Influenza treatment with neuraminidase inhibitors: cost-effectiveness and cost-utility in healthy adults in the United Kingdom.

We assessed the cost-effectiveness and cost-utility of treating influenza with neuraminidase inhibitors (oseltamivir and zanamivir) from a health care payer's and societal perspective in the United Kingdom. A simulation model was developed to predict morbidity and mortality due to influenza and its specified complications, comparing neuraminidase inhibitors with usual care in an otherwise healthy adult population. Robustness of the results was tested by one-way and multiway as well as probabilistic sensitivity analyses. Treatment with either neuraminidase inhibitor results in reduced morbidity and faster return to normal activities. However, oseltamivir dominates zanamivir in cost-utility analysis due to its lower costs. Comparing oseltamivir with usual care, the costs are pound14.36 per day of normal activity gained and pound5,600 per quality-adjusted life-year gained from the healthcare payer perspective. Oseltamivir dominates usual care from the societal perspective. Treatment with oseltamivir is a cost-effective strategy for otherwise healthy adults in the UK from both the healthcare payer and societal perspective.

Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance.

Although influenza vaccination remains the primary method for the prevention of influenza, efficacy may be limited by a poor match between the vaccine and circulating strains and the poor response of elderly patients. Hence, there is an important role for antiviral therapy in the management of influenza. While amantadine and rimantadine have been available for the treatment of influenza in some countries for several years, they are only effective against influenza A viruses, they can have neurological and gastrointestinal adverse effects, and resistant virus is rapidly generated. Neuraminidase inhibitors, a new class of drug, are potent and specific inhibitors of all strains of influenza virus, and they have minimal adverse effects. The greatest benefit is seen in those patients presenting <30 hours after development of influenza symptoms, those with severe symptoms or those in high-risk groups. In addition to treatment of the infection, both drugs are effective prophylactically and have been shown to limit spread of infection in close communities, such as families and in nursing homes. No resistant virus strains have been isolated from normal individuals treated with zanamivir. Resistant virus can be isolated from approximately 1% of adults and 5% of paediatric patients with influenza treated with oseltamivir. However, infectivity of mutant viruses is generally compromised. Governments spend millions of dollars on influenza vaccination campaigns; however, once influenza virus is circulating in the community, vaccination cannot limit the spread of disease. A greater promotion of the use of neuraminidase inhibitors for the treatment and prevention of influenza could have a significant impact on limiting its spread. This could result in saving millions of dollars, not only in direct costs associated with medical and hospital care, but also significant savings in indirect costs associated with the loss of productivity at work, school and home environments. For the benefit of all communities, there needs to be a greater awareness of the symptoms of influenza and the efficacy of neuraminidase inhibitors in disease treatment.

[Neuraminidase inhibitors oseltamivir and zanamivir: new means of defence against influenza]. / De neuraminidaseremmers oseltamivir en zanamivir: een nieuw schild in de verdediging tegen influenza.

Recently two new neuraminidase inhibitors zanamivir and oseltamivir have been marketed. They appear to considerably reduce morbidity and mortality from influenza. Their adverse effects are infrequent and mild and the chance of development of pathogenically significant resistant mutants appears to be small. During the first six months of a pandemic, neuraminidase inhibitors are the only defence against the virus. It is therefore important to stockpile in each country sufficient quantities of these drugs. During the usual influenza epidemics the main value of neuraminidase inhibitors lies in their use for therapy, prophylaxis and post-exposure prophylaxis in long-term care institutions for the elderly (for prophylaxis only oseltamivir is licensed). Although data on the effectiveness against complications of influenza and on the effect on people with an increased risk of (fatal) complications as a result of an influenza virus infection are limited, the available information on the effects of the neuraminidinase inhibitors indicates that these drugs will also protect against complications and that high-risk groups will benefit from the rapid deployment of these products. The cost-effectiveness of treatment and post-exposure prophylaxis with neuraminidinase inhibitors is probably not favourable for healthy children and adults but seems to be favourable for the high-risk groups (vaccinated or not) in winter.

