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

Abstract

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.

Comparative efficacy and safety of nirmatrelvir/ritonavir and molnupiravir for COVID‐19: A systematic review and meta‐analysis

“…After screening based on title and abstract, 28 studies were qualified for fulltext review. Eighteen studies [13][14][15][19][20][21][24][25][26][28][29][30][31][32][33][34][35][36] involving 57 659 were included in the meta-analysis. The study by Wong et al 37 was excluded due to insufficient data.…”

“…The data that support the findings of this study are openly available. [13][14][15][19][20][21][24][25][26][28][29][30][31][32][33][34][35][36]…”

“…Ten studies 15,[19][20][21]24,25,28,29,31,33 involving 35 603 patients were included in the meta-analysis. The pooled estimate of included studies showed a significant difference in all-cause mortality rate between patients receiving nirmatrelvir/ritonavir and molnupiravir-treated ones (OR = 0.54, 95% CI: 0.44-0.67, p = 0.00, I 2 = 0%) (Figure 2A).…”

“…Nine studies 14,15,19,26,[28][29][30][31][33][34][35] involving 35496 patients were included in the meta-analysis. The meta-analysis results showed a significant difference between the nirmatrelvir/ritonavir and molnupiravir groups in terms of all-cause hospitalization rate (OR = 0.61, 95% CI: 0.54-0.69, p = 0.00, I 2 = 19.39%) (Figure 2B).…”

“…Six studies 15,19,28,29,31,33 involving 9243 patients reported the incidence of any adverse events in patients receiving nirmatrelvir/ritonavir and molnupiravir. The pooled estimate revealed a significant difference between the two groups in terms of the incidence of any adverse events (OR = 2.52, 95% CI: 1.57-4.06, p = 0.00, I 2 = 72.73%) (Figure 3A).…”