Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 community, highly vaccinated patients with high risk for severe disease: Evidence that both antivirals reduce the risk for disease progression and death

Besides the significant benefits of vaccination against COVID-19, the risk of severe disease and death from COVID-19 among highly vulnerable populations remains of concern. Implementation of oral antiviral treatment has shown significant benefits for outpatients with high risk for severe disease, however, their effectiveness remains to be evaluated in real-life settings and in the presence of new Omicron subvariants. We aimed to investigate the effectiveness of molnupiravir and nirmatrelvir/ritonavir using a retrospective cohort design with outcomes hospital admission and death from COVID-19, in Greece. The effectiveness of each drug was estimated through a comparison of the antivirals recipients with an age-matched control group of non-recipients, adjusted for age, previous SARS-CoV-2 infection, vaccination status, and vaccination recency. Our analysis showed that molnupiravir significantly reduced the risk for hospitalization (OR = 0.40, p < 0.001) and death from COVID-19 (OR = 0.31, p < 0.001), with the effect being more intense among elderly patients ([&ge;]75 years old). The effectiveness was higher among those with full adherence. Nirmatrelvir/ritonavir was found also to significantly reduce the risk of hospital admission (OR = 0.31, p < 0.001) and death (OR = 0.28, p < 0.001) and, similarly to molnupiravir, effectiveness was stronger among elderly patients and those with the highest levels of adherence. Analysis of the relative effectiveness of nirmatrelvir/ritonavir versus molnupiravir suggested that nirmatrelvir/ritonavir was associated with a reduced risk for hospital admission (OR = 0.58, p < 0.001) compared to molnupiravir, adjusted for age, previous SARS-CoV-2 infection, vaccination status, and co-morbidities. Our real-world study provides evidence about the reduced risk of hospitalization and death in highly vaccinated patients with a high risk for severe disease in Greece. These findings highlight that although the hospitalization and mortality risk has been reduced mainly due to vaccination and the emergence of Omicron variants, antivirals provide significant additional benefits in highly vulnerable patients and therefore their use is documented and strongly indicated.