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Rates and effectiveness of antiviral use among hospitalized influenza patients Expert Rev. Anti Infect. Ther. 13(7), 835–842 (2015)
Viroj Wiwanitkit Hainan Medical University, Hainan, China and Faculty of Medicine, University of Nis, Sˇumatovacˇka, Nis, Serbia and Joseph Ayobabalola University, Akure Ilesha Rd, Nigeria and Dr DY Patil Medical University, Pune, India and Wiwanitkit House, Bangkhae, Bangkok 10160, Thailand [email protected]
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The influenza virus is currently a global public health problem. There are several thousand cases of classic and newly emerging atypical influenza virus infections around the world annually. Prevention, early diagnosis and treatment are the keys to managing influenza outbreaks. Some influenza treatments have proven to be more useful than others. A standard antiviral drug has been developed and is recommended for the management of hospitalized influenza patients. This article briefly outlines the rates and effectiveness of antiviral use among hospitalized influenza patients. It also discusses some important considerations regarding controversial issues and future perspectives on antiviral use for the management of hospitalized influenza patients. KEYWORDS: antiviral . effectiveness . influenza . patient . rate
Infectious diseases are still important threats to public health at present. There are several kinds of infectious diseases, including viral and bacterial infections. Viral infections are of great concern. Many new emerging viral infections are currently of interest. Emerging viral diseases are usually problematic and have a high risk for causing a worldwide pandemic. Due to the nature of viral infections, specific treatments are usually unavailable and death rates are usually high. Of several new viral diseases, influenza is an important disorder. Influenza is the general name of viral infections caused by influenza virus [1], which has been known for many decades. The virus can cause human and nonhuman infections. Several species of animals can also be infected [2]. The virus mainly attacks the respiratory system and can cause acute respiratory tract manifestations. The infection can occur in both the upper and lower respiratory tracts. In the upper respiratory tract, the virus can affect the nose and pharynx. In the lower respiratory tract, the virus can affect the bronchus and lung. The severity of the infection varies. There is a wide clinical spectrum from asymptomatic to deadly infection. However, in
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general, the classical signs and symptoms of influenza include high fever, headache, sore throat, myalgia, cough, stiff nose and runny nose [3]. The clinical signs and symptoms usually occur abruptly and can last for 5–14 days [3]. Influenza can attack humans, mainly via the respiratory route. Generally, infected patients can spread the virus via droplets generated by coughing and sneezing. The contaminated, aerosolized droplets will disperse in the air and other humans can inhale the contaminated droplets into their respiratory tract. This is the starting point for a new infection, which will occur within 1–3 days. Virologically, the influenza virus is classified under the family orthomyxoviridae [4]. The influenza virus is a genus. The size of the virus in this genus is an estimated 80–120 nm and it possesses filaments. There are many viruses in the genus of the influenza virus. Generally, it can be divided into three main types: influenza A, B and C [4]. All groups are important and are the focus of interest of virologists at present. In order to classify the influenza virus into these three types, antigenic classification is required. The main antigens used for classification are the antigens at the
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virus envelope and nucleoprotein. Viruses of all the three groups can infect human beings. However, influenza A is the main group that infects humans. In addition to the classification on the basis of influenza type, subtype classification can also be carried out. At present, the subtype classification is generally used to specify the problematic influenza virus. To classify subtypes of influenza virus, the antigen at the envelope of the virus is used. There are two main focused antigens for this purpose: hemagglutinin (H) and neuraminidase (N) [4]. Focusing on the influenza type A, there are 15 varieties of H antigen (H1–H15) and nine varieties of N antigen (N1–N9). In order to name an influenza virus, the type, subtype, origin, time or isolation are required [5]. Focusing on the current status of influenza infections, the influenza virus has become the present concern of global public health. Several new human influenza infections have emerged within the past decade. The risk of pandemics is usually mentioned. In addition to the new emerging influenza virus infections, classical influenza virus infections are still problematic. Similar to the new emerging influenza, the risk of a worldwide pandemic of classical influenza can be expected as well. Influenza can be seen to occur at any time of the year. However, there are typically higher incidences of infection during the winter and rainy seasons. During these times of the year, a significantly greater number of patients are treated [5]. Of interest is the fact that humans can be infected with more than one subtype of influenza virus, and that infections may occur repeatedly during an individual lifetime; no lifelong protective antibody against influenza exists naturally. In addition, influenza is easily transmitted by air. Therefore, it is unsurprising that influenza outbreaks are difficult to control [6,7]. The cross species of influenza, which is a new and problematic type of emerging influenza, is usually very hard to manage. As a cross species infection, also known as a zoonosis, this new virus causes atypical clinical symptoms. This causes difficulty in the diagnosis and management of the virus [6,7]. There is no doubt that influenza is presently an important issue to consider in the fields of medicine and public health. There are several international collaborations in place to fight influenza. The concept of primary prevention has proved useful but has been difficult to implement. Basic sanitation also helps prevent influenza, but as a whole it is an ineffective way to fully control an easily transmitted and airborne infection like influenza. Vaccination is the newest form of and possibly the best hope for influenza prevention. However, there are currently several subtypes of influenza circulating around the world, and there is no universal influenza vaccine that can act against all of these subtypes. This seriously reduces the success of using influenza vaccinations to fully manage influenza [6,7]. Additionally, the coverage of the influenza vaccine is usually a problem in many countries and areas within countries. Due to the availability and cost of the influenza vaccine, 100% coverage does not usually occur in any country. Early diagnosis and treatment are required for the management of influenza. However, the diagnosis of influenza is 836
usually based on clinical diagnosis. The confirmation usually requires sophisticated diagnostic tests. Antiviral drug is available for specific influenza treatment [8,9]. After the big pandemic H1N1 influenza 2009, the antiviral drug is easily available [10]. However, the presently available 2011 US CDC guidelines [11] for antiviral treatment of hospitalized patients with influenza are not up-to-date. There is currently not a lot of comprehensive or systematic data regarding the rates of antiviral use in hospitalized patients with influenza. Potential relevant research questions in this area might focus on the potential for antiviral use, including the availability of drugs, laboratory investigations, typical delays from influenza onset to hospital admission, knowledge of antivirals among practitioners and reasons for use or non-use. Presently available antiviral drug for influenza
