Efficacy of COVID-19 Oral antivirals in hospitalised oldest-old with high morbidity burden: a target trial emulation study

Background: Molnupiravir and nirmatrelvir-ritonavir are orally administered pharmacotherapies for mild to moderate COVID-19. However, the effectiveness of these drugs among very old (≥80 years), hospitalised patients remains unclear, limiting the risk–benefit assessment of these antivirals in this specific group. This study investigates the effectiveness of these antivirals in reducing mortality among this group of hospitalised patients with COVID-19. Methods: Using a territory-wide public healthcare database in Hong Kong, a target trial emulation study was conducted with data from 13 642 eligible participants for the molnupiravir trial and 9553 for the nirmatrelvir-ritonavir trial. The primary outcome was all-cause mortality. Immortal time and confounding bias was minimised using cloning-censoring-weighting approach. Mortality odds ratios were estimated by pooled logistic regression after adjusting confounding biases by stabilised inverse probability weights. Results: Both molnupiravir (HR: 0.895, 95% CI: 0.826–0.970) and nirmatrelvir-ritonavir (HR: 0.804, 95% CI: 0.678–0.955) demonstrated moderate mortality risk reduction among oldest-old hospitalised patients. No significant interaction was observed between oral antiviral treatment and vaccination status. The 28-day risk of mortality was lower in initiators than non-initiators for both molnupiravir (risk difference: −1.09%, 95% CI: −2.29, 0.11) and nirmatrelvir-ritonavir (risk difference: −1.71%, 95% CI: −3.30, −0.16) trials. The effectiveness of these medications was observed regardless of the patients’ prior vaccination status. Conclusions: Molnupiravir and nirmatrelvir-ritonavir are moderately effective in reducing mortality risk among hospitalised oldest-old patients with COVID-19, regardless of their vaccination status.