visits and hospitalizations[9][15]. This finding was robust to changes in the price of LAIV and the trivalent vaccine or with changes in the risks associated with the vaccination.
  • LAIV too expensive for annual vaccination of healthy adults in terms of cost-effectiveness [4]
  • A RCT conducted among 1,602 healthy children initially aged 15–71 months assessed the efficacy of trivalent LAIV against culture-confirmed influenza during two seasons.[16]
  • In season one, when vaccine and circulating virus strains were well-matched, efficacy in preventing laboratory-confirmed illness from influenza was 93% for participants who received two doses of LAIV.
  • In season two, when the A (H3N2) component was not well-matched between vaccine and circulating virus strains, efficacy was 86% overall.
  • A randomized, double-blind, placebo-controlled trial among 4,561 healthy working adults aged 18–64 years assessed multiple endpoints (i.e., targeted outcome measures), including reductions in self-reported respiratory tract illness without laboratory confirmation, absenteeism, health care visits, use of antibiotics, and use of over-the-counter medications for illness symptoms during peak and total influenza outbreak periods[17]). The study was conducted during the 1997-1998 influenza season, when the influenza vaccine and circulating A (H3N2) viruses were poorly matched. LAIV vaccination was associated with reductions in severe febrile illnesses of 19%, and febrile upper respiratory tract illnesses of 24%.
  • Vaccination was also associated with fewer days of illness, fewer days of work lost, fewer days with health care provider visits, and reduced use of prescription antibiotics and over-the-counter medications. Among a subset of 3,637 healthy adults aged 18–49 years, LAIV recipients (n = 2,411) had 26% fewer febrile upper-respiratory illness episodes; 27% fewer lost work days as a result of febrile upper respiratory illness; and 18%–37% fewer days of health care provider visits caused by febrile illness, compared with placebo recipients (n = 1,226). Days of antibiotic use were reduced by 41%–45% in this age subset.

Chemoprophylaxis

  • 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 [18]. They are not a substitute for influenza vaccination.
  • 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 [18].
  • 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.[19][20]
  • Annual vaccination saves $41,000 per QALY compared to chemoprophylaxis[4]. Despite this, chemoprophylaxis is more cost-effective than no intervention for preventing influenza viral infection.

Adamantanes

  • Because of widespread resistance among currently circulating influenza A virus strains and inherent non-susceptibility among influenza B viruses, adamantanes have limited use in the prevention of influenza.
  • Amantadine ranges in cost per QALY from $7,066 (£4,535) per QALY for high-risk patients (over 65 or immunosuppressed) to $9,645 (£6,190) for healthy adults, meaning it is a cost-effective form of prophylaxis.
  • It is a relatively inexpensive form of prophylaxis, but because of side effects and its low efficacy in targeting type B influenza lineages, it is not always preferred.

Neuraminidase Inhibitors

  • Postexposure chemoprophylaxis with neuraminidase inhibitors generally should be reserved for those who have had recent close contact with a person with influenza.
  • Zanamivir may be a more cost-effective form of prophylaxis compared to oseltamivir (more inexpensive, less adverse side effects), but still has a higher cost-effectiveness ratio than vaccination, likely due to problems in effectiveness in patient-administration of the medication.
  • 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%)[21][22][23][24][25][26].

Treatment

  • 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 [27][28][29][30][31] and the temporal and causal relationships between changes in influenza viral shedding and clinical outcomes have not been well-established.
  • Insufficient data exist regarding the effectiveness of any of the influenza antiviral drugs for use among children aged younger than 1 year.
  • 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.[32]

Adamantanes

  • One study found that in older adults, compared to no intervention, amantadine cost $1,129 per quality adjusted life year, or QALY [4]. Because of the medication's low cost, it is cost-effective to administer ion channel inhibitors empirically to patients with low ability to pay [33]. Prevaccination, however is still more cost-effective.

