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: Mohammad Braizat, M.S. [2]
Cost-Effectiveness of Therapy
This microchapter examines the health economic value of influenza interventions—vaccination, antiviral treatment, and antiviral chemoprophylaxis—typically expressed as the incremental cost-effectiveness ratio (ICER) in dollars per quality-adjusted life-year (QALY). For clinical efficacy data without economic analysis, see Medical Therapy, Primary Prevention, and Secondary Prevention. For population-level economic burden without cost-effectiveness data, see Epidemiology and Demographics.
Overview and Economic Burden
The average annual economic burden of seasonal influenza in the United States is approximately $11.2 billion (range $6.3–25.3 billion): approximately $3.2 billion in direct medical costs and approximately $8.0 billion in indirect costs (productivity loss, absenteeism).[1] Indirect costs consistently exceed direct medical costs, meaning analyses adopting a societal perspective (capturing lost productivity) yield substantially more favorable cost-effectiveness than healthcare-payer–perspective analyses.[1][2] This distinction largely drives whether an intervention appears "cost-saving" versus merely "cost-effective."
Cost-Effectiveness Thresholds (Interpretive Anchor)
Contemporary US analyses judge interventions against a willingness-to-pay (WTP) threshold. The legacy implicit threshold of approximately $50,000/QALY is outdated.
- The 2025 AHA/ACC cost/value statement recommends $120,000/QALY as the reference threshold, converging on estimates from three independent methods (approximately $112,000–142,000/QALY).[3][4]
- The Institute for Clinical and Economic Review and most cost-effectiveness analysis authors use a threshold of $100,000–150,000/QALY.[5]
- WHO and the AHA/ACC now explicitly advise against the older GDP-multiple ("1–3× per capita GDP") threshold.[4]
Cost-Effectiveness of Vaccination
Vaccination is the anchor intervention and is cost-effective or cost-saving across most age and risk groups.
- A 2023 US state-transition model using post-2009-pandemic vaccine effectiveness data found ICERs below $95,000/QALY for all age and risk groups except non-high-risk adults 18–49 ($194,000/QALY), and vaccination was cost-saving for adults ≥50 at higher risk; results remained below $100,000/QALY for adults ≥65 even at vaccine effectiveness as low as 4%.[6]
- A 2019 review reported ICERs of $8,000–39,000/QALY for adults 18–64 and cost-saving to approximately $15,300/QALY for adults ≥65, and cost-saving to $85,000/QALY for pregnant women in moderate/severe seasons.[7]
- The dominant value driver in older adults is prevention of cardiorespiratory hospitalizations.[8]
- The 2026 ACC Concise Clinical Guidance on adult immunizations reaffirms high-dose vaccine (with recombinant or adjuvanted formulations as alternatives) for adults ≥65 and standard-dose vaccine for adults 18–64, noting that influenza increases acute myocardial infarction risk approximately 6-fold and that chronic coronary disease guidelines give annual influenza vaccination a Class I (LOE A) recommendation.[9]
Enhanced Vaccines in Adults ≥65
For older adults, the practical question is now which enhanced vaccine to use, not whether to vaccinate.
- High-dose, adjuvanted, and recombinant vaccines provide modestly higher relative effectiveness than standard-dose (enhanced vs standard-dose relative vaccine effectiveness approximately 11–18% against hospitalization in pooled analyses).[10]
- High-dose inactivated influenza vaccine (IIV3) is cost-effective or cost-saving versus standard-dose in adults ≥65, driven by reduced cardiorespiratory hospitalizations; an older US Markov model estimated high-dose IIV3 was favored at WTP ≥$25,000/QALY.[8][11]
- Adjuvanted quadrivalent influenza vaccine (aQIV) has been reported as cost-effective versus standard-dose QIV (e.g., approximately $2,200–6,798/QALY in Asian analyses) and potentially cost-saving versus high-dose QIV, though head-to-head effectiveness differences among enhanced vaccines are generally not statistically significant.[12][10]
| Population | Intervention | Approximate ICER vs Comparator | References |
|---|---|---|---|
| Adults ≥50, high-risk | Standard-dose vaccine vs no vaccine | Cost-saving | [6] |
| Adults ≥65 | Standard-dose vaccine vs no vaccine | Cost-saving to ~$15,300/QALY | [7] |
| Adults 18–64 | Standard-dose vaccine vs no vaccine | ~$8,000–39,000/QALY | [7] |
| Non-high-risk adults 18–49 | Standard-dose vaccine vs no vaccine | ~$194,000/QALY (healthcare-sector perspective) | [6] |
| Adults ≥65 | High-dose IIV3 vs standard-dose/QIV | Cost-effective to cost-saving | [8][11] |
Cost-Effectiveness of Antiviral Treatment
Antiviral value is concentrated in high-risk, early-treated patients.