The management of any viral infection is usually difficult. Unlike a bacterium, a virus is not a living thing, but is considered an infectious particle. Specific antiviral drugs are usually difficult to develop. Many viral infections still lack specific antiviral drugs for their management. However, in the case of influenza, antiviral drugs are available. There are many kinds of new drugs that are known to efficiently manage influenza. However, the classical well-known antiviral drug for the management of influenza is oseltamivir. Oseltamivir is usually recommended as the first-line drug of choice for the management of influenza in both classical and atypical new emerging influenza infections [8,9]. The use of this classical antiviral drug for the treatment of influenza has been widely practiced around the world for a few years. There are also many reports on the use of this classical drug for the management of new atypical influenza. The efficacy and effectiveness of the antiviral drug (including cost–effectiveness) are important topics that should be considered [10]. To support this, the collation of knowledge from available data around the world is required [10]. As previously mentioned, oseltamivir is currently the antiviral drug that is most widely used for the management of influenza. However, other groups of antiviral drugs have been used in the past, for example, the M2 inhibitors (in particular, amantadine and rimantadine), which were commonly used to manage influenza before the availability of oseltamivir. Amantadine and rimantadine inhibit proton transport within the M2 protein channel, which effectively impedes the influenza virus [12]. However, these M2 inhibitors are no longer in use on account of reported side effects and resistance [13,14]. For example, emerging influenza viruses, such as the swine flu, have proven resistant to the M2 inhibitors [15]. The drug oseltamivir acts on pathways that are different from those of the M2 inhibitors. Oseltamivir and several other drugs, such as zanamivir, are classified as neuraminidase inhibitors, which suppress viral activity by inhibiting neuraminidase [16,17]. Oseltamivir and zanamivir are both currently recommended for the effective management of influenza infection, and are also recommended for the management of newly emerging influenza virus infections [8,9]. Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Rates & effectiveness of antiviral use among hospitalized influenza patients
Present recommendations specify that oseltamivir be administered orally within 2 days of the onset of illness, at a recommended dosage of 3 mg/kg, twice daily [8,9]. From a pharmacokinetic and pharmacodynamic perspective, the drug is rapidly absorbed in the gastrointestinal tract, is modified into its active form in the liver and is finally excreted, mainly via the urinary tract (half-life, 6–10 h) [8,9]. The drug is considered safe and has no hepatotoxicity; however, problems related to drug use have been reported, especially the emergence of resistance [18,17]. However, the problems associated with oseltamivir resistance are not frequently detected by clinicians. Crusat and de Jong noted that factors causing the limited efficacy of neuraminidase inhibitors include ‘suboptimal dosing or routes of administration, suboptimal timing of treatment and the inability of antiviral drugs to interfere with immunopathology, and the development of drug resistance [17]’. Although oseltamivir is available, the limitations related to its effectiveness [19] and use are prompting efforts to develop new replacements [8,9,19]. The search for new anti-influenza drugs is an engaging topic for continued biomedical research. As already mentioned, the interesting consideration for oseltamivir use at present is the emergence of antiviral drug resistant influenza virus [20]. A possible new problem for influenza management is drug resistance when using oseltamivir in the treatment of classical H1NI influenza virus infection [20]. As noted by Wiwanitkit [20], good planning for the management of cases of emerging oseltamivir drug resistance is required. In the USA, oseltamivir is still confirmed as having no drug resistance problems [15]. However, there are continuing reports of oseltamivir resistance. Therefore, it is no doubt that drug resistance already occurs. In fact, it is an important consideration with regard to oseltamivir. The problem is usually due to a genetic mutation. If there is a significant genetic mutation within the influenza virus, oseltamivir resistance can occur, and if there is a sense mutation that can seriously affect the virus nanostructure, the present oseltamivir will be out of use. For classical influenza, oseltamivir drug resistance is already observed, but the problem does not extend worldwide [21–23]. Focusing on the root of the cause, the problem usually results from inappropriate use of antiviral drugs, especially when used with no indication [20]. In cases of a pandemic situation, the problem of oseltamivir resistance can also be seen. However, it is not extensively problematic. In the case of pandemic H1N1 influenza, the problem of oseltamivir resistance has been reported, but it was confined. Nevertheless, if there is a new viral variant that is highly resistant to oseltamivir, the serious problem of an uncontrollable pandemic can be expected [20]. Spanakis et al. recently noted that, ‘permissive drift mutations and reassortment of viral gene segments have resulted in neuraminidase inhibitor oseltamivir-resistant A/(H1N1) variants that rapidly became predominant worldwide’ [24]. This situation confirms the importance of the necessity of close surveillance of oseltamivir drug resistance. Spanakis et al. also concluded that, ‘the emergence of oseltamivir-resistant influenza variants that could retain viral transmissibility highlights the necessity for informahealthcare.com
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enhanced epidemiological and microbiological surveillance and clinical assessment of antiviral resistance’ [24]. Focusing on newer neuraminidase inhibitors, such as zanamivir, the problem of drug resistance is also reported. However, the problem is less prevalent [24]. There is an interesting report from China indicating a new problematic mutation, the NA R292K mutation, which results in both oseltamivir and zanamivir resistance [25]. Wei et al. concluded that, ‘other medications would be preferred over oseltamivir or zanamivir,’ in cases with NA R292K mutation [25]. In fact, there are also other new antivirals such as peramivir and laninamivir. Peramivir is a neuraminidase inhibitor that was developed for intravenous administration [26], while laninamivir was developed for use in an inhaler [27]. At present, both peramivir and laninamivir have not received US FDA approval [27,28]. In addition to the two new neuraminidase inhibitors, arbidol is another new drug. It is an antiviral drug in an indole-derivative molecule group [29]. It is a broadspectrum antiviral drug, not specific for influenza [29]. Similar to peramivir and laninamivir, arbitol is still not approved by the US FDA. However, these new drugs are registered in some countries (such as Japan, China and Russia) [27–29]. Although many new reports, with supporting funds from drug companies, show possible good efficacy of the new drugs against influenza, there are still no clinical practice guidelines recommending the use of the new drugs for the management of hospitalized patients with influenza. For these drugs, the data on the drug resistance are limited (however, there are already reports on peramivir [30] and laninamivir resistance [31]). As mentioned, these new drugs are not easily available and registered for use as standard antiviral drugs for influenza worldwide. Hence, these new drugs will not be mentioned much in the present article that focuses mainly on the drugs that are used worldwide for hospitalized patients, and not those drugs in trial or under development. Rates of antiviral use among hospitalized influenza patients
As already mentioned, antiviral drug treatment is the specific treatment for influenza infection. The usefulness of antiviral drug treatment is confirmed, and is presently indicated in any cases with confirmed diagnosis of influenza infection. The rate of antiviral use is interesting. Of course, rates of antiviral use among hospitalized influenza patients in different settings might be different. In a recent report from Philadelphia, ‘of 305 patients (32.8%) eligible for treatment with oseltamivir, 49 (16.1% of those eligible) were prescribed oseltamivir during hospitalization [32]’. In contrast, another report from a less developed country, Thailand, showed that ‘oseltamivir was prescribed in 7.7% of influenza infections [33]’. The reported rate in this Thai study [33] is half of that of a previous report from the USA [32]. These reports show many inappropriate nonprescriptions of antiviral drug for the management of influenza virus infection. At present, there is a lack of comprehensive and systematic data on the rates of antiviral use in hospitalized patients. 837
