Nitazoxanide: a first-in-class broad-spectrum antiviral agent

Jean-François Rossignol, Jean-François Rossignol

Abstract

Originally developed and commercialized as an antiprotozoal agent, nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. A Phase 2b/3 clinical trial recently published in The Lancet Infectious Diseases found that oral administration of nitazoxanide 600mg twice daily for five days reduced the duration of clinical symptoms and reduced viral shedding compared to placebo in persons with laboratory-confirmed influenza. The same study also suggested a potential benefit for subjects with influenza-like illness who did not have influenza or other documented respiratory viral infection. From a chemical perspective, nitazoxanide is the scaffold for a new class of drugs called thiazolides. These small-molecule drugs target host-regulated processes involved in viral replication. Nitazoxanide is orally bioavailable and safe with extensive post-marketing experience involving more than 75 million adults and children. A new dosage formulation of nitazoxanide is presently undergoing global Phase 3 clinical development for the treatment of influenza. Nitazoxanide inhibits a broad range of influenza A and B viruses including influenza A(pH1N1) and the avian A(H7N9) as well as viruses that are resistant to neuraminidase inhibitors. It is synergistic with neuraminidase inhibitors, and combination therapy with oseltamivir is being studied in humans as part of ongoing Phase 3 clinical development. Nitazoxanide also inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays. Clinical trials have indicated a potential role for thiazolides in treating rotavirus and norovirus gastroenteritis and chronic hepatitis B and chronic hepatitis C. Ongoing and future clinical development is focused on viral respiratory infections, viral gastroenteritis and emerging infections such as dengue fever.

Keywords: Antiviral therapy; Broad-spectrum; Influenza; Nitazoxanide; Thiazolides.

Copyright © 2014 The Author. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Chemical structures of nitazoxanide, tizoxanide and RM-5038.
Fig. 2
Fig. 2
Kaplan–Meier plot of time from first dose to alleviation of symptoms for subjects with confirmed influenza enrolled in a Phase 2b/3 clinical trial of nitazoxanide in subjects with uncomplicated influenza-like illness (Haffizulla et al., 2014, reprinted with permission from Elsevier).
Fig. 3
Fig. 3
Mean change in influenza TCID50 viral titer from baseline during Phase 2b/3 clinical trial in patients with uncomplicated influenza-like illness. Analysis of change in TCID50 viral titer for subjects with confirmed influenza that participated from whom daily nasopharyngeal swabs were collected. Statistical comparison using mixed model for repeated measures including baseline viral titer, treatment group and geographic location: p = 0.0006 for the difference between nitazoxanide 600 mg and placebo, p = 0.1553 for the difference between nitazoxanide 300 mg and placebo (Haffizulla et al., 2014, reprinted with permission from Elsevier).

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