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 antiviral’s 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 (≥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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Data Protection Officer (DPO) of the Ministry of Health and the ethical committee of the National Public HEalth Organization (NPHO) in Greece. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript