Background
Oral Antiviral (OAV) COVID-19 treatments are widely used, but evidence for their effectiveness against the Omicron variant in higher risk, vaccinated individuals is limited.

Methods
Retrospective study of two vaccinated cohorts of COVID-19 cases aged ≥70 years diagnosed during a BA.4/5 Omicron wave in Victoria, Australia. Cases received either nirmatrelvir-ritonavir or molnupiravir as their only treatment. Data linkage and logistic regression modelling was used to evaluate the association between treatment and death and hospitalisation and compared with no treatment.

Findings
Of 38,933 individuals in the mortality study population, 13.5% (n = 5250) received nirmatrelvir-ritonavir, 51.3% (n = 19,962) received molnupiravir and 35.2% (n = 13,721) were untreated. Treatment was associated with a 57% (OR = 0.43, 95% CI 0.36–0.51) reduction in the odds of death, 73% (OR = 0.27, 95% CI 0.17–0.40) for nirmatrelvir-ritonavir and 55% (OR = 0.45, 95% CI 0.38–0.54) for molnupiravir. Treatment was associated with a 31% (OR = 0.69, 95% CI 0.55–0.86) reduction in the odds of hospitalisation, 40% (OR = 0.60, 95% CI 0.43–0.83) for nirmatrelvir-ritonavir and 29% (OR = 0.71, 95% CI 0.58–0.87) for molnupiravir. Cases treated within 1 day of diagnosis had a 61% reduction in the odds of death (OR = 0.39, 95% CI 0.33–0.46) compared with 33% reduction for a delay of 4 or more days (OR = 0.67, 95% CI 0.44–0.97).

Interpretation
Treatment with both nirmatrelvir-ritonavir or molnupiravir was associated with a reduction in death and hospitalisation in vaccinated ≥70 years individuals during the Omicron era. Timely, equitable treatment with OAVs is an important tool in the fight against COVID-19.