Measures for control of influenza

Influenza viruses cause recurring illnesses among individuals and recurring epidemics among populations. The major effective control measure for preventing infection and illness is inactivated vaccine, which can prevent influenza illnesses and their complications when given before exposure to the virus. While inactivated vaccine is effective for preventing influenza in most individuals, recommendations for its use focus on the prevention of severe disease and death among those who are at high risk of complications. Live attenuated cold-adapted influenza vaccines are nearing availability. They are given by nasal spray and are particularly effective for preventing influenza among young children, but also for preventing influenza among young adults, and enhancing protection against influenza when given with inactivated vaccine to elderly persons. The antiviral agents amantadine and rimantadine are related compounds that are effective for the prevention and treatment of influenza A virus infections and illnesses. Disadvantages are the rapid development of resistance during treatment and CNS adverse effects with amantadine. These drugs are also effective for outbreak control. Ribavirin is an antiviral given by small particle aerosol that is approved for the treatment of respiratory syncytial virus disease; it is also effective for the treatment of influenza. Two new antiviral agents inhibit influenza viral neuraminidase activity; one is given by inhalation or intranasally (zanamivir) and the other orally (GS4104). The former is free of adverse effects, while the latter induces nausea and vomiting in some individuals. Both are effective for the prevention as well as the treatment of influenza A and B illnesses. Thus, various measures for preventing and treating influenza are nearing availability. Their optimal use should further improve the control of influenza in individuals and populations as well as permit efforts to prevent community epidemics.     

Combating influenza with antiviral therapy in the pediatric population

Influenza viruses are accountable for annual epidemics worldwide that result in significant morbidity and mortality. In preschool and school-aged children, prospective surveillance of influenza demonstrates yearly infection rates of 15-42%. Children can easily transmit the virus to other children, to employees in day-care and school settings, and to family members. Two classes of antiviral drugs, the adamantine derivatives (amantadine, rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir), have been approved for treatment and prophylaxis of influenza in the pediatric population. Duration of clinical symptoms decreases and daily activities are resumed sooner when therapy is begun within 48 hours of the onset of influenza symptoms. Mechanism of action, adverse effects, and development of resistant variants differ between the two drug classes. To our knowledge, head-to-head clinical trials between the classes and involving the neuraminidase inhibitors are nonexistent. Antiviral agents do not replace the annual influenza vaccine, and clinical trials indicate that amantadine, rimantadine, zanamivir, and oseltamivir are safe and effective for administration in the pediatric population.     

Influenza

The currently available antiviral drugs rimantadine and amantadine are effective only for influenza A viruses. Another class of influenza antiviral drugs is the neuraminidase inhibitors, which selectively inhibit both influenza A and B viruses. Recent studies have found the neuraminidase inhibitors zanamivir and oseltamivir to be 67 - 82% effective in preventing laboratory-confirmed infection when administered as prophylaxis during the influenza season. As treatment, they reduce the duration of illness by 1 - 1.5 days when started within 36 - 48 h of illness onset. The reported adverse effects of these drugs are minimal, and unlike amantadine and rimantadine, the drugs do not appear to affect the central nervous system. Poor oral bioavailability and rapid renal clearance limit the use of zanamivir to inhalation and concern has been raised about its use in asthmatics. The sialic acid analogue, GS4071, has been shown to be a potent inhibitor of neuraminidase activity and is shown to be effective in controlling influenza, and its prodrug form - GS4104 (oseltamivir) can be given orally. Direct comparison of zanamivir and oseltamivir, their use for prophylaxis and treatment in high-risk groups, and evaluation of their cost effectiveness are all required before they enter routine clinical practice.     