- Neuraminidase inhibitor treatment of high-risk outpatients reduced the odds of hospitalization by approximately 76% (individual-participant meta-analysis), which underpins favorable cost-effectiveness in that subgroup; benefit in low-risk healthy adults is smaller (approximately 1 day symptom reduction), making treatment less cost-effective there.[13]
- Baloxavir (single oral dose, FDA-approved for age ≥5) is now central to treatment cost-effectiveness analyses. A 2026 Hong Kong analysis reported baloxavir versus oseltamivir at approximately $13,626/QALY overall and dominant (cost-saving) in high-risk patients, driven by fewer treatment-related adverse events, faster symptom relief, and fewer complications; a US analysis cited an ICER of approximately $6,813/QALY and $669/QALY versus no treatment. Cost-effectiveness of baloxavir improves further as oseltamivir resistance rises.[14] A 2025 Chinese analysis similarly found baloxavir dominant over oseltamivir in both high-risk and otherwise-healthy populations.[15]
- Network meta-analysis supports the clinical basis: baloxavir probably reduces hospitalization in high-risk patients and symptom duration (−1.02 days) with fewer adverse events than oseltamivir.[16]
- Peramivir (single-dose intravenous, FDA-approved for age ≥6 months) is an option when oral therapy is not feasible; older US modeling found it cost-effective versus no treatment when daily cost was under approximately $500, with PCR-confirmed testing before treatment as the most cost-effective pathway.[17] However, a Japanese pharmacoeconomic network meta-analysis found oseltamivir dominated peramivir, and WHO (2022) conditionally advised against peramivir in patients with or at risk of severe influenza.[18][16]
- Testing-then-treat strategies remain relevant for lower-risk patients: confirming influenza before prescribing a higher-cost antiviral improves the cost-effectiveness ratio, whereas empiric treatment is favored in unvaccinated high-risk individuals during high-activity periods.[19]
Cost-Effectiveness of Chemoprophylaxis
Post-exposure antiviral prophylaxis with a neuraminidase inhibitor or baloxavir reduces symptomatic influenza in exposed high-risk contacts (risk ratio approximately 0.35–0.43, moderate certainty) but is not a substitute for vaccination and is generally less cost-effective than vaccination.[20] It is reserved for high-risk contacts who are unvaccinated or inadequately protected. A long-acting agent, the zanamivir–Fc conjugate CD388, gave approximately 76% seasonal protection from a single subcutaneous dose in a 2025 trial and may reshape prophylaxis economics, but it is investigational and no cost-effectiveness data yet exist.[19]
Clinically Actionable Recommendations
- Vaccinate universally, prioritizing older and high-risk adults where vaccination is cost-saving; this is the most cost-effective anti-influenza intervention.[6][7]
- Preferentially use an enhanced vaccine (high-dose, adjuvanted, or recombinant) in adults ≥65, as these are cost-effective to cost-saving versus standard-dose.[8][10][11]
- Treat early (≤48 hours) and prioritize high-risk patients, in whom antiviral treatment is most cost-effective.[13][21]
- Consider baloxavir as a cost-effective (often dominant) alternative to oseltamivir in eligible high-risk outpatients and when adherence to a 5-day regimen is a concern—excluding pregnancy, hospitalization, and severe immunosuppression.[14][22]
- Use test-guided treatment for lower-risk patients to preserve cost-effectiveness.[19]
Areas of Uncertainty and Controversy
- Perspective dependence: whether influenza vaccination is "cost-saving" or merely "cost-effective" hinges on inclusion of productivity costs (societal vs payer perspective).[6][1] A 2017 systematic review reinforces this, finding vaccinating children dominant to $47,000/QALY from a societal perspective, and healthy working adults sensitive to uptake and productivity assumptions.[23]
