Favipiravir and ivermectin show in vitro synergistic antiviral activity against SARS-CoV-2

Despite the urgent need for effective antivirals against SARS-CoV-2 to mitigate the catastrophic impact of the COVID-19 pandemic, favipiravir and ivermectin are among the common repurposed drugs that have been provisionally used in some countries. There have been clinical trials with mixed results, and therefore, it is still inconclusive whether they are effective or should be dismissed. It is plausible that the lack of clear-cut clinical benefits was due to the finding of only marginal levels of in vivo antiviral activity. An obvious way to improve the activity of antivirals is to use them in synergistic combinations. The in vitro antiviral activity of the combinations of favipiravir, ivermectin, niclosamide, and chloroquine against SARS-CoV-2 was assessed in Vero E6 cells and the lung epithelial cell, Calu-3. Here we show that favipiravir and ivermectin had synergistic effects against SARS-CoV-2 in Vero E6 cells. In addition, we found that favipiravir had an additive effect with niclosamide, another repurposed anti-parasitic drug with anti-SARS-CoV-2 activity. However, the anti-SARS-CoV-2 activity of favipiravir was drastically reduced when evaluated in Calu-3 cells. This suggested that this cell type might not be able to metabolize favipiravir into its active form and that this deficiency in some cell types may affect the in vivo efficacy of this drug. Favipiravir and ivermectin show the best synergistic effect. This combination is being tested in a randomized controlled clinical trial (NCT05155527).