Anti-Influenza Therapy: the Emerging Challenge of Resistance

REVIEW Anti-influenza therapy: the emerging challenge of resistance Influenza is a common cause of respiratory infections, with an annual peak incidence in the late fall, winter and early spring. It is associated with significant morbidity and mortality, particularly in those at the extremes of life and with underlying medical conditions, as well as self-limited illness with reduced productivity in otherwise healthy individuals. Two classes of antiviral medications, M2 inhibitors and neuraminidase inhibitors, are widely available. Use of these agents is associated with reduction in severity and duration of illness, and may be associated with reduced risk of death in certain patient populations. They also are effective in preventing influenza, in addition to or instead of immunization. Unfortunately, widespread resistance to one of the two classes of drugs is now common among most circulating strains of influenza. KEYWORDS: adamantine amantadine influenza M2 inhibitor neuraminidase Michael G Ison inhibitor oseltamivir peramivir resistance rimantadine zanamivir Divisions of Infectious Diseases & Organ Transplantation, Influenza viruses cause annual epidemics of ill- with underlying immune compromise, such as Northwestern University ness characterized by the rapid onset of constitu- transplant recipients [2,6]. As we have learned Feinberg School of Medicine, tional and respiratory tract symptoms [1]. There in the development of vaccines for H5N1 [7], 645 N. Michigan Avenue Suite are three subtypes of influenza: A, B and C [1]. developing novel vaccines directed against pan- 900, Chicago, IL 60611, USA Influenza A viruses are further classified into demic strains pose formidable challenges, and Tel.: +1 312 695 4186 subtypes on the basis of their surface proteins such vaccines will likely be either completely Fax: +1 312 695 5088 (16 hemagglutinins and nine neuraminidases or partially unavailable during the first wave of [email protected] are currently recognized) [1]. Annually, influ- infection. As a result of limitations of the cur- enza affects approximately 5–10% of adults, rent vaccines, antiviral and nonpharmacologic with higher rates in children [2]. In the USA, measures, such as social distancing, will play influenza causes an average of 36,000 deaths an important role in retarding the spread of the and 130,000–170,000 hospitalizations during infection [2,8] during a pandemic. each epidemic [3,4]. Hospitalization and death Once infection is established, antiviral appear to be more common in the very young medications have been shown to decrease the and very old patients, those with abnormal severity of influenza, shorten the duration of immune systems, and those with significant illness, and reduce infectious and noninfectious underlying medical conditions, particularly complications [9,10]. cardio pulmonary disease [2]. In addition, there is a significant financial impact of influenza in the Available anti-influenza agents USA annually, with US$8–12 billion in direct Approved agents medical costs and economic losses due to lost Currently, there are four drugs in two antiviral productivity [5]. classes available for the prevention and treat- The cornerstone of prevention of influenza is ment of influenza: M2 inhibitors (amantadine vaccination [2]. These vaccines are reformulated and rimantadine) and neuraminidase inhibi- each year to attempt to match circulating strains, tors (NAIs; zanamivir and oseltamivir) (FIGURE 1) and availability varies from year to year [2]. [9,10]. Recently, the increase in resistance glob- Vaccination has been shown to reduce the risk of ally to both classes of agents has significantly hospitalization, morbidity and mortality among limited the effectiveness of our current antiviral high-risk patients and be cost-effective, in part, armamentarium [11–14]. secondary to retained productivity among work- ing adults [2,5]. Recommendations for their use M2 inhibitors are updated annually, and the most recent advice The M2 ion channel allows the influx of protons should be consulted [2]. Unfortunately, response into the viral particle which, in turn, facilitates to vaccine is limited in the elderly and those uncoating [9]. M2 inhibitors bind to the M2 ion 10.2217/THY.09.61 © 2009 Future Medicine Ltd Therapy (2009) 6(6), 883–891 ISSN 1475-0708 883 REVIEW Ison Anti-influenza therapy: the emerging challenge of resistance REVIEW channel and limit the influx of protons, result- The proprietary inhaler device for delivering ing in its antiviral effect. Since the M2 protein is zanamivir is breath-actuated and requires a present only on influenza A viruses, M2 inhibitors cooperative patient [20]. Zanamivir may cause have no activity against influenza B[9] . bronchosconstriction with