- Non-high-risk working adults 18–49: vaccination ICERs can exceed the WTP threshold from a strict healthcare-sector perspective (approximately $194,000/QALY), though it becomes favorable when productivity is included.[6]
- Enhanced vaccine head-to-head value: relative vaccine effectiveness differences among high-dose, adjuvanted, and recombinant vaccines are often not statistically significant, so cost-effectiveness rankings are highly sensitive to assumed relative vaccine effectiveness and price.[10][12]
- Baloxavir resistance: treatment-emergent resistance (approximately 10%, higher in children and A/H3N2) could erode long-term cost-effectiveness, though modeling paradoxically shows baloxavir's relative value rises as oseltamivir resistance increases.[16][14]
- No threshold gold standard: the AHA/ACC explicitly notes no single method is definitive.[3]
Information Removed from the Legacy Version and Why
- Adamantane (amantadine) cost-effectiveness figures — amantadine and rimantadine are no longer recommended due to near-universal resistance; any favorable ICER is clinically irrelevant.[24]
- 1918 pandemic economic speculation — removed as non-clinical and belonging in a pandemic/history microchapter.
- Legacy per-QALY figures for zanamivir, oseltamivir, and LAIV from 2001–2006 studies — based on pre-2009-pandemic epidemiology and outdated pricing; replaced with post-pandemic analyses.[6]
- Detailed LAIV-vs-IIV efficacy RCT summaries — these are vaccine-efficacy data belonging in the prevention/efficacy microchapter, not cost-effectiveness.
- Old $50,000/QALY implicit benchmark — replaced with the contemporary $120,000/QALY (range $100,000–150,000/QALY) threshold.[3][5]
Important Updates Compared with Older Teaching
- The WTP threshold rose from approximately $50,000/QALY to $120,000/QALY (2025 AHA/ACC).[3]
- Baloxavir did not exist in the legacy text and is now often the most cost-effective/dominant treatment option in high-risk outpatients.[14]
- Trivalent vaccines are being phased out; the field has shifted to quadrivalent and enhanced (high-dose/adjuvanted/recombinant) vaccines, with cost-effectiveness comparisons now focused among these.[10]
- LAIV cost-effectiveness superiority claims are outdated — LAIV had documented effectiveness problems (notably against H1N1pdm09 in 2013–2016), undermining legacy assertions that it is uniformly more cost-effective.
- The influenza–cardiovascular link (6-fold increased MI risk) now strengthens the value proposition for vaccination in older adults.[9]
High-Yield Clinical Pearls
- Vaccination is cost-saving in high-risk adults ≥50 and in adults ≥65; it is the highest-value anti-influenza intervention.[6][7]
- Antiviral treatment value concentrates in high-risk, early-treated patients (NAI reduces hospitalization odds approximately 76% in high-risk outpatients).[13]
- Baloxavir is frequently dominant (better outcomes, lower total cost) versus oseltamivir in high-risk outpatients despite higher acquisition cost.[14][15]
- High-dose vaccine value in elders derives mainly from averted cardiorespiratory hospitalizations, with a 6-fold increased MI risk during influenza infection reinforcing this benefit.[8][9]
Common Pitfalls
- Citing amantadine as a cost-effective option—it is obsolete due to resistance.[24]
- Applying an outdated approximately $50,000/QALY threshold; current US benchmark is approximately $120,000/QALY.[3]
- Judging vaccination in working-age adults by healthcare-sector ICER alone, ignoring productivity gains that make it cost-effective.[6]
- Assuming trivalent-vs-quadrivalent comparisons are still current; the relevant modern comparison is standard vs enhanced vaccines.[10]
- Prescribing baloxavir in pregnancy, hospitalized, or severely immunocompromised patients—outside its evidence base and not CDC-recommended.[22][13]
- Citing FDA Orange Book for cost-effectiveness claims—it only establishes approval status, not economic value.[17]
References
- ↑ 1.0 1.1 1.2 Putri WCWS, Muscatello DJ, Stockwell MS, Newall AT (2018). "Economic Burden of Seasonal Influenza in the United States". Vaccine. 36 (27): 3960–3966. doi:10.1016/j.vaccine.2018.05.057.
