A systematic review of nirmatrelvir/ritonavir and molnupiravir for the treatment of COVID-19

Abstract

Background To address the need for treatments for patients with COVID-19, three therapies have been given either full approval or Emergency Use Authorization. These were based on randomized data showing a reduction in deaths/hospitalization, but since then, circulating viral strains and population immunity has changed. Methods We identified all trials testing nirmatrelvir/ritonavir and molnupiravir in patients with COVID-19 and assessed the pooled efficacy in a meta-analysis. We searched PubMed, Web of Science, Embase, and clinicaltrials.gov for clinical trials testing nirmatrelvir/ritonavir and molnupiravir for COVID-19. We calculated pooled estimates of hospitalization and death in patients with COVID-19 and the number of studies with published/reported data. Results Of the 23 studies found, 11 tested nirmatrelvir/ritonavir, 10 tested molnupiravir, and two tested both agents. The pooled estimate in reducing deaths and hospitalization for molnupiravir was 0.62 (95% CI: 0.15 to 2.53), and the pooled estimate for nirmatrelvir/ritonavir was 0.33 (95%CI: 0.03 to 3.35). The one nirmatrelvir/ritonavir trial that reported significant improvements tested people who were predominantly infected with earlier COVID-19 variants, whereas the two null trials were tested in people infected with more recent variants. The two positive molnupiravir trials included participants primarily with the delta variant, whereas the null trials were tested later, against more recent variants. Conclusions While early trial data show effectiveness of these therapies, the overall pooled effects are non-significant, suggesting that recommendations and use of approved oral COVID-19 treatment therapies need to be re-evaluated in the context of current viral strains and population immunity.