Potential role for nitazoxanide in treating SARS-CoV-2 infection

to the editor: Until specific and effective antiviral therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) become available, the management of coronavirus disease (COVID-19) is primarily based on supportive care and treatment of complications. On April 13, 2020, Sanders et al. (7) published in the Journal of the American Medical Association a comprehensive review summarizing current evidence regarding major proposed treatments, repurposed or experimental, for COVID-19. Despite that remdesivir seems to be the most promising antiviral agent in ongoing randomized trials, the authors mentioned nitazoxanide as a potential treatment option for SARS-CoV-2.

Nitazoxanide is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea and enteritis with a favorable safety profile. However, this thiazolide antimicrobial agent has been considered a prospective candidate for viral respiratory infections. A previous study (1) with cell cultures found that nitazoxanide may have antiviral effects by depleting ATP-sensitive intracellular Ca²⁺ stores leading to phosphorylation of protein kinase R (PKR) and eukaryotic translation initiation factor 2α (eIF2α), downregulation of cellular translation machinery, and impairment of viral reproduction and spread. It has been found that SARS-CoV envelope (E) protein induces ionic disturbances especially related to Ca²⁺ homeostasis with important consequences on cell physiology and overproduction of proinflammatory cytokines (5). Moreover, existing literature suggested a potential role for nitazoxanide in treating Middle East respiratory syndrome (MERS)-CoV infection (6) and suppression of interleukin-6 (IL-6) production in mice (4). Hypothetically, nitazoxanide can have a potential antiviral effect and can influence host immune responses against SARS-CoV-2.

Efficacy results of nitazoxanide in humans with respiratory infections are limited to a small number of trials and the results are contrasting. In a double-blind, randomized, placebo-controlled, phase 2b/3 trial (3) enrolling 624 participants aged 12–65 years with influenza-like illness, it was shown that 600 mg nitazoxanide twice daily for 5 days decreased the time from first dose to alleviation of symptoms compared with placebo with a low rate of severe adverse events (4%). In addition, a significant reduction of viral titers was recorded during the treatment. Recently, contrasting findings were reported in a small phase 2 clinical study (2) evaluating hospital discharge for patients with severe acute respiratory illness treated with nitazoxanide. However, the need for ongoing hospitalization may be driven by factors other than respiratory symptoms. To date, 10 clinical trials protocols are registered in the ClinicalTrials.gov evaluating the effects of nitazoxanide in the treatment of COVID-19 but preliminary results have not yet been reported.

Although theoretical considerations are reasonable and there is potential for in vitro activity against coronaviruses, controlled clinical trials evaluating the safety and efficacy of nitazoxanide as a potential antiviral treatment of COVID-19 are still lacking. High-quality trial evidence on nitazoxanide in the treatment of SARS-CoV-2 infection is urgently needed.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

P.R.M.-F. drafted manuscript; P.R.M.-F., J.A.B.-A., and R.F. edited and revised manuscript; P.R.M.-F., J.A.B.-A., and R.F. approved final version of manuscript.