Population-Based Propensity Score-Matched Analysis of Paxlovid and Molnupiravir Effectiveness in High-Risk COVID-19 Patients

Introduction: COVID-19 poses a severe threat to high-risk populations, such as the elderly and those with incomplete vaccination. Despite the availability of treatments like Paxlovid and Molnupiravir, their relative effectiveness in preventing severe outcomes remains inadequately explored in these vulnerable groups. Methods: This population-based retrospective cohort study included COVID-19 patients aged over 65 or with significant comorbidities, meeting criteria for antiretroviral therapy, from April 1 to June 12, 2022, in Taiwan. Patients who received Paxlovid or Molnupiravir were propensity score-matched (PSM) with untreated controls. The primary outcome was the composite of severe symptoms or related mortality occurring within 30 days from symptom onset. Multivariable logistic regressions adjusted for confounders, including: age, sex, living in municipalities, Charlson Comorbidity Index (CCI), vaccine status and period of confirmation. Results: A total of 71,160 patients received Paxlovid and 18,577 received Molnupiravir, each matched with 1:2 controls. The incidence of the composite outcome (per 1000) was 8.3 in the Paxlovid group versus 30.8 in controls, and 41.1 in the Molnupiravir group versus 66.9 in controls. After adjusting for confounders, Paxlovid was associated with a 75% lower risk of the composite outcome (adjusted odds ratio [aOR] = 0.25, 95% CI: 0.23-0.28), while Molnupiravir was associated with a 39% lower risk (aOR = 0.61, 95% CI: 0.56-0.67). Subgroup analyses showed patients over 75 had notably reduced risk in both the Paxlovid group (aOR = 0.16, 95% CI: 0.14-0.20) and the Molnupiravir group (aOR = 0.55, 95% CI: 0.50-0.61). Those with less than two doses of vaccination also showed a marked reduction in risk, with aORs of 0.22 (95% CI: 0.19-0.25) in the Paxlovid group and 0.49 (95% CI: 0.43-0.55) in the Molnupiravir group. Additionally, Molnupiravir was effective in patients with severe hepatic or renal dysfunction (aOR = 0.44, 95% CI: 0.35-0.54), who are not eligible for Paxlovid. Discussion: In this study, the incidence of the composite outcome was higher in the Molnupiravir group (42.9 per 1000) compared to the Paxlovid group (8.4 per 1000). This disparity is likely due to patients prescribed Molnupiravir being older, having more comorbidities, and less adequately vaccinated as observed at baseline. Patients with severe conditions were often prescribed Molnupiravir due to potential drug-drug interactions or specific indications that made Paxlovid unsuitable. This confounding by indication required PSM to adjust these biases and accurately estimate treatment effectiveness. Subgroup analyses showed that elderly patients (>75 years) and those with incomplete vaccination benefitted more from both treatments. Additionally, Molnupiravir was effective in patients with severe hepatic or renal dysfunction, highlighting its importance for these vulnerable populations. Conclusion: Paxlovid and Molnupiravir effectively reduced severe outcomes in high-risk patients, especially the elderly and those with incomplete vaccination. Molnupiravir also benefitted patients with severe hepatic or renal dysfunction.