Neuraminidase Inhibitors

  • 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).
  • Neuraminidase inhibitors such as oseltamivir and zanamivir are more expensive forms of antiviral treatment, but they are good options for high-risk unvaccinated patients.
  • Because of their high price, if a patient is low-risk and vaccinated, they should undergo rapid diagnosis before reviewing oseltamivir or zanamivir as treatment [33].
  • Oseltamivir ranges in cost per QALY from $29,629 (£19,015) per QALY for healthy adults to $35,063 (£22,502) for high risk population [4]. Because of this high cost-effectiveness ratio, oseltamivir is less cost-effective than vaccination.
  • In a study of adults older than 75, diagnostic testing and then (if necessary) administeration of oseltamavir cost $5,025 per QALY compared to no vaccination[33]. However, when administering the drug based on empirical evidence, there was a cost of $10,296 per QALY. Oseltamivir may therefore be a cost-effective candidate for empirical treatment of unvaccinated, high-risk individuals.
  • 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.
  • 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).[34]
  • 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.[34]
  • One randomized, controlled trial found a decreased incidence of otitis media among children treated with oseltamivir. [35]
  • Zanamivir ranges in cost per QALY from $26,207 (£16,819) for the elderly to $49,128 (£31,529) for healthy adults[4]. Another study found lower, though still high relative to vaccination, cost effectiveness ratios of $11,671 (£7,490) including inpatient costs[36]. Both findings indicate that Zanamivir is still less cost-effective than vaccination.
  • 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[37][38][39][35]
  • Rapivab, or peramivir, an intravenous emergency treatment for influenza, costs less than $10,000 per QALY compared to no treatment when the treatment cost less than $500 per day, making it a cost-effective treatment [40]. This computer simulation model finding was robust to changes in drug efficacy, influenza strain, etc. The most cost-effective manner of administration was found to be PCR testing to confirm influenza, followed by treatment with peramivir.

