Table 1.
Real-world evidence for use of oral antivirals in the treatment of mild to moderate COVID-19 disease in the outpatient setting
| Study design and setting | Sample size | Characteristics of antiviral users | Major findings |
| Molnupiravir | |||
| Najjar-Debbiny et al.[14] Retrospective cohort Two healthcare organization databases in Israel Jan to Feb 2022 |
2661 molnupiravir users 2661 PS-matched nonusers |
Age 73.1 ± 11.7 Male 50.4% ≥2 doses of vaccine with last dose within 180 days: 77.3% Hypertension 73.6% Cardiovascular disease 47.7% Diabetes 44.0% |
Severe COVID-19a or mortality HR 0.83 (95% CI 0.57–1.21) Subgroup analysis Age>75 years: HR 0.54 (0.34–0.86) Females: HR 0.41 (0.22–0.77) Inadequately vaccinated: HR 0.45 (0.25–0.82) |
| Wai et al.[12] Retrospective outpatient cohort Hong Kong Feb to Mar 2022 |
5345 molnupiravir users 23430 nonusers |
Age >60 years: 97.8% Male 46.7% Diabetes 9.6% Stroke 4.9% |
Hospital admission within 28 days OR 0.72 (95% CI 0.52–0.98) |
| Wong et al.[13] Retrospective cohort study Hong Kong Feb to Jun 2022 |
4983 molnupiravir users 49 234 matched nonusers |
Age >60 years: 88.7% Male 47.5% ≥2 doses of mRNA or ≥3 doses of inactivated vaccine 16% Charlson comorbidity index score 0–4: 89.8% |
All-cause mortality 17.9 vs. 22.1 per 100 000 person-days, HR 0.76 (95% CI 0.61–0.95) Hospital admission due to COVID-19 107.6 vs. 104.0 per 100 000 person-days, HR 0.98 (95% CI 0.89–1.06) >60 years: HR 0.89, 95% CI 0.81–0.97 |
| Yip et al.[68] Retrospective cohort study Electronic healthcare database in Hong Kong Feb to Mar 2022 |
4798 molnupiravir users 4758 nonusers with PS weighting |
Age 71.1 ± 11.7 Male 46.8% ≥2 doses of mRNA or ≥3 doses of inactivated vaccine 43% Diabetes 28% |
Hospital admission by 30 days 7.5 vs. 1.6%, weighted HR 1.17 (95% CI 0.99–1.39) Death, ICU or mechanical ventilation 0.9 vs. 0.2%, weighted HR 1.12 (95% CI 0.68–1.82) |
| Nirmatrelvir-ritonavir | |||
| Arbel et al.[17] Retrospective cohort Electronic health record from large healthcare organization in Israel Jan to Mar 2022 |
3902 nirmatrelvir-ritonavir users 105352 nonusers |
Age 40–64: 36%, ≥65: 64% Male 40% Previous immunity induced by vaccination and/or infection 90% Hypertension 49% Obesity 42% Diabetes 40% Immunosuppression 23% |
40–64 years Adjusted HR for hospitalization: 0.74 (95% CI 0.35–1.58) Adjusted HR for death: 1.32 (95% CI 0.16–10.75) ≥65 years Adjusted HR for hospitalization: 0.27 (95% CI 0.15–0.49) (without previous immunity: 0.15, 95% CI 0.04–0.60; with previous immunity 0.32, 95% CI 0.17–0.63) Adjusted HR for death: 0.21 (95% CI 0.05–0.82) |
| Dryden-Peterson et al.[18] Retrospective analysis of an electronic healthcare system database in US Jan to July 2022 |
11797 nirmatrelvir-ritonavir users 32248 nonusers |
Age ≥65 years: 46% Male 41% Vaccinated 23%, boosted 68% Last vaccine dose >20 weeks: 74% Immunocompromised 36% Solid tumour 23% Diabetes 19% |
Hospitalization with 14 days or death within 28 days 0.55 vs. 0.97%, adjusted HR 0.56 (95% CI 0.42–0.75) Subgroup analysis Age 50–64 years: relative risk 0.55 (95% CI 0.30–1.03) Age ≥65 years: 0.55 (0.40–0.77) Not fully vaccinated 0.19 (0.08–0.49) Vaccinated 0.69 (0.50–0.94) Last vaccine <20 weeks 0.87 (0.51–1.50) Last vaccine >20 weeks 0.45 (0.32–0.64) |
