BMJ  2007;334:293-294 (10 February), doi:10.1136/bmj.39105.428981.BE

Analysis

Role of combination antiviral therapy in pandemic influenza and stockpiling implications

¹ Fourth Academic Department of Internal Medicine, University of Athens Medical School, Athens 12462, Greece, ² South West Public Health Training Programme, Dorset, ³ Department of Hygiene and Epidemiology, University of Athens Medical School

It is impossible to predict which drugs will be effective against a new pandemic strain of influenza. Sotirios Tsiodras and colleagues argue that failure to stockpile both major classes of antiviral drugs could prove costly

We currently have two classes of drugs that are effective against influenza viruses: the M2 ion channel inhibitors (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir, zanamivir).¹ Although ion channel inhibitors are effective against several subtypes of influenza A viruses,² they are not being widely stockpiled for a future influenza pandemic.³ This is because they cause unacceptable side effects¹ and their use is associated with a rapid emergence of resistance^{1 4 5} without any demonstrable reduction in transmissibility or pathogenicity.⁶ Resistance of influenza A viruses to amantadine is increasing worldwide,⁷ and the US Centers for Disease Control and Prevention recommended against the use of ion channel inhibitors for treatment or prophylaxis during the 2005-6 influenza season.⁸ Policy makers and some medical experts thus consider ion channel inhibitors inappropriate as first line treatment or prophylaxis for pandemic influenza. We believe their role should be reconsidered for three reasons: firstly, the unpredictability of antiviral susceptibility in novel strains of influenza; secondly, on economic grounds; and lastly, for reasons of long term chemical stability.

Why stockpile ion channel inhibitors?

The strongest argument for having ion channel inhibitors available for a pandemic is that we cannot predict the antiviral susceptibility of a novel influenza strain. Ion channel inhibitors show a broad antiviral spectrum against influenza A strains and naturally occurring resistance in new strains is very low.^{9 10} In addition, a recombinant virus possessing the M segment of the 1918 strain was inhibited effectively both in tissue culture and in vivo by amantadine and rimantadine.¹¹ Similarly, influenza strains with pandemic potential occurring later in the 20th century were susceptible to ion channel inhibitors.¹²

Moreover, avian H5N1 strains continue to evolve.¹³ Isolates from human cases in Vietnam, Thailand, and Cambodia differ genotypically from isolates from Indonesia, China, and Eastern European cases¹³ and these differences affect their antiviral susceptibility. The strains from Vietnam, Thailand, and Cambodia have characteristic polymorphisms that confer amantadine resistance¹⁴ whereas isolates from the other countries are mostly susceptible to ion channel inhibitors.¹⁵

Emergence of a pandemic strain resistant to neuraminidase inhibitors cannot be excluded, especially as the use of these drugs is expected to increase. Only one mutation is required to lead to full resistance,^{16 17} as is the case for resistance to M2 ion channel inhibitors, and resistance has already occurred in H5N1 strains that have infected humans.¹⁸ Moreover, wide scale prophylaxis with a single drug may lead to resistance becoming commonplace.

Combination therapy

Importantly, the combination of ion channel and neuraminidase inhibitors in vitro reduced the emergence of resistance and may even act synergistically against influenza A viruses.^{19 20} Even low concentrations of oseltamivir prevented the emergence of amantadine resistant variants of the highly pathogenic avian influenza H5N1 virus isolated from Hong Kong in 1997.¹⁹ Combination therapy may also allow the use of a lower dose of ion channel inhibitors, which is known to reduce side effects.²¹

Thus combined use of these drugs may be useful in a future pandemic either for prophylaxis (this needs to be further assessed) or, more importantly, for treatment. The World Health Organization recently recommended combined use of ion channel and neuraminidase inhibitors against the H5N1 subtype.²² However, this recommendation was deemed weak because it was based on low quality evidence (largely because of a scarcity of good trial data), and neuraminidase inhibitors continue to be the preferred treatment when available.²² We urgently need adequately sized trials with combinations of anti-influenza drugs to improve the evidence base.

Costs

Ion channel inhibitors are an older and considerably cheaper class of drug than neuraminidase inhibitors (a sevenfold difference in the September 2006 British National Formulary). The additional cost implications of maintaining stocks of both types of antiviral drug are therefore modest. The low cost of ion channel inhibitors, however, could also be a disincentive for drug companies to research their potential role in a flu pandemic. This may partly explain the current lack of evidence and suggests that we may need publicly funded trials into combined regimens. The potential benefits of other therapies alone or in combination with existing antiviral drugs also needs exploring. Interventions against the inflammatory cascade that is believed to explain the lethality of H5N1 have been recently highlighted²³ and statins may have a role here.²⁴

In conclusion, ion channel inhibitors could yet have an important role in our armoury against a future flu pandemic. To preserve their activity we recommend that they are not used as monotherapy or for prophylaxis against seasonal or avian influenza. Several countries including the US, the UK, and Greece are already stockpiling ion channel inhibitors. Other countries should consider following suit. As well as being cheap, these drugs are chemically stable, giving them a long shelf life.²⁵ Combined antiviral therapy with neuraminidase inhibitors has the potential to reduce both their side effect profile and the likelihood of resistance. More clinical data are urgently needed to verify such an effect.

Summary points Ion channel inhibitors are not recommended for monotherapy or prophylaxis against seasonal or avian influenza Combined use with neuraminidase inhibitors may reduce side effects and the risk of resistance Adequately sized trials of such combinations are urgently needed Stockpiling of ion channel inhibitors should be considered for potential use in a flu pandemic

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Contributors and sources: ST, JDM and AH have all worked extensively in public health issues relevant to pandemic influenza in their respective countries. This article arose from discussions and planning for pandemic preparedness. ST and AH conceived the idea of the manuscript and ST, JDM and AH drafted and critically revised the manuscript. ST and AH can serve as guarantors for this article.

Competing interests: None declared.

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(Accepted 16 January 2007)

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