Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture

There is a need of effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proven effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. Here we document that remdesivir and ribavirin exert a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasispecies. The results suggest the participation of lethal mutagenesis in this synergy-based extinction, and offer prospects of triple drug treatments for effective SARS-CoV-2 suppression.