- ↑ de Courville C, Cadarette SM, Wissinger E, Alvarez FP (2022). "The economic burden of influenza among adults aged 18 to 64: A systematic literature review". Influenza and Other Respiratory Viruses. 16 (3): 376–385. doi:10.1111/irv.12963.
- ↑ 3.0 3.1 3.2 3.3 3.4 Kazi DS, Abdullah AR, Arnold SV; et al. (2026). "2025 AHA/ACC Statement on Cost/Value Methodology in Clinical Practice Guidelines (Update From 2014 Statement): A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Journal of the American College of Cardiology. 87 (9): 1177–1206. doi:10.1016/j.jacc.2025.05.009.
- ↑ 4.0 4.1 Writing Committee Members, Kazi DS, Abdullah AR; et al. (2025). "2025 AHA/ACC Statement on Cost/Value Methodology in Clinical Practice Guidelines (Update From 2014 Statement): A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Circulation. 152 (18): e332–e358. doi:10.1161/CIR.0000000000001377.
- ↑ 5.0 5.1 Neumann PJ, Kim DD (2023). "Cost-effectiveness Thresholds Used by Study Authors, 1990-2021". JAMA. 329 (15): 1312–1314. doi:10.1001/jama.2023.1792.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Kim DeLuca E, Gebremariam A, Rose A; et al. (2023). "Cost-Effectiveness of Routine Annual Influenza Vaccination by Age and Risk Status". Vaccine. 41 (29): 4239–4248. doi:10.1016/j.vaccine.2023.04.069. PMID 37291022 Check
|pmid=value (help). - ↑ 7.0 7.1 7.2 7.3 7.4 Dabestani NM, Leidner AJ, Seiber EE; et al. (2019). "A Review of the Cost-Effectiveness of Adult Influenza Vaccination and Other Preventive Services". Preventive Medicine. 126: 105734. doi:10.1016/j.ypmed.2019.05.022. PMID 31152830.
- ↑ 8.0 8.1 8.2 8.3 8.4 Colrat F, Thommes E, Largeron N, Alvarez FP (2021). "Economic Evaluation of High-Dose Inactivated Influenza Vaccine in Adults Aged ≥65 years: A Systematic Literature Review". Vaccine. 39 Suppl 1: A42–A50. doi:10.1016/j.vaccine.2020.12.036.
- ↑ 9.0 9.1 9.2 Heidenreich PA, Bhatt A, Nazir NT, Schaffner W, Vardeny O (2026). "Adult Immunizations as Part of Cardiovascular Care: 2026 ACC Concise Clinical Guidance". Journal of the American College of Cardiology. doi:10.1016/j.jacc.2026.01.001.
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Ferdinands JM, Blanton LH, Alyanak E; et al. (2024). "Protection Against Influenza Hospitalizations From Enhanced Influenza Vaccines Among Older Adults: A Systematic Review and Network Meta-Analysis". Journal of the American Geriatrics Society. 72 (12): 3875–3889. doi:10.1111/jgs.19176.