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A more relevant question might be on the potential for antiviral use, including the availability of drugs and laboratory investigations, typical delays from onset to admission, knowledge of antivirals among practitioners, reasons for use or non-use, etc. There are many possible factors that can affect the rate of antiviral use among hospitalized influenza patients who are eligible and who fulfill indication. The important factors that should be mentioned include diagnosis of infection, availability of drug, cost of drugs, physician’s perception toward antiviral drug use and national policy for antiviral drug use. Focusing on the first factor, diagnosis of infection, there is no doubt that there is some under-diagnosis of influenza at present. Delayed diagnosis can also be problematic. Of interest, Rorat et al. reported that ‘delayed diagnosis and antiviral treatment initiation has a significant impact on mortality in A (H1N1) influenza [34].’ In fact, patients with delayed diagnosis are considered not eligible for antiviral drug use, and this can affect the overall rate of antiviral drug use in hospitalized influenza patients in each setting. Focusing on availability of drugs, this was a big problem in the past. However, due to several new emerging atypical influenza infections, the drug has become more easily available. The cost of the drug is also significantly reduced from the past. It is noted that oseltamivir is more readily available compared to vaccine [35]. In addition to availability of antiviral drug, concern should be on the availability of the physician to prescribe for the antiviral drug. In some countries where the number of physicians in charges is extremely limited, this problem can be expected. The new idea to make antiviral drugs available without prescription is proposed and was first used in New Zealand [36]. This alternative channel seems to be a solution to the problem of availability. However, consideration of patient safety becomes an emerging issue against the concept that ‘individuals can receive treatment without having to consult a medical practitioner, by simply answering a set of questions online or over the telephone [37].’ A good case study from the UK [37] on a patient who suffered side effects from nonprescription oseltamivir is the best example for bringing attention to further risk–benefit studies on the nonprescription availability of antiviral drug. Focusing on national policy toward antiviral drug use, it seems to be an important determinant for success in using antiviral drug for the management of the influenza problem. According to a recent report from Taiwan, Liu et al. reported that ‘the number of prescriptions for oseltamivir increased with a change in government policy [38].’ Finally, not only the rate, but also the onset of drug used should be carefully considered. According to the CDC recommendation, the early antiviral treatment should be given for ‘suspected or confirmed influenza among persons with severe influenza [39]’ and ‘suspected or confirmed influenza among persons at higher risk for influenza complications [39]’. However, it is still a controversial issue on the effect of early use of antiviral drug for treatment of influenza. Tanaka et al. recently reported an interesting finding on how ‘timing of antimicrobial use influences the evolution of antimicrobial resistance during 838
disease epidemics [40].’ Tanaka et al. proposed that ‘the early use of antimicrobials disproportionately drives emergence and spread of antibiotic resistance, leading to subsequent treatment failure [40].’ The risk–benefit analysis toward early antiviral treatment for hospitalized influenza patients is a topic for further study. Of interest, recent research from Taiwan shows that ‘delayed oseltamivir treatment increased the likelihood of in-hospital mortality [41].’ Based on this study, Huang et al. recommended ‘early antiviral treatment for at-risk populations [41].’ A similar observation was reported from Israel by Hiba et al. [42]. Hiba et al. found benefits of early antiviral drug use and recommended that ‘initiation of oseltamivir within 48 h of symptom onset was associated with fewer complications in patients hospitalized with 2009 influenza A (H1N1) [42].’ Adalja concluded that the optimization time of antiviral drug use was the key point for success in the management of hospitalized patients with influenza infection [43]. There are some reports on how to increase the rate of appropriate antiviral drug treatment. For example, Wilkes et al. suggested using of electronic reminder for any eligible case [43]. The continuous medical education to improve the knowledge of the practitioner toward the updated guideline is required. Effectiveness of antiviral use among hospitalized influenza patients
In the preceding section, the author addressed antiviral resistance. In fact, this concern is not very important given the fact that a small amount of transmission occurs from hospitalized patients compared to the amount of transmission among the general population. Of greater concern for more critical appraisal should be the effectiveness of antivirals in hospitalized patients. In clinical practice, apart from the consideration of the rate of antiviral use among hospitalized influenza patients, the effectiveness of antiviral use among this group is another interesting topic to be discussed. In fact, although we can increase the rate of antiviral drug use for 100% of all eligible influenza patients, it will be useless if the effectiveness of the antiviral drug is not sufficient. With regard to the widely used drug, oseltamivir, there are some interesting reports on its effectiveness. To be most effective, the drug has to be used according to the indications given and advised method of administration. Machala et al. found that the ‘administration of the drug within 36 h from the onset of symptoms is one of the factors conditioning the effectiveness of antiviral therapy’ [38]. Nevertheless, Viasus et al. noted that ‘timely oseltamivir administration has a beneficial effect on outcomes in hospitalized adults with A (H1N1), even in those who are admitted beyond 48 h after onset of symptoms’ [44]. As objective evidence, Viasus et al. proved that early administration of antiviral drugs in influenza patients was related to reducing the requirements of mechanical ventilation [44]. In hospitalized patients, it is concluded that the early administration of oseltamivir results in a reduction in mortality [45]. Also, ‘virus isolation rates after treatment’ are significantly lower for cases receiving antiviral treatment [46]. However, it should be noted that although the drug is proven Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Rates & effectiveness of antiviral use among hospitalized influenza patients
