Could Molnupiravir Be the First-Line Alternative Oral Antiviral Agent for COVID-19 Patients at High Risk?

Nirmatrelvir-ritonavir (RTV-boosted nirmatrelvir) and molnupiravir (MOV) were granted Emergency Use Authorization by the U.S. Food and Drug Administration in December 2021 for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in patients at high risk of progression to severe COVID-19.1

In the first clinical trial, RTV-boosted nirmatrelvir was reported to reduce hospitalization and death by 89% and MOV was shown to reduce hospitalization and death by 30%.2,3 The National Institutes of Health's COVID-19 treatment guidelines recommend using MOV as an alternative regimen when both RTV-boosted nirmatrelvir and remdesivir are not available, feasible, or clinically appropriate.4 They also state that this treatment strategy can be used for COVID-19 patients hospitalized for reasons other than COVID-19. However, many of these patients may not be able to receive RTV-boosted nirmatrelvir due to drug-drug interactions, severe renal impairment with an estimated glomerular filtration rate of less than 30 mL/min/1.73m² or severe hepatic impairment equivalent to Child-Pugh Class C, in which case MOV should be considered. There are also concerns that RTV-boosted nirmatrelvir may be less effective when crushed or administered in water to patients with nasogastric tubes or dysphagia.

Jang and his colleagues5 suggested that MOV could be considered as a first-line alternative to RTV-boosted nirmatrelvir, rather than a second-line alternative, to prevent patients from progressing to severe COVID-19. In this study, there were more patients with older age, neurologic disease, and renal impairment in the MOV arm, but there was no significant difference in progression to severe COVID-19 or all-cause mortality compared to the RTV-boosted nirmatrelvir arm.

Recent observational studies in Hong Kong, Israel, and Korea have also shown that MOV is associated with a reduced risk of death, especially in high-risk patients aged 65 years and older.6,7,8,9

However, these data are not sufficient to conclude that MOV can replace RTV-boosted nirmatrelvir. In the PANORAMIC study, a national, multicenter, open-label, randomized controlled trial conducted in the United Kingdom, MOV did not reduce the risk of hospitalization or death in patients with COVID-19 compared with usual care.10 Because the study population was predominantly Caucasian (94%) and only one-quarter were 65 years of age or older, extrapolating the results of the PANORAMIC study to Korean patients should be done with caution. However, subgroup analyses stratified by those aged ≥ 65 years and those aged < 65 years, as well as subgroup analyses stratified by risk factors for severe disease progression into five quintiles reported in this study, also did not show that MOV treatment reduced severe COVID-19 progression compared to usual care.

A nationwide, well-controlled study comparing MOV and RTV-boosted nirmatrelvir with usual care in the Korean population is needed. Specifically, a study analyzing whether MOV has a protective effect against severe COVID-19 progression in patients with mild or moderate COVID-19 who are ineligible for treatment with remdesivir or RTV-boosted nirmatrelvir would adequately answer our question.