References

  1. ↑ Brainerd, E. and M. Siegler (2003), “The Economic Effects of the 1918 Influenza Epidemic”, CEPR Discussion Paper, no. 3791.
  2. ↑ Poland G (2006). "Vaccines against avian influenza—a race against time". N Engl J Med. 354 (13): 1411–3. PMID 16571885.
  3. ↑ 3.0 3.1 3.2 3.3 Prosser LA, Bridges CB, Uyeki TM, Hinrichsen VL, Meltzer MI, Molinari NA; et al. (2006). "Health benefits, risks, and cost-effectiveness of influenza vaccination of children". Emerg Infect Dis. 12 (10): 1548–58. doi:10.3201/eid1210.051015. PMC 3290928. PMID 17176570.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Rothberg MB, Rose DN (2005). "Vaccination versus treatment of influenza in working adults: a cost-effectiveness analysis". Am J Med. 118 (1): 68–77. doi:10.1016/j.amjmed.2004.03.044. PMID 15639212.
  5. ↑ "CDC Flu Vaccine Effectiveness".
  6. ↑ "CDC Guidance on the Use of Influenza Antiviral Agents".
  7. ↑ 7.0 7.1 Lee BY, Bartsch SM, Willig AM (2012). "The economic value of a quadrivalent versus trivalent influenza vaccine". Vaccine. 30 (52): 7443–6. doi:10.1016/j.vaccine.2012.10.025. PMC 3696129. PMID 23084849.
  8. ↑ Van Bellinghen LA, Meier G, Van Vlaenderen I (2014). "The potential cost-effectiveness of quadrivalent versus trivalent influenza vaccine in elderly people and clinical risk groups in the UK: a lifetime multi-cohort model". PLoS One. 9 (6): e98437. doi:10.1371/journal.pone.0098437. PMC 4048201. PMID 24905235.
  9. ↑ 9.0 9.1 9.2 9.3 Pitman RJ, Nagy LD, Sculpher MJ (2013). "Cost-effectiveness of childhood influenza vaccination in England and Wales: Results from a dynamic transmission model". Vaccine. 31 (6): 927–42. doi:10.1016/j.vaccine.2012.12.010. PMID 23246550.
  10. ↑ Lugnér AK, van Boven M, de Vries R, Postma MJ, Wallinga J (2012). "Cost effectiveness of vaccination against pandemic influenza in European countries: mathematical modelling analysis". BMJ. 345: e4445. doi:10.1136/bmj.e4445. PMC 3395306. PMID 22791791.
  11. ↑ Sander B, Nizam A, Garrison LP, Postma MJ, Halloran ME, Longini IM (2009). "Economic evaluation of influenza pandemic mitigation strategies in the United States using a stochastic microsimulation transmission model". Value Health. 12 (2): 226–33. doi:10.1111/j.1524-4733.2008.00437.x. PMC 3710126. PMID 18671770.
  12. ↑ Fleming DM, Crovari P, Wahn U, Klemola T, Schlesinger Y, Langussis A; et al. (2006). "Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma". Pediatr Infect Dis J. 25 (10): 860–9. doi:10.1097/01.inf.0000237797.14283.cf. PMID 17006278.
  13. ↑ Belshe RB, Edwards KM, Vesikari T, Black SV, Walker RE, Hultquist M; et al. (2007). "Live attenuated versus inactivated influenza vaccine in infants and young children". N Engl J Med. 356 (7): 685–96. doi:10.1056/NEJMoa065368. PMID 17301299.
  14. ↑ Ashkenazi S, Vertruyen A, Arístegui J, Esposito S, McKeith DD, Klemola T; et al. (2006). "Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections". Pediatr Infect Dis J. 25 (10): 870–9. doi:10.1097/01.inf.0000237829.66310.85. PMID 17006279.
  15. ↑ Tarride JE, Burke N, Von Keyserlingk C, O'Reilly D, Xie F, Goeree R (2012). "Cost-effectiveness analysis of intranasal live attenuated vaccine (LAIV) versus injectable inactivated influenza vaccine (TIV) for Canadian children and adolescents". Clinicoecon Outcomes Res. 4: 287–98. doi:10.2147/CEOR.S33444. PMC 3468276. PMID 23055756.
  16. ↑ Longini IM, Halloran ME, Nizam A, Wolff M, Mendelman PM, Fast PE; et al. (2000). "Estimation of the efficacy of live, attenuated influenza vaccine from a two-year, multi-center vaccine trial: implications for influenza epidemic control". Vaccine. 18 (18): 1902–9. PMID 10699339.
  17. ↑ Nichol KL (1999). "Influenza vaccination for healthy working adults". Minn Med. 82 (11): 24–6. PMID 10589210.
  18. ↑ 18.0 18.1 "CDC. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009--10 season. Atlanta, GA: US Department of Health and Human Services, CDC; 2009. Available at http://www.cdc.gov/H1N1flu/recommendations.htm". External link in |title= (help); Missing or empty |url= (help)
  19. ↑ Lee, Vernon J; Yap, Jonathan; Tay, Joshua K; Barr, Ian; Gao, Qiuhan; Ho, Hanley J; Tan, Boon; Kelly, Paul M; Tambyah, Paul A; Kelso, Anne; Chen, Mark I (2010). "Seroconversion and asymptomatic infections during oseltamivir prophylaxis against Influenza A H1N1 2009". BMC Infectious Diseases. 10 (1): 164. doi:10.1186/1471-2334-10-164. ISSN 1471-2334.