effective in hospitalized cases in many studies, some new data show that administering antiviral drugs results in different outcomes in mild influenza cases [47]. In addition, a new report from Europe also showed that using the antiviral drug did not affect the rate of complications (such as otitis and superimposed bacterial pneumonia) [48]. For classical influenza, there are many reports, based on an observational descriptive study, retrospective study or nonplacebo controlled/noncontrolled trials, on the effectiveness of antiviral drugs for treatment of the infection. The effectiveness might be different depending on the time and place. In fact, it has been shown that an effective drug in one study might not be effective in another study. The best example of this is the M2 inhibitor, which was an effective drug in the past, but presently has been shown to be ineffective. For new emerging atypical influenza, the effectiveness of the antiviral drug is usually a questionable issue. In the first phase of the emergence of a new viral disease, medical scientists generally have no knowledge of it. The practitioner is also lacking in preparedness and skill to manage it [8,9]. Indeed, to perform a critical appraisal of the evidence on the effectiveness of antiviral use among hospitalized patients, the quality of evidence to support the effectiveness of antivirals in hospitalized patients should be considered. The lack of evidence-based data from placebo-controlled studies is the main problem with judging the effectiveness of the antivirals presently used among hospitalized patients with influenza. Effectiveness of antiviral drugs is based on several factors covering the pathogen, the host and the antiviral drug. The emerging drug resistance problem requires further drug research to address the future problems. The epidemiological data on the drug resistance is useful information to be followed. First, the mutated pathogen can result in failure of antiviral drug treatment. Matzusaki et al. reported that ‘influenza surveillance to monitor oseltamivir-resistance would aid clinicians in determining an effective antiviral treatment strategy [49]’ Focusing on the drug resistant mutant influenza strain, molecular studies can reveal the alteration of molecular structure that can affect the binding property between antiviral drug and drug target site on the virus and further cause ineffectiveness in infection treatment [50,51]. ‘The large-scale use of drugs for chemoprophylaxis and treatment’ is the main cause of the loss of effectiveness of oseltamivir [52]. The problem of emerging resistant strain becomes the big global problem at present. In addition to the pathogen, the problem of failure of antiviral drug treatment can also be due to the host (patient). For any viral infection, the immunity of the host becomes the important determinant for the success of treatment. For sure, an antiviral drug cannot be used in those cases. In clinical practice, some infected patients are considerably problematic for antiviral treatment. Allergic reaction to the antiviral drug is the simplest case. The others are specific groups of patients with low immune status, such as those with human immunodeficiency virus infection, those who are on immunosuppressive drugs and those with end-stage renal disease are also groups that have a trend of treatment failure [20]. The basic problem for these patients is the informahealthcare.com
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lack of the information on the appropriate dosage of antiviral drug for the management of the infection. For the patients who receive an immunosuppressive drug, temporary cessation of that drug during antiviral therapy might be considered [53]. In addition, careful consideration is needed for some specific age groups (the infant and the elderly) as well as during a pregnancy [20]. In young children, rapid antiviral drug elimination can be observed, implying the need for greater doses, compared to adults [8,9]. For pregnancy, there is still a lack of information on safety of an antiviral drug in the long term [54]. There is also a similar lack of information on the immunocompromised patient (such as those who have had transplants) [8,9]. For obese patients, a recent pharmacokinetics study showed that the pharmacobiological process is not different from the general population, implying no need for dosage adjustment [55]. Problems that arise from use of an antiviral drug should not be forgotten. The availability of drugs in a pandemic situation is usually problematic; therefore, adequate stocks of a drug to meet demands posed by a possible pandemic should be planned. A more direct problem to be discussed is the stability of the drug [56]. If an oral antiviral drug is too labile in the gastrointestinal tract, its effectiveness can decrease [56]. It is hoped that ongoing new research to find a prodrug that can decrease the problem of instability of the present antiviral drugs [57]. Rodrı´guez et al. suggest that ‘new antiviral drugs, especially those formulated for intravenous administration, may be the best choice in future epidemics [58]’. Finally, as earlier noted, the cost–effectiveness of an antiviral treatment should also be mentioned. You et al. performed a medical economic study in Hong Kong and concluded that ‘during influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza [57]’. A similar report derives from the USA by Lavelle et al. [59]. Also, considering the argument that the use of antiviral drug treatment can result in drug resistance, Nagase et al. recently performed cost–effectiveness analysis comparing the usefulness of antiviral treatment versus the chance of drug resistance development. They found clear advantages of using antiviral drugs and that the chance of resistance is problematic only if ‘the emerging rate becomes larger than 27% (which has never been reported at this level) [60]’. Hence, antiviral treatments are cost-effective in terms of medical economics. Expert commentary
Influenza remains a highly problematical viral infection. Instability within the viral molecule means that new mutations can be expected, and if a sense mutation occurs, a new and problematic emerging influenza infection can be expected. Early diagnosis is the main step for successful management of infected cases. Antiviral drugs are one of the standard treatments for influenza. Drugs that belong to the group known as neuraminidase inhibitors are recommended. The most widely used antiviral drug at present is oseltamivir. It is recommended 839
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for hospitalized patients as its effectiveness has been confirmed, and prompt drug administration to eligible patients is recommended. To use the antiviral drug treatment, the practitioner has to consider each and every case. Lack of evidence-based data from placebo-controlled studies is the main problem when judging the effectiveness of antiviral treatments currently used among hospitalized patients who have influenza. Effectiveness of an antiviral drug is based on several factors that include the pathogen, the host and the type of antiviral drug. The emerging drug resistance problem requires further drug research to counteract future problems. Epidemiological data on drug resistance is useful information to consult and follow.
of antiviral drug management of the hospitalized infected cases. With the extension of the problem to worldwide scale, international collaboration to perform a good disease surveillance and control can be expected. The use of new computational and IT technology will help identify the geographic distribution of disease and support information for both practitioners and patients toward the use of antiviral drugs. Research scientists continue to find more sensitive and rapid methods for diagnosing influenza that help recruit eligible cases for early antiviral treatment. A critical area of research is to identify the mechanism of drug response and resistance of the circulating influenza virus strain. Also, new drug searches to find updated effective antiviral drug will be continuously performed.
Five-year view
The author expects that there will be continuous reports on the outbreak of classic and newly emerging atypical influenza viral infections. Also, there will be a number of reported cases of drug resistant influenza infections. The use of antiviral drugs continue to rise as the infection will still be persistent and clinicians get more knowledge and continue to become more aware of the infections, their clinical presentations and the usefulness
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
Antiviral drug management is the specific treatment for hospitalized influenza patients.
.
The usefulness of early antiviral treatment for hospitalized influenza patient in reducing mortality is confirmed.
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The cost–effectiveness of antiviral treatment is confirmed.
.
There are several factors affecting the rate of antiviral drug use among hospitalized influenza patients.
.
There are several factors affecting the effectiveness of antiviral drug use among hospitalized influenza patients.
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The practitioner’s role is to update knowledge about recommendations and changing patterns of effectiveness of antiviral drug toward influenza infections.