| Ganatra et al.[69] Retrospective analysis of electronic health records of >120 healthcare organizations in US Dec 2021 to Apr 2022 |
1131 nirmatrelvir-ritonavir users 1130 PS-matched nonusers |
Mean age 57.5 ± 16.3 Male 37% Vaccinated 100% Hypertension 52.2% Malignancy 45.3% Diabetes 22.1% |
Emergency room visits, hospitalization or death at 30 days 7.87 vs. 14.4%, OR 0.51 (95% CI 0.39–0.67) Hospitalization at 30 days 0.8 vs. 2.0%, OR 0.43 (95% CI 0.20–0.91) 30-day mortality 0 vs. 0.8% |
| Najjar-Debbiny et al.[19] Retrospective cohort Two healthcare organization databases in Israel Jan to Feb 2022 |
4737 nirmatrelvir-ritonavir users 175614 nonusers |
Age 68.5 ± 12.5 Male 42.1% ≥2 doses of vaccine with last dose within 180 days 77.8% Hypertension 51.7% Obesity 40.9% Diabetes 38.5% |
Severe COVID-193 or mortality adjusted HR 0.54 (95% CI 0.39–0.75) Subgroup analysis Adequate vaccination: adjusted HR 0.62 (95% CI 0.39–0.98) No adequate vaccination: adjusted HR 0.52 (95% CI 0.32–0.82) Age <60 years: adjusted HR 1.06 (0.36–3.15) Age ≥60 years: adjusted HR 0.52 (0.36–0.73) |
| Shah et al.[5] Retrospective analysis of electronic health record data set in USA Apr to Aug 2022 |
198 927 nirmatrelvir-ritonavir users 500 921 nonusers |
Age ≥65 years 37.9% Male 38.2% Previous infection 15.0% ≥2 doses of vaccine 68.8% ≥2 underlying health conditions 66.8% Immunocompromised 9.9% |
Overnight COVID-19-associated hospitalization by day 30 0.47 vs. 0.86%, adjusted HR 0.49 (95% CI 0.46–0.53) Subgroup analysis Similar reduction in persons with 2 and ≥3 doses of vaccines, and in all age groups (18–49, 50–64 and ≥65 years) No significant reduction in age group 18–49 with ≥3 mRNA doses, or only one underlying health condition |
| Wai et al.[12] Retrospective outpatient cohort Hong Kong Feb to Mar 2022 |
4442 nirmatrelvir-ritonavir users 23430 nonusers |
Age >60 years: 98.3% Male 45.4% Diabetes 6.6% Cancer 2.7% |
Hospital admission within 28 days OR 0.37 (95% CI 0.23–0.60) |
| Wong et al.[13] Retrospective cohort study Hong Kong Feb to Jun 2022 |
5542 nirmatrelvir-ritonavir users 54672 matched nonusers |
Age >60 years: 85.9% Male 46.3% ≥2 doses of mRNA or ≥3 doses of inactivated vaccine 33.4% Charlson comorbidity index score 0–4: 95.5% |
All-cause mortality 4.2 vs. 11.6 per 100 000 person-days, HR 0.34 (95% CI 0.22–0.52) Hospital admission due to COVID-19 48.5 vs. 61.0 per 100 000 person-days, HR 0.76 (95% CI 0.67–0.86) |
| Yip et al.[68] Retrospective cohort study Electronic healthcare database in Hong Kong Feb to Mar 2022 |
4921 nirmatrelvir-ritonavir users 4758 nonusers with PS weighting |
Age 70.8 ± 12.1 Male 45.7% ≥2 doses of mRNA or ≥3 doses of inactivated vaccine 43% Diabetes 27% |
Hospital admission by 30 days 3.5 vs. 1.6%, weighted HR 0.79 (95% CI 0.65–0.95) Death, ICU or mechanical ventilation 0.4 vs. 0.2%, weight HR 0.81 (95% CI 0.47–1.39) |
CI, confidence interval; HR, hazard ratio; OR, odds ratio; PS, propensity score.
a
Oxygen saturation <94%, arterial partial pressure of oxygen to fraction of inspired oxygen <300 mmHg or respiratory rate >30 breaths.