Background. Several drugs which are easy to administer in outpatient settings have been authorized and endorsed for high-risk
COVID-19 patients with mild-moderate disease to prevent hospital admission and death, complementing
COVID-19 vaccines. However, the evidence on the efficacy of
COVID-19 antivirals during the Omicron wave is scanty or conflicting. Methods. This retrospective controlled study investigated the efficacy of
Molnupiravir or
Nirmatrelvir/Ritonavir (Paxlovid®) or
Sotrovimab against standard of care (controls) on three different endpoints among 386 high-risk
COVID-19 outpatients: hospital admission at 30 days; death at 30 days; and time between
COVID-19 diagnosis and first negative swab test result. Multivariable logistic regression was employed to investigate the determinants of hospitalization due to COVID-19-associated
pneumonia, whereas time to first negative swab test result was investigated by means of multinomial logistic analysis as well as Cox regression analysis. Results. Only 11 patients (overall rate of 2.8%) developed severe COVID-19-associated
pneumonia requiring admission to hospital: 8 controls (7.2%); 2 patients on
Nirmatrelvir/Ritonavir (2.0%); and 1 on
Sotrovimab (1.8%). No patient on
Molnupiravir was institutionalized. Compared to controls, hospitalization was less likely for patients on
Nirmatrelvir/Ritonavir (aOR = 0.16; 95% CI: 0.03; 0.89) or
Molnupiravir (omitted estimate);
drug efficacy was 84% for
Nirmatrelvir/Ritonavir against 100% for
Molnupiravir. Only two patients died of
COVID-19 (rate of 0.5%), both were controls, one (a woman aged 96 years) was unvaccinated and the other (a woman aged 72 years) had adequate vaccination status. At Cox regression analysis, the negativization rate was significantly higher in patients treated with both
antivirals-
Nirmatrelvir/Ritonavir (aHR = 1.68; 95% CI: 1.25; 2.26) or
Molnupiravir (aHR = 1.45; 95% CI: 1.08; 1.94). However,
COVID-19 vaccination with three (aHR = 2.03; 95% CI: 1.51; 2.73) or four (aHR = 2.48; 95% CI: 1.32; 4.68) doses had a slightly stronger effect size on viral clearance. In contrast, the negativization rate reduced significantly in patients who were immune-depressed (aHR = 0.70; 95% CI: 0.52; 0.93) or those with a Charlson index ≥5 (aHR = 0.63; 0.41; 0.95) or those who had started the respective treatment course 3+ days after
COVID-19 diagnosis (aOR = 0.56; 95% CI: 0.38; 0.82). Likewise, at internal analysis (excluding patients on standard of care), patients on
Molnupiravir (aHR = 1.74; 95% CI: 1.21; 2.50) or
Nirmatrelvir/Ritonavir (aHR = 1.96; 95% CI: 1.32; 2.93) were more likely to turn negative earlier than those on
Sotrovimab (reference category). Nonetheless, three (aHR = 1.91; 95% CI: 1.33; 2.74) or four (aHR = 2.20; 95% CI: 1.06; 4.59) doses of
COVID-19 vaccine were again associated with a faster negativization rate. Again, the negativization rate was significantly lower if treatment started 3+ days after
COVID-19 diagnosis (aHR = 0.54; 95% CI: 0.32; 0.92). Conclusions.
Molnupiravir,
Nirmatrelvir/Ritonavir, and
Sotrovimab were all effective in preventing hospital admission and/or mortality attributable to
COVID-19. However, hospitalizations also decreased with higher number of doses of
COVID-19 vaccines. Although they are effective against severe disease and mortality, the prescription of
COVID-19 antivirals should be carefully scrutinized by double opinion, not only to contain health care costs but also to reduce the risk of generating resistant SARS-CoV-2 strains. Only 64.7% of patients were in fact immunized with 3+ doses of
COVID-19 vaccines in the present study. High-risk patients should prioritize
COVID-19 vaccination, which is a more cost-effective approach than
antivirals against severe SARS-CoV-2
pneumonia. Likewise, although both
antivirals, especially
Nirmatrelvir/Ritonavir, were more likely than standard of care and
Sotrovimab to reduce viral shedding time (VST) in high-risk SARS-CoV-2 patients, vaccination had an independent and stronger effect on viral clearance. However, the effect of
antivirals or
COVID-19 vaccination on VST should be considered a secondary benefit. Indeed, recommending
Nirmatrelvir/Ritonavir in order to control VST in high-risk
COVID-19 patients is rather questionable since other cheap, large spectrum and harmless nasal
disinfectants such as
hypertonic saline solutions are available on the market with proven efficacy in containing VST.