DISCUSSION
Nitazoxanide is a broad-spectrum antiparasitic and antiviral drug, originally approved for the treatment of parasite-mediated infectious diarrhea and enteritis, that has been tested for COVID-19 due to the anti-inflammatory effects [19] and in vitro anti-viral activity and promising clinical benefits against influenza and other viruses [20-22]. Moreover, there is in vitro evidence that nitazoxanide may induce a significant down-regulation of IL-6/JAK2/STAT3 [23] and may increase the eIF2α and PKR phosphorylation, critical mediators involved in IFN-induced antiviral response [24].
Individual studies [15] have suggested that nitazoxanide reduces SARS-CoV-2 viral load in Vero E6 cells by 75% at a minimal dose of 0.1 μM with no cytotoxic effects. High SARS-CoV-2 viral load was found to be associated with lymphopenia, increased markers of inflammation, and poor clinical outcomes in hospitalized patients with COVID-19 [25,26]. Therefore, the use of nitazoxanide might accelerate viral clearance, improve clinical symptoms, and decrease the risk of hospitalization and death for patients with SARS-CoV-2 infection.
Despite promising theoretical and experimental findings, this systematic review showed no evidence of clinical benefits on the use of nitazoxanide to treat patients with mild or moderate COVID-19. To date, there is still no optimal approach toward COVID-19 management. Symptomatic cases require supportive care with medical evaluation, risk factor stratification for unfavorable clinical outcomes, and clinical monitoring of symptoms. In outpatients, symptomatic treatment includes analgesics and antipyretics. In the hospital setting, patients may need supplemental oxygen and adequate management of pulmonary ventilation. The use of dexamethasone has been indicated for patients with COVID-19 who are receiving respiratory support [27]. Recently, open-label RCTs showed that prophylactic or therapeutic anticoagulation did not result in clinical improvement for hospitalized patients with COVID-19, except in the context of diagnosing a thromboembolic event [28,29].
Our study has some major limitations and include trials with a high-risk of reporting and operational bias. Despite most studies were double-blinded, changes in urine color caused by nitazoxanide could potentially induce a high-risk of performance or detection bias. In one trial [17], the patients received a vitamin B complex supplement to mask any potential chromaturia attributed to nitazoxanide. Finally, the results of this study cannot be generalized to severe or critical COVID-19.
In this systematic review and meta-analysis, we found no current evidence from blinded, placebo-controlled, RCT on the efficacy of nitazoxanide in treating patients with COVID-19. The quality of evidence for most outcomes analyzed in this study is limited. This living systematic review should be updated as soon as the results of ongoing RCT are published.