Influenza antivirals and resistance: the next 10 years?

Keywords::

• antiviral
• drug resistance
• influenza virus
• neuraminidase inhibitor
• novel target

Antivirals against influenza first became available in the 1960s when an adamantane compound, amantadine, was approved for the treatment and prophylaxis of influenza A viruses. Rimantadine, another adamantane drug with fewer side effects than amantadine, was approved for use in the 1990s. In the late 1990s, a new class of rationally designed influenza antivirals known as the neuraminidase (NA) inhibitors (NAIs; namely oseltamivir [Tamiflu^™, Hoffmann-La Roche] and zanamivir [Relenza^™, GlaxoSmithKline]) became available. Since this time oseltamivir has become the most widely used influenza antiviral drug around the world, due in part to widespread resistance to the adamantanes and lower patient acceptance of inhaled zanamivir. However, with increasing concerns about oseltamivir resistance in A(H1N1)pdm09 viruses, the case for the development of new influenza antivirals is compelling. Here, the authors highlight some novel anti-influenza compounds that are in late-phase clinical trials, and discuss the likelihood of resistance to these and the current NAI compounds emerging in the next 10 years.

The changing influenza antiviral landscape

New NAIs

Two new NAIs, peramivir (Biocryst Pharmaceuticals) and laninamivir (Daiichi-Sankyo/Biota Holdings) were approved for use in Japan in 2010, and in the coming 10 years are likely to be licensed elsewhere. Peramivir is approved for use intravenously (iv.) in seriously ill patients and those with uncomplicated influenza infections, although its high cost (twice that of a course of oseltamivir) and iv. route of administration suggest that it is unlikely to be widely used in patients with mild infections. Phase III trials to evaluate efficacy and safety in adults and adolescents hospitalized with influenza in the USA are due to start shortly (NCT00958776, [101]). Peramivir given intramuscularly has also been trialed but did not prove to be efficacious. Iv. formulations of zanamivir and oseltamivir have also been developed for the treatment of critically ill patients, and are currently in Phase III and I trials, respectively (NCT01527110 and NCT01053663 [101]). Under emergency-use authorization requests, iv. NAIs were extensively used in some countries to treat hospitalized patients during the 2009 pandemic [1]. Licensure of these iv. formulations in the future should improve the speed with which clinicians can access these formulations for patient care, resulting in improved and easier treatment for seriously ill patients, especially those on ventilators.

Laninamivir is a new NAI with structural similarities to zanamivir. However, unlike the older NAIs, laninamivir has a considerably longer retention time, such that a single inhaled dose is sufficient for 1 week, avoiding the twice-daily administration needed for both oseltamivir and zanamivir. After just 1 year on the market, laninamivir has become the highest selling NAI in Japan (1.7 million retail and hospital sales vs 1.4 million for oseltamivir; IMS Health [102]), possibly due to the ease of a single-dose administration and the ongoing concerns in Japan regarding neuropsychiatric events associated with oseltamivir use. Clinical trials in the USA are planned for the 2012/13 influenza season.

Novel virus targets

A large number of novel compounds with anti-influenza virus activity are currently being investigated. These include small-molecule drugs, monoclonal antibodies, therapeutic proteins, peptides and short interfering RNAs. Although most of these are in early development, two small-molecule drugs, T-705 (favipiravir, Toyama Chemical) and NT-300 (nitazoxanide, Romark Laboratories) are in late-phase clinical trials and have the potential to be licensed in the near term.

T-705 is metabolized to a nucleotide analog that interferes with the synthesis of influenza viral RNA [2]. T-705 inhibits a wide range of human and animal RNA viruses including influenza, but unlike ribavirin it does not interfere with host cell DNA or RNA synthesis, and therefore is less cytotoxic with potentially fewer side effects [2,3]. Mouse studies have shown T-705 to be effective against highly pathogenic A(H5N1) viruses even when administered 72 h postinfection [3], an encouraging finding given that antiviral treatment is often delayed in A(H5N1) infected patients. T-705 and oseltamivir have also been shown to have a synergistic effect when used in combination [4].

Nitazoxanide is a thiazolide compound that has antiviral activity against influenza, rotavirus, chronic hepatitis B and C, and other RNA and DNA viruses, and has already been licensed in the USA for treating the parasites Cryptosporidium and Giardia in children and adults [5]. Nitazoxanide inhibits influenza virus replication by blocking the maturation of the hemagglutinin (following translation of viral proteins in the cytoplasm), impairing intracellular trafficking of the glycoprotein to the cell surface [6]. Although there are only limited in vitro and animal data demonstrating the anti-influenza effect of nitazoxanide [6,7], a Phase II/III study of the compound in adults and adolescents with acute uncomplicated influenza demonstrated good efficacy in reducing the duration of clinical symptoms (NCT01227421 [101]). A further Phase III study is starting soon (NCT01610245 [101]).

