Background: Molnupiravir has been considered a promising candidate for COVID-19. Its efficacy and safety in non-severe COVID-19 patients and the differences between patients with different risk factors need further evaluation.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials that allocated adult patients with non-severe COVID-19 to molnupiravir or a control. We used random-effects models, and conducted subgroup analyses and meta-regression for COVID-19 patients with high-risk factors. The GRADE approach was used to rate the certainty of evidence.

Results: Fourteen trials with 34 570 patients were included. Moderate- to low-certainty evidence showed that molnupiravir was associated with a reduction in the risk of hospitalization (relative risk [RR] = 0.63, 95% CI: 0.47-0.85), risk of mechanical ventilation (RR = 0.37, 95% CI: 0.19-0.72) and time to symptom resolution (mean differences [MD] = -2.91 days, 95% CI: -3.66 to -2.16). However, no significant differences were found in adverse events, all-cause mortality, rate of and time to viral clearance, or duration of hospitalization. For the rate of viral clearance, subgroup effects were found between trials with low and high risk of bias (P = 0.001) and between trials with male or female majority (P < 0.001). For admission to hospital, subgroup effects were also found between trials with ≥50% and <50% of the participants being female (P = 0.04). Meta-regression showed a significant association between higher trial mean age and elevated risk of hospitalization (P = 0.011), and female majority and elevated risk of hospitalization (P = 0.011).

Conclusions: Molnupiravir was found to be effective in non-severe COVID-19, but the efficacy varied with age and sex.