Influenza

The currently available antiviral drugs rimantadine and amantadine are effective only for influenza A viruses. Another class of influenza antiviral drugs is the neuraminidase inhibitors, which selectively inhibit both influenza A and B viruses. Recent studies have found the neuraminidase inhibitors zanamivir and oseltamivir to be 67-82% effective in preventing laboratory-confirmed infection when administered as prophylaxis during the influenza season. As treatment, they reduce the duration of illness by 1-1.5 days when started within 36-48 h of illness onset. The reported adverse effects of these drugs are minimal, and unlike amantadine and rimantadine, the drugs do not appear to affect the central nervous system. Poor oral bioavailability and rapid renal clearance limit the use of zanamivir to inhalation and concern has been raised about its use in asthmatics. The sialic acid analogue, GS4071, has been shown to be a potent inhibitor of neuraminidase activity and is shown to be effective in controlling influenza, and its prodrug form--GS4104 (oseltamivir) can be given orally. Direct comparison of zanamivir and oseltamivir, their use for prophylaxis and treatment in high-risk groups, and evaluation of their cost effectiveness are all required before they enter routine clinical practice.     

Antivirals for influenza: what is their role in the older patient?

Influenza infection is a cause of high morbidity and mortality in the elderly living in the community or in long-term care facilities. Yearly immunisation is the most important means for prevention of infection. However, protection by vaccination in the elderly is incomplete, and influenza infections and outbreaks in long-term care facilities still occur. Symptoms of influenza include fever, chills, headache, myalgia and respiratory symptoms. These clinical features overlap considerably with other co-circulating respiratory viruses such as respiratory syncytial virus and parainfluenza virus. Elderly and debilitated patients with influenza may present with less prominent respiratory symptoms and may present only with fever, lassitude and confusion. Antiviral prophylaxis and treatment with amantadine and rimantadine have been given in the past but adverse effects and early development of drug resistance have limited their use. The newer antivirals zanamivir and oseltamivir are equally effective and have the advantage of being well tolerated and active against both influenza A and B without the development of resistance. However, they are costly. Early identification and diagnosis of influenza illnesses are crucial since treatment with antiviral agents should be started within 48 hours of the beginning of illness.     

M2 protein-a proton channel of influenza A virus

Recent outbreaks of highly pathogenic avian influenza A virus infections (H5 and H7 subtypes) in poultry and humans have raised concerns that a new influenza pandemic will occur in near future. Currently, four antivirals have proven efficacy in the treatment and prophylaxis of influenza A infections: two M2 inhibitors (amantadine and rimantadine) and two neuraminidase inhibitors (zanamivir and oseltamivir). Early treatment with antivirals reduces the duration of symptoms and the time to recovery by one to two days. However, when antivirals are used for the treatment the antiviral resistance develops rapidly, limiting their use. There is an urgent need for research on newer antiviral agents and "universal" vaccine against influenza virus. The M2 protein from the influenza A virus forms a proton channel in the virion and is essential for infection. As a relatively conserved protein, the M2 protein seems to be a suitable candidate for development of a new generation of vaccine or antiviral agents. This review describes the role of the M2 ion channel in virus replication and the structure-function relationship of the channel.     

Clinical use of antiviral drugs

Remarkable progress has been made in antiviral chemotherapy. Six approved antiviral drugs are now available for the treatment of various viral infections. Trifluridine, idoxuridine and vidarabine are all effective in patients with herpes keratitis; trifluridine is preferred due to its low toxicity. Acyclovir is the drug of choice in patients with infections due to herpes simplex viruses, including genital herpes, herpes encephalitis, and neonatal herpes, and infections due to varicella-zoster virus. Amantadine is the only drug currently available for prophylaxis and treatment of influenza A, but an investigational drug, rimantadine, appears to be equally effective and less toxic than amantadine. Ribavirin is the most recently approved antiviral agent for the treatment of respiratory syncytial virus infections. Numerous antiviral drugs are being studied in patients with acquired immunodeficiency syndrome. Although currently available drugs have improved our ability to manage a variety of viral illnesses, much needs to be learned about specific dosage guidelines based on the studies of pharmacokinetics, pharmacodynamics, potential adverse effects and viral resistance, and the role of combination therapy to optimize therapy.     