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Huang WT, Chang CH, Hsu YF, Chuang JH. Prognostic factors for mortality in patients hospitalized with influenza complications, in Taiwan. Int Health 2015; 7(1):73-5
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Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza – recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011;60(1): 1-24
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Tran-To Su C, Ouyang X, Zheng J, Kwoh CK. Structural analysis of the novel influenza A. H7N9) viral Neuraminidase interactions with current approved neuraminidase inhibitors Oseltamivir, Zanamivi r, and Peramivir in the presence of mutation R289K. BMC Bioinformatics 2013;14(Suppl 16):S7
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A report on treatment with oseltamivir among hospitalized patients. Viasus D, Pan˜o-Pardo JR, Pachon J, et al. Timing of oseltamivir administration and outcomes in hospitalized adults with pandemic 2009 influenza A(H1N1) virus infection. Chest 2011;140(4):1025-32 Report on timing of oseltamivir administration. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014;2(5):395-404
Jefferson T, Jones M, Doshi P, et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545
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Rodrı´guez A, Alvarez-Rocha L, Sirvent JM, et al. Recommendations of the Infectious Diseases Work Group (GTEI) of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) and the Infections in Critically Ill Patients Study Group (GEIPC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) for the diagnosis and treatment of influenza A/ H1N1 in seriously ill adults admitted to the Intensive Care Unit. Med Intensiva 2012; 36(2):103-37
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You JH, Chan ES, Leung MY, et al. A cost-effectiveness analysis of “test” versus “treat” patients hospitalized with suspected influenza in Hong Kong. PLoS One 2012; 7(3):e33123
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Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Rates and effectiveness of antiviral use among hospitalized influenza patients Expert Rev. Anti Infect. Ther. 13(7), 835–842 (2015)
Viroj Wiwanitkit Hainan Medical University, Hainan, China and Faculty of Medicine, University of Nis, Sˇumatovacˇka, Nis, Serbia and Joseph Ayobabalola University, Akure Ilesha Rd, Nigeria and Dr DY Patil Medical University, Pune, India and Wiwanitkit House, Bangkhae, Bangkok 10160, Thailand [email protected]
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The influenza virus is currently a global public health problem. There are several thousand cases of classic and newly emerging atypical influenza virus infections around the world annually. Prevention, early diagnosis and treatment are the keys to managing influenza outbreaks. Some influenza treatments have proven to be more useful than others. A standard antiviral drug has been developed and is recommended for the management of hospitalized influenza patients. This article briefly outlines the rates and effectiveness of antiviral use among hospitalized influenza patients. It also discusses some important considerations regarding controversial issues and future perspectives on antiviral use for the management of hospitalized influenza patients. KEYWORDS: antiviral . effectiveness . influenza . patient . rate
Infectious diseases are still important threats to public health at present. There are several kinds of infectious diseases, including viral and bacterial infections. Viral infections are of great concern. Many new emerging viral infections are currently of interest. Emerging viral diseases are usually problematic and have a high risk for causing a worldwide pandemic. Due to the nature of viral infections, specific treatments are usually unavailable and death rates are usually high. Of several new viral diseases, influenza is an important disorder. Influenza is the general name of viral infections caused by influenza virus [1], which has been known for many decades. The virus can cause human and nonhuman infections. Several species of animals can also be infected [2]. The virus mainly attacks the respiratory system and can cause acute respiratory tract manifestations. The infection can occur in both the upper and lower respiratory tracts. In the upper respiratory tract, the virus can affect the nose and pharynx. In the lower respiratory tract, the virus can affect the bronchus and lung. The severity of the infection varies. There is a wide clinical spectrum from asymptomatic to deadly infection. However, in
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general, the classical signs and symptoms of influenza include high fever, headache, sore throat, myalgia, cough, stiff nose and runny nose [3]. The clinical signs and symptoms usually occur abruptly and can last for 5–14 days [3]. Influenza can attack humans, mainly via the respiratory route. Generally, infected patients can spread the virus via droplets generated by coughing and sneezing. The contaminated, aerosolized droplets will disperse in the air and other humans can inhale the contaminated droplets into their respiratory tract. This is the starting point for a new infection, which will occur within 1–3 days. Virologically, the influenza virus is classified under the family orthomyxoviridae [4]. The influenza virus is a genus. The size of the virus in this genus is an estimated 80–120 nm and it possesses filaments. There are many viruses in the genus of the influenza virus. Generally, it can be divided into three main types: influenza A, B and C [4]. All groups are important and are the focus of interest of virologists at present. In order to classify the influenza virus into these three types, antigenic classification is required. The main antigens used for classification are the antigens at the
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virus envelope and nucleoprotein. Viruses of all the three groups can infect human beings. However, influenza A is the main group that infects humans. In addition to the classification on the basis of influenza type, subtype classification can also be carried out. At present, the subtype classification is generally used to specify the problematic influenza virus. To classify subtypes of influenza virus, the antigen at the envelope of the virus is used. There are two main focused antigens for this purpose: hemagglutinin (H) and neuraminidase (N) [4]. Focusing on the influenza type A, there are 15 varieties of H antigen (H1–H15) and nine varieties of N antigen (N1–N9). In order to name an influenza virus, the type, subtype, origin, time or isolation are required [5]. Focusing on the current status of influenza infections, the influenza virus has become the present concern of global public health. Several new human influenza infections have emerged within the past decade. The risk of pandemics is usually mentioned. In addition to the new emerging influenza virus infections, classical influenza virus infections are still problematic. Similar to the new emerging influenza, the risk of a worldwide pandemic of classical influenza can be expected as well. Influenza can be seen to occur at any time of the year. However, there are typically higher incidences of infection during the winter and rainy seasons. During these times of the year, a significantly greater number of patients are treated [5]. Of interest is the fact that humans can be infected with more than one subtype of influenza virus, and that infections may occur repeatedly during an individual lifetime; no lifelong protective antibody against influenza exists naturally. In addition, influenza is easily transmitted by air. Therefore, it is unsurprising that influenza outbreaks are difficult to control [6,7]. The cross species of influenza, which is a new and problematic type of emerging influenza, is usually very hard to manage. As a cross species infection, also known as a zoonosis, this new virus causes atypical clinical symptoms. This causes difficulty in the diagnosis and management of the virus [6,7]. There is no doubt that influenza is presently an important issue to consider in the fields of medicine and public health. There are several international collaborations in place to fight influenza. The concept of primary prevention has proved useful but has been difficult to implement. Basic sanitation also helps prevent influenza, but as a whole it is an ineffective way to fully control an easily transmitted and airborne infection like influenza. Vaccination is the newest form of and possibly the best hope for influenza prevention. However, there are currently several subtypes of influenza circulating around the world, and there is no universal influenza vaccine that can act against all of these subtypes. This seriously reduces the success of using influenza vaccinations to fully manage influenza [6,7]. Additionally, the coverage of the influenza vaccine is usually a problem in many countries and areas within countries. Due to the availability and cost of the influenza vaccine, 100% coverage does not usually occur in any country. Early diagnosis and treatment are required for the management of influenza. However, the diagnosis of influenza is 836
