Comparative effectiveness of combination therapy with nirmatrelvir-ritonavir and molnupiravir versus monotherapy with molnupiravir or nirmatrelvir-ritonavir in hospitalized COVID-19 patients: A target trial emulation study

Background Molnupiravir and nirmatrelvir-ritonavir have demonstrated efficacy in reducing hospitalization and mortality among unvaccinated, high-risk COVID-19 outpatients. However, their impact on hospitalized adults remains unclear. Preclinical studies suggest that combining these antivirals may reduce viral shedding and enhance survival. Methods This target trial emulation study compared the safety and efficacy of combined molnupiravir and nirmatrelvir-ritonavir versus monotherapy in hospitalized COVID-19 patients in Hong Kong. Data from 28,355 patients aged 18 and older, treated within five days of hospital admission between March 16, 2022, and March 31, 2024, were analyzed. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics and outcomes, including mortality, ICU admission, and ventilatory support, which were analyzed using Cox proportional hazards models. Results Nirmatrelvir-ritonavir monotherapy significantly reduced mortality risk (HR: 0.62; 95% CI 0.50-0.77; ARR: -3.16%) compared to combination therapy, with no differences in ICU admission or ventilatory support. It also lowered risks of acute liver injury (HR: 0.53 [95% CI 0.32-0.88]), kidney injury (HR: 0.61 [95% CI 0.51-0.74]), and hyperglycaemia (HR: 0.73 [95% CI 0.57-0.93]). Conclusion Combining nirmatrelvir-ritonavir and molnupiravir does not significantly reduce mortality, ICU admissions, or ventilatory support needs in hospitalized COVID-19 adults. Nirmatrelvir-ritonavir monotherapy is more effective, but further randomized controlled trials are required to confirm these findings. Funding The Health & Medical Research Fund Commissioned Research on COVID-19 (COVID1903010, COVID1903011; COVID19F01).