Nirmatrelvir/Ritonavir for Non-Hospitalized Adults With Mild/Moderately Severe COVID-19: A Systematic Evidence Review of Randomized Controlled Trials and Real-World Studies With Meta-Analysis and Trial Sequential Analysis

OBJECTIVES: Efficacy/effectiveness and safety of the approved nirmatrelvir/ritonavir regimen (300mg of nirmatrelvir with 100mg of ritonavir administered twice daily over 5 days) for treatment of adults with mild/moderately severe coronavirus disease 2019 (COVID-19) remains unclear.

METHODS: We conducted a systematic evidence review of published peer-reviewed randomised controlled trials (RCTs) and real-world studies (RWS) of efficacy/effectiveness and/or safety of the approved nirmatrelvir/ritonavir regimen for treatment of non-hospitalised adults (≥18-year-olds) with mild/moderately severe laboratory-confirmed COVID-19. We pooled appropriate data (for RWS, the adjusted estimates) using an inverse variance, random-effects model, and calculated statistical heterogeneity using the I² statistic. Results are relative risk with associated 95% confidence intervals. Further, we assessed risk of bias/study quality of the included studies, and conducted trial sequential analysis (TSA) of the evidence from RCTs.

RESULTS: From a retrieved total 1,104 literature citations, we included three RCTs (2,774 persons) and 16 RWS (1,925,047 persons). The RCTs were of unclear risk of bias while the RWS were of good quality. Nirmatrelvir/ritonavir significantly reduced worsening COVID-19 severity (0.19 [0.06 – 0.66], I² 54.8%, three RCTs, 2,774 persons) but increased adverse events (1.83 [1.35 – 2.48], I² 0%, three RCTs, 2,774 persons) compared with placebo/no treatment. There was no significant difference for clearance of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and all-cause mortality although TSA suggested more sample size for these outcomes before any conclusions. Further, compared with no treatment, nirmatrelvir/ritonavir appeared to significantly reduce hospitalisation (0.48 [0.37 – 0.60], eleven RWS, 1,421,398 persons) and all-cause mortality (0.24 [0.14 – 0.34], seven RWS, 286,131 persons).

CONCLUSIONS: The approved nirmatrelvir/ritonavir treatment regimen appears promising against worsening severity and suggestively, against hospitalisation and all-cause mortality in non-hospitalised adults with mild/moderately severe laboratory-confirmed COVID-19. However, the evidence is generally weak, and therefore, more studies are necessary for a stronger evidence base.