Data on the effectiveness of oral antivirals in patients with mild-to-moderate COVID-19 are urgently needed. This retrospective cohort study aimed to evaluate the clinical and virological outcomes associated with molnupiravir or nirmatrelvir–ritonavir use in hospitalised patients with mild-to-moderate COVID-19 during a pandemic wave dominated by the omicron BA.2 subvariant.

We analysed data from a territory-wide retrospective cohort of patients in Hong Kong who were hospitalised with a confirmed diagnosis of SARS-CoV-2 infection between Feb 26 and April 26, 2022. Data were extracted from the Hospital Authority, the Department of Health, and the Hong Kong Death Registry. Patients were eligible for inclusion if their admission date was within 3 days before or after confirmation of their COVID-19 diagnosis. Those who were admitted to hospital more than 5 days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required supplemental oxygen on admission, had drug-related contraindications to nirmatrelvir–ritonavir use, or had severe renal or severe liver impairment were excluded. Patients who received the oral antivirals molnupiravir or nirmatrelvir–ritonavir were matched with controls using propensity-score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes included a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], intensive care unit [ICU] admission, or the need for oxygen therapy) and each of these individual disease progression outcomes, and time to reaching a low viral burden (RT-PCR cycle threshold value ≥30). For each event outcome, crude incidence rates were calculated and hazard ratios (HRs) estimated using Cox regression models.

We identified 40 776 patients hospitalised with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, we included 1856 molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events [95% CI 16·91–23·45]) versus matched controls (38·07 events [33·85–42·67]; HR 0·48 [95% CI 0·40–0·59], p<0·0001) and in nirmatrelvir–ritonavir recipients (10·28 events [7·03–14·51]) versus matched controls (26·47 events [21·34–32·46]; HR 0·34 [0·23–0·50], p<0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 [95% CI 0·52–0·69], p<0·0001; nirmatrelvir–ritonavir 0·57 [0·45–0·72], p<0·0001) and need for oxygen therapy (molnupiravir 0·69 [0·57–0·83], p=0·0001; nirmatrelvir–ritonavir 0·73 [0·54–0·97], p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 [95% CI 1·15–1·64], p=0·0005; nirmatrelvir–ritonavir 1·38 [1·07–1·79], p=0·013). Significant differences in initiation of IMV and ICU admission were not found.

During a wave of SARS-CoV-2 omicron BA.2, initiation of novel oral antiviral treatments in hospitalised patients not requiring oxygen therapy on admission showed substantial clinical benefit. Our findings support the early use of oral antivirals in this population of patients.

Health and Medical Research Fund (Health Bureau, Government of the Hong Kong Special Administrative Region).

For the Chinese translation of the abstract see Supplementary Materials section.