170 Treatment and Prophylaxis

Chapter 9: Treatment and Prophylaxis

C. Hoffmann, S. Korsman and B.S. Kamps

Introduction

Most patients with uncomplicated human influenza, especially adolescents and young adults, can be treated symptomatically and need no specific intervention. In the elderly, however, treatment with antiviral drugs is a good option. These drugs should further be considered for high-risk individuals, especially patients with underlying medical conditions, as well as in a number of special situations.

Neuraminidase inhibitors are effective against all variants that have caused disease in humans, including the virus of the 1918 pandemic (Tumpey 2005). In human H5N1 influenza, treatment with an oral neuraminidase inhibitor, oseltamivir, seems to be effective in some cases, but may fail in others. Recently, resistant strains have been reported (de Jong 2005). In addition, the dosage and duration of treatment appear to be different in severe H5N1 cases.

In the case of a future pandemic, antiviral drugs may play an important role in the early phase, when vaccines against the new strain are not yet available or as long as the available vaccine is in short supply.

Antiviral Drugs

Of the four antiviral drugs currently available for the treatment of influenza A infection (two neuraminidase inhibitors and two M2 ion channel inhibitors), only the neuraminidase inhibitors oseltamivir and zanamivir are also active against influenza B. All drugs are most effective if started within a few hours of the onset of symptoms and are generally licensed for use within 48 hours of the first symptoms. They can modify the severity of illness, as well as reducing the intensity of influenza symptoms and decreasing the duration of illness by about 1 to 3 days. However, the extent to which antiviral treatment leads to a reduction of serious complications and hospitalisation is still subject to debate. Treatment success is, in part, a variable of the time between the onset of symptoms and the beginning of antiviral treatment: the sooner after onset treatment begins, the better.

The neuraminidase inhibitors, oseltamivir and zanamivir, have fewer side effects than the M2 ion channel inhibitors rimantadine and amantadine, and drug resistance seems to develop less frequently. The clinical pharmacology, adverse effects and resistance profiles of these drugs are discussed in detail in the Drugs chapter.

The neuraminidase inhibitor, oseltamivir (Tamiflu®), is currently the drug of choice for the treatment of human H5N1 influenza.

Neuraminidase Inhibitors

These drugs – introduced in 1999 and 2000 – interfere with the normal function of the influenza neuraminidase by mimicking sialic acid, the natural substrate of the

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neuraminidase (Varghese 1992, Varghese 1995). The viral neuraminidase is responsible for cleaving sialic acid residues on newly formed virions, playing an essential role in their release and facilitating virus spread within the respiratory tract. When exposed to neuraminidase inhibitors, the influenza virions aggregate on the surface of the host cell, limiting the extent of infection within the mucosal secretions (McNicholl 2001) and reducing viral infectivity (see Figure at http://content.nejm.org/cgi/content/full/353/13/1363/F1). Experimental evidence further suggests that influenza neuraminidase may be essential at the early stage of virus invasion of the ciliated epithelium of human airways (Matrosovich 2004). The design of the neuraminidase inhibitors was a result of the analysis of the threedimensional structure of influenza neuraminidase which disclosed the location and structure of the catalytic site (Colman 1983).

Numerous treatment studies in healthy adults have shown that neuraminidase inhibitors, when taken within 36 to 48 hours after the onset of symptoms, decrease the symptomatic illness by one or two days (Hayden 1997, Monto 1999, Treanor 2000, Nicholson 2000, Hedrick 2000, Cooper 2003, Whitley 2001, Aoki 2003). Early initiation of treatment is decisive for treatment efficacy (Aoki 2003, Kawai 2005). When started within the first 12 hours following the onset of fever, neuraminidase inhibitors shortened the illness by more than three days, in comparison to treatment that was started at 48 hours. The duration of fever, severity of symptoms, and time to return to normal activity also correlated with the time of initiation of antiviral intervention.

A study in Canadian long-term care facilities showed that older nursing home residents who were treated with oseltamivir within 48 hours after the onset of symptoms were less likely to be prescribed antibiotics, to be hospitalised, or to die (Bowles 2002). Side effects were rare (4.1 %), the most common being diarrhoea (1.6 %), cough (0.7 %), confusion (0.5 %) and nausea (0.5 %). Another study suggested that oseltamivir treatment of influenza illness reduces lower respiratory tract complications, antibiotic use, and hospitalisation in both healthy and “at-risk” adults (Kaiser 2003).