Development of antivirals against influenza

Morbidity and mortality due to influenza virus infections remain a major problem throughout the world. Yearly, medical costs and loss of productivity resulting from influenza infection are estimated to be in the range of 12 dollars bn in the USA. The predicted increases in the elderly and immune-deficient populations will make influenza an even greater threat in the future. Despite the availability of vaccines, they have been least effective in these high-risk populations. Coupled with the requirement for routine revaccination, the need for effective antiviral agents is illustrated. The currently approved drugs, amantadine, rimantadine and ribavirin (in some countries), have limitations. They are only inhibitory against influenza A viruses, are prone to adverse reactions and quickly give rise to resistant virus. This review examines current drug therapies, antivirals in development and possible future opportunities for anti-influenza drugs.     

Therapeutic options for the management of influenza.

Over the past few years a novel class of antiviral agents, the neuraminidase inhibitors, has been found to be safe and effective in the prevention and treatment of influenza. Previously available agents, the M2 inhibitors amantadine and rimantadine, could only be used to treat influenza A infections and resistance develops rapidly. Zanamivir (Relenza) and oseltamivir (Tamiflu), the two clinically available neuraminidase inhibitors, are effective for treating both influenza A and B infections in adults and children and have also been shown to reduce the frequency of antibiotic-requiring complications of influenza infections. Inhaled zanamivir has shown benefit in treating acute influenza with mild to moderate underlying asthma or chronic obstructive pulmonary disease. Studies are needed to examine the use of these agents, alone or in combination with M2 inhibitors or ribavirin, in the management of severe infections in hospitalized patients and immunocompromised hosts. Studies are also needed to address other groups at increased risk for influenza complications, such as pregnant women and children below one year of age.     

New small-molecule drug design strategies for fighting resistant influenza A

Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two main treatment strategies–vaccination and small molecule anti-influenza drugs are currently available. As an effective vaccine usually takes at least 6 months to develop, anti-influenza small molecule drugs are more effective for the first line of protection against the virus during an epidemic outbreak, especially in the early stage. Two major classes of anti-influenza drugs currently available are admantane-based M2 protein blockers (amantadine and rimantadine) and neuraminidase (NA) inhibitors (oseltamivir, zanamivir, and peramivir). However, the continuous evolvement of influenza A virus and the rapid emergence of resistance to current drugs, particularly to amantadine, rimantadine, and oseltamivir, have raised an urgent need for developing new anti-influenza drugs against resistant forms of influenza A virus. In this review, we first give a brief introduction of the molecular mechanisms behind resistance, and then discuss new strategies in small-molecule drug development to overcome influenza A virus resistance targeting mutant M2 proteins and neuraminidases, and other viral proteins not associated with current drugs.KEY WORDS: Influenza A virus, Drug discovery, Resistance, M2 ion channel, Neuraminidase     

Recent advances in antiviral therapy

Virus replication is described, and the clinical trials and indications for amantadine, rimantadine, vidarabine, vidarabine phosphate, acyclovir, ribavirin, and other promising antiviral agents are reviewed. Amantadine and rimantadine are useful for the treatment and prophylaxis of viral influenza A infections. Vidarabine is a second-line agent and is effective for the treatment of herpes simplex encephalitis, neonatal herpes simplex types 1 and 2, and varicella-zoster infections. Vidarabine phosphate (also known as vidarabine monophosphate) has a similar spectrum of activity and can be administered in smaller volumes than vidarabine. Acyclovir has demonstrated clinical efficacy for chickenpox, shingles (herpes zoster), genital herpes, and other herpes simplex infections. Acyclovir is also useful for the suppression of herpes infections. Systemically administered ribavirin is indicated for the treatment of Lassa fever. Aerosol ribavirin is effective for the treatment of respiratory syncytial virus pneumonia in children and infants and influenza A infections in adults. Only acyclovir, amantadine, ribavirin, and vidarabine are used in clinical practice. Vidarabine phosphate and investigational agents such as rimantadine, ganciclovir (DHPG, BW B759U), phosphonoformate, and bromovinyl-deoxyuridine (BVDU) need further investigation.     

Current and future antiviral therapy of severe seasonal and avian influenza

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children ("seasonal influenza"), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people ("avian influenza"). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.     