usually based on clinical diagnosis. The confirmation usually requires sophisticated diagnostic tests. Antiviral drug is available for specific influenza treatment [8,9]. After the big pandemic H1N1 influenza 2009, the antiviral drug is easily available [10]. However, the presently available 2011 US CDC guidelines [11] for antiviral treatment of hospitalized patients with influenza are not up-to-date. There is currently not a lot of comprehensive or systematic data regarding the rates of antiviral use in hospitalized patients with influenza. Potential relevant research questions in this area might focus on the potential for antiviral use, including the availability of drugs, laboratory investigations, typical delays from influenza onset to hospital admission, knowledge of antivirals among practitioners and reasons for use or non-use. Presently available antiviral drug for influenza
The management of any viral infection is usually difficult. Unlike a bacterium, a virus is not a living thing, but is considered an infectious particle. Specific antiviral drugs are usually difficult to develop. Many viral infections still lack specific antiviral drugs for their management. However, in the case of influenza, antiviral drugs are available. There are many kinds of new drugs that are known to efficiently manage influenza. However, the classical well-known antiviral drug for the management of influenza is oseltamivir. Oseltamivir is usually recommended as the first-line drug of choice for the management of influenza in both classical and atypical new emerging influenza infections [8,9]. The use of this classical antiviral drug for the treatment of influenza has been widely practiced around the world for a few years. There are also many reports on the use of this classical drug for the management of new atypical influenza. The efficacy and effectiveness of the antiviral drug (including cost–effectiveness) are important topics that should be considered [10]. To support this, the collation of knowledge from available data around the world is required [10]. As previously mentioned, oseltamivir is currently the antiviral drug that is most widely used for the management of influenza. However, other groups of antiviral drugs have been used in the past, for example, the M2 inhibitors (in particular, amantadine and rimantadine), which were commonly used to manage influenza before the availability of oseltamivir. Amantadine and rimantadine inhibit proton transport within the M2 protein channel, which effectively impedes the influenza virus [12]. However, these M2 inhibitors are no longer in use on account of reported side effects and resistance [13,14]. For example, emerging influenza viruses, such as the swine flu, have proven resistant to the M2 inhibitors [15]. The drug oseltamivir acts on pathways that are different from those of the M2 inhibitors. Oseltamivir and several other drugs, such as zanamivir, are classified as neuraminidase inhibitors, which suppress viral activity by inhibiting neuraminidase [16,17]. Oseltamivir and zanamivir are both currently recommended for the effective management of influenza infection, and are also recommended for the management of newly emerging influenza virus infections [8,9]. Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Rates & effectiveness of antiviral use among hospitalized influenza patients
Present recommendations specify that oseltamivir be administered orally within 2 days of the onset of illness, at a recommended dosage of 3 mg/kg, twice daily [8,9]. From a pharmacokinetic and pharmacodynamic perspective, the drug is rapidly absorbed in the gastrointestinal tract, is modified into its active form in the liver and is finally excreted, mainly via the urinary tract (half-life, 6–10 h) [8,9]. The drug is considered safe and has no hepatotoxicity; however, problems related to drug use have been reported, especially the emergence of resistance [18,17]. However, the problems associated with oseltamivir resistance are not frequently detected by clinicians. Crusat and de Jong noted that factors causing the limited efficacy of neuraminidase inhibitors include ‘suboptimal dosing or routes of administration, suboptimal timing of treatment and the inability of antiviral drugs to interfere with immunopathology, and the development of drug resistance [17]’. Although oseltamivir is available, the limitations related to its effectiveness [19] and use are prompting efforts to develop new replacements [8,9,19]. The search for new anti-influenza drugs is an engaging topic for continued biomedical research. As already mentioned, the interesting consideration for oseltamivir use at present is the emergence of antiviral drug resistant influenza virus [20]. A possible new problem for influenza management is drug resistance when using oseltamivir in the treatment of classical H1NI influenza virus infection [20]. As noted by Wiwanitkit [20], good planning for the management of cases of emerging oseltamivir drug resistance is required. In the USA, oseltamivir is still confirmed as having no drug resistance problems [15]. However, there are continuing reports of oseltamivir resistance. Therefore, it is no doubt that drug resistance already occurs. In fact, it is an important consideration with regard to oseltamivir. The problem is usually due to a genetic mutation. If there is a significant genetic mutation within the influenza virus, oseltamivir resistance can occur, and if there is a sense mutation that can seriously affect the virus nanostructure, the present oseltamivir will be out of use. For classical influenza, oseltamivir drug resistance is already observed, but the problem does not extend worldwide [21–23]. Focusing on the root of the cause, the problem usually results from inappropriate use of antiviral drugs, especially when used with no indication [20]. In cases of a pandemic situation, the problem of oseltamivir resistance can also be seen. However, it is not extensively problematic. In the case of pandemic H1N1 influenza, the problem of oseltamivir resistance has been reported, but it was confined. Nevertheless, if there is a new viral variant that is highly resistant to oseltamivir, the serious problem of an uncontrollable pandemic can be expected [20]. Spanakis et al. recently noted that, ‘permissive drift mutations and reassortment of viral gene segments have resulted in neuraminidase inhibitor oseltamivir-resistant A/(H1N1) variants that rapidly became predominant worldwide’ [24]. This situation confirms the importance of the necessity of close surveillance of oseltamivir drug resistance. Spanakis et al. also concluded that, ‘the emergence of oseltamivir-resistant influenza variants that could retain viral transmissibility highlights the necessity for informahealthcare.com
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enhanced epidemiological and microbiological surveillance and clinical assessment of antiviral resistance’ [24]. Focusing on newer neuraminidase inhibitors, such as zanamivir, the problem of drug resistance is also reported. However, the problem is less prevalent [24]. There is an interesting report from China indicating a new problematic mutation, the NA R292K mutation, which results in both oseltamivir and zanamivir resistance [25]. Wei et al. concluded that, ‘other medications would be preferred over oseltamivir or zanamivir,’ in cases with NA R292K mutation [25]. In fact, there are also other new antivirals such as peramivir and laninamivir. Peramivir is a neuraminidase inhibitor that was developed for intravenous administration [26], while laninamivir was developed for use in an inhaler [27]. At present, both peramivir and laninamivir have not received US FDA approval [27,28]. In addition to the two new neuraminidase inhibitors, arbidol is another new drug. It is an antiviral drug in an indole-derivative molecule group [29]. It is a broadspectrum antiviral drug, not specific for influenza [29]. Similar to peramivir and laninamivir, arbitol is still not approved by the US FDA. However, these new drugs are registered in some countries (such as Japan, China and Russia) [27–29]. Although many new reports, with supporting funds from drug companies, show possible good efficacy of the new drugs against influenza, there are still no clinical practice guidelines recommending the use of the new drugs for the management of hospitalized patients with influenza. For these drugs, the data on the drug resistance are limited (however, there are already reports on peramivir [30] and laninamivir resistance [31]). As mentioned, these new drugs are not easily available and registered for use as standard antiviral drugs for influenza worldwide. Hence, these new drugs will not be mentioned much in the present article that focuses mainly on the drugs that are used worldwide for hospitalized patients, and not those drugs in trial or under development. Rates of antiviral use among hospitalized influenza patients