Prevention trials have shown that neuraminidase inhibitors administered prophylactically reduce the risk of developing influenza by 60-90 % when given at the start of the influenza outbreak (Monto 1999b, Cooper 2003). When administered prophylactically to household contacts of an influenza index case, protective efficacy against clinical influenza was generally > 80 % (Hayden 2000, Kaiser 2000, Welliver 2001, Monto 2002).

Neuraminidase inhibitors are generally well-tolerated. Transient gastrointestinal disturbance (nausea, vomiting) is the major adverse effect of oseltamivir. In particular, the observed safety profile of oseltamivir and zanamivir compares favourably with the M2 inhibitors rimantadine and amantadine (Freund 1999, Doucette 2001).

Rarely, with oseltamivir, serious skin/hypersensitivity reactions may occur, and patients should, therefore, be cautioned to stop taking oseltamivir and contact their healthcare providers if they develop a severe rash or allergic symptoms (FDA 2005). Bronchospasm and a decline in lung function (FEV1 or peak expiratory flow) have been reported in some patients with underlying pulmonary conditions, such as asthma or chronic obstructive pulmonary disease, on zanamivir. Zanamivir is therefore not generally recommended for the treatment of patients with underly-

172 Treatment and Prophylaxis

ing airways disease, and should also be discontinued in patients who develop bronchospasm or who have a decline in respiratory function (Relenza 2003).

The potential for drug-drug interactions is low, both for oseltamivir and zanamivir. In oseltamivir, competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter may occur. Probenecid may more than double systemic exposure to oseltamivir carboxylate (Hill 2002).

Naturally occurring virus strains resistant to neuraminidase inhibitors are believed not to exist in human influenza A (McKimm-Breschkin 2003). In vitro, the NA mutations E119V, R292K, H274Y, and R152K were associated with resistance to oseltamivir (McKimm-Breschkin 2003). Some mutations, i.e., the R292K and H274Y mutation, lead to a functionally defective enzyme with compromised viral fitness, and it has been suggested that viruses carrying these mutations are unlikely to be of significant clinical consequence in man (Tai 1998, Carr 2002, Ives 2002, Herlocher 2004). However, a recent report describes a resistant H5N1 strain carrying the H274Y mutation causing viremia in two patients who subsequently died from avian influenza (de Jong 2005). Zanamivir seems to retain in vitro activity against some oseltamivir-resistant strains (McKimm-Breschkin 2003, Mishin 2005).

Following clinical use, the incidence of development of resistant strains is lower among adults and adolescents older than 13 years, than among children. One study found neuraminidase mutations in strains from 9/50 children (18 %) taking oseltamivir. (Kiso 2004). These findings are reason for concern, since children are an important transmission vector for the spread of influenza virus in the community. In the case of an H5N1 pandemic, the frequency of resistance emergence during oseltamivir treatment of H5N1 paediatric patients is uncertain, but it is likely to be no less than that observed in children infected with currently circulating human influenza viruses (Hayden 2005).

Neuraminidase inhibitors are effective against the virus that caused the 1918 pandemic (Tumpey 2002).

Indications for the Use of Neuraminidase Inhibitors

Oseltamivir (Tamiflu®) and zanamivir (Relenza®) are currently licensed for the treatment of influenza A and B. They should be used only when symptoms have occurred within the previous 48 hours and should ideally be initiated within 12 hours of the start of illness.

In addition, oseltamivir – but not zanamivir (with the exception of two countries) – is also licensed for prophylaxis when used within 48 hours of exposure to influenza and when influenza is circulating in the community; it is also licensed for use in exceptional circumstances (e.g. when vaccination does not cover the infecting strain) to prevent an influenza epidemic.

Oseltamivir and zanamivir seem to have similar efficacy, but they differ in their modes of delivery and tolerability. Zanamivir is delivered by inhalation and is well tolerated; however, children, especially those under 8 years old, are usually unable to use the delivery system appropriately and elderly people may have difficulties, too (Diggory 2001). Oseltamivir is taken in the form of a pill but may produce nausea and vomiting in some patients.