Molnupiravir for Treatment of Non-Hospitalized Adults With Laboratory-Confirmed, Mild/Moderately Severe COVID-19: A Systematic Evidence Review With Meta-Analysis and Trial Sequential Analysis

OBJECTIVES: For insights into antivirals for coronavirus disease 2019 (COVID-19), we summarised published evidence on the approved molnupiravir regimen (800mg twice daily over 5 days) for treatment of non-hospitalised adults with mild/moderately severe COVID-19.

METHODS: We systematically searched for randomised controlled trials (RCTs) of molnupiravir for COVID-19 and included only laboratory-confirmed infections. We conducted pooled analysis of appropriate data using an inverse variance, random-effects model, and presented results as relative risk with associated 95% confidence intervals. We assessed for statistical heterogeneity using the I² statistic. Further, we graded and conducted trial sequential analysis (TSA) of the evidence.

RESULTS: Nine RCTs (30,971 persons) met the eligibility. There was a small but significant evidence to suggest more viral clearance (of the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) for molnupiravir compared with no treatment/placebo (RR 1.08 [1.01 – 1.16], I² 40.8%, 5 RCTs, 1,785 persons; moderate quality evidence). However, molnupiravir did not reduce the risk of hospitalisation (RR 0.73 [0.47 – 1.14], I² 58.3%, 5 RCTs, 28,626 persons; high quality evidence) and all-cause mortality (RR 0.51 [0.15 – 1.69], I² 36.8%, 4 RCTs, 27,445 persons; high quality evidence). Further, molnupiravir was not associated with significantly more adverse (RR 1.02 [0.90 – 1.14], I² 16.3%, 7 RCTs, 3,368 persons; moderate quality evidence) or serious adverse (RR 0.91 [0.71 – 1.16], I² 0%, 5 RCTs, 27,562 persons; high quality evidence) reactions. Nevertheless, TSA suggested that more RCTs are required before any conclusions regarding viral clearance, all-cause mortality, and adverse reactions, but that more RCTs on the risk of hospitalisation, and serious adverse events may be futile as the efficacy of molnupiravir for these outcomes is unlikely.

CONCLUSIONS: Molnupiravir may be promising for clearance of SARS-CoV-2, but generally does not seem better than usual care. However, more RCTs are necessary for a stronger evidence base.