Assessment of development of resistance to antivirals in the ferret model of influenza virus infection.

We attempted to develop in vivo resistance of influenza virus to amantadine and to zanamivir, by use of the ferret model of influenza virus infection. Resistance of influenza virus A/LosAngeles/1/87 (H3N2) to amantadine was generated within 6 days, during a single course of treatment, and mutations in the M2 gene that are characteristic of human infections were observed. In contrast, during an identical single course of treatment with zanamivir, no evidence of reduced susceptibility was demonstrated. Pooled virus shed by zanamivir-treated ferrets was used to infect another group of ferrets. Twenty virus clones grew in plaque assays containing zanamivir, indicating possible reduced susceptibility; however, none exhibited reduced susceptibility to zanamivir in neuraminidase (NA) inhibition assays. Sequencing of the NA gene of these clones revealed only a noncoding nucleotide mutation at position 685. Sequencing of the hemagglutinin gene revealed mutations at positions 53, 106, 138, 145, 166, and 186. Similar to the situation in humans, amantadine use in ferrets rapidly produces antiviral resistance, but zanamivir use does not, although nucleotide changes were observed.

Management of influenza in adults older than 65 years of age: cost-effectiveness of rapid testing and antiviral therapy.

BACKGROUND: Although antiviral therapy is cost-effective in adults, its cost-effectiveness in older adults has not been studied. OBJECTIVE: To determine the cost-effectiveness of influenza testing and treatment strategies for older adults. DESIGN: Cost-utility decision model. DATA SOURCES: Clinical trials of antiviral drugs and epidemiologic data. TARGET POPULATION: Noninstitutionalized adults older than 65 years of age with influenza-like illness. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Rapid diagnostic testing or empirical therapy with antiviral drugs. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) saved. RESULTS OF BASE-CASE ANALYSIS: Compared with no intervention, empirically treating an unvaccinated 75-year-old patient with amantadine increased life expectancy by 0.0014 QALY at a cost of 1.57 dollars, a cost-effectiveness ratio of 1129 dollars per QALY saved. Compared with amantadine, rapid diagnostic testing followed by treatment with oseltamivir cost 5025 dollars per QALY saved and empirical treatment with oseltamivir cost 10,296 dollars per QALY saved. Testing and treatment strategies were less cost-effective if the patient was vaccinated, ranging from 2483 dollars per QALY saved with amantadine to 70,300 dollars per QALY saved with oseltamivir. RESULTS OF SENSITIVITY ANALYSIS: The decision was sensitive to the probability of influenza, the efficacy of oseltamivir in preventing hospitalizations, and hospitalization and case-fatality rates. The decision was not sensitive to the probability or severity of medication side effects, the quality of life for influenza illness or hospitalization, the efficacy of antiviral therapy in shortening influenza illness, or the rapid diagnostic test characteristics. CONCLUSIONS: For unvaccinated or high-risk vaccinated patients during the influenza season, empirical oseltamivir treatment is cost-effective. For other patients, rapid diagnostic testing followed by treatment with oseltamivir is cost-effective. Empirical amantadine treatment offers a low-cost alternative if patients cannot afford oseltamivir.

Zanamivir in the treatment of influenza.

Influenza is a common illness, affecting many people every winter, with a considerable impact on mortality, hospital admissions, healthcare utilisation and sickness absence from work and school. Influenza management is currently focused on annual vaccinations for those in certain risk groups. Risk is determined by age and chronic illness, particularly diabetes, chronic respiratory and cardiac disease, and persons immunocompromised from disease or concomitant therapy. Amantadine (and in some countries, rimantadine is available but has not been widely used, because it is only effective against influenza A infections. The use of amantadines for treatment has been associated with the rapid emergence of resistant viruses capable of transmission, compromising its potential as a prophylactic, as well as a treatment. Side effects are well recognised and are a particular problem in the most vulnerable elderly populations, where dose restriction is necessary and prior knowledge of creatinine clearance desirable. The potential market for a new influenza treatment is large and the potential role of neuraminidase inhibitors in addressing this market has been covered in several review articles [1-4]. This review reports on the introduction of zanamivir (Relenza) to the market with particular reference to experience in the UK.

