RATIONALE: Five years from the start of the COVID-19 pandemic, morbidity and mortality have subsided. Vaccines have contributed to reducing the risk of infection and severe disease. However, new COVID-19 variants continue to emerge, and the role of oral antivirals such as molnupiravir in preventing progression of disease or hospitalisation must be assessed.
OBJECTIVES: To assess the effects of molnupiravir in people with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mild to moderate symptoms.
SEARCH METHODS: We identified all relevant randomised controlled trials (RCTs) by searching the Cochrane COVID-19 Study Register, Science Citation Index Expanded, the World Health Organization (WHO) Global Literature on Coronavirus Disease database, and the COVID Network Meta-Analysis database with no language restrictions up to 26 April 2024.
ELIGIBILITY CRITERIA: We considered full-text articles, preprints, abstracts, trial registry records, and reports of ongoing trials. Cluster-RCTs were eligible for inclusion, but cross-over trials were ineligible. Participants had confirmed SARS-CoV-2 infection with or without risk factors for severe disease. The intervention was molnupiravir 800 mg taken orally every 12 hours for five days, and control was no treatment, placebo, or standard of care, as defined by the study authors. We excluded studies comparing molnupiravir with treatment strategies that included molnupiravir.
OUTCOMES: Our critical outcomes were all-cause mortality and hospitalisation. Our important outcomes were change in clinical status, viral clearance, quality of life, adverse events, and serious adverse events.
RISK OF BIAS: Two review authors independently assessed the risk of bias in each included study using the Cochrane risk of bias tool (RoB 2). Disagreements were resolved through discussion.
SYNTHESIS METHODS: We conducted a meta-analysis where two or more studies with reasonably similar clinical and methodological characteristics reported the same outcome. We used data from intention-to-treat analysis where available. We analysed all outcomes at the participant level using the generic inverse variance method, applying a random-effects model. We used the GRADE approach to assess the certainty of evidence.
INCLUDED STUDIES: This review included 11 studies (31,272 participants). Eight studies recruited outpatients and three recruited inpatients. We did not meta-analyse inpatient studies, as characteristics varied widely. All outpatient studies included participants with mild to moderate COVID-19, with a mean age ranging from 35 years to 57 years and variable prevalences of comorbidities and COVID-19 vaccination. We excluded suboptimal molnupiravir dosing arms in four outpatient studies and one inpatient study.
SYNTHESIS OF RESULTS: Outpatients Molnupiravir compared to placebo or usual care probably results in little to no difference in all-cause mortality at 28 to 30 days (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.04 to 0.65; 7 RCTs, 29,238 participants; moderate-certainty evidence). The absolute reduction in mortality is nine fewer deaths per 10,000 people treated (95% CI 10 fewer to four fewer per 10,000), which we consider clinically insignificant. Molnupiravir may result in little to no difference in hospitalisation (RR 0.70, 95% CI 0.43 to 1.12; 6 RCTs, 29,228 participants; low-certainty evidence), symptom resolution by day 14 (RR 1.20, 95% CI 0.84 to 1.71; 3 RCTs, 22,400 participants; low-certainty evidence), and symptom resolution by day 28 (RR 1.06, 95% CI 0.89 to 1.26; 3 RCTs, 24,728 participants; low-certainty evidence). Four studies reported viral clearance by day 5, which was higher in people receiving molnupiravir compared with those receiving placebo or usual care (RR 3.40, 95% CI 2.15 to 5.36; 3067 participants). The effect size decreased by day 10 (RR 1.58, 95% CI 1.07 to 2.34; 2 RCTs, 2438 participants) and indicated little to no difference between molnupiravir and control by day 14 to 15 (RR 1.05, 95% CI 0.98 to 1.13; 4 RCTs, 3062 participants). The results at day 28 to 30 again showed higher virus clearance in the molnupiravir arm (RR 1.11, 95% CI 1.03 to 1.19; 3 RCTs, 397 participants), although there were few participants in this analysis. Molnupiravir probably results in little to no difference in adverse events (RR 1.00, 95% CI 0.87 to 1.15; 7 RCTs, 4304 participants; moderate-certainty evidence). Molnupiravir results in little to no difference in serious adverse events (RR 0.86, 95% CI 0.62 to 1.21; 8 RCTs, 30,009 participants; high-certainty evidence). Inpatients The effect of molnupiravir in inpatients is unclear; substantial heterogeneity precluded meta-analysis. Risk of bias and certainty of the evidence We assigned high risk of bias judgements to one of seven RCTs for all-cause mortality, one of six RCTs for hospitalisation, two of three RCTs for symptom resolution at 14 days and 28 days, three of seven RCTs for adverse events, and three of eight RCTs for serious adverse events. We downgraded the certainty of the evidence for serious indirectness as well as risk of bias, as the populations across trials differed by vaccination status. There was no serious imprecision identified for any outcome. Publication bias is likely high in this review, as we identified 16 unpublished trials. Six were listed as complete, but only one had available data.
AUTHORS' CONCLUSIONS: In outpatients with mild to moderate COVID-19, molnupiravir 800 mg taken orally every 12 hours for five days probably results in little to no difference in all-cause mortality and may result in little to no difference in rates of hospitalisation and symptom resolution. There is evidence of increased viral clearance by day 5, but the clinical relevance of this finding is unclear. There is probably little to no difference in adverse events, and there is little to no difference in serious adverse events, with molnupiravir versus placebo or standard care. Inpatient data are lacking, and there is no evidence of benefit of molnupiravir in this population. Further research involving inpatients may change this.
FUNDING: The editorial base of the Cochrane Infectious Diseases Group is funded by UK aid from the UK Government for the benefit of low- and middle-income countries (project number 300342-104). The views expressed herein do not necessarily reflect the UK Government's official policies.
REGISTRATION: Protocol available at https://doi.org/10.1002/14651858.CD015381.