use; it should be used There are two US FDA-approved M2 inhibi- with caution in patients with underlying lung tors: amantadine (Symmetrel®, Endo, PA, disease, and these patients should have ready USA) and rimantadine (Flumadine®, Forest access to a rapidly acting bronchodilator in the Laboratories, NY, USA) [15]. Although the event of bronchospasm [10]. Few other side effects mechanism of action and spectrum of activ- are noticed, since there is limited systemic expo- ity are similar, there are important pharmaco- sure [10]. Oseltamivir carboxylate is an orally kinetic differences between the two drugs [16]. bioavailable ethyl ester prodrug of oseltamivir Amantadine, which has a half-life of 12–18 h, phosphate [10]. The prodrug is rapidly converted is not extensively metabolized and is excreted to active drug by intestinal and hepatic esterases. unchanged in the urine [9]. Therefore, aman- Oseltamivir is eliminated primarily by tubular tadine accumulates rapidly in patients with secretion unchanged. As a result, oseltamivir reduced renal function, including the elderly [9]. requires dose adjustment in individuals with The most common side effects of amantadine a creatinine clearance rate of less than 30 ml/ are minor, reversible CNS effects, such as insom- min [10]. The most common side effect of osel- nia, dizziness and difficulty in concentrating[9] . tamivir is gastrointestinal upset, which is ame- Side effects appear to be more common among liorated with co-administration with food [10]. the elderly; confusion is noted in approximately 18% of elderly recipients [17]. In addition, aman- Investigational agents tadine use has been associated with seizures in The threat of an A/H5N1 pandemic and emerg- individuals with a prior seizure disorder [18]. ing resistance to both M2 inhibitors and NAIs Dose adjustment of amantadine is therefore has stimulated research into several investiga- indicated in those with renal dysfunction and tional anti-influenza agents; these have been in the elderly [9,16]. In contrast, rimantadine is reviewed extensively elsewhere [21,22]. Many extensively metabolized, with less than 15% of of the agents under current investigation are the drug excreted unchanged in the urine [9,16]. new NAIs [23,24]. Peramivir is also undergoing As a result, rimantadine is associated with con- investigation as both an intravenous and an siderably fewer CNS side effects and is better intramuscular formulation [23,24]. Two topical tolerated by the elderly. Rimatadine needs to long-acting NAIs are also being developed; their be adjusted in the elderly and those with severe major advantage is the less frequent dosing for renal dysfunction (<10 ml/min) [9,16]. prophylaxis. In addition, several compounds with novel mechanisms of action are being devel- Neuraminidase inhibitors oped (TABLE 1) [21–24]. These newer agents typi- The influenza neuraminidase has enzymatic cally remain active against viruses resistant to activity that cleaves terminal sialic acid residues M2 inhibitors and NAIs, and have been recently and destroys the receptors recognized by viral reviewed elsewhere [21,22]. hemagglutinin [10,19]. This activity is essential for release of virus from infected cells, for pre- M2 inhibitor resistance vention of viral aggregates and for viral spread Resistance to the available M2 inhibitors has within the respiratory tract [19]. The NAIs are been recognized since early in their development. sialic acid analogs that potently and specifically Mutations in the M2 inhibitor gene at one of five inhibit influenza A and B neuraminidases by commonly recognized sites (position 26, 27, 30, competitively and reversibly interacting with 31 or 34 of the M2 protein) results in reduced the active enzyme site [10]. binding of the M2 inhibitors or in enlargement There are currently two NAIs approved by the of the pore diameter; by either mechanism, the FDA: zanamivir (RelenzaTM, GlaxoSmithKline, function of the M2 pore is preserved in the pres- ® London, UK) and oseltamivir (Tamiflu , Roche, ence of the inhibitor [25–27]. Resistance muta- Basel, Switzerland) [10]. Although each drug has tions do not affect transmissibility or replica- unique pharmacologic properties, both have tion fitness as compared with wild-type viruses; identical mechanisms of action and similar documented transmission from person to person profiles of antiviral activity [10]. Zanamivir is has been well established [28]. Resistance affects not orally bioavailable and is therefore admin- both drugs in the class equally, and appears to istered topically by dry-powder inhalation [10]. be persistent over time [26,29]. 884 Therapy (2009) 6(6) future science group REVIEW Ison Anti-influenza therapy: the emerging challenge of resistance REVIEW Table

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