NIRMATRELVIR/RITONAVIR — In a medical record review of about 700,000 outpatient adults with COVID-19, use of nirmatrelvir/ritonavir was associated with a ~50% reduction in the rate of hospitalization within 30 days after diagnosis in the overall population and in the subgroup of patients who had received ≥3 mRNA COVID-19 vaccine doses.2 In a database review of about 180,000 high-risk outpatients, use of nirmatrelvir/ritonavir was associated with a reduced risk of severe COVID-19 or death within 28 days in both vaccinated and unvaccinated patients.3 Similar results were observed in a database review of about 21,000 outpatient adults.4

In a cohort study of about 45,000 high-risk outpatients ≥50 years old with COVID-19, 90% of whom had received ≥3 vaccine doses, the rate of hospitalization within 14 days or death within 28 days was significantly lower in those who took nirmatrelvir/ritonavir compared to those who did not (0.52% vs 0.93%).5

In another cohort study, 1130 high-risk, vaccinated, outpatient adults with COVID-19 who received nirmatrelvir/ritonavir were compared with an equal number of matched controls. The rate of emergency department visits, hospitalization, or death within 30 days was significantly lower in the nirmatrelvir/ritonavir group (7.9% vs 14.4%).6

REMDESIVIR — Well-designed studies on use of remdesivir in vaccinated outpatients with COVID-19 are lacking. In a randomized, observer-blind trial in China, 771 high-risk outpatient adults with COVID-19 (76% vaccinated) received either an oral, deuterated remdesivir analog (VV116) or nirmatrelvir/ritonavir. Time to sustained recovery, the primary endpoint, with VV116 was noninferior to that with nirmatrelvir/ritonavir. Vaccination status did not significantly alter the relative differences between the two groups.7

MOLNUPIRAVIR — In an open-label trial in the UK, about 25,000 high-risk outpatient adults with COVID-19 were randomized to receive usual care with or without molnupiravir; about 95% of patients had previously received ≥3 COVID-19 vaccine doses. There was no significant difference between the two groups in the rate of all-cause hospitalization or death within 28 days.8

In a database review, 2661 high-risk outpatient adults with a first-time diagnosis of COVID-19 who received molnupiravir were compared with an equal number of matched controls. The rate of severe or fatal COVID-19 within 28 days, the primary endpoint, did not differ significantly between the two groups in the overall population or in the subgroup of patients who were adequately vaccinated against COVID-19, but it was significantly lower in the molnupiravir group among patients who were inadequately vaccinated.9

GUIDELINES — NIH guidelines currently recommend use of either ritonavir-boosted nirmatrelvir or remdesivir in high-risk, nonhospitalized adults with COVID-19; nirmatrelvir/ritonavir is preferred. If these drugs are inappropriate or unavailable, use of molnupiravir is recommended. According to the NIH, the efficacy of antiviral drugs for COVID-19 in vaccinated patients is unclear, but observational studies suggest a benefit. 10

CONCLUSION — Data on the effectiveness of antiviral drugs for treatment of COVID-19 in vaccinated, high-risk, outpatient adults are mixed. Ritonavir-boosted nirmatrelvir (Paxlovid) is the treatment of choice in such patients; it has been associated with improved clinical outcomes in large observational studies. Trials of remdesivir (Veklury) in vaccinated outpatients are lacking, but results from one randomized trial of an oral remdesivir analog suggest that it may be noninferior to Paxlovid. Treatment with molnupiravir (Lagevrio) was was not associated with a reduction in the rate of hospitalization or severe or fatal COVID-19 among vaccinated adults in a large randomized trial and a retrospective review.

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