Is resistance likely to be a problem in the future?

Although the development of resistance in patients undergoing antiviral therapy can limit therapeutic options for individual patient treatment, it is the widespread transmission of resistant viruses in the absence of antiviral use that is of most risk to public health. Such a scenario occurred in the mid 2000s with the global spread of adamantane-resistant A(H3N2) viruses [8], in 2007/2008 with oseltamivir-resistant seasonal A(H1N1) viruses with a H275Y NA mutation [9,10], and in 2009 with the emergence and persistence of the adamantane-resistant A(H1N1)pdm09 viruses [11]. In each case, the resistant viruses spread rapidly around the world and became the predominant strain within their respective subtype. The adamantane-resistant A(H3N2) and A(H1N1)pdm09 viruses continue to circulate, resulting in recommendations against the use of both amantadine and rimantadine [103]. It is important to note that the emergence and spread of these resistant strains have occurred despite negligible drug use. While it is unknown whether the initial resistant viruses arose under drug selection pressure, it is clear that the mutations that conferred resistance did not adversely affect the viruses’ ability to replicate or transmit. But how likely is it that new ‘fit’ resistant strains will arise in the future?

The most immediate concern is that oseltamivir-resistant A(H1N1)pdm09 viruses with a H275Y NA mutation will spread in a similar manner to that seen with the seasonal A(H1N1) viruses in 2007/2008. Recent increases in the frequency of oseltamivir-resistant A(H1N1)pdm09 H275Y variants in the UK and USA [12,13] and a cluster of cases in Australia in 2011 [14] demonstrate that these viruses are now able to transmit from person to person and highlight the potential for global spread. The H275Y variants remain sensitive to zanamivir and laninamivir, but have reduced sensitivity to peramivir in vitro. Although there is considerable focus on the H275Y A(H1N1)pdm09 variants, it should not be forgotten that apparently fit oseltamivir-resistant viruses of other influenza types/subtypes have also been detected. For example, a cluster of influenza B viruses with reduced oseltamivir sensitivity due to an I221T NA mutation was detected in North Carolina (USA) during the 2010/2011 season [15], and oseltamivir-resistant A(H3N2) viruses with an E119V mutation, which demonstrate fitness in animal experiments [16], are detected in treated patients on occasions.

Zanamivir resistance has rarely been detected in any influenza types/subtypes, presumably due to the drug’s structural similarity to sialic acid (the natural substrate of influenza), meaning that resistant viruses may be unable to replicate efficiently. Laninamivir is structurally similar to zanamivir, and therefore it is assumed that resistance to this drug will also occur infrequently. However, the increasing use of laninamivir in Japan and the prospect of licensure in other countries in the next 5 years mean that monitoring of circulating strains for laninamivir sensitivity will be important to confirm this prediction.

Little is currently known about the likelihood that influenza viruses will develop resistance to the two novel compounds T-705 and nitazoxanide, although some insights may be gained from the use of these drugs against other viruses. Although ribavirin-resistant polio and hepatitis C viruses have been reported [17,18], resistant influenza viruses have not, suggesting that T-705-resistant influenza may not readily arise. Serial passaging of hepatitis C virus in increasing concentrations of nitazoxanide failed to select viruses that were drug resistant [19] and no resistance has been reported in treated patients with chronic hepatitis infections. However, as the mechanisms of action of both T-705 and nitazoxanide differ between these viruses, studies investigating the propensity for influenza viruses to develop resistance to these drugs are needed.

Conclusion

The influenza antiviral drug landscape in 10 years time is likely to be considerably more populated than it currently is. However, there is also the possibility that one of the new drugs will dominate the market to the point that other compounds become scarce. Such an outcome would be undesirable for public health, and create a reliance on a single antiviral drug, similar to that currently seen with oseltamivir. New NAIs such as laninamivir offer a more convenient single-dose administration and are less likely to select for viral resistance than oseltamivir, while iv. NAI formulations will be relied upon for the treatment of critically ill patients. Most significantly, influenza antivirals will expand beyond the NAIs and target viral proteins that may be less prone to resistance mutations. With an increase in the available antiviral drugs comes the ability to use combination therapies, potentially improving patient outcome and reducing the chances of resistance selection. History shows that the emergence of antiviral-resistant influenza viruses has been unpredictable and, as new drugs come onto the market during the next ten years, it will be important to determine the viral mutations that confer resistance to these compounds and the fitness of any resistant strains that arise.

Financial & competing interests disclosure

The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health and Ageing. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.