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Nitazoxanide for Treatment of Drug-resistant Influenza

By Amesh A. Adalja, MD, FACP, March 22, 2013

The antiviral armamentarium against influenza consists primarily of 2 classes of drugs: adamantanes and neuraminidase inhibitors. In the US, 2 adamantanes (amantadine and rimantidine) and 2 neuraminidase inhibitors (oseltamivir and zanamivir) are available. Other neuraminidase inhibitors not approved for use in the US include peramivir and lanamivir; the antiviral ribavirin that is approved for use against hepatitis C and RSV infections also has activity against influenza.

With resistance to adamantanes now widespread, the neuraminidase inhibitors are the primary treatment option; however, use of zanamivir is limited because it requires administration by an often cumbersome inhalation device. Of late, resistance to neuraminidase inhibitors has been limited, except during the 2008-2009 seasonal influenza season, during which the seasonal H1N1 virus exhibited widespread resistance to oseltamivir. Thus, oseltamivir has the almost exclusive status as the antiviral of choice.

Given the 2008-2009 experience, coupled with sporadic reports of other instances of antiviral resistance, oseltamivir resistance is a real concern, and few options exist for treating drug-resistant influenza.

A Role for Nitazoxanide?

Nitazoxanide, an oral antiparasitic that is FDA-approved for treatment of Giardia and Cryptosporidium infections (and used off-label regularly for infections caused by the bacterium Clostridium difficile) was recently the subject of a $44 million BARDA contract for advanced development as a treatment for of drug-resistant influenza.1

Nitazoxanide’s ability to halt influenza viral replication is derived from an as-yet not fully described mechanism of action that is distinct from those employed by other influenza antivirals. By blocking the glycosylation of the viral hemagglutinin in the Golgi apparatus of a cell, nitazoxanide prevents the molecule from reaching the cell surface, being incorporated into the viral particle, and exiting the cell.2

In Vivo Studies Needed

Thus far, the publicly available published data regarding nitazoxanide and influenza consist of in vitro studies demonstrating that nitazoxanide has activity against influenza viruses. However, in vivo studies assessing efficacy and dosing in humans and animals are needed before the drug can become an accepted treatment. Given that nitazoxanide is already FDA-approved for 2 indications and used off-label for another, clinicians can be confidant of its safety profile. Other questions remain, though, including that of efficacy compared with other influenza antivirals, the role of nitazoxanide in combination with other drugs for treating severe influenza, and the frequency of resistance. Nevertheless, the possibility of a new antiviral option for treating drug-resistant influenza is an important advancement.

References

  1. HHS awards contract for advanced development of novel flu treatment: new antiviral could counter growing problem of antiviral resistance to existing influenza drugs [news release]. Washington, DC: US Department of Health and Human Services; February 28, 2013. http://www.phe.gov/Preparedness/news/Pages/novelflutreatment.aspx. Accessed March 19, 2013.
  2. Rossignol JF, La Frazia S, Chiappa L, et al. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. 2009;284:29798-29808.