Bedside rapid flu test and zanamivir prescription in healthy working adults: a cost-benefit analysis.

BACKGROUND: Zanamivir, a neuraminidase inhibitor, reduces the number of days of illness in influenza-positive patients. New bedside rapid flu tests (RFT) should increase the number of influenza-positive patients whom receive zanamivir appropriately. OBJECTIVE: To estimate the economic effects of implementing RFT and zanamivir among unvaccinated healthy working adults who consult within 2 days of the onset of influenza-like symptoms. METHODS: We constructed a decision tree to perform a cost-benefit analysis from a societal perspective. Clinical outcome, i.e. number of influenza days averted, and societal costs were compared for three strategies: RFT and conditional zanamivir prescription;systematic zanamivir prescription; and no zanamivir. A two-way sensitivity analysis was performed including the proportion of influenza-positive patients. RESULTS: During influenza epidemics, systematic zanamivir prescription provided the best health outcome (0.81 influenza days averted) and minimised societal costs (reduced by 29.80 US dollars per person compared with no zanamivir; 1999 values). RFT with conditional zanamivir averted 0.65 influenza days and saved 14.40 US dollars per person. When the proportion of influenza-positive patients was under 39%, the no zanamivir strategy yielded the greatest societal savings; otherwise, systematic zanamivir was the dominant strategy. Medical costs associated with no zanamivir were 88.70 US dollars per patient consulting with influenza-like illness, and increased to 125.50 US dollars with systematic zanamivir and to 127.60 US dollars with RFT and conditional zanamivir. CONCLUSIONS: Due to poor sensitivity of current RFT, systematic zanamivir prescription without RFT for unvaccinated healthy working adults should be recommended during influenza epidemics.

Risk for respiratory events in a cohort of patients receiving inhaled zanamivir: a retrospective study.

BACKGROUND: Inhaled zanamivir is indicated for treatment of uncomplicated acute illness due to influenza A and B viruses in patients aged > or = 12 years who have been symptomatic for no more than 2 days. OBJECTIVE: The primary objective of this study was to estimate the incidence of adverse respiratory events among zanamivir-treated patients under conditions of usual care. METHODS: The Ingenix research database includes insurance claims for all dispensations, inpatient and outpatient services, and procedures including the associated diagnoses and costs for a subset of all enrolled UnitedHealthcare members. We identified all persons with a dispensation of zanamivir recorded between October 1, 1999, and April 30, 2000. We captured medical and pharmaceutical claims data for the 6 months before the dispensation to obtain information about comorbidities, overall health status, and respiratory events. Medical and hospital record abstraction and clinical review served to confirm inpatient/emergency department (ED) events. We also examined the records of an approximately 10% random sample of patients treated for a potential respiratory event in an outpatient/ physician office visit during the 10-day follow-up period. Respiratory events not sufficiently severe to result in medical care were not captured in this study. RESULTS: A total of 5498 eligible zanamivir dispensations contributed by 5450 patients (2911 females, 2539 males; mean age, 38.8 years), with 40 confirmed inpatient/ED respiratory events, were included in the study. Of these 40 events, 31 were pneumonia, bronchitis, or exacerbations of existing chronic respiratory disease; none required intubation or ventilation. No events occurred on the dispensation date. The overall risk for an inpatient/ ED respiratory event was 0.7 per 100 episodes (95% CI, 0.5-1.0). Seven events of wheezing or shortness of breath were not an obvious extension of the original influenza-like illness or of a complicating bronchitis (risk = 0.13 per 100 episodes; 95% CI, 0.06-0.26). CONCLUSIONS: No immediate or severe bronchoconstrictive responses occurred among 5498 zanamivir dispensations. The overall risk for any respiratory event was low, and none was sufficiently severe to suggest respiratory failure.

The effect of zanamivir treatment on influenza complications: a retrospective cohort study.

