New Perspectives on Antimicrobial Agents: Molnupiravir and Nirmatrelvir/Ritonavir for Treatment of COVID-19

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged to cause pandemic respiratory disease in the past 2 years, leading to significant worldwide morbidity and mortality. At the beginning of the pandemic, only nonspecific treatments were available, but recently two oral antivirals have received emergency use authorization from the U.S. Food and Drug Administration for the treatment of mild to moderate coronavirus disease (COVID-19). Molnupiravir targets the viral polymerase and causes lethal mutations within the virus during replication. Nirmatrelvir targets SARS-CoV-2's main protease, and it is combined with ritonavir to delay its metabolism and allow nirmatrelvir to inhibit proteolytic cleavage of viral polyproteins during replication, preventing efficient virus production. Both drugs inhibit in vitro viral replication of all variants tested to date. Each is taken orally twice daily for 5 days. When started in the first 5 days of illness in persons at risk for complications due to COVID-19, molnupiravir and nirmatrelvir/ritonavir significantly decreased severe outcomes (hospitalizations and death) with adjusted relative risk reductions of 30% and 88%, respectively, for the two treatments. Molnupiravir should not be used in children or pregnant persons due to concerns about potential toxicity, and reliable contraception should be used in persons of childbearing potential. Nirmatrelvir/ritonavir may cause significant drug-to-drug interactions that limit its use in persons taking certain medications metabolized by certain cytochrome P450 enzymes. Both treatment regimens are important additions to the management of early COVID-19 in at-risk patients in the outpatient setting.