Objective:

To evaluate the efficacy and safety of antiviral therapies (molnupiravir, nirmatrelvir–ritonavir, simnotrelvir–ritonavir, and ensitrelvir) in improving recovery time among adult outpatients with COVID-19 during the Omicron period.

Approach:

Key Findings:

• Molnupiravir likely improves recovery and reduces time to recovery, with a median recovery time of 9 days compared to 15 days for usual care.
• Nirmatrelvir–ritonavir increases recovery rates but is associated with higher adverse events.
• Simnotrelvir–ritonavir shortens recovery time but also increases adverse events.
• Ensitrelvir does not improve recovery outcomes and significantly raises adverse events.

Interpretation:

Three antiviral therapies (molnupiravir, nirmatrelvir–ritonavir, simnotrelvir–ritonavir) show potential to improve recovery in COVID-19 outpatients, though with varying adverse event profiles that must be considered in treatment decisions. Ensitrelvir is not recommended due to lack of benefit and increased adverse events.

Limitations:

• Risk of bias in studies due to open-label designs and subjective recovery assessments.
• Limited evidence for several clinical endpoints, particularly mortality and hospitalization, including specific examples such as lack of data on long-term outcomes.
• High vaccination rates in study populations may limit generalizability.

Conclusion:

Molnupiravir likely offers long-term benefits, while nirmatrelvir–ritonavir and simnotrelvir–ritonavir improve recovery but with increased adverse events. Ensitrelvir is not recommended for outpatient use due to its lack of efficacy and higher adverse event rates.

Sources:

• American College of Physicians
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