  20. ↑ Khazeni N, Bravata DM, Holty JE, Uyeki TM, Stave CD, Gould MK (2009). "Systematic review: safety and efficacy of extended-duration antiviral chemoprophylaxis against pandemic and seasonal influenza". Ann Intern Med. 151 (7): 464–73. PMID 19652173. Review in: Ann Intern Med. 2010 Mar 16;152(6):JC3-3
  21. ↑ Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D; et al. (1999). "Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza". N Engl J Med. 341 (18): 1336–43. doi:10.1056/NEJM199910283411802. PMID 10536125.
  22. ↑ Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM; et al. (2000). "Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group". N Engl J Med. 343 (18): 1282–9. doi:10.1056/NEJM200011023431801. PMID 11058672.
  23. ↑ Eiland LS, Eiland EH (2007). "Zanamivir for the prevention of influenza in adults and children age 5 years and older". Ther Clin Risk Manag. 3 (3): 461–5. PMC 2386359. PMID 18488077.
  24. ↑ Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J; et al. (2001). "Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial". JAMA. 285 (6): 748–54. PMID 11176912.
  25. ↑ Monto AS, Webster A, Keene O (1999). "Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis". J Antimicrob Chemother. 44 Suppl B: 23–9. PMID 10877459.
  26. ↑ Monto AS, Pichichero ME, Blanckenberg SJ, Ruuskanen O, Cooper C, Fleming DM; et al. (2002). "Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households". J Infect Dis. 186 (11): 1582–8. doi:10.1086/345722. PMID 12447733.
  27. ↑ Carrat F, Vergu E, Ferguson NM, Lemaitre M, Cauchemez S, Leach S; et al. (2008). "Time lines of infection and disease in human influenza: a review of volunteer challenge studies". Am J Epidemiol. 167 (7): 775–85. doi:10.1093/aje/kwm375. PMID 18230677.
  28. ↑ Cowling BJ, Chan KH, Fang VJ, Lau LL, So HC, Fung RO; et al. (2010). "Comparative epidemiology of pandemic and seasonal influenza A in households". N Engl J Med. 362 (23): 2175–84. doi:10.1056/NEJMoa0911530. PMC 4070281. PMID 20558368.
  29. ↑ Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE (1998). "Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense". J Clin Invest. 101 (3): 643–9. doi:10.1172/JCI1355. PMC 508608. PMID 9449698.
  30. ↑ Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M; et al. (1999). "Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment". JAMA. 282 (13): 1240–6. PMID 10517426.
  31. ↑ Sato M, Hosoya M, Kato K, Suzuki H (2005). "Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors". Pediatr Infect Dis J. 24 (10): 931–2. PMID 16220098.
  32. ↑ Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A (2006). "Antivirals for influenza in healthy adults: systematic review". Lancet. 367 (9507): 303–13. doi:10.1016/S0140-6736(06)67970-1. PMID 16443037. Review in: Evid Based Nurs. 2006 Oct;9(4):108 Review in: ACP J Club. 2006 Sep-Oct;145(2):45 Review in: Evid Based Med. 2006 Oct;11(5):141
  33. ↑ 33.0 33.1 33.2 Rothberg MB, Bellantonio S, Rose DN (2003). "Management of influenza in adults older than 65 years of age: cost-effectiveness of rapid testing and antiviral therapy". Ann Intern Med. 139 (5 Pt 1): 321–9. PMID 12965940.
  34. ↑ 34.0 34.1 Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F (2003). "Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations". Arch Intern Med. 163 (14): 1667–72. doi:10.1001/archinte.163.14.1667. PMID 12885681.
  35. ↑ 35.0 35.1 Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D; et al. (2001). "Oral oseltamivir treatment of influenza in children". Pediatr Infect Dis J. 20 (2): 127–33. PMID 11224828.
  36. ↑ Griffin AD, Perry AS, Fleming DM (2001). "Cost-effectiveness analysis of inhaled zanamivir in the treatment of influenza A and B in high-risk patients". Pharmacoeconomics. 19 (3): 293–301. PMID 11303417.
  37. ↑ Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG; et al. (1997). "Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group". N Engl J Med. 337 (13): 874–80. doi:10.1056/NEJM199709253371302. PMID 9302301.
  38. ↑ Monto AS, Fleming DM, Henry D, de Groot R, Makela M, Klein T; et al. (1999). "Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections". J Infect Dis. 180 (2): 254–61. doi:10.1086/314904. PMID 10395837.
  39. ↑ Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH; et al. (2000). "Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group". Lancet. 355 (9218): 1845–50. PMID 10866439.
  40. ↑ Lee BY, Tai JH, Bailey RR, McGlone SM, Wiringa AE, Zimmer SM; et al. (2011). "Economic model for emergency use authorization of intravenous peramivir". Am J Manag Care. 17 (1): e1–9. PMC 3763185. PMID 21485418.

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