BACKGROUND: Complications of influenza are a major cause of morbidity and mortality during the influenza season. Clinical trials of zanamivir have reported a reduced incidence of influenza complications among high-risk patients. OBJECTIVES: This retrospective study sought to determine whether the use of zanamivir lowers the risk of acute influenza complications in a broader population, based on an analysis of claims data from a large managed care organization. METHODS: Medical and pharmacy health insurance claims data from October 1, 1999, through April 30, 2000, were compiled for UnitedHealthcare members in 19 states. All patients with a diagnosis of influenza (International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code 487.xx) associated with a physician visit were identified. From these, all patients were selected who had received zanamivir on the same day as the diagnosis of influenza. The propensity score matching technique was used to identify a comparison group with similar health service utilization and comorbidities who received a diagnosis of influenza but no antiviral therapy. Follow-up started the day after the influenza diagnosis and continued for 21 days. RESULTS: From the 43,741 patients originally identified, 2341 were selected who received a simultaneous diagnosis of influenza and a prescription for zanamivir. The untreated comparator group numbered 2337. Fewer zanamivir patients than untreated patients were hospitalized for complications, and the absolute risks were low (0.6% and 1.0%, respectively; risk ratio [RR], 0.58; 95% CI, 0.30-1.12). Zanamivir-treated patients had an excess of outpatient visits (16.9% vs 14.5%; RR, 1.16; 95% CI, 1.02-1.33) and antibiotic use (16.3% vs 14.8%; RR, 1.10; 95% CI, 0.97-1.26), although the RRs were modest. CONCLUSIONS: In the setting of a large managed care plan, patterns of influenza complications were similar in zanamivir-treated and untreated patients with a diagnosis of influenza. The results of this study are in contrast to those of published clinical trials reporting a reduction in the risk of influenza complications in zanamivir-treated patients.

Cost-effectiveness of newer treatment strategies for influenza.

PURPOSE: Recent advances in the diagnosis and treatment of influenza, such as rapid testing and neuraminidase inhibitor therapy, are available, but their place in clinical practice and their cost-effectiveness have not been determined. MATERIALS AND METHODS: To estimate the cost-effectiveness of these newer interventions, we used a decision model that compared several influenza management strategies: no testing or treatment, amantadine or rimantadine treatment without testing, testing then amantadine or rimantadine treatment, neuraminidase inhibitor treatment without testing, or testing then neuraminidase inhibitor treatment. Antiviral therapy began within 48 hours in febrile patients with characteristic symptoms of influenza. We assumed that antiviral treatment did not change rates of influenza complication or mortality, and chose parameter values in the baseline analysis to bias slightly against antiviral treatment and toward testing strategies. RESULTS: In the baseline analysis, testing strategies are more expensive and less effective than treatment strategies. Amantadine costs $9.06 per illness day avoided or $11.60 per quality-adjusted day gained. Compared with amantadine, zanamivir costs $198 per illness day avoided or $185 per quality-adjusted day gained, whereas oseltamivir costs $252 per illness day avoided or $235 per quality-adjusted day gained. In elderly patients who require reduced dosage, rimantadine costs $128 per quality-adjusted day gained compared with amantadine. In younger patients, amantadine is favored if the likelihood of influenza A is >67%; otherwise, neuraminidase inhibitors are favored. Testing strategies are more costly and less effective when the influenza probability is >30%. No testing or treatment is favored if the influenza probability is <32% and the influenza utility is >0.77. In elderly patients, amantadine is favored over rimantadine if the utility of medication side effects is >0.94. CONCLUSIONS: Antiviral treatment of influenza without rapid testing is reasonable economically in febrile patients with typical symptoms during influenza season. The choice of antiviral agent depends on age, the likelihood of influenza A, and the willingness to pay per quality-adjusted day gained.

Current strategies for management of influenza in the elderly population.