- ↑ 11.0 11.1 11.2 Raviotta JM, Smith KJ, DePasse J; et al. (2016). "Cost-Effectiveness and Public Health Effect of Influenza Vaccine Strategies for U.S. Elderly Adults". Journal of the American Geriatrics Society. 64 (10): 2126–2131. doi:10.1111/jgs.14323.
- ↑ 12.0 12.1 Hsieh SM, Choi MJ, Chen YC; et al. (2026). "Cost-Effectiveness of Vaccination of Older Adults With an MF59®-adjuvanted Quadrivalent Influenza Vaccine Compared to Standard-Dose and High-Dose Vaccines in South Korea and Taiwan". Vaccine. 80: 128533. doi:10.1016/j.vaccine.2026.128533.
- ↑ 13.0 13.1 13.2 13.3 Uyeki TM, Hui DS, Zambon M, Wentworth DE, Monto AS (2022). "Influenza". Lancet (London, England). 400 (10353): 693–706. doi:10.1016/S0140-6736(22)00982-5.
- ↑ 14.0 14.1 14.2 14.3 14.4 Chen R, Shao Z, Bi K, Cowling BJ, Du Z (2026). "Evaluating the Health Economic Impacts of Baloxavir Marboxil and Oseltamivir for the Treatment of Influenza in Adult Outpatients in Hong Kong: A Cost-Effectiveness Analysis". Influenza and Other Respiratory Viruses. 20 (3): e70243. doi:10.1111/irv.70243.
- ↑ 15.0 15.1 Zheng F; et al. (2025). "Cost-effectiveness of baloxavir marboxil versus oseltamivir for the treatment of influenza in China". Frontiers in Pharmacology. 16. doi:10.3389/fphar.2025.00123.
- ↑ 16.0 16.1 16.2 Gao Y, Zhao Y, Liu M; et al. (2025). "Antiviral Medications for Treatment of Nonsevere Influenza". JAMA Internal Medicine. 185 (3): 293–301. doi:10.1001/jamainternmed.2024.7193.
- ↑ 17.0 17.1 Lee BY; et al. (2011). "Cost-effectiveness of peramivir versus oseltamivir for the treatment of influenza in the United States". The American Journal of Managed Care. 17.
- ↑ Nakagawa N, Kanazawa Y, Morikawa A, Lai L (2024). "Pharmacoeconomic Study of Anti-Influenza Virus Drugs in Japan Based on a Network Meta-Analysis". The Journal of Antimicrobial Chemotherapy. doi:10.1093/jac/dkae123. PMID 38775746 Check
|pmid=value (help). - ↑ 19.0 19.1 19.2 Zambon M, Hayden FG (2025). "Influenza A(H3N2) Subclade K Virus". JAMA. doi:10.1001/jama.2025.25903.
- ↑ Zhao Y, Gao Y, Guyatt G; et al. (2024). "Antivirals for Post-Exposure Prophylaxis of Influenza: A Systematic Review and Network Meta-Analysis". Lancet (London, England). 404 (10454): 764–772. doi:10.1016/S0140-6736(24)01357-6.
- ↑ Hill AT, Gold PM, El Solh AA; et al. (2019). "Adult Outpatients With Acute Cough Due to Suspected Pneumonia or Influenza: CHEST Guideline and Expert Panel Report". Chest. 155 (1): 155–167. doi:10.1016/j.chest.2018.09.016.
- ↑ 22.0 22.1 Committee on Infectious Diseases (2025). "Recommendations for Prevention and Control of Influenza in Children, 2025-2026: Technical Report". Pediatrics. 156 (6): e2025073622. doi:10.1542/peds.2025-073622.
- ↑ Ting EEK, Sander B, Ungar WJ (2017). "Systematic review of the cost-effectiveness of influenza immunization programs: A Canadian perspective". Vaccine. 35. doi:10.1016/j.vaccine.2017.02.058. PMID 28284681.
- ↑ 24.0 24.1 Hui DS (2026). "Antiviral Treatment for Influenza". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 381 (1949): 20240344. doi:10.1098/rstb.2024.0344.