Antiviral therapy for influenza : a clinical and economic comparative review

Each year influenza epidemics cause a considerable burden of disease. Vaccination against influenza A and B viruses has been and remains the cornerstone of influenza prevention, but antiviral therapy can serve as an important adjunct to vaccination in controlling the impact of the disease. Two classes of drugs are currently licensed in a large number of countries for the treatment of influenza. The M2 ion channel blockers or amantadanes (amantadine and rimantadine) are specific inhibitors of influenza A virus replication, whereas the neuraminidase inhibitors (zanamivir and oseltamivir) are active against influenza A and B viruses. Readily transmissible drug-resistant viruses develop frequently during amantadane treatment but not during neuraminidase inhibitor treatment. In this review, efficacy and safety data from randomised controlled trials are evaluated to gain an understanding of what we can and cannot expect from antiviral treatment. All four drugs shorten the course of influenza disease by approximately 1 day and relieve symptoms to some extent, but there is still uncertainty as to whether antiviral therapy leads to a reduction of serious complications and hospitalisation. The results of cost-effectiveness analyses are very diverse, in part because of differences in methodology but also because there is no consensus on what probabilities to assign to the key risks and benefits that form the basis of these studies. Consensus statements by advisory bodies in England and Germany recommend neuraminidase inhibitors for the therapy of influenza in high-risk individuals such as people over 65 years or under 2 years, and individuals with chronic cardiovascular, pulmonary or renal disease, diabetes mellitus or immunosuppression. However, there is no agreement as to whether antiviral therapy can be generally recommended for otherwise healthy children and adults. The availability of safe and effective antiviral therapy options should be kept in mind by the practising clinician, while more specific recommendations and policy formulation will depend on additional efficacy data that include frequency of complications and hospitalisation as outcome measures.     

Molecular strategies to inhibit the replication of RNA viruses

There are virtually no antiviral drugs available for the treatment of infections with RNA viruses. This is particularly worrisome since most of the highly pathogenic and emerging viruses are, and will likely continue to be, RNA viruses. These viruses can cause acute, severe illness, including severe respiratory disease, hemorrhagic fever and encephalitis, with a high case fatality rate. It is important to have potent and safe drugs at hand that can be used for the treatment or prophylaxis of such infections. Drugs approved for the treatment of RNA virus infections (other than HIV) are the influenza M2 channel inhibitors, amantadine and rimantadine; the influenza neuraminidase inhibitors, oseltamivir and zanamivir, and ribavirin for the treatment of infections with respiratory syncytial virus and hepatitis C virus. The molecular mechanism(s) by which ribavirin inhibits viral replication, such as depletion of intracellular GTP pools and induction of error catastrophe, may not readily allow the design of analogues that are more potent/selective than the parent drug. Highly pathogenic RNA viruses belong to a variety of virus families, each having a particular replication strategy, thus offering a wealth of potential targets to selectively inhibit viral replication. We here provide a non-exhaustive review of potential experimental strategies, using small molecules, to inhibit the replication of several RNA viruses. Other approaches, such as the use of interferon or other host-response modifiers, immune serum or neutralizing antibodies, are not addressed in this review.     

Influenza viruses: basic biology and potential drug targets

Influenza A and influenza B viruses are continuing causes of morbidity and mortality on an annual basis. Influenza A viruses have historically caused periodic pandemics in the human population, sometimes with devastating consequences, such as in 1918. Fears of a new pandemic have increased in recent years because of continuing outbreaks of highly pathogenic H5N1 avian influenza viruses in birds with occasional, but often lethal infection of humans. Despite their importance as human pathogens, the antiviral drugs approved to treat influenza virus infections are currently limited to two targets, the viral neuraminidase and the viral ion channel, M2. The use of the M2 inhibitors amantadine and rimantadine is further limited by the propensity of these drugs to select for drug resistant variants. However, the replication cycle of influenza viruses has been intensively studied and is receiving increased attention. New opportunities exist to develop novel antiviral strategies targeting these viruses.     

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.     