Influenza virus remains among the most important pathogens infecting elderly people. Vaccination is the most cost-effective strategy to reduce morbidity and mortality due to influenza. For persons who are not vaccinated or for whom vaccines fail to prevent influenza, there are 2 classes of efficacious drugs for treatment or chemoprophylaxis: M2 channel inhibitors and neuraminidase inhibitors. Effective treatment, however, must commence within 48 h of the onset of symptoms, which can create problems for patients who wait to see whether their symptoms worsen or improve. Older adults who have relocated to the congregate housing environments of assisted living and long-term care facilities deserve special consideration, because influenza exposure risks are different for this group. Strategies for control of influenza must combine preventive approaches, such as vaccination, educational approaches, and the introduction of policies that allow health care professionals anticipate, identify, and efficiently respond to influenza outbreaks.

Economic analysis of influenza vaccination and antiviral treatment for healthy working adults.

BACKGROUND: Physicians have several treatment options for influenza, including vaccination and various antiviral therapies. However, the optimal influenza prevention and treatment strategy is unknown. OBJECTIVE: To compare the relative health values of contemporary treatment strategies for influenza in a healthy sample of working adults. DESIGN: Cost-benefit analysis using a decision model. DATA SOURCES: Previously published data. TARGET POPULATION: Healthy employed adults 18 to 50 years of age. TIME HORIZON: A complete influenza season. PERSPECTIVE: Societal. INTERVENTIONS: Eight treatment options (yes or no) based on the possible combinations of vaccination and antiviral therapy (rimantadine, oseltamivir, or zanamivir or no treatment) should infection develop. OUTCOME MEASURES: Cost in U.S. dollars, including the value of symptom relief and medication side effects, which was assigned a monetary value through a conjoint analysis that used a "willingness-to-pay" approach. RESULTS: In the base-case analysis, all strategies for influenza vaccination had a higher net benefit than the nonvaccination strategies. Vaccination and use of rimantadine, the most cost-beneficial strategy, was $30.97 more cost-beneficial than nonvaccination and no use of antiviral medication. The health benefits of most antiviral treatments equaled or exceeded their costs for most scenarios. The choice of the most cost-beneficial antiviral strategy was sensitive to the prevalence of influenza B and to the comparative workdays gained by each antiviral therapy. CONCLUSIONS: Vaccination is cost-beneficial in most influenza seasons in healthy working adults. Although the benefits of antiviral therapy for persons with influenza infection appear to justify its cost, head-to-head trials of the various antiviral therapies are needed to determine the optimal treatment strategy.

Antiviral therapy for influenza virus infections.

Every year, influenza viruses cause global epidemics that result in significant morbidity and mortality. Influenza infections can be serious in children, especially infants and toddlers. Four antiviral agents, amantadine, rimantadine, oseltamivir, and zanamivir, are available for the treatment or prophylaxis of influenza. Experience with the use of these antiviral drugs for influenza in children is limited. Given the small degree of therapeutic gain that is reported from clinical trials, considerations about cost effectiveness are important in deciding whether to use these agents in the treatment of suspected or proven influenza infections in healthy children.

Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP).

This report updates the 2001 recommendations by the Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine and antiviral agents (MMWR 2001;50 [No. RR-4]:1-44). The 2002 recommendations include new or updated information regarding 1) the timing of influenza vaccination by risk group; 2) influenza vaccine for children aged 6-23 months; 3) the 2002-2003 trivalent vaccine virus strains: A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like strains; and 4) availability of certain influenza vaccine doses with reduced thimerosal content. A link to this report and other information related to influenza can be accessed at the website for the Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC, at http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.

Neuraminidase inhibitors for the treatment and prevention of influenza.

The impact of influenza virus infection is estimated to run into billions of dollars worldwide. Vaccination plays a key role in prevention; however, vaccines do not provide complete protection against influenza due to the constant mutation of the virus responsible. Unlike amantadine and rimantadine, which are only effective against influenza A, the new neuraminidase inhibitors zanamivir (Relenza), GlaxoSmithKline) and oseltamivir (Tamiflu), Gilead/Roche) are potent and specific inhibitors of influenza types A and B and have minimal side effects. The greatest benefit is derived if treatment commences as soon as possible after symptoms develop. In order for these inhibitors to have a significant impact on the disease, clinicians and the general public need to be made more aware of the symptoms of influenza and the availability of these new drugs.