Remdesivir was the first targeted antiviral agent to gain widespread use based on ACTT-1, which demonstrated a four-day-shorter time to recovery versus placebo.² Closer review of the data, however, demonstrated that the benefit was only seen in those receiving oxygen but not high-flow or non-invasive ventilation. Additionally, although recovery was more rapid, hospital length of stay was unchanged (perhaps due to the need to finish the course of remdesivir, which is only available intravenously). Subsequent data from the World Health Organization demonstrated no significant benefit in mortality, initiation of mechanical ventilation or duration of hospital stay with remdesivir treatment.³ These findings were echoed in the DisCoVeRy trial, and ultimately, we should conclude from the available high-quality evidence that remdesivir does not have a significant benefit in patients requiring hospitalization for COVID-19.⁴ This makes sense because patients requiring hospitalization are likely out of the early phase of infection where antivirals have benefit and have entered the inflammatory phase.

More recently, the PINETREE investigators found a 4.6 percent absolute reduction in hospitalization (NNT ~22) when remdesivir was given to outpatients with COVID-19 early in the disease course (<7 days from onset) as three once-daily infusions.⁵ This significant reduction is important but will require validation. Additionally, many hospital systems and communities are unable to support outpatient infusion.

The major limitation with remdesivir treatment is the resource utilization required by an intravenous medication. This limitation has seemingly been overcome with the more recent emergency use authorizations for nirmatrelvir/ritonavir (Paxlovid). Molnupiravir was shown to result in a 2.7 percent absolute decrease (30 percent relative reduction) in hospitalization when administered within five days of disease onset.⁶ Molnupiravir appears to have teratogenic properties limiting its use. 

When compared to placebo, nirmatrelvir/ritonavir  resulted in a 5.8 percent absolute reduction (89 percent relative reduction) in hospitalization or death when given within five days of symptom onset.⁷ Side effects were minimal. Nirmatrelvir/ritonavir use is limited by availability as well as numerous drug interactions.

The major issue with both oral antivirals is the ability to get these to patients early in the disease process. This requires that patients immediately recognize their symptoms could be due to SARS-CoV-2 infection, get rapid access to a diagnostic test, get test results quickly, get a prescription from a clinician and get that prescription filled. Overcoming these obstacles is a massive challenge for many.

Bottom line: Remdesivir does not appear to play a significant role in patients requiring hospitalization with COVID-19 but may be beneficial early in disease to prevent hospitalization; however, massive resources are required for administration. Molnupiravir and nirmatrelvir/ritonavir both offer significant benefit if early administration is possible.