As already mentioned, antiviral drug treatment is the specific treatment for influenza infection. The usefulness of antiviral drug treatment is confirmed, and is presently indicated in any cases with confirmed diagnosis of influenza infection. The rate of antiviral use is interesting. Of course, rates of antiviral use among hospitalized influenza patients in different settings might be different. In a recent report from Philadelphia, ‘of 305 patients (32.8%) eligible for treatment with oseltamivir, 49 (16.1% of those eligible) were prescribed oseltamivir during hospitalization [32]’. In contrast, another report from a less developed country, Thailand, showed that ‘oseltamivir was prescribed in 7.7% of influenza infections [33]’. The reported rate in this Thai study [33] is half of that of a previous report from the USA [32]. These reports show many inappropriate nonprescriptions of antiviral drug for the management of influenza virus infection. At present, there is a lack of comprehensive and systematic data on the rates of antiviral use in hospitalized patients. 837
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A more relevant question might be on the potential for antiviral use, including the availability of drugs and laboratory investigations, typical delays from onset to admission, knowledge of antivirals among practitioners, reasons for use or non-use, etc. There are many possible factors that can affect the rate of antiviral use among hospitalized influenza patients who are eligible and who fulfill indication. The important factors that should be mentioned include diagnosis of infection, availability of drug, cost of drugs, physician’s perception toward antiviral drug use and national policy for antiviral drug use. Focusing on the first factor, diagnosis of infection, there is no doubt that there is some under-diagnosis of influenza at present. Delayed diagnosis can also be problematic. Of interest, Rorat et al. reported that ‘delayed diagnosis and antiviral treatment initiation has a significant impact on mortality in A (H1N1) influenza [34].’ In fact, patients with delayed diagnosis are considered not eligible for antiviral drug use, and this can affect the overall rate of antiviral drug use in hospitalized influenza patients in each setting. Focusing on availability of drugs, this was a big problem in the past. However, due to several new emerging atypical influenza infections, the drug has become more easily available. The cost of the drug is also significantly reduced from the past. It is noted that oseltamivir is more readily available compared to vaccine [35]. In addition to availability of antiviral drug, concern should be on the availability of the physician to prescribe for the antiviral drug. In some countries where the number of physicians in charges is extremely limited, this problem can be expected. The new idea to make antiviral drugs available without prescription is proposed and was first used in New Zealand [36]. This alternative channel seems to be a solution to the problem of availability. However, consideration of patient safety becomes an emerging issue against the concept that ‘individuals can receive treatment without having to consult a medical practitioner, by simply answering a set of questions online or over the telephone [37].’ A good case study from the UK [37] on a patient who suffered side effects from nonprescription oseltamivir is the best example for bringing attention to further risk–benefit studies on the nonprescription availability of antiviral drug. Focusing on national policy toward antiviral drug use, it seems to be an important determinant for success in using antiviral drug for the management of the influenza problem. According to a recent report from Taiwan, Liu et al. reported that ‘the number of prescriptions for oseltamivir increased with a change in government policy [38].’ Finally, not only the rate, but also the onset of drug used should be carefully considered. According to the CDC recommendation, the early antiviral treatment should be given for ‘suspected or confirmed influenza among persons with severe influenza [39]’ and ‘suspected or confirmed influenza among persons at higher risk for influenza complications [39]’. However, it is still a controversial issue on the effect of early use of antiviral drug for treatment of influenza. Tanaka et al. recently reported an interesting finding on how ‘timing of antimicrobial use influences the evolution of antimicrobial resistance during 838
disease epidemics [40].’ Tanaka et al. proposed that ‘the early use of antimicrobials disproportionately drives emergence and spread of antibiotic resistance, leading to subsequent treatment failure [40].’ The risk–benefit analysis toward early antiviral treatment for hospitalized influenza patients is a topic for further study. Of interest, recent research from Taiwan shows that ‘delayed oseltamivir treatment increased the likelihood of in-hospital mortality [41].’ Based on this study, Huang et al. recommended ‘early antiviral treatment for at-risk populations [41].’ A similar observation was reported from Israel by Hiba et al. [42]. Hiba et al. found benefits of early antiviral drug use and recommended that ‘initiation of oseltamivir within 48 h of symptom onset was associated with fewer complications in patients hospitalized with 2009 influenza A (H1N1) [42].’ Adalja concluded that the optimization time of antiviral drug use was the key point for success in the management of hospitalized patients with influenza infection [43]. There are some reports on how to increase the rate of appropriate antiviral drug treatment. For example, Wilkes et al. suggested using of electronic reminder for any eligible case [43]. The continuous medical education to improve the knowledge of the practitioner toward the updated guideline is required. Effectiveness of antiviral use among hospitalized influenza patients
In the preceding section, the author addressed antiviral resistance. In fact, this concern is not very important given the fact that a small amount of transmission occurs from hospitalized patients compared to the amount of transmission among the general population. Of greater concern for more critical appraisal should be the effectiveness of antivirals in hospitalized patients. In clinical practice, apart from the consideration of the rate of antiviral use among hospitalized influenza patients, the effectiveness of antiviral use among this group is another interesting topic to be discussed. In fact, although we can increase the rate of antiviral drug use for 100% of all eligible influenza patients, it will be useless if the effectiveness of the antiviral drug is not sufficient. With regard to the widely used drug, oseltamivir, there are some interesting reports on its effectiveness. To be most effective, the drug has to be used according to the indications given and advised method of administration. Machala et al. found that the ‘administration of the drug within 36 h from the onset of symptoms is one of the factors conditioning the effectiveness of antiviral therapy’ [38]. Nevertheless, Viasus et al. noted that ‘timely oseltamivir administration has a beneficial effect on outcomes in hospitalized adults with A (H1N1), even in those who are admitted beyond 48 h after onset of symptoms’ [44]. As objective evidence, Viasus et al. proved that early administration of antiviral drugs in influenza patients was related to reducing the requirements of mechanical ventilation [44]. In hospitalized patients, it is concluded that the early administration of oseltamivir results in a reduction in mortality [45]. Also, ‘virus isolation rates after treatment’ are significantly lower for cases receiving antiviral treatment [46]. However, it should be noted that although the drug is proven Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Rates & effectiveness of antiviral use among hospitalized influenza patients
