Treatment of Non-severe COVID-19 with Molnupiravir: A Systematic Review with Meta-analysis and Trial Sequential...

BACKGROUND AND OBJECTIVE: The evidence on molnupiravir for the treatment of adults with nonsevere coronavirus disease 2019 (COVID-19) remains underexplored. We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of clinically relevant outcomes from randomized controlled trials (RCTs) of molnupiravir for treatment of nonsevere COVID-19 in adults.

We searched for publications of RCTs of molnupiravir for nonsevere COVID-19 in appropriate bibliographic databases up to 1 February 2025. We pooled appropriate data utilizing an inverse variance, random-effects model, with results expressed as relative risk (RR) with associated 95% confidence intervals (CIs), and statistical heterogeneity between pooled estimates calculated using the I² statistic. We appropriately conducted risk of bias assessment for the included RCTs and graded the quality of pooled evidence for each outcome using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Out of 680 screened literature citations, nine RCTs involving a total of 30,971 patients met the eligibility criteria for inclusion in this review. The majority (78%) of these RCTs were of a low risk of bias. We determined that there was more viral clearance with molnupiravir treatment compared with placebo or no treatment (RR 1.08 [95% CI 1.01-1.16], I² 40.8%, five RCTs, 1785 patients, moderate quality evidence) and that treatment with molnupiravir did not reduce the risk of hospitalization (RR 0.73 [95% CI 0.47-1.14], I² 58.3%, five RCTs, 28,626 patients; high quality evidence), and all-cause mortality (RR 0.51 [95% CI 0.15-1.69], I² 36.8%, four RCTs, 27,445 patients; high quality evidence). We also determined that molnupiravir did not increase adverse or serious adverse reactions. However, TSA suggested more RCTs should be conducted before any conclusions can be reached for viral clearance, all-cause mortality, and adverse reactions, but that further RCTs on the risk of hospitalization and serious adverse reactions may not be needed.

Notwithstanding a paucity of RCTs, our findings suggest that molnupiravir may only be efficacious for clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus responsible for COVID-19) in adults with nonsevere COVID-19 although the evidence is not sufficient for conclusions to be drawn. More high quality RCTs are needed for a stronger evidence base.