The influence of the antiviral drugs amantadine and rimantadine on erythrocyte and platelet membranes and its comparison with that of tetracaine

The influence of the antivirus drugs amantadine and rimantadine and of the anionic analogue 1-adamantane-carboxylic acid on a range of properties of human erythrocyte membrane and of thrombocytes has been compared with the effect of the local anaesthetic tetracaine. At low antiviral drug concentrations the abilities of the drugs to induce erythrocyte shape change and suppress osmotic haemolysis were quantitatively proportional to their clinical potency (rimantadine more effective than amantadine at the same concentration). Rimantadine was also more effective than amantadine in suppressing influenza virus-erythrocyte fusion and viral induced haemolysis. The antiviral drug effects were qualitatively similar to those induced by tetracaine. At the quantitative level, tetracaine was more efficient than the antiviral drugs in inhibiting osmotic haemolysis, virus membrane fusion and platelet aggregation. In the absence of any specificity of the antiviral drug effects we argue for a lysosomotropic mode of drug action, i.e. that the drugs modify virus-membrane interactions by changing the endosomal or lysosomal pH.     

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.     

Antiviral drugs in influenza: an adjunct to vaccination in some situations

(1) Influenza is a common acute respiratory disease due to a virus that causes annual seasonal epidemics. Three major pandemics occurred in the 20th century, in 1918-1919, 1957 and 1968, mainly due to genetic variants of type A influenza virus. (2) In temperate regions the incidence of hospitalisation increases during annual influenza epidemics. More than 90% of deaths linked to influenza involve people over 65 years of age. (3) The clinical manifestations of influenza virus infection are non specific. The main complications are secondary bacterial respiratory tract infections (especially pneumonia); those most at risk are people over 65, infants less than one year old, and people with underlying chronic disorders (pulmonary, cardiac, renal or metabolic) or immune deficiencies. (4) Vaccination is the main preventive measure. During most years the vaccine strain closely matches the epidemic strain. In relative terms, vaccination of people over 65 reduces the number of deaths linked to influenza by about 80%, hospitalisation and pneumonia by about 50%, and symptomatic influenza by about 30%. Yearly vaccination is recommended for younger people with serious chronic disease. (5) Three antiviral drugs are currently approved in France for prevention or treatment of influenza: amantadine and the neuraminidase inhibitors zanamivir and oseltamivir. (6) Efficacy of antiviral drugs has not been evaluated in comparative randomised trials in which death and influenza complications were the primary outcome measures. (7) A systematic review of 20 comparative randomised trials involving about 2500 healthy people showed that amantadine reduced the frequency of flu-like syndromes by about 7% in absolute terms (26.3% versus 33.1% with placebo). Zanamivir and oseltamivir have only been shown to reduce the frequency of serologically confirmed episodes of influenza (0.4% to 2.5%, compared to 4.4% to 14.9% with placebo). (8) In a randomised placebo-controlled trial of oseltamivir, involving 548 institutionalised subjects over 65 years of age, more than 80% of whom had been vaccinated, respiratory tract infections were less frequent in the oseltamivir group, but the relevance of this result is undermined by the small number of observed cases. (9) Efficacy of antiviral drugs on avian influenza (bird flu) was studied during a 2003 Dutch outbreak due to a type A/H7N7 virus. Among the 38 exposed persons who were treated, about 3% developed symptoms, compared with about 10% of 52 exposed persons who refused treatment (p = 0.38). The low statistical power and the lack of randomisation rule out any firm conclusions on preventive effects. (10) The three antiviral drugs have different profiles of adverse effects and drug interactions. Amantadine carries a risk of neuropsychological, atropinic and dopaminergic adverse effects, and can interact with drugs that have similar effects. Zanamivir carries a risk of life-threatening bronchospasm. Oseltamivir was approved relatively recently and its full spectrum of adverse effects is not yet known; its main adverse effects appear to be mild gastrointestinal disturbances, although a few cases of serious cutaneous reactions have been reported. (11) In vitro resistance to the three drugs has been demonstrated, but the possible clinical and epidemiological consequences are unclear. (12) In situations warranting antiviral therapy for the prevention of influenza, oseltamivir, at a dose of 75 mg/day for 10 days, is the drug with the best risk-benefit balance. Its use should be limited to situations where a major potential benefit exists in order to avoid selection for resistant strains. (13) Testing of oseltamivir in children is limited. Oseltamivir should be avoided during pregnancy, because of evidence that it may harm the unborn child. (14) In practice, the use of antiviral drugs in otherwise healthy adults and children is not generally recommended. (15) Despite the lack of convincing data regarding the efficacy of oseltamivir in preventing complications of influenza, its effect on documented infections suggests it may be useful for unvaccinated individuals who are at high risk of infection and severe complications. Under these conditions, treatment should be started within 48 hours after contact with a person who has flu-like symptoms during a seasonal epidemic; residents in institutions in which influenza cases occur may also qualify for preventive treatment. Other preventive measures should also be used, including immediate vaccination, case isolation, use of face masks, and more frequent hand washing. (16) During seasonal influenza epidemics due to viral strains against which the current vaccine is of limited effectiveness, the utility, target populations and optimal duration of preventive antiviral treatment must be determined by examining the groups most at risk and the severity of complications. (17) Most flu-like syndromes are not due to the influenza virus, and the preventive effect of antiviral drugs on complications in persons at risk has not yet been demonstrated. (18) In practice, antiviral drugs are not an alternative to influenza vaccination, but may be a useful adjunct in some situations. It is best to limit their use to short-term prophylaxis of vulnerable persons in situations where the risk of contracting influenza virus infection is high.     