effective in hospitalized cases in many studies, some new data show that administering antiviral drugs results in different outcomes in mild influenza cases [47]. In addition, a new report from Europe also showed that using the antiviral drug did not affect the rate of complications (such as otitis and superimposed bacterial pneumonia) [48]. For classical influenza, there are many reports, based on an observational descriptive study, retrospective study or nonplacebo controlled/noncontrolled trials, on the effectiveness of antiviral drugs for treatment of the infection. The effectiveness might be different depending on the time and place. In fact, it has been shown that an effective drug in one study might not be effective in another study. The best example of this is the M2 inhibitor, which was an effective drug in the past, but presently has been shown to be ineffective. For new emerging atypical influenza, the effectiveness of the antiviral drug is usually a questionable issue. In the first phase of the emergence of a new viral disease, medical scientists generally have no knowledge of it. The practitioner is also lacking in preparedness and skill to manage it [8,9]. Indeed, to perform a critical appraisal of the evidence on the effectiveness of antiviral use among hospitalized patients, the quality of evidence to support the effectiveness of antivirals in hospitalized patients should be considered. The lack of evidence-based data from placebo-controlled studies is the main problem with judging the effectiveness of the antivirals presently used among hospitalized patients with influenza. Effectiveness of antiviral drugs is based on several factors covering the pathogen, the host and the antiviral drug. The emerging drug resistance problem requires further drug research to address the future problems. The epidemiological data on the drug resistance is useful information to be followed. First, the mutated pathogen can result in failure of antiviral drug treatment. Matzusaki et al. reported that ‘influenza surveillance to monitor oseltamivir-resistance would aid clinicians in determining an effective antiviral treatment strategy [49]’ Focusing on the drug resistant mutant influenza strain, molecular studies can reveal the alteration of molecular structure that can affect the binding property between antiviral drug and drug target site on the virus and further cause ineffectiveness in infection treatment [50,51]. ‘The large-scale use of drugs for chemoprophylaxis and treatment’ is the main cause of the loss of effectiveness of oseltamivir [52]. The problem of emerging resistant strain becomes the big global problem at present. In addition to the pathogen, the problem of failure of antiviral drug treatment can also be due to the host (patient). For any viral infection, the immunity of the host becomes the important determinant for the success of treatment. For sure, an antiviral drug cannot be used in those cases. In clinical practice, some infected patients are considerably problematic for antiviral treatment. Allergic reaction to the antiviral drug is the simplest case. The others are specific groups of patients with low immune status, such as those with human immunodeficiency virus infection, those who are on immunosuppressive drugs and those with end-stage renal disease are also groups that have a trend of treatment failure [20]. The basic problem for these patients is the informahealthcare.com
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lack of the information on the appropriate dosage of antiviral drug for the management of the infection. For the patients who receive an immunosuppressive drug, temporary cessation of that drug during antiviral therapy might be considered [53]. In addition, careful consideration is needed for some specific age groups (the infant and the elderly) as well as during a pregnancy [20]. In young children, rapid antiviral drug elimination can be observed, implying the need for greater doses, compared to adults [8,9]. For pregnancy, there is still a lack of information on safety of an antiviral drug in the long term [54]. There is also a similar lack of information on the immunocompromised patient (such as those who have had transplants) [8,9]. For obese patients, a recent pharmacokinetics study showed that the pharmacobiological process is not different from the general population, implying no need for dosage adjustment [55]. Problems that arise from use of an antiviral drug should not be forgotten. The availability of drugs in a pandemic situation is usually problematic; therefore, adequate stocks of a drug to meet demands posed by a possible pandemic should be planned. A more direct problem to be discussed is the stability of the drug [56]. If an oral antiviral drug is too labile in the gastrointestinal tract, its effectiveness can decrease [56]. It is hoped that ongoing new research to find a prodrug that can decrease the problem of instability of the present antiviral drugs [57]. Rodrı´guez et al. suggest that ‘new antiviral drugs, especially those formulated for intravenous administration, may be the best choice in future epidemics [58]’. Finally, as earlier noted, the cost–effectiveness of an antiviral treatment should also be mentioned. You et al. performed a medical economic study in Hong Kong and concluded that ‘during influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza [57]’. A similar report derives from the USA by Lavelle et al. [59]. Also, considering the argument that the use of antiviral drug treatment can result in drug resistance, Nagase et al. recently performed cost–effectiveness analysis comparing the usefulness of antiviral treatment versus the chance of drug resistance development. They found clear advantages of using antiviral drugs and that the chance of resistance is problematic only if ‘the emerging rate becomes larger than 27% (which has never been reported at this level) [60]’. Hence, antiviral treatments are cost-effective in terms of medical economics. Expert commentary
Influenza remains a highly problematical viral infection. Instability within the viral molecule means that new mutations can be expected, and if a sense mutation occurs, a new and problematic emerging influenza infection can be expected. Early diagnosis is the main step for successful management of infected cases. Antiviral drugs are one of the standard treatments for influenza. Drugs that belong to the group known as neuraminidase inhibitors are recommended. The most widely used antiviral drug at present is oseltamivir. It is recommended 839
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Wiwanitkit
for hospitalized patients as its effectiveness has been confirmed, and prompt drug administration to eligible patients is recommended. To use the antiviral drug treatment, the practitioner has to consider each and every case. Lack of evidence-based data from placebo-controlled studies is the main problem when judging the effectiveness of antiviral treatments currently used among hospitalized patients who have influenza. Effectiveness of an antiviral drug is based on several factors that include the pathogen, the host and the type of antiviral drug. The emerging drug resistance problem requires further drug research to counteract future problems. Epidemiological data on drug resistance is useful information to consult and follow.
of antiviral drug management of the hospitalized infected cases. With the extension of the problem to worldwide scale, international collaboration to perform a good disease surveillance and control can be expected. The use of new computational and IT technology will help identify the geographic distribution of disease and support information for both practitioners and patients toward the use of antiviral drugs. Research scientists continue to find more sensitive and rapid methods for diagnosing influenza that help recruit eligible cases for early antiviral treatment. A critical area of research is to identify the mechanism of drug response and resistance of the circulating influenza virus strain. Also, new drug searches to find updated effective antiviral drug will be continuously performed.
Five-year view
The author expects that there will be continuous reports on the outbreak of classic and newly emerging atypical influenza viral infections. Also, there will be a number of reported cases of drug resistant influenza infections. The use of antiviral drugs continue to rise as the infection will still be persistent and clinicians get more knowledge and continue to become more aware of the infections, their clinical presentations and the usefulness
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
Antiviral drug management is the specific treatment for hospitalized influenza patients.
.
The usefulness of early antiviral treatment for hospitalized influenza patient in reducing mortality is confirmed.
.
The cost–effectiveness of antiviral treatment is confirmed.
.
There are several factors affecting the rate of antiviral drug use among hospitalized influenza patients.
.
There are several factors affecting the effectiveness of antiviral drug use among hospitalized influenza patients.
.
The practitioner’s role is to update knowledge about recommendations and changing patterns of effectiveness of antiviral drug toward influenza infections.
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