Elsevier

Vaccine

Volume 21, Issue 16, 1 May 2003, Pages 1796-1800
Vaccine

The role of antivirals in the control of influenza

https://doi.org/10.1016/S0264-410X(03)00075-6Get rights and content

Abstract

Antivirals are effective in the prophylaxis and therapy of influenza and are likely to be active against a new pandemic variant. They can be divided into the M2 inhibitors, amantadine and rimantadine, and the neuraminidase inhibitors (NIs), zanamivir and oseltamivir. The former are limited in activity to type A viruses, while the latter are also active against type B viruses. Both classes of drugs are approximately 70–90% efficacious when used as prophylaxis. However, the use of M2 inhibitors in therapy is frequently limited by side effects, more common with amantadine, by the emergence of antiviral resistance and by the lack of demonstrated prevention of complications. In contrast, the NIs are better tolerated, antiviral resistance has not emerged as a significant problem and limited evidence suggests they may reduce the frequency of influenza complications. Antiviral agents have not been widely used for either prophylaxis or treatment of annual influenza epidemics. During the early months of the next pandemic they will be the only specific agents that could be used for prevention and treatment. Their availability will depend entirely on the creation of stockpiles of these agents well in advance of the arrival of the pandemic.

Introduction

Vaccines protect against influenza by stimulating an immune response in recipients. To do so, the antigens contained in the vaccine must resemble those of the circulating viruses. In contrast, the mechanism of action of influenza antivirals is independent of the antigenic make-up of the circulating viruses. The drugs are active in treatment as well as prophylaxis, but in prophylaxis they must be administered daily throughout the period of risk of exposure. They may be particularly important for pandemics when supplies of vaccines, especially in the early months, are likely to be severely limited.

Two classes of influenza antivirals are available for use. Each class inhibits a different step in the viral replication cycle. Type A but not type B influenza viruses contain an M2 protein. This protein is responsible for uncoating the viral nucleoprotein during replication. It functions as an ion channel, preventing exposure of the viral hemagglutinin to low intracellular pH to which it is sensitive. Amantadine and rimantadine inhibit this activity and they are termed ‘M2 inhibitors’ [1], [2]. These drugs have no effect on type B influenza viruses because B viruses do not possess an M2 protein.

The viral neuraminidase of both type A and B viruses facilitates the release of virus from the infected cell after replication is complete and prevents viral clumping before the next infectious cycle begins. Zanamivir and oseltamivir are the two licensed neuraminidase inhibitors. They have been specifically designed to interrupt the replication cycle by preventing virus release and allowing virus to clump [3], [4]. Zanamivir is administered by inhalation, while oseltamivir is taken orally, as are amantadine and rimantadine.

Section snippets

Characteristics of M2 and neuraminidase inhibitors

The M2 inhibitors, amantadine and rimantadine, are similar in their antiviral activities but differ in their metabolic and safety profiles. These differences are of considerable importance and will affect their potential use in a pandemic. Amantadine, the more widely available of the two, is excreted by renal tubular secretion with little metabolic change [5]. Therefore, the dose must be reduced in anyone with renal insufficiency [6]. In contrast, rimantadine is extensively metabolized by the

Use in prophylaxis and therapy: M2 inhibitors

Amantadine and rimantadine are similar in their activity against type A viruses and they will be considered together. The studies summarized in Table 1 demonstrate the efficacy of both drugs when given as ‘seasonal prophylaxis’ during 4–6-week periods of peak influenza virus activity. During the influenza A (H1N1) epidemic in 1978, amantadine was 71% effective in preventing infection in a group of subjects never previously exposed to this virus [11]. This experience was similar to what can be

Use in prophylaxis and therapy: neuraminidase inhibitors

With the neuraminidase inhibitors, a large amount of data has been collected on their efficacy in prophylaxis and therapy. Although the two drugs are administered differently, the clinical trial results have been similar and they will be reviewed together. In seasonal prophylaxis, zanamivir was studied over a 4-week period and oseltamivir over a 6-week period [21], [22]. As shown in Table 2, the efficacies of the two drugs in preventing both type A and type B influenza were similar to each

Side effects associated with the M2 and neuraminidase inhibitors

In the prophylaxis studies of M2 inhibitors shown in Table 1, withdrawal from treatment was used to indicate more severe adverse effects. In the study of amantadine only, there was a 6% excess withdrawal rate in treated subjects compared with those taking placebo. In the second study, the excess withdrawal rate associated with amantadine was 11%, but there were no excess withdrawals in those given rimantadine. Side effects associated with amantadine in these and other studies included

Use of the antivirals in pandemics

Since pandemics are caused by type A influenza viruses, both classes of antiviral agents could be used in prevention and treatment. Recommendations for their use in a pandemic have recently been developed by the World Health Organization [38]. These recommendations are based on what is currently known. Additional studies could help define more precisely how they might be used in a pandemic. For example, if NIs are preferred for therapy, it would help to know if treatment could be given for less

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