Antiviral agents for influenza: a comparison of cost-effectiveness data

The economic burden of influenza-related illness has been estimated to be 71.3-166 billion US dollars in the US, the majority of which is attributable to indirect costs as a result of lost productivity. There are currently four antiviral drugs available for the treatment of influenza: two ion channel blockers, amantadine and rimantadine; and two neuraminidase inhibitors, zanamivir and oseltamivir. The objective of this paper was to review the studies evaluating the cost effectiveness of currently available antiviral treatment and prophylaxis management strategies for influenza. Published studies that reported both costs and effectiveness of influenza management were extracted using MEDLINE, pre-MEDLINE and EMBASE. To facilitate a broad comparison, all costs were inflated to 2003 US dollars. Fifteen studies met the inclusion criteria of the review, with 14 analyses based on decision-analytic modelling and one economic analysis performed alongside a clinical trial. Management strategies included antiviral influenza prophylaxis or vaccination, empiric treatment of suspected disease, or antiviral treatment following rapid influenza testing. Study populations included healthy adults, adults at risk of influenza-related adverse outcomes, institutionalised and non-institutionalised elderly, and children. The comparator in all studies was standard care (i.e. over-the-counter medications only), and analyses were carried out from both the societal and payer perspectives. The only dominant strategy relative to standard care was vaccination of the institutionalised elderly. All other strategies in all populations were both more costly and more effective than standard care. Depending on the population and the perspective, the incremental cost-effectiveness ratios (ICERs) for antiviral treatment strategies ranged from 5000 US dollars/QALY for amantadine in test-and-treat studies to >400,000 US dollars/QALY for zanamivir or oseltamivir treatment in children. Sensitivity analysis in all studies consistently reported a strong influence of the population prevalence or diagnostic accuracy of influenza on the cost effectiveness of all strategies. Baseline influenza prevalence varied widely between studies, ranging from 15% to 68%. There was also a wide variation in the assumption about the disutility of influenza (ranging from -0.137 to -0.983 for the elderly requiring hospitalisation), which also impacted the cost effectiveness. Given the variation in the ICERs of antiviral treatment and prophylaxis, the uncertainty around many model parameters, and the dynamic nature of influenza from year to year, one can only conclude that antiviral treatment or prophylaxis for influenza is likely to be more cost effective in specific populations at specific times during the influenza season, and during influenza seasons when the population prevalence reaches epidemic levels or there is mismatch between the vaccine and the circulating virus.