Two large phase II/III trials in hospitalized (NCT04575584) and nonhospitalized (NCT04575597) patients with COVID-19 began in October 2020. Based on this trial, a dose of 800 mg BID was selected for further study. Among 74 patients with positive baseline cultures, 6/25 (24%) placebo patients versus 0/49 pooled molnupiravir patients ( P = 0.001) had positive cultures at day 5 ( 371). MolnupiravirĪ phase II trial examined virological endpoints among persons receiving molnupiravir 200 mg twice daily (BID), 400 mg BID, and 800 mg BID compared to placebo in 176 nonhospitalized COVID-19 patients with fever and/or signs of a respiratory illness (NCT04405570). Remdesivir was not associated with reductions in either upper or lower respiratory tract virus load levels in the one study that examined this outcome ( 42), possibly because virus levels typically have already begun to decrease by the time patients require hospitalization. Another randomized controlled trial compared remdesivir for 10 days versus 5 days versus placebo in persons with moderate disease detected no difference between each of the three arms ( 43). It has been proposed that Solidarity trial may not have observed shortened hospital stays with remdesivir because it was an open-label trial that studied patients who received highly heterogenous routine care and because it required patients receiving remdesivir to remain hospitalized until they completed the full 10-day course of intravenous treatment ( 44, 45). The open-label WHO Solidarity trial which included 2,750 persons randomized to remdesivir and 4,800 to standard-of-care detected no reduction in mortality, requirement for ventilation, or reduction in hospital stay for those receiving remdesivir ( 41). Finally, some nucleoside analogs are incorporated into viral genomes and inhibit replication by introducing mutations during subsequent rounds of virus replication. Others contain a 3′-hydroxyl group and yet still result in immediate or delayed chain termination. Most antiviral polymerase inhibitors lack a 3′-hydroxyl group and act as nucleoside analog chain terminators ( 12). For example, tenofovir and lamivudine are among the mainstays of therapy for treating human immunodeficiency virus and hepatitis B infections ( 12). Because of their broad spectrum of activity, nucleoside analog polymerase inhibitors have been the only successful repurposed directly acting antivirals. Nucleoside analog polymerase inhibitors are the most common antiviral compounds comprising a plurality of all licensed antivirals. RdRps are highly conserved in their structural and functional features, even among diverse RNA viruses belonging to different families ( 11). RNA-dependent RNA polymerases (RdRps) catalyze phosphodiester bond formation between nucleoside triphosphates in an RNA-templated manner.
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